IGDEPARTMENT OF HEALTH AND HUMAN SERVICES

> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> FOOD AND DRUG ADMINISTRATION
>
> **CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE**
>
> **98th MEETING**
>
> Monday, January 6, 2003
>
> 8:30 a.m.
>
> Kennedy Ballroom
>
> Holiday Inn
>
> 8777 Georgia Avenue
>
> Silver Spring, Maryland
>
> PARTICIPANTS
>
> Jeffrey Borer, M.D., Chairman
>
> Jayne Peterson R.Ph., J.D., Acting Executive Secretary
>
> MEMBERS:
>
> Michael F. Artman, M.D.
>
> Thomas Fleming, Ph.D.
>
> JoAnn Lindenfeld, M.D.
>
> Paul Armstrong, M.D.
>
> Alan T. Hirsch, M.D.
>
> Steven D. Nissen, F.A.C.C.
>
> Beverly H. Lorell, M.D.
>
> Susanna L. Cunningham, Ph.D., Consumer Representative
>
> John Neylan, M.D., Acting Industry Representative
>
> Thomas G. Pickering, M.D., D.Phil., Consultant
>
> FDA:
>
> Robert Temple, M.D.
>
> Douglas Throckmorton, M.D.

John Lawrence, Ph.D. (Presentation Only)

> [C O N T E N T S]{.underline}
>
> Call to Order and Introductions
>
> Jeffrey Borer, M.D. 4
>
> Conflict of Interest Statement,
>
> Jayne Peterson, R.Ph., J.D. 5
>
> **NDA 20-386/S-032 Cozaar (Losartan Potassium) Tablets, Merck and
> Company:**
>
> Introduction, Jeffrey R. Tucker, M.D. 8
>
> Background and Rational; Study Results,
>
> Jonathan M. Edelmann, M.D. 13
>
> Review of Evidence and Conclusions,
>
> William F. Keane, M.D. 134
>
> Open Public Hearing 159
>
> **FDA Presentation:**
>
> Ethnic Subgroup Analysis from the LIFE Study,
>
> John Lawrence, Ph.D. 162
>
> Committee Discussion of FDA Questions 235
>
> (Committee Reviewer: Thomas Fleming, Ph.D.)
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Introductions**
>
> DR. BORER: Good morning. We will begin the 98th meeting of the
> Cardiovascular and Renal Drugs Advisory Committee. We will introduce
> the committee members who are sitting around the table. Mike, why
> don\'t you just state your name and, for everyone, when you want to
> speak turn the microphone on so that we can see the light, and turn it
> off when you are done.
>
> DR. ARTMAN: My name is Mike Artman. I am with the New York University
> School of Medicine.
>
> DR. CUNNINGHAM: Susanna Cunningham, University of Washington.
>
> DR. ARMSTRONG: Paul Armstrong, University of Alberta.
>
> DR. LINDENFELD: JoAnn Lindenfeld, University of Colorado.
>
> DR. PETERSON: I am Jayne Peterson. I am the acting executive secretary
> of the committee. I would remind you when you get done talking, you
> have to remember to turn the mike off.
>
> DR. BORER: Jeff Borer. I am the committee chairman.
>
> DR. LORELL: Beverly Lorell, from Harvard Medical School and Beth
> Israel Deaconess Medical Center.
>
> DR. FLEMING: Thomas Fleming, University of Washington.
>
> DR. HIRSCH: Alan Hirsch, University of Minnesota Medical School.
>
> DR. NISSEN: Steve Nissen, from the Cleveland Clinic Lerner School of
> Medicine.
>
> DR. PICKERING: Tom Pickering, from Mount Sinai Medical Center in New
> York.
>
> DR. NEYLAN: John Neylan, from Wyeth Research. I am the industry
> representative to the committee.
>
> DR. BORER: I want to announce that Tom Pickering is an adjunct member
> of the committee. He is an SGE consultant for this meeting. John
> Neylan, the acting industry representative, who is a non-voting
> member\--Tom will be voting\--is sitting on the committee as an
> industry representative for the first time. That is, we have not had
> an industry representative on the committee before so this is a new
> situation for us.
>
> Do we have a conflict of interest statement, Jayne?
>
> **Conflict of Interest Statement**
>
> DR. PETERSON: I will read the statement. The following announcement
> addresses conflict of interest with regard to this meeting and is made
> a part of the record to preclude even the appearance of such at this
> meeting. Based on the submitted agenda for the meeting and all
> financial interests reported by the committee participants, it has
> been determined that all interests in firms regulated by the Center
> for Drug Evaluation and Research present no potential for an
> appearance of a conflict of interest at this meeting, with the
> following exceptions:
>
> Dr. Susanna Cunningham has been granted a waiver under 18 U.S.C.
> 208(b)(3) and a 505(n)(4) waiver for her ownership of stock in the
> sponsor. The stock is valued between \$25,001 to \$50,000.
>
> Dr. Thomas Fleming has been granted a waiver under 18
> U.S.C.(208)(b)(3) for his consulting for a competitor on an unrelated
> matter. He receives less than \$10,001 a year.
>
> Dr. Alan Hirsch has been granted a waiver under 18 U.S.C. (208)(b)(3)
> for serving on a speakers\' bureau for a competitor on an unrelated
> matter. He receives less than \$10,001 a year.
>
> Finally, Dr. JoAnn Lindenfeld has been granted a waiver under 18
> U.S.C. (208)(b)(3) for serving as a consultant to a competitor on an
> unrelated matter. She receives less than \$10,001 a year.
>
> A copy of these waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30, Parklawn Building.
>
> In addition, we would like to disclose for the record that Dr. John
> Neylan, a full-time employee with Wyeth Research Labs, is
> participating in this meeting as an acting industry representative,
> acting on behalf of regulated industry.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participants are aware of the need to exclude themselves
> from such involvement and their exclusion will be noted for the
> record. With respect to all other participants, we ask in the interest
> of fairness, that they address any current or previous financial
> involvement with any firm whose products they may wish to comment
> upon. Thank you.
>
> DR. BORER: We will proceed with the presentation. This presentation is
> relevant to supplement NDA 20-386/S-032 for Cozaar, losartan
> potassium, tablets made by Merck and Company. The company is proposing
> a new indication for the reduction in the risk of cardiovascular
> morbidity and mortality as measured by the combined incidence of
> cardiovascular death, stroke and myocardial infarction in hypertensive
> patients with left ventricular hypertrophy. The sponsor\'s
> presentation will be introduced by Dr. Jeffrey Tucker, the director of
> regulatory affairs of Merck.
>
> **Sponsor Presentation**
>
> **Introduction**
>
> DR. TUCKER: Mr. Chairman, members of the advisory committee, FDA,
> ladies and gentlemen, my name is Jeff Tucker, in the Department of
> Regulatory Affairs at Merck Research Laboratories.
>
> Thank you for the opportunity to present Merck\'s data on the efficacy
> and safety of losartan in reducing the risk of cardiovascular
> morbidity and mortality in hypertensive patients with left ventricular
> hypertrophy.
>
> This morning we are discussing the results of Merck\'s cardiovascular
> outcome study LIFE, Losartan Intervention For Endpoint Reduction in
> Hypertension Study. The agenda for Merck\'s presentation is as
> follows: After my introduction, Dr. Jonathan Edelmann, the medical
> monitor of the LIFE study, will present the background and rationale
> and then describe the efficacy and safety results of the LIFE study.
> Finally, Dr. William Keane, vice president of clinical development,
> will provide interpretation of the data from the LIFE study and
> summarize the evidence that supports our proposed new indication.
>
> LIFE was an active-control, double-blind, multicenter study conducted
> in 945 sites in seven countries, and 9193 hypertensive patients with
> left ventricular hypertrophy were enrolled in the study and were
> followed for four years for occurrence of cardiovascular endpoints.
>
> We believe the results of the LIFE study merit modification of our
> product label to support the following new indication: Cozaar is
> indicated to reduce the risk of cardiovascular morbidity and mortality
> as measured by the combined incidence of cardiovascular death, stroke
> and myocardial infarction in hypertensive patients with left
> ventricular hypertrophy. You will see in our main presentation that
> the single study provides compelling evidence to support our proposed
> claim.
>
> As you know, in 1998 the FDA issued guidelines entitled \"Providing
> Clinical Evidence of Effectiveness for Human Drug and Biological
> Products.\" This included the agency\'s thinking about approval of new
> claims based on data from a single study. As noted in the document,
> relying on a single study is generally limited to situations in which
> one is dealing with serious outcomes where performing a second
> confirmatory trial is not ethical or practical. We believe the LIFE
> study results represent just such a situation.
>
> The guidelines document also points out that additional data from
> within a study or from other sources can provide evidence to help
> independently substantiate the results of the single study. During
> today\'s presentation we will provide confirmatory evidence from
> within the study and external to it that substantiates our results.
>
> When evaluating the LIFE study to support the proposed indication, it
> is important to consider that the LIFE study compared losartan to
> atenolol, an active antihypertensive medication that is known to
> reduce cardiovascular morbidity and mortality in hypertensive
> patients.
>
> The primary hypothesis of the LIFE study was that compared to
> atenolol, losartan reduced the incidence of cardiovascular morbidity
> and mortality in patients with essential hypertension and LVH. In the
> LIFE study the primary endpoint was a composite of the combined
> incidence of cardiovascular mortality, stroke and myocardial
> infarction.
>
> The study evaluated whether a losartan-based regimen would reduce the
> risk of cardiovascular morbidity and mortality more than an
> atenolol-based regimen in the face of comparable blood pressure
> control in both treatment groups.
>
> As you will see in Dr. Edelmann\'s presentation, the LIFE study
> demonstrated that compared to atenolol losartan reduced the risk of
> the primary composite endpoint. Both the atenolol- and losartan-based
> regimens reduced blood pressure to a comparable level. Losartan was
> well tolerated. No new clinically significant adverse experiences were
> uncovered in the LIFE study. In fact, the safety profile of losartan
> was consistent with the currently approved U.S. product circular for
> Cozaar.
>
> Merck has invited several consultants to the meeting. These experts
> are available to facilitate the advisory committee\'s discussions and
> deliberations. Here today are Dr. Bjorn Dahlof, of Sahlgrenska
> University Hospital in Goteborg, who served as chair of the LIFE
> steering committee; Dr. Richard Devereux, of the Cornell Medical
> Center in New York, who is vice chair of the LIFE steering committee;
> Dr. John Kjekshus, from the University of Oslo, who is chair of the
> data and safety monitoring board; Dr. Stevo Julius, from the
> University of Michigan in Ann Arbor, who is the U.S. national
> coordinator and a member of the steering committee; and Dr. Peter
> Kowey, from Jefferson Medical College in Philadelphia.
>
> Our statistical consultants are Dr. James Neaton, from the University
> of Minnesota, Minneapolis, and Dr. Scott Zeger, from Johns Hopkins
> University in Baltimore.
>
> The advisory committee members have previously received a briefing
> document from Merck that provides more detailed information than time
> allows us to present here this morning. I would now like to turn the
> podium over to Dr. Edelmann.
>
> **Background and Rationale; Study Results**
>
> DR. EDELMANN: Good morning, ladies and gentlemen. My names is Jonathan
> Edelmann and I am senior director in clinical development in Merck\'s
> US Human Health Department. As Dr. Tucker indicated, I have been the
> medical monitor for the LIFE study since its inception in 1995.
>
> My presentation this morning will include a discussion of the
> background and rationale for the LIFE study during which I will try to
> highlight the issues that we considered in arriving at the final study
> design. I will then review the LIFE study population and study results
> for efficacy and safety before turning the podium over to Dr. Keane,
> who will conclude with a review of the evidence to support our
> proposed claim.
>
> As you well know, hypertension is a major public health concern. It is
> the most common cardiovascular condition in the world and a risk
> factor for the development of complications of the heart, brain,
> kidney and peripheral vasculature. Over the course of the last 50
> years or more we have come to understand that the systemic
> manifestations of hypertension derive not just from elevations in
> blood pressure but also from adverse morphologic and functional
> changes in these organ systems including, for example, changes in the
> wall of the left ventricle and the blood vessels.
>
> Data from the Framingham Heart Study help to highlight the fact that
> patients with hypertension are at increased risk of cardiovascular
> disease compared to normotensive patients. This slide shows the age
> adjusted risk per 1000 patients on the vertical axis for
> normotensives, shown in white, and hypertensives, shown in green. You
> can see that in both men and women the risk of cardiovascular disease
> is more than two times higher in hypertensives.
>
> These epidemiologic observations were confirmed in a series of
> prospective, randomized, controlled hypertension treatment trials
> during the 1970s and \'80s which show that lowering blood pressure in
> hypertensive patients with pharmacologic agents resulted in reduction
> in the incidence of cardiovascular morbidity and mortality.
>
> In 1993 Rodgers and MacMahon summarized the results of five studies,
> involving more than 12,000 patients over the age of 60 years, which
> compared the effects of diuretic- and beta-blocker-based regimens to
> placebo or no treatment. In these five studies antihypertensive
> treatment lowered blood pressure by about 14 mm Hg systolic and 6 mm
> Hg diastolic more than control. This slide shows the number of
> vascular deaths, strokes and coronary heart disease events among
> patients treated with blood pressure lowering medication in green and
> control patients in white. For all these manifestations of
> cardiovascular morbidity and mortality treatment was associated with a
> lower risk, and with the same 15 mm Hg reduction in systolic blood
> pressure the magnitude of benefit varied depending on the endpoint.
> From this analysis, it was noted that the benefit of treating
> hypertension was greatest for stroke and less for coronary heart
> disease.
>
> When the LIFE study was conceived in early 1994 it was intended to ask
> a simple but important question about the consequences of treating
> hypertension in patients at high risk of cardiovascular morbidity and
> mortality, namely, does the mechanism of lowering blood pressure
> matter in reducing the adverse cardiovascular consequences of
> hypertension? We were specifically interested in asking that question
> in terms of angiotensin II receptor blockade with losartan in
> comparison to conventional antihypertensive therapy when peripheral
> blood pressure was similarly controlled.
>
> In order to answer this question the LIFE study was designed with
> specific choices in terms of the primary endpoint to be measured, the
> patients to be studied and the comparator against which losartan would
> be evaluated.
>
> First, a composite cardiovascular endpoint was chosen in recognition
> of the systemic effects of hypertension on multiple organ systems, and
> in order to describe the effects of blocking angiotensin II with
> losartan on the heart and brain the composite endpoint included the
> occurrence of cardiovascular death, stroke and myocardial infarction.
>
> Next, we chose to study patients with hypertension who were at
> increased risk of cardiovascular events because of the presence of
> left ventricular hypertrophy. We focused on LVH for three important
> reasons: First, LVH is known to be a consequence of long-standing
> hypertension as well as a manifestation of the systemic effects of
> angiotensin II throughout the cardiovascular system. So, these
> patients were expected to benefit from angiotensin II receptor
> antagonism.
>
> Second, LVH could be easily detected using the electrocardiogram and
> was known to have a prevalence of between 10 percent and 25 percent
> depending on the age of the population. This graph shows the
> increasing prevalence of LVH with increasing age among U.S.
> hypertensive patients from the NHANES III database. The average
> prevalence in those aged 55-80, as in the LIFE study, is around 20
> percent which made it feasible to recruit patients into the study.
>
> Third, LVH had been established as a marker of high risk of developing
> both cardiac and non-cardiac complications of hypertension independent
> of blood pressure level, as shown on this chart from the Framingham
> Heart Study. This chart compares the risk of CHD and stroke events in
> elderly patients with ECG-LVH, shown in green, and patients without
> LVH, shown in white. You can see for both men and women a three- to
> five-fold increase in the risk of an event in patients with left
> ventricular hypertrophy. So, hypertensive patients with ECG-LVH were
> expected to be at increased risk of experiencing stroke and myocardial
> infarction in the LIFE study.
>
> Finally, in designing the LIFE study it was necessary to utilize a
> comparator agent that would provide effective blood pressure lowering
> by a different pharmacologic mechanism of action than losartan, and
> one that itself had an established track record in reducing
> cardiovascular morbidity and mortality in hypertensive patients. At
> the time the LIFE study design was finalized in 1995, only
> beta-blocker and diuretic based regimens had demonstrated through
> controlled clinical trials benefits on cardiovascular morbidity and
> mortality.
>
> The available evidence for the benefit of diuretic and beta-blocker
> regimens, including the studies I just reviewed in the analysis by
> Rodgers and MacMahon, were summarized in JNC V in 1993. To paraphrase,
> because diuretics and beta-blockers are the only classes of drugs that
> have been shown to reduce morbidity and mortality, they are
> recommended as first-choice agents. This was the first time in the JNC
> document series that any class of agents achieved a preferred status.
> Thus, the obvious comparator regimen was one that included
> beta-blocker and diuretic therapies and we were left to decide which
> agent would be the anchor compound. As you well know, we chose
> atenolol as the comparator agent in the LIFE study and this was for a
> variety of reasons.
>
> First, as I mentioned, beta-blockers were recommended as appropriate
> first-line antihypertensive agents because of their demonstrated
> benefit on cardiovascular morbidity and mortality. Among the many
> antihypertensive trials, five have used a beta-blocker as the anchor
> compound in the treatment regimen. We have summarized these trials in
> a meta-analysis which is presented in this plot.
>
> The diamond represents the odds ratio and the 95 percent confidence
> interval for a cardiovascular event from the pooled data. The odds
> ratio and 95 percent confidence intervals for the individual studies
> are shown below in green. The size of the dot is proportional to the
> number of patients in each study, which is listed to the left of the
> dot. The number of cardiovascular events in each study is shown next
> to the study name. Points to the left of the line of unity favor
> antihypertensive therapy; to the right of the line favor the control
> group. The majority of these trials used atenolol as the beta-blocker.
> You can see that beta-blocker-based therapy was associated with an
> odds ratio of 0.79, or a 21 percent risk reduction in cardiovascular
> events, compared to control.
>
> In addition, although there were no specific data for the use of
> beta-blockers in hypertensive patients with left ventricular
> hypertrophy, beta-blockers were known to be effective in the
> prevention of myocardial infarction and, more recently, in the
> treatment of heart failure patient populations with a high prevalence
> of antecedent LVH. Atenolol had been shown to be effective in
> combination with diuretics and, importantly, had demonstrated
> comparable antihypertensive efficacy with losartan.
>
> By making atenolol the anchor compound in the comparator regimen the
> study could be designed to allow the addition of diuretics to both
> arms. This enabled us to use a beta-blocker/diuretic comparator
> regimen as recommended in JNC V and, at the same time, to ensure
> balance in the treatment arms with regard to additional treatments for
> control of blood pressure.
>
> Thus, the losartan intervention for endpoint reduction in hypertension
> study was designed as a multicenter, multinational, double-blind,
> randomized trial to investigate the effect of a losartan-based regimen
> compared to an atenolol-based regimen on the reduction of
> cardiovascular morbidity and mortality in hypertensive patients with
> left ventricular hypertrophy.
>
> The study was conducted under the scientific leadership of a steering
> committee, chaired by Dr. Bjorn Dahlof of the Sahlgrenska University
> Hospital in Sweden. Dr. Richard Devereux, of the Cornell Medical
> Center, was the vice chair. There was an independent blinded endpoint
> committee comprised of Dr. Daniel Levy, of the Framingham Heart Study,
> and Dr. Kristian Thygesen, of the Arhus University Hospital in
> Denmark. The study was monitored by an unblinded data safety
> monitoring committee chaired by Dr. John Kjekshus, of the University
> of Oslo in Norway. Merck served as the coordinating and data
> management center for the 945 sites in seven countries that
> participated in the LIFE study.
>
> As you have heard, the primary hypothesis of the LIFE study was that,
> compared to atenolol, losartan would reduce the incidence of
> cardiovascular morbidity and mortality in patients with essential
> hypertension and left ventricular hypertrophy. The primary endpoint
> was a composite of cardiovascular mortality, fatal and non-fatal
> stroke and fatal and non-fatal MI.
>
> The components of the primary endpoint were analyzed as secondary
> endpoints. For both the primary and secondary endpoints we used an
> intention-to-treat approach. Before I go on with a description of the
> study design, let me illustrate how we handled patients with multiple
> events in the primary analysis.
>
> This slide shows two hypothetical patients and the endpoints they
> experienced in the order in which they occurred. So, patient A was
> randomized in 1995 and first experienced a non-fatal MI in 1997; then
> a non-fatal stroke two years later; and then finally died of a fatal
> MI in 2000. For patient B the first and only occurrence of an endpoint
> was a fatal stroke around one and a half years after randomization.
> Both patients would count only once in the analysis of the primary
> endpoint based on the first event they experienced. I will come back
> to how the analyses of secondary component endpoints were performed
> when I review the efficacy results of the study.
>
> In addition to the primary composite and secondary component
> endpoints, a variety of other cardiovascular endpoints were collected
> in the trial and adjudicated by the endpoint committee. These included
> the cause of death; the occurrence of angina pectoris or heart failure
> that required hospitalization; the occurrence of coronary-artery or
> peripheral arterial revascularization events; or the occurrence of
> resuscitated cardiac arrest.
>
> There were two central reading laboratories in the LIFE study, one for
> reading ECGs and one for echocardiography. The ECG core reading center
> was located at the Goteborg University in Sweden and was responsible
> for assessment of LVH from yearly electrocardiograms on all patients.
> In addition, the reading center evaluated these ECGs for the presence
> of silent myocardial infarction.
>
> In a subset of patients echocardiograms were performed to assess left
> ventricular mass index, and the central reading center for
> echocardiography was the Cornell Medical Center in New York.
>
> Investigators measured sitting trough peripheral blood pressure at
> each clinic visit. At four centers in Denmark ambulatory 24-hour blood
> pressure was measured in 110 patients at baseline and year one as part
> of a substudy. Investigators recorded the occurrence of adverse
> experiences throughout the trial. Investigators also diagnosed newly
> occurring diabetes according to an algorithm based on a World Health
> Organization guideline that included multiple measurements of fasting
> glucose or oral glucose tolerance testing.
>
> Two important disease categories within the hypertensive population
> were prespecified to be of special interest in the LIFE study. These
> were patients who at baseline had diabetes or isolated systolic
> hypertension. In these patients we planned to analyze the primary
> endpoint and the secondary component endpoints, as well as the cause
> of death in cases of mortality and hospitalization for angina pectoris
> and heart failure.
>
> To qualify for entry into the trial patients were required to be
> between the ages of 55 and 80 years, and have hypertension, as
> evidenced off therapy by an elevated systolic blood pressure between
> 160-200 mm Hg, or elevated diastolic blood pressure between 95-115 mm
> Hg. In addition, all patients were required to have evidence of LVH
> confirmed by the central ECG reading center, as measured either by the
> Cornell voltage duration product or the Sokolow-Lyon voltage.
>
> Patients who had secondary hypertension or who had experienced a
> myocardial infarction or stroke within six months of the planned
> randomization date were excluded from the trial. In addition, patients
> who had angina pectoris that required treatment with either a
> beta-blocker or a calcium channel antagonist were not permitted to
> enter the study, nor were patients with active heart failure or known
> left ventricular ejection fractions of 40 percent or less. Conditions
> other than hypertension that required treatment with a study therapy,
> that is angiotensin receptor antagonists, beta-blockers or diuretics,
> or conditions that required therapy with an ACE inhibitor were also
> reasons for exclusion.
>
> This diagram shows the planned visit schedule and the study drug
> titration scheme that was used for the trial. You will notice that the
> losartan arm of this schematic is in yellow and the atenolol arm is in
> blue. This is a color code that will continue throughout the
> presentation. Eligible patients entered a placebo run-in period during
> which their active antihypertensive therapy was discontinued and
> baseline vital signs and left ventricular hypertrophy measurements
> were obtained.
>
> Qualifying patients were randomized to receive 50 mg of study therapy
> and over the next six months returned to the clinics for assessment of
> blood pressure and titration of study drug, if necessary, to achieve a
> goal blood pressure of below 140 systolic and below 90 diastolic. If
> patients required additional therapy beyond 50 mg of study drug a low
> dose of hydrochlorothiazide was added. If further therapy was required
> the dose of study drug was doubled to 100 mg. If further titration was
> required, additional antihypertensive medication could be added to
> achieve blood pressure control, with the exception of ACE inhibitors,
> angiotensin receptor antagonists or beta-blockers. Once patients
> achieved blood pressure control, they were maintained on that regimen
> and returned to the clinic for semi-annual visits throughout the
> study.
>
> The study was designed to continue for a minimum of four years for all
> patients and to conclude not before at least 1040 patients had
> experienced a primary cardiovascular event. Our intention was to
> follow patients until death or study termination. In that regard, the
> study was designed so that patients were to remain on study drug even
> if they experienced a study endpoint unless it was clinically
> contraindicated, at which point they would discontinue study therapy.
> However, even if they discontinued study therapy patients were to
> continue in the clinic with the semi-annual visits. If it was not
> practical for patients to come to the clinic telephone contact was
> maintained between the site and the patient to determine the presence
> of endpoints in the trial.
>
> If the occurrence of a study endpoint was detected, the investigator
> gathered the necessary documentation and made a full report to the
> endpoint committee for adjudication. If at any time it became
> appropriate for patients to restart study therapy, this was permitted
> in order to ensure that patient exposure to study drug was maximized
> throughout the trial.
>
> Investigators were encouraged to report all potential events that
> might qualify as endpoints in order to allow the endpoint committee to
> adjudicate them. Merck personnel made regular monitoring visits at
> each center to ensure that investigators reported all potential
> endpoints to the endpoint committee. Each endpoint committee member
> reviewed and classified each endpoint on his own. If either member
> felt that more information was necessary to classify an event, this
> was requested from the site and provided to both members. Differences
> between the initial classification of each member were resolved at
> periodic meetings of the two endpoint committee members. Although
> cases could be referred to the steering committee for final
> adjudication if there was a persistent disagreement, this was never
> necessary in the LIFE study. In total, more than 4000
> investigator-reported endpoints were adjudicated by the endpoint
> committee. In every case the committee had sufficient information to
> permit adjudication.
>
> Approximately 21 percent were determined not to be an endpoint. There
> were seven deaths for which the endpoint committee was unable to
> obtain enough information to permit the determination of the cause of
> death. These seven cases were treated as non-cardiovascular deaths in
> agreement with the steering committee. Four occurred in the losartan
> group and three in the atenolol group.
>
> As you can see on this time line, the study commenced in June of 1995
> and by May of 1997 enrollment was complete. In March of 2001 the
> steering committee established the endpoint cut-off date of September
> 16, 2001, representing four years and four months of follow-up for the
> last patient in the study. When the endpoint database was locked 1096
> patients had had a primary endpoint adjudicated by the endpoint
> classification committee.
>
> In the next section of the presentation I will provide a description
> of the study population. Over 10,000 patients entered the placebo
> run-in period and 9222 were randomized in the LIFE study. Early on in
> the study irregularities at one site led the steering committee to
> disqualify that site and instruct that all patients there be
> discontinued. Further, the steering committee decided to exclude these
> 29 patients from all analyses. As a result, there were 9193 patients
> who were followed for the duration of the study. These patients were
> equally randomization between the treatment groups. Of course, all
> available follow-up information was included in the intention-to-treat
> analyses. Complete follow-up about all endpoints was available for 98
> percent of patients, accounting for almost 99 percent of potential
> patient days. We were able to determine if another one percent of
> patients were alive or dead at the end of the trial so that follow-up
> on vital status was available for more than 99 percent of potential
> patient days. The remaining one percent of patients discontinued
> follow-up prior to the termination of the study. Approximately 80 of
> these patients did so by withdrawing consent and 12 patients were lost
> to follow-up, four in the losartan group and eight in the atenolol
> group.
>
> We have performed a sensitivity analysis with patients for whom we
> have only partial follow-up information, and concluded that these
> missing days of follow-up do not alter the interpretation of the study
> results.
>
> Investigators in the seven countries listed here participated in the
> LIFE study. You can see that five are Nordic countries, the other two
> are the United Kingdom and the United States. The patients were
> roughly evenly divided among the countries, with the notable exception
> of Iceland which contributed relatively few patients.
>
> The next several slides show the baseline characteristics of the
> patients in the LIFE study. All baseline characteristics were well
> balanced between the treatment groups. The mean age of patients was 67
> years. Slightly more than half of the patients were women. Not
> surprisingly, the overwhelming majority of patients in the LIFE study
> were white. Almost all of the non-white patients were randomized in
> the United States. Black patients represented about six percent of the
> total population. Other ethnic groups represented one percent or less
> of study patients.
>
> Blood pressure, as expected, was elevated. Systolic blood pressure was
> about 174 mm Hg and diastolic blood pressure was about 98 mm Hg. Heart
> rate was similar between the groups at baseline. The patients were
> slightly overweight and about 16 percent of them were current smokers
> at the time of randomization. The patients were also well balanced
> with respect to preexisting medical conditions like diabetes, isolated
> systolic hypertension and prior coronary heart of cerebrovascular
> disease.
>
> Patients were also well matched for the baseline variables that were
> prespecified as covariates in the primary analysis, the presence of
> LVH by both the Cornell product and Sokolow-Lyon methods and the
> Framingham risk score. The Framingham risk score is a predictor of the
> five-year risk of new coronary heart disease determined from the
> baseline characteristics of gender, age, systolic blood pressure,
> smoking status, ratio of total to HVL cholesterol and the presence of
> diabetes and left ventricular hypertrophy. This turned out to be a
> very strong predictor of risk in the LIFE study patients. Despite the
> small and non-significant difference noted in the baseline score, when
> it was used as a baseline covariate this parameter had an influence on
> the analysis. So, when I present the results in just a moment you will
> see both the adjusted and the unadjusted analyses for the primary
> endpoint.
>
> Finally, before I present the efficacy results from the trial, I would
> like to review the distribution of study drug dose level that was
> achieved during the trial. I described to you earlier the titration
> scheme that was followed in the LIFE study.
>
> This slide depicts the distribution of study drug in each treatment
> group at the end of follow-up or at the occurrence of a primary
> endpoint, whichever came first. You can see that only a small fraction
> of patients, around ten percent, remained on 50 mg of study therapy
> for the entire duration of the study. Most patients required the
> addition of other drugs to their regimen and about half required an
> increase in the dose of study drug to 100 mg. At the end of follow-up
> or the occurrence of an endpoint approximately 25 percent of patients
> had discontinued study therapy. Most of the patients who required
> additional therapy received hydrochlorothiazide, but more than a
> quarter of the patients received other drugs beyond
> hydrochlorothiazide, largely calcium channel antagonists or other
> diuretics.
>
> Although approximately 25 percent of patients were off drug at the
> time of a primary endpoint or the end of follow-up, the mean
> proportion of time that patients remained on study therapy was in
> excess of 80 percent of the days of follow-up in both treatment
> groups. The average dose of study drug was about 80 mg in both
> treatment groups. Hydrochlorothiazide and other diuretics were taken
> on approximately 71 percent of the days of follow-up. For study,
> hydrochlorothiazide average dose was 20 mg in both treatment groups.
> On average, patients in both treatment arms received 2.3
> antihypertensive agents, counting study drug and hydrochlorothiazide.
>
> Having reviewed the characteristics of the patients enrolled in the
> LIFE study, the level of study drug and concomitant medication use,
> what was the effect of treatment on the primary outcome in the life
> study?
>
> DR. BORER: Can we just hold it for one minute and make sure that
> everybody is clear on the characteristics of the study design? Are
> there any specific questions from the committee about the study
> design? Susanna?
>
> DR. CUNNINGHAM: I wasn\'t going to ask about the design, I was going
> to ask for the age of the patients. I notice that some of the patients
> in the study were actually younger than 55.
>
> DR. EDELMANN: Yes, there was a small number of patients whose age at
> randomization was below 55 in violation of the protocol, a small
> number.
>
> DR. BORER: In addition, there seemed to have been a very small number
> that, if I read the data correctly, didn\'t have baseline blood
> pressures measured per protocol but they were included as hypertensive
> with LVH. Can you tell us how that happened, or am I misunderstanding
> the data?
>
> DR. EDELMANN: I guess I am not sure what you are referring to.
>
> DR. BORER: From the way I read the data, it appeared that
> determination of blood pressure according to when it should be
> determined in the protocol to define blood pressure was not done in
> some patients who, however, were followed up.
>
> DR. EDELMANN: That is correct, although those patients were randomized
> into the trial before it was discovered that their blood pressure
> regimens were not done exactly in accordance with the protocol.
> Because of our plan for intention-to-treat, they were continued in the
> protocol in any case and followed.
>
> DR. BORER: That was a very small percentage I guess.
>
> DR. EDELMANN: Yes.
>
> DR. BORER: Paul?
>
> DR. ARMSTRONG: Jeff, I had three questions, one of which I will need
> Tom\'s help with and you may want to rule discussion later. The first
> relates to the withdrawal of prior antihypertensive therapy which
> occurred in a significant proportion of patients. It wasn\'t clear to
> me from your presentation or the written material, other than the fact
> that there was a two-week placebo run-in period, what length of time
> and what manner of withdrawal strategy was used in the two treatment
> groups vis-a-vis prior exposure to therapy?
>
> DR. EDELMANN: Sure. Obviously, there was not a different strategy for
> the two randomized groups because this would have occurred prior to
> randomization. The discontinuation of antihypertensive therapy before
> randomization was left to the discretion of the investigator in terms
> of method. So, if it was appropriate to down-titrate the
> antihypertensive therapy, that was the prerogative of the
> investigator.
>
> Then, patients were monitored with frequency specified by the protocol
> and investigators were free to see their patients more frequently if
> there was concern. Patients whose blood pressure rose dramatically and
> too high were excluded. That was one of the reasons for not being
> randomized, if blood pressure levels exceeded the upper limit.
> Likewise, if blood pressure did not rise to the appropriate level
> patients were supposed to be excluded, and in almost all cases that
> was true. Does that answer your question?
>
> DR. ARMSTRONG: Do we have information then apropos the two treatment
> groups as to whether there was a difference in the time of withdrawal
> of therapy prior to the two-week placebo run-in?
>
> DR. EDELMANN: What we have is the blood pressure at the first visit,
> which would in most cases have been on therapy, and we have the
> therapy that they were on and then we have the blood pressure at
> randomization, which is off therapy. I guess we have the duration
> between those two but I don\'t think we have more information
> particularly about the strategy of withdrawal in patients. That is not
> something we collected.
>
> DR. ARMSTRONG: My second question relates to your slide 23. That was
> the meta-analysis of beta-blocker regimens and hypertension. Could you
> help partition for me the distribution of cardiovascular events
> vis-a-vis myocardial infarction as opposed to stroke since that,
> obviously, is relevant to the discussion we will have in terms of the
> results? What is the evidence that there was a reduction or not a
> reduction in myocardial infarction as opposed to the other events
> within this meta-analysis?
>
> DR. EDELMANN: Sure, I would be happy to. First, this represents a
> composite of the events that are similar to the primary endpoint of
> LIFE. So, it is the occurrence as reported in the trials of stroke,
> myocardial infarction and cardiovascular death. As in the example I
> showed you from the Rodgers and MacMahon paper among these trials,
> when you do the meta-analysis of the individual components we see the
> same kind of distribution with a greater reduction in the risk of
> stroke and a smaller reduction in the risk of coronary heart disease
> events. Cardiovascular mortality is kind of in the middle between
> those two. So, it is very similar to what I showed you from the
> Rodgers and MacMahon paper.
>
> DR. ARMSTRONG: Maybe I haven\'t asked the question properly. Just to
> sharpen the point, if we were to try to impute placebo, as ultimately
> we will in terms of assessing the study under discussion, what is the
> evidence that there was any effect on myocardial infarction?
>
> DR. EDELMANN: Sure, why don\'t I show you the results for the three
> components individually? Maybe that will help clarify.
>
> DR. ARMSTRONG: Great!
>
> DR. EDELMANN: Let\'s look at stroke, myocardial infarction and
> cardiovascular death. Stroke first. I don\'t know if this is exactly
> how you want to see it but this represents the composite of all five
> studies for these three endpoints. Here is what I showed you for all
> cardiovascular events and this is the pattern that I was describing
> before. You can see a greater effect on stroke; less of an effect on
> coronary heart disease; and an intermediate effect on cardiovascular
> death.
>
> DR. ARMSTRONG: If you recall, the question was about myocardial
> infarction.
>
> DR. EDELMANN: Yes. Actually, I beg your pardon but myocardial
> infarction is not explicitly reported in most trials and coronary
> heart disease events include myocardial infarction, fatal and
> non-fatal, and in some cases it includes cases of angina and in some
> cases it includes sudden death. But it wasn\'t possible for us to
> parse out specifically myocardial infarction based on those data.
>
> DR. ARMSTRONG: So we don\'t have that information?
>
> DR. EDELMANN: Yes.
>
> DR. ARMSTRONG: Okay. The third question\--
>
> DR. FLEMING: Would you put that slide back on the screen again before
> we leave Paul\'s point? When we talk about all CV events, and you have
> specifically confirmed we are talking about stroke, MI and
> cardiovascular death, are there any other events beyond those three
> included in all CV events?
>
> DR. EDELMANN: I do not believe there are but I would like to just be
> able to verify that from the five trials. There is a limit in terms of
> how the trials were reported, but if I am not mistaken, I think all CV
> events represent just those three. To be clear, this is CHD rather
> than MI as the label given to it, which may have more than MI in it.
>
> DR. ARMSTRONG: And the third question was in setting up a statistical
> point on heterogeneity when one is dealing with a primary composite,
> what are the implications of when that heterogeneity is found relative
> to the validity of the composite? I would appreciate some discussion
> and, obviously, Tom\'s advice on this point, Mr. Chairman.
>
> DR. EDELMANN: If you will permit me, that is a topic that we will
> cover so, if it is all right with you, I would just as soon finish
> with the presentation and then if there is further discussion\--would
> that be okay?
>
> DR. BORER: Sure. Tom, you had some questions?
>
> DR. FLEMING: Could we return to your slide 28? You give a very nice
> diagram that really gets at one of the issues I wanted to confirm. I
> think this is one of the strengths of your trial and I would like to
> confirm it, that is, when you randomize patients you are both managing
> them and following them until this late 2001 date even beyond the
> occurrence of the primary endpoints. This first patient that had a
> non-fatal MI in May of 1997, you continued to follow that patient with
> exactly the same intensity for other endpoints such as stroke, such
> that you were able to, in fact, detect and document the February, 1999
> non-fatal stroke. Is that correct?
>
> DR. EDELMANN: That is exactly correct.
>
> DR. FLEMING: As you present these results, and this is somewhat
> related to Paul\'s point, clearly we are going to be interested in
> looking at your composite but we will also be interested in looking at
> the effects on the elements, and not the elements as censored at the
> time of the primary\--
>
> DR. EDELMANN: That is right.
>
> DR. FLEMING: \--but, in fact, you can emphasize this as you are
> presenting. When we look at stroke we want to look at this as all
> strokes over time.
>
> DR. EDELMANN: Yes, as you will see when I get to the presentation of
> the data, I have another illustration to actually highlight the point
> about the secondary endpoints but I can confirm that we have done it
> just the way you said. I think when I get to it, it will be helpful,
> and it comes just before the results so it will be a reminder.
>
> DR. BORER: Steve?
>
> DR. NISSEN: Yes, I am still a little confused on slide 23, if you
> could help me with that? Would you put that up there? There are a
> couple of things. One, are these all placebo-controlled trials?
>
> DR. EDELMANN: They are either placebo- or no treatment-controlled
> trials. It varies by study.
>
> DR. NISSEN: One of the things that confused me is after the STOP there
> is a cross and there is a double-cross. The cross says an atenolol
> arm; the double-cross says beta-blocker and/or diuretic arm.
>
> DR. EDELMANN: Let me clarify. You are probably familiar with the STOP
> trial. STOP was a trial in which patients were allocated either to a
> beta-blocker regimen or a diuretic regimen or no treatment. In the
> beta-blocker there was a choice of three and atenolol was one of them
> but there were two others. So, it is not purely data from a
> beta-blocker anchored regimen because there is a mix. I think about a
> quarter of the patients got a diuretic, if I am not mistaken.
