**Docket 77N-0094**

**Proposed Amendment to Final Rule for Professional Labeling of
Aspirin**

**Primary Prevention of Myocardial Infarction**

**in those Individuals at Sufficient Risk**

Briefing Book

**November 5, 2003**

Bayer HealthCare LLC

PO Box 1910

36 Columbia Road

Morristown, NJ 07962-1910

Table of Contents

LIST OF ABBREVIATIONS [6](#list-of-abbreviations)

executive summary [8](#executive-summary)

1 Introduction [10](#introduction)

1.1 Rationale for Approval of ASA for the Prevention of MI in Moderate
Risk Individuals
[10](#rationale-for-approval-of-asa-for-the-prevention-of-mi-in-moderate-risk-individuals)

1.2 The Role of Aspirin in Coronary Heart Disease
[14](#the-role-of-aspirin-in-coronary-heart-disease)

1.2.1 ASA's pharmacology explains its cardiovascular benefits
[14](#asas-pharmacology-explains-its-cardiovascular-benefits)

1.2.2 ASA is widely used as a safe and cost effective treatment for
cardiovascular disease prophylaxis
[15](#asa-is-widely-used-as-a-safe-and-cost-effective-treatment-for-cardiovascular-disease-prophylaxis)

1.2.3 Regulatory History of ASA [16](#regulatory-history-of-asa)

1.2.3.1 U.S. Aspirin OTC Labeling [18](#u.s.-aspirin-otc-labeling)

1.2.3.2 U.S. Aspirin Professional Labeling
[18](#u.s.-aspirin-professional-labeling)

1.2.3.3 Worldwide Approvals Overview [19](#worldwide-approvals-overview)

2 cardiovascular disease has a major Public health impact
[20](#cardiovascular-disease-has-a-major-public-health-impact)

2.1 Cardiovascular Disease is a Serious Public Health Threat
[20](#cardiovascular-disease-is-a-serious-public-health-threat)

2.2 Economic Costs of Cardiovascular Disease
[21](#economic-costs-of-cardiovascular-disease)

2.3 Cardiovascular Risk is Definable
[22](#cardiovascular-risk-is-definable)

2.3.1 Individual Risk and Global Risk Assessment
[22](#individual-risk-and-global-risk-assessment)

2.3.2 Tools and Calculators [23](#tools-and-calculators)

2.4 Cardiovascular Events are Preventable
[23](#cardiovascular-events-are-preventable)

3 efficacy: ASA prevents Mi and Cardiovascular events
[25](#efficacy-asa-prevents-mi-and-cardiovascular-events)

3.1 ASA Prevents Cardiovascular Events in Low Risk Populations
[25](#asa-prevents-cardiovascular-events-in-low-risk-populations)

3.1.1 Description of Individual Randomized Studies Supporting the
Effectiveness of ASA in the Prevention of a First MI
[27](#description-of-individual-randomized-studies-supporting-the-effectiveness-of-asa-in-the-prevention-of-a-first-mi)

3.1.1.1 Physicians' Health Study (PHS)
[27](#physicians-health-study-phs)

3.1.1.2 British Doctors' Trial (BDT) [29](#british-doctors-trial-bdt)

3.1.1.3 Thrombosis Prevention Trial (TPT)
[29](#thrombosis-prevention-trial-tpt)

3.1.1.4 Hypertension Optimal Treatment Study (HOT)
[31](#hypertension-optimal-treatment-study-hot)

3.1.1.5 Primary Prevention Project (PPP)
[33](#primary-prevention-project-ppp)

3.1.2 Meta-Analysis of Low Risk Trials
[34](#meta-analysis-of-low-risk-trials)

3.1.2.1 Meta-Analysis -- Nonfatal MI [35](#meta-analysis-nonfatal-mi)

3.1.2.2 Meta-Analysis - Any Important Vascular Event
[36](#meta-analysis---any-important-vascular-event)

3.1.2.3 Meta-Analysis: Vascular Death
[36](#meta-analysis-vascular-death)

3.1.2.4 Meta-Analysis: Stroke [36](#meta-analysis-stroke)

3.1.3 A Range of Doses Are Effective
[37](#a-range-of-doses-are-effective)

3.1.4 Relevant Subgroup Analyses [37](#relevant-subgroup-analyses)

3.1.5 Other Relevant Meta Analyses [38](#other-relevant-meta-analyses)

3.2 ASA Prevents Cardiovascular Events in High Risk Populations
[39](#asa-prevents-cardiovascular-events-in-high-risk-populations)

3.2.1 The Antithrombotic Trialists' Collaboration (ATT)
[40](#the-antithrombotic-trialists-collaboration-att)

3.2.2 Effect of ASA Dose on Vascular Events
[41](#effect-of-asa-dose-on-vascular-events)

3.2.3 Relevant Subgroup Analysis [42](#relevant-subgroup-analysis)

3.2.4 Meta-Analysis of Six High Risk Trials (Secondary Prevention
Trials)
[42](#meta-analysis-of-six-high-risk-trials-secondary-prevention-trials)

3.2.5 High Risk Patients Provide Insight Regarding Effectiveness in
Moderate Risk Populations
[43](#high-risk-patients-provide-insight-regarding-effectiveness-in-moderate-risk-populations)

3.3 ASA's Effectiveness in Preventing Cardiovascular Events Across a
Variety of Patient Populations: Conclusions
[44](#asas-effectiveness-in-preventing-cardiovascular-events-across-a-variety-of-patient-populations-conclusions)

4 safety: the evidence for ASA safety
[45](#safety-the-evidence-for-asa-safety)

4.1 4.1 Safety Profile Overview [45](#safety-profile-overview)

4.2 4.2 Mechanism Of Action [45](#mechanism-of-action)

4.3 4.3 Safety by Body System [46](#safety-by-body-system)

4.3.1 Gastrointestinal Effects [46](#gastrointestinal-effects)

4.3.1.1 Overall Rate of GI Effects [46](#overall-rate-of-gi-effects)

4.3.1.2 GI Data From Controlled Trials
[46](#gi-data-from-controlled-trials)

4.3.1.3 GI Data from Meta-Analyses [47](#gi-data-from-meta-analyses)

4.3.1.4 Labeling for GI Warnings [49](#labeling-for-gi-warnings)

4.3.2 Intracerebral Bleeding (Hemorrhagic Stroke)
[49](#intracerebral-bleeding-hemorrhagic-stroke)

4.3.2.1 Overall Rate of Intracerebral Bleeding
[49](#overall-rate-of-intracerebral-bleeding)

4.3.2.2 Intracerebral Bleeding Data from Controlled Trials
[49](#intracerebral-bleeding-data-from-controlled-trials)

4.3.2.3 Intracerebral Bleeding Data from Meta-Analyses
[50](#intracerebral-bleeding-data-from-meta-analyses)

4.3.2.4 Labeling for Intracerebral Bleeding Warnings
[51](#labeling-for-intracerebral-bleeding-warnings)

4.3.3 Renal Effects [51](#renal-effects)

4.3.3.1 Overall Rate of Renal Effects
[51](#overall-rate-of-renal-effects)

4.3.3.2 Labeling for Renal Warnings [52](#labeling-for-renal-warnings)

4.4 ASA Drug Interactions [52](#asa-drug-interactions)

4.4.1 Interactions with prescription medications
[52](#interactions-with-prescription-medications)

4.4.2 Interactions with other Analgesics
[52](#interactions-with-other-analgesics)

4.5 Post Market Surveillance [53](#post-market-surveillance)

4.5.1 Published ASA Safety Evaluations
[53](#published-asa-safety-evaluations)

4.5.2 Bayer Sponsored Post Marketing Study
[54](#bayer-sponsored-post-marketing-study)

4.5.3 Bayer Post Marketing Experience
[54](#bayer-post-marketing-experience)

4.5.4 FDA Office of Drug Safety Postmarketing Safety Review
[55](#fda-office-of-drug-safety-postmarketing-safety-review)

4.7 Conclusion [56](#conclusion)

5 patients can be identified for whom the cardiovascular benefits of
aspirin outweigh the risks
[57](#patients-can-be-identified-for-whom-the-cardiovascular-benefits-of-aspirin-outweigh-the-risks)

5.1 Overview of the Risk/Benefit Analysis
[57](#overview-of-the-riskbenefit-analysis)

5.1.1 Extrapolation to Broad Patient Groups is Appropriate
[57](#extrapolation-to-broad-patient-groups-is-appropriate)

5.1.2 Risk Assessment Can be Guided With Appropriate Tools
[59](#risk-assessment-can-be-guided-with-appropriate-tools)

5.2 The Risk-Benefit Relationship of ASA in Moderate Risk Patients
[60](#the-risk-benefit-relationship-of-asa-in-moderate-risk-patients)

5.2.1 Benefits of ASA Treatment in Moderate Risk Patients
[60](#benefits-of-asa-treatment-in-moderate-risk-patients)

5.2.2 Risks of ASA in Moderate Risk Patients
[61](#risks-of-asa-in-moderate-risk-patients)

5.2.3 The Benefit to Risk Relationship is Favorable in Moderate Risk
Patients
[61](#the-benefit-to-risk-relationship-is-favorable-in-moderate-risk-patients)

5.3 Recommendations [62](#recommendations)

5.3.1 The U.S. Preventive Services Task Force Recommendations
[62](#the-u.s.-preventive-services-task-force-recommendations)

5.3.2 The AHA Recommendations [63](#the-aha-recommendations)

5.3.3 Bayer HealthCare Recommendations
[63](#bayer-healthcare-recommendations)

5.4 Conclusions: ASA Therapy Should Be Recommended for Those Individuals
for Whom the Benefit Outweighs the Risk
[64](#conclusions-asa-therapy-should-be-recommended-for-those-individuals-for-whom-the-benefit-outweighs-the-risk)

6 Goals of Labeling ASA for Primary Prevention
[65](#goals-of-labeling-asa-for-primary-prevention)

6.1 Benefit-Risk Assessment [65](#benefit-risk-assessment)

6.2 Underutilization of Treatment [65](#underutilization-of-treatment)

7 EDUCATION [66](#education)

7.1 Patient/Consumer Education [66](#patientconsumer-education)

7.2 Physician Education [67](#physician-education)

7.3 Professional Associations [67](#professional-associations)

8 Conclusion [69](#conclusion-1)

9 List of Appendices [70](#list-of-appendices)

10 references [71](#references)

Table of Tables

[Table 1: Relative Risk Reductions of MI in High Risk and Low Risk
Patient Populations are Similar 13](#__RefHeading___Toc55791503)

[Table 2: Professional Labeling Indications/Dosing
19](#__RefHeading___Toc55791504)

[Table 3: Prevalence, Mortality, Hospital Discharges and Cost of CVD in
the U.S. population. 20](#__RefHeading___Toc55791505)

[Table 4: Effects of the Multiple Therapies on the Risks of Ischemic
Heart Disease and Stroke After Two Years of Treatment at Age 55-64
24](#__RefHeading___Toc55791506)

[Table 5: Summary of Studies Evaluating ASA Prevention of First
Cardiovascular Event 26](#__RefHeading___Toc55791507)

[Table 6: Confirmed Cardiovascular End Points in the ASA Component of
the Physicians' Health Study, According to Treatment Group\*
28](#__RefHeading___Toc55791508)

[Table 7: Risk Reductions for Prevention of Cardiovascular Events in the
HOT Study 32](#__RefHeading___Toc55791509)

[Table 8: Relative Risk Reductions with Aspirin and Vitamin E Treatment
34](#__RefHeading___Toc55791510)

[Table 9: Nonfatal Myocardial Infarction (MI) in the Randomized Trials
of ASA in the Primary Prevention of Cardiovascular Disease
35](#__RefHeading___Toc55791511)

[Table 10: Any Important Vascular Event in the 5 Randomized Trials of
ASA in the Primary Prevention of Cardiovascular Disease
36](#__RefHeading___Toc55791512)

[Table 11: Ages of Subjects 37](#__RefHeading___Toc55791513)

[Table 12: Summary of Risk Ratio Estimates for 6 Studies Evaluating ASA
For the Prevention of Stroke in High Risk Patients (adapted from Weisman
and Graham, 2002). 43](#__RefHeading___Toc55791514)

[Table 13: Relative Risk Reductions of MI in High Risk and Low Risk
Patient Populations are Similar 44](#__RefHeading___Toc55791515)

[Table 14: Major Gastrointestinal Events in Primary Prevention Trials
47](#__RefHeading___Toc55791516)

[Table 15: Estimates of the Role of ASA in Gastrointestinal Bleeding\*
48](#__RefHeading___Toc55791517)

[Table 16: Hemorrhagic Stroke / Intracranial Hemorrhage in Primary
Prevention Trials 50](#__RefHeading___Toc55791518)

[Table 17: Drug-Drug Interactions with ASA that Warrant Caution
52](#__RefHeading___Toc55791519)

[Table 18: Adverse Event Rates in Post Marketing Surveillance Study
54](#__RefHeading___Toc55791520)

[Table 19: Number of GI Events 56](#__RefHeading___Toc55791521)

[Table 20: Estimates of Benefits and Harms of Aspirin Given for 5 years
to 1000 Persons with Various Levels of Baseline Risk for Coronary Heart
Disease\* 63](#__RefHeading___Toc55791522)

Table of Figures

[Figure 1: ASA Should Be Indicated for All Populations Where Benefits
Outweigh the Risks (Including Moderate Risk)
11](#__RefHeading___Toc55791523)

[Figure 2: Cumulative proportion (%) of men with IHD, main effects
(Figure 2 from TPT Study) 31](#__RefHeading___Toc55791524)

[Figure 3: ATT Collaboration Data: Non-Fatal Myocardial Infarction
40](#__RefHeading___Toc55791525)

[Figure 4: ATT Collaboration Data: Vascular Events
41](#__RefHeading___Toc55791526)

[Figure 5: ATT Collaboration Data: Effect of Dose
42](#__RefHeading___Toc55791527)

[Figure 6: Vascular Event Risk 58](#__RefHeading___Toc55791528)