>
> DR. NISSEN: So, shouldn\'t that really be in the meta-analysis?
>
> DR. EDELMANN: I guess that is a matter of\--
>
> DR. NISSEN: I mean, it was the strongest effect but it wasn\'t really
> a beta-blocker versus placebo trial, it seems to me. It sort of
> violates the rules of meta-analysis unless there is some homogeneity
> here, I would think. I just wanted to clarify that.
>
> Then, I have another question about your final slide before we started
> this discussion, which was slide 48. I would like to see p values,
> particularly for the off-study drug and the numbers of patients that
> got additional drugs, other than losartan or atenolol. Are those
> differences statistically significant and at what level of
> significance are they?
>
> DR. EDELMANN: I can tell you that the difference between the off-study
> drug at this time is significant. I have to confer about the exact p
> value. This bottom 23/27 difference is significant. I can get you the
> p value in just a second. In terms of the others, is there one
> particular that you are interested in?
>
> DR. NISSEN: I guess I am interested in the number of patients that got
> an additional drug. So, I would like to know whether there is a
> statistically significant difference in the number of patients on
> combination therapy and losartan and combination therapy and atenolol
> because this, obviously, has a lot of implications.
>
> DR. EDELMANN: Let us work on that and I will come back when I have the
> answers. Is that acceptable?
>
> DR. NISSEN: Sure; sure.
>
> DR. BORER: Other questions? JoAnn?
>
> DR. LINDENFELD: In follow-up to slide number 48, I noticed that there
> was an amendment made in the protocol to be able to decrease the dose
> of study drug to 25 mg. I wonder if you could show us how often that
> was done with each of the two regimens.
>
> DR. EDELMANN: First of all, that was an amendment made during the
> course of the trial because of the desire to maintain patients on
> study therapy. It was implemented as needed at a site so it wasn\'t
> implemented at all sites. It was not a frequent occurrence. It is not
> a number that I know off the top of my head but it was a relatively
> small number of patients. I will get you the number of patients.
>
> DR. LINDENFELD: I think it becomes a little bit important. This is an
> older subgroup and 50 mg of atenolol in a patient group whose average
> age is 70 is a fair amount of atenolol.
>
> DR. BORER: Other questions? Mike?
>
> DR. ARTMAN: Along those lines, still with slide 48 up there, I had a
> question. In addition to pharmacologic management were there
> differences in non-pharmacologic therapy\--weight reduction, smoking
> cessation, exercise, etc.\--do you have information on that?
>
> DR. EDELMANN: We have some limited information, for example, on weight
> and smoking only at baseline so not in trial. There was reasonably
> good balance; small differences between the treatment groups but
> nothing substantial. By the protocol, there was obviously no
> intentional difference in the way the treatment arms were to be
> managed in terms of weight reduction, smoking cessation and so on. But
> the kinds of things that you would expect to happen to a population
> under supervision happened by things that we did measure. Concomitant
> use of statins, for example, went up. The behavior of patients being
> actively looked after was apparent in the trial, but not to a
> different degree between the treatment groups.
>
> DR. BORER: John and Tom?
>
> DR. NEYLAN: I have a question about slide 40. I was wondering if you
> could provide a bit more detail about some 1500 patients who were
> excluded during the placebo run-in period, and speak to their
> potential differences demographically or with regard to baseline
> antihypertensive regimens as contrasted to those patients randomized?
> This gets to the applicability to general clinical practice.
>
> DR. EDELMANN: Yes. Well, to answer the second part of your question
> first, one of the things we looked at as applicability to general
> practice was to look at the patients who did qualify for the study in
> comparison to a similar population, a reference population in the U.S.
> of hypertensives with left ventricular hypertrophy, which we took from
> the NHANES database. There we saw very similar\--I can show it to you,
> but very similar characteristics based on the study patients in LIFE
> and similar patients from this reference database.
>
> In terms of the reasons that patients were excluded, largely that was
> due to blood pressure reasons. A substantial proportion, and I will
> have to get the specific numbers, were patients whose blood pressure
> failed to rise to the right level upon discontinuing prior
> antihypertensive therapy; some for rising to a level that was too
> high; and then there were other patients who were discovered during
> the process to have had a recent myocardial infarction or stroke which
> disqualified them. So, those are the kinds of things.
>
> I am not sure that we have\--in fact I know we don\'t have a detailed
> breakdown of the demographics of those patients, but we may be able to
> get some information beyond what I have told you about the ones who
> did not qualify. But that was because our procedure at the time was
> not to collect a lot of information about patients who were not
> randomized. You know, there was some information collected but not
> with the same level of detail as for patients who did get randomized.
>
> DR. BORER: Tom Pickering?
>
> DR. PICKERING: I have a couple of questions about slide 23. HEP is not
> an acronym with which I am familiar. Could you enlighten me?
>
> DR. EDELMANN: This is hypertension in the elderly so this is the Coope
> and Warrender study.
>
> DR. PICKERING: All right. In the UKPDS, my memory is that those
> patients could be on diuretics. Is that correct?
>
> DR. EDELMANN: Yes, they could have a diuretic added to their regimen
> in the UKPDS. That is right. I believe that is right.
>
> DR. BORER: Any other issues with regard to the trial design or
> characteristics?
>
> DR. NISSEN: I was just wondering if we could have those p values
> before we leave the thought.
>
> DR. EDELMANN: I have made a note of it.
>
> DR. NISSEN: Okay.
>
> DR. EDELMANN: Shall I continue?
>
> DR. BORER: Yes, just make a bookmark and we will get to it later.
>
> DR. EDELMANN: Yes, I have it.
>
> DR. BORER: Why don\'t you just go right ahead then? I am sorry, one
> second. Tom?
>
> DR. FLEMING: Just to revisit the meta-analysis that you were showing,
> if you could put that slide back up for a moment? You refer to the
> Psaty meta-analysis in your briefing document as potentially one that
> is especially relevant here because it is looking at, if one is trying
> to get a sense of what is the effect of the active comparator\-- it is
> looking at diuretics and atenolol. Essentially that focuses on the
> SHEP study and the MRCII trial. Is that, in fact, your perspective of
> what would be potentially the most relevant studies to assess the
> effect of the active comparator?
>
> DR. EDELMANN: Well, part of the reason that we elected to do our own
> meta-analysis is because none of the published meta-analyses, and
> there are several, had accounted for all of the data that was based on
> beta-blocker specific anchored therapy. SHEP, for example, is
> diuretic-based with the addition of a beta-blocker. So, I think from
> our perspective these studies represent the best estimate that you
> could have, imperfect though it is, of what a beta-blocker anchored
> therapy does as antihypertensives to reduce cardiovascular morbidity
> and mortality.
>
> DR. BORER: Bob?
>
> DR. TEMPLE: I am sorry, could you just say what comparison from STOP
> is shown there because I am still confused? What odds ratio was
> actually shown there?
>
> DR. EDELMANN: In case you don\'t know, the STOP trial was only ever
> reported with active versus placebo so it is not available, at least
> it wasn\'t available to us in any of the places we looked to be able
> to break it out. So, this is the finding of all of the patients in the
> study, and there was a mixture of patients whose anchor therapy was
> beta-blocker or diuretic.
>
> DR. BORER: All of the patients in the study or all of the patients in
> the study on atenolol whether or not they were getting a diuretic?
>
> DR. EDELMANN: Although we would have loved to do that, it is all the
> patients in the study because it wasn\'t ever reported as only the
> patients taking a beta-blocker.
>
> DR. TEMPLE: There were three different beta-blockers but were most of
> the people on a beta-blocker?
>
> DR. EDELMANN: Yes, it was roughly evenly divided between the four
> choices, diuretic was one choice and three beta-blockers. So, I think
> it is predominantly beta-blocker but it is never broken out as either
> the beta-blockers together and diuretic or the individual components.
>
> DR. TEMPLE: And did you do a red box without STOP? How much difference
> does that make?
>
> DR. EDELMANN: Right, that is something we have done but I don\'t have
> the numbers right at the top of my head, but it is something that I
> can give you. We did a couple of different iterations of this. You
> know, the bottom line is that it really did not make a lot of
> difference but you can see that STOP is, I guess, the most positive.
>
> DR. TEMPLE: Yes, but it is still only ten percent of the events.
>
> DR. EDELMANN: Right.
>
> DR. FLEMING: But in the MRCII you are quoting the atenolol results.
>
> DR. EDELMANN: That is right.
>
> DR. FLEMING: In MRCII, if you were looking at the diuretics and
> atenolol results, if you put them together the relative risk is 6.7.
>
> DR. EDELMANN: That is exactly right. We have done a version of this
> meta-analysis including the trials that have a diuretic-based therapy
> with a reasonable add-on of beta-blocker to kind of look at the other
> side. I can show you that as an example of another iteration of this.
> Effectively what it does, it reinforces the fact that active treatment
> with these diuretic/beta-blocker anchored regimens alone and in
> combination in the face of differences in blood pressure reduction is
> effective in preventing cardiovascular morbidity and mortality. If you
> would like, I can show the one that includes the diuretic with
> additional beta-blocker added to the overall. If you are interested, I
> can show that. I don\'t know if it is in the briefing document.
>
> DR. BORER: Does anyone need to see that? Okay, let\'s put it up.
>
> DR. TEMPLE: Jeff, I guess you are arguing, at least slightly, that
> this was a trial of a beta-blocker added to a diuretic because most
> people had a diuretic so that that is relevant?
>
> DR. EDELMANN: That is right; that is the idea. So, here the five
> trials are supplemented with a couple more, and they are listed at the
> bottom here. We used 20 percent beta-blocker concomitant use as our
> threshold. In other trials the concomitant beta-blocker was less which
> we elected to leave out. So, that is MRCII, SHEP and OSLO. I guess it
> is only seven new trials because MRCII was already counted once. In
> any case, what you see is what I was describing. The benefit shifts a
> little bit to the left, but it confirms the idea that active
> antihypertensive therapy with a beta-blocker/diuretic regimen is
> effective in reducing cardiovascular events.
>
> DR. FLEMING: On this point, I look at this as a comparison against the
> regimen where the active comparator regimen is the diuretic and
> atenolol. So, technically the active comparator effect is the effect
> of the diuretic and atenolol so this really gets more directly to what
> the active comparator effect is.
>
> DR. BORER: Doug?
>
> DR. THROCKMORTON: Yes, I wanted to return to slide 40 and just
> something different. We have been interested for a while in the number
> of patients that you needed to screen to get your trial under way. Do
> you have the screening population number and then the number that got
> into baseline?
>
> DR. EDELMANN: Yes, I cannot give you the screening number specifically
> but it was substantially higher than the 10,000 who actually got to
> the point of entering the run-in. The reason is that the centers used
> a variety of different screening techniques which would not really
> fairly represent the effort. There were centers that took every ECG
> they had and sent them in, and those that got a positive reading from
> the core center, they went forward with. There were others who
> reviewed their patients and talked to them, more akin to what you
> would expect would be an appropriate effort in terms of judging it
> where the physician or the site is involved with the patient, and then
> they went forward; sent in a screening ECG and it was, you know,
> rejected.
>
> So, one way to look at that in our trial would have been to count the
> number of ECGs that were evaluated at the screening center and it was
> probably ten-fold that. But, as I said, it had a dramatic influence.
> With almost a thousand centers there were almost a thousand different
> strategies and it had a tremendous influence, you know, what strategy
> was used on the number of ECGs that were looked at.
>
> DR. BORER: Are there any other issues before we go on to the results?
> If not, why don\'t you just go right ahead?
>
> DR. EDELMANN: Thank you. If I could move to slide 51, this is the
> result for the primary endpoint, as is shown here in a Kaplan-Meier
> presentation. The horizontal axis represents time of follow-up in
> months and the vertical axis shows the percentage of patients with a
> primary cardiovascular event. The yellow solid line represents
> losartan and the blue dashed line represents atenolol. Depicted at the
> bottom of the slide is the number of patients by year who were at risk
> of developing an event.
>
> You can see that the lines diverge for the entire duration of
> follow-up, representing an adjusted risk reduction of 13 percent
> favoring losartan, with a p value of 0.021, which was the primary
> analysis. The unadjusted risk reduction, that is, without adjustment
> for baseline Framingham risk score and ECG-LVH, is slightly larger,
> about 14 percent and the p value is 0.009.
>
> This slide depicts the hazard ratio for the primary composite endpoint
> and its 95 percent confidence interval. The solid line represents the
> primary adjusted analysis, and the dashed line the analysis without
> adjustment for baseline Framingham risk score and ECG-LVH. To the left
> of the vertical line favors losartan; to the right favors atenolol.
>
> You can see that there were 508 patients in the losartan group who
> experienced a primary cardiovascular event compared to 588 in the
> atenolol group. This significant advantage of the losartan-based
> regimen over the atenolol-based regimen was achieved with comparable
> and substantial blood pressure lowering in both treatment groups, as
> you will see in the next several slides.
>
> This figure illustrates the change in systolic blood pressure during
> the study. Depicted on the horizontal axis is time in months and on
> the vertical axis is the mean systolic pressure. You can see that
> beginning with randomization and continuing through the first six
> months of titration, there was a prompt and substantial decline in
> systolic blood pressure which was slightly greater in magnitude for
> the losartan group. Systolic blood pressure was lowered by around 13
> mm Hg in each group. However, the reduction with losartan was
> approximately 1 mm Hg more than with atenolol. This difference was
> statistically significant.
>
> Here is the figure for diastolic blood pressure. Again, a prompt and
> substantial decline of around 17 mm Hg in each group was seen over the
> first six months. There was a slightly greater reduction in magnitude
> in the atenolol-treated patients for mean diastolic blood pressure,
> although the difference between the two treatment groups was quite
> small and did not achieve significance.
>
> Study therapy was titrated to achieve a goal blood pressure of 140
> systolic and 90 diastolic. This table shows the percentage of patients
> who achieved the diastolic goal blood pressure, the systolic blood
> pressure or both pressure goals for each treatment group. You can see
> that the majority of patients in both groups achieved the diastolic
> blood pressure goal. Slightly under half of the patients achieved the
> systolic blood pressure goal or both targets, more in the losartan
> than the atenolol group. So, blood pressure was similarly and
> substantially reduced in both treatment groups, with better diastolic
> than systolic control.
>
> This slide shows the effect of treatment on heart rate. As expected,
> atenolol had a significantly greater effect on mean heart rate than
> losartan of about six beats per minute throughout the study.
>
> To summarize the findings of the primary endpoint of the LIFE study,
> in hypertensive patients with ECG evidence of LVH, losartan-based
> therapy was associated with a 13 percent reduction in the combined
> risk of cardiovascular death, stroke and myocardial infarction
> compared to an atenolol-based regimen with comparable levels of blood
> pressure.
>
> Next, I will review the results\--
>
> DR. BORER: May I ask you to just stop for one second?
>
> DR. EDELMANN: Yes.
>
> DR. BORER: Only ten percent of the population was on monotherapy by
> the end of the trial, and certainly you don\'t have enough power to
> look for anything with a reasonable likelihood of finding statistical
> significance but do you have data to show whether nominally at least
> the overall results were also seen in patients who were on
> monotherapy?
>
> DR. EDELMANN: One of the things that we have not done, and
> specifically not looked at in detail for interpretation, is the
> assessment within the trial of things that changed by the patient\'s
> response and, thus, a non-random comparisons and that is a good
> example of one. We have looked at this in some cases but I can tell
> you we did not look at monotherapy because the numbers were so small.
> But we are hesitant about drawing conclusions from those kinds of
> analyses in any case because so much of the basis for change of
> therapy is response to prior therapy that it barely really makes sense
> with think.
>
> DR. BORER: Steve and then Beverly.
>
> DR. NISSEN: That is what I was also trying to get at, Jeff, with this
> question of whether there were differences in number of patients on
> combination therapy within the two arms. So, to me, that is really a
> pivotal thing to understand here since this wasn\'t really a
> monotherapy trial; it was a combination therapy trial.
>
> DR. EDELMANN: What I would like to point out, and we will come to this
> in the final presentation, is a way that we did try to look at whether
> or not differences, even small differences in the therapy that
> patients received might have accounted for the outcome advantage,
> which I think is really at the root of the question you are getting
> at. Again, if you will permit me, that is a little bit later in the
> presentation and it makes more sense to go through in order, but we
> will come to it and, you know, if you would like further discussion we
> can certainly do that.
>
> DR. BORER: Beverly?
>
> DR. LORELL: I think one of the things that is quite striking about
> slide 55 in thinking about how this evaluation might relate to best
> practice in the United States is that less than 50 percent of patients
> met goal for treatment of systolic hypertension.
>
> So, a couple of questions. Are you going to show us later in the
> efficacy section how the adverse events were distributed among those
> patients who achieved a systolic blood pressure of less than or equal
> to 140 and those that did not? The reason I think that it is terribly
> important is that if half of the patients in this study were
> inadequately treated by national standards, it raises the question as
> to how do we think about this recommendation. I think in real practice
> what physicians would do with this group of patients would be to add
> on a beta-blocker if they were not getting it, or an angiotensin
> inhibiting drug if they were not getting that drug and were still
> nearly to goal for therapy. So, it would be very interesting to see, I
> think, in this population how the distribution of adverse events,
> including stroke, were distributed.
>
> DR. BORER: In fairness, I think that analysis is in the FDA review. I
> don\'t want to misquote it but the events were far more frequent in
> people who weren\'t well controlled but the distribution or the
> relative proportion of events was sort of similar in the two treatment
> groups.
>
> DR. EDELMANN: Right.
>
> DR. BORER: Steve?
>
> DR. NISSEN: I guess before we move on, you know, on slide 53 and 54 we
> get the systolic and diastolic and I was very interested in the same
> graph for pulse pressure and the p values since some folks have
> suggested that pulse pressure is probably the best predictor.
>
> DR. BORER: That is in the FDA review and it shows what you are
> suggesting.
>
> DR. NISSEN: Yes, I wonder if you have your pulse pressure data.
>
> DR. EDELMANN: I think I can show you the blood pressure. As you would
> expect, it is the sum of opposite effect so it is a little bit bigger.
> It is about 2 mm Hg difference in pulse pressure across the study. I
> think if you will just give us a second I will be able to pull up the
> slide for you but it is as you would expect based on the numbers you
> saw.
>
> Here is the difference in pulse pressure, wider in the beginning,
> narrowing at the end. The stars represent time point comparisons of
> significant difference. So, it is exactly as you would expect. We have
> looked at this just as we have looked at all of the blood pressure
> effects, and again that is part of the discussion, to see whether or
> not these differences could explain the treatment difference and we
> will cover that.
>
> DR. BORER: Why don\'t you go ahead?
>
> DR. EDELMANN: As I was saying, will review next the results of the
> other endpoints in the LIFE study, beginning with the secondary
> component endpoints. But before I present these results, let me
> describe how we accounted for the occurrence of multiple endpoints in
> an individual patient in these analyses. To do that, I will go back to
> the hypothetical patients.
>
> Again, here is hypothetical patient A and his endpoints. This patient
> has multiple endpoints, as shown on the slide. For the analyses of the
> secondary component endpoints each patient was counted if they
> experienced that component. So, patient A would be counted in the
> analysis of MI based on the May, 1997 occurrence of non-fatal of MI,
> the first occurrence of MI. The patient would be included in the
> analysis of stroke on the basis of the February, 1999 occurrence of
> non-fatal stroke. Finally, the patient would be included in the
> analysis of cardiovascular death based on the September, 2000 fatal
> MI.
>
> To recap, for the secondary component endpoints we used an
> intention-to-treat approach. The occurrence of an endpoint of one type
> did not censor the patient from the analysis of endpoints of a
> different type and, therefore, each patient counted in all relevant
> analyses. However, each patient was included only once in any
> particular endpoint analysis.
>
> This plot summarizes the hazard ratio and 95 percent confidence
> intervals for the secondary component endpoints. The number of events
> for each treatment group, for each endpoint is listed on the left side
> of the slide. You can see that more than 500 patients experienced a
> stroke, making this the most commonly experienced of the secondary
> component endpoints. From this plot you will also notice that there is
> variability in the relative risk reductions observed among the
> secondary component endpoints, which was evaluated with a prespecified
> test for heterogeneity which was significant, with a p value of 0.02.
> This indicates that the variation in hazard ratios among the secondary
> component endpoints was more than would be expected by chance alone.
>
> The next several slides will depict the results of the individual
> secondary component endpoints in Kaplan Meier format. The first graph
> shows the occurrence of stroke, again with time on the horizontal axis
> and the proportion of patients who had a stroke on the vertical axis.
> You will notice that the scale is smaller than for the composite
> endpoints since fewer patients had this endpoint. This scale will be
> used for the other secondary component endpoints as well. You can see
> that the curves separate over the course of the trial. This represents
> a 25 percent risk reduction for losartan, with a p value of 0.001.
>
> Here is the occurrence of MI which, as you can see, was similar in the
> two treatment groups across the entirety of the study. Although as an
> adjusted risk reduction this represents a slight increase in risk for
> losartan, the p value is 0.05.
>
> DR. BORER: Before you to on to the next slide, did you attempt, just
> for my information, to break down between the treatment groups for
> fatal MIs alone?
>
> DR. EDELMANN: Yes, and I am going to come to that in just a second.
>
> DR. BORER: Okay. Bob?
>
> DR. TEMPLE: Is this category just documented heart attacks? This
> doesn\'t include things like sudden death which were included in some
> analyses of coronary-artery deaths which I found a little confusing.
>
> DR. EDELMANN: That is right. To be clear about this, investigators had
> the opportunity to report the occurrence of a myocardial infarction
> and did so on a specific work sheet. The endpoint committee reviewed
> those data and made a determination of MI, yes or no. If the patient
> died, in addition to that, the investigator completed a death package.
> So, the endpoint report of MI is without regard to whether it was
> fatal or not. When the endpoint committee classified death, one of the
> choices that they had was a coronary heart disease death, and I will
> show that in just a second. So, it wasn\'t precisely reported as a
> fatal MI, or classified as a fatal MI; just an MI. Both fatal and
> non-fatal endpoints were reported in exactly the same fashion. In
> fact, that is true for fatal and non-fatal stroke, the same thing.
>
> DR. TEMPLE: But this is just documented MIs. It doesn\'t include other
> kinds of things that you call coronary deaths?
>
> DR. EDELMANN: On this report, that is correct.
>
> DR. BORER: Steve?
>
> DR. NISSEN: As I understand it, a number of these patients had had
> previous myocardial infarctions. Is that correct?
>
> DR. EDELMANN: A small percentage had, at least six months prior to
> randomization, an MI.
>
> DR. NISSEN: So, the thinking here was that it was acceptable to
> withhold beta-blockers post myocardial infarction for the purposes of
> the trial?
>
> DR. EDELMANN: Well, that decision was left to the individual
> practitioner because the patients had a requirement for a beta-blocker
> that was an exclusion from the trial so only patients who, in the view
> of the investigator, were appropriate to not be on a beta-blocker were
> permitted to be randomized.
>
> DR. NISSEN: About 20 percent or so had a prior MI, something like
> that?
>
> DR. EDELMANN: No, no, it was about six percent.
>
> DR. NISSEN: Six percent? Okay.
>
> DR. EDELMANN: Finally, here are the results for cardiovascular
> mortality. A separation between the two curves appears to occur by 12
> months and continues thereafter through the course of the study,
> representing an 11 percent risk reduction with a p value of 0.2.
>
> This slide again displays the hazard ratio and 95 percent confidence
> intervals for the cardiovascular death endpoint which can be further
> subdivided into death due to stroke, death due to coronary heart
> disease and death due to other cardiovascular causes like heart
> failure and aortic disease which are shown here. Among the
> cardiovascular causes of death, CHD was the most common cause and was
> not different between the treatment groups. Losartan significantly
> lowered the risk of fatal stroke by 35 percent. Other cardiovascular
> causes of death favored losartan although the difference was not
> significant.
>
> So, the 11 percent reduction in the risk of CV death with losartan
> appears to be driven by the 35 percent reduction in fatal stroke, with
> no difference in CHD death. This pattern of a greater benefit for
> losartan on fatal stroke and no difference on fatal CHD is similar to
> that for the other secondary component endpoints of stroke and
> myocardial infarction, as you can see.
>
> DR. TEMPLE: Not a major point but the other category which favored
> losartan was mostly driven by events called peripheral vascular
> disease deaths. I just wondered what that meant.
>
> DR. EDELMANN: It was non-coronary vascular events, and almost all of
> them were aortic related, aortic aneurysms, ruptured aortic aneurysm
> and so on.
>
> DR. TEMPLE: I didn\'t think of that as peripheral.
>
> DR. BORER: Can I ask the committee members sitting around the table,
> if you want to say something, if you will press your button in
> addition, or not in addition, to raising your hand that would help
> because it is easier for me to pick up the red light and the hand.
> Beverly?
>
> DR. LORELL: Did you do a hazard ratio analysis to be able to give us
> what that number is on non-stroke cardiovascular death? You have the
> two components, but if you were to make it even a little bit simpler
> as stroke death and non-stroke cardiovascular deaths, what was the
> reduction?
>
> DR. EDELMANN: So, you are suggesting combining the bottom two?
>
> DR. LORELL: Yes.
>
> DR. EDELMANN: That is not something that we have done but it is
> something we can do.
>
> DR. LORELL: Thank you.
>
> DR. BORER: Bob?
>
> DR. TEMPLE: It is 172 versus 164, slightly favoring losartan.
>
> DR. EDELMANN: Yes.
>
> DR. TEMPLE: And that difference is mostly driven by these aortic
> phenomena, whatever they are, because you can see the coronary ones
> are dead even, so to speak.
>
> DR. EDELMANN: On the next two slides I will review the additional
> endpoints that were adjudicated by the endpoint committee. The risk
> reduction with losartan for total mortality was consistent with that
> for CV mortality but it did not achieve statistical significance. You
> can see on this slide the individual cardiovascular causes of death,
> as well as the results for non-cardiovascular deaths which were
> largely due to cancer.
>
> The remaining cardiovascular endpoints are depicted on this slide.
> Angina pectoris or heart failure requiring hospitalization and
> coronary or non-coronary revascularization were not different between
> losartan and atenolol. Resuscitated cardiac arrest occurred too
> infrequently to evaluate.
>
> Next, I will present the results that were obtained from the ECG core
> center. The core center evaluated yearly electrocardiograms for the
> magnitude of left ventricular hypertrophy by both the Cornell voltage
> duration product and the Sokolow-Lyon methods, as well as the
> occurrence of silent MI. Only 27 patients were detected as having
> silent MI, 13 in the losartan group and 14 in the atenolol group, so
> no analyses were performed on this endpoint.
>
> This slide shows the change in ECG-LVH as measured by the Cornell
> voltage duration product for losartan and atenolol over the course of
> the study. You can see that there was a significant and steep decline
> in this parameter for patients treated with losartan that was present
> by six months and continued in its decline over two years before it
> plateau\'d. In the atenolol-treated group there was a decline which
> also continued over two years but was significantly less than that
> seen with losartan over the course of the study.
>
> In like fashion, as measured by the Sokolow-Lyon voltage, there was a
> significant and greater decline with losartan treatment that continued
> over pretty much the entire course of the study.
>
> A similar pattern is seen in the subset of patients who had yearly
> echocardiography performed. Losartan resulted in a larger decline in
> left ventricular mass index compared to atenolol.
>
> Let me next turn to the efficacy results in predefined subsets of the
> population. As described earlier, we defined diabetes and isolated
> systolic hypertension as disease categories of special interest. In
> these patients we evaluated the primary endpoint, the secondary
> component endpoints, as well as total mortality and hospitalization
> for angina and heart failure.
>
> In addition, we prespecified 23 subgroups of the population based on
> demographics, disease history and clinical characteristics at
> baseline. In these patients only the primary endpoint was evaluated
> using a test for treatment by subgroup interaction.
>
> First I will review the results in the high risk disease categories of
> special interest, diabetes and isolated systolic hypertension. As
> expected, we observed a higher event rate in these patients in the
> LIFE study. This slide depicts the rate of the primary endpoint per
> 1000 patient years in the LIFE study on the vertical axes. Diabetic
> patients, shown in green, and non-diabetic patients, shown in white,
> are presented in the left panel. Patients with isolated systolic
> hypertension, in green, and without isolated systolic hypertension, in
> white, are presented in the right panel.
>
> As you can see, for the diabetic patients the risk of the primary
> endpoint was twice the rate observed in non-diabetics. In patients
> with isolated systolic hypertension the risk was increased 1.2-fold as
> compared to patients without isolated systolic hypertension.
>
> This slide summarizes the results of the primary endpoint in diabetic
> and non-diabetic patients and patients with and without isolated
> systolic hypertension. Again, the size of the dot is proportional to
> the sample size of the population in this plot. The dashed white line
> shows the hazard ratio for the total population as a reference. There
> was no treatment by subgroup interaction in either of these
> populations, as indicated by the p values to the right of the subgroup
> results.
>
> The next series of slides will display the individual endpoints in the
> diabetic and isolated systolic hypertensive patients. This slide shows
> a Kaplan-Meier presentation for the primary endpoint in diabetic
> patients. The separation between losartan and atenolol continues
> through the course of the study, representing almost a 25 percent risk
> reduction, with a p value of 0.031. Remember that diabetic patients
> represented only around 13 percent of the entire population.
>
> This plot summarizes the results for the secondary component endpoints
> in diabetic patients. All of these results appear to be consistent
> with the primary endpoint result.
>
> Total mortality was reduced by nearly 40 percent in diabetic patients
> treated with losartan, as was hospitalization for heart failure.
> Angina pectoris was not different between the treatment groups.
>
> In patients with isolated systolic hypertension a similar finding of
> benefit for losartan was present in the primary endpoint. A separation
> between losartan and atenolol persisted over the course of follow-up,
> showing a 25 percent risk reduction which approached but did not
> achieve statistical significance on its own. This population
> represented about 14 percent of the entire study group.
>
> Here, similarly summarized, you can see the secondary component
> endpoints for the patients with isolated systolic hypertension. The
> benefit for losartan among the secondary component endpoints is again
> consistent with the primary endpoint.
>
> The remaining endpoints in isolated systolic hypertensive patients are
> displayed on this slide and show a similar pattern as was seen with
> diabetics.
>
> Now, for the 23 subgroups, demographic, clinical and disease history
> subgroups, analyses of an interaction with treatment were performed
> for the primary endpoint. A p value of less than 0.05 was
> predetermined to indicate a positive treatment by subgroup
> interaction. In none of the subgroups did we find a test for
> interaction that achieved this threshold with a p value of less than
> 0.05, as reflected in this table.
>
> Please note that the p values are not adjusted for multiplicity.
> However, I will point out that the test for interaction between
> treatment and ethnic subgroup had a p value that was close to 0.05
> that caused us to look more closely at this subgroup.
>
> This plot shows the hazard ratio and 95 percent confidence intervals
> for each of the ethnic subgroups. In this plot, again, the size of the
> point is proportional to the sample size in the subgroup and the white
> dashed line shows the hazard ratio for the total population for
> reference. The p value for the interaction test is shown on the right
> side of the graph.
>
> What you can see is that the white subgroup, which included the vast
> majority of patients, had a benefit that was consistent with the
> overall population. In contrast, black patients had an effect that
> appeared to favor atenolol. Because the test for interaction that was
> used could be influenced by the small size of the remaining subgroups,
> we further evaluated the ethnic subgroup by creating a dichotomization
> into black and non-black patients and repeating the interaction test,
> which is reflected in the next slide. As you can see, the interaction
> remained and, in fact, was highly statistically significant, with a p
> value of 0.005. We then applied a test for qualitative interaction and
> found that it was also significant.
>
> To try to understand the qualitatively different response of black
> patients in the LIFE study we undertook a large number of exploratory
> analyses. These included looking at and adjusting for differences in
> the baseline characteristics between black and non-black patients and
> between the losartan and atenolol treatment groups among black
> patients.
>
> In addition, we looked at the influence of site and region both in the
> U.S. and in the overall study. We further explored the treatment
> effects of losartan and atenolol on the secondary clinical endpoints,
> as well as for vital signs and left ventricular hypertrophy.
>
> While there were some baseline differences between black and non-black
> patients, for example, there were more smokers and diabetics among
> black patients and there were higher rates of stroke and lower rates
> of coronary heart disease in the black population compared to
> non-black patients, adjustment of the analysis of the primary endpoint
> for these differences did not explain the interaction, nor did
> adjusting for small differences between black patients randomized to
> losartan and atenolol.
>
> The next series of slides present the blood pressure as well as heart
> rate and ECG-LVH data in black versus non-black U.S. patients. As you
> can see on the left, losartan and atenolol provided significant and
> comparable reductions in systolic blood pressure in black patients,
> similar to the findings in the non-black patients. The same finding
> was present for diastolic pressure, shown on the right.
>
> This slide depicts the effect of treatment on heart rate for non-black
> patients on the left and black patients on the right. As with the
> blood pressure data, the black patients responded similarly as the
> non-black patients.
>
> We next looked at the impact of treatment on LVH in black and
> non-black patients. Again as shown in these charts, the black patients
> appeared to behave similarly to non-black patients, with a larger
> decrease in ECG-LVH with losartan as compared to atenolol measured
> either by the Cornell product method, shown on the left, or the
> Sokolow-Lyon method, shown on the right.
>
> To summarize, black patients behaved differently from the non-black
> patients in the LIFE study with respect to the primary endpoint as
> indicated by a significant test for interaction. Black patients
> appeared to have a greater reduction in risk with atenolol.
>
> This observation was not explainable by small differences in baseline
> characteristics between black and non-black patients or in differences
> among black patients randomized to losartan and atenolol. In contrast,
> black patients behaved similarly to non-black patients with respect to
> the effect of treatment on blood pressure, heart rate and left
> ventricular hypertrophy.
>
> So, we were unable to find any explanation for this interaction from
> within the LIFE study data. Nonetheless, we believe this is important
> information that prescribing physicians should be aware of and are
> recommending that a description of these findings be included in the
> product circular.
>
> To summarize the overall\--
>
> DR. BORER: Excuse me, can you just go back to the results in blacks?
>
> DR. EDELMANN: Yes?
>
> DR. BORER: The FDA review actually identified some baseline
> differences among the black and white patients that might be important
> in modifying the results that you found. Have you done an analysis of
> the baseline data that would confirm or refute that fact?
>
> DR. EDELMANN: This is again a topic that we intend to cover in some
> detail and that I expect would be part of the discussion afterwards.
>
> DR. BORER: That is fine.
>
> DR. EDELMANN: To summarize the overall efficacy results of the LIFE
> study, losartan-based treatment of hypertensive patients with
> electrocardiographic evidence of LVH was superior to atenolol-based
> treatment as shown by a 13 percent reduction in the risk of the
> primary endpoint of cardiovascular morbidity and mortality.
>
> Among the secondary endpoints, the risk of stroke was significantly
> decreased with losartan, by 25 percent, and there was a
> non-significant benefit on cardiovascular death that favored losartan,
> driven by a significant reduction in fatal stroke. There was no
> difference in the risk of MI or in death due to coronary heart
> disease.
>
> In addition, there was a significantly greater reduction in ECG-LVH
> with losartan and these results were obtained in comparison to an
> established antihypertensive regimen with comparable blood pressure
> lowering with both treatments.
>
> With the exception of black patients, as I have just mentioned, the
> benefit of losartan was generally consistent among a wide range of
> subgroups of patients, including those at higher risk of
> cardiovascular events, patients with diabetes or isolated systolic
> hypertension.
>
> Next I will review the results of the adverse event reporting and
> other safety parameters that were evaluated in the LIFE study.
>
> DR. BORER: Dr. Edelmann, perhaps we can stop here for a moment. I am
> going to resist the tendency, in view of the Giants horrible collapse
> in the fourth quarter yesterday, to punish everybody by making them
> sit at the table but I have been reminded that we need a break. So, it
> is 10:15. We will take a 15-minute break and then you can go ahead.
>
> \[Brief recess\]
>
> DR. BORER: Let\'s get back and get started again. Dr. Edelmann, before
> you present any of the safety data, I would like to ask everyone
> around the table if they have any specific questions about
> clarification of your efficacy data. I am sure there will be some. Why
> don\'t we start on my left-hand side and we will come around the
> table. John, do you have any questions for clarification here?
>
> DR. NEYLAN: If you will perhaps give me a minute I will come up with a
> couple.
>
> DR. BORER: Okay, we will come back to you. Tom?
>
> DR. PICKERING: Yes, with regard to how the composite endpoints were
> determined, in the [Lancet]{.underline} paper, in Table 3, it gives
> the number of endpoints, and there are about between 500 and 600, and
> yet the total for mortality, stroke and MI is over 1000 per group. So,
> could you give us a breakdown of which type of events were actually
> used in the composite endpoints?
>
> DR. EDELMANN: Yes, this is a descriptive analysis that was in both the
> medical and statistical reviewers\' reports from the FDA and one that
> we have done ourselves. I can show you but I just want to be clear
> that the primary endpoint, of course, counted the first event. For the
> second and component endpoints we counted the first event of that type
> without regard to whether the patients had had a prior event of a
> different type, as I described. So, this is really just an accounting
> and we have done it.
>
> DR. PICKERING: Could you show us the numbers?
>
> DR. EDELMANN: Yes. Let me just get the slide up, but I think what we
> have is a comparison; I think it is a side by side presentation.
>
> DR. BORER: While you are pulling up those numbers, John, you had a
> question to ask?
>
> DR. NEYLAN: A couple. The first question I would like to ask is for
> perhaps a bit more detail regarding the study\'s conduct and
> interaction with the investigators as they monitored the degree of
> blood pressure control in these two treatment arms. Looking at the
> overall result at the end of the five-year period, the degree of blood
> pressure control is roughly in the ball park of what might be expected
> for general clinical practice, but could you speak a little bit more
> as to what procedures you had in place to try to improve upon that
> kind of baseline?
>
> DR. EDELMANN: Yes, sure. This was something that was, as you
> mentioned, carefully monitored, and there were regular reviews
> conducted between the monitoring personnel and the investigator about
> the level of blood pressure control for each individual patient and
> the dose level of blinded study therapy and discussions about
> appropriate up-titrating or adjusting therapy to achieve blood
> pressure control.
>
> This was an active campaign, if you will, that the steering committee
> orchestrated to ensure that, as much as possible, therapy was applied
> to attain control in as many patients as possible. You can see that it
> was a lot more effective at the diastolic level than it was at the
> systolic level, but it was an organized effort that continued through
> pretty much the whole study.
>
> DR. PICKERING: And a follow-up to that, if, indeed, this attempt was
> applied universally were there any distinguishing characteristics to
> the institutions or the subsets of patients to which this application
> of increased effort was successful or not?
>
> DR. EDELMANN: No, it was equally successful, to the degree that it
> was, pretty much across the different centers in the study, including
> across countries, in terms of getting additional patients to goal who
> weren\'t there to begin with.
>
> DR. BORER: Do you have the numbers in response to Tom\'s question yet?
>
> DR. EDELMANN: Yes. Could I see slide 382? What we have on the left is
> using the intention-to-treat approach that I presented counting the
> number of patients who experienced the event. This is the way the
> Merck analysis was done. Both Merck and FDA agree this is the
> appropriate way of doing the analysis of each of the components.
>
> There are 204 patients who had a cardiovascular death, irrespective of
> whether they had an MI and survived or stroke that they survived prior
> to that, in the losartan group and 234 in the atenolol group. You can
> just read the numbers across for stroke and MI.
>
> Looking just at the primary composite endpoint, that is, the first
> event of any type, the numbers break down in this fashion so you can
> see that there were fewer cardiovascular deaths, 137 versus 154, a
> difference of 3.0 and 3.4 percent for the losartan group. There were
> many fewer strokes as a first event, 197 versus 266, and slightly more
> MIs in the losartan group than the atenolol. If you add these up,
> these will come out to 508 and 588 because that is the number of
> patients that experienced a primary endpoint in the losartan and
> atenolol groups. This may be instructive but it is not the kind of
> thing that we have done any inferences on.
>
> DR. BORER: Bob?