# LIST OF ABBREVIATIONS {#list-of-abbreviations .unnumbered}

**ACC** -- American College Of Cardiology

**ADA** -- American Diabetes Association

**AHA** -- American Heart Association

**ANPR** -- Advanced Notice Of Proposed Rulemaking

**ASA** -- Acetylsalicylic Acid

**ATT** -- Antithrombotic Trialists' Collaboration

**BDT** -- British Doctors' Trials

**CAD** -- Coronary Artery Disease

**CHD** -- Coronary Heart Disease

**COX** -- Cyclooxygenase

**CV** -- Cardiovascular

**CVD** -- Cardiovascular Disease

**FDA** -- Food And Drug Administration

**GI** -- Gastrointestinal

**HDL** -- High Density Lipoprotein

**HOT** -- Hypertension Optimal Treatment Trial

**IHD** -- Ischemic Heart Disease

**JNC** -- Joint National Commission

**LDL** -- Low Density Lipoprotein

**MI** -- Myocardial Infarction

**NCEP** -- National Cholesterol Education Program

**NDA**-- New Drug Application

**NHLBI** -- National Heart, Lung, And Blood Institute

**NHBPEP** -- National High Blood Pressure Education Program

**NSAID** -- Non--Steroidal Anti--Inflammatory Drug

**OTC** -- Over--The--Counter

**PHS** -- Physicians' Health Study

**PPP** -- Primary Prevention Project

**SALT** -- Swedish Aspirin Low--Dose Trial

**TFM** -- Tentative Final Monograph

**TIA** -- Transient Ischemic Attack

**TPT** -- Thrombosis Prevention Trial

**UK--TIA** -- United Kingdom Transient Ischemic Attack Trial

**USPSTF** -- U.S. Preventive Services Task Force

# executive summary {#executive-summary .unnumbered}

This briefing book is provided to assist the Committees in their review
of the appropriateness of aspirin (ASA) for preventing a first
myocardial infarction (MI) in patients at sufficiently elevated risk. It
specifically advocates **Bayer HealthCare's position that the benefits
of low dose (75 -- 325 mg) ASA can be extended to patients at "Moderate
Risk", defined as a 10 year risk of coronary heart disease (CHD) that
exceeds 10%, where the benefits of therapy would be expected to outweigh
the risks.**

*Statement of Purpose*

**Cardiovascular disease is the leading cause of death and disability in
this country and strategies to reduce its impact must actively be
embraced. ASA is highly effective in reducing the risk of MI and its
broader use in appropriate patients can significantly reduce the
tremendous personal and societal impact of this disease. For this
benefit to be realized there is a need to align ASA labeling with
current scientific knowledge and clinical practice guidelines as this is
a critical and essential step in encouraging patients and physicians to
discuss and appropriately manage cardiovascular risk. Because underlying
cardiovascular risk is the single most important determinant of an
individual's likelihood of experiencing an MI, labeling that reflects
and endorses treatment based on a patient's global risk will have
significant public health benefit. As there is no question that the
absolute benefits of ASA accrue to those at Moderate to High Risk,
effort should focus on how best to ensure that all individuals falling
into these groups have access to this important therapeutic option. An
approved indication is essential to this goal.**

*Rationale*

Because absolute benefit of intervention is enhanced by ensuring that
those who are at greatest CHD risk are the ones who receive treatment,
strategies that define appropriate patient populations for intervention
with ASA by risk would be expected to be most successful in reducing the
burden of MI. The current FDA labeling paradigm that mandates the
presence of a previous cardiovascular event is not a sufficient
indicator of who should be a candidate for ASA treatment. This is
because it fails to acknowledge that patients who may have not suffered
a previous cardiovascular event could be at equal or greater risk
compared to patients who have suffered such an event. Adoption of ASA
labeling that focuses on underlying global risk and its management would
better define appropriate populations for ASA intervention and would
therefore be expected to have a major public health impact.

*The Benefits of ASA Are Well Established Across the Underlying Risk
Continuum*

ASA has been shown to be effective in preventing MI in a large array of
patient groups. The available evidence of benefit is derived from two
distinct risk populations (Low and High) and consists of studies
including over 55,000 Low Risk patients that have not experienced a
previous cardiovascular event (i.e., the primary prevention database) as
well as over 150,000 High Risk patients. The consistency of findings
across these populations highlights the reliability and homogeneity of
these findings and supports the view that Moderate Risk patients,
although not specifically studied would also benefit from ASA therapy. A
clinically important reduction of 14 MIs can be avoided for every 1000
patients treated in this population.

*The Risks of ASA Are Low and Constant Across the Underlying Risk
Continuum*

Numerous controlled clinical trials and tens of millions of patients
exposed to ASA a year for cardiovascular indications provide a clear
picture regarding the potential risks associated with chronic low dose
ASA use and highlight that these risks do not vary as a function of
underlying cardiovascular risk. From the clinical trials and
postmarketing adverse event tracking experience, it is clear that the
most clinically important adverse events associated with the long-term
cardiovascular use of ASA are related to bleeding complications. The
data reveal that while gastrointestinal (GI) bleeding is a clinical
concern, its rate of occurrence in clinical trials is relatively low
(2.3% compared to a rate of 1.45% among patients taking placebo).
Hemorrhagic stroke, which has also been reported to be associated with
ASA, occurs at rates far lower (75 hemorrhagic strokes per 28,570
individuals or 0.26%) than that of GI bleeding. Clear and precise
professional labeling will assist physicians in evaluating these risks
and ensure that patients at elevated risk from such injuries are
selectively excluded from ASA use.

*The Benefit to Risk Relationship Is Clearly Favorable in Moderate Risk
Patients*

Selecting patients for ASA treatment at Moderate Risk based on global
risk will enhance the benefit to risk relationship. While the benefits
of ASA in preventing non-fatal MI were observed in the Low Risk trials,
the selection of Moderate Risk patients in the proposed labeling for ASA
was conservatively chosen to further enhance the benefit to risk
relationship. Treating a thousand Moderate Risk Patients, i.e. those who
have a 10-year risk of CHD greater or equal to 10%, with ASA for 5 years
would be expected to prevent 14 MIs per 1000 patients treated. In this
population, the same rate of serious adverse effects as observed in the
High Risk and Low Risk studies would be expected (0-2 hemorrhagic
strokes and 2-4 major GI bleeds per 1000 patients treated), resulting in
a favorable benefit to risk relationship. The adoption of risk based
labeling and a recognition of the benefits of ASA in Moderate Risk
patients would be expected to enhance appropriate utilization of this
effective therapy, as it would clarify those patients who should be on
ASA and those who should not.

*ASA Use in Moderate Risk Patients Is Consistent With Recommendation by
the Medical Community*

The use of ASA in a wider population of appropriate patients based on
underlying cardiovascular risk is supported by recent publication of
clinical guidelines by the American Heart Association (AHA) and the U.S.
Preventive Services Task Force (USPSTF). These organizations recommend
that individuals with a 10-year risk of CHD in the range of 6-10% be
considered as candidates for ASA therapy. Their guidelines are based on
their finding that clinically meaningful MI risk reduction will be
achieved at this Moderate Risk level.

Bayer HealthCare looks forward to a partnership with the Food and Drug
Administration (FDA), the medical community and patient advocacy groups
to better communicate the importance of cardiovascular risk evaluation
and management and the appropriate use of ASA. An approved expanded
professional indication will provide clarity of communication to help
ensure that the right patients are on ASA therapy and the wrong ones are
not. Bayer Healthcare is committed to responsible marketing of this
important therapeutic agent and looks forward to the input of the
Committees with respect to how best to label ASA in the interest of
improving public heath.

# Introduction

## Rationale for Approval of ASA for the Prevention of MI in Moderate Risk Individuals

This section provides the rationale for Bayer HealthCare's request that
ASA be approved for the prevention of MI in individuals at "Moderate
Risk" of CHD. The support for this request is highlighted by the
following well-substantiated findings:

-   ASA has been clearly shown to be effective in the prevention of MI
    in a wide variety of patient populations, including "Low Risk" and
    "High Risk" populations, with similar proportional risk reductions
    observed across the studies.

-   Patients can be at sufficient risk of CHD to warrant treatment in
    spite of the absence of a previous event. Global, or underlying CHD
    risk is the more appropriate determinant of the type and intensity
    of intervention.

-   The adverse event risks associated with chronic low-dose (75mg-325
    mg/d) ASA therapy are the same regardless of underlying
    cardiovascular risk.

-   Labeling can define a Moderate Risk population where the benefits of
    treatment far outweigh the risks.

*Underlying Cardiovascular Risk Should Define Eligible Candidates for
Treatment*

It is well accepted within the medical community that an understanding
of an individual's cardiovascular risk profile (global risk), defined by
number and severity of risk factors, is the key determinant in assessing
that patient's likelihood of developing CHD. A major component of the
risk assessment is the presence or absence of symptomatic disease.
Patients who have a history of cardiovascular events -- specifically,
who have experienced an acute myocardial infarction (MI) or have a
history of previous MI, stroke, transient ischemic attack (TIA), stable
or unstable angina pectoris, chronic non-valvular atrial fibrillation,
or peripheral vascular disease, as well as those requiring
revascularization procedures or hemodialysis -- are at substantially
increased risk of experiencing subsequent occlusive vascular events and
would be considered High Risk. At the other extreme of this spectrum
would be patients who have no history of cardiovascular disease and who
do not have cardiovascular risk factors and would be appropriately
classified as "Low Risk.\"

While the risk paradigm described above assumes the presence or absence
of a previous cardiovascular event as the defining factor in
establishing level of risk, recent advances in risk assessment have
suggested that a more appropriate model should be one based on global
risk. With a thorough understanding of an individual's risk profile, the
clinician can guide therapy appropriately and, more importantly
accurately evaluate the likely benefit and compare it to potential for
harm. In fact, numbers of events prevented can be compared to the number
of adverse events caused in a manner that will allow patients and
physicians to evaluate the appropriateness of treatment. Encouraging
broader treatment of patients where the benefit is expected to be
greatest (i.e., those at elevated risk) will have significant public
health impact.

Considering risk as a continuum, a third group can be defined that is
intermediate between the High and Low Risk populations described above.
This Moderate Risk population can be described as having no history of
cardiovascular disease; however, they do have an increased level of
underlying CHD risk as a result of a combination of factors.
Importantly, the level of risk in this population can vary greatly, and
while asymptomatic, many of these patients could be at a significantly
high risk of an event, which in some cases could exceed the rate in the
High Risk group addressed above. The following factors can affect risk
appreciably, highlighting the importance of a detailed risk assessment
as part of a patient's annual physical exam: hypercholesterolemia,
smoking, diabetes, hypertension, age, obesity, and family history.
Importantly, both lifestyle modifications and pharmacologic
interventions have been shown to effectively reduce the risk of MI in
this Moderate Risk population.

To illustrate the utility of a global risk based approach for evaluating
at what level of underlying risk ASA therapy may be appropriate, a model
addressing underlying cardiovascular risk is depicted in Figure 1.

[]{#__RefHeading___Toc55791523 .anchor}Figure 1: ASA Should Be Indicated
for All Populations Where Benefits Outweigh the Risks (Including
Moderate Risk)

*Basis for Including Moderate Risk Patients in ASA labeling*

ASA is indicated in numerous countries for the secondary prevention of
MI and stroke, for the prevention of cardiovascular events after
coronary bypass surgery and interventions, and for the primary
prevention of MI in subjects with a history of angina pectoris. The
approvals to date have reflected a bias towards "event based" labeling,
suggesting that a candidate must have a history of a cardiovascular
event or symptomatic disease. In spite of these approvals, there are
many more patients who are at sufficiently high risk to warrant
treatment whom could benefit from the cardio-protective effects of ASA
and for who the benefits outweigh the risks. Extending the labeling to
these patients will result in significant reductions in morbidity.

It is clear that there are many Moderate Risk patients -- i.e., people
who are at increased risk for serious cardiovascular events -- who are
not included in the current ASA labeling. Because of the common
pathophysiology of coronary events across the disease continuum, there
is sufficient evidence to support the view that the same preventive
interventions (e.g., behavioral and pharmacological) would be effective
in this population.

*The Benefits and Risks of ASA Therapy can be Appropriately Extended to
Moderate Risk Patients*

The available scientific evidence clearly supports the utility of ASA in
preventing MI across the risk spectrum, including patients at Moderate
Risk. The data conclusively demonstrate that ASA prevents cardiovascular
events (most notably and consistently MI) across the risk continuum
(i.e., high risk, moderate risk, and low risk patients) as summarized
below.

-   High Risk Populations: Clinical studies and meta-analyses have
    provided conclusive evidence that low-dose ASA can prevent
    subsequent cardiovascular events (e.g., MI, stroke, and vascular
    death) in High Risk patient groups (i.e., MI relative risk
    reductions of 30%).

-   Low Risk Populations: More recent evidence from clinical studies and
    meta-analyses demonstrates the effectiveness of ASA in preventing
    non-fatal MI in Low Risk patients (i.e., patients that have not
    experienced a previous cardiovascular event) (MI relative risk
    reductions of 32%).

-   Moderate Risk Populations: While not specifically studied in
    controlled trials, the available evidence suggests that the benefit
    to risk relationship is favorable for the use of aspirin in this
    population.

The diversity of the data (approximately 150 studies involving over
200,000 patients, including over 55,000 apparently healthy Low Risk
individuals and over 150,000 High Risk patients), coupled with robust
and consistent findings across the studies, provides confidence in the
broad applicability of the observed benefits with respect to the ability
of ASA to prevent MI in all at risk patients.

*Extrapolation Across Risk Strata*

The fact that the proportional risk reductions are essentially identical
for the High Risk and Low Risk studies (as outlined in Table 1 below)
highlights the homogeneous population across the risk continuum and the
ability to extrapolate findings to intermediate groups that have not
been specifically evaluated.

[]{#__RefHeading___Toc55791503 .anchor}Table 1: Relative Risk Reductions
of MI in High Risk and Low Risk Patient Populations are Similar

  ------------------------- ----------------------- ---------------------
  **Trial**                 **Underlying Risk of    **Relative Risk
                            Patient Population**    Reduction for MI**

  PHS                       Low Risk                40%

  BDT                                               3%

  TPT                                               32%

  HOT                                               \--

  PPP                                               31%

  Overall                                           32%

  Weisman and Graham        High Risk               30%
  meta-analysis                                     
  ------------------------- ----------------------- ---------------------

While comparable proportional risk reductions are observed across the
risk continuum, very different absolute benefits would be expected in
distinct risk strata based on the differing levels underlying risk of
CHD. As noted in Figure 1 (diagonal line), the absolute benefit
increases as a function of underlying risk. Such a relationship would be
expected for any effective intervention. The point is further
exemplified when the baseline risks for each of the five primary
prevention studies and the mean of the High Risk (secondary) prevention
studies are included. The fact that a line can be drawn between these
databases highlights that an extrapolation can be made to other groups
between the two studied extremes, suggesting that a predictable benefit
can be achieved in Moderate Risk patients as well.

To complete the evaluation as to the appropriateness of treating
Moderate Risk patients with ASA, it is important to also consider the
potential hazards of treatment. Unlike benefit (which increases linearly
with underlying risk), the well-documented adverse event rate (primarily
gastrointestinal bleeding and hemorrhagic stroke) associated with ASA
therapy would be conservatively expected to be constant across the risk
continuum (lower risk patients could theoretically be healthier and at
lower risk of adverse events) (Figure 1 -- horizontal line).

In reviewing the model depicted above, it is clear that at global risk
levels exceeding 10%, the absolute benefit of treatment outweighs the
risk, highlighting the need for recognition of the need to treat
patients with this risk level and above.

*ASA Should Be Indicated for Prevention of MI in Moderate Risk
Populations*

Based on the construct presented above, it is clear that a broader group
of patients than currently included in the professional labeling for ASA
should be candidates for ASA therapy. Likewise, in any revisions to the
labeling for aspirin, attention should be paid to the fact that there is
significant utilization in all "at risk" populations. To that end, the
following points should be considered:

-   Low Risk Population (\<10% risk): ASA use would not be appropriate
    because the benefits of treatment may not exceed the potential for
    adverse effect.

-   Moderate Risk Population (10-20% risk): As with High Risk
    populations, ASA should be used for prevention in this population as
    it can be predicted that the benefit will consistently exceed the
    potential for an adverse outcome.

-   High Risk Population (\>20% risk): While this level of risk is
    comparable to the level of risk in the secondary prevention studies,
    the current labeling of ASA does not acknowledge that such a level
    of risk can exist in the absence of a previous event. Amendments to
    the labeling to reflect the impact of global risk will ensure that
    ASA is prescribed in all patients with a 20% or greater 10- year
    risk regardless of whether a previous event has been experienced.

*Labeling Can Effectively Guide Appropriate Treatment*

Because the underlying cardiovascular risk can be reliably predicted
through clinical judgment supported by a variety of risk evaluation
tools (Discussed in Section 2.3) the population in which the benefit of
ASA treatment is likely to outweigh the risks can be adequately defined.
Importantly, effective labeling can be developed that clearly
communicates the appropriate patient populations for using ASA in
patients at sufficiently high risk of a first MI. Both the U.S.
Preventive Services Task Force \[[^1]\] and the American Heart
Association \[[^2]\] have developed an effective risk/benefit approach
that recommends use of low-dose ASA for primary prevention of CVD in
appropriate patient populations. Earlier recommendations were issued by
the American Diabetes Association in 1997 \[[^3]\] (latest update in
2003 \[[^4]\]) and by the Second Joint Task Force of European and Other
Societies on Coronary Prevention in 1998 \[[^5]\].

## The Role of Aspirin in Coronary Heart Disease

The information presented below provides the reviewer with background on
ASA, including its pharmacology, marketing and regulatory history.

### ASA's pharmacology explains its cardiovascular benefits

The role of platelets, platelet-derived products, and thrombosis in the
pathogenesis of vascular disease, particularly atherothrombotic
disorders, is well documented \[[^6]\]. The principle mechanism of ASA
involves inhibition of platelet activation and resulting aggregation in
the early stages of thrombus formation, occurring as a result of the
irreversible inhibition of cyclooxygenase. ASA has powerful
antithrombotic effects and has been studied in various categories of
patients at risk of occlusive thromboembolic events.

The initial phase of arterial thrombus formation is postulated to result
from aggregation of platelets to a damaged endothelial surface. Other
clotting mechanisms then complete the process of thrombus formation.
Platelet aggregation appears to be mediated mainly by an increase in
cytoplasmic calcium caused by the release of platelet granule contents,
mainly ADP, by the synthesis and release of thromboxane A~2~ and by
various external stimuli \[[^7]\]. Within this pathway, the enzyme
cyclooxygenase converts arachidonic acid to the unstable endoperoxide
prostaglandin G~2~. Prostaglandin G~2~ is reduced to prostaglandin H~2~
and this compound is then metabolized to thromboxane A~2~ by thromboxane
synthase within the platelets or to prostacyclin (prostaglandin I~2~) by
prostacyclin synthase in the vascular endothelium \[[^8]\]. Thromboxane
A~2~ also constricts vascular smooth muscle \[Error: Reference source
not found\], and the prevention of thromboxane A~2~-induced vasospasm
may be an additional benefit of ASA in patients at high risk of
occlusive vascular disease.

ASA is the prototype of a class of drugs that decrease platelet
aggregation via inhibition of the production of the principal platelet
pathway product, thromboxane A~2~ \[[^9]\]. The molecular mechanism of
the antiplatelet action of ASA is the irreversible acetylation and thus
permanent inactivation of the key-enzyme cyclooxygenase (COX) or
prostaglandin G/H syn­thase \[[^10]\], which catalyses the first step of
prostaglandin synthesis by the so-called arachi­donic acid cascade. ASA
selectively acetylates the hydroxyl group of a single serine residue at
position 529 \[[^11], [^12]\] within the polypeptide chain of human
platelet prostaglandin G/H synthase-1, causing the irreversible loss of
its cyclooxygenase activity by blocking the active centre of this enzyme
\[[^13], [^14]\]. This blockade results in the suppression of the main
product of the arachidonic acid cascade in the platelet, thromboxane
A~2~ that exhibits pronounced aggregating and vasoconstricting effects.
Its counterpart, prostacyclin (PGI~2~), is produced by endothelial cells
of the vessel wall, acting as an antiaggregant and vasodilator.

Thus, by inhibiting the COX enzyme and subsequently inhibiting
thromboxane formation in platelets, ASA reduces the tendency of
platelets to clot, decreasing platelet aggregation and ultimately
decreasing the risk of coronary artery thrombosis. Thus, the
cardiovascular benefits of ASA are clearly understood from its
pharmacological action on the COX enzyme.

### ASA is widely used as a safe and cost effective treatment for cardiovascular disease prophylaxis

ASA is indicated for both consumer (OTC) and professional uses. As a
highly effective pain reliever and antipyretic agent, ASA can be used
safely and effectively under OTC-compliant short-term dosing conditions.
Under a physician's guidance, ASA is indicated for preventing
cardiovascular events, as well as to treat a variety of inflammatory
conditions. Today, over 10 billion tablets are consumed a year
\[[^15]\], with a total 6 billion tablets consumed as a cardiovascular
therapy. The FDA has recognized this use for over a decade.

The analgesic effects of ASA-like substances have been known since the
ancient Romans prescribed the bark and leaves of the willow tree (rich
in salicin) to relieve pain and fever. In 1897, a Bayer chemist named
Felix Hoffman chemically synthesized a stable form of acetylsalicylic
acid powder. Bayer introduced ASA powder in 1899, and it soon became the
number one drug worldwide.

In 1948, Dr. Lawrence Craven, a California general practitioner, noted
that the 400 men to whom he provided ASA hadn't suffered any heart
attacks. Prompted by this observation, he recommended to all patients
and colleagues that "an aspirin a day" could dramatically reduce the
risk of heart attack. With further scientific study, FDA recognized ASA
as an effective preventive tool in reducing the risk of stroke in 1980
and recurrent myocardial infarction in 1985.

With over 100 years of history of use, ASA is one of the most
extensively studied drugs in the history of medicine and is still the
focus of current research efforts. Bayer HealthCare is the proud
marketer of Bayer^®^ Aspirin and is a leader in the scientific
advancement of ASA. It has also had a major role in the creation of
programs to ensure that appropriate patients have access to ASA with
dedicated focus on healthcare professional programs, as well as public
education programs urging patients to speak to their doctor. Bayer has
worked extensively with the FDA and is committed to continuing to work
with the Agency to ensure appropriate use and labeling of ASA.

### Regulatory History of ASA

ASA is unique among the cardiovascular drugs and differs in many ways
from other products with similar pharmacological properties marketed as
prescription drugs. Most noteworthy, is its extensive worldwide history
of consumer use extending over 100 years, with a significant scientific
body of evidence supporting the safety and efficacy of the product as a
cardiovascular agent. In addition, it is unique with respect to the
regulatory process of review and approval. It is a product reviewed as
part of the FDA's Over-the-Counter Monograph process, both as an
internal analgesic/antipyretic OTC drug product and as a cardiovascular
and antirheumatic drug product labeled for professional use.

The Internal Analgesic, Antipyretic and Antirheumatic Drug Products for
Over-the-Counter Human Use; Tentative Final Monograph (TFM), issued by
the FDA (1988) \[[^16]\] establishes proposed conditions under which
over-the-counter analgesic, antipyretic, and antirheumatic drug products
are generally recognized as safe and effective. It provides for approved
active ingredients, dosing regimens, and permissible combinations of
active ingredients, as well as labeling requirements for such products.
The Monograph process allows for the evaluation of information from a
variety of sources and scientific agreement in determining indications
and claims. While the TFM details use conditions for a variety of OTC
analgesic ingredients, the focus of this briefing book is the review of
professional rulemakings pertinent to ASA.

The monograph process for OTC analgesics was initiated with a July 21,
1972 Federal Register notice requesting the submission of data and
information on OTC internal analgesic and antirheumatic drugs. Data
submitted for review included that for Bayer^®^ Aspirin supporting its
use as a safe and effective ingredient for the temporary relief of
self-limited symptoms. At the time, ASA was the most widely used single
drug in the U.S.; with its extensive use, long marketing history, and a
relatively low incidence of serious side effects associated with
short-term use, the safety was considered well-established for the
majority of the population and the risk-benefit ratio is favorable.
Following review of the data by the Advisory Review Panel on
Over-the-Counter Internal Analgesic and Antirheumatic Products (the
Panel), a report was submitted to FDA. The Advanced Notice of Proposed
Rulemaking (ANPR) was issued on July 8, 1977, followed by issuance of
the TFM on November 16, 1988.

The Panel recommended the use of ASA as an antirheumatic drug product to
be considered only under the advice and supervision of a physician,
i.e., professional labeling. The professional labeling indications in
the 1977 ANPR included: rheumatoid arthritis, juvenile rheumatoid
arthritis, systemic lupus erythematosus, osteoarthritis (degenerative
joint disease), ankylosing spondylitis, psoriatic arthritis, Reiter's
syndrome, and fibrositis.

The TFM proposed to expand the professional labeling recommendations to
include the preliminary cardiovascular indications for ASA. Based upon
the data submitted \[[^17], [^18]\] and the August 28, 1979 Peripheral
and Central Nervous System Drugs Advisory Committee recommendation
\[[^19]\], the use of ASA for reducing the risk of recurrent transient
ischemic attacks or stroke in men was included; based upon data
submitted and reviewed by FDA, the use of ASA was determined to be
effective in reducing the risk of death and/or non-fatal myocardial
infarction in patients with a previous infarction \[[^20], [^21], [^22],
[^23], [^24], [^25]\] or unstable angina pectoris \[[^26]\]. Thus, the
professional labeling proposed reflected these indications. The
following cardiovascular statements were added to the proposed
professional labeling:

> *For reducing the risk of recurrent transient ischemic attacks (TIA's)
> or stroke in men who have had transient ischemia of the brain due to
> fibrin platelet emboli. There is inadequate evidence that ASA or
> buffered ASA is effective in reducing TIA's in women at the
> recommended dosage. There is no evidence that ASA or buffered ASA is
> of benefit in the treatment of completed strokes in men or women.*
>
> *To reduce the risk of death and/or non-fatal myocardial infarction in
> patients with a previous myocardial infarction or unstable angina
> pectoris*

The indication for use of ASA as a prophylaxis for primary myocardial
infarction has been the subject of scientific and regulatory
consideration in the past. On October 6, 1989, the FDA's Cardiovascular
and Renal Drugs Advisory Committee considered the claim for ASA for the
prevention of primary (first) heart attack based upon the Physicians'
Health Study \[[^27]\]. The Committee recommended (voting 5 to 3) that,
although an indication should be considered for some high-risk group of
patients, ASA should not be used routinely in patients without risk
factors or in women, until such patients had been studied. The Committee
minority was concerned about the toxicity of ASA and the number of
normal individuals at low risk of having a heart attack who would be
treated long-term.

The prophylaxis indication was again the subject of discussion at a
joint meeting of the Cardiovascular and Renal Drugs and Nonprescription
Drugs Advisory Committees on January 23, 1997 in response to a petition.
At that time, the Committee recommended that ASA be labeled for primary
prevention of myocardial infarction based upon the data submitted in the
form of a Citizen Petition from the Physicians' Health Study \[Error:
Reference source not found\].

The FDA published the Final Rule for professional labeling on October
23, 1998. The final rule, which includes full prescribing information
for the professional uses of ASA was established. The submission of two
Citizen's Petitions provided support to amend the professional labeling
section of the TFM to include an indication for aspirin for suspected
acute MI. Data from published reports \[[^28], [^29], [^30], [^31],
[^32]\] was used to support the use of aspirin for cardiovascular uses
in women. The rule also recommended that aspirin at low-dose levels
(e.g., 50 - 325 mg) be used based upon positive study findings \[Error:
Reference source not found, [^33], [^34], [^35], [^36]\]. Based upon
data \[Error: Reference source not found, [^37], [^38], Error: Reference
source not found\] reviewed and the January 23, 1997 Cardiovascular and
Renal Drugs Advisory Committee recommendation, the indication for
aspirin for subjects to reduce the combined risk of death and nonfatal
stroke in patients who have had ischemic stroke or transient ischemia of
the brain due to fibrin emboli, and to reduce the combined risk of MI
and sudden death in subjects with chronic stable angina pectoris was
approved. In addition, aspirin use in subjects who have had specific
arterial revascularization procedures \[[^39], [^40], [^41], [^42],
[^43]\] (i.e., coronary artery bypass graft \[CABG\], primary
percutaneous transluminal cardiac angioplasty \[PTCA\], or carotid
endarterectomy) was also included. The FDA did not find data from the
PHS \[Error: Reference source not found\] and BDT \[[^44]\] trials
sufficient to support the primary prevention indication.

Since the FDA's review of the PHS and BDT trials, new data has been
published that supports the re-review of use of ASA in patients at lower
cardiovascular risk than currently approved. The data to be considered
include the PHS, the BDT, and the three new published reports:
Thrombosis Prevention Trial \[[^45]\], Hypertension Optimal Treatment
Trial \[[^46]\], and the Primary Prevention Project \[[^47]\]. The
diverse make up of these studies and consistent findings has led to a
discussion of recommendations for ASA use based on risk rather than
event-based considerations.

Following the publication of the three additional primary prevention
trials (TPT and HOT in 1998, and PPP in 2001), and the subsequent United
States Preventive Services Task Force (USPSTF) and American Heart
Association recommendations \[Error: Reference source not found, Error:
Reference source not found\] for an expanded use of ASA for men and
women at risk of a first coronary event, Bayer HealthCare filed a
Citizen's Petition on February 11, 2003 requesting approval for
"expanded cardiovascular indications and professional labeling for the
use of ASA to reduce the risk of a first myocardial infarction in
at-risk patients" based on this scientific consensus.

#### U.S. Aspirin OTC Labeling

ASA is labeled for OTC use as an analgesic and antipyretic ingredient in
accordance with FDA's 1988 TFM. The recommended analgesic/antipyretic
OTC treatment encompasses a broad dosing margin, with single doses
ranging from 325 mg to 1000 mg, with a 4,000 mg maximum daily limit.
Bayer ASA is available as 500 mg, 325 mg, as well as the 81 mg tablets.
The products contain warnings in accordance with the TFM.