>
> DR. TEMPLE: It is just worth noting that cardiovascular deaths, which
> you did break down in your background, are a mixture of things that
> look cardiac and things that look cerebral. In fact, most of them are
> cerebral.
>
> DR. EDELMANN: Yes.
>
> DR. TEMPLE: So, most of that 30 patient difference is due to what
> looked like cerebral deaths. There is overlap. There are deaths in all
> three groups.
>
> DR. EDELMANN: Yes, that is definitely true in this analysis, that
> there are deaths in all three groups.
>
> DR. BORER: Do you have more questions?
>
> DR. PICKERING: Yes, I have a question regarding the isolated systolic
> hypertension subgroup. In the publication it looks as though only
> about one or two percent were on just a single drug. There were more
> withdrawals in the atenolol group than the losartan group. Was that
> significant, do you know, this 169 versus 216?
>
> DR. EDELMANN: Yes, I am not positive about the level of significance.
> Let me just make sure that I understand your question. You are
> referring just to the isolated systolic hypertension in the paper?
>
> DR. PICKERING: Yes.
>
> DR. EDELMANN: And you want to know whether the difference between
> those who were on monotherapy for the entire trial was different?
>
> DR. PICKERING: No, because that was just one and two percent in the
> two groups, but discontinued therapy appears to be quite a lot higher
> in the atenolol group.
>
> DR. EDELMANN: Yes, it is something that we can look at. The ones who
> discontinued therapy in the overall population were higher in the
> atenolol group compared to the losartan group, as I showed you
> earlier. I don\'t know what the p value is. The pattern is similar.
>
> DR. BORER: Any other issues, Tom?
>
> DR. PICKERING: No.
>
> DR. NISSEN: On your slide 79 you gave us the patients with diabetes. I
> would be interested in a similar Kaplan-Meier sort of analysis with
> the non-diabetics.
>
> DR. EDELMANN: Right. Well, I don\'t have a Kaplan-Meier but I can go
> back to, I think, just one slide before this. You can see the risk
> reduction in the non-diabetic population. It is just slightly less
> than that for the overall population.
>
> DR. NISSEN: Right, but again not statistically different from
> atenolol.
>
> DR. EDELMANN: Yes, again, this is an opportunity to provide the way in
> which we looked at subgroups. In this case we are talking about the
> subgroup of diabetic versus non-diabetic. We have taken, as I think
> has the FDA, a cautious approach in evaluating subgroups in wanting
> not to over-interpret them. We looked to see whether or not the
> difference between the subgroups varies to a greater degree than might
> be expected at random, and we do that with this test for interaction.
> In this case, with the diabetic patients there is no significant test
> for interaction, which suggests that the best treatment effect is that
> of the entire population irrespective of whether patients had diabetes
> or not; the same for isolated systolic hypertension.
>
> DR. NISSEN: We still don\'t have those p values. The reason I keep
> coming back to this combination therapy is because it is a paradox for
> me which I don\'t understand. If you could put up slide 48, I think
> Tom was trying to get at the same question. Let me see if I can state
> the paradox for you and why I think it would be helpful to the
> committee to answer it.
>
> Basically, what we see is that more patients on atenolol were off
> study drug and more patients on losartan were on combination therapy.
> Now, since losartan lowered blood pressure nominally more than
> atenolol, what I don\'t understand then is why should there be more
> combination therapy use. You would expect if atenolol were a less
> effective antihypertensive that there would be much more combination
> therapy with atenolol. It is exactly the opposite of what one would
> expect knowing the blood pressure data. My p values here, and I will
> be interested if you can confirm these, for the off-study drug is
> 0.001 for the differences, and for the combination therapy it is also
> 0.001. So, statistically significantly more patients on losartan got
> combination therapy even though their blood pressures were lower, and
> I don\'t understand why that happened.
>
> DR. EDELMANN: First, let me just refer to this slide. This represents
> an accounting of patients at a particular time point, that is, at the
> end of follow-up for patients who did not have an event and just at
> the last available point prior to an event for those who did. Right
> there is a basis for understanding some of the differences because
> there are more events in the atenolol patients and they happened
> earlier in the trial so there is more of an opportunity for a
> difference there.
>
> Also, it is very difficult to tease out of this kind of data reported
> as a single point in time for why things happened because patients are
> being treated continuously through the trial. So, another way of
> thinking about this is to look at the proportion of time rather than
> the proportion of patients. It is something that we are going to
> provide for you because I think it is very useful. We are working on
> it and as soon as we have it, I think it will be helpful to make the
> distinction that although the differences might appear to be big when
> you take any one point in time, if you look over the entire time of
> follow-up, which is probably a better reflection of what happens in
> the trial, the differences are not as big as you might think. I will
> show you that as soon as I get it.
>
> DR. BORER: As part of answer to Steve\'s question, do you believe
> there may be some contribution of incomplete blinding to the selection
> of adjunctive therapy here? You know, there was a significant
> difference in heart rate, as you would expect and maybe there is no
> way to avoid this, in fact, I am sure there is no way to avoid it, but
> to what extent might the therapy and adjunctive therapy specifically
> have been a response to the perception of investigators that patients
> were on one drug or another?
>
> DR. EDELMANN: First of all, as you said, the study was a blinded trial
> and it followed all GCPs so there wasn\'t any unblinding per se. I
> presume you are talking about educated guesses.
>
> DR. BORER: Yes, exactly.
>
> DR. EDELMANN: We did look at this a little bit. Of course, anything I
> say is speculation about what happened but we did look to see how well
> an investigator could guess what treatment a person was on, on the
> basis of heart rate reduction. What we observed was that heart rate
> reductions although on average were greater with atenolol than
> losartan, were present nonetheless in both treatment groups. So, every
> time an investigator saw a reduction in heart rate and guessed that a
> patient was on atenolol, they would have been wrong more than a third
> of the time. So, we think that it is unlikely to have had a
> substantial contribution to their decisions.
>
> DR. BORER: Just for the record, I agree completely with what you say.
> I don\'t think that it is possible with any certainty to guess what
> drug people are on by just looking for the presence or absence of a
> heart rate reduction. I would expect that most people on average would
> have some heart rate reduction. The issue, I would think, might be
> with people who have rather marked reductions in whom a better
> educated guess might be made, and that might affect the way other
> therapy was given. I don\'t know if it did. I have no reason to
> suggest that it did but I just raise it as a question. Steve, you had
> other points I think?
>
> DR. NISSEN: Actually, that was the end of my questions.
>
> DR. GOLDMAN: Dr. Bonnie Goldman, from regulatory from Merck. I just
> wanted to answer Steve. As Jonathan said, that is a particular time
> point. Importantly, if you look at how many patients in either
> treatment group are on any diuretic, and as we said this is over time,
> it was pretty evenly balanced. Any of the ways you look at this,
> obviously there is a disproportion because more patients stayed on
> losartan longer. That is why we wanted to give it to you looking at
> the percentage over time.
>
> In addition, we did look at this using HCTZ as a covariate\--I am
> sorry, this is any diuretic, not just HCTZ. As you can see, it really
> had minimal effect.
>
> DR. NISSEN: Let me see if I can help you see where I am going because
> I am struggling with this a little bit. You know, we know more now
> than we knew a month ago, and one of the things we have, of course, is
> the ALLHAT database and what we saw in ALLHAT was that drugs mediated
> through the renin angiotensin system or a drug like lisinopril was the
> least effective at stroke reduction compared to diuretics and
> amlodipine which were more effective at stroke reduction than a drug
> with similar mechanism of action.
>
> So, what I was trying to understand here is if a lot more patients on
> the losartan arm got concomitant therapy with other agents that are
> more effective at stroke reduction, that could have really a pretty
> substantial effect on the endpoint. When I looked at the data, what I
> saw were what looked to me to be highly statistically significant
> differences in the number of patients getting combination therapy, at
> least in slide 48 that you showed. I know you are making some other
> calculations but, to me, that is an important consideration because it
> appears from ALLHAT that drugs that work through the renin angiotensin
> system are not particularly effective at stroke reduction.
>
> DR. EDELMANN: Let me just respond again about the difference in counts
> of patients at any one point in time which I think can mislead you
> into believing that there were substantial differences in treatment,
> rather than looking at the time course. What we are pulling together
> for you is combination therapy, not just diuretics, but I think you
> can see that the differences are not large between the treatments over
> the course of the study even though the differences were larger at the
> time that\--
>
> DR. NISSEN: The time was at the end of the study though where there is
> more opportunity to add concomitant therapy, so you would expect the
> effect to get bigger over time.
>
> DR. EDELMANN: I don\'t want to speculate but if we could put back up
> the diuretic over time I think this pattern is what we are going to
> see. That is slide 1026. As you would expect in this trial based on
> the design which was to achieve goal blood pressure within the first
> six months by adjusting therapy, the addition, in this case of a
> diuretic but it would be similar with concomitant therapy I am sure;
> maybe a little bit delayed, is pretty prompt and then thereafter is
> fairly stable through the course of the trial. As I said, if you pick
> a single point in time based on the occurrence of an event or an
> endpoint it varies. For patients who have an event you are picking a
> level of concomitant use at any point just prior to when they had an
> event, whereas patients who go to the end of the trial, you are
> picking the last time point. I think this is the basis for why you can
> see a difference in the accounting. I think this is probably a better
> reflection of whether or not there were differences between the
> treatment groups. Then the question becomes is this magnitude of
> difference observed over the course of the treatment important in
> explaining the outcome advantage of losartan over atenolol?
>
> For diuretics, let me just reiterated it if I can just show the
> time-varying covariates slide again, one of the approaches we have
> taken, imperfect as it is, is to account for, as a time-varying
> covariate, things changing during the course of the trial. In this
> case it is the time-varying use of a diuretic up to the point where an
> endpoint occurs. What you see on this slide for the primary endpoint
> is the unadjusted result, so that is the hazard ratio of 0.85 and a 15
> percent risk reduction. Now, taking into account that slight
> difference that you saw over the course of the trial by adjusting what
> happens to the hazard ratio it goes to 0.87 or it changes by two
> percentage points.
>
> So, there are all kinds of limitations to this in terms of
> interpretation but it certainly suggests that this magnitude of
> difference observed over the entire course of the trial in concomitant
> diuretic use does not explain the advantage of losartan over atenolol
> for the majority.
>
> DR. BORER: Bob, then Tom and Beverly.
>
> DR. TEMPLE: Two observations. One is that the ALLHAT data on
> lisinopril are very race dependent. In the white population, it
> didn\'t look to me like there was really any difference.
>
> The other observation is that there is a difference between a study in
> which people are randomized to a treatment and everybody gets a
> diuretic, and one in which where there is a two percent difference in
> concomitant diuretic. I mean, one of them is where 100 percent of the
> people are on a drug; the other is a small difference. It is not easy
> to think how a small differences of that size would account for the
> differences seen here.
>
> DR. KEANE: I am sorry, I was just going to follow-up on Dr. Temple\'s
> comment because it gets back to ALLHAT a little bit. I think it is
> important for us to recognize that the ALLHAT diuretic arm was an arm
> that actually employed a beta-blocker very, very frequently. You know,
> 28 percent of the patients started off in that trial on a beta-blocker
> and some 60-plus percent actually were titrated on a beta-blocker as
> well.
>
> So, when we are thinking of regimens and comparing, even though these
> are very different trials, what we have and what the ALLHAT did I
> think it is very important for us to recognize that there were a lot
> of regimens there. The same is true for lisinopril. The lisinopril arm
> in their secondary analysis, as you know, where the issues came out,
> again was a very different regimen because they excluded diuretics as
> the agent because that was their primary comparator; the
> chlorthalidone was their primary comparator in that arm. So, they went
> to other non-diuretic-based regimens. So, it distinctly separates some
> aspects of what this trial did versus the ALLHAT trial. I wanted to
> make that clear. I will be back up in a few moments to actually talk a
> little bit about these issues.
>
> DR. BORER: Before you go away, can you say your name into the
> microphone?
>
> DR. KEANE: I am sorry, I did forget. I apologize. I am Dr. Bill Keane.
>
> DR. BORER: Thank you, Dr. Keane. Can I suggest though that we try to
> avoid intensive reference to the ALLHAT trial for the simple reason
> that we have not been given the database to review. All of us have
> seen only the publication whereas here we have a complete dossier.
> Tom?
>
> DR. PICKERING: Yes, I am a little confused. You showed a slide showing
> that about 70 percent in both groups had been treated with diuretics
> at one time and, yet, there is a table that shows that at the end of
> the trial 26 percent of losartan patients were on diuretics and 22
> percent of the atenolol group. Could you reconcile those two?
>
> DR. EDELMANN: I think 48 is the table you are referring to.
>
> DR. PICKERING: Well, I am looking at the FDA.
>
> DR. EDELMANN: This is the accounting for the proportion of patients at
> the time point which represents the occurrence of an endpoint or the
> end of follow-up for patients who did not have a primary endpoint. You
> have to sum a couple of different lines in order to get it, but 14
> percent in both groups with 50 mg plus diuretic; another two and four
> percent with other drugs plus diuretic; and then of those on 100 mg,
> you see 18 and 16 and addition of 26 and 22.
>
> This slide, 29, shows this which is a reflection not of patients but
> of time, proportion of time, to account for the fact that all of those
> different groupings were possible for all patients throughout the
> trial. It is impossible in one number to summarize that in a
> meaningful way looking at counts of patients, but it is possible to
> account for the amount of time and that is what this does. This
> difference of 72 and 70 percent is a reflection of the graph that I
> showed. Maybe I could throw that up again, 1026. That is the use of
> diuretic over the time of the trial. So, this 72 and 70 percent
> represents the amount of time that this proportion of patients, which
> is increasing rapidly and then is pretty much stable, were on
> diuretics. The 72 percent of the time in yellow and 70 percent in blue
> reflects the difference in the two treatment groups. Does that clarify
> it for you?
>
> DR. PICKERING: Well, that is just the patients who got diuretics. Is
> that right? Not the whole population?
>
> DR. EDELMANN: That is correct. This is the proportion of the whole
> population who received a diuretic at any time, and time is on the
> horizontal axis. So, it is accounting for the entire study group by
> treatment group and what fraction of them at any moment were on a
> diuretic as concomitant therapy\--actually on diuretic.
>
> DR. BORER: Beverly and then Alan?
>
> DR. LORELL: Thank you very much. I think maybe another way of thinking
> about this issue of whether these seemingly small perturbations in
> extra drug use or diuretic use were meaningful is asking the question
> as to whether or not there is a difference in the proportion of
> patients who had endpoints who had severely poor blood pressure
> control. I think one of the things that the committee is wrestling
> with is whether the differences that are seen are drug specific or
> relate more generally to the issue of hypertension control.
>
> I would welcome your comments. I hope you have had a chance to see
> this. The FDA review Table 36, page 63, indicates that rates of
> extreme poor blood pressure control, systolic blood pressure greater
> than 160 or diastolic blood pressure greater than 100, were more
> prevalent for every endpoint among the atenolol receiving group as
> opposed to the group randomized to losartan. So, in some ways this
> raises the question as to whether, for whatever reason, the net effect
> of these perturbations in other drug use or slight differences over
> time in diuretic use translated into the variable of very poor blood
> pressure control being a variable that contributed to the outcome.
> Maybe you could comment.
>
> DR. EDELMANN: Sure. This is an important issue and in Dr. Keane\'s
> presentation he is going to go over this. But let me just give you our
> general response about this. As with the discussion about use of
> concomitant therapy, blood pressure control is something that varied
> over the course of the study and at the beginning of the study
> naturally was low because patients were just beginning therapy, and
> improved over the course of the trial. The table you are referring to
> in the medical reviewer\'s document picks a single time point again
> and accounts for patients at that time point who did and did not
> achieve that level of poor blood pressure control. It is limited in
> the same ways as the concomitant therapy is. It is a non-random
> comparison. It is not protected by randomization anymore because the
> decision about titration and, therefore, the level of blood pressure
> response is something that is influenced by actions within the trial
> after randomization.
>
> Nonetheless, it is still possible to do the same kind of analysis to
> account for all of the time and to look at the level of blood pressure
> goal between the treatment groups, not just poor blood pressure
> response but devise a method of accounting for level of blood pressure
> control that includes the entire population and divide the patients
> into losartan and atenolol groups into those control groups, good
> control, moderate, poor and so on, and then see to what extent the
> difference in that categorization explains the treatment advantage of
> losartan over atenolol. It is much the same as looking at individual
> blood pressure values, systolic blood pressure level and diastolic
> blood pressure level, and to what extent do the differences explain
> the treatment benefit.
>
> We have done that using the same time-varying covariate approach. It
> explains a very small proportion. I think it is less than one
> percentage point of the treatment benefit that is explained that way.
> Although if you look at a specific time point, one time point for the
> proportion of patients at poor control and then go back and say how
> many of those patients had events you can get the mistaken impression
> that that explains the whole difference.
>
> The findings we observe in the LIFE study are exactly what you would
> expect, that is, the occurrence of an event is more likely among
> patients whose blood pressure is less well controlled. If you are
> looking at event numbers, you know there are more patients that had
> events on atenolol and you are undoubtedly going to see more patients
> who are at poorer control in the atenolol group just because of the
> numbers.
>
> DR. BORER: Before we go on to Alan, Paul and back to our rotation
> here, I am going to make a statement that I hope will be helpful in
> the committee\'s thinking about this very important issue that Beverly
> is raising. There are two separate issues that might be considered
> with this supplemental NDA, only one of which is highlighted by the
> sponsor and that is really the one we have to focus on. That is, does
> their regimen, their product and regimen, reduce cardiovascular
> endpoint risk as opposed to just reducing blood pressure? That is
> number one. In that regard, the comparator is just a comparator.
> Either the proposed regimen is better, not better or the same.
>
> The second issue is whether the proposed regimen is actually superior
> to some other regimen. That is not what the sponsor is asking about
> and our response to that might be different than the response to does
> this regimen work. That will come up again in the questions but I
> think we have to keep that in mind as we look at this. It may not be
> so critically important that one regimen may have been a little less
> effective in lowering blood pressure. The question is does the other
> regimen reduce cardiovascular event risks. So, just with that thought
> in mind. Bob?
>
> DR. TEMPLE: If I can, I would like to dilate slightly on that
> question. There is some discussion of comparisons in the ICH document
> called E10. If you want to say that something is better than something
> else it is crucial that the comparison be fair in every way, that each
> drug was used optimally, etc., etc., etc. If you merely want to show
> that your drug works you don\'t have to use the comparator regimen
> optimally. In fact, you could use a placebo to show that your drug
> works but no one will let you do that in hypertension.
>
> So, it is a fundamentally different question and even if there are
> imbalances in this and imbalances in that which disfavored one of the
> treatments, you might still reach the conclusion that the drug was
> shown to be effective.
>
> I just want to make one other point about that. The most tempting
> thing to think about here is, obviously, if you have learned something
> about how best to treat people with hypertension, and it is reasonable
> to consider that and the questions go to that. There is another
> important factor that needs to be weighed here, which is that current
> labeling for antihypertensives uniformly fails to include any outcome
> data and what Merck is doing here\--I don\'t know if they intended it
> but they are really performing a very valuable service\--they are
> provoking the question of whether it is time to start to put outcome
> data into any hypertensive labeling.
>
> We have been thinking about this in a somewhat desultory way for at
> least six years and we will eventually propose language to the
> committee on how to do that but they are forcing the question because
> they are saying, \"hey, we\'ve shown something; you owe us reference
> to that in labeling.\" So, it is a very interesting thing to think
> about but, of course, that question doesn\'t require that it be better
> than atenolol. It just requires that it be better than nothing, which
> is the exact point you made. So, there are two very different kinds of
> questions for us. Then, how you say it and what you say, and all those
> things, are obviously crucial in labeling too. But from a regulator\'s
> narrow point of view it is sort of forcing the issue of outcome data
> in labeling for clinical trials which, as I said, we don\'t have. Some
> people think we do in the form of ramipril but we didn\'t think that
> was a hypertension claim. Steve may be right; it maybe was but we
> didn\'t think it was. We thought it was something else.
>
> DR. FLEMING: Jeff, can I comment on the last two points? Beverly was
> referring to data from the FDA document and Dr. Edelmann was
> responding about a time-varying covariate analysis. I just wanted to
> close the loop on that. It is Table 30 I think in the FDA briefing
> document, page 61 that I think Dr. Edelmann is referring to. If you
> look at any point in time of systolic blood pressure as a time-varying
> covariate and look at differences between the two regimens in being
> able to maintain systolic blood pressure, does that explain the
> treatment effect? It would suggest, as he said, that it explains very
> little. Now, it may be the wrong surrogate. It may be pulse rate,
> pulse pressure or other markers that should have been used in there,
> but if you just use systolic blood pressure it explains very little.
>
> I wanted to return to Bob Temple\'s point because this is a refinement
> of what we talked about this morning. What is the question? We are
> going to be asked a number of questions about the experimental regimen
> here with losartan and what is the role of losartan, and we are
> looking at is losartan against atenolol in the presence of diuretics.
> A comment that I had made earlier today is if you look at the
> comparator regimen, diuretics plus atenolol, there is considerable
> evidence, as we were discussing this morning, that that regimen has a
> considerable influence on outcome. So, now if you look at the regimen
> of losartan plus diuretics one question is, is that regimen going to
> be effective?
>
> I think a very relevant and much more difficult question is what is
> the role of atenolol in those regimens? The LIFE study is going to be
> able to tell us what is the comparison of losartan versus atenolol in
> this LVH population in the presence of diuretics. Is losartan
> effective there? And, one question that is relevant is, is atenolol
> effective? So, specifically, what is the effect of atenolol in the
> combination with diuretics in this LVH population?
>
> At some point I would like to return\--I don\'t know if you want to
> return to it now or later\--at some point I would like to have a clear
> indication of the exact data that are relevant to that question.
>
> DR. BORER: Maybe we can hold that for a little bit later because that
> is going to be an important point of deliberation. Just to come back
> to the point that Bob was discussing though, it may not be necessary
> to know exactly how effective atenolol is or isn\'t. It may be
> important to know that there is a reasonable basis for concluding that
> it is not harmful. We will come back to that but let\'s hold that.
>
> DR. TEMPLE: Jeff, can I just add one thing? There is some reason to
> think that it matters whether it is known to be effective, and that
> goes to strength of evidence. It is remarkable how similar this is;
> this is exactly like our considerations of clopidogrel at the time
> when we were considering the CAPRE study. I don\'t know if you
> remember, but it sort of beat aspirin with a p of 0.052 or something
> like that, not a very strong finding. However, everybody believed that
> aspirin itself was far, far better than placebo so when you did a
> putative placebo or whatever kind of analysis you wanted to do, the
> strength of the evidence that clopidogrel was effective\--which is all
> its labeling says; it doesn\'t say it is better\--was very, very
> strong.
>
> So, if you believe that there is some effect of an atenolol regimen,
> if you don\'t know exactly what that is, that makes this single study,
> with a p of about 0.02 or 0.03, much stronger than it would otherwise
> be. So, it is relevant how much you believe in the control regimen.
>
> DR. FLEMING: I am jumping ahead but that is exactly the issue. That is
> exactly why this question is important. We are jumping ahead, but if
> we believe LIFE nails adequately on the strength of evidence of
> however many trials you think we need of losartan versus atenolol, we
> don\'t need to know any more than that atenolol isn\'t harmful. But if
> we think the evidence is suggestive but not compelling, then it
> becomes very important to understand how effective atenolol is in the
> context of administration with diuretics in the LVH population.
>
> DR. BORER: Alan and then Paul?
>
> DR. HIRSCH: Well, I am going to take us back to something more mundane
> and we will come back to the philosophical argument about atenolol\'s
> effect in a minute. I want to follow-up a little bit on a point that
> both Steve made and that Bev made and make sure that we are
> understanding what caused the endpoint of stroke reduction.
>
> I think we are all impressed and happy, as Bob said, that we actually
> have a hypertension trial where we actually have a hard clinical
> endpoint that changes. So, for stroke I just want to make certain that
> there isn\'t any other concomitant or confounding variable that was
> not accounted for and I couldn\'t quite pull it out of the packet you
> provided or the FDA packet.
>
> For the use of aspirin, clopidogrel, other antithrombotic drugs at any
> time point during the study, one of the packets showed that it was a
> low use and equal at least at one time point. But I would think it
> important for the committee to be sure there are no other
> stroke-preventing therapies that are not imbalanced between the two
> groups. So, I am wondering, just as you showed us the diuretic usage
> across time, do you have other antithrombotic usage over time?
>
> DR. EDELMANN: We have looked at that and I mentioned this point a
> little earlier. There was balance at baseline in the use of
> concomitant aspirin, for example, and increase in the use of aspirin
> during the trial as I guess you would expect when these patients are
> followed regularly, but no imbalance between the treatment groups. So,
> we have looked and haven\'t found that.
>
> DR. HIRSCH: Again, you don\'t have any graph of that over time?
>
> DR. EDELMANN: Not over time, no. I can give you concomitant\--
>
> DR. HIRSCH: I do worry a bit. I always like to see data.
>
> DR. EDELMANN: Well, I can tell you that 35 percent\--you can see this
> is the concomitant co-administration of study drug with aspirin
> between the treatment groups.
>
> DR. HIRSCH: I am sorry, this is?
>
> DR. EDELMANN: This is aspirin.
>
> DR. HIRSCH: At what time point?
>
> DR. EDELMANN: It is the proportion of patients who received
> concomitant aspirin with study drug between the treatment groups. It
> is 35 percent. At baseline it was lower than that but also equal.
>
> DR. HIRSCH: That is not quite how I would like to see it. For
> warfarin?
>
> DR. EDELMANN: I don\'t know if I have warfarin on a slide. It was
> smaller in number and, again, comparable between the two. I guess
> maybe in the same category you might consider statin therapy and,
> again, it was the same pattern. It was 19.8 and 21.1 percent for HMD
> reductase drugs.
>
> DR. BORER: Doug?
>
> DR. THROCKMORTON: I was just going to give you those numbers, but they
> did.
>
> DR. ARMSTRONG: I am still trying to understand the role of myocardial
> infarction in the composite and its play-out in the mortality. As you
> pointed out in slide 62, stroke certainly comprises the majority of
> the endpoints, but in slide 68 it is clear that whereas it comprises
> the majority of the endpoints, it comprises less than a quarter of the
> mortality, and myocardial infarction presumably is grouped within the
> CHD and accounts for more than half the mortality. So, again, I would
> like to understand what is the mortality rate of myocardial
> infarction.
>
> DR. EDELMANN: Unfortunately, I am not able to give you an explicit
> answer to that question based on the way the endpoint committee
> classified the events. An event was determined to be a myocardial
> infarction, and you saw those results, irrespective of whether it was
> fatal or not. When there was a fatality, if it was determined to be
> related to coronary heart disease or a fatal MI as you would say in
> clinical practice, the endpoint committee called it coronary heart
> disease death and categorized the time between the onset of symptoms
> and the death into less than an hour, an hour, one hour to 24 hours or
> more than 24 hours, but didn\'t specifically call it fatal myocardial
> infarction.
>
> DR. TEMPLE: There is a table. Why don\'t you show the table? It is not
> what you are asking but it is as close as you are going to get.
>
> DR. ARMSTRONG: You make the point that\--
>
> DR. TEMPLE: It is in the briefing book so it must exist.
>
> DR. ARMSTRONG: You make the point that the mortality rate of stroke
> accentuates the overall effect on stroke. So, you have very clear data
> on mortality from stroke and unclear data on myocardial infarction,
> which is the other part of your composite, and I am unclear why you
> would have better data on one component and not on the other.
>
> DR. EDELMANN: There was a lengthy discussion on the steering committee
> about how to do this and one of the concerns was the ability to
> actually determine whether or not someone had a fatal MI. In deference
> to the debate, and there was debate about it, the decision was made,
> rather than make that determination, MI or not MI, to call it a
> coronary heart disease event and anchor it in terms of time between
> the onset of symptoms and the occurrence of death. So, within the
> coronary heart disease deaths are the kinds of things that you would
> think of as associated with that\--fatal MI, sudden death.
>
> This was part of the debate and I can recreate a little bit of it for
> you, if a patient presents with an MI and presents with symptoms of
> chest pain and an arrhythmia and dies, is that a fatal MI or is that
> sudden death if it all happens within an hour or if it happens within
> 24 hours? So, rather than try to make an arbitrary decision and
> distinction among those otherwise potentially overlapping clinical
> conditions, this was the way in which the endpoint committee
> classified things.
>
> DR. ARMSTRONG: Can you tell us what proportion of those were
> hospitalized deaths versus non-hospitalized deaths?
>
> DR. EDELMANN: Well, I am not sure that I have the figures right at the
> tip of my fingertips but the overwhelming majority, vast majority of
> all endpoints were hospital-based. There were some deaths that
> occurred outside of hospital, sudden deaths, and it is something I can
> probably get for you. But the vast, vast majority of endpoints, fatal
> endpoints included, occurred in hospital.
>
> DR. ARMSTRONG: The second point was just to return to this composite.
> We had tabled the issue of statistical heterogeneity and I don\'t know
> whether this is the time but it seems to me we do need to address the
> occurrence of the heterogeneity and its impact on our acceptance or
> non-acceptance or better understanding of the primary composite, Mr.
> Chairman. I would welcome Tom\'s view and the response of the sponsor.
>
> DR. EDELMANN: If I might, this is an issue which we know is important
> to the discussion and Dr. Keane will present our perspective on it.
> So, if you wouldn\'t mind holding just a little bit more.
>
> DR. BORER: JoAnn and then Susanna?
>
> DR. LINDENFELD: I have two slightly different issues. The baseline ECG
> that was used for evaluation of LVH, was that done at entry into the
> study or was that a screening ECG?
>
> DR. EDELMANN: There was an ECG by which patients qualified for entry
> into the trial. That was read by the core center and given a thumbs up
> or a thumbs down. Separate from that, there was an ECG on the day or
> near to the day of randomization which we called the baseline ECG and
> that was the ECG that served as the ECG for baseline measures and
> adjustments for the covariate, and so on.
>
> DR. LINDENFELD: And can you tell me, and I am sorry for asking this
> question but I just don\'t know the answer, if acutely lowering the
> heart rate changes the ECG criteria of LVH?
>
> DR. EDELMANN: I am not sufficiently expert to tell you the answer to
> that. I don\'t know if one of our consultants\--no. No, so says Dr.
> Devereux.
>
> DR. LINDENFELD: Okay. Then, my next question is, again, a little bit
> different. We haven\'t discussed at all the urinary albumin-creatinine
> ratio in this study. I guess I would expect that there might be a
> subgroup which would have a fairly larger effect of losartan than
> atenolol. I wondered if you could show us the endpoints by the group
> with an abnormal urinary albumin-creatinine ratio and those without.
> We already know that is a subgroup that has a particular effect of
> this type of drug and it seems to me, if we are really going to get at
> who is benefiting we have to know that data.
>
> DR. EDELMANN: This is using microalbuminuria, the presence of
> microalbuminuria as a place of dichotomization for subgroup with and
> without. Here is the treatment effect. So, those with microalbuminuria
> and those without, and it is a relatively small fraction who had
> reported microalbuminuria. Again, our thinking on this is that the
> best way to interpret it is in terms of the degree to which these vary
> from one another as reflected in the test for interaction. So, the
> interaction test is not significant.
>
> DR. LINDENFELD: I believe data from this study has reported that the
> effect of microalbuminuria is related to LVH perhaps more
> significantly than the blood pressure effect. Is that a correct
> statement?
>
> DR. EDELMANN: I am not sure\--
>
> DR. LINDENFELD: I didn\'t say that very well. In other words, isn\'t
> there data from the LIFE trial published that suggest that there is an
> independent effect of drug treatment on microalbuminuria and the
> decrease in LVH separate from the blood pressure effect?
>
> DR. EDELMANN: I don\'t believe there are any publications yet relating
> to treatment and their relationship, but it is baseline levels\--
>
> DR. LINDENFELD: Baseline, I am sorry, yes.
>
> DR. EDELMANN: So, it is in pooled groups.
>
> DR. LINDENFELD: Right.
>
> DR. EDELMANN: Let me refer to Dr. Devereux.
>
> DR. DEVEREUX: Hi, Dr. Richard Devereux, from Cornell. We haven\'t yet
> done the analyses you suggested to evaluate the association between
> changes in albuminuria and changes in LVH and outcome as a three-way
> association. We have shown very strong cross-sectional associations
> between albuminuria and LVH at baseline that are independent of blood
> pressure level. We intend to do those analyses. We have about 40
> papers we plan to write.
>
> DR. LINDENFELD: You may be collecting this data. I just wanted to come
> back to this issue of the individual centers that requested the use of
> a 25 mg dose of both drugs, could you just show us, in those centers,
> how often each of the groups were decreased to 25 mg?
>
> DR. EDELMANN: Well, I don\'t have a slide but I have the numbers now.
> As I mentioned, it was an option available on a center by center basis
> and it was used relatively infrequently. Less than one percent of
> patients in both treatment groups; 78 atenolol patients total went to
> the 25 mg dose and 32 losartan patients went to the 25 mg dose.
>
> DR. LINDENFELD: Could you just give me a rough idea of how many
> patients were in centers that could have reduced the dose?
>
> DR. EDELMANN: Well, it was an option that was available to all
> centers. In other words, if the center felt that a lower dose was
> necessary we instituted the paperwork, the protocol amendment and so
> on to make it possible but it was available at all centers; it just
> wasn\'t used very frequently.
>
> DR. LINDENFELD: Right, but I guess what I am getting is that twice as
> many patients had the atenolol dose reduced as losartan. Again, I
> think this is a bit of an issue because in this older patient
> population 25 mg of atenolol could be effective therapy. I am not too
> concerned about this but I worry a little bit because it was an
> amendment made well into the study I think in 1998, and I worry that
> some of the withdrawal may have been because the option wasn\'t there
> to reduce the dose in those older patients. I think that is an issue
> in these older patients.
>
> DR. BORER: Susanna?
>
> DR. CUNNINGHAM: Yes, I was curious about the left ventricular
> hypertrophy. You chose your population because age increases risk of
> morbidity and mortality so I was wondering what your data shows that
> happens to morbidity and mortality with a reduction in LVH since that
> would be something of interest. Sort of the implied assumption I think
> is that if you did reduce LVH it would reduce morbidity and mortality.
>
> DR. EDELMANN: Right, well, this is another example of things changing
> in the protocol during the course of the study simultaneously so we
> have used the same kind of approach here. LVH, as you saw, was reduced
> over time. There were fewer endpoints. To what extent does the change
> in LVH explain the benefit? And, we used the same time-varying
> covariate method. Again, I will remind you this is a method for
> adjustment that starts with the unadjusted result of the 14.6 percent
> risk reduction and then accounts for differences between the treatment
> groups in left ventricular hypertrophy and looks at the relative risk.
>
> What you see is that the risk reduction goes from 14 percent to a
> little under 10 percent. So, this is almost a five percent endpoint
> change. This is a more substantial magnitude of change being accounted
> for by differences in left ventricular hypertrophy and probably
> consistent with what you would expect if left ventricular hypertrophy
> is actually having some effect given the limits of the analysis and
> the methods. LVH was measured only once a year. It was measured on the
> electrocardiogram which has its own imperfections in accuracy of
> measurement. So, for all these reasons it is not a precise or exact
> thing but it shows an association of some of the benefit of losartan
> over atenolol associated with left ventricular hypertrophy.
>
> DR. FLEMING: Before leaving this point, does this explain at all the
> interaction by race, blacks/whites, if you did a similar type of
> analysis?
>
> DR. EDELMANN: No, it does not.
>
> DR. HIRSCH: That same analysis for stroke alone?
>
> DR. EDELMANN: For stroke alone for LVH reduction? I can show you that.
> Essentially, when we did the time-varying covariate on the primary
> composite and then looked at the secondary component endpoint we saw
> roughly the same thing, that is, an effect of about four percentage
> points, just focusing on the change here\--about four percentage
> points to be explained or associated with accounting for the left
> ventricular hypertrophy change. I think this makes sense. Left
> ventricular hypertrophy is certainly not causing stroke but is
> associated with stroke, as I reviewed in the beginning part of my
> talk, because it is a surrogate and a marker for other processes that
> are occurring outside of the heart but in response to the same things,
> like blood pressure and angiotensin II, and when you take into account
> the change in left ventricular hypertrophy you see some effect.
>
> DR. BORER: Susanna, did you have some other points?
>
> DR. CUNNINGHAM: No.
>
> DR. BORER: Mike?
>
> DR. ARTMAN: Along those lines, sticking with LVH, the ECG criteria and
> the question I think Tom raised about does this explain the ethnic
> differences that were seen, in the black population, by the
> Sokolow-Lyon criteria they had greater LVH and by the Cornell time
> product less LVH. I am wondering, in that subset analysis about ten
> percent of patients had ECHOs and there was a predominance of black
> patients in that. If you look at that subset of patients that had ECO
> assessment of LV mass, which I think is a little more reliable, does
> that provide us any insight?
>
> DR. EDELMANN: Unfortunately, it doesn\'t. As you pointed out, it is a
> subset of a subset so we had only about ten percent of the overall
> patients in the LIFE study who were in the ECHO substudy to begin with
> and only a fraction of those were black. We are talking about 64
> losartan patients and 65 atenolol patients. When you look at the LV
> mass change there, there is no difference between the treatment
> groups. Both treatments regress left ventricular mass but there is no
> difference between the two. Numerically, I think it is a little bit in
> favor of atenolol but there is not anywhere near the kind of power
> that you need to draw any conclusions.
>
> DR. BORER: Tom?
>
> DR. FLEMING: You have talked about the subgroups and the need for
> caution in interpreting those subgroups. I have a couple of quick
> specific questions. If you don\'t know the answer, you can provide it
> to us at the break. You have indicated that when you look at the
> diabetic subgroups, yes versus no, and look at the primary endpoint
> the test for interaction is 0.17. Basically you are seeing a bigger
> difference in effect in the diabetics, 24 percent reduction rather
> than 11 percent reduction. Mortality breaks out a bit more strikingly
> though, all of the mortality differences in the diabetics. Could you
> at some point give us the test for interaction p value for that?
>
> DR. EDELMANN: Yes, we have done that. For total mortality you are
> asking?
>
> DR. FLEMING: Yes.
>
> DR. EDELMANN: I don\'t know if I can give you the p value but the
> magnitude of difference is significant.
>
> DR. FLEMING: Maybe you could get that for us later. Let me move on.
> When we look at race, you have indicated a 0.005 significance level
> for the test for interaction for the primary endpoint. Stroke shows a
> very similar interaction. If we could get that significance level,
> just looking at the stroke component, that would be helpful.
>
> DR. EDELMANN: Okay.
>
> DR. FLEMING: Then my other question is we are looking at the LIFE
> study as the primary source of evidence here for losartan or more
> generally ARBs in the presence of diuretics. If you are going to come
> back to this later on just let me know, but is there any additional
> evidence that you think we should be considering when you are looking
> at the effects of ARBs in the presence of diuretics on this composite
> endpoint of death, MI and stroke in hypertensive patients with LVH?
>
> DR. EDELMANN: I don\'t know that there is specific evidence about the
> addition of a diuretic to an angiotensin receptor antagonist, but I am
> sure you are aware that the blood pressure lowering effects are well
> studied when a diuretic is added to an angiotensin receptor antagonist
> and augment the benefit in terms of blood pressure. I think that is
> probably the most relevant bit of information. That is to say, the
> combination of an angiotensin receptor antagonist and a diuretic has a
> substantial benefit on blood pressure which is contributing in some
> fashion to the benefit that you see in absolute terms. The
> contribution of the relative difference between losartan and atenolol
> on diuretic I think is probably best addressed by the in-trial
> accounting for the use of diuretics that we have been over and
> doesn\'t really seem to explain very much the treatment advantage.
>
> DR. BORER: Steve and then JoAnn?
>
> DR. NISSEN: Because it appears that more atenolol patients were
> withdrawn from therapy than losartan patients I would be very
> interested in seeing the pro-protocol analysis. Now, I recognize that
> the intent-to-treat analysis is the preferred one but when you see
> these kind of differences in withdrawal of therapy it is helpful to me
> to look at a pro-protocol analysis. I am sure you have slides for
> that.