#### U.S. Aspirin Professional Labeling

Table 2 provides the professional labeling indications and dosing
currently approved for aspirin. For full professional labeling for
aspirin, refer to Appendix 1.

[]{#__RefHeading___Toc55791504 .anchor}Table 2: Professional Labeling
Indications/Dosing

  -----------------------------------------------------------------------
  **Indications**        **Recommended Daily Dosing (Duration)**
  ---------------------- ------------------------------------------------
  **Vascular             
  Indications:**         

  Ischemic Strokes and   50-325 mg daily (Indefinitely)
  TIA                    

  Suspected Acute MI     160-162.5 mg taken as soon as infarction is
                         suspected; then once daily (For 30 days post
                         infarction - after 30 days consider further
                         treatment based on indication for previous MI)

  Prevention of          75-325 mg daily (Indefinitely)
  Recurrent MI           

  Unstable Angina        75-325 mg daily (Indefinitely)
  Pectoris               

  Chronic Stable Angina  75-325 mg daily (Indefinitely)
  Pectoris               

  **Revascularization    
  Procedures:**          

  Coronary Artery Bypass 325 mg daily starting 6 hrs. postprocedure (1
  Graft                  year)

  Primary Percutaneous   325 mg 2 hrs. pre-surgery; Maintenance therapy:
  Transluminal Cardiac   160-325 mg daily (Indefinitely)
  Angioplasty            

  Carotid Endarterectomy 80 mg daily to 650 mg twice a day started
                         pre-surgery (Indefinitely)

  **Rheumatologic        
  Disease Indications:** 

  Rheumatoid Arthritis   Initial dose 3 g daily. Target plasma salicylate
                         levels 150-300 μg/mL (As indicated)

  Juvenile Rheumatoid    Initial dose 90-130 mg/kg/day. Target plasma
  arthritis              salicylate levels 150-300 μg/mL (As indicated)

  Spondylarthropathies   Up to 4 g daily (As indicated)

  Osteoarthritis         Up to 3 g daily (As indicated)

  Arthritis and Pleurisy Initial dose 3 g daily. Target plasma salicylate
  of Systemic Lupus      levels 150-300 μg/mL (As indicated)
  Erythematosus          
  -----------------------------------------------------------------------

#### Worldwide Approvals Overview

ASA is currently approved for primary and secondary prevention in the
following countries outside the United States: Argentina, Belgium, Belo
Russia, Brazil, Canada, Chile, Columbia, Ecuador, Denmark, Georgia,
Greece, Italy, Kazakhstan, Korea, Mexico, Norway, Peru, Philippines,
Poland, Portugal, Russia, Slovenia, Switzerland, Turkey, Ukraine,
Uzbekistan, Venezuela. Approved doses vary and range from 75 mg to 325
mg per day use.

For an overview of ASA worldwide cardiovascular indications, refer to
Appendix 2.

# cardiovascular disease has a major Public health impact

Coronary heart disease (CHD) is a significant and growing public health
concern impacting all populations, with broad personal and economical
implications. The risks associated with CHD are well established and
should be evaluated with regard to behavioral and therapeutic options to
reduce the overall incidence of CHD and CHD events through regulatory
action.

## Cardiovascular Disease is a Serious Public Health Threat

Cardiovascular disease affects over 60 million Americans and results in
substantial disability, loss of productivity, and a marked reduction in
quality of life \[[^48]\]. The American Heart Association reports CVD as
the primary cause of death in the U.S., accounting for approximately one
million deaths annually \[[^49]\]. This year an estimated 650,000
Americans will experience a first MI while 450,000 will have a recurrent
attack.

[]{#__RefHeading___Toc55791505 .anchor}Table 3: Prevalence, Mortality,
Hospital Discharges and Cost of CVD in the U.S. population.

+-------------------+------------+------------+-----------+----------+
| **Population      | **Pr       | **M        | **H       | **Cost** |
| Group**           | evalence** | ortality** | ospital** |          |
|                   |            |            |           |          |
|                   |            |            | **Dis     |          |
|                   |            |            | charges** |          |
+-------------------+------------+------------+-----------+----------+
| Total population  | 61,800,000 | 945,836    | 6,294,000 | \$351.8  |
|                   |            |            |           | billion  |
+-------------------+------------+------------+-----------+----------+
| Total males       | 29,700,000 | 440,175    | 3,115,000 | \--      |
+-------------------+------------+------------+-----------+----------+
| Total females     | 32,100,000 | 505,661    | 3,179,000 | \--      |
+-------------------+------------+------------+-----------+----------+
| White males       | 30.0%      | 382,516    | \--       | \--      |
+-------------------+------------+------------+-----------+----------+
| White females     | 23.8%      | 440,903    | \--       | \--      |
+-------------------+------------+------------+-----------+----------+
| Black males       | 40.5%      | 48,708     | \--       | \--      |
+-------------------+------------+------------+-----------+----------+
| Black females     | 39.6%      | 57,063     | \--       | \--      |
+-------------------+------------+------------+-----------+----------+
| Mexican-American  | 28.8%      | \--        | \--       | \--      |
| males             |            |            |           |          |
+-------------------+------------+------------+-----------+----------+
| Mexican-American  | 26.6%      | \--        | \--       | \--      |
| females           |            |            |           |          |
+-------------------+------------+------------+-----------+----------+

> *Sources: **Prevalence**: NHANES III (1988-94), CDC/NCHS; data for
> white and black males and females are for non-Hispanics. Total
> population data include children; percentages for racial/ethnic groups
> are age-adjusted for Americans age 20 and older. **Mortality:**
> CDC/NCHS; data for white and black males and females include
> Hispanics; data include congenital cardiovascular disease. **Hospital
> discharges:** CDC/NCHS; data include people both living and dead.
> **Cost:** NHLBI*

CVD risk is prevalent in all populations and interventions are necessary
to reduce the numbers of associated deaths. CVD has claimed the lives of
more females than males, with the gap between male and female deaths
increasing dramatically. Heart disease in women often goes untreated and
undetected until it has progressed to a severe state, resulting in a
high rate of fatal first cardiovascular events or expensive intensive
medical treatment \[Error: Reference source not found, [^50]\].
Intervention is imperative to reduce a first MI in this population. The
prevalence in racial and ethnic minority populations is a significant
and growing public health concern, particularly for African-Americans,
Asian/Pacific Islanders, Hispanics/Latinos, and American Indian/Alaska
natives. Compared to other sex/race groups, coronary heart disease
mortality rates are particularly high in middle-aged African-American
men, and stroke mortality rates are relatively high for African-American
men in general \[[^51]\].

## Economic Costs of Cardiovascular Disease

The CVD-associated cost in the U.S. in 2003 is estimated at \$351.8
billion, which exceeds that of all cancers and HIV infections \[Error:
Reference source not found\]. The estimate includes health expenditures
and lost productivity resulting from morbidity and mortality. The costs
associated with non-fatal MI are associated with direct medical costs,
costs of medicines, lost work time, as well as rehabilitation costs. In
fact, the first-year incidence cost in the U.S. was approximately \$16.3
billion (1996 dollars); the adjusted estimates for 2003 for per patient
non-fatal MI costs would be approximately \$19,000 and a 5-year per
patient estimate for direct medical costs at nearly \$100,000. This is a
growing problem, especially with the prevalence of U.S. heart disease
expected to double in the next half century \[[^52], Error: Reference
source not found\], thus the need for education on the changes in
behavior modification and ready availability of effective therapeutic
agents such as ASA, statins and antihypertensive agents will have a
significant impact on public health as it relates to CVD.

Preventing a greater number of first heart attacks in the U.S.
population would result in a substantial reduction in the associated
personal and national health economic costs. The significant costs for
follow-up treatment from a non-fatal MI includes diagnostic costs, and
premature, permanent disability in the U.S. labor force and disability
allowances costs, as well as the treatment of associated depression. The
reduction in the occurrence of these events, across patients of any risk
of having a heart attack, will have significant public health
consequences.

In addition to the direct costs of hospitalization, diagnostics and drug
therapy associated with a myocardial infarction in the acute and
peri-infarction period, the indirect costs of managing the sequelae and
the cost attributed to diminished quality of life must be considered
when assessing the healthcare burden. In individuals who have suffered
an MI, the risk of another heart attack or stroke is substantial; it is
estimated that 18% of men and 35% of women will have a second MI. The
most debilitating illness resulting from myocardial ischemia and cell
death is decreased ventricular contractility leading to congestive heart
failure (CHF), seen in about 22% of men and 46% of women in the years
following a heart attack. CHD is the leading cause of premature,
permanent disability in the U.S. labor force, accounting for 19% of
disability allowances by the Social Security Administration. Patients
experiencing CHF have varying degrees of physical limitation secondary
to the limited ability of the heart to deliver oxygen to tissues, and
are at risk of serious complications including pulmonary edema. Also,
various long-term drug therapies are typically required to manage this
disorder. Another consideration in patients who survive a myocardial
infraction, particularly those who have subsequent disability, is
depression. It is estimated that up to 25% of patients with a chronic
medical condition will develop a major depressive episode during the
course of the condition, and medical management of this depression also
has an impact on health care costs.

## Cardiovascular Risk is Definable

### Individual Risk and Global Risk Assessment

Based on the advancements in our understanding of the risk factors for
CVD, it is now possible to better define an individual's CVD risks and
thus define populations at sufficient risk to warrant intervention. The
estimates of absolute risk usually require that the contribution of each
risk factor be identified and be evaluated as a global risk assessment
(i.e., the global risk is a summation of individual risks to assess the
progression of CVD). The data supporting these principles largely
originate with the Framingham Study.

The Framingham Study \[[^53]\], using an epidemiologic approach, has
successfully identified or documented major contributors (or risk
factors) of CVD; they include atherogenic personal attributes, living
habits that promote these, signs of preclinical disease and host
susceptibility to these influences. Established atherogenic traits
include blood lipids, blood pressure and blood sugar. Elevated LDL has
been shown to be positively related and increased HDL inversely related
to the subsequent rate of occurrence of coronary disease. The total/HDL
cholesterol ratio was established as an efficient lipid risk profile.
Hypertension was shown to be powerfully and independently related to the
occurrence of CVD. The importance of isolated systolic hypertension was
established. Diabetes was shown to make a unique contribution to risk of
atherosclerotic CV events with a greater relative impact on women than
men.

The Framingham data provide a realistic picture of a given individual's
true absolute and relative risks. Therefore, they can be helpful in
identifying patients where risk factor management is appropriate. The
National Cholesterol Education Program (NCEP) \[[^54], [^55]\] used
Framingham data to link recommended intensity of cholesterol management
to absolute risk. The paradigm of matching intensity of therapy to
absolute risk was further endorsed and developed in a consensus
conference sponsored by the American College of Cardiology (ACC)
\[[^56]\]. The National High Blood Pressure Education Program Joint
National Commission (JNC), which sets forth guidelines for treatment of
hypertension, also adjusted intensity of antihypertensive therapy to
absolute risk in its guidelines \[[^57]\]. Matching intensity of
preventive regimens to absolute risk is attractive because it offers a
way to achieve an appropriate balance of efficacy, safety, cost of
therapy and professional time commitment. The effort to quantify each
component of this balance requires an estimate of absolute risk. Because
estimates of absolute risk require that the contribution of each risk
factor be summed, the summation has been called global risk assessment.

As previously described, the Framingham Study provides a model for
quantitative estimate of risk based on the contribution of each risk
factor. Framingham data therefore can be used as the foundation of a
risk-assessment program. Framingham investigators \[[^58]\] have
proposed an approach to global risk assessment. Because of the
continuous relationship between intensity of risk factors and risk for
CHD, Framingham researchers have delineated a risk scoring technique
founded on the summation of graded risk factors. This technique is based
on the theory that the relation between risk factors and the likelihood
of developing CHD is continuous rather than threshold. The advantage of
continuous risk factors over the use of categorical risk factors is that
the former should provide more quantitative estimates of global risk.
For example, by combining multiple marginal risk factors, the estimate
of total risk should be more accurate in circumstances in which
categorical risk factors are absent but multiple risk factors are
present. Adoption by FDA of this risk paradigm in the labeling for ASA
will ensure that appropriate patients are prescribed an ASA regimen.

### Tools and Calculators

Several Framingham-based risk calculators are available. These tools are
published in several forms including risk charts and computerized
calculators for personal digital assistants, personal computers, and
web-based use. They require information on age, smoking status, blood
pressure, total and HDL cholesterol, and the presence or absence of
diabetes. These tools include: the National Cholesterol Education
Program (NCEP) calculator; the American Heart Association calculator;
the Med-decisions.com calculator; the Medical College of Wisconsin
calculator. A recent review \[[^59]\] of several of these tools
concludes that, compared to the full Framingham equations, accuracy for
identifying patients at increased risk was generally quite high.

The AHA recommends in their 2002 update \[Error: Reference source not
found\] that risk factor screening should begin at age 20 and global
risk estimation be done every 5 years on healthy adults age 40 and
older. In addition, AHA offers guidance with respect to specific risk
factors and the goals of treatment. Specifically, low-dose ASA is
recommended for persons at higher CHD risk (especially those with
10-year risk of CHD greater than or equal to 10%).

Currently available Framingham-based risk prediction tools can be used
as an aid to clinical judgment in the identification of appropriate
patients and guide primary prevention strategies. The use of these tools
along with proper management of risk factors provides the best
opportunity for reducing the incidence of CHD.

The Coronary Risk Prediction Score Sheets for men and women based on
total cholesterol level are included in Appendix 3.

## Cardiovascular Events are Preventable

Preventive strategies aimed at the first cardiovascular events are
immensely valuable in lowering morbidity, mortality, and economic cost.
Considering the magnitude of CHD as a health problem, more should and
can be done for population-wide primary prevention.

The causes of CHD are mostly known and modifiable. Except in patients
with congenital heart defects and other cardiovascular ailments, heart
disease is the end result of a combination of lifestyle and
environmental factors \[Error: Reference source not found\]. It has been
demonstrated in the Nurses Health Study for example, that managing these
risk factors -- controlling body weight, maintaining good nutrition,
exercising regularly, not smoking, limiting alcohol intake --
dramatically reduces the risk of developing CVD (by 84% in the women
studied) \[[^60]\]. More people need to be aware of these risk factors
and educated on behavior modification, and physicians need guidance with
respect to which patients to treat and aggressively manage. The AHA
Guidelines provide a framework for primary care physicians to reinforce
the public health recommendations of healthy lifestyle habits and drug
interventions for primary prevention of CVD for at-risk patients
\[Error: Reference source not found\].

Existing effective therapeutic agents such as ASA, statins, and
antihypertensive agents should be made available to appropriate at-risk
populations. Wald & Law collectively present the results of several
published studies on these therapeutic agents \[[^61]\]. (Refer to Table
4, below) Widespread appropriate use of available treatments would have
a profound impact on public health.