>
> DR. EDELMANN: I can show you that, sure. As you said, pro-protocol has
> the disadvantage of eliminating information because patients who are
> no longer on therapy are not considered for future events; they are
> censored.
>
> DR. NISSEN: Yes.
>
> DR. EDELMANN: So not surprisingly, the number of endpoints in the
> pro-protocol analysis is a lot less because you have censored out a
> lot of the patients, but you can see that the hazard ratio and
> confidence intervals are really pretty similar.
>
> DR. NISSEN: In the FDA\'s analysis though the p value is
> non-significant for the pro-protocol.
>
> DR. EDELMANN: Yes, as it is here. I think it is just barely above
> 0.05. Maybe it is because of the dashed line, but you can see that the
> confidence bound is just barely approaching the unity line. So, it is
> 0.05 and another digit, not significant.
>
> DR. BORER: JoAnn?
>
> DR. LINDENFELD: Just a quick question. I notice that the losartan
> blood levels are twice as high in women as men in this study. The
> metabolite levels aren\'t different. Then, also, the sensitivity, the
> ECG for LVH is half that for women that it is for men. I wondered if
> you could show us the difference by sex in this study.
>
> DR. EDELMANN: Sure.
>
> DR. LINDENFELD: And maybe if you have the blood pressure differences.
> In other words, did the blood pressure drop equally in men and women?
>
> DR. EDELMANN: Well, let me start with the first one. I can show you
> the primary endpoint by gender as a subgroup. You can see, again,
> looking at the interaction p value for a method for interpreting this
> that there is no interaction. So, we assess this to say that the best
> treatment effect in men and women is reflected by the overall.
>
> In terms of blood pressure response by gender, that is not something
> that I have off the top of my head but I know it is something we have
> looked at so I may be able to get that information to you.
>
> DR. BORER: If there are no other clarifications of the efficacy
> data\--Mike?
>
> DR. ARTMAN: I just have one more question. I realize we have talked
> about subgroups, and when you tested for interaction among the
> different countries there was no overall interaction, yet, the only
> country where there is no overlap of 1 for the confidence intervals
> for the primary endpoint was Norway. Norwegians also have lower
> baseline stroke rates. I just wonder if I am reading too much into
> that or is it better to be in Norway?
>
> DR. EDELMANN: I have been in Norway; it is a nice place! As I said now
> several times and I will repeat it again, we have been very
> conservative in our view of how to interpret subgroups because there
> are all kinds of pitfalls in over-interpreting. Our conclusion is that
> it is essentially the same story; there is no evidence of a treatment
> by country interaction, and our interpretation for the primary
> endpoint is that the best estimate of the treatment benefit is for the
> overall population. Yes, there is a variation that you describe but it
> is not more than would be expected to occur at random with this
> distribution of patients among countries.
>
> DR. BORER: Let\'s see if we can go on to the safety assessment.
>
> DR. EDELMANN: Next I am going to review the results of adverse event
> reporting and other safety parameters that were evaluated in the LIFE
> study.
>
> This table summarizes the overall adverse event reporting in the LIFE
> study. Not surprisingly, in a study of this duration almost all
> patients in both treatment groups experienced at lease one adverse
> event. However, patients treated with losartan experienced
> significantly fewer drug-related adverse events compared to those
> treated with atenolol and discontinued due to adverse events with
> lower frequency compared to those patients treated with atenolol.
>
> At the outset of the trial the steering committee defined nine adverse
> events of special interest. Chosen based on the comparator agents in
> the trial, these adverse events are shown on this slide. AEs of
> special interest that occurred with higher frequency in the losartan
> group are shown on the top half of the slide and those occurring more
> frequently in the atenolol group are shown on the bottom half of the
> slide. On both halves the AEs are listed in decreasing order of
> frequency for losartan.
>
> Most of the AEs occurred with equal likelihood between the treatment
> groups. Hypotension was more likely to occur in the losartan group
> whereas bradycardia, cold extremities and sexual dysfunction were more
> likely to occur with atenolol.
>
> Other adverse events occurring with a frequency of at least five
> percent in either treatment group but differing between the treatment
> groups by at least one percent are depicted on this slide, again in
> order of decreasing frequency in the losartan group. This is a
> complete list of such adverse events. The differences between the
> treatment groups are not of clinical significance.
>
> Laboratory values, including serum electrolytes, hematologic and
> metabolic parameters, as well as urinary albumin and creatinine were
> measured in the LIFE study. There were no important differences
> between the treatment groups in these parameters whether measured by
> absolute value or predefined limits of change from baseline.
>
> The occurrence of new diabetes was prespecified by the steering
> committee to be of interest and was diagnosed by the investigator
> according to an algorithm based on WHO guidelines. The diagnosis of
> diabetes required documentation of at least two fasting blood glucose
> values above 140 mg/dl or a positive oral glucose tolerance test.
> Patients treated with losartan were significantly less likely to
> develop new diabetes, representing a 25 percent risk reduction
> compared to atenolol.
>
> To summarize the safety findings of the LIFE study, losartan was well
> tolerated and associated with fewer drug-related adverse events and
> fewer discontinuations due to adverse events than atenolol. New
> diabetes was more likely to occur in patients treated with atenolol.
>
> The observed AE profile for losartan in the LIFE study was consistent
> with the profile observed in the general hypertensive population as
> reflected in our current product circular.
>
> Depicted here again are the results of the primary endpoint and
> secondary component endpoints as a summary of the major findings of
> the study. The important reductions in these cardiovascular morbidity
> and mortality endpoints with losartan, coupled with the excellent
> tolerability which was observed, lead us to a favorable benefit to
> risk assessment for the use of losartan in these patients.
>
> I will now turn the podium over to Dr. William Keane who will conclude
> our presentation by reviewing the evidence within an external study
> that supports our application for a new indication.
>
> DR. BORER: Thank you, Dr. Edelmann. Does anybody have any questions
> specifically about the safety data? If not, let\'s move right on.
>
> **Review of Evidence and Conclusions**
>
> DR. KEANE: Thank you, Dr. Edelmann. Dr. Borer, members of the advisory
> committee, ladies and gentlemen, my name is Bill Keane and I am vice
> president for clinical development at U.S. Human Health at Merck and
> Company. I joined Merck about a year ago, just as the LIFE study was
> concluding. Prior to that I was in the academic practice of nephrology
> at the University or Minnesota for 28 years, and for the last ten of
> these years I was chairman of the Department of Medicine at Hennepin
> County Medical Center, University of Minnesota Medical School.
>
> The purpose of my presentation is to describe why we believe the LIFE
> study is sufficiently strong as a single trial to support our request
> for a new indication. As Dr. Tucker pointed out during his initial
> presentation, there is an FDA document which provides guidance on
> making regulatory decisions based on a single study that I will use to
> help frame my discussions.
>
> As I go through my presentation I will specifically try to provide our
> perspective on some of the questions that the committee has been asked
> to address. First of all, the ability to consider a single study for
> an effectiveness claim is generally limited to situations such as the
> LIFE study where there is a clinically meaningful benefit on
> irreversible outcomes and it is unethical or impractical to repeat the
> study. The additional characteristics of the LIFE study that support
> the proposed claim include the study design, the consistency of the
> results in multiple subsets of the population, the demonstrated
> effects on additional endpoint and the consistency of the study
> findings with data from the scientific literature.
>
> Let me discuss each of these points with a bit more detail. First of
> all, the characteristics of the design and execution of the LIFE study
> provide support for the strength of the results. LIFE was a large
> multicenter, multinational, double-blind study conducted according to
> good clinical practice standards. The study enrolled over 9100
> patients and followed them for an average of 4.8 years at 945 centers
> in seven countries. More than 1000 patients reported at least one
> primary endpoint and complete endpoint adjudication was reported for
> approximately 99 percent of potential patient days of follow-up.
>
> An independent blinded endpoint committee adjudicated cardiovascular
> morbidity and mortality endpoints. The LIFE study focused on
> hypertensive patients with left ventricular hypertrophy, a group at
> particularly high risk for cardiovascular events. Importantly, the
> control group of the LIFE study received an atenolol-based
> antihypertensive regimen that has established benefits in the
> reduction of cardiovascular morbidity and mortality.
>
> One question that this committee will be asked to comment on is what
> is known about the effects of antihypertensive therapy with
> beta-blockers and angiotensin receptor antagonists in patients like
> those in the LIFE study. The LIFE study is the first to exclusively
> target hypertensive patients with LVH. However, none of the studies
> that established the cardiovascular benefit of treating high blood
> pressure excluded patients with LVH. As you know, one reason
> hypertensive patients with LVH were included in the LIFE study is
> because they are at high risk of experiencing cardiovascular outcomes.
>
> Blood pressure reduction is a well accepted surrogate for benefit on
> cardiovascular outcomes and there is no reason to expect that blood
> pressure lowering in patients with LVH would result in less benefit
> than in patients without LVH. The prevalence of LVH increases with age
> and elderly patients, like younger individuals, experience significant
> benefit on cardiovascular outcomes with blood pressure lowering.
>
> This slide, which you have already seen, and the next several slides
> show meta-analyses of hypertension treatment trials looking at the
> impact of treatment on all cardiovascular events. As was discussed in
> Dr. Edelmann\'s presentation, this first slide shows the results of
> our meta-analysis of five hypertension trials comparing a
> beta-blocker-anchored regimen to either placebo or no treatment.
>
> Again, the red diamond shows the odds ratio and 95 percent confidence
> intervals for the pooled data for the occurrence of all cardiovascular
> events, and the individual studies are shown below in green. These
> historical data indicate that blood pressure lowering with
> beta-blocker-based regimens is associated with a significant reduction
> in cardiovascular morbidity and mortality.
>
> This slide shows the results of a meta-analysis of nine hypertension
> studies performed by Staessen and colleagues comparing regimens based
> on either calcium channel blockers or ACE inhibitors to regimens that
> used diuretic and/or beta-blocker therapy.
>
> This plot shows the number of events, number of patients and the odds
> ratio for all cardiovascular events for both comparisons. The CCB- and
> ACE inhibitor-based regimens showed similar rates of total
> cardiovascular events compared to diuretic/beta-blocker-based therapy.
>
> As you are all undoubtedly aware, most recently the ALLHAT study
> confirmed the effectiveness of conventional therapy based on diuretic
> with added beta-blocker treatment in the reduction of cardiovascular
> morbidity and mortality. Considering this established benefit of
> beta-blocker-based therapy in reducing cardiovascular morbidity and
> mortality in hypertensive patients, I would now like to provide an
> overview of the findings from the LIFE study.
>
> Losartan, as you have already seen today, was associated with a 13
> percent reduction in the risk of the primary endpoint, a composite of
> cardiovascular death, stroke and MI after adjusting for the baseline
> level of the Framingham risk score and the degree of left ventricular
> hypertrophy.
>
> As I mentioned, this is a particularly important result when one
> considers that this finding was achieved by the losartan-based regimen
> compared to an established and active antihypertensive regimen in the
> face of comparable blood pressure levels in each of the treatment
> groups.
>
> Another question that the committee will be asked to address is
> whether the treatment benefits of losartan on cardiovascular morbidity
> and mortality could be explained by differences in blood pressure
> control between the treatment groups. I would like to briefly discuss
> several observations that lead us to conclude that these small
> differences are unlikely to explain the benefit of losartan in the
> LIFE study.
>
> First, as was summarized by Dr. Edelmann, there was a small, albeit
> significant, difference in systolic pressure of l.2 mm Hg between the
> groups in favor of losartan, and a small non-significant difference in
> the diastolic blood pressure in favor of atenolol. The proportion of
> patients reaching the protocol-specified target blood pressure of
> 140/90 was similar between the groups, as was the number of patients
> with poor blood pressure control, that is, 160/100 or above.
>
> One obvious concern in terms of blood pressure measurements is whether
> the trough blood pressure measured in the clinic accurately reflects
> the true blood pressure effects of the treatments during the course of
> the day. Very recently we were able to obtain data from a LIFE
> substudy conducted at four Danish centers that measured ambulatory
> blood pressure at baseline and at one year. These data have been
> submitted to and reviewed by the agency, but they were not available
> in time to be included in the briefing documents you received.
>
> This slide shows the baseline and year one systolic blood pressure
> measurement over 24 hours for 110 patients, 57 in the losartan group,
> shown in yellow, and 53 in the atenolol group, shown in blue. The
> horizontal axis shows the time of the day over the 24-hour period,
> starting from 10:00 a.m. The vertical axis shows the systolic blood
> pressure level.
>
> You can see the usual shape of the 24-hour blood pressure curve with
> the overnight dip in pressure and the rise towards the early morning
> hours. There was a significant decrease in systolic blood pressure
> after one year in both treatment groups. The box on the right of the
> slide shows the 24-hour mean systolic pressure readings at one year.
> You can see that the 24-hour curves are slightly lower in the
> atenolol-treated patients throughout the day. This translates into a
> mean 24-hour systolic blood pressure difference of 1.4 mm Hg in favor
> of atenolol. A similar result in favor of atenolol was seen for
> diastolic pressure measurements. The ABBM data observed in this
> substudy are consistent with the trough blood pressure measurements
> obtained at all sites, and corroborate the finding of comparable blood
> pressure reductions in both treatment groups in the LIFE study.
>
> We next evaluated this 1.2 mm difference in trough systolic blood
> pressure by two different approaches. The first uses a time-varying
> covariate method to look at the impact of the small observed
> differences in blood pressure treatments based on LIFE data. The
> second uses historical study data to estimate the benefit of an
> outcome of the observed 1.2 mm difference in systolic blood pressure.
>
> This slide depicts our time-varying covariate analysis of the impact
> of blood pressure differences on the primary endpoint. Although there
> are limitations to this methodology, this statistical approach
> provides one way of adjusting for small in-trial blood pressure
> differences. The slide shows what happens to the primary endpoint
> result when such adjustments are made.
>
> The first line of this table shows the unadjusted result for the
> primary endpoint in the LIFE study, that is, a 14.6 risk reduction
> with losartan. The subsequent lines in this table show the effect of
> adjusting for in-trial levels of systolic or diastolic blood pressure
> for the category of blood pressure control. You can see that when the
> adjustment is made using small blood pressure level or response
> category as a time-varying covariate there is a very small change in
> the primary endpoint result.
>
> Within the limitations of these analyses, these findings suggest that
> the vast majority of the benefit of losartan on the primary endpoint
> is due to factors other than the small differences in blood pressure
> between the treatment groups.
>
> The next several slides illustrate how historical study data can be
> used to estimate the expected benefit on cardiovascular outcomes of
> the observed 1.2 mm Hg reduction in blood pressure using stroke as an
> example.
>
> This is a graph that shows the relationships between the level of
> blood pressure lowering, which is shown on the horizontal axis, and
> the percent risk reduction in the outcomes of stroke, which is shown
> on the vertical axis. Here are the point estimates from three
> different meta-analyses of clinical trials in hypertension, one by
> Staessen and colleagues, on the left; one by He and colleagues, in the
> middle; and one by MacMahon and Rodgers, on the right.
>
> The dots represent the percent risk reduction for the specified
> differences in systolic blood pressure. The lines show the 95 percent
> confidence intervals around the estimate of risk reduction. These
> meta-analyses were chosen since they represent studies of over 38,000
> patients with hypertension and provide estimates on the occurrence of
> stroke.
>
> As you can see by the highlighted bars on each axis, for a difference
> of between 10-15 mm Hg in systolic blood pressure there is an expected
> 30-40 percent risk reduction in the occurrence of stroke. Assuming a
> linear best-fit line going through zero, this slide shows the
> relationship between systolic blood pressure and the risk of stroke.
>
> The arrow shows that in the LIFE study there was a 1.2 mm Hg
> difference in systolic blood pressure which, as you can see, would
> correspond with a less than five percent risk reduction in stroke, as
> indicated by the solid white lines.
>
> In contrast, and as you heard this morning, we observed a 25 percent
> risk reduction for stroke in the LIFE study, as is shown here by the
> yellow dot. Therefore, based on both the time-varying adjustments for
> blood pressure level or the achieved blood pressure control category
> using LIFE data only, as well as a secondary method using external
> reference data, it is unlikely that the benefit of losartan can be
> explained by this level of systolic blood pressure difference.
>
> Returning to our considerations of the characteristics of a single
> study to support an effectiveness claim, another characteristic is the
> presence of consistent results in important subsets of patients. In
> the prespecified analyses of subgroups in the LIFE study there were no
> significant interactions with treatment. In the two special interest
> population of patients of high risk categories, patients with diabetes
> and patients with isolated systolic hypertension, a consistent benefit
> was observed for the primary endpoint.
>
> In the analyses of the 23 baseline demographic disease history and
> clinical characteristics subgroups consistent benefit of losartan on
> the primary endpoint was observed. These findings indicate that the
> benefits of losartan in the LIFE study are applicable to patients with
> varying clinical and demographic characteristics.
>
> However, there was a suggestion of an interaction between ethnic group
> and treatment. In post hoc analysis dichotomizing the population into
> black and non-black patients, black patients treated with the
> atenolol-based regimen appeared to have a greater reduction in the
> risk of the primary endpoint compared to those treated with losartan.
>
> As presented in detail by Dr. Edelmann, further exploration failed to
> reveal any basis for the apparent qualitative difference in response
> in the black patients. As he showed, blood pressure reduction, LVH
> regression and heart rate responses were similar in the black
> population compared to the overall population. Thus, we were unable to
> find a clinical explanation for this finding. These observations,
> together with our entire clinical database for losartan, lead us to be
> confident that black patients receiving losartan are not being harmed
> by treatment. Still, we believe it is important that the information
> from the LIFE study about black patients be available to physicians as
> they make their treatment decisions and, thus, believe a description
> of this finding should be included in the clinical study sections of
> the label.
>
> Another consideration for a single trial is the presence of benefit in
> endpoints involving different events. In the LIFE study we observed a
> substantial and meaningful 25 percent reduction in the risk of the
> secondary endpoint of stroke with a losartan-based regimen. The
> reduction in cardiovascular deaths seen with losartan, although not
> significant, was consistent with the primary endpoint, largely due to
> a significant 35 percent reduction in the risk of fatal stroke with
> losartan. Importantly, there was no significant difference in the rate
> of fatal and non-fatal myocardial infarctions between the treatment
> groups.
>
> Consistent with our hypothesis, there was also a significant reduction
> in the endpoint of LVH with losartan compared to atenolol. There were
> several other observations in the LIFE study which may have
> contributed to the observed benefit of losartan on stroke that I would
> like to mention briefly.
>
> One is its effect on the carotid artery wall thickness, which was
> measured in a LIFE substudy, and the other is its effect on the
> occurrence of atrial fibrillation which we evaluated after discussion
> with the FDA reviewer. In a small substudy of patients in LIFE, called
> ICARUS, there was evidence for a greater benefit of losartan than
> atenolol on the carotid artery. As you are aware, increased carotid
> artery wall thickness correlates with the risk of stroke. Ultrasound
> of the carotid was conducted at baseline and yearly for three years in
> 57 patients. As depicted on this slide, for the 39 patients with data
> at year three, losartan reduced the intima-media cross-sectional area
> while atenolol had little effect. These data support the presence of a
> structural benefit to the carotid artery of losartan, independent of
> blood pressure reduction, which may have contributed to its beneficial
> effect on stroke.
>
> Another question that this committee is asked to address concerns the
> relationship between atrial fibrillation and the occurrence of stroke.
> It is well-known that atrial fibrillation is associated with a two- to
> a five-fold increase in the risk of stroke. Data from the LIFE study
> confirm this finding.
>
> The diagnosis of atrial fibrillation in the LIFE study was made in two
> ways. First, investigators reported a. fib. as an adverse event or as
> part of an endpoint narrative. The second way that a. fib. was
> diagnosed was based on ECGs as determined by the core reading center.
> By either method, the presence of atrial fib. at baseline was
> associated with a 3.5-fold increased risk of stroke when the data were
> pooled across treatment arms. Again, as detected by either method
> during the trial, the development of new a. fib. was associated with a
> five-fold increase in the risk of stroke when the data were pooled
> across treatment arms.
>
> As was pointed out in the FDA briefing document, losartan was
> associated with a lower incidence of a. fib. in the LIFE study. This
> conclusion was based on investigator reports of atrial fibrillation as
> adverse events. After discussions with the FDA reviewer, we performed
> several post hoc analyses that were based on information about atrial
> fibrillation that was contained in the ECG database as well.
>
> We looked at the occurrence of new a. fib. during the trial, as
> described on this slide. Patients with a. fib. at baseline, determined
> either by investigator report or ECG codes, were excluded from this
> analysis. Of the remaining patients, those who experienced a. fib.
> during the trial, based either on the investigator report or the
> presence of a. fib. on the ECG or both, were evaluated using the same
> statistical methodology as for other endpoints.
>
> Among those patients without a. fib. at baseline, this plot shows the
> hazard ratio for developing a. fib. during the trial. The first line
> shows the hazard ratio for a. fib. determined by the investigator. The
> second line shows the hazard ratio for a. fib. determined by the ECG
> core lab only. The third line shows the hazard ratio for a. fib.
> determined by either method. To the left of each point is the number
> of patients with a. fib. in each treatment group as determined by the
> method indicated. You can see that there were some 762 cases of new
> atrial fibrillation during the LIFE study. Regardless of the
> diagnostic method, losartan was associated with fewer cases of a. fib.
> than atenolol. Consistent with the FDA reviewer\'s assessment, the
> finding of less a. fib. with losartan may have contributed to the
> observed 25 percent reduction in the risk of stroke with losartan.
>
> Another aspect of the benefit on multiple endpoints involving
> different events is the effect of treatment on the components of the
> composite endpoints. As noted during our presentation, there was
> variability in the results among the secondary component endpoints in
> the LIFE study, with no evidence of difference in the risk of MI and a
> greater reduction in the risk of stroke with losartan.
>
> Although consistency in the treatment effect of secondary component
> endpoints is often supportive, the presence of heterogeneity in these
> components in the LIFE study does not diminish our confidence in the
> results. In trials in which different active treatment regimens are
> being compared, differences in outcomes may be less than those
> observed in studies comparing active therapy with placebo. Thus, the
> finding of no difference between losartan and atenolol in the risk of
> MI is understandable given the known cardioprotective benefit of
> beta-blockers and the benefit of losartan on LVH.
>
> In contrast, the statistically persuasive benefit of losartan on
> stroke is consistent with the known biological actions of angiotensin
> receptor blockade with losartan such as the reduction in arterial wall
> thickness. In addition, the benefits of losartan on atrial
> fibrillation may have contributed to its benefit on stroke.
>
> Data external to the LIFE study are important when considering the use
> of this single study to support the proposed new claim. While LIFE is
> the first trial to evaluate cardiovascular outcomes with an
> angiotensin receptor antagonist in hypertensive patients with LVH,
> there are additional published data that are consistent with the
> findings of the LIFE study.
>
> Preclinical models of hypertension have shown a particular benefit on
> stroke with AT I receptor blockade independent of blood pressure
> level. Myocardial hypertrophy and fibrosis have been reduced by
> treatment with losartan. In clinical trials, interruption of the
> angiotensin II axis with ACE inhibitors and AT I receptor blockers has
> been shown to reduce LVH to a greater degree than with other blood
> pressure lowering agents. Structural and functional benefit of
> losartan on the vasculature has also been demonstrated in human
> peripheral arteries.
>
> Let me summarize these findings in light of the considerations for an
> effectiveness claim based on a single study. First of all, the LIFE
> study showed that losartan provided a clinically meaningful reduction
> in irreversible cardiovascular morbidity and mortality compared to the
> active antihypertensive agent atenolol. This result was achieved with
> substantial and comparable reductions in blood pressure. Given these
> findings, it is impractical to repeat this trial.
>
> LIFE was a large, multicenter study that followed a rigorous design
> according to good clinical practice standards. Consistent reductions
> in the primary endpoint with losartan were observed in the subsets of
> the population that were assessed, including those at high risk of
> cardiovascular events like diabetic patients.
>
> In the LIFE study there were additional benefits of losartan on
> multiple events, including a significant 25 percent reduction in the
> risk of stroke and a greater reduction in LVH, consistent with the
> study hypothesis. There were also findings of benefit on carotid
> artery wall thickness and a lower incidence of atrial fibrillation
> with losartan. Both of these latter effects may have contributed to
> the benefit on stroke.
>
> Finally, the study findings of losartan\'s benefit on stroke, LVH and
> vascular structure are consistent with data external to the study
> showing a similar benefit with angiotensin receptor blockade in
> preclinical models and in humans.
>
> In addition to the significant benefits of losartan therapy on
> cardiovascular morbidity and mortality, losartan was well tolerated in
> the study. Losartan was better tolerated than atenolol, with an
> adverse experience profile consistent with its current prescribing
> information. There was also a lower incidence of new onset diabetes in
> patients treated with losartan in comparison to atenolol. In total,
> these findings lead to a favorable benefit to risk assessment. Thus,
> we believe that the LIFE study is sufficient to support our request
> for a new claim for losartan.
>
> In conclusion, based on the rigorous design as well as results that
> are clinically important, internally consistent and supported by
> external scientific data, the results of the LIFE study provide strong
> support for the proposed new indication. Cozaar is indicated to reduce
> the risk of cardiovascular morbidity and mortality as measured by the
> combined incidence of cardiovascular death, stroke and myocardial
> infarction in hypertensive patients with left ventricular hypertrophy.
> Thank you for your attention.
>
> DR. BORER: Thank you very much, Dr. Keane. Before we raise any further
> questions for you and for your colleagues prior to our discussion of
> the FDA questions, since it is 12:15 we will take a one-hour lunch
> break, so that I don\'t get lynched, until 1:15. But I am going to
> just ask you, during that lunch break after you have your lunch, if
> you could pull together the data that would allow us to look at the
> event rates\--I don\'t need statistics; I just need event rates\--for
> the subgroups on monotherapy, on the primary therapy plus diuretics
> alone and for the primary therapy plus diuretics plus anything else. I
> understand the company\'s aversion to providing these analyses earlier
> but I would like to see them anyway.
>
> With that having been said, let\'s break and we will come back here at
> 1:15.
>
> \[Whereupon, at 12:15 p.m., the proceedings were recessed, to resume
> at 1:21\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> DR. BORER: We are six minutes behind schedule and that is really
> completely unacceptable for a government organization! So, we are
> going to begin.
>
> I would like to take a minute to frame the issues, as I see them, that
> we need to discuss before we move on to the questions which frames
> everything more precisely. We will have an FDA presentation but we
> will have that after the sponsor finishes its grilling, and my
> comments are really specifically related to how the sponsor is going
> to answer what we ask it. Through the morning several issues have
> surfaced and I would like to state them so that they are out in front
> as we continue this discussion, and then get the FDA presentation and
> any public statements that need to be made.
>
> The first, of course, is whether the data here show that one regimen
> is better than another regimen. Let\'s say that it is, then we have to
> know how much better to determine what we can conclude from that and
> that requires that we have some idea whether the comparator regimen
> truly is effective or questionably effective. It has never been
> labeled or reviewed for this, for effectiveness for event reduction
> and, as a corollary, how much each component of the comparator regimen
> contributes to whatever the effectiveness of the comparator regimen
> is, and that will be important in our determining whether a single
> trial is adequate to draw any conclusions if one regimen is better
> than another.
>
> Assuming we get through all that, we have to know what the regimen is
> that the sponsor is proposing. The stated requested labeling says that
> it is losartan but we have to be sure that it really is that rather
> than a regimen that contains losartan 80 percent of the time and has a
> lot of other stuff too.
>
> Finally, if we get through that we have to know whether that regimen
> can be accepted as effective for all patients, the way the requested
> indication would seem to suggest, or whether that needs to be
> circumscribed with regard to descriptive factors that might exclude
> part of the population, like age, race or LVH or EF.
>
> So, I think those are the key issues that we have to be thinking about
> as we are asking questions and as you are giving responses. With that
> in mind, shall we ask for public comments now? Let me momentarily
> please open the hearing for public comment if there is any. Is there
> any member of the public that wants to make a comment? If not, then we
> will move on with the questions to the sponsor.
>
> One that I had asked that is specifically relevant to the issue of
> what regimen we are talking about is the one I asked about the rates
> of events for the various subgroups. Ray Bain gave me a chart here.
> You may have some way of putting it up for everybody so that we can
> see what happened to people who were on monotherapy, monotherapy plus
> hydrochlorothiazide, monotherapy plus whatever else, and whatever else
> without the monotherapy. Maybe you can go through this for us.
>
> DR. SNAPINN: Steve Snapinn, from Merck. Let me just run through the
> tables. There are two separate tables here, one describing crude event
> rates, numbers of events divided by the numbers of patients, and
> another table giving event rates per 1000 patient years of follow-up.
> In each of these two tables the results are broken into four columns,
> the columns representing four cohorts of patients. Just as a reminder,
> these are cohorts of patients defined by the therapies they were
> taking at the end of the study. That is, they are not randomized
> cohorts of patients and, as such, these results need to be interpreted
> with caution because of the potential for bias here.
>
> But the four cohorts represent first patients who were taking blinded
> study drug only, that is, without additional hydrochlorothiazide or
> other antihypertensives; patients who were taking blinded study drug
> along with hydrochlorothiazide as study therapy but no other
> antihypertensives; patients who were taking blinded study drug and
> other antihypertensives in addition to hydrochlorothiazide; and
> patients who at the end of the trial were no longer taking blinded
> study medication.
>
> In this table there are four rows representing the composite endpoint
> and the three components of the composite, cardiovascular death,
> stroke and myocardial infarction. That is orientation to the table.
>
> In terms of running through the results, we are only beginning to
> absorb the results ourselves and I am not sure how much I can say
> about them, but you do see little difference here in the first column
> between the two treatment groups for those patients on blinded
> medication only; a benefit for losartan in the second cohort with
> hydrochlorothiazide; no difference for those with other
> antihypertensives; and a benefit for those who are off study
> medication.
>
> DR. BORER: Does anybody want to question these data further or just
> try to digest them and include them?
>
> DR. LINDENFELD: Would it be possible for us to get a copy?
>
> DR. BORER: Could everybody get a copy? Can we get copies of this chart
> for everybody, please?
>
> DR. SNAPINN: Yes, we will do that.
>
> DR. FLEMING: There is a lot to absorb here but, as Steve points out,
> one needs to be careful since these aren\'t randomly configured, what
> we call proper subgroups. Looking at stroke, which is where the signal
> seems to be in these data, the stroke differences are of different
> magnitude but in the same direction in all of these four subgroups,
> improper subgroups.
>
> DR. BORER: We will get copies of these. Everybody can look at them.
> Maybe we will ask you some questions about them later but thank you
> for providing this information.
>
> I am sorry, I should have done this earlier but before we continue our
> grilling of you, Dr. Keane, and your colleagues, because the
> information that he will present is undoubtedly relevant to the
> questions we are going to ask, I would like to ask Dr. John Lawrence,
> who is the mathematical statistician for the FDA, to present the
> ethnic subgroup analysis that he did. Then we can move on to ask you
> more about that.
>
> **FDA Presentation**
>
> **Ethnic Subgroup Analysis from the LIFE Study**
>
> DR. LAWRENCE: Good afternoon. My name is John Lawrence. I am a
> statistician with the FDA.
>
> First, the outline of my presentation, I will start with some general
> issues about subgroup analysis and talk a little bit about some other
> studies, and then talk about the LIFE study subgroup analysis, and
> then a summary.
>
> In a clinical trial we are trying to make an inference about the
> overall effectiveness in a population and the trial is designed to
> answer that single question. The effectiveness is not uniform across
> individuals or across subgroups. For example, if a drug lowers
> diastolic blood pressure by 8 mm you know that every single patient is
> not going to get exactly an 8 mm reduction so you have to increase the
> dose or add different drugs. There are many possible explanations for
> this, including pharmacokinetic variability, genetic or environmental
> differences and differences in the disease pathogenesis.
>
> A successful clinical trial shows that as a group a large number of
> patients treated with the test drug will be better off, and it does
> not show that every individual will be better off by taking the test
> drug. Subgroups can be surrogate markers for genetic or other factors
> that affect individual responses to a drug. So, you might think that
> individuals within a subgroup would be more like each other than they
> would be to the other members of the population.
>
> In general, we use confidence intervals for treatment effects within
> subgroups to describe what was observed in the trial, and we expect to
> see differences in the point estimates. Generally we don\'t do any
> formal test of hypotheses for subgroups because there are small sample
> sizes and there is low power to do any of these tests. The analysis is
> usually post hoc and there are different ways of testing for
> interactions.
>
> In general, a subgroup analysis is intended to explore the uniformity
> of the overall effect and it is usually informative only when there is
> a significant overall effect. If there is no overall effect, then
> there is a relatively high chance of finding false-positive effects in
> subgroups. If there is an overall effect, there is a relatively high
> chance of finding false negatives, at least in terms of point
> estimates going in the opposite direction.
>
> Interactions can be separated into two different types. A quantitative
> interaction is when the treatment effect varies in magnitude by the
> subgroup but it is in the same direction. This is the kind of
> interaction that we expect to see and it doesn\'t worry us too much.
>
> A qualitative interaction is a more serious kind of interaction. This
> is when the direction of the treatment effect varies by subgroups, in
> some cases positive and in other cases negative.
>
> This is a picture to show the different kinds of interactions. This
> line, here, shows that two drugs would be equal. On this side it would
> favor the test drug; on this side it favors the control. This is
> exaggerated. We usually don\'t have this level of precision in
> subgroups in a clinical trial, but just to make the point here, in a
> quantitative interaction, in both subgroups it is on the same side so
> it is in favor of the test drug. But these are clearly of different
> magnitude. For a qualitative interaction they are on different sides
> of the line. So, here it is pretty clear that for this subgroup the
> test drug is worse than the control, and here the test drug is better
> than the control. With this type of interaction it is not so serious
> because although the subgroup doesn\'t appear to have the same
> magnitude as this one, it is still in favor of the test drug.
>
> Usually the first level of screening is to just look for the
> quantitative interaction as the first level of screening. If a
> quantitative interaction is found, then you can go further and look
> for a qualitative interaction. There is a test that can be used to
> test for that. It is a likelihood ratio test. It tests the null
> hypothesis that the treatment effect in all subgroups is in the same
> direction, and the test is defined by calculating the probability of
> the data under the null hypothesis and the probability of the data
> under the alternative hypothesis and looking at that ratio. If that
> ratio is large, that would indicate that one of the hypotheses is more
> likely to produce the data than the other one.
>
> There is a more intuitive way of thinking about this test. If the
> point estimate of the hazard ratio in both subgroups is on the same
> side of 1, then there doesn\'t appear to be any evidence of a
> qualitative interaction and you could define the test statistic to be
> zero. If the point estimates are on opposite sides of 1, then the
> further they are from 1 gives you more evidence of a qualitative
> interaction. So, you could standardize each of the point estimates by
> the standard error and take the one which is smaller in magnitude.
> That is the level of evidence of a qualitative interaction. These are
> definitions of the Gail-Simon test.
>
> So, the summary of the general approach to subgroup analysis is that
> it is generally an exploratory exercise. There are different types of
> interactions and, because it is normally post hoc and hypothesis
> generating, if you find something there to really find out whether it
> is real or not you tend to look for biological plausibility or
> evidence from other studies to confirm what was observed.
>
> Now I will move on to some evidence that is external to the LIFE
> study. From hypertension studies there are sometimes differences in
> effects by racial subgroup. In the losartan label it says that Cozaar
> was effective in reducing blood pressure regardless of race, although
> the effect was somewhat less in black patients. So, this is an example
> again of a qualitative interaction. Similar statements can also be
> found on labels for beta-blockers.
>
> I don\'t want to make too much out of the other studies because some
> of this data has not been reviewed by the FDA, but I just want to
> report what the authors said. For the SOLVD trial the authors reported
> that a significant reduction in the risk of hospitalization was found
> among white patients but not in blacks.
>
> For V-Heft II the authors reported a reduction in mortality was
> observed in whites but not in blacks. Those authors also point out
> that these conclusions must be viewed as hypothesis generating and
> that a prospective trial in black patients would be needed to test
> this hypothesis.
>
> In the LIFE study, you have already see some of this already,
> approximately 9000 patients were randomized and about 500 were blacks
> and nearly all the blacks were from the United States.
>
> The subgroups we generally tend to focus most on are the United States
> region, gender, race and age. So, when you look at the subgroups this
> way these are the confidence intervals that you see. Again, for most
> of them you see quantitative interactions, differences in the point
> estimates but on the same side of 1. But here you see a difference
> kind of interaction.
>
> Since most of the patients in the study were white, these two survival
> curves for white patients alone look similar to the overall results.
> The way that you have seen the curves before was upside down. I am
> showing the event-free rates so to start out nobody has any events and
> at five years 90 percent still do not have an event, or 10 percent do
> have an event. So, this is in favor of losartan.
>
> In the black patients it is in the opposite direction. The survival
> curves are in favor of atenolol. Nominally, this is a significant p
> value here.
>
> A different way of looking at the same information is to look at the
> hazard rates. The survival curves accumulate over time, whereas the
> hazard rate shows the risk only during that time. For example, during
> the first year there were approximately 30 events per 1000 patient
> years in the atenolol group and approximately 25 in the losartan group
> during the first year for white patients. This hazard stays fairly
> constant during the whole six years of the study and it is nearly
> uniformly in favor of the losartan group. The vertical lines here show
> the confidence intervals.
>
> When you look at the black patients, the confidence intervals are
> going to be much wider because of fewer patients. Nonetheless, it
> looks like during each of the years the difference is in favor of
> atenolol having a smaller risk each year.
>
> Now I am going to show the three components of the primary endpoint by
> race. For CV mortality in white patients, it is in favor of losartan.
> In black patients it starts out in favor of losartan but at about year
> two the curves cross over and there appears to be an advantage to
> atenolol. These p values are not significant. I am just showing
> whatever the data there is.
>
> For MIs there is no difference in white patients. There appears to be
> an advantage to atenolol for black patients, with a non-significant p
> value again.
>
> For stroke, a very significant advantage for the losartan group in
> whites and a nominally significant advantage for atenolol in blacks.
>
> To try to look for internal consistency of the result I looked at the
> demographic subgroups within the black subgroup. In the top row here
> is the overall comparison for all blacks. This is the number of events
> and the total number of patients in the losartan group and the number
> of events in the atenolol group. For all blacks the hazard ratio is
> 1.67. If I look at black females alone the point estimate is about 3.
> For black males the point estimate is about 1.2. For blacks under 65
> the point estimate is 2.5 and for blacks over 65 it is 1.31. Two of
> these p values are nominally significant but the point here is that
> they all point in the same direction.
>
> If I apply the Gail-Simon test that I talked about earlier for a
> qualitative interaction, the p value is 0.016. However, you have to be
> cautious in interpreting this p value because there were many
> different subgroups that I could have looked at and it is impossible
> to correctly adjust this p value for the multiple comparisons.
>
> There were three subgroups prespecified in the statistical analysis
> plan as being of special importance, U.S. region, diabetics and
> patients with isolated systolic hypertension. The black subgroup was
> not one of those subgroups. A formal analysis plan would list all the
> important groups and specify a method to correctly adjust for the
> number of tests.
>
> Nonetheless, it still is a pretty rare finding that a confidence
> interval for a subgroup would go in the opposite direction than the
> overall effect. So, to get some idea of how unlikely this is you can
> do these following calculations. If I assume that the true hazard
> ratio in all subgroups is 0.869\--that was the point estimate for the
> overall effect\--the probability that the point estimate for the black
> subgroup would go in the opposite direction is 28 percent, and the
> probability that the point estimate for any of those subgroups listed
> would go in the opposite direction is 37 percent. So, it is not very
> unusual to see one of the point estimates in the wrong direction.
>
> However, it is very rare to see the entire confidence interval go in
> the wrong direction. The probability that the black subgroup would be
> in the opposite direction, the whole confidence interval, is 0.003.