Appropriate patients for ASA therapy can be identified with confidence
based on Framingham risk assessment models. The use of risk assessment
and the appropriate intensity of treatment that follows is the basis for
current hyperlipidemia and hypertension guidelines. The same strategy
can be put in place for ASA and is supported by AHA guidelines. Patients
deemed at sufficient risk should be offered ASA along with all other
applicable risk modifying strategies (i.e., diet and exercise regimen,
lipid and blood pressure lowering therapies, smoking cessation, etc).

[]{#__RefHeading___Toc55791506 .anchor}Table 4: Effects of the Multiple
Therapies on the Risks of Ischemic Heart Disease and Stroke After Two
Years of Treatment at Age 55-64

  -------------- -------------- -------------- ----------- ------------ ------------
  **Risk         **Agent**      **Reduction in **%                      **Source of
  Factor**                      risk factor**  reduction                evidence**
                                               in risk                  
                                               (95% CI)                 
                                               \***                     

                                               **IHD       **Stroke**   
                                               event**                  

  LDL            Statin ^†^     1.8 mmol/l     61 (51 to   17 (9 to 25) Law et al
  cholesterol                   (70mg/dl)      71)                      [^62]
                                reduction in                            
                                LDL                                     
                                cholesterol                             

  Blood pressure Three classes  11 mm Hg       46 (39 to   63 (55 to    Law et al
                 of drug at     diastolic      53)         70)          [^63]
                 half standard                                          
                 dose                                                   

  Serum          Folic acid     3 μmol/l       16 (11 to   24 (15 to    Wald et al
  homocysteine   (0.8mg/day)                   20)         33)          [^64]

  Platelet       Aspirin (75    Not quantified 32 (23 to   16 (7 to 25) ATT[^65]
  function       mg/day)                       40)                      

  Combined       All                           88 (84 to   80 (71 to    
  effect                                       91)         87)          
  -------------- -------------- -------------- ----------- ------------ ------------

> LDL = low density lipoprotein
>
> \* 95% confidence intervals include imprecision of the estimates of
> both the agent reducing the risk factor and the risk factor reducing
> risk
>
> † Atorvastatin 10 mg/day, or simvastatin or lovastatin 40 mg/day taken
> in the evening or 80mg/day taken in the morning

To obtain the highest possible level of CV risk reduction in the U.S.,
it is important for the FDA to approve the indications in accordance
with the supporting data. Furthermore, it is necessary for patients,
clinicians, and health delivery systems alike to be knowledgeable about
the benefit of applicable prevention guidelines \[[^66], Error:
Reference source not found\]. In line with FDA's approval and preventive
guidelines, the keys to preventing CVD are education, access to
treatment, and behavioral change.

# efficacy: ASA prevents Mi and Cardiovascular events

This section reviews the available evidence supporting the efficacy of
ASA in the prevention of MI and cardiovascular events across the risk
continuum. The extensive evidence includes a totality of 150 studies
involving over 200,000 patients. These trials have studied over 55,000
Low Risk individuals and over 150,000 High Risk patients.

In contrast to other development programs, the overall database for ASA
is incredibly diverse, including studies with the following factors:

-   Broad continuum of age

-   Patients with different underlying baseline risk (Low, Moderate, and
    High Risk patients)

-   Different doses and formulations of ASA studied

-   Geographical and ethnic/cultural diversity

This diversity, coupled with consistent findings across the studies
provides added reliability of the findings as well as confidence in the
broad applicability of the observed benefits. Thus, despite the fact
that the ASA prevention database does not precisely meet the new drug
approval requirement of two pivotal trials demonstrating significant
effects in Moderate Risk patients, the available data are robust and
consistent, adding, rather than detracting from the reliability of the
overall findings and allowing an extrapolation from patients at Low and
High Risk to patients at Moderate Risk.

Taken as a whole, the data support the effectiveness of ASA in
preventing MI and cardiovascular events in patients at all levels of
underlying risk.

The relevant efficacy prevention data are described first for Low Risk
populations (Section 3.1) and next for the High Risk populations
(Section 3.2).

## ASA Prevents Cardiovascular Events in Low Risk Populations

This Section summarizes the evidence that ASA prevents a first MI in
apparently healthy individuals as well as in subjects selected for
evaluation based on identified cardiovascular risk factors.

The effectiveness of low-dose ASA in the prevention of a first
myocardial infarction is supported by five prospective, randomized
clinical trials conducted by independent researchers. These studies will
be referred to throughout this document as follows:

-   BDT: British Doctors' Trial (Appendix 4)

-   HOT: Hypertension Optimal Treatment Trial (Appendix 5)

-   PHS: Physicians' Health Study (Appendix 6)

-   PPP: Primary Prevention Project (Appendix 7)

-   TPT: Thrombosis Prevention Trial (Appendix 8)

These studies have been conducted in subjects with a variety of entry
criteria, including elevated baseline cardiovascular risk in three of
the studies. The data taken as a whole lend strong support to the view
that ASA effectively prevents MI in Low Risk populations and provide a
critical anchor point for ASA's role in preventing MI across the risk
continuum.

An overview of these studies, including their methodologies is
summarized in the table below.

[]{#__RefHeading___Toc55791507 .anchor}Table 5: Summary of Studies
Evaluating ASA Prevention of First Cardiovascular Event

+--------------+----------+----------+----------+----------+----------+
| **Variable** | **BDT**  | **PHS**  | **TPT**  | **HOT**  | **PPP**  |
+--------------+----------+----------+----------+----------+----------+
| Year         | 1988     | 1989     | 1998     | 1998     | 2001     |
+--------------+----------+----------+----------+----------+----------+
| Duration of  | 5.8 y    | 5 y      | 6.8 y    | 3.8 y    | 3.6 y    |
| therapy, †   |          |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Patients     | 5139 (0) | 22 071   | 2540 (0) | 18 790   | 4495     |
| (women), n   |          | (0)      |          | (8883)   | (2583)   |
+--------------+----------+----------+----------+----------+----------+
| ASA therapy  | 500 mg/d | 325 mg   | 75 mg/d  | 75 mg/d  | 100 mg/d |
| dose         |          | qod      |          |          |          |
|              | 300 mg/d |          | (cont.   | \(9399\) | \(2226\) |
| \(N\)        | if later | (11 037) | rel.)    |          |          |
|              | r        |          |          |          |          |
|              | equested |          | \(1268\) |          |          |
|              |          |          |          |          |          |
|              | \(3429\) |          |          |          |          |
+--------------+----------+----------+----------+----------+----------+
| Control      | No       | Placebo  | Placebo  | Placebo  | No       |
|              | placebo  |          |          |          | placebo  |
| \(N\)        |          | (11 034) | \(1272\) | \(9391\) |          |
|              | \(1710\) |          |          |          | \(2231\) |
+--------------+----------+----------+----------+----------+----------+
| Additional   | None     | β-       | W        | Fe       | Vitamin  |
| therapies    |          | Carotene | arfarin‡ | lodipine | E        |
|              |          | (50% of  |          | with or  |          |
|              |          | p        |          | without  |          |
|              |          | atients) |          | ACE      |          |
|              |          |          |          | i        |          |
|              |          |          |          | nhibitor |          |
|              |          |          |          | or       |          |
|              |          |          |          | β        |          |
|              |          |          |          | -blocker |          |
+--------------+----------+----------+----------+----------+----------+
| Subjects     | Healthy  | Healthy  | Men at   | Men and  | Men and  |
|              | males    | males    | high     | women    | women    |
|              |          |          | risk for | with DBP | with \>1 |
|              |          |          | CHD      |          | risk     |
|              |          |          |          | 100-115  | factors  |
|              |          |          |          | mm Hg    | for CHD  |
+--------------+----------+----------+----------+----------+----------+
| Age          | \<60 y   | Mean, 53 | Mean,    | Mean,    | \<60 y   |
|              | (46.9%); | y        | 57.5 y   | 61.5 y   | (29%);   |
|              |          | (range,  | (range,  |          |          |
|              | 60-69y   | 40-84 y) | 45-69 y) | (range,  | 60-69 y  |
|              | (39.3%); |          |          | 50-80 y) | (45%);   |
|              |          |          |          |          |          |
|              | 70-79 y  |          |          |          | 70-79 y  |
|              | (13.9%)  |          |          |          | (24%)    |
+--------------+----------+----------+----------+----------+----------+

***BDT: British Doctors' Trial; HOT: Hypertension Optimal Treatment
Trial; PHS: Physicians' Health Study; PPP: Primary Prevention Project;
TPT: Thrombosis Prevention Trial.***

***† Values given are means except for the TPT value, which is the
median.***

***‡ Data from patients who received warfarin are not included in this
table.***

It must be noted at the outset that these trials were not conducted as
part of a clinical trial program initiated by a pharmaceutical company.
Rather, they were conducted by independent research­ers in different
parts of the world as separate but related research initiatives. This
explains the differences in study designs, populations, primary
objectives, ASA doses, and other differences between trials.

In these studies, a total of 2402 CVD end points occurred among nearly
55,000 randomized participants, including 11,466 women. There was no
significant evidence of heterogeneity among the trials.

The results from these studies supporting the effectiveness of ASA in
the prevention of MI will first be presented individually. Following a
description of each individual study, they will be considered in
aggregate and evaluated by meta-analyses.

### Description of Individual Randomized Studies Supporting the Effectiveness of ASA in the Prevention of a First MI

A brief description of each individual trial demonstrating the
effectiveness of ASA in preventing cardiovascular events in Low Risk
populations is provided in this section.

#### Physicians' Health Study (PHS)

The PHS was a randomized, double-blind, placebo controlled prevention
trial of 22,071 healthy male U.S. physicians, using a factorial design
to evaluate the role of low-dose ASA (325 mg every other day) in the
prevention of cardiovascular mor­tality and beta-carotene in the
reduction of cancer incidence. The study, initiated in 1982 was designed
to test two primary-prevention hypotheses in a population of healthy
male physicians: (1) whether ASA in low doses reduces mortality from
CVD; and (2) whether beta-carotene decreases the incidence of cancer.
Although the beta-carotene portion of the study continued, the ASA
component was terminated on January 25, 1988 after approximately 5 years
of study (3 years ahead of schedule).[^67]

Subjects were randomly assigned to one of four treatment groups: (a) ASA
and beta-carotene; (b) ASA and beta-carotene placebo; (c) ASA placebo
and beta-carotene; and (d) ASA placebo and beta-carotene placebo.
Altogether 11,037 physicians were randomly assigned to receive ASA and
11,034 to receive ASA placebo.

After five years of follow-up, the reported consumption of ASA or other
platelet-active drugs was 85.7% in the ASA group and 14.2% in the
placebo group. At this time, the investigators reported 139 MIs among
those taking ASA and 239 among those taking placebo. This represents a
44 percent reduction in risk (relative risk, 0.56; 95% CI, 0.45 to 0.70;
p\<0.00001). The risk reduction was limited to those 50 years of age or
older (p=0.02). The incidence of fatal MI was also significantly lower
with ASA therapy as compared to placebo (10 vs. 26, respec­tively;
relative risk 0.34; CI 0.15 - 0.75; p=0.007). Finally, the incidence of
non-fatal MI was also significantly reduced in those patients exposed to
ASA by 31% (129 vs. 213, respectively; RR=0.59; CI = 0.47-0.74). The
relevant MI data are compiled in the table, below.

[]{#__RefHeading___Toc55791508 .anchor}Table 6: Confirmed Cardiovascular
End Points in the ASA Component of the Physicians' Health Study,
According to Treatment Group\*

+---------------------+--------+---------+-------+---------+--------+
| **End Point**       | *      | **Pl    | **    | **95%** | **P    |
|                     | *ASA** | acebo** | Relat |         | V      |
|                     |        |         | ive** | **Confi | alue** |
|                     | **G    | **      |       | dence** |        |
|                     | roup** | Group** | **R   |         |        |
|                     |        |         | isk** | **      |        |
|                     |        |         |       | Level** |        |
+---------------------+--------+---------+-------+---------+--------+
| Type of MI          |        |         |       |         |        |
+---------------------+--------+---------+-------+---------+--------+
| Fatal               | 10     | 26      | 0.34  | 0.      | 0.007  |
|                     |        |         |       | 15-0.75 |        |
+---------------------+--------+---------+-------+---------+--------+
| Nonfatal            | 129    | 213     | 0.59  | 0.      | \<0    |
|                     |        |         |       | 47-0.74 | .00001 |
+---------------------+--------+---------+-------+---------+--------+
| Total               | 139    | 239     | 0.56  | 0.      | \<0    |
|                     |        |         |       | 45-0.70 | .00001 |
+---------------------+--------+---------+-------+---------+--------+
| Person-years of     | 54     | 5       | \--   | \--     | \--    |
| observation         | ,560.0 | 4,355.7 |       |         |        |
+---------------------+--------+---------+-------+---------+--------+

> *\* Additional events that could not be confirmed because records were
> not available included*
>
> *17 myocardial infarctions (10 in the ASA group and 7 in the placebo
> group)*

No reduction in mortality from all CV causes was associated with ASA
(relative risk, 0.96; 95% CI, 0.60 to 1.54; p=0.87). A combined endpoint
consisting of non-fatal MI, non-fatal stroke and death from a CV cause
yielded a statistically significant 18% reduction in those who were
assigned to ASA (relative risk, 0.82; 95 % CI, 0.70 to 0.96; p=0.01).

*7-Year Follow Up of PHS*

After the ASA portion of the study was terminated in 1988 (following
five years of study), the population was evaluated seven years later
\[[^68]\]. At this time point, 99.7% of participants were providing
morbidity information, and mortality information was complete for all
but 1 of the 22,071 participants. At that time, 78.7% of participants
were still taking beta-carotene or placebo.

In order to obtain information about the effect of ASA after the
randomization period, the investigators questioned all participants
about self-selected ASA use and obtained the following data:

-   59.5% reported taking ASA at least 180 days during the past year;

-   11.6% reported taking ASA 121 to 179 days during the past year;

-   8.1% reported taking ASA 14 to 120 days during the past year; and

-   20.8% reported taking ASA 0 to 13 days during the past year.

The investigators were then able to use these data to evaluate the
relationship between self-selected post-trial ASA use with subsequent
CVD and mortality in the period from 7 to 12 years of follow-up among
those with no CVD before this time. During the five-year post-trial
follow-up period, there were 311 unrefuted reports of MI, 266 strokes
(including 185 ischemic and 34 hemorrhagic), 205 cardiovascular-related
deaths, and 782 total deaths.

During the five-year follow-up, there was a statistically significant,
28% lower rate of MI in self-reported frequent ASA users
([\>]{.underline}180 d/y) compared with the nonusers (0-13 d/y) RR =
0.72; 95% CI = 0.55-0.95). This 28% reduction, therefore, confirms and
extends the 44% reduction observed during the randomization period.

The investigators also observed a significant reduction in CVD-related
mortality with self-selected ASA use (RR = 0.65; 95% CI = 0.47 -- 0.89)
and, as a result, in total mortality (RR = 0.64; CI = 0.54 -- 0.77),
findings that were not seen during the randomization period, suggesting
that the original observation period was not sufficiently long to obtain
meaningful mortality benefit.

#### British Doctors' Trial (BDT)

In this open study involving 5,139 physicians, ASA was administered for
an average of 4 years. The study was randomized but not placebo
controlled: 3,429 of the doctors were assigned ASA (500 mg/day ordinary,
soluble or effervescent ASA or 300 mg enteric-coated ASA tablets), while
the remaining 1,710 doctors were to avoid ASA. Regard­ing the incidence
of myocardial infarction or stroke, no difference was observed in the
study; total mortality was 10% lower in the ASA group than in the
control group, but this difference was not statistically significant.
The incidence of cerebral transient ischemic attacks (TIAs) was
significantly reduced to 15.9% in the ASA group as compared to 27.5% in
the control group.

The authors themselves attributed the lack of significance regarding
their main objective to the fact that during the study period 30% of the
participants in the ASA group ceased taking ASA whereas 12% in the
control group abandoned their regimen and started taking ASA. The final
evaluation, however, had to be based on the original assignment of the
subjects to the two groups at the time of randomization. The fact that
so many doctors changed from one group to the other meant that on the
one hand the results of ASA therapy were diluted while on the other hand
the control group results appeared to be better than they really were.
Moreover, it might be speculated that concerning healthy individuals a
much larger study population is necessary in order to demonstrate any
clinically relevant effect on the incidence of vascular events.

#### Thrombosis Prevention Trial (TPT)

The aim of the TPT was to evaluate low-dose ASA and low-intensity oral
anticoagulation with warfarin in the primary prevention of ischemic
heart disease (IHD). The primary endpoint was all IHD defined as the sum
of fatal and non-fatal events (i.e. coronary death, and fatal MI, and
nonfatal MI). Treatment effects on fatal and non-fatal MI were also
separately examined. Fatal IHD was defined as the sum of coro­nary death
and fatal MI (death within a month), since there was often little
distinction be­tween the clinical and pathological characteristics of the
two groups. Stroke was a secondary endpoint, with results for thrombotic
and hemorrhagic events distinguished as far as possible, depending on
whether appropriate imaging or necropsy findings were available.

5499 men aged between 45 and 69 years were recruited from 108 practices
in the UK that belonged to the Medical Research Council\'s General
Practice Research Framework. Initially, warfarin or placebo was randomly
allocated to 1,427 men; 1,013 of these men later moved to a factorial
stage of the trial, retaining their warfarin or placebo-warfarin
allocation and adding randomly allocated active or placebo ASA. Another
4072 men entered directly into the factorial stage of the trial making a
total of 5085 men in the trial.

The four factorial treatment groups were: active ASA and active warfarin
(WA; n = 1277), active ASA and placebo warfarin (A; n = 1268), active
warfarin and placebo ASA (W; n = 1268), and placebo warfarin and placebo
ASA (P; n = 1272). Subjects in this trial were given 75 mg/d of
controlled release ASA.

The participants were regarded as being at a high risk of ischemic heart
disease at entry defined as the top 20% of a risk score distribution
based on smoking history, blood pressure, body mass index, blood
cholesterol, fibrinogen and factor VII activity. These variables were
weighted according to their relationship with ischemic heart disease in
the Northwick Park Heart Study \[[^69]\]. The observation period was 8
to 13 years, median participation 6.8 years.

The primary effect of low-dose ASA was a 32% reduction in non-fatal MI
(p=0.004). This robust finding was largely responsible for the 20%
reduction of all IHD (p=0.04). The findings are summarized in the figure
below.

[]{#__RefHeading___Toc55791524 .anchor}Figure 2: Cumulative proportion
(%) of men with IHD, main effects (Figure 2 from TPT Study)

![](media/image1.png){width="6.295833333333333in"
height="5.274305555555555in"}

The results of the TPT Study clearly confirm the effectiveness of ASA in
the prevention of MI in persons having cardiovascular risk factors. ASA
had no effect on stroke or total mortality.

#### Hypertension Optimal Treatment Study (HOT)

The main objectives of the Hypertension Optimal Treatment (HOT) Study
were to evaluate the effects of antihypertensive and antiplatelet
therapy on the incidence of adverse car­diovascular outcomes. The
investigators aimed to assess the optimum target diastolic blood
pressure and the potential benefit of low-dose ASA (75 mg daily) in
addition to the medical treatment of hypertension.

In this trial, 18,790 patients from 26 countries were randomly as­signed
a target blood pressure of ≤90 mmHg, ≤85 mmHg or ≤80 mmHg. The average
follow-up time was 3.8 years (range: 3.3 to 4.9 years) and the total
number of patient years was 71,051. The age of patients ranged from 50
to 80 years (mean: 61.5 years); 53% were male, 47% female. If necessary,
felodipine was given as a baseline therapy plus other hypertensives,
according to a five-step regimen. 9399 patients were randomly assigned
low-dose ASA and 9391 patients were assigned placebo.

ASA reduced all MI (combined fatal and nonfatal MI) by 36% (p=0.002). It
should be noted, however, that the effects of ASA on major
cardiovascular events and on MIs were no longer significant when silent
myocardial infarctions were included in the analysis. However, silent
myocar­dial infarctions were not included as endpoints in any of the
other randomized controlled studies examining the role of ASA in the
prevention of cardiovascular events in high risk or low risk patients
with ASA. The consensus of investigators in the field is that the
analysis is most appropriate without the inclusion of silent MI, as this
endpoint represents a very different clinical picture than a documented
clinical event.

ASA also exerted a statistically significant reduction on major
cardiovascular events by 15% (p=0.03). Finally, it should be noted that
there were no differences in antihypertensive therapy between the ASA
and the placebo group. The data demonstrating the relevant risk
reductions are provided below.

[]{#__RefHeading___Toc55791509 .anchor}Table 7: Risk Reductions for
Prevention of Cardiovascular Events in the HOT Study

+------------------+------------+------------+------------+------------+
| *Events*         | *Number of | *E         | *p*        | *Relative  |
|                  | events*    | vents/1000 |            | risk*      |
|                  |            | pati       |            |            |
|                  |            | ent-years* |            | *(95% CI)* |
+------------------+------------+------------+------------+------------+
| Major            | 315        | 8.9        | 0.03       | 0.85       |
| cardiovascular   |            |            |            | (          |
| events           | 368        | 10.5       |            | 0.73-0.99) |
|                  |            |            |            |            |
| Acetylsalicylic  |            |            |            |            |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Major            | 388        | 11.1       | 0.17       | 0.91       |
| cardiovascular   |            |            |            | (          |
| events,          | 425        | 12.2       |            | 0.79-1.04) |
| including silent |            |            |            |            |
| myocardial       |            |            |            |            |
| infarction       |            |            |            |            |
|                  |            |            |            |            |
| Acetylsalicylic  |            |            |            |            |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| All myocardial   | 82         | 2.3        | 0.002      | 0.64       |
| infarction       |            |            |            | (          |
|                  | 127        | 3.6        |            | 0.49-0.85) |
| Acetylsalicylic  |            |            |            |            |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| All myocardial   | 157        | 4.4        | 0.13       | 0.85       |
| infarction,      |            |            |            | (          |
| including silent | 184        | 5.2        |            | 0.69-1.05) |
| cases            |            |            |            |            |
|                  |            |            |            |            |
| Acetylsalicylic  |            |            |            |            |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| All stroke       | 146        | 4.1        | 0.88       | 0.98       |
|                  |            |            |            | (          |
| Acetylsalicylic  | 148        | 4.2        |            | 0.78-1.24) |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Cardiovascular   | 133        | 3.7        | 0.65       | 0.95       |
| mortality        |            |            |            | (          |
|                  | 140        | 3.9        |            | 0.75-1.20) |
| Acetylsalicylic  |            |            |            |            |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Total mortality  | 284        | 8.0        | 0.36       | 0.93       |
|                  |            |            |            | (          |
| Acetylsalicylic  | 305        | 8.6        |            | 0.79-1.09) |
| acid             |            |            |            |            |
|                  |            |            |            |            |
| Placebo          |            |            |            |            |
+------------------+------------+------------+------------+------------+

**Events in relation to acetylsalicylic acid (n=9399) or placebo
(n=9391)**

It must be emphasised that the HOT Study is the first to demonstrate a
beneficial effect of low-dose ASA in addition to antihypertensive
therapy in the prevention of myocardial infarction and major
cardiovascular events in patients with treated high blood pressure. As
the number of patients who had a previous cardiovascular event was small
(1.6% had a previous MI, 1.2% had a previous stroke, approximately 6%
had other previous coronary heart disease), the HOT Study can be
regarded as a major primary prevention study. In addition to high blood
pressure, approximately 16% of the HOT Study population were smokers and
8% suffered from diabetes mellitus.

#### Primary Prevention Project (PPP)

The aim of the Primary Prevention Project (PPP) was to investigate the
efficacy of 100 mg ASA per day given as enteric-coated tablets and/or
vitamin E (300 mg/day) in the primary prevention of cardiovascular
events in addition to the treatment of specific risk factors. In this
study, 4495 subjects (57.4% women; mean age 64.4 y) with at least one
vascular risk factor (e.g., old age, hypertension, diabetes, obesity,
hypercholesterolemia, and family history of premature myocardial
infarction) were included in an open, randomised, controlled 2x2
factorial design. The primary endpoint was the cumulative rate of
cardiovascular death, non-fatal MI and non-fatal stroke. Secondary
endpoints were each component of the primary endpoint, total deaths and
other CVDs or events. Most of the participants were screened for
eligibility by general practitioners.

The trial was prematurely stopped for ethical reasons because newly
available evidence from the Thrombosis Prevention Trial and the HOT
Study on the benefit of ASA in primary prevention was strictly
consistent with the results of the second interim analysis after a mean
follow-up of 3.6 years.

Specifically, ASA lowered the frequency of all endpoints, being
significant for cardiovascular deaths (RR = 0.56; 95% CI = 0.31 -- 0.99;
p=0.049) and for any cardiovascular events including cardiovascular
death, non-fatal MI, non-fatal stroke, TIA, angina pectoris, peripheral
artery disease and revascularisation proce­dures (RR = 0.67; 95% CI =
0.62 -- 0.95; p=0.014). Because vitamin E showed no effect on any
pre-specified endpoint, it could be argued that the vitamin E group
served as a "placebo control."

The relevant risk reduction data are presented below in a copy of the
table extracted from the publication.

[]{#__RefHeading___Toc55791510 .anchor}Table 8: Relative Risk Reductions
with Aspirin and Vitamin E Treatment

+-------------+-------+-------+---------+-------+-------+---------+
|             | *Asp  | *No   | *R      | *Vi   | *No   | *R      |
|             | irin* | asp   | elative | tamin | vi    | elative |
|             |       | irin* | risk*   | E*    | tamin | risk    |
|             | *(n=2 |       |         |       | E*    | (95%    |
|             | 226)* | *(n=2 | *(95%   | *(n=2 |       | CI)*    |
|             |       | 269)* | CI)*    | 231)* | *(n=2 |         |
|             |       |       |         |       | 264)* |         |
+-------------+-------+-------+---------+-------+-------+---------+
| Main        | 45    | 64    | 0.71    | 56    | 53    | 1.07    |
| combined    | (     | (     | (0.4    | (     | (     | (0.7    |
| endpoint    | 2.0%) | 2.8%) | 8-1.04) | 2.5%) | 2.3%) | 4-1.56) |
| (car        |       |       |         |       |       |         |
| diovascular |       |       |         |       |       |         |
| death,      |       |       |         |       |       |         |
| non-fatal   |       |       |         |       |       |         |
| myocardial  |       |       |         |       |       |         |
| infarction, |       |       |         |       |       |         |
| and         |       |       |         |       |       |         |
| non-fatal   |       |       |         |       |       |         |
| stroke)     |       |       |         |       |       |         |
+-------------+-------+-------+---------+-------+-------+---------+
| Total       | 141   | 187   | 0.77    | 158   | 170   | 0.94    |
| car         | (     | (     | (0.6    | (     | (     | (0.7    |
| diovascular | 6.3%) | 8.2%) | 2-0.95) | 7.1%) | 7.5%) | 7-1.16) |
| events of   |       |       |         |       |       |         |
| diseases\*  |       |       |         |       |       |         |
+-------------+-------+-------+---------+-------+-------+---------+
| All deaths  | 62    | 78    | 0.81    | 72    | 68    | 1.07    |
|             | (     | (     | (0.5    | (     | (     | (0.7    |
| Car         | 2.8%) | 3.4%) | 8-1.13) | 3.2%) | 3.0%) | 7-1.49) |
| diovascular |       |       |         |       |       |         |
|             | 17    | 31    | 0.56    | 22    | 26    | 0.86    |
| Non-car     | (     | (     | (0.3    | (     | (     | (0.4    |
| diovascular | 0.8%) | 1.4%) | 1-0.99) | 1.0%) | 1.1%) | 9-1.52) |
|             |       |       |         |       |       |         |
|             | 45    | 47    | 0.98    | 50    | 42    | 1.21    |
|             | (     | (     | (0.6    | (     | (     | (0.8    |
|             | 2.0%) | 2.0%) | 5-1.46) | 2.2%) | 1.9%) | 0-1.81) |
+-------------+-------+-------+---------+-------+-------+---------+
| All         | 19    | 28    | 0.69    | 22    | 25    | 0.89    |
| myocardial  | (     | (     | (0.3    | (     | (     | (0.5    |
| infarction  | 0.8%) | 1.2%) | 8-1.23) | 1.0%) | 1.1%) | 2-1.58) |
|             |       |       |         |       |       |         |
| Non-fatal   | 15    | 22.(  | 0.69    | 19    | 18    | 1.01    |
| myocardial  | (     | 1.0%) | (0.3    | (     | (     | (0.5    |
| infarction  | 0.7%) |       | 6-1.33) | 0.8%) | 0.8%) | 6-2.03) |
+-------------+-------+-------+---------+-------+-------+---------+
| All stroke  | 16    | 24    | 0.67    | 22    | 18    | 1.24    |
|             | (     | (     | (0.3    | (     | (     | (0.6    |
| Non-fatal   | 0.7%) | 1.1%) | 6-1.27) | 1.0%) | 0.8%) | 6-2.31) |
| stroke      |       |       |         |       |       |         |
|             | 15    | 18    | 0.84    | 20    | 13    | 1.56    |
|             | (     | (     | (0.4    | (     | (     | (0.7    |
|             | 0.7%) | 0.8%) | 2-1.67) | 0.9%) | 0.6%) | 7-3.13) |
+-------------+-------+-------+---------+-------+-------+---------+
| Angina      | 54    | 67    | 0.82    | 66    | 55    | 1.22    |
| pectoris    | (     | (     | (0.5    | (     | (     | (0.8    |
|             | 2.4%) | 3.0%) | 8-1.17) | 3.0%) | 2.4%) | 6-1.73) |
+-------------+-------+-------+---------+-------+-------+---------+
| Transient   | 28    | 40    | 0.71    | 33    | 35    | 0.96    |
| ischaemic   | (     | (     | (0.4    | (     | (     | (0.6    |
| attack      | 1.3%) | 1.8%) | 4-1.15) | 1.5%) | 1.5%) | 0-1.53) |
+-------------+-------+-------+---------+-------+-------+---------+
| Periph      | 17    | 29    | 0.60    | 16    | 30    | 0.54    |
| eral-artery | (     | (     | (0.3    | (     | (     | (0.3    |
| disease     | 0.8%) | 1.3%) | 3-1.08) | 0.7%) | 1.3%) | 0-0.99) |
+-------------+-------+-------+---------+-------+-------+---------+
| Revasc      | 20    | 29    | 0.70    | 27    | 22    | 1.25    |
| ularisation | (     | (     | (0.4    | (     | (     | (0.7    |
| procedure   | 0.9%) | 1.3%) | 0-1.24) | 1.2%) | 1.0%) | 1-2.18) |
+-------------+-------+-------+---------+-------+-------+---------+

All data are n (%) unless otherwise indicated. \*Participants with one
or more of the following events: cardiovascular death, non-fatal
myocardial infarction, non-fatal stoke, angina pectoris, transient
ischaemic attack, peripheral-artery disease, revascularisation
procedure.