> The probability that any of those subgroups would have a confidence
> interval in the wrong direction is 0.005. That means that another way
> of looking at this is that you could look at a thousand different
> clinical trials and in only five of them would you see one of the
> confidence interval, out of those demographic subgroups, go in the
> wrong direction. So, it is very rare to see it.
>
> There are other approaches. For example, in those calculations I just
> showed you I assumed that the overall treatment effect, 0.869, applies
> equally to all the subgroups. You can instead assume that the
> treatment effect varies by subgroup and the effects come from some
> distribution. However, to do this you need to make some assumptions
> about this distribution that the effects come from. For example, what
> is the variability and do they have a common mean, or would you expect
> one of the subgroups to have a larger effect? Without a consensus in
> the scientific community about these assumptions, you cannot make any
> strong conclusion.
>
> In summary, it is not rare for a subgroup to have a point estimate in
> the wrong direction, but it is rare to have a confidence interval in
> the wrong direction. Exactly how rare is impossible to determine from
> a post hoc analysis. In general, post hoc analyses are hypothesis
> generating.
>
> Although the p value from the test for qualitative interaction is
> significant nominally, there are many factors that can mitigate that
> value. Some factors that may decrease the strength of evidence are
> that there were multiple subgroups and, therefore, many chances to
> find something unusual, and there was no prespecified analysis to
> control for multiplicity.
>
> There are factors that may increase the strength of evidence. There
> may be racial differences that were observed in other related studies.
> There appears to be a consistency of the effect within black
> subgroups. There appears to be a consistency in the three components
> of the primary endpoint, and there was a consistency across different
> analysis methods. That is it.
>
> DR. BORER: Thank you, Dr. Lawrence. Are there any questions from the
> committee about Dr. Lawrence\'s presentation? Tom?
>
> DR. PICKERING: You showed, and didn\'t comment on it, a similar
> analysis with age which looked as though the younger and older groups
> were on the opposite side of the null point but there wasn\'t a
> genuine qualitative difference. Is that correct? Could you show that
> slide again?
>
> DR. LAWRENCE: It certainly appears that this is a difference in
> magnitude at least because the confidence intervals appear not to
> overlap. It is hard to say whether this is a genuine qualitative
> interaction or not. My memory is that the sponsor did this. I don\'t
> know if they did it exactly by categorizing age in this way so I am
> not sure.
>
> DR. BORER: Yes, the FDA medical review showed a progression of benefit
> as patients got older, so consistent with this. Any other issues that
> we want to raise with Dr. Lawrence now? We can always ask him more
> questions as we go along. No? If not, thank you very much. That was a
> very illuminating presentation. Now, Dr. Keane, if you want to come
> back we will move ahead. John?
>
> DR. NEYLAN: Thank you. Bill, let me see if I can develop a line of
> thought with you and perhaps you can then clear up some holes in my
> understanding. To start, and I wish I had a visual aid here but to
> start, the primary endpoint is in large measure driven by the
> difference in the rates of stroke. In the agency\'s analysis there is
> a very strong interaction between the occurrence of CVA and atrial
> fibrillation. The appearance of atrial fibrillation appears to peak
> bimodally, that is very early, first quarter and then at the end of
> the study, fifth year. My question is, it is a bit counter-intuitive
> to me why the atenolol-treated group should have a higher rate of
> atrial fibrillation, and I am wondering if there may be a methodologic
> issue that plays into that, namely, the possibility that we are
> witnessing a rebound effect with the withdrawal of beta-blockers from
> the group randomized to receive the atenolol.
>
> With that hypothesis, you might then expect that there would be a
> higher rate of atrial fibrillation in patients who were withdrawn from
> beta-blockers and that, in turn, might predispose them to the risk of
> CVA. So, I am wondering if you have any data that begins to address
> this issue with on-therapy analyses, the occurrence of atrial
> fibrillation, its relationship to the occurrence of stroke and, again,
> the occurrence of atrial fibrillation in the presence or absence of
> the assigned treatment regimen.
>
> DR. KEANE: Thanks, John. Yes, there are a number of data analyses that
> we can look at and we have looked at atrial fibrillation in a number
> of different ways. Probably the most effective way of looking at this
> is with a time-varying covariate analysis that we had. Clearly, it had
> an impact upon it. We have additional data that we would like to share
> with you but I just wonder if I could just make a couple of comments
> before we get into the question.
>
> Doug and I chatted a little bit before the meeting, and I guess I may
> have mis-spoken about the ambulatory blood pressure monitoring data.
> Just so that we are absolutely clear about it, we have submitted the
> data to the agency. The agency has the data and they are in the
> process of reviewing it, and I think that covers what Doug wanted me
> to say. So, we have actually been in communication with them and they
> know what we are doing so we are both on target with that, but just to
> clarify the record.
>
> I might just make one other comment too about the presentation on the
> black subgroups. In a sense, we actually agree with much that has been
> presented today by the FDA, and in fact we don\'t really see very much
> of a difference. I just would also like to underscore the fact that in
> the black population, which represented only 550 patients, the event
> rate was also very low. We saw less than 50 in each of the arms. So,
> as you are thinking about these things, I think it is important to
> recognize that it is a small group with a small event rate and, yet,
> we did see this important qualitative interaction. That qualitative
> interaction was really the only one that we were able to observe here,
> and we felt very strongly that we should bring it forth as an issue
> that we have uncovered during the analysis. So, I think that would set
> this straight.
>
> Now let\'s get back to a. fib., John. I think we have some data that
> we can present here, which I have already alluded to, John, in terms
> of the atrial fibrillation data that provides the time-varying
> covariate analysis of atrial fibrillation.
>
> John, just to be clear, we felt that probably the most reasonable way
> to look at something that was not measured consistently on a daily
> basis or even on a monthly visit\--probably the best way to do this,
> and there were three different approaches that we used, we had it as
> an AE event that was reported. We had it in the narrative that the
> investigators provided to us. And, we had it at the ECG level and this
> is new onset atrial fibrillation looking at our event rate.
>
> As you can see, the hazard ratios are approximately the same, 0.85,
> and when we adjust for this it is 0.87. So, there really isn\'t very
> much of an impact of atrial fibrillation in terms of the occurrence of
> this during in-trial. So, I think that was one of your questions that
> you had.
>
> I think the other question\--John, was there something else that you
> brought up?
>
> DR. NEYLAN: Yes. First, let me harken back to what you just showed
> there. If you look not at the composite but at the relation of atrial
> fibrillation and the occurrence of CVA, is there significance seen
> there? In the agency\'s document it appears to be so.
>
> DR. KEANE: Yes, and if you look at what the agency has done, it is all
> a. fib. in whatever proximity to the event. So, it is anybody who may
> have had a dose adjustment in their atenolol and whether or not that
> was associated with the onset of new a. fib. I think, you know, from a
> clinical perspective one has to sort of at least raise the question
> whether or not that is a completely fair analysis because stopping or
> changing a dose months or years out of sync with an event might
> provide some question.
>
> I think, nonetheless, what we did see is that both in the atenolol
> group and in the losartan group there were approximately the same
> numbers of events in terms of changes of occurrence of atrial
> fibrillation when one looked at dosage change. Again, we didn\'t have
> it in immediate proximity. The closest we could look at was about 14
> days. Within that, with any dosage adjustment it was about the same
> percentage. Within that context, losartan consistently had an effect
> that seemed to have a lower outcome result in terms of the outcomes
> that we saw associated with atrial fibrillation.
>
> DR. NEYLAN: Could I ask a few follow-ons? I am wondering if you have
> any data that look at the possibility that the new onset of atrial
> fibrillation may have any relationship to the withdrawal of atenolol
> as possibly a consequence of a rebound phenomenon?
>
> DR. EDELMANN: A couple of things in regard to that. First of all, I
> just want to go back to one thing that Dr. Keane presented in his main
> presentation and just confirm this, atrial fibrillation that developed
> during he course of the trial was associated with a significant
> increase in risk, a five-fold increase risk of an event of any type
> irrespective of treatment. So, the develop of a. fib. was a harbinger
> of events no matter what therapy patients were on.
>
> With regard to the occurrence of events, particularly stroke, in
> relation to dose change mediated through atrial fibrillation, that is
> something that we looked at in detail and I want to respond about
> that. We looked at this in a couple of ways. The first was to look at
> the consequence of dose change on the risk of an event. We did in the
> pooled treatment groups and then by individual treatment groups.
>
> I think it is not a surprise that when we look at dose change the
> event rate is extremely high in the following period. We believe that
> this is a consequence of the fact that the reason for dose change and
> the reason for the event are often one and the same, rather than that
> the dose change leads to the event. So a patient, for example, is
> hospitalized. Their drug is stopped and then they die of some
> cardiovascular cause. So, it is the same thing that is causing the
> event is causing the dosage change. Therefore, when you look at it you
> see a high rate of events associated with dosage change not just in
> the atenolol group but in the losartan group as well. They are really
> quite high depending upon which event you are looking at, extremely
> high for example for cardiovascular death. But, again, I think this is
> a function of the way we collect data and the inability to separate
> cause and effect.
>
> In terms of the relationship between atrial fibrillation and stroke,
> another thing you asked particularly about, again, the medical
> reviewer for the FDA, if I have understood it right, has done the
> analysis on the basis of adverse events reported by investigators of
> atrial fibrillation. We have supplemented that with the ECG
> information so we have a couple of ways of diagnosing atrial
> fibrillation.
>
> What I can show you, similar to the analysis that Dr. Keane put up, is
> a presentation of impact the impact of accounting for the difference
> in the new occurrence of atrial fibrillation during the trial. It is
> patients who didn\'t have a. fib. at baseline and then did go on to
> develop a. fib. during the trial, accounting for that, what happens to
> the outcome on stroke.
>
> If I could have slide 998? Just to be clear, this one is not new onset
> but all a. fib. so all patients are included here, including those who
> might have had atrial fibrillation at baseline. You see when you
> account for the endpoint of stroke for the hazard ratio, changing from
> 0.74 or 26 percent risk reduction; when you adjust for the occurrence
> of atrial fibrillation during the trial it goes to 24 percent.
>
> So, it is not a big effect. But if you look just at the new onset,
> slide 1001, now just by eliminating the patients who had atrial
> fibrillation at baseline and looking only at the new occurrence of
> atrial fibrillation during the trial\--this is for the primary
> endpoint, you see there is a bigger effect here.
>
> Within the limits of this kind of an approach, and again I remind you
> atrial fibrillation was measured by investigator report whenever it
> happened and/or as detected on the annual ECG at the ECG core center
> so it is an imperfectly measured thing and not 100 percent measured in
> connection with the event, there does appear to be some magnitude of
> benefit on the primary endpoint.
>
> DR. TEMPLE: Can you show us this for stroke?
>
> DR. EDELMANN: For stroke, yes. It is the same thing for stroke. This
> is again among the cohort of patients who started out without baseline
> atrial fibrillation, the consequence of adjusting for new atrial
> fibrillation on stroke. It is a similar magnitude of effect. So, the
> hazard ratio goes from 0.74 to 0.8 or 26 percent risk reduction to 20
> percent risk reduction. So, it does suggest that there is some
> association within the limits of such an analysis.
>
> DR. NEYLAN: Then, could I ask even though this is a population at risk
> for new onset development of atrial fibrillation, I would expect that
> it would be fairly evenly distributed between these two treatment
> groups. The possibility of a withdrawal syndrome as a result of
> removal of a beta-blocker might potentially increase the risk in that
> population of patients. Do you have any data that looks at the
> incidence of new onset atrial fibrillation development in those
> patients in whom atenolol was withdrawn, and is there any data also
> looking at the time course between that development and the withdrawal
> of the drug?
>
> DR. EDELMANN: You are talking specifically about the development of
> atrial fibrillation so what I mentioned before is the development of
> endpoints that we measured as part of our primary composite of the
> secondary component endpoint. As I said, there is a strong connection
> between the risk of an event and dosage change, including largely
> discontinuations.
>
> This is discontinuation and a. fib. Let\'s see this one. The same kind
> of thing is seen. This is the relative risk increase, so the hazard
> ratio for the occurrence of atrial fibrillation when there is a
> discontinuation of drug. You asked about atenolol. That is over here.
> It is almost a 13-fold increase in risk but it is not specific to
> atenolol. It is associated with losartan to the same degree, which
> leads us to think this is not unique to beta-blocker withdrawal but,
> again, there is cause and effect mixed up here. The reason for
> discontinuing the study drug and the reason for the development of
> atrial fibrillation may be one and the same so they appear to be
> highly associated like this.
>
> DR. BORER: Does that answer the question, John?
>
> DR. NEYLAN: I will accept that.
>
> DR. BORER: JoAnn?
>
> DR. LINDENFELD: Just a follow-up on this atrial fibrillation issue.
> Amniodarone is used much more commonly in Europe than it is here for
> atrial fibrillation. I wonder if you can tell us what the use of
> amniodarone was at baseline and maybe at one year? I guess what I am
> getting is was amniodarone withdrawn more commonly in the beta-blocker
> group because of bradycardia? Is that the explanation for this?
>
> DR. EDELMANN: Right, it is not data that I have at my fingertips. We
> can look to see what the use of amniodarone particularly was at
> baseline and then in concomitant therapy and see if I can come back to
> you with those numbers.
>
> DR. KOWEY: Jon, can I make a comment? Peter Kowey, consultant for
> Merck. The atrial fibrillation data I think is extremely important;
> obviously very, very important. But just so that the committee
> understands that this was not a study that was really out to look at
> atrial fibrillation as an endpoint, there were very infrequent
> samplings of echocardiograms throughout the course of the study. It
> wasn\'t systematically looked at. The analysis that you saw was a post
> hoc analysis. So, I really think that it is extremely hazardous to get
> too involved in a discussion of atrial fibrillation.
>
> Having said that, there is certainly biological plausibility that a
> drug such as losartan could have an effect on atrial fibrillation,
> given what we have seen recently with this whole class of compounds
> and drugs in general which have an effect on the angiotensin system in
> terms of fibrosis and also in terms of the changes in left ventricular
> hypertrophy.
>
> In addition, I would not be one bit surprised if a large proportion of
> the contribution to the stroke reduction that was seen in the study
> had something to do with AF. It is certainly plausible. But I think to
> try to drill down any further on that, either from the point of view
> of concomitant antiarrhythmic therapy or beta-blocker use or
> withdrawal, is just probably stretching it a little bit further than
> you can do it. It is very interesting though, I must say.
>
> DR. KEANE: Dr. Borer, I wonder if I could respond actually to some of
> the questions that were raised this morning, to go through some of the
> discussion points that came up and we can get some further discussion
> on that. Is that okay with you?
>
> DR. BORER: It is but can you begin with the questions that came up
> about the effectiveness of the comparator?
>
> DR. KEANE: We can.
>
> DR. BORER: Can you provide us the evidence that, a) the comparator
> regimen is effective and, b) that atenolol is important in that
> effectiveness?
>
> DR. KEANE: Well, I think what we have already discussed and presented
> this morning was in a part of my presentation and also some of the
> data from our meta-analysis looking at a number of different trials.
> So, let me just re-review that with you, if that is of help.
>
> DR. BORER: Yes, I think we are going to need a little more detail. We
> saw your meta-analysis but you heard the questions about it. Tom?
>
> DR. FLEMING: Yes, Dr. Keane, the meta-analysis was certainly very
> helpful. Rather than revisiting that entire meta-analysis, the aspect
> that at least I would like to better understand is what the historical
> data would tell us what is known in this setting about the effect of
> atenolol in the presence of a diuretic\'s regimen. So, what I would
> really like to see is comparative data that looks at diuretics and
> atenolol against diuretics so that we can get a sense of what atenolol
> is adding in the presence of diuretics ideally in an LVH population.
>
> DR. KEANE: I think one of the problems that you are having and we had
> with this data is that when you look at what has actually been
> published, most of the studies either had diuretics added to
> beta-blockers or beta-blockers added to diuretics. It is very
> difficult, and it has been very difficult for us to tease out, if you
> will, the difference of beta-blocker effects specifically or
> beta-blocker/diuretic effects specifically within any of the clinical
> trials that have been done. Lots of patients clearly have been treated
> with the combination, and we have seen some of those data this
> morning. Both Dr. Edelmann and I have presented them and if you don\'t
> wish, we don\'t have to go through them.
>
> I think one of the things that we should recognize is that at least in
> the populations with hypertension that we are talking about, you know,
> most of the studies that have been done haven\'t specifically
> addressed the patient population that we have, i.e., with left
> ventricular hypertrophy. But as I alluded to in my presentation, it
> doesn\'t mean that they weren\'t included. They were not excluded from
> these trials.
>
> If you look at epidemiologic data and what-have-you the association of
> hypertension with left ventricular hypertrophy, particularly in this
> patient population, is some 20 percent. So, that is why we pooled all
> of these studies in a meta-analysis to try and come up with the best
> estimate for the beneficial effect that we are seeing.
>
> The other reason, of course, that we used left ventricular hypertrophy
> is because I think it is clearly a marker of risk in those patients
> that have left ventricular hypertrophy. Based on a variety of
> different epidemiologic-based data, they are clearly at increased risk
> for cardiovascular events. So, that is really what I have in terms of
> information to shed some light on this particular complicated issue.
>
> DR. PICKERING: I would like to have further discussion about the
> meta-analysis. Could you show slide 23 again, please? If you look at
> the JNC VI recommendations, they actually quote a meta-analysis done
> by Bruce Psaty where he had 18 randomized studies with beta-blockers
> and diuretics. They concluded that beta-blockers protect against
> strokes and congestive heart failure, whereas diuretics not only
> protect against them but also MI and total mortality.
>
> If you look at your meta-analysis, I think the only two studies where
> there was a randomized comparison between a beta-blocker, a diuretic
> and a placebo were the two MRC trials. I think those results are
> largely driven by MRC where there are 13,000 patients. These were
> younger patients. I think the average age was 55 whereas the average
> age in LIFE was 67, and that is closer to the MRCII where the average
> age was 70 and where there was no hint of any benefit from
> beta-blockers.
>
> Certainly in my practice I would not use a beta-blocker as a
> first-line drug in patients over the age of 60 or 65. The analysis
> that we just saw suggests that there was, again, no suggestion of any
> benefit. If anything, it was going the other way in patients under the
> age of 65. So, how did you select these particular studies for your
> meta-analysis?
>
> DR. EDELMANN: As I alluded to before, the Psaty meta-analysis is one
> that we are familiar with but it did not include, I think, the UKPDS
> study for whatever reason; I think it probably wasn\'t out at the
> time. What we did, we looked at all the antihypertensive treatment
> trials and selected, in this grouping of five, those trials that had
> at least a beta-blocker-anchored regimen as one of the options, if not
> the only option. So, that was our criterion. There were a couple of
> other things. There had to be a sufficient exposure in terms of
> patient years and there had to be information on endpoints reported in
> the papers that would permit us to provide the cardiovascular event
> analysis.
>
> We went to this step because we felt that we could focus on any one
> individual trial but that the best estimate for the effect of atenolol
> as represented by beta-blockers is from all of the data, not just any
> one individual study. For example, the MRCII trial, which you said is
> the likeliest similar population in age, is a trial that had a
> tremendous amount dropouts and lost follow-ups. So there are
> limitations to the strength of the conclusion from that trial just on
> the basis of how it was done.
>
> So, rather than rely on that kind of picking and choosing, we had a
> more general approach, looking only at the studies that involved
> beta-blocker-anchored therapy to start with. Then we supplemented
> that\--and maybe I can just show it again\--with the other direction,
> the diuretic plus beta-blocker studies and that added an additional
> three. That just strengthens the evidence that this approach, a
> regimen of diuretic and beta-blocker, is effective in reducing
> outcomes including coronary heart disease outcomes in hypertensive
> patients.
>
> So, it is our view that the best estimate of the data, not exactly
> perfectly applicable to the LIFE study population but a pretty good
> assessment, supports the notion that this treatment approach is
> effective. The ALLHAT trial confirms that. A diuretic regimen with a
> large proportion of patients having beta-blocker added on is quite
> effective in preventing outcomes in hypertensive patients.
>
> DR. BORER: I think one of the issues here that everyone is trying to
> grapple with is what is the contribution of the beta-blocker to this
> regimen. The reason for that may be that there will be a question
> about the strength of the excess benefit of your regimen versus the
> comparator regimen. Some idea about the contribution of the components
> of the comparator to the overall effect of the comparator might be
> helpful in giving us some sense of the strength of evidence that we
> are going to be judging. You know, that is sort of what we are looking
> for. It sounds like you don\'t really have much information.
>
> DR. EDELMANN: I think it is an excellent point and it is exactly the
> issue, but there are two ways of looking at this. The perfect study
> that you are referring to would be one in which there was only a
> beta-blocker compared to no treatment or there was a beta-blocker
> added on to an equal background of treatment, and that information is
> just not available, or at least to our understanding it is not
> available in the literature.
>
> The one place where there is evidence of a comparison of a
> beta-blocker/atenolol with an equal concomitant medication applied
> where you could tease out the difference in the impact of the
> beta-blocker is the LIFE study which shows the benefit of losartan.
> Not wanting to get into a circular argument, I think if we relied on
> the external historical data to establish a beta-blocker-including
> regimen as being effective, the LIFE study then serves as evidence of
> the contribution of losartan over atenolol on that similar background.
> Maybe that is helpful.
>
> DR. BORER: Just for argument\'s sake before we get to all the other
> comments, did you look at the hypertensive subgroups of any of the
> post myocardial infarction studies?
>
> DR. EDELMANN: Well, we looked at this but they are not well reported
> and we felt that the post MI studies randomized patients only after
> the occurrence of myocardial infarction, which represents a different
> kind of patients. Rather, in our assessment we focused on the
> hypertension trials because we thought that was the most relevant.
>
> DR. BORER: Bob and then Tom?
>
> DR. TEMPLE: Actually, Jeff, this is for you. The multiple drugs in
> hypertension regimens are used to get the pressure down to some goal.
> Are you expressing doubt as to whether lowering the blood pressure 6
> mm or 7 mm more with, say, a beta-blocker has some role in improving
> outcome compared to using a diuretic alone?
>
> DR. BORER: Certainly not, Bob. I would never suggest such a thing.
>
> DR. TEMPLE: Well, the difficulty with all these things is that what I
> understand them to be trying to do is to show that regimens based
> predominantly on having a beta-blocker in one group and not having a
> beta-blocker and accepting whatever you accept, and the other to show
> some expected benefit on outcomes. It is hard nowadays to test that
> prospect any further because no one will allow you to leave a patient
> incompletely controlled, and that has been a problem actually for many
> years. What the old data show is that even if you add it to a diuretic
> or have it alone you have sort of the predicted, expected every drug
> has this favorable effect on outcome from a beta-blocker.
>
> DR. KEANE: Dr. Borer, I want to reemphasize what Dr. Temple has said.
> I mean, it is very clear that in the practice of medicine in today\'s
> world you are looking at how to get the blood pressure down to a
> specific target. Therefore, the issue that we are all confronted with
> is, in fact, getting the blood pressure down. Dr. Neaton is our
> statistical consult and I am just wondering if he could actually make
> some comments about these issues.
>
> DR. NEATON: Yes, I was going to respond to two points. I am Jim
> Neaton, from the University of Minnesota. First, Tom, in response to
> one of your earlier questions, there are actually four trials that
> have been head-to-head comparisons between diuretic and beta-blocker.
> Those are the two MRC trials, IPPPSH and HAPPHY. The point estimate
> for the odds ratio which favors the diuretic is by seven percent, and
> it is not statistically significant. The bounds are minus 18 to 5
> percent favoring the diuretic.
>
> If you go back I guess almost ten years now to one of the original
> overviews by Collins, and I don\'t think the story has changed that
> much, they actually reviewed the beta-blocker trials, the diuretic
> trials, as well as the head-to-head comparisons and concluded that
> there really isn\'t sufficient data to argue that one is superior to
> the other. I believe that was Psaty\'s kind of conclusion as well in
> 1997 or 1998 in which he looked at these trials minus the diabetic
> trial in the U.K.
>
> Concerning Bob\'s last point, just listening to some of the questions
> this morning, two about sorting out the types of therapy, I don\'t
> think you can have it both ways. If you are going to do a trial to
> test the paradigm that really equivalent blood pressure lowering with
> different regimens gives rise to differential clinical events, strokes
> and heart attacks, then I think you have to accept the fact that to
> control blood pressure many treatments have to be used. To sort them
> out I think really is a very hard thing to do in a trial like this.
>
> So, I think what you have here is a very well done trial with a
> regimen which is predominantly losartan and one that is predominantly
> atenolol that you can kind of compare. Actually, it has the merit
> compared to some other trials, in which the regimens which are being
> used where the comparator is one which is used an awful lot in the
> real world.
>
> DR. BORER: Can I just clarify one thing? I don\'t disagree with
> anything that you said. I think you are absolutely right and I think
> this was a superb trial and on, and on, and on. That is not the
> question I am asking. I am asking to what extent I can infer from the
> comparator data that this trial has shown an important difference from
> what we could see with the comparator or with nothing.
>
> DR. NEATON: I think the response earlier was that there are no trials,
> there is no big set of data that you can go to among people with LVH.
> Unfortunately, even the trials that have been done have not published
> those subgroups to look at. However, as the discussion earlier alluded
> to on subgroup analyses, I think it is very unusual to see the kind of
> differences in response in those with LVH compared to other subgroups.
> So, I think it is a very reasonable inference to assume that the
> effects you see in the diuretic/beta-blocker trials apply here to this
> population.
>
> DR. FLEMING: Jeff, can I follow-up?
>
> DR. BORER: Yes, please.
>
> DR. FLEMING: Jim, just to have you kind of respond to this as well I
> think just to try again to at least phrase the question as I see it,
> suppose one looked at the LIFE trial and says, all right, we have a
> comparison of two regimens and we have losartan with diuretics and we
> have atenolol with diuretics. Suppose you look at these data and you
> say I am not fully persuaded here that even though there are
> suggestions of differences, particularly in stroke\--I am not fully
> persuaded by the standard of strength of evidence of two positive
> trials that we have shown superiority of losartan to atenolol. If, in
> fact, you did I would have much less concern about the next issue.
>
> But if you are not fully persuaded, then one is left with trying to
> see what supportive evidence there is that is relevant here. I am
> persuaded by the historical data that had been presented, the
> meta-analyses, that diuretics and atenolol as a therapeutic strategy
> is effective. It is not clear to me, however, what atenolol is
> providing in that therapeutic strategy.
>
> So if, in fact, I am looking now at diuretics plus losartan against
> diuretics plus atenolol, if I know that atenolol itself is very
> influential in that combination, in the active comparator, then I am
> reinforcing the strength of evidence that I have that losartan is
> truly contributing meaningfully to the beneficial effects in the
> outcome.
>
> What you have said is that diuretics as compared to atenolol\--you are
> talking about those differences and atenolol may, in fact, be
> effective but is it additively effective in the presence of diuretics?
> And, we can\'t entirely rely on blood pressure because the whole
> argument that the sponsor is giving here is that there is a lot more
> to effects on clinical endpoints than blood pressure. In fact, LIFE is
> attempting to tell us that even though we see minimal differences at
> least in systolic blood pressure, we are seeing substantial
> differences in stroke.
>
> So, if we are left with some uncertainties. I mean, the bottom line,
> the negative side of this would be to say, sure, atenolol is important
> but in the presence of diuretics it doesn\'t add a lot. If, in fact,
> it doesn\'t add a lot how do I know for sure that in our regimen with
> losartan it is not mostly the diuretics? So, it becomes very important
> to try to understand historically how much does atenolol add to the
> diuretics.
>
> DR. NEATON: Well, I think some of the trials that Bill showed earlier
> that used both contributed to that. Plus, most of the old trials that
> looked at diuretics, atenolol or beta-blocker was a second-line agent.
> That is the way the trials were done because there blood pressure
> wasn\'t controlled to the same level that we try to control it these
> days but additional drugs were added.
>
> DR. FLEMING: But what I am hearing, just in closing, is that at least
> you are not able at this point to put forward randomized comparative
> strategies that look fairly clearly at what addition of atenolol to
> diuretics would provide.
>
> DR. NEATON: I think the best data to address that question are the
> four trials that have a head-to-head comparison of a diuretic versus a
> beta-blocker. There at least you have good evidence that they are
> pretty comparable.
>
> DR. FLEMING: But that doesn\'t tell us that when you then add in the
> beta-blocker to the diuretic you get something even better than the
> diuretic-based regimen would provide.
>
> DR. KEANE: Except for blood pressure control. I think that is an
> important factor to remember here.
>
> DR. FLEMING: Well, can you show us that?
>
> DR. KEANE: The blood pressure control? Sure, we can go back over that.
> In fact, that was in Dr. Edelmann\'s presentation. Do you have the
> blood pressure slides? I am sorry, I maybe misunderstood what you were
> saying. You were looking for the blood pressure in the historical
> trials or in our trial?
>
> DR. FLEMING: No, I am looking for the meta-analysis historical
> evidence to try to provide a clear understanding of what atenolol is
> adding to the regimen based on diuretics to basically refute an
> argument that would say once you got diuretics you get a favorable
> result and the addition of atenolol, or losartan for that matter,
> doesn\'t meaningfully influence outcome.
>
> DR. ZEGER: I am Scott Zeger, from Johns Hopkins. I just wanted to say
> if this trial gives evidence, strong evidence that losartan plus
> concomitant therapies is better than atenolol which is useless, let\'s
> suppose, and concomitant therapies, if you believe those concomitant
> therapies are effective, then you have the added strength of evidence
> I think you are asking for.
>
> DR. BORER: That would be true if the benefit of the combined losartan
> plus whatever clearly is strongly compellingly better than the
> comparator. I think the question that Tom is raising here is what is
> the strength of evidence that the losartan-based regimen actually is
> better than the atenolol-based regimen. It is one trial with a p value
> that is not as strong as we would usually see for one trial.
>
> DR. ZEGER: I understand your question but I think Tom\'s point, if I
> understand it correctly, is if this were 0.02 and 0.01 on stroke
> against something that was useless you might have some reservation.
> But if it is something that has been demonstrated to be effective,
> whether that effect is the result of the atenolol or the diuretics,
> what is the difference?
>
> DR. BORER: Tom?
>
> DR. PICKERING: Yes, I would like to get back to the age issue. You
> raised two other studies, IPPPSH and HAPPHY. IPPPSH was stated to be a
> comparison of beta-blockers and non-beta-blockers versus diuretics but
> in both IPPPSH and HAPPHY the average age was 52 so they are
> comparable to the MRC mild hypertension trial but not to the LIFE
> population where, again, the average age was 67. If you look at the
> data on the handouts, there is no suggestion of any benefit from
> losartan in the blinded only group or really in the blinded plus other
> group. It is all in the blinded plus hydrochlorothiazide group where
> it was 17.6 per 1000 patient years in the losartan group and 26.1 in
> the atenolol group.
>
> DR. EDELMANN: I am not sure if there was a question there but if the
> implication of the statement is that the difference in diuretic use
> between the treatment groups is where the benefit is, we don\'t think
> that explanation follows based on not just accounting for those
> non-random groups but accounting for the entire time for diuretic use
> and then adjusting for it. This is something I went through before.
> That is to say, about 70 percent of the time patients were on
> concomitant diuretics. When we accounted for that in a time-varying
> covariate adjustment it didn\'t really make much of a difference in
> explaining the treatment benefit.
>
> So, that leads us to conclude that, although diuretics may have added
> to the level of benefit, they don\'t contribute to the difference in
> benefit observed in the LIFE study. It is like if you take an analogy
> of being in a high-rise building and being in an elevator, and the
> higher up you go the greater the benefit. Where you are off the ground
> in terms of absolute benefit is something that may be impossible to
> determine and what got you there, atenolol or diuretic or both. But
> relative to one another, losartan is at a higher level of benefit than
> atenolol and both are likely to be off the ground, in other words not
> no benefit, based on the evidence from the regimen trials where you
> can\'t dissect out whether it is the diuretic or a beta-blocker that
> is getting you up the elevator, if you follow my analogy.
>
> DR. BORER: Beverly and then Steve?
>
> DR. LORELL: Well, I would enjoy hearing you respond a little bit more
> in depth to Dr. Pickering\'s comment that I think raised some concern.
> This is a highly specific and somewhat narrow hypertension population.
> As has been measured earlier, it is skewed toward the older patient.
> It applies to the 20 percent of patients who have ECG evidence of
> hypertrophy and I am concerned about his comment that among prior
> comparator studies the one that is, in fact, relevant or most relevant
> to this group is MRCII in which an older population was looked at and
> his comment that no benefit appeared to have been seen, at least as
> illustrated in slide number 23.
>
> DR. JULIUS: I am Steva Julius, from the University of Michigan and I
> was the U.S. coordinator of the LIFE study. You know about MRCII.
> Fifty percent were lost up front. At the end, only 32 percent were on
> beta-blocker. So, it is a large trial in the beginning and it is a
> small trial at the end, and it doesn\'t affect my thinking as to how
> useful beta-blockers are.
>
> DR. LORELL: Part two of that question then might be phrased a little
> bit differently, can you help us with a population from studies done
> in the elderly, forgetting about the LVH\--we appreciate that the data
> just isn\'t there, but in a population that is skewed toward this much
> more older group of people who are at higher risk of stroke than,
> obviously, a 55-year old person is?
>
> DR. KEANE: Right, there are a couple of data sets we can show from the
> literature, and one that has been commented upon is the Psaty
> database. Maybe we ought to show the meta-analysis from Psaty from a
> number of years ago so that you can actually appreciate it.
>
> I will mention again, as we have said earlier in the presentation, you
> know, when we did look at age as a subgroup and we looked at treatment
> by subgroup interactions there was no interaction term that we could
> define within the different age groups of individuals within the LIFE
> study. Nonetheless, we could show this data. Jon, do you want to run
> through this?
>
> DR. EDELMANN: Yes. Before reviewing those data I just want to go back
> to a point that I made before which I think is so important I want to
> reemphasize it. It is possible to draw lots of different conclusions
> depending upon which study you choose to believe is the right study.
> So, if you look at the MRCII trial and say that is the truth, then
> that tells you one thing about the effect of beta-blocker- or
> atenolol-based regimens. But we think that it makes more sense to
> consider all of the data, and in terms of the representativeness of
> the populations, studies even in younger hypertensive patients and the
> benefits that are seen in younger hypertensives, we think that it
> makes sense to apply those data to assessing the benefit of a
> beta-blocker-based regimen as it does in applying the benefit of the
> losartan-based regimen based on the LIFE study.
>
> I didn\'t show you but I mentioned a comparison of the LIFE population
> to a reference population in the U.S., that is, patients who were
> eligible for the LIFE study inclusion from the NHANES database. So,
> that is older patients with hypertension and LVH and very similar
> characteristics. But I can show you, and I would like to show you if I
> have the overhead, the same comparison. Now, this is a reference
> population in the U.S., but not limited to the older group. This is
> hypertensives who are above the age of 40, I think it is. So, above
> the age of 40, and then do they have left ventricular hypertrophy? In
> other words, they have hypertension with left ventricular hypertrophy
> but they are not limited to being 55 and above.
>
> If I can find that, what you will see is that the baseline
> characteristics are very similar between U.S. patients in the LIFE
> study and this reference population. So, I think based on the
> characteristics of the patients we enrolled it is not necessary to
> constrict the applicability of this trial to only older patients and,
> for the reasons I said before, doesn\'t make sense to only focus on
> one trial, particularly MRC II, because of the issues of its conduct
> and how much you can believe the result. Rather, to look at all of the
> data for beta-blocker including from the younger hypertensive patients
> and make an assessment of the relative benefit of a beta-blocker
> regimen in providing benefit.
>
> DR. BLACK: My name is Tom Black and I am from Merck. The idea is that
> we are discussing here where there is blood pressure lowering in both
> groups and there is more blood pressure lowering, and part of that
> blood pressure reduction is attributable to both the atenolol and to
> the diuretic, attributable to the losartan and the diuretic. So, the
> assumption is that the diuretic is providing all the endpoint benefit,
> whereas we know from many studies that the further you reduce down in
> blood pressure, like in HOT, the further reduction in endpoints.
>
> The FDA and medical practice accepts that the more you reduce blood
> pressure, the better effect you are going to have on reducing
> endpoints. So, the implied assumption here is that even if atenolol is
> reducing blood pressure more it is not affecting the endpoints at all
> and, therefore, sort of how do you know that you are getting any
> benefit.
>
> DR. FLEMING: I am not assuming that. My questions, which still aren\'t
> answered but it may be because there are no data to answer them\--just
> to reiterate, if we go through the progression of controls here you
> are looking at losartan in addition to a diuretic against atenolol in
> addition to a diuretic, and ultimately to know what losartan is doing
> against placebo the comparator is the diuretic. If you are saying the
> diuretic is not capable of achieving the blood pressure lowering that
> you saw in your control regimen here, okay, show me that and that is
> relevant to me but show me that.
>
> DR. EDELMANN: I think you are right to say the data you are asking for
> aren\'t available, and that is because blood pressure treatment
> trials\--this is what Jim Neaton was saying before\--have taken the
> approach of controlling blood pressure by adding therapy as needed.
> Trials to look at the efficacy in blood pressure, just on blood
> pressure, have done what you are asking about but trials that have
> looked at outcomes have not done that. they have added therapy as
> needed, just like ALLHAT. So, I mean, if that is the evidence you are
> looking for, it is certainly not there.
>
> But I think it is reasonable to look at the blood pressure lowering
> data with the knowledge that lowering blood pressure is beneficial
> from all of these outcome trials to look at the incremental benefit of
> adding a diuretic to a beta-blocker or a beta-blocker to a diuretic
> and showing that, when you do that, you see an effective blood
> pressure effect of one and an incremental effect to that blood
> pressure lowering when you add a diuretic to a beta-blocker for
> example.
>
> DR. TEMPLE: Can I just mention something?
>
> DR. BORER: Yes, please do.
>
> DR. TEMPLE: There are hundreds of studies of combination products
> containing a diuretic with whatever that show that the effects of the
> two components are roughly additive. That is really not in question.
> It is true that all the outcome studies we know of take a baseline and
> then add something to it, leaving unanswered the question of suppose
> you didn\'t have the baseline therapy. You never get a specific answer
> because nobody ever does a factorial outcome study, or hardly ever.
> But on the mere question of blood pressure, that is really not
> debatable.
>
> DR. LORELL: But I don\'t think that was quite what we are trying to
> get at.
>
> DR. TEMPLE: No, I know that.
>
> DR. LORELL: I think we would all agree with that a hundred percent. I
> think the concern that was raised in my mind earlier by Dr. Fleming\'s
> comment really goes back to the issue that we are here today to look
> at labeling for an outcome measure, and that is predicated on a
> comparator being superior to a placebo since placebo was not tested,
> for good reasons, in this study.
>
> So, the question that was raised earlier was, whether a diuretic or
> beta-blocker was added first or second, whether the combination
> therapy of a beta-blocker and a diuretic is, in fact, superior in an
> older population to placebo. That was the concern that Dr. Fleming\'s
> comment raised and why I was interested not so much in the age 40-year
> old patient but what can you tell us about this combination relative
> to placebo in a much older population?
>
> DR. EDELMANN: And that is one of the reasons why in my talk I showed
> Rodgers and MacMahon. That was an assemblage of data on older
> hypertensive patients and those were all trials that were based either
> on a beta-blocker regimen or a diuretic regimen, and in most cases if
> it was one, then the other was added.
>
> Let me put that up again. This is not in the form of whisker plots but
> what you can see is the reduction in the odds down here for stroke,
> coronary heart disease and vascular deaths. So, these are five trials
> in elderly hypertensives. This is Coope and Warrender, SHEP, MRCII.
> There are two more that over age, SYSTUR and STOP. So, they are all
> beta-blocker and/or diuretic-based regimens and they show, in what we
> thought was a relevant population, the benefit of lowering blood
> pressure with a regimen approach to attaining blood pressure control.
> You can see the magnitude of benefit there. Does that help?
>
> DR. LORELL: It may be that the data that we are trying to tease out
> specifically about the combination is not quite there to be pulled out
> from this.
>
> DR. BORER: Steve?
>
> DR. NISSEN: First of all, I don\'t think we have actually said this
> well enough, but let me say that I really want to compliment the
> sponsor and the investigators for doing this study in the first place.
> I think it is to the credit of the company and of the investigators.
> This is an important study and, you know, obviously we are drilling
> down to some very narrow details here but it doesn\'t take away from
> the fact that you all invested a lot of time and energy in doing this.
>
> Having said that, I want you to put up slide 109, if you would, and I
> want to narrow down a question just to make sure I understand what you
> are asking us. You know, Jon Staessen and others have convinced a lot
> of people, I guess me included, that in the wisdom of Bob Temple,
> \"it\'s the blood pressure, stupid.\" He said that once in this
> committee and I happen to think it was rather relevant.
>
> What you see here is that basically it doesn\'t seem to matter how you
> lower blood pressure, based upon tens of thousands of patients. I know
> we haven\'t seen ALLHAT but, you know, ALLHAT seemed to show the same
> thing. I mean, those ratios were 1.0, 0.99 and 0.98 for three
> different regimens. So, we have this history, this incredible body of
> data that says \"it\'s the blood pressure, stupid.\"
>
> Is what you are asking us to say here no, that is not right? If you
> lower the blood pressure with losartan you get more bang for the buck
> than you do with an alternative regimen. Is that really what you are
> asking us to do? Then, the question we have to ask ourselves is, given
> this body of evidence, what will it take to convince us that you are
> the first folks in history to prove beyond a shadow of a doubt that a
> specific regimen for lowering the blood pressure, for a comparable
> degree of lowering, is better than another regimen? Is that what you
> are asking us to do?
>
> DR. KEANE: I think we are looking at understanding the effects of
> losartan in this trial, and I think that is the question you are sort
> of looking at yourself. I think there are, as I have tried to present,
> some biologically plausible explanations as to why the observed
> effects may, in fact, be true. We looked at left ventricular
> hypertrophy regression. We looked at a carotid artery ultrasound study
> that showed regression. It is biologically plausible from existing
> data and a whole host of preclinical data and stroke prone SHR rats.
> There are data in a variety of different preclinical studies that
> would support this. We have data from Schiffrin which again shows that
> independent of blood effects there may be some biological effect on
> the arteries that is different from what we have seen in atenolol. So,
> you have a number of things out there that are beginning to coalesce
> and merge into exactly what I think you are saying, that there is a
> difference and it matters how you actually lower blood pressure.
>
> DR. NISSEN: The ALLHAT investigators had the same hypothesis and they
> didn\'t prove it.
>
> DR. TEMPLE: I appreciate the quote and slightly regret being the wise
> guy. I think the evidence is overwhelming that lowering blood pressure
> is good for you and it doesn\'t matter how you do it, but that
> doesn\'t mean that drugs can\'t be distinguished. For example, without
> judging it at all, it doesn\'t surprise me entirely that treating the
> heart failure before it occurs in a hypertension population leaves you
> less likely to see manifestations of heart failure later, which could
> be what ALLHAT proved. We don\'t know.
>
> DR. NISSEN: We will see.
>
> DR. TEMPLE: So, there could be differences even though probably all
> drugs are good for you to some degree.
>
> DR. NISSEN: But you understand what I am getting at?
>
> DR. TEMPLE: Can I ask one thing that I didn\'t understand? I thought
> the meta-analyses that you showed were all situations in which
> atenolol or sometimes atenolol and other beta-blockers were better
> than nothing. In some cases this was when they were added to a
> diuretic; in some cases when they were not. So, I want to go back to
> the question that has been raised. The fact that something is better
> than nothing when used alone doesn\'t absolutely tell you that it is
> better than nothing when you add it to a diuretic. That is
> specifically the question. There is evidence that in the absence of a
> diuretic this has an independent effect on these outcomes. So, the
> question is only whether it still works.
>
> So, that is like the question we ask in heart failure: you have a
> diuretic; you add this; you add this and you don\'t really know you
> need the diuretic anymore and no one is willing to find out as a
> general matter because you would have to leave out a drug that
> everybody thinks saves life. So, you have the same situation here. In
> hypertension nobody is going to go back and leave people inadequately
> controlled by taking the diuretic away anymore.
>
> That is the question. It seems to me the thing one has to think about
> is if you have persuasive\--and I don\'t know whether you think it is
> persuasive or not\--evidence that atenolol by itself, in the absence
> of a diuretic, has a favorable effect on cardiovascular outcomes what,
> if anything, does that tell you about an effect of lowering blood
> pressure in the presence of a diuretic on similar outcomes?
>
> DR. BORER: I think you are starting to go down a path where you may
> not mean to go down. You know, it doesn\'t seem as if you are actually
> asking us to support the concept that losartan plus whatever is really
> better than some specific alternative regimen but, rather, that
> losartan plus or minus anything works; that it reduces cardiovascular
> events. It is in that context that these questions that we are trying
> to articulate in a more and more focused way are emanating from.
>
> If you have evidence that a diuretic works you don\'t know if the
> atenolol is adding anything or not but the regimen that has the
> atenolol works, and you are not sure exactly how well it works. Now we
> have a data set that says a diuretic plus something else works better
> but not overwhelmingly statistically significantly better. Can you
> conclude that the new regimen, because of its new component, actually
> is better than just giving the diuretic alone, which we all accept
> works?
>
> I don\'t know if I have made what I am mean clear enough so that you
> can respond to that, but that seems to be the issue that we are
> grappling with, not so much is there a biologically plausible basis
> for assuming that one drug is better than another drug for treating
> people with hypertension. Maybe it is; maybe it isn\'t. I think it is
> plausible enough. The question is have you actually shown in a
> statistically reliable way that you have a regimen that works and that
> is what we are sort of trying to grapple with by looking at the
> strength of evidence that the comparator works.
>
> DR. GOLDMAN: Bonnie Goldman, regulatory. If you look at the way we did
> our claim structure, it is not a superiority claim structure so you
> are correct.
>
> DR. BORER: Steve and then Paul?
>
> DR. NISSEN: I want to continue along those lines. There is one other
> thing I really think I have to help clarify here, and that is slide
> 118, if you could put that up. I think there obviously are some
> differences in blood pressure and one has to do some thinking about
> this. You might argue that it doesn\'t matter; that it doesn\'t matter
> how you got there but I do think this has to be discussed.
>
> If you look at Staessen\'s meta-analysis and, by the way, I reviewed
> it in great detail before this meeting because I wanted to be
> comfortable about it, he shows very strikingly a non-linear model. I
> don\'t know if you have his meta-analysis that you can put up there
> but I certainly have it here. What he shows is that the first few
> millimeters of difference account for the vast majority of the
> differences in the stroke events. In other words, a little bit of
> blood pressure difference on the stroke endpoint goes a long way.
> Another example of that would be a trial I am not particularly fond
> of, the HOPE trial where they had a 3 mm difference reported and a 25
> percent difference in stroke. It is a 0.75 risk ratio.
>
> You know, I guess the problem with what you did here is you drew a
> straight line and we know the straight line is not the right
> relationship. In fact, we know it is curvolinear.
>
> DR. EDELMANN: If I could just respond to that, the Staessen
> meta-analysis that you are referring to accounts for the individual
> trials, including the ones with active comparators against one
> another. So, the first thing to say is that when you plot this point
> on that curve the finding of losartan\'s benefit over atenolol is even
> outside the 95 percent confidence interval that Staessen draws around
> the curve. So, I think it is still consistent. But the reason we
> chose\--
>
> DR. FLEMING: And so is HOPE actually. I mean, when you look at his
> curve, it is a trial that shows more effect on outcome than you would
> expect just by blood pressure alone, as obviously with LIFE in that
> curve.
>
> DR. EDELMANN: Just to reiterate, even if you take that as the proper
> model as reflected in that publication, this is still outside of the
> 95 percent bounds. The reason that we chose to draw this as linear is
> because these are data taken from the meta-analysis only looking at
> the no treatment trials. In other words, this is the \"pure\" effect
> of blood pressure and not the concomitant effects that the active
> drugs have on outcome, which would then be an inevitable confounder
> and might serve to make the line curve.
>
> I mean, I take your point. I am not sure this is right but that is the
> reason we did it. Even if we looked at it straight out of the Staessen
> paper the point is still the same. Blood pressure doesn\'t seem to
> explain the benefit.
>
> DR. NISSEN: Just to conclude though, one conclusion that someone might
> draw is that blood pressure accounts for a much larger proportion of a
> difference between two regimens than would be accounted for by this.
> That was my only point. Whether it accounts for all of it or not, we
> can argue about it and we probably will, but in point of fact\--and
> keep in mind this is based upon systolic pressure and pulse
> pressure\--the differences were somewhat larger. So, again, we are
> looking at issues as they relate to strength of evidence. It suggests
> that a drug has effects that are independent of its blood pressure
> lowering effects; that it has some special magical properties that are
> going to reduce events. To do that, I want to know for a given degree
> of blood pressure reduction what the reduction in events would be
> because we treat patients to goal.
>
> I think one has to argue here that you have taken a best-case scenario
> for losartan and I can think of a number of intermediate scenarios and
> even a worst-case scenario that, in terms of how one regulates, one
> has to think about when one does this analysis.
>
> DR. EDELMANN: Just to respond to the issue about pulse pressure and,
> in fact, blood pressure in general, we have taken this in a very
> detailed way and looked with the available data in the literature for
> what is reported as the external source for reference here, but we
> have also done the internal analyses which are easier to do because it
> is completely internal to the LIFE study database. When we adjust for
> the differences in systolic blood pressure, diastolic blood pressure,
> systolic and diastolic simultaneously, pulse pressure, mean pressure,
> it doesn\'t make much of a difference. It matters one percentage point
> on the hazard ratio.
>
> I think we are asking more of the data than is reasonable to expect to
> be able to parse it to say how much of the benefit you could attribute
> to blood pressure. What we can say is that it is pretty likely, in
> fact very likely, that the benefit of losartan over atenolol in the
> LIFE study is not explained by blood pressure, certainly not to any
> large degree.
>
> DR. BORER: Paul and then Tom, and then we are going to take a break.
>
> DR. ARMSTRONG: I am remaining optimistic that Tom, as the primary
> reviewer, is going to come back to the question on statistical
> heterogeneity so I will pass on that, Mr. Chairman. But as I reflected
> on the discussion over the last hour and a half, I feel that the
> atenolol has been wrestled to the ground as almost a neutral component
> of the comparator arm. Before accepting that and reflecting on stroke
> as the dominant feature of the composite, and reflecting on the
> discussion that the beta-blocker in fact could be a progenitor of the
> atrial fibrillation which is strongly associated with stroke, I
> suppose one should at least raise, if only to dismiss, the rather
> outlandish proposition that there could be a negative interaction
> between atenolol and the thiazide diuretic in the comparator arm such
> that it would appear less good than it might if it was thiazide alone.
> I will just put that on the table to chew on.
>
> DR. BORER: Does anyone want to respond to that?
>
> DR. KEANE: Just to make it clear, the use of the diuretic in both of
> the treatment arms was the same.
>
> DR. BORER: Tom?
>
> DR. PICKERING: I have two questions. One is have you done the same
> analysis looking at the composite endpoint, which is what you are
> requesting rather than stroke? The other has to do with the 24-hour
> blood pressures.
>
> DR. EDELMANN: Sure, yes. Using the same assumption of a linear model,
> we are limited by the data as they were reported. There is only one
> trial that reports all cardiovascular events. But the same finding is
> true. Slide 217.
>
> It is the same pattern of developing the evidence. The only difference
> is we have only one published meta-analysis to estimate here. So, this
> is risk of the cardiovascular event difference based on blood
> pressure, constraining the point through zero, and here is the primary
> endpoint for LIFE with the magnitude of blood pressure difference. So,
> it is the same point with less precise ability to estimate best fit
> because we have only one point here.
>
> DR. PICKERING: Thank you. The other question had to do with slide 112,
> the 24-hour blood pressure. What this shows to me is that the effects
> of losartan tend to wear off at the end of the 24-hour period, which I
> think has been documented in other studies. If you look at the early
> morning period, which is the time of highest risk, the effects of
> atenolol appear to be much greater. My question is that about 50
> percent of the patients were on 100 mg of losartan and were they
> taking it twice a day or once a day, because that could make a
> difference?
>
> DR. EDELMANN: A couple of points about this. First, the answer to your
> last question is that losartan was once a day throughout the trial.
> The second thing has to do with the data at the end of the 24-hour and
> the beginning of the 24-hour period. There are fewer data points that
> comprise this because not every tape ran to fully 10:00 a.m. While I
> agree with your observation about the results, there is more
> variability at the very ends of both of these curves, just inherent in
> the fact that not everybody\'s tapes were started and ended at exactly
> the same time.
>
> DR. BORER: Dr. Keane and Dr. Edelmann, I think we have grilled you
> sufficiently, which is our traditional manner of operation. So, we are
> going to stop now. It is 3:04. At 3:19 we will reconvene and we will
> begin with a formal discussion around the questions.
>
> DR. KEANE: Dr. Borer, we still have some responses to questions that
> were raised this morning that we haven\'t had a chance to get through.
> So, if we have some time, maybe after the break, we will be more than
> happy to go through those.
>
> DR. BORER: Okay, if there are questions that people on the committee
> think haven\'t been answered sufficiently. We will take some time
> after the break.
>
> \[Brief recess\]
>
> DR. BORER: Dr. Keane, you wanted to respond to some specific questions
> that had been raised before that we haven\'t yet discussed. Why don\'t
> you go ahead and do that? We will try to take no more than ten minutes
> to go through these, and then we will begin a discussion focused
> around the structured questions.
>
> DR. KEANE: Thank you, Dr. Borer. I think one of the first things that
> I would like to start out with is really to review an important point
> about blood pressure lowering and the efficacy of blood pressure
> lowering with the beta-blocker and the diuretics.
>
> One of the key trials that has been performed in the last decade has
> been the STOP trial. Dr. Bjorn Dahlof, one of the principal
> investigators, has asked to make a comment on that to underscore the
> importance of how these regimens, which is a beta-blocker or a
> diuretic regimen, influences blood pressure and influences outcomes.
>
> DR. DAHLOF: I was also the principal investigator of the STOP trial. I
> just want to emphasize that I think that study is one of the few
> studies that actually can bring more light to the discussion than we
> maybe think because three-quarters of the patients in this elderly
> population, 72 to 84 years of age or on average 75 years, were
> starting on a beta-blocker and they had added diuretic in the majority
> to control blood pressure. The outcome versus placebo was about 40
> percent for stroke; 50 percent for total cardiovascular and also an
> effect on all-cause mortality. It was a very, very effective treatment
> and it was based on beta-blockers. We also looked at LVH afterwards
> with the LIFE criteria and about 30 percent of the patients had LVH,
> and the event rate on average was the same as in the
> beta-blocker/diuretic arm in the LIFE trial. So, I think it is one of
> the best trials. I am biased, of course, since I did the trial but I
> still think so. Thank you.
>
> DR. KEANE: Thanks, Bjorn. There was another question that came up this
> morning about male/female differences in achieved blood pressure
> during the trial, those in losartan or the atenolol group. Making a
> long story short, and we can certainly provide the data for that, the
> females in the atenolol group compared to the females in the losartan
> group had basically a very similar antihypertensive response, about 29
> mm Hg systolic and 17 mm diastolic in the atenolol arm, while the
> females in the losartan arm had about a 30 mm systolic decline and a
> 17 mm diastolic decline. So, they were very similar.
>
> I think one of the points I did want to make is that when there was a
> discussion about our achievement of control, we did achieve an
> effective level of control in some 50 percent of the patients. That is
> quite different than what is going on in the community. I think if you
> use the NHANES data to look at effectiveness of control, it is still
> down below 25 percent. So, I think it is important to recognize that
> this was a very well conducted and solid trial from the perspective of
> actually trying to achieve blood pressure.
>
> The other points that I would like to address that came up this
> morning in terms of questions, we have already heard the overall
> prevalence of left ventricular hypertrophy in the populations,
> particularly that are of our age group. They fall in the range of
> approximately 20-25 percent of the older population. It is clear that
> those patients with left ventricular hypertrophy are at increased risk
> for a cardiovascular event. It is about twice as great as one might
> anticipate. So, when we look at this, the important point of
> recognizing this risk associated with left ventricular hypertrophy
> when we looked at our treatment effect of losartan, the benefit
> occurred across the entire range of tertiles of left ventricular
> hypertrophy. So, we saw the lowest tertile, the middle tertile and the
> upper tertile both in men and women in terms of the beneficial effect
> of losartan. So, it occurred across all levels of left ventricular
> hypertrophy.
>
> I think if you look at some of the other trials that have actually
> been discussed today, in many ways it doesn\'t make a heck of a lot of
> sense to say that all of the risk is actually associated with just
> left ventricular hypertrophy because to see the beneficial effects, if
> one extrapolates a 20 percent prevalence of left ventricular
> hypertrophy to the beta-blocker and diuretic studies only to that
> subpopulation which represented no more than 20 percent, the other
> part of that population would have actually had no benefit whatsoever.
> So, I think it is an important thing.
>
> There are a couple of other questions that came up, and I think they
> came up with regard to the type of medications that people were on.
> One of them was focused around concomitant use of warfarin. There was
> about 4.9 percent in the losartan group and 5.9 percent in the
> atenolol group. That was statistically significant, with a p of 0.03.
>
> With regard to amniodarone usage in these patients, from the
> perspective of prior use of therapy there were only two patients that
> were on this medication in the losartan group and five in the atenolol
> group, and it increased slightly in losartan to 17 and increased to 16
> in the atenolol group, and there was no difference between the two
> groups.
>
> I think one of the last sets of issues that came up, and I think we
> have discussed many of the other questions but there was some question
> about the p value for test of interaction for all-cause mortality in
> the diabetic patient population. That achieved a p value of 0.006, a
> highly significant event.
>
> Finally, I just wanted to mention a little bit about heterogeneity.
> Clearly, I think this was mentioned by the FDA and I mentioned this in
> my presentation. The finding of heterogeneity within the context of an
> active comparator trial does not really invalidate the conclusions. We
> found that there was a significant difference in the different
> effects, particularly as it pertains to stroke. Stroke had a p value
> of 0.001 in this clinical trial so it was a very robust observation
> and it was a very important observation.
>
> This heterogeneity issue that has been discussed and been talked about
> within the clinical trial, as the FDA reviewer has underscored and
> pointed out, to achieve a p value of 0.02 on our composite means that
> at least one of the components in our composite has to be robustly
> statistically significant. Again, that appears to be related very
> specifically to stroke where we, again, found this very robust p value
> of 0.001.
>
> I think I have touched upon all of the outstanding questions and
> issues that were raised this morning and this afternoon. We have a
> couple more data points that I can provide to you. The p value for
> interaction for blacks for stroke was another question that we didn\'t
> have a specific p value to provide this morning. That had a p value of
> 0.004, again, a highly statistically significant observation.
>
> The percent of time on combination, let me get you that information as
> well. The percent of time that patients were on combination therapy,
> the diuretic, was between 65 and 74 percent and between 62 and 73
> percent, the former being the losartan and the latter being the
> atenolol arm. Is that right?
>
> DR. SNAPINN: Steve Snapinn. Can I clarify? Let me just clarify that.
> There was a question about how much time patients were on combination
> therapy. We looked at the number of days the patients were taking
> blinded study drug along with another antihypertensive and calculated
> that as a percentage of two different things, as a percentage of total
> study follow-up and as a percentage of the time when they were on
> blinded therapy at all.
>
> As a percentage of total study follow-up, it was 65.5 percent of the
> time with losartan versus 62.4 percent of the time with atenolol, a
> difference of three percentage points. However, as a percentage of
> time on blinded study drug, it was 73.9 percent with losartan versus
> 73.1 percent with atenolol, very similar numbers.
>
> DR. KEANE: I think that actually covers all the additional questions
> that came up. If there are no further questions, I think we will leave
> the podium.
>
> DR. BORER: That is fine. Thank you very much, Dr. Keane and everyone
> else from Merck. That was really a very informative presentation. As
> Steve pointed out earlier, we are all very impressed with the study
> and with the analyses, etc., etc. However, it is our job to make you
> feel bad when you are standing there.
>
> \[Laughter\]
>
> **Committee Discussion of FDA Questions**
>
> We will move on to a discussion of the questions and if we have any
> other clarifications we need, we will ask for them in that context.
>
> The Cardiorenal Advisory Committee is asked to provide an opinion on
> the relative effects of an antihypertensive regimen containing
> losartan compared with a regimen containing atenolol, both
> administered once per day. Specific guidance is sought on the adequacy
> of the current program to support a claim of superior efficacy for
> losartan at reducing the incidence of the combined endpoints of
> cardiovascular mortality, MI and stroke, as well as guidance on how to
> describe any relevant differences in labeling. That sounds a little
> confusing. You are not really asking primarily whether the regimen is
> superior but whether it works, I think. Right?
>
> DR. THROCKMORTON: Well, I think while the sponsor is not interested in
> that, as we will come to when we come to the questions, there is at
> least some interest in that.
>
> DR. BORER: Yes, there are questions that deal with that. All right.
>
> DR. NISSEN: I am not sure though I understand the question.
>
> DR. BORER: Well, this is the preamble. The questions divide the issue
> into does it work and is it superior so maybe we can sort of gloss
> over that one.
>
> Specific guidance is sought on the adequacy of the current program to
> support a claim of superior efficacy for losartan at reducing the
> incidence of the combined endpoints of cardiovascular mortality, MI
> and stroke, as well as guidance on how to describe any relevant
> differences in labeling. Additionally, guidance is sought regarding
> the relevance and appropriate description for an observed qualitative
> interaction between race and the effects of the two study drugs.
>
> In the past, the agency has told sponsors that a robust demonstration
> of a clinically relevant difference between the two drugs, if done
> fairly, would be appropriate for inclusion in labeling. There are few
> examples of such trials being presented to the agency and being
> incorporated into labeling, such that the current trial has some value
> as precedent.
>
> So, with that as a preamble, the first question, the LIFE trial
> compares the effects of losartan and atenolol on cardiovascular
> outcomes. For a population like that studied in LIFE, what is known
> from external sources about the effects of beta-blockers, including
> atenolol, and angiotensin receptor blockers, including losartan, on
> the incidence of death, MI or stroke? Describe the basis for your
> opinion.
>
> We have some options here: 1.1, cannot be determined; 1.2, both are
> superior to placebo and equivalent to each other; 1.3, one or both are
> superior to placebo, but not equivalent to each other; 1.4 both are
> equivalent to placebo.
>
> The committee reviewer is Tom Fleming. Tom, do you want to take the
> lead in that discussion and we will see if there are any other
> comments?
>
> DR. FLEMING: Sure. Let me just begin the discussion and I will focus
> my comments as it relates to the atenolol part of the question.
>
> We have been provided a very informative meta-analysis by the sponsor
> that provides a lot of insight about regimens that are diuretics,
> diuretics plus atenolol, atenolol-based regimens, and where one is
> using titration strategies in helping to achieve targeted blood
> pressure levels. It seems that there is considerable evidence to
> indicate that those strategies, in fact, do have a very favorable
> impact on the composite clinical endpoint of death, MI and stroke.
>
> But an additional element of this question that is really important is
> that the question is specifically in part asking what is atenolol\'s
> influence. I think this is really critical in an active comparator
> trial. Ultimately, we are looking at understanding the influence of
> losartan. If one simply looks at the regimen and concludes, as I have,
> that the atenolol plus a diuretics regimen is effective, then there
> is, with the addition of the LIFE data, considerable evidence that the
> losartan/diuretics regimen, in fact, is also effective.
>
> But what is much more difficult to understand is, is losartan integral
> to that benefit. Working backwards, where we have in the LIFE study
> evidence of a direct comparison of diuretics and losartan versus
> diuretics and atenolol, it would be extremely important with diuretics
> and atenolol now as the active comparator to understand whether
> atenolol is, in fact, also positively influential in that combination.
> This is an issue we have been struggling with now for a considerable
> amount of time in our questions. It is unclear to me at this point
> whether a strategy that is based on diuretics, titrating to an
> achieved or targeted blood pressure, would yield a different outcome
> in the clinical endpoints than a strategy that is based on diuretics
> plus atenolol.
>
> Essentially, I am giving two different answers to this. If one is
> simply asking whether the entire regimen of atenolol plus diuretics
> influences these clinical outcomes, I believe there is considerable
> evidence that it does, and that is relevant because that provides
> further reinforcement when we look at whether the regimen of losartan
> plus diuretics influences the composite clinical endpoint.
>
> However, if we are also required to go beyond that and say we all
> accept that this class of agents that involves diuretics or
> beta-blockers are capable of influencing clinical endpoints, mediated
> in large part through effects on blood pressure, now the question is
> what is the integral role of atenolol in that strategy so that
> ultimately when we ask what the integral role of losartan is we can
> then determine whether or not the evidence of losartan\'s superiority
> to placebo is more than what its superiority is against atenolol.
>
> This is my own reason for interest in understanding what the effect of
> atenolol is. I am coming to the conclusion, based on evidence and
> perspectives that I am hearing from the committee, that a strategy
> that would titrate to a targeted blood pressure based on diuretics or
> a strategy based on diuretics plus atenolol probably would yield
> comparable effects on clinical endpoints. As a result, if we are going
> to conclude that losartan provides even more influence or more benefit
> on these clinical endpoints, one is going to have to show superiority
> in the LIFE study.
>
> DR. BORER: Let me raise one additional point and maybe, Tom, you can
> respond to this\--Tom Pickering. I don\'t think anybody would have any
> other opinion than the one you just stated, Tom, but in terms of the
> combination, in all fairness, versus diuretics alone, my understanding
> is that one of the reasons that we combine these drugs is that the
> effort to achieve blood pressure control with diuretics alone leads to
> the use of doses of diuretics that have harm associated with them, and
> that is one of the bases for putting together the combination to
> control blood pressure. That might influence our concern about the
> independent contribution of atenolol to the atenolol plus diuretic
> combination. Tom, can you discuss that?
>
> DR. PICKERING: Well, I think one issue is that the question addresses
> two specific drugs and a lot of what we are talking about with
> beta-blockers is general, and the question is whether you can
> generalize from atenolol to all the others. In the post MI trials, we
> know that you can\'t because the ones with intrinsic sympatomimatic
> activity didn\'t confer protection but the others did.
>
> Again harping back to the MRCII trial, this was about the only trial
> where there was a direct comparison between atenolol, a diuretic and
> placebo. I accept that it was a flawed study but that is the closest
> that we can get. Again, I think the age factor is an issue here. Most
> of the beta-blocker trials, not necessarily with atenolol, that showed
> a positive effect were in younger patients. I acknowledge the STOP
> trial but, again, I would interpret that as a combination of a
> beta-blocker and diuretic trial which certainly was superior to
> placebo, and I don\'t think any of us would question that. So, I think
> the age and the drug are potentially important questions.
>
> DR. BORER: Yes, again, a little information might be helpful about the
> possibility of achieving the blood pressure control, which was the
> target in the trials of atenolol where diuretics were used versus
> using diuretics alone. My understanding is that one of the reasons
> that one would not do that, and the algorithms have been developed, is
> that driving the dose of diuretics high enough to control blood
> pressure has potentially deleterious effects if the dose is pushed
> beyond 50 mg a day of hydrochlorothiazide for example. I don\'t know
> about chlorthalidone.
>
> DR. PICKERING: Yes, I think that was in the HAPPHY study where sudden
> death was much lower with the beta-blockers, and one issue was that a
> lot of the patients were on a very big dose of diuretics and there was
> a lot of hypokalemia and there was a question of whether that was an
> issue. But, again, in practice all these trials are going to need
> combination therapy to achieve the blood pressure control,
> particularly in people of this age group.
>
> DR. BORER: Yes, that was the point. Tom was raising the issue of did
> atenolol really add anything compared with just treating with
> diuretics alone, and the practical matter is that one might not be
> able to do that if you are treating to a blood pressure endpoint.
>
> Tom, do you want to respond to the specific questions 1.1, 1.2, 1.3
> and 1.4 or do we not need to do that?
>
> DR. TEMPLE: I just want to ask Tom a little bit about what he said
> because some of the words being said would have a lot of implications.
> Since Tom is sort of \"Mr. Surrogate\" let me put it this way, we
> start out with a strong bias that blood pressure has something to do
> with outcome. We have a lot of epidemiology and also a lot of clinical
> trials of various drugs.
>
> But it is still relevant to ask for any particular drug whether
> lowering blood pressure with it has the expected favorable effect on
> outcome. So, the meta-analysis presented to us, while not in most
> cases on top of the diuretic, is an attempt to show that lowering
> blood pressure with atenolol has a favorable effect on outcome, just
> like the epidemiology would suggest it does. That doesn\'t mean some
> other drug isn\'t better or anything like that.
>
> What I hear coming from you is the question of whether that remains
> true when there is a background of diuretic. That is an interesting
> question but it poses major problems. For example, we have no doubt
> that chlorthalidone, SHEP, has a major effect on outcomes. Does that
> mean that if somebody started out those people on an ACE inhibitor and
> added a diuretic to get control we now would be dubious as to whether
> that was still true? My answer would be no, we would not because we
> have concluded from SHEP that lowering blood pressure with this
> diuretic, or a diuretic, perhaps has the expected, based on
> epidemiologic considerations, effect on outcome just like you would
> have predicted.
>
> So, I guess my question is if you believe the meta-analysis\--I make
> no judgment on that\--wouldn\'t that apply to lowering the blood
> pressure with atenolol whether or not the person was already on a
> diuretic, already on\--I don\'t know, something else? How reasonable
> is it to make a distinction there? In other words, does the
> meta-analysis tell you that blood pressure lowering with atenolol is
> good for you or does it only tell you that it is good for you when
> used alone and you are completely at sea about the question whether it
> is still good for you when you add it to a diuretic or you add it to,
> you know, anything else?
>
> DR. FLEMING: Let me try to begin answering that by putting us in a
> different context, which doesn\'t apply here but it is an easier one
> to think through. That is, suppose you had a control regimen of
> diuretics and then you had an alternative regimen of diuretics and
> atenolol and a third regimen of diuretics and losartan\--I will call
> them D, D plus A and D plus L. Suppose that these were fixed dose
> regimens. What ultimately I think, in my view, we would want to be
> able to show is that D plus L is more effective than D to conclude
> that L is, in fact, favorably influential in achieving benefit.
>
> DR. TEMPLE: But you are going to lower the blood pressure more. Two
> drugs lower the blood pressure more.
>
> DR. FLEMING: You are ahead of me.
>
> DR. TEMPLE: All right.
>
> DR. FLEMING: So, in this line of reasoning it is not necessary to show
> that D plus L is superior to D plus A if, in fact, D plus A is better
> than D. If you knew how much D plus A was better than D, you are now
> in a non-inferiority situation, and if you have marginal evidence,
> strength of one study evidence to show that D plus L is better than D
> plus A and D plus A is better than D at some level, you may well be
> able to conclude superiority.
>
> DR. TEMPLE: We all know the best non-inferiority study is where you
> win.
>
> DR. FLEMING: Well, if in fact the judgment\--
>
> DR. TEMPLE: And that is the question here.
>
> DR. FLEMING: If the judgment here is D plus L is better than D plus A
> at the strength of evidence necessary to conclude superiority, unless
> you think A is harmful I don\'t have to worry about how much D plus A
> is better than D.
>
> DR. TEMPLE: This has come up before on the strength of evidence
> matter. One study at a p of 0.02 as a basis of effectiveness is
> generally considered sort of marginal. You make what you will of the
> stronger effect on stroke alone, but leaving that aside, one study at
> a p of 0.02 against a drug that you are quite sure has some effect has
> been taken for clopidogrel and something as representing quite a high
> level of evidence. So, it does matter what you think of the atenolol
> data.
>
> DR. FLEMING: Yes, you are exactly right. That is my view as well. That
> is why I believe that the time this committee has spent struggling
> with what is ultimately this first question is very important for that
> very reason.
>
> What I have just described though is not exactly the situation we are
> in. It is not exactly the situation we are in because when you are
> comparing D plus A versus D, those aren\'t the same Ds because what
> you are going to do with the diuretics without the beta-blocker is
> that you are likely going to have to achieve higher doses, etc. So, we
> are really confusing the issue. If ultimately now I believe in
> surrogates, if I believe in blood pressure and I believe that you
> could, in fact, effectively titrate to a targeted blood pressure with
> either D or D plus A, if I believed all of that, then I am saying
> technically A isn\'t adding anything over D that I could get unless
> there are some harmful things happening when I have to titrate to such
> high doses of the diuretic.
>
> DR. TEMPLE: If in this case D was much greater in one of the groups,
> then that would be a concern but my recollection is that D was pretty
> much the same in both groups.
>
> DR. FLEMING: What I am hearing from all of the data is that D plus A
> and D and A are really good, even though none of them are labeled for
> this setting. They are all really good in terms of achieving blood
> pressure adjustment and in a lot of cases we have data to show that
> they influence this composite clinical endpoint. Hence, the importance
> of that conclusion is we now know that our active comparator regimen,
> D plus A, is very effective and the LIFE study, to my way of thinking,
> unequivocally is going to show that D plus L as a regimen is having
> favorable effects on this clinical composite endpoint.
>
> The tougher part if you, in fact, wish to answer this question is, is
> L integral to that\--although we don\'t have to know the answer to
> this\--partly mediated through mechanisms beyond its effect on blood
> pressure? Then I circle back to your point. My view of the LIFE study
> is it is an important step in saying D plus L, hence L, is better than
> D plus A, hence A, but only at the 0.02 level can I reinforce against
> placebo.
>
> DR. TEMPLE: It is that last part that confuses me. There isn\'t any
> data, I don\'t think, that D plus L is better than D at lowering blood
> pressure. I mean, that is hardly news and that shows up all the time.
> Two drugs are always better than one. We have a thousand combination
> studies that show that.
>
> DR. FLEMING: To a point that you would believe that there is adequate
> evidence to conclude we have affected the clinical endpoints?
>
> DR. TEMPLE: No, no, that is a different question.
>
> DR. FLEMING: That is a relevant question.
>
> DR. TEMPLE: I am going back to my original question. I would have said
> that the question of blood pressure surrogacy can be answered by a
> study in which you showed lowering blood pressure with drug X has the
> expected, the epidemiologically predicted effect on outcome. That then
> tells you that this drug\'s blood pressure lowering is a good kind of
> blood pressure lowering. That is the reasoning I have had. Okay? I
> would have said that applies whether you use the drug to lower blood
> pressure from a systolic of 180 to 160 originally or whether you add
> it to another drug to lower it from 160 to 140 because what you have
> learned is that lowering blood pressure with this kind of drug is good
> for you. Everybody feels comfortable with that with chlorthalidone,
> say, because there is such a lot of recent data.
>
> But that is the general approach that I think we have thought of. Your
> question gets answered once. Now, maybe that is wrong thinking and
> maybe you want to challenge that, but that is what I would have
> thought the idea is. The question is if I lower blood pressure with
> drug X, does that have the expected, epidemiologically predicted
> favorable effect on outcome? So, it shouldn\'t really matter whether
> you add it to a third drug, a second drug, a first drug if you now
> have come to believe that you now know that lowering blood pressure
> with drug X is good for you. So, it shouldn\'t matter whether it is
> alone, on top of a diuretic or any of those things unless there is a
> flaw in the reasoning here. I am laying out the reasoning because that
> is how we have been thinking about it, and also because I, frankly,
> don\'t know what we would do if every conclusion about outcome was
> based on a specific drug. You would never get anywhere.
>
> DR. FLEMING: I would just ask you though, and it doesn\'t argue
> against what you are stating, that lowering blood pressure is a good
> thing, are you prepared to label every agent now, and there is an
> array of them in this setting that have been shown to lower blood
> pressure\--are you prepared to give them a label for effects on this
> clinical endpoint?
>
> DR. TEMPLE: That may well be, but in this case what Merck is doing is
> saying something different. They are saying we already know from
> outcome studies that atenolol blood pressure lowering is good for you.
> They are saying, okay, in a population where the diuretic treatment is
> the same not only were we equivalent but, in this study, we were
> actually better. Ergo, we must be good for outcome too. That is all
> they are asking. They are not asking for a superiority claim. Whether
> they should get one is a question you are being asked but they are
> only saying doesn\'t the conclusion that you have already reached
> about atenolol now support, on the basis of a single study with a p of
> 0.02 or thereabouts, the same conclusion for losartan? I think that is
> what they are asking.
>
> DR. FLEMING: The easy part to this for me is that the regimen of
> diuretics and atenolol or the regimen of diuretics and losartan
> favorably influence the clinical composite endpoint potentially
> largely, fully\--at least largely mediated probably through some type
> of blood pressure effect.
>
> The question though, as I see it, that is much more difficult and I
> would think integral for this committee to answer is how influential
> is losartan for achieving that effect? Is it contributing to achieve
> that effect? Ultimately what is making this complicated to answer is
> that it is being given in combination with diuretics which, obviously,
> are very influential in both lowering blood pressure and achieving the
> beneficial clinical endpoint. So, the complications here are that it
> is not enough just to say we know atenolol or we know diuretics or
> atenolol and diuretics are all effective. What is important is, if the
> active comparator, as it is in the LIFE study, is diuretics plus
> atenolol, is atenolol itself adding to that combination on the
> clinical endpoint, more so than diuretics?
>
> The reason that is an important answer to get is what you mentioned up
> front, Bob. That is, if you are looking at the LIFE study and you are
> saying it is getting a favorable result but the strength of evidence
> is marginal, if you know that atenolol is integral in adding benefit
> then you are in a superiority against placebo, if not superiority
> against atenolol\--
>
> DR. TEMPLE: Right.
>
> DR. FLEMING: \--which is essentially the minimum that we want to
> achieve.
>
> DR. TEMPLE: So, it adds to the strength of the evidence from a single
> study at a not extreme p value.
>
> DR. FLEMING: Yes.
>
> DR. TEMPLE: Right.
>
> DR. BORER: Steve? While you are making your comment maybe you can take
> a stab at 1.1, 1.2, 1.3 and 1.4 so that it is on the record.
>
> DR. NISSEN: I will but first let me just say that there is a conundrum
> here and I want to see if I can state this properly. What the sponsor
> had to do here, they wanted to do an active control trial, which is
> always very difficult when event rates are relatively low. So, they
> studied an enriched population. The way they enriched the population
> in events was that they went to an elderly population with left
> ventricular hypertrophy. And, there is one other thing that is a
> little bit different from, say, our population, it was largely white
> and we have more African Americans particularly with hypertension.
>
> So, you asked the question for a population like that studied in LIFE,
> what do we know? You know, that is the problem here because there is
> evidence that these drugs have differential effects among younger
> versus older patients. In fact, you see that in LIFE because what you
> actually see is that among the younger patients it actually goes in
> the opposite direction.
>
> So, it makes it much harder for me. I am not saying the sponsor made a
> mistake or did anything wrong; they had no alternative. If they wanted
> to have any chance in four or five years to see a difference between
> the regimens they couldn\'t have studied a general U.S. hypertension
> population because they wouldn\'t have gotten enough events to do that
> or they would have had a sample size of 40,000. So, they studied a
> very specific population. Now what you really want to know, Tom, to
> add to your puzzle here, is for that kind of population what do we
> know about atenolol? The answer is we know precious little.
>
> So, my answer to the question, to get back to it, is that I don\'t
> know what the effect of either of these agents is from external
> sources on a largely elderly, LVH\--only 20 percent of the population
> has LVH, largely white population. I am suspicious here that those
> demographics are what drove all of this and not necessarily the
> biology. Of course, the label is not going to say, you know, this drug
> is indicated for elderly, LVH, white people, you know, living in
> Nebraska. So, you see, we are trapped. There is a trap here and I
> don\'t know how you get out of the trap because I don\'t know very
> much about atenolol in this population. What I do know suggests that
> atenolol didn\'t work very well in that population.
>
> DR. BORER: You know, one way out of this might be to suggest the label
> say something fairly specific.