In summary, the PPP adds to the evidence that low-dose ASA is effective
in the prevention of cardiovascular events, especially myocardial
infarction, in persons at increased vascular risk. The risk factors
investigated included hyperten­sion, diabetes, hyperlipidemia, old age,
family history and others. It must be emphasised that the beneficial
effects of ASA occurred in addition to the treatment of these specific
risk factors in individual patients.

The PPP was the first primary prevention trial showing a beneficial and
significant effect of low-dose ASA on cardiovascular death. The lack of
a placebo control is practically com­pensated by the fact that vitamin E
did not show an effect on any pre-specified endpoint.

The authors interpreted the study results as follows: "In women and men
at risk of having a car­diovascular event because of the presence of at
least one major risk factor, low-dose ASA given in addition to treatment
of specific risk factors contributes an additional preventive effect,
with an acceptable safety profile."

### Meta-Analysis of Low Risk Trials

Eidelman and colleagues conducted a computerized search of the English
literature from 1988 to 1998 and identified 4 published randomized
trials of ASA in the primary prevention of CHD \[[^70]\]. In a previous
meta-analysis of these trials, ASA therapy was shown to significantly
reduce the risk of a first MI by 32% and the risk of any important
vascular event (nonfatal MI, nonfatal stroke, or vascular death) by 13%.
From 1998 to the present, a subsequent review of the English literature
revealed 1 additional primary prevention trial of aspirin as well as new
guidelines on the use of aspirin in the primary prevention of CHD. The
fifth and most recently published trial of aspirin in the primary
prevention of MI is the PPP. These investigators therefore updated their
meta-analysis to include all five primary prevention trials.

To perform the meta-analysis, the investigators used the published data
from the PHS, the BDT, the TPT, the HOT study, and the PPP. The outcomes
examined were a combined end point of any important vascular event
(non-fatal MI, nonfatal stroke, or vascular death), and each of these
individual components separately.

The criteria for inclusion of trials were as follows: (1) aspirin alone
was used for the primary prevention of CHD, as opposed to combined
interventions; (2) comparisons of outcomes were made between aspirin
groups and either placebo or open control groups; and (3) data were
available on MI, stroke, and vascular deaths. Eidelman and colleagues'
complete analysis report can be found in Appendix 9.

#### Meta-Analysis -- Nonfatal MI

Eidelman and colleagues reported a statistically significant risk
reduction of 32% for nonfatal MI associated with ASA therapy (RR = 0.68;
95% CI = 0.59 - 0.79). A tabular summary of the data making up this
analysis is presented in the table below.

[]{#__RefHeading___Toc55791511 .anchor}Table 9: Nonfatal Myocardial
Infarction (MI) in the Randomized Trials of ASA in the Primary
Prevention of Cardiovascular Disease

+----------------+-------------+-----------+-----------+-------------+
|                | **ASA**     |           | **        |             |
|                |             |           | Control** |             |
+----------------+-------------+-----------+-----------+-------------+
| Trial          | Nonfatal    | Subjects  | Nonfatal  | Subjects    |
|                |             |           |           |             |
|                | MI (No.)    | R         | MI (No.)  | Randomized  |
|                |             | andomized |           |             |
|                |             |           |           | (No.)       |
|                |             | (No.)     |           |             |
+----------------+-------------+-----------+-----------+-------------+
| PHS            | 129         | 11,037    | 213       | 11,034      |
+----------------+-------------+-----------+-----------+-------------+
| BDT            | 80          | 3,429\*   | 41        | 1,710\*     |
+----------------+-------------+-----------+-----------+-------------+
| TPT            | 94          | 2,545     | 137       | 2,540       |
+----------------+-------------+-----------+-----------+-------------+
| HOT            | \-          | \-        | \-        | \-          |
+----------------+-------------+-----------+-----------+-------------+
| PPP            | 15          | 2,226     | 22        | 2,269       |
+----------------+-------------+-----------+-----------+-------------+
| Total          | 318         | 19,237    | 413       | 17,553      |
+----------------+-------------+-----------+-----------+-------------+
| Relative Risk  | 0.68        |           |           |             |
|                |             |           |           |             |
| (95% CI)       | (0.59 --    |           |           |             |
|                | 0.79)       |           |           |             |
+----------------+-------------+-----------+-----------+-------------+

> ***\* A 2:1 randomization of ASA to control was used***

#### Meta-Analysis - Any Important Vascular Event

The meta-analysis also reported a statistically significant 15%
reduction in the risk of any important vascular event associated with
ASA therapy (RR -- 0.85; 95% CI = 0.79 - 0.93), driven in large part by
the statistically extreme finding of reduced MI risk. A tabular summary
of the important data contributing to this analysis is presented below.

[]{#__RefHeading___Toc55791512 .anchor}Table 10: Any Important Vascular
Event in the 5 Randomized Trials of ASA in the Primary Prevention of
Cardiovascular Disease

+-------------+--------------+-------------+--------------+-----------+
|             | **ASA**      |             | **Control**  |           |
+-------------+--------------+-------------+--------------+-----------+
| Trial       | Any          | Subjects    | Any          | Subjects  |
|             | Important    |             | Important    |           |
|             |              | (No.)       |              | (No.)     |
|             | Vascular     |             | Vascular     |           |
|             | Event (No.)  |             | Event (No.)  |           |
+-------------+--------------+-------------+--------------+-----------+
| PHS         | 307          | 11,037      | 370          | 11,034    |
+-------------+--------------+-------------+--------------+-----------+
| BDT         | 289          | 3,429       | 147          | 1,710     |
+-------------+--------------+-------------+--------------+-----------+
| TPT         | 228          | 2,545       | 260          | 2,540     |
+-------------+--------------+-------------+--------------+-----------+
| HOT         | 315          | 9,399       | 368          | 9,391     |
+-------------+--------------+-------------+--------------+-----------+
| PPP         | 47           | 2,226       | 71           | 2,269     |
+-------------+--------------+-------------+--------------+-----------+
| Total       | 1,186        | 28,636      | 1,216        | 26,944    |
+-------------+--------------+-------------+--------------+-----------+
| Relative    | 0.85         |             |              |           |
| Risk        |              |             |              |           |
|             | (0.79 --     |             |              |           |
| (95% CI)    | 0.93)        |             |              |           |
+-------------+--------------+-------------+--------------+-----------+

#### Meta-Analysis: Vascular Death

For vascular deaths, there was no significant reduction in risk although
the CIs were wide and included the plausible decrease seen in the trials
of secondary prevention, as well as a small increase (RR = 0.98; 95% CI
= 0.85-1.12).

#### Meta-Analysis: Stroke

It is difficult to interpret the overall effect of ASA on stroke because
the effect differs for different types of stroke. Overall stroke rates
were lower than expected (based on age and risk factors) in all 5 Low
Risk trials. In each trial, control participants who had not been given
ASA had a less than 2% incidence of total strokes over 5 years. Because
of the lower-than-expected stroke rates, the individual trials had a
limited statistical power to reliably detect the true effect of aspirin
on stroke. Summary estimates showed no statistically significant
reduction in total stroke overall (OR =1.02; 95% CI = 0.85-1.23).

### A Range of Doses Are Effective

The doses of ASA used in the five primary prevention trials ranged from
75 mg per day (in TPT and HOT) to 500 mg/day (in the BDT). While the BDT
did not report a significant effect of 500 mg/day ASA on the prevention
of nonfatal MI, the consensus view is that this trial was too small to
detect a significantly meaningful benefit. The PHS did report a robust
and statistically significant reduction in prevention of nonfatal MI of
44% at a dose of 325 mg every other day (details of this study are
provided in Section 1.2.6.1). Studies in higher risk populations confirm
that a wide range of ASA doses are effective in preventing
cardiovascular events and support the proposed labeling to include doses
of 75 mg -- 325 mg/day \[[^71]\].

### Relevant Subgroup Analyses

*Gender*

The vast majority of the subjects in the five primary prevention trials
were men (41,569 participants) and therefore the observed benefits are
most easily generalizable to men.

Despite the preponderance of male subjects in the five trials, there
were a substantial number of women represented across the trials. Of the
five primary prevention trials, HOT randomized 8883 women and the PPP
2583, for a total of 11,466 women. In HOT, subgroup analyses were
presented for women and there was a possible but nonsignificant 19%
reduction in risk of a first MI. In PPP, the authors reported that the
magnitude of benefit in women and men equaled the overall 31% reduction
in risk of a first MI. Thus, the overall point estimate of the reduction
in risk of a first MI for women is about 22% (consistent with the
overall benefits observed among the trials).

*Age*

The five primary prevention trials evaluated subjects over a variety of
ages. A summary of the age ranges in each of the trials is provided
below.

[]{#__RefHeading___Toc55791513 .anchor}Table 11: Ages of Subjects

  ------------------------ ----------------------------------------------
  **Trial**                **Age Range**

  BDT                      \< 60 y -- 79 y

  PHS                      40 -- 84 y

  TPT                      45 -- 69 y

  HOT                      60 -- 80 y

  PPP                      \< 60 y -- 79 y
  ------------------------ ----------------------------------------------

It is evident from the Table that a broad range of ages were studied in
these trials (through an upper range of 84 years-old in the PHS) and
therefore the results should be generalizable for individuals over 40
years of age.

*Diabetes*

The proportion of patients with diabetes mellitus was small in each
trial (PPP: 17%; HOT: 8%; PHS: 2%; BDT: 2%; TPT: 2%). In PHS, patients
with diabetes derived greater benefit from ASA than those without
diabetes (RR 0.39 vs. 0.60) \[[^72]\].

*Hypertension*

The influence of hypertension on the effectiveness of ASA
chemoprevention has been examined in subgroup analyses. In TPT, Meade et
al., \[Error: Reference source not found\] found that ASA reduced total
cardiovascular events in patients whose systolic blood pressure (SBP)
was less than 130 mm Hg (RR = 0.59) but not in patients whose SBP was
greater than 145 mm Hg (RR = 1.08). Patients with SBP between 130 and
145 mm Hg also had reduced risk (RR = 0.68). In PHS, patients who were
taking ASA and had SBP greater than 150 mm Hg had a relative risk of
0.65 for MI, compared with relative risks of 0.55 for those with SBP
between 130 and 149 mm Hg and 0.52 for those with SBP between 110 and
129 mm Hg. The HOT trial found significant reductions in CHD events
among patients with treated hypertension, but did not have a comparison
group without hypertension.

### Other Relevant Meta Analyses

*CTSU Analysis*

Under the auspices of the Clinical Trial Service Unit (CTSU) of the
University of Oxford, the Antithrombotic Trialists' Primary Prevention
Group (ATT) was assembled in February 2001 to conduct a comprehensive
meta-analysis based on individual patient data from the five available
primary prevention trials. The principal investigators of each of the
major trials agreed to collaborate in this meta-analysis in order to
address additional questions that could not be answered by meta-analyses
based on data derived from publications alone. The meta-analysis was
designed to assess the proportional effects of aspirin on major
cardiovascular outcomes (vascular events \[as defined by non-fatal MI,
non-fatal stroke, or vascular death\], CHD events \[non-fatal MI or CHD
death\], presumed ischemic stroke, hemorrhagic stroke, vascular or
non-vascular causes of death, and major extracranial bleeds) and to
compare these effects with the analogous results from long-term trials
of aspirin involving high-risk patients (secondary prevention). As
individual primary prevention trials have suggested that the net effects
of aspirin might be different in certain populations, the effects of ASA
on pre-specified subgroups (as defined by age, gender, smoking history,
blood pressure, etc) were to be considered.

A particular goal of the collaboration was to assess whether there might
be selected patients within the primary prevention studies that could be
identified as being at Moderate Risk (annual risk of \>1%) of a CHD
event, and to compare the effects of aspirin in these individuals to
that observed in a high-risk setting. The intent of this analytical
approach was to determine if the benefit to risk relationship might be
enhanced by restricting use to a group with risk of a CHD event greater
than that generally observed in the primary prevention trials.

The ATT Primary Prevention Group recently met to discuss the
implications for broader use of aspirin based on the preliminary
findings of the analyses set forth above. It is important to note that
this analysis is based on the same five studies included in the
literature-based meta-analysis under review by the FDA. While this work
is still underway and not yet subjected to peer review, this
collaborative work by the principal investigators of the primary
prevention trials has helped to define the effects of aspirin across
different populations. It therefore clarifies the findings of the
previously conducted meta-analysis (and other published analyses)
submitted in consideration of the requested indication for the use of
aspirin in patients at increased risk of CHD events (as defined by a 10
year risk of at least 10%). The complete report of the ATT Primary
Prevention Group's meta-analysis can be found in Appendix 10.

Overall, in the ATT Primary Prevention Group analyses, which include
55,580 patients, there was a statistically significant 15%
[+]{.underline} 4 reduction in vascular events that was largely driven
by a 23% [+]{.underline} 5 reduced risk of CHD events. In contrast to
the secondary prevention database, there was no net reduction in the
risk of presumed ischemic stroke, and no reduction in vascular death.
Based on this analysis, it might be expected that, among healthy
individuals such as those generally studied in the 5 primary prevention
trials, aspirin would prevent approximately 4-5 CHD events for every
1000 patients treated for 5 years.

The proportional reduction of about one quarter on CHD events appeared
to be similar regardless of age, gender, history of hypertension,
diabetes or atrial fibrillation, smoking, cholesterol levels, body mass
index, or baseline risk of CHD. In addition, the one-quarter reduction
in CHD events also appeared similar to that observed in previous trials
for the secondary prevention of MI or of stroke among high-risk
patients.