>
> DR. NISSEN: So, my answer to 1.1 is \"cannot be determined.\"
>
> DR. BORER: Does anyone have a different opinion? If not, after Doug\'s
> comment we will move on.
>
> DR. THROCKMORTON: Steve, I want to pin you down just a little bit. In
> some places people on the committee have used some demographics like
> that, or sponsors have used demographics like that, as you pointed
> out, to get a high event population. For instance, you might use
> microalbuminuria as a sort of marker for cardiovascular disease, or
> something. Under some circumstances the committee sort of treated
> those as markers of high risk, not as things that necessarily
> precluded you from generalizing to a population that might not have
> those things. Here, I am hearing you say, no, that\'s it. LVH is a
> thing that sets you into a fairly restricted population. It is a thing
> that precludes your being able to understand the behavior of these
> drugs, the comparative behavior of these drugs in a non-LVH
> population. Am I hearing that right? If so, could you sort of tell me
> which of the demographics you picked up. I think you said Nebraska.
> Was that it?
>
> \[Laughter\]
>
> And LVH and elderly and race.
>
> DR. NISSEN: Well, let me tell you why it is so important. By the way,
> I forgot one other. The fourth one is people who are at lower risk for
> myocardial infarction than for stroke because the post MI patients
> were largely excluded. So, when we look at the general population at
> risk here with hypertension we have an awful lot of coronary disease
> people and a lot of them were pulled out of this trial because they
> needed a beta-blocker for other reasons. So, that is another
> cherry-picking\--
>
> DR. THROCKMORTON: As were patients with CHF.
>
> DR. NISSEN: Exactly. So, you know, it gets very complicated now. What
> we have is a very narrow slice and we have pretty good evidence, Doug,
> that those demographics, in fact, are major drivers. We know, for
> example, that the elderly respond differently to different drugs. We
> know, for example, that they don\'t do particularly well with
> beta-blockers; they do do particularly well with diuretics. We know
> that among African Americans, black versus white, drugs that work
> through the renin angiotensin system tend not to work very well. So,
> again, if we are going to apply this in the U.S.\--
>
> DR. TEMPLE: They don\'t lower blood pressure very well.
>
> DR. NISSEN: Yes, right.
>
> DR. TEMPLE: That is sort of irrelevant here because everybody\'s blood
> pressure got controlled.
>
> DR. NISSEN: Yes, I understand but I am just trying to say that we see
> evidence here of this kind of thing. If you have a marker which seems
> to be rather neutral in its effect in predicting the pharmacogenomics
> of drugs, okay. I mean, for example CRP or whatever. But the point
> here is that these factors appear to be fairly important in
> hypertension, and I kind of see that in the LIFE data and that is what
> makes me uncomfortable because among the younger patients, although
> the test for heterogeneity doesn\'t meet your statistical measure, it
> is on the opposite side of the line if you are under 65 years of age
> and that makes me think maybe what we are looking at is a population
> that was not necessarily deliberately selected to look better for
> losartan that had that effect.
>
> DR. BORER: If I can add to that just a little bit, one of the reasons
> that I agree with Steve is that these people had LVH and many of them
> had mild hypertension. A lot of people with mild hypertension don\'t
> have LVH. So, it is not \"blood pressure alone, stupid.\" There is
> some underlying biological difference in this defining its response to
> blood pressure as compared to another population with the same blood
> pressure, it seems. That doesn\'t mean that you can\'t extrapolate
> further; it just means that I feel uncomfortable extrapolating further
> because I don\'t understand the importance or basis of those
> biological differences. Given that, I would tend not to extrapolate
> widely. I am not suggesting that the LIFE data are in any way invalid
> or that the sponsor and the investigators haven\'t proven what they
> set out to prove. In fact, not to jump ahead, but I think they did.
> But I would be very concerned about extrapolating widely given the
> biological variations that I think we can infer in the population that
> we are talking about here, the hypertensives.
>
> DR. THROCKMORTON: But I really would like to understand what the basis
> for that concern is, and how you would you like us to do that? When
> the sponsor came and said we want to do a trial but we are concerned
> that it is either going to take a million years or the whole, say,
> State of Nebraska. So, we would like to choose a population that is
> enriched, let\'s say, but at the end of the day we would like to be
> able to understand that in a sort of continuum of disease rather than
> just your net narrow population.
>
> This sponsor has made one sort of choice. They have chosen a
> population that has been narrowed or enriched for events, and I am
> still not sure how narrow but Steve seems to think fairly narrow.
> Then, at the end of the day, they looked for heterogeneity in that
> population as an argument to say, look, you can, roughly speaking,
> understand the effects of these drugs in a larger population than the
> one we studied by applying largely covariate analyses post study
> results.
>
> Now, is that convincing to you? Or, am I hearing that that is not a
> way that you think the sponsor should think about this?
>
> DR. BORER: Beverly?
>
> DR. LORELL: I might answer question one a little bit differently than
> Dr. Nissen but with many similarities. I would say to this that it is
> likely that either of these regimens is superior to placebo based on
> the \"blood pressure, stupid.\" We keep coming back to that because
> both showed a large magnitude of reduction in blood pressure. But I
> think for these very issues that Dr. Nissen raised about some of the
> specifics of this population, the way it was enriched, that one cannot
> infer, using outside sources, that either one of them has a
> superiority over the other because I think his concern is that this an
> elderly population, is an unusual group, and most of us around the
> table treating patients would not choose a beta-blocker as the second
> choice after starting a diuretic if our patients were still not
> controlled in this age group.
>
> But it is also a little bit unusual in that you pulled out, as he
> said, the population that is at higher risk for cardiovascular events
> where a beta-blocker might have been beneficial in those that are
> having some angina and need beta blockade, or previous infarction. So,
> it is very complicated but I would say based on the magnitude of blood
> pressure reduction alone either of these regimens is likely to be
> better than placebo.
>
> DR. TEMPLE: This may be a regulatory nicety that nobody actually cares
> about but I will press on it anyway. We all act as if lowering the
> blood pressure is what counts. Drugs get approved because they lower
> blood pressure without showing any outcome data. People have
> criticized that, but that is still what is done.
>
> What is being sought here is not a claim that losartan is better than
> anything else but that it has been documented as having an effect on
> outcome specifically. Even though probably we all would assume it has
> an effect on outcome because it lowers the blood pressure, they want
> to write in labeling we have an effect on outcome which, by the way,
> no other antihypertensive except ramipril, by mistake, has. Steve
> thinks it is by mistake; we didn\'t think it was a blood pressure
> claim.
>
> So, that is the particular importance to us. I should tell you we are
> busily plotting to include outcome data of some kind in all of these
> drugs because certainly that is what everybody believes. We certainly
> haven\'t done it yet and are not particularly close to doing it.
>
> So, the question that this poses is does a study in which you beat
> something that probably has a favorable effect or, if you believe in
> the meta-analysis, definitely has a favorable effect at least in
> somebody, does this now provide documentation that losartan too has a
> favorable effect on outcome? It is true it is in a very specific
> population and you have to deal with that. How generalizable you would
> find that is something to debate.
>
> On the other hand, they would argue that in being better than
> something that has a favorable effect, they have a fairly strong level
> of evidence at least for this population\--and you have to think about
> whether to generalize it\--that they have a favorable effect on
> outcome. This is probably beyond what anybody really cares about but
> that is our immediate problem.
>
> DR. BORER: You are the one who is asking for advice so if you care
> about it, it is important.
>
> DR. NISSEN: May I respond to Doug\'s question?
>
> DR. BORER: Yes, briefly.
>
> DR. NISSEN: Very briefly, Doug, you asked me a direct question which
> is, you know, can you do this by going back and looking for
> heterogeneity. The four things I mentioned, elderly, LVH, race and
> absence of coronary disease, these are the four things that are here
> that are very specific, and in the case of the exclusion of patients
> that have coronary disease you can\'t go back and look because those
> patients weren\'t in the trial so you can\'t go back retrospectively
> and figure that out. In the case of race when you go back and look at
> it, it looks pretty ugly. In the case of LVH you can\'t go back and
> look at what happened to the non-LVH patients because there weren\'t
> any non-LVH patients in here. In case of the elderly you can go back
> and look by age and you see at least a signal there of a difference.
> So, for all four of the demographic characteristics that I mentioned
> that were very specific to this group either you don\'t know or what
> you do know makes you uncomfortable.
>
> DR. TEMPLE: But in the end what you have to decide is how much of a
> reservation that is. I mean, you only know about systolic hypertension
> in chlorthalidone in people over 70. Does that mean you don\'t treat
> anybody who is 60? I don\'t think so. So, somehow in your mind at
> least you have said it looks like chlorthalidone is a good thing for
> isolated systolic hypertension, which happens to be a problem more in
> the elderly than in other people so you tend to believe it.
>
> You are going to be faced with that. How much does the fact that it
> was done in people with LVH make you not believe that you have learned
> something about the drug itself but have only learned something very
> narrow about the population?
>
> DR. BORER: Can I suggest something? Dick, at this point of a meeting
> we don\'t entertain comments. I am sorry, I have left you standing
> there so long. Can I just suggest so we can move on here that we can
> say from outside sources that it seems reasonably clear that atenolol
> is a good thing in terms of these outcome events and we just don\'t
> have all that much information about the ARBs? That is not one of your
> options but that is what I am going to suggest. Unless anybody
> disagrees with that we will move on to number two. Oh, I am sorry,
> Tom?
>
> DR. FLEMING: I am not sure if I am disagreeing or not, except to say I
> think it is more complicated, as I think about it, than to say it is a
> good thing. Atenolol alone is a good thing. What atenolol is adding to
> diuretics is still relevant and uncertain in my mind.
>
> DR. BORER: Yes, but that is not what they asked, fortunately. It is
> just atenolol alone, it sounds like.
>
> Number two, regarding the LIFE trial data in the overall population
> studied, describe the overall difference between patients receiving
> the losartan-based regimen and the atenolol-based regimen in the
> trial.
>
> 2.1, was superiority of the losartan-based regimen demonstrated for
> the primary endpoint and for each of the three components of the
> primary endpoint? Tom, why don\'t you go ahead?
>
> DR. FLEMING: Let me try to initiate discussion on maybe 2.1 and 2.3
> initially. Was superiority established? I believe that the LIFE study
> provides a statistically significant difference on the primary
> endpoint at a level that I would say is consistent with the strength
> of evidence of a single positive study. In addition to providing, of
> course, evidence about the composite endpoint, one of the many
> strengths of this trial is that it provided a very appropriate
> continued management and follow-up of these patients beyond the
> occurrence of the initial primary endpoint, which was an extremely
> important element of this study in that it allowed us to more clearly
> understand what were the effects on the components.
>
> There is considerable heterogeneity, as has been pointed out, and the
> evidence seems fairly strong that there is a superiority, a
> statistically significant benefit overall in the composite endpoint
> but seems to be heavily driven by the stroke component. Of the other
> two components, the MI and the cardiovascular death, the
> cardiovascular death that is trending favorably, with a relative risk
> of 0.89, also seems to be heavily driven by stroke-related death.
>
> So, as I look at this, the overall benefit that has emerged with the
> significant positive endpoint seems to be fairly strikingly
> single-dimensional, i.e., we are favorably influencing stroke and
> stroke-related death; the other elements seem to be neutral. How does
> one interpret that? How do you address that statistically? You are
> spending your alpha on the primary composite endpoint and I think that
> rigorously that is true. They hit the positive primary endpoint. I
> think good statistics involves good common sense and good common sense
> here would say that when you look at the totality of these data the
> essence of the signal is in stroke. So, as I look at this from what I
> would call a common sense perspective, I think this study has
> established a favorable result for the combination with losartan over
> the combination with atenolol on the stroke endpoint.
>
> Where we will come back to this question in numbers 3, 4 and 5 is what
> is adequate strength of evidence here. This is a single study. We have
> often heard the term a single study that is positive where the results
> are robust or compelling\--many of us have said a single study that
> achieves 0.025 squared, which has a two-sided p value of 0.001, is a
> trial that contains essentially the equivalent strength of evidence of
> essentially two positive studies. So, the complication, at least as I
> look at it here, is that this is a study that is positive. Is it, in
> fact, a study that is sufficiently positive that it provides robust
> and compelling evidence?
>
> Let me move on though, having focused on stroke, to 2.3 and question
> 2.3 says could the observed differences in clinical outcomes be the
> result of differences in blood pressure control? Let me argue that in
> a certain sense it is not a fully well-defined question. It is a very
> relevant question. I say it is not fully well-defined because blood
> pressure control is a surrogate. It may be a very good surrogate but
> what do we mean by blood pressure control? There are many ways of
> characterizing blood pressure control. Is it adequate to talk about
> the average systolic blood pressure, or diastolic blood pressure, or
> pulse pressure, or is it the fraction of people who are below a
> targeted threshold of 160 systolic blood pressure? There are many
> variations and it may be that the effect of intervention is
> substantially mediated through its effect on blood pressure but we can
> get false-positive or false-negative conclusions if we are not
> characterizing that exact true functional relationship if we are
> looking at average blood pressure and, in fact, if we look at average
> blood pressure there is a one millimeter difference.
>
> The meta-analyses that I have looked at would indicate that if we have
> a 25 percent reduction in overall stroke rate and there is a
> difference in the two arms of a 1.2 mm Hg achieved in average systolic
> blood pressure, it seems that that would account for a three to six
> percent drop. So, at least by my own crude calculations here, it looks
> as though changes or differences in the two regimens in systolic blood
> pressure could be contributing to the difference in stroke, but it
> seems to me that the difference in stroke is of a magnitude three or
> four times larger than what would seem fully attributed to that.
>
> On the other hand, maybe it is because the systolic blood pressure
> average measure is looking at the wrong way in which the regimens are
> influencing risk of these clinical endpoints through blood pressure.
> It could be that it is the difference in the two regimens in the
> fraction of people who have very high uncontrolled systolic or
> diastolic blood pressure, in which case, as I said earlier, we may
> have false-positive or false-negative conclusions.
>
> So, in a certain sense the question is extremely difficult to answer
> and is, in fact, one of the reasons\--coming back to Bob\'s comment
> earlier\--that I have real concerns about reliance on surrogates if we
> are trying to draw conclusions about what effects are in clinical
> endpoints when we are only measuring the effects on the surrogate
> marker.
>
> In this setting, the sponsor has raised a number of potential
> mechanisms through which losartan or losartan versus atenolol could be
> influencing these clinical endpoints. It could be through any one of
> these arrays of different ways of formulating blood pressure changes.
> It could be through effects on LVH. It could be through carotid artery
> wall thickness. It could be through atrial fibrillation or an array of
> other yet to be specified effects. In all likelihood, it probably is
> through a complex combination of a myriad of different effects where
> blood pressure could be the leading or very significant aspect of it.
>
> If we, however, trivialize this and simply say is this effect of a 25
> percent reduction in stroke accounted for by differences in the
> average systolic blood pressure, at least that is simplifying the
> question and I am fairly comfortable to say, no, there is more effect
> than could be accounted for by that. Yet, I realize there may be other
> ways of characterizing effects on blood pressure that would maybe more
> fully capture the treatment effect.
>
> DR. BORER: Let\'s go on to 2.2 because I think we have to answer this
> in order to be able to answer some of the later questions. Was the
> comparison between the two regimens a fair one, as discussed in the
> ICH E10 guidance? For example, were appropriate doses of both
> medications used? We all received a copy of the ICH E10 guidance and
> on page six of that guidance is a discussion of the fairness of
> comparisons specifically related to dose, but the document not
> withstanding, would anybody like to offer an opinion about the
> fairness of the comparison? Tom, do you want to offer an opinion?
>
> DR. FLEMING: I will just be brief and then have others comment. There
> are two elements of this. One is dose, as you mentioned, and the
> sponsor indicated that dose was chosen based on label recommendations
> for treatment of hypertension. My own view about this in terms of a
> fair comparison is that I would like to see the regimens delivered as
> good clinical judgment would indicate they would best be delivered to
> achieve maximal benefit where we achieve levels of adherence that are
> what I always refer to as the high level of what would be achievable
> in the real world, whereas in retention I want perfection. I want
> everybody to be followed for outcome. For adherence to interventions,
> I would like to know in my clinical trials answers that are relevant
> to the real world. So, I don\'t want an extraordinary level of
> adherence that couldn\'t be achieved in the real world.
>
> So, in my own view, the essence of the answer to this as it relates to
> blood pressure because I know there needs to be a lot of discussion
> about the fact that only half the patients actually hit a targeted
> systolic blood pressure and 90 percent diastolic\--the essence of this
> from my perspective is, is that reflective of what we would see in the
> real world? If not, then that compromises to an extent the relevance
> of the conclusions.
>
> DR. BORER: Steve?
>
> DR. NISSEN: Yes, one of the problems that I guess I am having, and I
> might as well put it on the table, is that neither atenolol nor
> losartan would be the first choice drug in this population. I mean,
> you asked the question about how do clinicians treat elderly
> hypertensive patients like this, and the answer is we treat them with
> diuretics. We go to diuretics; if they don\'t work, depending on the
> patient, we add an ACE inhibitor or perhaps amlodipine, as was done in
> ALLHAT, but neither atenolol nor losartan. So, again, it is difficult
> to answer that question because I just wouldn\'t use atenolol in this
> population as a very common first-choice drug for hypertension. So, it
> sets up a bit of an artificial construct.
>
> I would be interested in other people\'s comments. Tom does this for a
> living and other people do, but do you all give atenolol to elderly
> hypertensive patients?
>
> DR. BORER: Beverly?
>
> DR. LORELL: I think your point is a good one, and it is difficult to
> know how to get around it. I think in an elderly population
> group\--not all, but I think many or most clinicians, unless there
> were compelling reason because of prior infarct or active poorly
> controlled angina, would not choose a beta-blocker as the second
> add-on to a diuretic. It would be extremely rare to start with a
> beta-blocker or an ARB in that setting.
>
> I think one of the problems in this fairness comparison\--and I don\'t
> even like using the word \"fairness\" because it is somewhat
> pejorative and I don\'t mean it that way at all\--is that, as was
> raised earlier, you know that when you are going to use a beta-blocker
> in an elderly population you may have more side effects and you may
> have more withdrawals from drug. That was, indeed, what was seen in
> this study and I think would have been predictable in the design. So,
> is that an issue of fairness as formally defined in this document?
> Maybe yes.
>
> DR. BORER: Is anybody disturbed at all by the fact that losartan was
> given to its maximum labeled dose but atenolol may not have been? Is
> that an issue here at all for anyone? If not, given the fact that this
> was the population that was studied, accepting that this was an
> elderly population and perhaps this regimen wouldn\'t have been the
> first choice for this population, within this population was there
> anything that would preclude us from judging that a fair trial was
> carried out? It doesn\'t sound like it. Bob?
>
> DR. TEMPLE: I know I said this before but I want to emphasize it,
> fairness is critical if you claim you are superior. Fairness is not
> relevant really if you just want to show you work.
>
> DR. BORER: That is clear. The only reason we have been asked to
> comment on this is because you do ask about superiority later.
>
> DR. THROCKMORTON: No, there is another reason. There is another reason
> why you might care about the beta-blocker part of this and that goes
> to Tom\'s level of evidence here. If you are using a trivial dose of a
> beta-blocker that you might imagine, in fact, was roughly placebo, to
> beat that would be sort of at the one trial level and you would have
> no additional cushion.
>
> DR. TEMPLE: Right, you are depending in this case for strength of
> evidence on it working. We had a big argument at the time atenolol was
> approved. We couldn\'t see any advantage to 100 over 50 but we left it
> in the label anyway. Some people think 25 is the right dose so 50 is
> not too bad.
>
> DR. BORER: On this next question, number three, we need a vote by the
> committee with a brief reason after you give your vote, if you don\'t
> mind, for the record. Number three, are the results of LIFE alone an
> adequate basis for approval of losartan to reduce the combination of
> cardiovascular mortality, MI and stroke? Tom, why don\'t we start with
> you and then we will go to John at the end of the table and come
> around?
>
> DR. FLEMING: Well, I have already stated in response to question two
> that I think the results of LIFE provide the strength of evidence of a
> single positive study. It is just over the edge of what we would
> require for statistical significance on the composite primary
> endpoint.
>
> In terms of whether I would interpret that to be robust and
> compelling, generally I would have expected we would need stronger
> evidence. We are going to talk, in question four, about other data.
>
> I will just mention as an aside at this point that external data
> certainly does give one some caution in the sense that what we are
> being asked to consider here in LIFE is that the effects on clinical
> endpoints are substantially being achieved, when you are at least
> looking at the comparison against the control arm, in manners other
> than blood pressure control, at least systolic and diastolic blood
> pressure control. In that regard, this study is moving us out into new
> frontiers and is the kind of result that generally you would like to
> have good reinforcement for from other relevant sources or else you
> would like to have a particularly strong result in the study.
>
> Now, what gets me in a sense to a stronger result ironically in
> looking at the elements. When I look at the components, the results on
> stroke are particularly intriguing with differences at the 0.001 level
> and, as we noted earlier, the differences we see on cardiovascular
> death are in a sense giving us a consistent picture because those are
> substantially driven by the stroke-related death.
>
> So, I struggle a bit as a statistician to say, all right, you have hit
> what I referred to earlier when I said 0.001 is the strength of
> evidence of two positive studies but it wasn\'t exactly the primary
> endpoint; it was a component of the primary endpoint. So, I am left
> very much on the fence here. My more rigorous side of me would say it
> doesn\'t hit it. My less rigorous side says that certainly there is
> considerable evidence as it relates to effects on stroke.
>
> DR. BORER: Can I ask for a clarification here? When I look at number
> three and number four, the only difference is that number four allows
> us to consider prior expectations. Do you mean by that that only in
> number four can we consider the known or reported effects of
> beta-blockers plus diuretics versus placebo or no?
>
> DR. THROCKMORTON: Yes, you should sort of think of three and four and
> five as a sort of ladder of\--I don\'t want to use the word claims but
> sort of descriptions of clinical effect. So, for the first one you
> could say, you know, this trial in and of itself, without needing to
> think anything about the comparative effects of the
> beta-blocker/diuretic regimen versus placebo or diuretics or anything
> else, is sufficient.
>
> Number four says no, you have to call on the things that I think I
> understand about the relative contribution that beta-blockers add to
> diuretics and diuretics add to placebo, however you want to parse
> that.
>
> Five then sort of takes you to the next level, the level that we have
> sort of alluded to in the first part, which is to say, well, is this
> trial, perhaps with other things that you think you understand, in
> fact sufficient to say that this regimen is, in fact, superior to a
> regimen based on atenolol? That is a level that the sponsor has
> proposed. I understand that, but that superiority is possible
> obviously for the primary endpoint or, as Tom suggests, some
> component. It may be that you may want to comment on that, that there
> may be more robust data for one or the other components.
>
> In that latter event, should you choose that in some way some
> superiority has been demonstrated, what we would need to have from you
> is a comment on how to describe that in labeling and that is where it
> would get somewhat more complicated. You can put things in a label in
> a couple of different places. You can put them in just the clinical
> trial section describing what you found, or you can give them a whole
> new claim. You can say this is something other than just blood
> pressure; this is a whole new effect of this drug. We would be
> interested in having some conversation about that as well, should we
> get to the end of, I guess, that tertiary branching in decisions.
>
> DR. TEMPLE: The immediate need is to distinguish three and four, which
> are about whether it works compared to nothing, and five, which is
> whether it is best. I thought what you were answering, Tom, was more
> related to five or perhaps three without considering whether atenolol
> works.
>
> DR. FLEMING: Bob, you are making a point here. I have difficulty not
> answering three, four and five together, not just because it is
> getting late in the day but because they are, in fact, interrelated.
> As I view it, three and four say is there adequate evidence to
> establish that we have efficacy? Whereas, five is saying, in fact, can
> you also say it is superior to atenolol? I believe my answers to
> three, four and five are no, yes and no but, in fact, I am not so sure
> why three is so important. Four seems to be the most important one and
> my answer yes to four, if it is acceptable to go into that\--
>
> DR. TEMPLE: We would agree with that. You should take into account
> what you know about atenolol.
>
> DR. FLEMING: Essentially, as I am answering four what I am really
> answering yes to is stroke. I am really moving in the direction of
> saying when I look at these data, what these data are telling me is
> that there is efficacy here as it relates to the stroke endpoint and
> what is reinforcing to me, even though I have expressed all my
> concerns in question one about how uncertain it is what atenolol\'s
> contribution is, when you look at the totality of the data that is
> provided by the sponsor in their very informative meta-analysis and
> their Table 2, what comes forward with atenolol pretty consistently is
> the effect on stroke. Now we are building on that with a result that
> is at the 0.001 level in the LIFE study on stroke.
>
> So, as I look at these data, on three it is not enough but in four,
> with that totality of evidence as it relates to stroke, I think there
> is adequate evidence for a label on stroke as efficacy. But in five I
> am back to the LIFE study alone and I am not persuaded that there is a
> superiority to atenolol in the LIFE study even on stroke.
>
> DR. BORER: Tom Pickering? I am sorry, John, I forgot that you are not
> voting. Tom Pickering, you can take three alone or, if you want to,
> three and four.
>
> DR. PICKERING: Again, I guess I don\'t vote but my answer to three
> would be yes, but I would be concerned if the labeling actually
> specifically said MI since somebody looking at it is going to say yes,
> losartan reduced MI and stroke because that is what the labeling would
> say and, clearly, it didn\'t reduce MI. If you look at the safety
> analysis, they concluded beta-blockers didn\'t reduce MI in that
> analysis. So, that would be one qualification. I think I am convinced
> that it reduced stroke better than atenolol in this population.
>
> My other reservation would be really what Steve has been raising, the
> issue of how generalizable these results are. Again, I would be
> concerned if there was just this blanket statement saying it reduces
> mortality, MI and stroke because I think we should limit it to include
> the people over the age of 65 and non-blacks. I guess the LVH is
> already in the proposed indication so that is not an issue.
>
> DR. BORER: Actually, you do vote, Tom. For the record, are you saying
> that you would vote yes on number three?
>
> DR. PICKERING: Well, only if it is modified.
>
> DR. BORER: Okay, only if it is modified. Were you answering number
> four at the same time or do you want to come back to that afterwards?
>
> DR. THROCKMORTON: Is that yes to number four and no to number five but
> yes for CVA?
>
> DR. PICKERING: Yes, I would accept the stroke.
>
> DR. TEMPLE: Jeff, could I just say I am personally overwhelmingly
> convinced that all the effect is on stroke-related matters and I can
> assure everybody that the labeling will convey that.
>
> DR. BORER: Steve?
>
> DR. NISSEN: I am pretty impressed with the stroke results in this very
> specific population. I think that it is pretty hard to argue with a p
> value that has a couple of zeroes in front of the one. So, you know, I
> find it convincing. However, I really do think it has to be modified
> by understanding in the label, or putting in the label very clearly
> the population so that clinicians can, in fact, interpret the data
> properly.
>
> I don\'t know if you want this now or later, I actually wrote
> something, which maybe at some point we can discuss, that I think gets
> at the heart of this. But the way the thing is written in three I
> can\'t vote for. I just simply can\'t because I don\'t think that the
> combination of cardiovascular mortality, MI and stroke was proven.
> Yes, I know you are going to fix it, but you asked the question that
> way. So, you know, if I am forced to answer the question that
> way\--now, I can come up with a label that states pretty clearly what
> I really think.
>
> The thing that actually worries me more is four. Jeff, I recognize
> that we have not had a chance as a committee to review ALLHAT but
> there is a signal there that makes me terribly nervous. Here is the
> signal, that the regimen that did the most poorly on the stroke
> endpoint was the lisinopril regimen. It was clearly inferior to both
> diuretic and amlodipine, and we have a drug that works by basically
> the same mechanism or extremely similar. Then, in most head-to-head
> trials, really only two that I know of, the ARBs have not done as well
> as the ACE inhibitors. So, many of us have suspected that ARBs are
> less effective agents than ACE inhibitors. In ALLHAT, in a huge
> population lisinopril was not the drug of choice for stroke
> prevention.
>
> So, if we do put this in the label, number four is actually much
> harder for me than number three. LIFE makes the case that compared to
> atenolol this is a good regimen. The problem is that I don\'t know
> whether agents that work through the renin angiotensin system are the
> best drugs to prevent stroke. So, we may be sending a message to
> clinicians which is a bad message, which is use ARBs for stroke
> prevention when, in fact, the best agents for stroke prevention are
> not ARBs.
>
> DR. FLEMING: Just to probe with Steve a bit, are you unpersuaded that
> losartan could have alternative mechanisms of action that might be
> particularly relevant in the LVH population?
>
> DR. NISSEN: You know, it is possible but all I know is that we have
> two trials where ARBs and ACEs went head-to-head, OPTIMAL and ELITE.
> In both cases the ARB didn\'t do as well.
>
> DR. TEMPLE: Low dose, Steve.
>
> DR. NISSEN: Yes, I understand. Bob, I understand all the caveats but I
> guess what I just trying to help you all understand is suppose that my
> hunch is right and that, in fact, the bradykinin effect of ACE
> inhibitors is important, then what has happened is we have now given
> the first label to reduce these endpoints to a drug which is actually
> inferior. We have already labeled losartan as inferior to kavisartin
> in blood pressure reduction.
>
> DR. TEMPLE: Only in once a day dosing.
>
> DR. NISSEN: I understand. So, we have the weakest drug in a class that
> may be a relatively weak class that happened to beat an even weaker
> drug, atenolol. So, we are getting onto a slipper slope here.
>
> DR. TEMPLE: Yes, you also don\'t know all those things. I mean, there
> are two massive meta-analyses comparing calcium channel blockers and
> ACE inhibitors and the results depend on who does it.
>
> DR. NISSEN: Yes.
>
> DR. TEMPLE: This is on stroke too. In one stroke looks better on CCBs,
> in the other it looks better on the other. All the numbers are very,
> very close.
>
> DR. NISSEN: In ALLHAT they weren\'t close.
>
> DR. TEMPLE: In ALLHAT you have to look at race specifically.
>
> DR. NISSEN: All right, all right. I will take a stab at it\--
>
> DR. BORER: Can we wait until we go through\--
>
> DR. NISSEN: Sure.
>
> DR. BORER: \--the discussion of these first few points because the
> specific labeling we could even deal with later, if we had to.
>
> DR. THROCKMORTON: Yes, I don\'t have a general labeling question. So,
> deal with that whenever.
>
> DR. BORER: If I am understanding correctly, Steve, for the record you
> are voting yes on three and no on four? Is that it?
>
> DR. NISSEN: I am voting no on both because the question is asked
> regarding the combination and I don\'t think I can say yes to that.
>
> DR. BORER: And you are not dealing with five yet, which is okay
> because I think we are going to have to come back to that.
>
> DR. TEMPLE: Jeff, it is important\--we should have done this but we
> didn\'t, assume for the moment that what I said is true, which is that
> if we think there is some claim in there it would be quite specific
> about what part of the combined endpoint was effective. Assume that
> and make it a separate question if you want. But I am completely
> convinced that there is no sign of anything once you leave the stroke
> area.
>
> DR. NISSEN: Then I would say yes to three but no to four.
>
> DR. BORER: Okay. Alan?
>
> DR. HIRSCH: Would you like me to be succinct or lengthy?
>
> \[Laughter\]
>
> DR. BORER: Succinct, please.
>
> DR. HIRSCH: I can try that; I have been trying all day. I am going to
> approach this from the point of view of a strict trialist. I think
> that LIFE was well designed, performed in a high risk population with
> appropriate following of a protocol. Within that context in this
> population, not yet worrying about how we extrapolate; not yet
> worrying about labeling, I think that the answer to three is yes, a
> combined endpoint reached a point of statistical significance for the
> three combined endpoints. But I am able to say that because Bob got me
> off the hook earlier.
>
> That means that number four I also think is yes because I think
> combined with other data we have I am not yet really ready to discard
> all the other blood pressure surrogate data that demonstrates the
> efficacy of beta-blockers, atenolol in particular, as being so weak as
> to have no impact. So, I think we have adequate information there. I
> will hold on five. I have different opinions.
>
> DR. BORER: Beverly?
>
> DR. LORELL: Your reassurance not withstanding, I do want to clarify
> that for both three and four I would say yes for the explicit measure
> of fatal and non-fatal stroke. I do not think the data, as presented,
> are an adequate basis for approval for the combination, including not
> only MI but also cardiovascular mortality, since there was not a
> strong signal of benefit for coronary heart disease and the mortality
> benefits also seemed to be driven by stroke.
>
> DR. BORER: Interpreting the questions as I do, I would vote no on
> three because I don\'t think without the prior knowledge of the effect
> of beta-blocker plus diuretic I could conclude that there is
> sufficient evidence for approvability. But for number four I would
> vote yes. That is, given what we have been presented and what we know
> about the effects of beta-blocker plus diuretic, the results of LIFE
> indicate an adequate basis for approval of losartan to reduce the
> cerebrovascular event rate and perhaps the associated cardiovascular
> mortality.
>
> But, certainly, I would concur with everyone else who has said that we
> need to remove MI from that approval. I would go one step further in
> that, as Tom suggested, and would only vote for approval for the
> losartan-based combination in number four if we are relatively strict
> about the population for whom the combination or the drug is approved.
> I wouldn\'t say 65. I think the investigators looked at a population
> older than age 55. That was the group they looked at. That is where
> they saw their results and I don\'t think we should subgroup but I
> would say over 55 because we have been presented with a great deal of
> information that suggests that in younger patients perhaps there would
> not be a benefit.
>
> In addition to the obvious left ventricular hypertrophy description of
> the population, I would say that we need to make some statement about
> race somewhere and we can talk about how we might do that. But with
> those caveats, I would vote yes on four. JoAnn?
>
> DR. LINDENFELD: Really restating what Jeff said, I would vote no on
> three but, believing that the active comparator is clearly effective,
> I would vote yes on four.
>
> With all the caveats you have mentioned, I would have one other. I am
> uncomfortable saying losartan is better than atenolol. I think this
> should strongly say in some way losartan included in a regimen use of
> diuretics because I don\'t think there is enough evidence here for me
> to say losartan is better than atenolol. I think we have to in some
> way phrase it that clearly the majority of the patients were on
> diuretics. Without that, I wouldn\'t be comfortable approving losartan
> alone.
>
> DR. THROCKMORTON: We are mixing things up. I think several of you
> chose not to answer number five.
>
> DR. BORER: We will get back to that.
>
> DR. THROCKMORTON: That is fine, we will come back to it.
>
> DR. BORER: I want to just amend what I said. I wasn\'t as clear as I
> should be. I agree completely with JoAnn. I am referring here to
> approval of the losartan-based regimen as opposed to losartan alone.
> Paul?
>
> DR. ARMSTRONG: I agree with JoAnn\'s caveat to your comments. I have
> nothing further to add.
>
> DR. BORER: Susanna?
>
> DR. CUNNINGHAM: The same for me.
>
> DR. BORER: So, that is a no on three; a yes on four for Paul and
> Susanna. Mike?
>
> DR. ARTMAN: I would reiterate everything everyone else has said, but I
> think I would vote yes on three and yes on four.
>
> DR. BORER: Okay, now we can go on to number five, and we need a vote
> on the first portion of that which is do you recommend approval of
> losartan as having demonstrated superior efficacy when compared with
> atenolol in the population studied in LIFE to reduce the incidence of
> the combination of cardiovascular mortality, MI and stroke? Forget
> about the endpoint for the moment, but Tom, who already voted on this,
> suggested that while there was enough information here to suggest that
> the drug works, there isn\'t enough information to state that the
> combination including losartan is clearly superior to the combination
> including atenolol. So, that would be a no on five. Tom?
>
> DR. FLEMING: Just to expand very slightly because I would just like to
> confirm what I have heard others recently say as well, that is, the
> refined wording on four that I had voted yes to is a losartan-based
> regimen involving combination with diuretics in the population, as
> Steve and others have pointed out, that was specific to the trial in
> which it was done. Yes, I did say no on five because I believe the
> evidence doesn\'t meet what I would consider the standard strength of
> evidence, even though it is that of a single positive study, to say
> that superiority has been demonstrated.
>
> DR. TEMPLE: Can I just ask Tom about that? In your first trip through
> this you were musing about what to make of the rather low p value for
> the stroke endpoint alone but you came out with not good enough
> because it wasn\'t the primary endpoint?
>
> DR. FLEMING: Well, in that regard my answers to three and five are
> very inter-related. The answers to three and five are based on LIFE
> alone\--
>
> DR. TEMPLE: Right.
>
> DR. FLEMING: \--and in LIFE alone we certainly have, as I have said,
> evidence of a single positive study but if it is going to meet what we
> call the robustness compelling, at least what I think of in a
> subjective way, the evidence from one and a half to two positive
> studies, it doesn\'t meet that.
>
> DR. TEMPLE: And your stroke endpoint didn\'t take you over the top.
>
> DR. FLEMING: And here is where my rigorous statistical side comes in,
> and I don\'t apologize for it, it wasn\'t the primary endpoint\--
>
> DR. TEMPLE: That is why you are here.
>
> DR. FLEMING: \-- and if we had said at the beginning that stroke was
> the primary endpoint, then I am going to look at that 0.002 or 0.001 p
> value in a different light. What I did when I took the liberty of
> saying the primary endpoint was 0.023, this 0.003 only came from an
> exploratory what I call common sense look at the data to say it is
> obviously stroke. But I don\'t believe any of us can interpret that
> 0.001 in the same light as if it had been the p value from the primary
> prespecified analysis. That is my basis.
>
> DR. TEMPLE: I understand. A brief observation, we are telling a lot of
> people now set your primary endpoint and do a sequential analysis such
> that you only get to look at your three components at\--I don\'t know,
> 0.0013 if you win on the first one. Had they done that, they would
> have had a fairly robust outcome but they didn\'t do that.
>
> DR. FLEMING: What you are saying, Bob, is very reasonable advice, but
> that 0.013 I would still interpret as the strength of evidence of a
> single study. If it is one-sided, what is 0.006 squared times two for
> the strength of evidence of two studies?
>
> DR. BORER: Tom Pickering?
>
> DR. PICKERING: I would answer yes given the same provisos as in three
> if it is limited to stroke in the population that we have already
> discussed.
>
> DR. BORER: Steve?
>
> DR. NISSEN: And since this question does, in fact, ask about labeling
> can I make a try at it, Jeff?
>
> DR. BORER: You can if you want to but first why don\'t we vote whether
> we agree that it is superior? If the answer would be no, then labeling
> would not be an issue.
>
> DR. NISSEN: I think on the stroke endpoint it is superior but the
> devil is in the details on how it is described. You know, I want us to
> weigh in very carefully what we think ought to be described and you
> will obviously write it the way you want. But, you know, I would be
> very, very uncomfortable if this were written excessively broadly.
>
> DR. TEMPLE: But even before we get to that, I mean, Tom looked at the
> same data and said \"close but no cigar\" on superiority.
>
> DR. NISSEN: Yes.
>
> DR. TEMPLE: Are you saying it makes it because of the stroke?
>
> DR. NISSEN: I am saying it makes it, and I am saying it makes it in
> part because I can\'t explain it all on blood pressure for stroke. You
> know, you can get some of it. I think atenolol, in fact, is effective.
> So, I think they beat a regimen that is effective. It is not the best
> regimen by any means. So, I feel okay in saying yes to number five but
> I have very significant concerns about how you say it that would make
> a big difference on whether I vote yes or no.
>
> DR. THROCKMORTON: Sorry, just to press on that a little bit more, you
> are voting yes and I guess Tom\--Tom Pickering\--is voting yes based
> only on the data from within this trial, or are you drawing on other
> things that you think you know about the relative efficacy of the two
> regimens?
>
> DR. PICKERING: This trial.
>
> DR. NISSEN: This trial in this very narrowly defined population.
>
> DR. BORER: Alan?
>
> DR. HIRSCH: It is interesting how we split on this one. I will vote no
> on this comparison for a series of reasons we have been over. I don\'t
> think that we quite have the robustness in the single trial
> demonstrating superiority. I have some doubt regarding the impact of
> the atenolol comparator. Back to the fairness doctrine, I am not quite
> sure that I am comfortable that we have a completely fair comparison
> across dose range, although on a real-life level it may not be
> practical.
>
> DR. BORER: Beverly?
>
> DR. LORELL: For number five I will vote no for the reasons already
> stated.
>
> DR. BORER: I vote no as well for exactly the reasons that Tom
> elucidated.
>
> DR. LINDENFELD: No as well for the same reasons.
>
> DR. ARMSTRONG: No.
>
> DR. CUNNINGHAM: No.
>
> DR. ARTMAN: No.
>
> DR. BORER: Given that, I don\'t think we actually have to go on to
> 5.1, 5.2. So, let\'s go to six. The sponsor has presented analyses
> looking at the comparative effects of the two drugs in a number of
> demographic subgroups. None of these analyses was allocated alpha as
> part of the statistical plan. We need to give an opinion on the record
> for the following portion of this question, do any of these analyses
> meet the standard for robustness of clinical data sufficient to
> support the description of the effects of losartan in the population?
> If so, please identify that population or populations. We need some
> statement on this. Mike, why don\'t we start on your side this time?
>
> DR. ARTMAN: Why don\'t we start on that side because I am still
> digesting the question?
>
> DR. BORER: Okay, let\'s start with Tom who is our committee reviewer?
>
> DR. FLEMING: Well, I assume when we are saying here do any of these
> meet the standard for robustness of clinical data sufficient to
> support the description, it really means do we believe that these are
> sufficiently well established that we need to include in the label an
> indication that these subgroup effects indicated a level of effect
> modification that we think is very likely not attributable to chance
> alone. Is that a fair summary?
>
> That being the case, I am of the perspective that I would say no for
> all four of these. I would acknowledge what has been said by many thus
> far, that is, in reality it is probably true that treatment effects do
> vary by characteristics of participants. The challenge is that we are
> generally just barely able to understand what the global effect is and
> unless there are very compelling effect modifications, which is a
> matter of strength of evidence, external validation and biological
> plausibility\--it sounds like you wanted to comment.
>
> DR. THROCKMORTON: It is just that I am puzzled. The entire study was
> done\--
>
> DR. LINDENFELD: In LVH.
>
> DR. THROCKMORTON: \--in the first population. I guess I thought it
> likely that that would be one\--
>
> DR. LINDENFELD: Number 6.1 is yes.
>
> DR. THROCKMORTON: \--given the answers that I heard before I was
> expecting a yes for. Then, the question would be whether the others
> came to that same level.
>
> DR. TEMPLE: But perhaps you think it is broadly applicable.
>
> DR. FLEMING: To be frank here, I was really focusing, I apologize, on
> the second, third and fourth of these. So, indeed, I agree with you.
>
> DR. THROCKMORTON: That was not a trick. I apologize.
>
> DR. FLEMING: I am looking in particular at the gender issue, the age
> issue and the diabetes issue. In diabetes what certainly in particular
> did catch my attention was the survival interaction. Of all of these,
> the one that, in fact, approached a level of statistical evidence that
> is not readily attributed to chance alone is the mortality. But unless
> there is fairly strong biological plausibility for effect modification
> by diabetes status on mortality, mortality is not a primary endpoint
> so where I have trouble giving it particular credence is it is a
> non-specified subgroup. It is not an alpha-spending subgroup and it is
> not even on the primary endpoint.
>
> But I would think it would certainly be appropriate in the future to
> be looking for whether there would be other data that could support
> potential effect modification on the mortality endpoint for 6.4.
>
> DR. BORER: Mike?
>
> DR. ARTMAN: for 6.1 I would say yes, and for 6.2, 6.3 and 6.4 I would
> say no.
>
> DR. BORER: Susanna?
>
> DR. CUNNINGHAM: I concur.
>
> DR. BORER: Paul?
>
> DR. ARMSTRONG: I agree.
>
> DR. LINDENFELD: Agreed.
>
> DR. BORER: I would vote the same way. Beverly?
>
> DR. LORELL: Agreed.
>
> DR. HIRSCH: Agreed.
>
> DR. NISSEN: Concur.
>
> DR. PICKERING: Again, I think the benefit seemed to be largely
> confined to the elderly so I was impressed by the isolated systolic
> hypertension group, which was the same group where there was the
> reduction of stroke and mortality.
>
> DR. BORER: Do you think that that is sufficient to warrant a
> description in a label for this combination for this drug?
>
> DR. PICKERING: I guess I would say yes.
>
> DR. BORER: Those are the components of the questions for which we
> needed individual answers. Let\'s go on to number seven, the FDA has
> identified an association between atenolol use, atrial fibrillation
> and stroke. Does this analysis, combined with other available data,
> meet the standard for robustness of clinical data sufficient to
> support a description of these effects? If so, where?
>
> I am going to suggest the answer is no. Does anybody have any
> disagreement with that? If not, then let\'s move on. I am sorry, Tom?
>
> DR. FLEMING: I do but, Bob, go ahead.
>
> DR. TEMPLE: I just wanted to compliment the reviewer, Dr. Marciniak,
> for noticing it. Even if we ultimately don\'t conclude that it is
> real, it just shows the value of a careful review.
>
> DR. BORER: My suggested answer is not meant to indicate that I think
> it is not real, just that it isn\'t sufficiently robust for us to
> warrant a description at this point. That is all.
>
> DR. TEMPLE: I understand.
>
> DR. HIRSCH: I would like to opine on that as well. I think that I
> would vote no but I think it is worth looking for a future generating
> hypothesis. It is important.
>
> DR. FLEMING: I actually spent a fair amount of time thinking about
> this and let me just try to summarize fairly concisely what that
> thinking is and it largely comes up with the same conclusions others
> have said.
>
> There are three or four specific issues that are arise here. One, is
> atrial fibrillation associated with increased risk of stroke? Yes, it
> is. That is very apparent. It is roughly three- to four-fold higher
> risk. Hence, it becomes very relevant to ask the question, as the FDA
> reviewer had asked.
>
> The second question, does treatment induce a change in atrial
> fibrillation? Well, there is certainly some evidence that the rate is
> higher on atenolol. Depending on which definition you are using, it is
> about an 8 percent versus 6.8 percent rate. Does treatment cause a
> change in stroke? Yes, it does.
>
> Now, ultimately the question is, is treatment\'s effect on stroke in
> part mediated through this differential effect on atrial fibrillation?
> Essentially, what I had done was to look at Table 48, which is from
> the FDA reviewer, on page 68. We see some of those things that I had
> just mentioned. That is, the rate of stroke is much higher in those
> with atrial fibrillation, but also the higher rate of stroke on
> atenolol versus losartan is more evident in those with atrial
> fibrillation.
>
> So, one can essentially try to get some sense of how much of this
> difference in stroke could be mediated through a differential effect
> on atrial fibrillation by recognizing that if the increase in stroke
> rate is about 25 percent going from losartan to atenolol in the
> non-atrial fibrillation group and about 50 percent in the atrial
> fibrillation group, then the fraction of patients who are more likely
> to have atrial fibrillation will then have an increase that will be
> induced both by having a larger fraction in the atrial fibrillation
> group and a larger fraction of stroke rate within the atrial
> fibrillation group.
>
> Without going through all the calculations, I did a crude
> approximation that said, under that assumption, about 20 percent to 25
> percent of the total effect of losartan over atenolol on stroke could
> be attributed to atrial fibrillation, but what I would really like to
> do is see a time-varying covariate analysis, which the sponsor did and
> came up with almost exactly the same answer in a more sophisticated
> analysis.
>
> That doesn\'t mean specifically that a quarter of the overall
> difference in stroke is specifically mediated through this lower level
> of atrial fibrillation, but it is suggestive that whatever it is that
> characterizes patients being different when they have atrial
> fibrillation that global mechanism could, in fact, be accounting for
> 25 percent.
>
> So, in a crude way trying to put pieces together here, we see a 25
> percent reduction in stroke on losartan versus atenolol. Of that 25
> percent reduction, maybe a quarter of it seems to be attributable to a
> difference in blood pressure. Maybe a quarter of it seems to be
> attributable to this difference in atrial fibrillation and the other
> half of it we still haven\'t figured out. And, all of those are still
> very crude calculations.
>
> The bottom line, having said all that, is in any way this isn\'t proof
> that these are the mechanisms by which these differences have
> occurred. So, I would agree that there wouldn\'t need to be any
> specific indication of this.
>
> DR. BORER: Alan, did you have a comment?
>
> DR. HIRSCH: This harkens back to the first part of the discussion when
> we asked was blood pressure really the key here. I think we have to
> circle back before we write a label, which is to say that if we are
> looking at an endpoint as important as stroke reduction and we are
> impugning that this is an aid to an ARB-mediated effect by blocking
> angiotensin effects, we will all go down the pathway of assuming there
> is some biologic effect on blood vessels unless we design trials to
> look at the multiplicity of mechanisms that create stroke. So, though
> we cannot answer the question from this single trial alone, I think it
> has real ramifications for future trials that I am sure we are going
> to see of this design to look at head-to-head comparisons. So, this is
> I think potentially a major point for future trial design.
>
> DR. BORER: Paul?
>
> DR. ARMSTRONG: Well, because it may be helpful to the agency, for the
> record I think the issues around withdrawal of therapy and the run-in
> period, which I tried to get at this morning which we really can\'t
> get at, are critical in terms of the potential first component of the
> bimodal distribution of atrial fib., with the second component being
> in the termination and the strategy with which withdrawal was
> accomplished I think is important if one is going to go after that.
>
> The second issue I think is that much of the atrial fib. was
> investigator determined, which is probably patient driven, which is
> probably, in the absence of beta-blocker, patient perception of atrial
> fibrillation, and we are uncertain about the role of perception versus
> reality with and without beta-blockers. So, there are several issues
> here of potential important for future study, just to put on the
> record.
>
> DR. BORER: Let\'s move on to the final question\--
>
> DR. THROCKMORTON: Sorry, Jeff, if we are done voting on this one I
> wanted to pick up on something Paul just said where you could give a
> little bit more help to us. This did have a run-in period and then a
> long-term comparison of two regimens. I wonder if anyone wanted to
> comment on whether that run-in period\--how critical was it to have
> that run-in period? How critical, in fact, was it to demonstrate that
> people had some level of hypertension over whatever period of time
> that was prior to randomization? Or, if this trial, like ALLHAT for
> instance which had no run-in period and patients were randomized
> directly, as I recall\--would that affect your interpretation of these
> results in a substantive way?
>
> DR. BORER: In terms of the atrial fibrillation issue?
>
> DR. THROCKMORTON: No, in terms of overall trial design.
>
> DR. BORER: Well, I will give you my opinion and everybody else can
> chime in. You know, it seems to me that if you are going to be
> treating people for high blood pressure, to reduce their blood
> pressure from a hypertensive level you have to have some evidence they
> were hypertensive in the first place. While there may have been superb
> documentation that that was true in many of these patients, I can\'t
> believe it was true in all 10,000 or perhaps even in a large portion
> of them.
>
> DR. THROCKMORTON: I think we had information that the sponsor
> presented that it was true in\--I don\'t know\--1000 out of 10,000
> that had blood pressures going too high or too low.
>
> DR. BORER: No, no that is not what I meant. What I meant was that
> before the drugs were taken away the only way you knew that the people
> were hypertensive was that they had a history of hypertension. There
> was no clear documentation, nor was there documentation of the
> severity which was, of course, an exclusion and inclusion factor. So,
> you know, I think it is important to document what it is you are
> giving drugs for before you give the drugs in a trial. Paul?
>
> DR. ARMSTRONG: I think it gives you insight into the heterogeneity of
> the population that was under study. There 1500 patients that didn\'t
> make it to the starting gate but were potentially screened and in the
> run-in period. Just as you have said, although we don\'t yet have the
> details and, it would be helpful if they are available, to get them,
> how many, in fact, had blood pressures that were too high? How many
> did not have hypertension that was of interest to the study? To me,
> that is a very germane point.
>
> DR. BORER: Beverly?
>
> DR. LORELL: I think that another difficult point, and I think the
> sponsor was asked and responded in detail that the data really wasn\'t
> there, but I think in planning trials it might be helpful, in
> informing the FDA about trial design, to have more data about adverse
> events that occur with drug withdrawal. I think all of us nervous
> about beta-blocker withdrawal in this trial. Those data are not
> traditionally either rigorously collected, nor are they paid for in
> terms of normal reimbursement for inclusions of subjects. So, that
> would be the kind of thing I might be worthy to think about
> prospectively.
>
> DR. BORER: Alan?
>
> DR. HIRSCH: Well, as long as you asked, since we are going to be asked
> to give opinions regarding the potential pleiotropic effects of blood
> pressure lowering drugs, this focus on the delta, whether it is 0.5 mm
> Hg, 1.0 mm Hg, 2.0 mm Hg is going to become increasingly important
> because there probably is both the traditional blood pressure effect
> as well direct vascular effects of these agents, and I think it is
> important to get this quality data at the beginning.
>
> DR. BORER: Steve?
>
> DR. NISSEN: Yes, I can\'t let that go unchallenged, Alan. I just find
> it absolutely not compelling that there is a mechanistic explanation
> for this, particularly in light of the ALLHAT data where a very
> similar drug that works through the renin angiotensin system was
> distinctly inferior to both diuretics and amlodipine in stroke
> reduction. You know, I have heard enough about angiotensin II being
> the Darth Vader of the cardiovascular system and I am tired of it. I
> don\'t think there is evidence for it, and you can scream and yell all
> you want about mechanism here but until somebody shows me robust
> evidence that drugs that work through the renin angiotensin system are
> superior at reducing any endpoint in prevention I am not convinced.
>
> DR. THROCKMORTON: Steve, what would robust data mean for you there?
> The sponsor and I think Tom laid out a bit earlier, and you can sort
> of think of lots of ways that blood pressure could vary between the
> two groups. You can think of it over time and you can think of it
> within day and just at the end of the trial. How many ways would you
> have a sponsor assess comparative antihypertensive efficacy to
> convince you that there was an effect above and beyond the effect of a
> given drug on blood pressure?
>
> DR. NISSEN: I was actually responding to something a little bit
> different. I guess I was responding to the issue about whether or not
> there is something we know about the mechanism of action of drugs that
> work through the renin angiotensin system that makes them particularly
> desirable. I mean, that was one of the principal questions underlying
> the ALLHAT trial, and it was one of the real failures, the failure of
> an ACE-based regimen to prove to be superior. So, it is troubling me
> because if you poll physicians, physicians have all bought this
> pleiotropic argument. If you ask everybody what was going to happen in
> ALLHAT, they all said, oh, the ACE inhibitor is going to win. Well, it
> didn\'t win; it came in third.
>
> DR. FLEMING: Steve, listening to you, could you remind me how did you
> vote for question number five?
>
> \[Laughter\]
>
> DR. NISSEN: Because, you know, the question was asked compared to an
> atenolol-based regimen was there, in fact, superiority for losartan?
> The answer is yes. What wasn\'t tested, however, were the other two
> agents, the agents which are much more likely to be used in this
> population which are diuretics and/or amlodipine.
>
> DR. FLEMING: But in a sense it doesn\'t matter too critically what
> that control is when now we are talking about is it superior to the
> control. We are using the data from the LIFE study and what I am
> hearing from you is a reason for some caution as to the biological
> plausibility that an ARB is going to be superior in clinical
> endpoints, particularly when there is no difference in blood pressure
> control. That is the sense I am getting, that at least we should be
> cautious. I understand that and I am thinking doesn\'t that, in fact,
> give you more reason for being cautious and saying five is a
> compellingly positive study that establishes superiority?
>
> DR. NISSEN: Superiority to something else. I mean, superiority is
> always made in context of something else. I wish this trial had been
> designed differently. I wish that atenolol was not the comparator. On
> the other hand, somebody spent a lot of time, energy and money to do
> this comparison and they ended up with a p value with two zeros in
> front of the one comparing these two regimens with respect to stroke
> and I think that ought to be described in the label and I wrote
> something to that effect. But I also wrote in there that it does not
> apply to comparisons of other agents because it isn\'t going to change
> my mind. I am not going to prescribe losartan as the first-line agent
> for prevention of stroke based upon the LIFE trial because they
> didn\'t compare against the agents that we all think are probably the
> most effective agents at stroke prevention.
>
> DR. BORER: You know, in all fairness though, we are not being asked to
> select the first-line agent for stroke prevention. That is a
> guidelines issue. We are just being asked to say whether we think this
> regimen works better than not giving something. I think that what we
> have said is, yes, it works better than not giving something. Beyond
> that, I think the consensus here has been we really don\'t want to go
> although you have suggested that perhaps we should be a little bit
> more descriptive.
>
> DR. HIRSCH: Just one more point. I think what you have said, Steve, is
> that you don\'t believe this pleiotropic effect and I think we are in
> a stage where all history in pharmaceutical trials in blood pressure
> lowering has not ended with ALLHAT or LIFE. We have ambiguous signals
> and I think what we have struggled with today is the ambiguity. So, I
> would like to leave sponsors in the future and other investigators
> with that ambiguity so that additional data can come forth to the
> committee.
>
> DR. TEMPLE: And the good news is they all do pretty well and you can
> treat people for \$10.00 a year. I wanted to go back to what Doug
> asked because sometimes we are asked this. He asked about how
> important you think the washout period is. The purpose of the washout
> in this case is really solely to see what their baseline blood
> pressure is. In this case, as it always does in very large studies,
> baseline blood pressures were virtually identical and it doesn\'t
> really help you much to have known that, except you are reassured that
> they are all hypertensive.
>
> Since we are going to get asked this sometimes, how much do you
> actually care about knowing that, first, in a non-inferiority study
> where you answer should be you care a lot and, second, in a
> superiority study where that doesn\'t seem so clear? Anybody want to
> briefly comment on that? I know it is late.
>
> DR. BORER: For all the reasons you have heard in answer to that
> question the first time it was asked, I think it is important to
> characterize the patients even for a superiority study.
>
> DR. TEMPLE: So you know who it applies to.
>
> DR. BORER: That is right, exactly. I mean, I could go on and on about
> this but I think that reason alone should be sufficient.
>
> Let\'s go on to number eight which is our final question and probably
> will generate some discussion here. You have heard a discussion of
> qualitative and quantitative interactions among subgroups. For one
> relevant subgroup, African-Americans in the United States, atenolol is
> apparently superior to losartan in its effects on the primary
> endpoint. Maybe. No biologic rationale for this apparent qualitative
> interaction with race has been identified by the FDA or the sponsor.
> Does the lack of this rationale matter to you? Then there are several
> other questions which we will get to.
>
> I would like to begin here by saying I find the statement that there
> is a lack of rationale in one sense perhaps irrelevant and in another
> sense perhaps not exactly a fair statement. I didn\'t hear any
> description of renin sodium profiles or renin levels measured any hway
> in either of these subpopulations. I understand the label for losartan
> says it is reasonably well accepted from a great deal of information
> that has been published that black people who are hypertensive more
> commonly have volume-dependent than renin-dependent mechanisms than
> would be true in a white population. Here, we are giving a drug that
> is specifically aimed at the renin-dependent mechanisms of
> hypertension.
>
> So, you know, I don\'t think it is fair to say there is lack of a
> rationale. On the other hand, I am not sure that it matters. We made
> an observation here and it is a pretty potent observation. As I have
> said before at these meetings, I am not sure exactly how any drug
> works. I know there are pharmacological effects but I don\'t know how
> those translate into clinical benefits. So, I am not sure it is
> terribly important.
>
> DR. TEMPLE: Just one observation. It is true for all renin intervening
> drugs, including beta-blockers for sure. None of them work very well
> alone in blacks. It is also true that when you add a diuretic the
> total blood pressure lowering of the combination is very similar in
> all races. So, I don\'t know what to make of that, except the diuretic
> makes you renin-dependent again, or something.
>
> DR. BORER: Whatever\--
>
> DR. TEMPLE: That is fair, we don\'t have to understand it. We hardly
> ever do.
>
> DR. BORER: But having said that, there are important parts of this
> question that I think we have to get to and I would like to generate
> some discussion before we close. Are there other data you feel
> illuminate the observed differences? Do you find this outcome
> surprising? Let\'s move beyond that\--
>
> DR. FLEMING: Well, before we do, before getting beyond 8.1 and 8.2 I
> would like to expand a bit more on 8.1 and 8.2 and, in fact, maybe
> mention up front that we have appropriately congratulated the sponsor
> on the conduct of a very important and informative trial, and we have
> appropriately congratulated and thanked the medical reviewer from FDA
> for an extremely informative summary. I would also like to thank the
> FDA statistical reviewer for providing a lot of insights which were
> the very issues I would have wanted to have better understood to
> answer this question.
>
> As I see it, when I look at subgroup analyses, effect modification\--I
> have probably already mentioned this, I really believe there are at
> least three factors to carefully consider. One is what is the strength
> of evidence in these data for effect modification? The second is, is
> it biologically plausible that there would be effect modification?
> Thirdly, is there independent confirmation?
>
> On that first point, strength of evidence, I found it very informative
> that in the FDA statistical review what was pointed out was that it is
> not uncommon in the context of seeing globally a 13 percent reduction
> in relative risk in the entire group that in a subgroup that would be
> fairly small in size for you to see by chance alone lack of any effect
> in that subgroup. In fact, as the statistical reviewer appropriately
> pointed out, it was a 28 percent chance. That goes up to a 37 percent
> chance when you take into account the fact that you have a lot of
> different covariates that are used for subgroup analyses. It is
> something that we need to be reminded about. That is, if we are seeing
> effects that are 13 percent reduction in relative risk and we allow
> ourselves to slice and dice the data in many ways in subgroups, by
> chance alone you are going to find some subgroups that don\'t show any
> effect.
>
> So, that in itself wouldn\'t constitute evidence that I would consider
> at all statistically strong evidence for effect modification. But as
> his review pointed out, this is more than that. This is a situation
> where there is a qualitative interaction of such a level that in the
> black subgroup the confidence interval is excluding equality. So, it
> is a very strong difference. His summary here provides a sense that it
> is something that would occur 0.003 in a fairly uncommon way.
>
> With the insight from his analysis, I would say, first of all, this is
> fairly strong evidence but it is not in its own right, I would say,
> sufficient to say it is conclusive. So, I go to the issue of
> biological plausibility and it is relevant from my perspective. I have
> always said, you know, show effect modification to a clinical and they
> will come up with an explanation for why there is effect modification.
> I always say I an complimenting my clinical colleagues because their
> knowledge is so broad they are always going to be able to come up with
> some way\--
>
> DR. TEMPLE: In either direction.
>
> DR. FLEMING: In either direction. So, one has to be somewhat cautious.
> But what you are saying, Jeff, to me is relevant and if there is, in
> fact, rational plausibility to blacks being less likely to have a
> renin response or other rationale, that is certainly relevant in
> weighing this out. But ultimately as well what is very relevant is, is
> this a pattern that has been seen frequently? I haven\'t been keeping
> score but my sense has been, in my years on this committee, that there
> have been a number of instances now, more so than what just seemed to
> be a chance alone event, where blacks have had much less or very
> different effects than what the aggregate study has shown. In fact, I
> think it has also been interesting to see that U.S. populations show
> less effect but those may be related points, and in fact it seems to
> be in this study, the fact that U.S. results were less favorable and
> the global results were entirely driven by the blacks within the U.S.
> because the whites within the U.S. actually had a very robust effect.
> But also the other studies, the SOLVD, what was already known about
> losartan in hypertension, all of these factors, to my way of thinking,
> now create much more of a sense, and this is what is in 8.2, there
> does seem to be a sufficient amount of additional data that, with the
> strength of evidence just from this study alone and this repeated
> pattern in other studies, does give me a sense that there is something
> here that is very plausibly effect modification and I would be very
> interested in hearing from other committee members as to their sense
> about independent external data and what their sense is of how
> strongly this would be reinforcing.
>
> DR. BORER: I would like to focus this discussion on what Tom said,
> that is, the data rather than biological plausibility because renin
> angiotensin system activity in some populations notwithstanding, I
> must say again that it would be probably naive to suggest that the
> only pharmacological effect of an ARB is to block the angiotensin
> receptor. I am sure that there are multiple other pharmacological
> effects that we haven\'t even identified yet. So, I don\'t think we
> can really deal with the biological plausibility, but the issue of
> whether we are seeing a pattern here so that we should really take
> this seriously\--if anybody wants to comment on that beyond what Tom
> has said? Steve?
>
> DR. NISSEN: Well, it is particularly troubling when you look at the
> ALLHAT data, which I know we haven\'t reviewed yet, but you see the
> same signal. I think you see it, you know, in all kinds of other data.
> So, I think that drugs that work via the renin angiotensin system
> appear not to work as well in African Americans, blacks as they do in
> whites and this difference is really robust. Just as I was willing to
> give the sponsor the benefit of the doubt with an 0.001 p value for
> benefit in the overall population, I think the same should be said for
> inferiority, if you will, in the African American population and I do
> think it ought to be in the label. Certainly if you give them the
> plus, you have to give them the minus.
>
> I think the prescribing physician has to be told about this just to
> amplify. You know, in this trial it was a small group of people but in
> the U.S. the number of African Americans with hypertension is not
> small. They are actually over-represented. What I worry the most about
> in whatever you do here is that it is very hard to get negative
> messages to the prescribing physicians, and the reason is that
> pharmaceutical detail people don\'t emphasize the negative messages.
> They are not going to come in and say, \"now, be sure you don\'t give
> this drug to African Americans.\" So, when you give a positive label,
> you know, there is going to be some leakage here and I think it is not
> 12 percent, it is more like 20 percent of the U.S. hypertension
> population that is African American. They are tough to control. I
> don\'t know whether the drug is actually worse than placebo here. I
> have no way of knowing that. What I sure know is that there is a very,
> very large disparity and it worries me, and I think it has to be in
> the label and has to be emphasized in public education.
>
> DR. BORER: I just want to point out that Steve answered another part
> of 8.3 that I would suggest that we accept as our answer, unless
> anybody disagrees with it, which is 8.3.5, \"cannot tell\" because we
> don\'t know whether L is greater than or less than or equal to imputed
> placebo.
>
> DR. THROCKMORTON: Sorry, just to break in there, Jeff, if someone has
> a strong feeling about that it would be very useful for us to hear.
> Part of the questions at the beginning of the disease and part of the
> discussion about beta-blockers relative to placebo, and things, were
> to either provide comfort or not. If you conclude that, in fact,
> losartan is inferior in some population to atenolol, are you concerned
> to any substantive extent that it is less than placebo?
>
> DR. BORER: Tom?
>
> DR. PICKERING: Yes, I was impressed by the FDA analysis this afternoon
> that there is a significant difference between the blacks and the
> whites. I don\'t think one can say that losartan was harmful.
>
> The other thing is I don\'t think you can explain it by differences in
> blood pressure, from what we heard, which were relatively minor. So,
> this may be another example of a blood pressure independent difference
> going in the other way, so to speak.
>
> DR. BORER: Are you ready to answer the next point?
>
> DR. PICKERING: I am not sure which.
>
> DR. BORER: He is saying that he believes that this is a real effect
> and he is not sure that losartan can be said to be harmful. I would
> guess that you really can\'t say anything about the relation of
> losartan to imputed placebo given that.
>
> DR. HIRSCH: It is not a matter of harmful; it is just relative order
> of efficacy here.
>
> DR. LORELL: I think one of the challenges for the FDA, and I am glad I
> don\'t have to do it, is how to correctly word a message that in this
> trial for black Americans losartan was inferior to atenolol and
> whether you have to address issues beyond stroke. Because I think one
> of the concerns in the data that we were presented from the FDA is
> that there is a consistency on every measure including cardiovascular
> mortality, MI and even total mortality. So, it is an odd conundrum to
> be in; you might need to say more about black Americans than you
> needed to say in terms of the overall labeling.
>
> DR. BORER: Can we make a clear statement about this? The FDA medical
> reviewer concluded that the data suggesting that there is a difference
> between the atenolol regimen and losartan regimen did not reach the
> level of robustness that would allow you to say that losartan was
> harmful, which would mean losartan is worse than placebo, but it does
> look as if losartan is less good than atenolol. Do we all agree with
> that?
>
> DR. FLEMING: Well, I am really uncertain. What I do feel very
> confident about is that something needs to be said because there is
> considerable evidence here that there is effect modification by race.
> I think where we are here is that we believe there is evidence in the
> global data set that losartan has efficacy. There are differences in
> opinion on the committee as to whether it is superior to atenolol.
> Certainly, I would feel extremely uncomfortable for the impression to
> be given that in blacks losartan is superior to atenolol. My own sense
> is I don\'t know whether it is truly inferior. The confidence interval
> says it is inferior but that is truly data dredging to say that that
> confidence interval that indicates that atenolol is superior to
> losartan in blacks is in any way reliable for inferiority against
> atenolol but it surely is, from my perspective, very strong evidence
> against superiority of losartan in that population. I am left more
> with \"the can\'t tell.\" I would actually encourage FDA, that is in a
> position to really see globally what is happening in a lot of very
> relevant studies, to look at this.
>
> To come back to what I said before, I see three very relevant elements
> here. One is what we know from this trial; another is plausibility;
> and, thirdly, relevant external data and there is a lot of it that
> could be very helpful and it is what is persuading me, and I am
> hearing reinforcement of that from my clinical colleagues, is
> substantial. I would at this point really wish to see much more
> clearly what an analysis would show from relevant agents, and agents
> in similar classes to losartan to come up with a better sense of the
> manner in which race is an effect modifier before at least I would be
> comfortable drawing a conclusion about whether it is harmful. I don\'t
> know. I am not saying I believe these data establish that losartan is
> harmful in blacks, but it surely leaves me completely uncertain about
> its benefit and I think, as Steve said\--I think it was Steve that
> said it, this label has to make it very clear, as a result, that these
> conclusions about efficacy shouldn\'t be extrapolated to conclusions
> within blacks until we know a lot more.
>
> DR. LORELL: Tom, may I ask you a question? From the data, and
> understanding this has to be read by real-world patients and doctors,
> would you be comfortable with language emphasizing that there is lack
> of superiority and maybe inferior?
>
> DR. FLEMING: Well, I would like to get some insight from all of you.
> You are getting at an important issue, which is question 8.4. When I
> looked at 8.4 I ruled out the first and last options. I didn\'t feel
> the results were so strongly negative that there should be a
> contraindication, although I am leaning toward the warning. I think
> the sponsor had taken the third option. They were talking about a
> description in the clinical trials section. Contraindication to the
> use of losartan, to my way of thinking, would be justified if we had
> concluded that there was something bad about its use in that
> population. My own sense about this is that there is enough evidence
> here to suggest that there is substantial uncertainty and, certainly,
> I believe we shouldn\'t come away with the conclusion that the results
> of efficacy in the global population would be attributed to the black
> subgroup.
>
> So, either the warning or the description, but I was inclined to think
> in terms of the warning as being necessary to make sure that this was
> clearly understood.
>
> DR. HIRSCH: Could I jump in here and emphasize one more point? What is
> so wonderful about LIFE is that we are measuring hard outcomes in a
> prospective clinical trial. This is different from what we had,
> differences in effects of ARBs and ACE inhibitors on blood pressure
> responsiveness and surrogate endpoints that didn\'t respond quite as
> well. So, to me, I find it relatively unnerving that, you are right,
> from the robustness of the data we don\'t really know if there is lack
> of superiority, inferiority or harm. But not knowing and having so
> many signals going in the wrong direction I think should really give
> us caution. We see hepatotoxicity at a small rate that doesn\'t quite
> achieve significance, and that gets back to our responsibility for
> including enough individuals who are African Americans or blacks to
> finally answer these questions, especially now when we are measuring
> hard endpoints. So, I am leaning towards the precaution or warning
> and, again, it has implications for future trials since we have a
> first early signal.
>
> DR. BORER: Bob?
>
> DR. TEMPLE: We have confronted subgroups with uncertain results on
> other occasions. You may remember that in MERIT, where we could think
> of no conceivable rationale for the failure of the U.S. population to
> have a survival benefit we, nonetheless, included wording and took a
> lot of stuff for it internationally, but made it clear that the
> apparent lack of benefit was not a sure thing; that sometimes things
> work out when you look at subgroups; and presumably would say
> something similar to that here although I hear a higher level of
> concern here than I did in MERIT because at least in MERIT the major
> endpoint went the right way even if mortality didn\'t.
>
> DR. BORER: Yes, this wasn\'t a lack of benefit; this was a clear
> distinction in the direction of effect of the comparators.
>
> DR. FLEMING: Not too surprisingly, stroke and the composite show
> exactly the same pattern.
>
> DR. LINDENFELD: Could I just suggest a choice that is not in here? I
> think what we are all concerned about is that physicians understand
> that there is this real concern about black patients. I wonder if that
> couldn\'t just be in the approval, in non-black patients. Then you can
> discuss the results but, rather than putting it back in a warning
> section, is there anything wrong with the indication for this being in
> non-black patients for a regimen of losartan\--would anyone have any
> objections to that?
>
> DR. TEMPLE: Are you distinguishing between use of the drug or who this
> study result applies to?
>
> DR. LINDENFELD: Who this study result applies to.
>
> DR. TEMPLE: It would be hard to think that one say on the basis of
> this you mustn\'t ever use this drug in black patients.
>
> DR. LINDENFELD: No, no, I wouldn\'t say you mustn\'t use it; I would
> say who you should use it in. There is a difference.
>
> DR. TEMPLE: Again, are you saying about use of the drug altogether or
> who the outcome data apply to?
>
> DR. LINDENFELD: Who the outcome data apply to.
>
> DR. TEMPLE: That is what I hear everybody saying, that there ought to
> be some clear reference to this in some part of the label, to be
> figured out which part.
>
> DR. LINDENFELD: But I understand you could have it right up front in
> the initial indication.
>
> DR. THROCKMORTON: But that is a step beyond what Tom was saying. Tom
> was saying he is not sure you can say it is worse than atenolol. You
> are saying you can\'t tell it is better than nothing. Is that correct?
>
> DR. LINDENFELD: That is correct.
>
> DR. TEMPLE: There is no question from everything you have said that
> you think the observation ought to be clearly described in the
> clinical trial section. That, of course, means no one will notice it.
> So, there is some feeling for putting it somewhere else. I have heard
> one suggestion that it actually ought to be part of the indications to
> the extent that the indication refers to outcome data. That is one
> possibility. The other, perhaps is a warning or precaution. I must
> say, it feels more like a precaution to me given our uncertainty, but
> whatever. So, those are two possible choices. I take it you don\'t
> think putting it just in the clinical trials is noticeable enough.
> Would that be a true statement?
>
> DR. HIRSCH: Precaution is more like it. I think, again, where this
> precaution warning comes from a little bit is the history we have been
> trying to do for the last ten or twenty years, which is to elucidate
> the LVH and hypertension in African Americans in particular as a
> reason to treat because of the high risk of stroke. So, we have been
> teaching physicians to have a reflex, to notice this and to treat but
> this may not be the first choice. So, I think it is a precaution or
> warning.
>
> DR. BORER: Can I ask, just to sort of bring this to some closure, for
> an opinion from each of the members of the committee about how this
> finding should be described, whether it should be a contraindication,
> a warning, a precaution, some statement in the indication as JoAnn has
> suggested, one or the other, a description of the clinical trials, or
> forget about it? John?
>
> DR. NEYLAN: So, this is a non-voting issue?
>
> DR. BORER: Well, there is no binding vote here. We are giving advice
> to the FDA.
>
> DR. NEYLAN: Okay. My feeling would be that this would be very useful
> information to the prescribing physician and that information might
> get lost somewhat if it was merely put in the description of the
> clinical trial. I favor the use of non-black in description of the
> changed indication and also a precaution, rather than a warning,
> further detailing this effect.
>
> DR. BORER: Tom?
>
> DR. PICKERING: I don\'t think it should be a contraindication. There
> are a lot of black patients, particularly with diabetes, who need
> multiple drugs and this could certainly be one of them. I do think
> there should be some warning or precaution, I don\'t know the
> difference, about the effects not being demonstrated in black
> patients.
>
> DR. BORER: Steve?
>
> DR. NISSEN: I am little bit of the odd man out here because I would
> not have commented on the LIFE trial in the indications section at
> all. I would put the entire description of the trial in the clinical
> trials section because I think that is about all the conclusion I can
> come to. I would describe what happened, and I have written something
> and we are not going to get to it and that is fine, which describes
> the population that was studied and what was found and also describes
> the finding in the black population, a simple, fair description of
> what LIFE showed. I also added the comment that the comparative
> efficacy of losartan in other populations, in comparison to other
> antihypertensive agents, has not been tested, as a way of letting
> physicians know that this is really only a trial in which atenolol was
> compared.
>
> That is why, Tom, I voted the way I did. I felt that there wasn\'t
> enough information to give a general indication for the use of
> losartan but only a comparative indication in comparison to an agent
> which I happen to think is a relatively weak agent, but an agent
> nonetheless. In addition, I would say something in the warning section
> as well about the African American population, and I would do that in
> part because in America hypertension is not, you know, some small,
> isolated, unimportant group. Those of us who treat patients know that
> these are very large numbers of African Americans with hypertension.
> They can be difficult to treat. And, I think the physician needs to
> know as much as they can about what works and what doesn\'t work, and
> I think there is a pretty strong suggestion here that agents that work
> through the renin angiotensin system, not just in this trial but in
> others, don\'t work very well in African Americans and I want my
> colleagues to know that so that they will choose other regimens
> preferentially in such patients.
>
> So, my advice to the agency is to describe LIFE in the clinical trials
> section, not in the indications section. Describe it in a fair and
> balance way, and I have written something which you can look at later
> if you are interested. But then also to put that warning in there. I
> think we have done due diligence and we have given the sponsor, you
> know, what they have earned here, which is I think they beat atenolol
> and I am willing to give them that. I am just not willing to say that
> this is the way to reduce stroke because I don\'t know if losartan is
> the best way to reduce stroke.
>
> DR. BORER: Alan?
>
> DR. HIRSCH: Well, this should not be in the indications section. All
> patients of any ethnicity, race or gender should have access to the
> agents they require based on their particular clinical
> characteristics. I think precaution is appropriate. I would like to
> again sort of give kudos to both the sponsor and the FDA reviewer for
> pointing out the data so clearly.
>
> DR. BORER: Beverly?
>
> DR. LORELL: I agree with a precaution.
>
> DR. BORER: Tom, did you want to say anything else? No? Mike?
>
> DR. ARTMAN: Yes, I think rather than just a precaution, it should be a
> warning. I think it needs to be clearly stated.
>
> DR. BORER: Susanna?
>
> DR. CUNNINGHAM: I would prefer either a warning or precaution.
>
> DR. ARMSTRONG: Precaution.
>
> DR. BORER: JoAnn, do you want to add anything?
>
> DR. LINDENFELD: No, I still like the population that benefited in the
> indications because I think then people have to see it when they are
> presented with the data.
>
> DR. BORER: I voted that this drug should receive in indication
> paralleling the indication that was requested, with some modifications
> that are all in the record. I am not going to rescind that opinion; I
> believe that that is correct. But if I believe that, then something
> has to be said that clearly demarcates the potential lack of efficacy
> in this population. So, I would favor a precaution in bold black
> letters somewhere in the label, and I would think about, although I am
> not sure without having the time to do some word-smithing how to do
> this, if it actually even doable, the additional solution that JoAnn
> has suggested, which is describing the population for which the drug
> applies to the new indication very narrowly. I am not sure that that
> is a practical solution but I think that is something to consider in
> addition to a precaution.
>
> I think we have covered all the items on the set of questions here. I
> think, in summary, the consensus of the committee has been that the
> evidence that is presented is sufficient as stated in number four,
> with all the caveats that we all gave. The strength of evidence is
> sufficient for some new indication, appropriately circumscribed, to be
> granted in the labeling. Is there any other issue that you want us to
> raise before we adjourn?
>
> DR. TEMPLE: Thank you. This has been fascinating for all of us too.
>
> DR. BORER: Then we stand adjourned.
>
> \[Whereupon, at 5:45 p.m., the proceedings were recessed to resume at
> 8:30 a.m., Tuesday, January 7, 2003.\]

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