While additional analyses are underway to further evaluate the absolute
benefits and risks of ASA treatment based on underlying cardiovascular
risk, the analyses suggest that there may be selected individuals at
Moderate risk of a CHD event (i.e., greater than 1% per annum) who would
be possible candidates for long-term ASA therapy. However, the analyses
also highlight a relative lack of information from randomized trials
concerning the effects of aspirin among moderate-risk individuals (such
as those with "metabolic syndrome", for example), and suggest that the
decision regarding the appropriateness of long-term aspirin in a given
patient should give due consideration to these uncertainties as well as
the underlying risk of CHD.

Finally, it should be noted that two other meta-analyses \[[^73], Error:
Reference source not found\] arrived at a similar findings to the CTSU
and Eidelman and colleagues' analyses.

## ASA Prevents Cardiovascular Events in High Risk Populations

As stated above, the efficacy of ASA as an antiplatelet drug in the
prevention of cardiovascular events has been demonstrated in a large
number of trials in a diversity of patient populations. The data
obtained from patients that have already experienced a cardiovascular
event (High Risk populations) are instructive in addressing questions
that are not answerable with the Low Risk studies. In addition, studies
in these High Risk populations provide the "anchor point" for the
benefits of ASA for the high end of the risk continuum establishing the
basis for extrapolating the benefits to Moderate Risk patients.

To provide support for the appropriateness of broadening the labeling of
ASA to include Moderate Risk patients, the evidence from the secondary
prevention database (i.e., High Risk patients) is described below.
Because the populations in the High Risk and the Low Risk studies are
homogeneous, the evidence obtained in High Risk patients helps to
confirm and extend the findings presented for Low Risk patients and
provide insight with respect to subgroups.

### The Antithrombotic Trialists' Collaboration (ATT)

The systematic overview of the effects of antiplatelet therapy on
vascular events conducted by the Antithrombotic Trialists Collaboration
(ATT) \[Error: Reference source not found\] evaluated data from the
following high risk patient populations:

-   Patients with Acute Evolving MI

-   Patients with Prior MI

-   Patients with Unstable Angina Pectoris

-   Patients with Prior Stroke or Transient Ischemic Attack

-   Patients with Chronic Stable Angina

-   Patients with Chronic Non-Valvular Atrial Fibrillation

-   Patients Undergoing Revascularization Procedures and Those Requiring
    Establishment of Hemodialysis Access

This massive collection of data shows that, in approximately 200
randomized trials, antiplatelet therapy (with ASA being the most widely
studied antiplatelet therapy) is highly effective in reducing the
incidence of non-fatal MI in High Risk patients, at a similar rate (34%)
as that observed in the Low Risk populations described above.

Figure 3 below provides a summary of the reductions in non-fatal MI
demonstrated across a variety of patient populations.

[]{#__RefHeading___Toc55791525 .anchor}Figure 3: ATT Collaboration Data:
Non-Fatal Myocardial Infarction

![](media/image1.wmf)

In addition, antiplatelet therapy was also highly effective in reducing
the number of vascular events across a wide range of High Risk patients.
The risk reduction data are summarized in the following figure extracted
from the ATT publication.

[]{#__RefHeading___Toc55791526 .anchor}Figure 4: ATT Collaboration Data:
Vascular Events

![](media/image1.wmf)

These studies in a variety of High Risk patient populations demonstrated
that the proportional risk reductions for both non-fatal MI as well as
for any vascular events are similar across populations. The authors of
the ATT conclude: "Our results suggest that among individuals at high
risk of occlusive vascular disease, the proportional risk reductions
with antiplatelet therapy were roughly similar in most categories of
patient (although they are smaller in acute stroke)."

### Effect of ASA Dose on Vascular Events

The investigators reported a 26% -- 32% reduction of the combined end
points of MI, stroke, or vascular death by treatment with ASA alone at
doses of 75 mg to 325 mg. Analysis of the overall data in high risk
individuals shows that low doses of ASA ([\<]{.underline} 325 mg/day)
exerts at least as great a protective effect as higher doses (326 to
1500 mg/day).

These cardiovascular risk reductions in these patient populations
exposed to ASA therapy are summarized in the Figure, below.

[]{#__RefHeading___Toc55791527 .anchor}Figure 5: ATT Collaboration Data:
Effect of Dose

![](media/image1.wmf)

Based on these data, there does not appear to be a significant effect of
ASA dose (in the range studied) on the prevention of vascular events in
this High Risk patient population.

### Relevant Subgroup Analysis

The analyses from the ATT have found that there was no significant
effect of age or gender on the ability of antiplatelet therapy to
prevent vascular events in a variety of High Risk patients. With respect
to diabetes, according to these analyses, antiplatelet therapy was
associated with a nonsignificant 7% proportional reduction in serious
vascular events among patients with diabetes (but predominantly, no
history of MI or stroke). The authors do not interpret this lack of
statistical finding as indicating a lack of worthwhile benefit in such
patients. Rather, taken as a whole, the ATT investigators interpret this
finding as consistent with a benefit of antiplatelet therapy in this
patient population. They specifically state that ASA "is likely to be
effective for the primary prevention of vascular events among diabetic
populations."

With respect to the effect of antiplatelet therapy in specific subgroups
generally, the investigators state: "...these findings can reasonably be
extrapolated to a far wider range of high risk patients than those
studied..."

### Meta-Analysis of Six High Risk Trials (Secondary Prevention Trials)

To specifically address the effects of ASA in FDA-approved indications,
Weisman and Graham (2002) identified a subset of studies in which
secondary prevention patients were treated with low dose ASA \[[^74]\].
Specifically, they identified all randomized, placebo controlled
interventions with an ASA-only arm with low dose ASA (defined as daily
doses of 50 -- 325 mg) for FDA-approved secondary prevention indications
as summarized in the FDA's 1998 rule and updated professional labeling
for ASA. These uses included stroke in those who had a previous event or
a TIA and MI in those who had a previous MI or a history of angina.

Six studies were identified meeting these inclusion criteria: \[Error:
Reference source not found, Error: Reference source not found, [^75],
Error: Reference source not found, [^76], [^77]\]. According to this
analysis, among 6300 patients, 2427 experienced a previous MI and 1757
had a history of TIA or stroke. Among these patients, there were 558
subsequent MIs, 424 strokes, and 91 other vascular events. All of the
assessments demonstrated a trend in favor of ASA reducing the risks of
cardiovascular events (MI) and cerebrovascular events (stroke) with
relative risk reductions between 20% and 30%.

Risk ratio estimates obtained from this meta-analysis are summarized in
Table 12 below.

[]{#__RefHeading___Toc55791514 .anchor}Table 12: Summary of Risk Ratio
Estimates for 6 Studies Evaluating ASA For the Prevention of Stroke in
High Risk Patients (adapted from Weisman and Graham, 2002).

+-----------------+-----------------+-------+-----------+-------------+
| **[Outcome      | **Risk Ratio    | **P** | **Risk**  | **Ho        |
| ]{.underline}** | (95%)**         |       |           | mogeneity** |
|                 |                 | **[   | **Red     |             |
|                 | **Confidence**  | Value | uction,** | **P**       |
|                 |                 | ]{.un |           |             |
|                 | **[Interval)    | derli | *         | *           |
|                 | ]{.underline}** | ne}** | *[%]{.und | *[Value]{.u |
|                 |                 |       | erline}** | nderline}** |
+-----------------+-----------------+-------+-----------+-------------+
|                 |                 |       |           |             |
+-----------------+-----------------+-------+-----------+-------------+
| Death           | 0.82 (0.7-0.99) | .03   | 18        | .7          |
+-----------------+-----------------+-------+-----------+-------------+
| Vascular events |                 |       |           |             |
+-----------------+-----------------+-------+-----------+-------------+
| Vascular        | 0.7 (0.6-0.8)   | \     | 30        | \<.001      |
| events\*        |                 | <.001 |           |             |
+-----------------+-----------------+-------+-----------+-------------+
| Myocardial      | 0.7 (0.6-0.8)   | \     | 30        | \<.001      |
|                 |                 | <.001 |           |             |
| Infarction      |                 |       |           |             |
+-----------------+-----------------+-------+-----------+-------------+
| Stroke          | 0.8 (0.7-1.0)   | .07   | 20        | \>.99       |
+-----------------+-----------------+-------+-----------+-------------+

### High Risk Patients Provide Insight Regarding Effectiveness in Moderate Risk Populations

As mentioned previously, the available data confirm that similar
proportional risk reductions for MI are obtained from patients that have
experienced a previous serious cardiovascular event (High Risk
populations) compared to risk reductions obtained from apparently
healthy individuals that did not experience a previous cardiovascular
event (Low Risk populations). This finding is evident from a review of
the relative risk reductions for MI in the various groups of high risk
and low risk patient populations studied, as shown below.

[]{#__RefHeading___Toc55791515 .anchor}Table 13: Relative Risk
Reductions of MI in High Risk and Low Risk Patient Populations are
Similar

  ------------------ ---------------------------- -----------------------
  **Trial**          **Underlying Risk of Patient **Relative Risk
                     Population**                 Reduction for MI**

  PHS                Low Risk                     40%

  BDT                                             3%

  TPT                                             32%

  HOT                                             \--

  PPP                                             31%

  Overall                                         32%

  ATT\*                                           34%

  Weisman and Graham High Risk                    30%
  meta-analysis                                   
  ------------------ ---------------------------- -----------------------

> \* Includes data for other antiplatelet studies in addition to ASA

Because the relative risk reductions are similar in High Risk and Low
Risk patient populations, the results can be extrapolated across these
risk strata to include Moderate Risk populations. They also highlight
that the large and robust secondary prevention database can be used to
address questions regarding effectiveness of ASA in subgroups such as
gender, age, and diabetes subjects where the primary prevention database
is either too small or not sufficient to address these issues
statistically. Specifically, the relative risk reduction of 34% should
be expected to prevent over 20 MIs for every 1000 patients treated for
10 years.

The final decision as to which patients should be considered for ASA
preventative therapy based on their particular level of risk then
becomes a risk benefit evaluation that will be discussed in Section 5,
below.

## ASA's Effectiveness in Preventing Cardiovascular Events Across a Variety of Patient Populations: Conclusions

The following clear and compelling factors support the broadening of the
labeling for ASA to include Moderate Risk individuals:

-   The database clearly supports the efficacy of ASA in preventing
    thromboembolic MI in patients at increased risk as well as "healthy"
    patients;

-   The database is extremely robust with strong consistent findings in
    a large number of studies;

-   14 MIs can be prevented for every 1000 Moderate-Risk patients
    treated for 5 years

# safety: the evidence for ASA safety

## 4.1 Safety Profile Overview

ASA is one of the most extensively studied drugs and its adverse event
profile is well understood. The safety profile has been established
largely from experience with analgesic and anti-inflammatory use. As is
the case for most drugs, adverse events associated with the use of ASA
are dose and duration dependent. With short-term, episodic, OTC labeled
use, the rate of adverse events does not significantly differ from other
OTC analgesics, including acetaminophen. In fact, a retrospective
meta-analysis of 3700 patients in 54 single-dose ASA (325-1300 mg)
dental pain studies found that occurrences of adverse events did not
differ from placebo \[[^78]\].

Several factors distinguish the use of ASA in cardiovascular prevention
from its use for analgesic and anti-inflammatory indications.
Cardiovascular dosing is typically lower than that used for analgesia
and inflammation, but the duration of use is long-term rather than
episodic. In addition, patients at risk for cardiovascular events are
more likely to have underlying disease (e.g., diabetes mellitus,
hypertension, hyperlipidemia) and are likely to be using other
medications. For these reasons, the large, controlled clinical trials
evaluating ASA for the prevention of cardiovascular events (i.e., the
primary and secondary prevention trials) and the extensive postmarketing
experience are used to evaluate the potential risks of treatment.

Due to the multitude of studies with large numbers of patients in
secondary prevention of cardiovascular events it has been possible to
obtain information on the risk of ASA associated with its use as a
platelet aggregation inhibitor in lower doses for a time period of up to
7 years. In these clinical trials, the most important adverse events due
to ASA are gastrointestinal side effects and intracerebral hemorrhage.

Based on the totality of the cardiovascular use evidence, it is
reasonable to estimate that for every 1000 patients treated for a 5-year
period, ASA therapy would be expected to cause an average of 3
significant gastrointestinal episodes and 1 case of hemorrhagic stroke.
In contrast to other drugs, clinically relevant hazards of aspirin
(bleeding) are related to the mechanism of action underlying its
therapeutic utility.

## 4.2 Mechanism Of Action

As described above (section 1.3.1), ASA's beneficial mechanism of action
is mediated by its ability to inhibit prostaglandin synthesis through an
inhibitory effect on the cyclooxygenase enzyme (COX). The mechanism of
action responsible for its analgesic and anti-inflammatory effect also
has safety-related impact that is affected by dose and duration.

Inhibition of prostaglandin synthesis by ASA has been implicated in its
tendency to cause gastrointestinal (GI) adverse reactions \[[^79]\],
including, in rare cases, gastric perforations, ulcers and bleeding.
This effect is largely due to the inhibitory effects on a normally
gastroprotective substance. ASA has been shown to affect neutrophil
adherence, thus increasing the risk of mucosal injury. In addition, at
the superficial mucosal level, ASA is a weak acid. In the highly acidic
environment of the stomach, however, ASA is non-ionized and able to
migrate across cell membranes into the superficial epithelium where it
is metabolized. In its ionized form, ASA traps hydrogen ions and can
attenuate the protective effects of gastric mucosa, leading to
epithelial damage \[[^80]\].

Through its inhibitory role in thromboxane synthesis, and its subsequent
inhibitor effects on platelet aggregation, ASA has been associated with
the rare but unwanted side effect of increasing the risk of unintended
bleeding, leading to an increased risk of intracerebral hemorrhage
(i.e., hemorrhagic stroke). As such, the risk of hemorrhagic side
effects is not likely to be separated from the antithrombotic effect,
even by low doses of ASA.

Renal blood flow is prostaglandin mediated, and thus can be affected by
analgesic ingredient use.

## 4.3 Safety by Body System

The evidence for the safety of ASA is reviewed in the sections below,
with an emphasis on gastrointestinal effects, intracerebral effects and
renal effects.

### Gastrointestinal Effects

### Overall Rate of GI Effects

GI adverse effects are by far the most important and consistently
reported safety concern with ASA therapy. Serious adverse GI reactions
have been reported to occur at an annual rate of 1-2% in individuals who
take prescription strength NSAIDs and ASA regularly \[[^81]\].
Nonetheless, recent data suggest that the suspected risk of ASA-induced
GI injury, even under such use conditions, has been overestimated.

The risk of developing GI injury due to ASA is influenced by several
factors, including dose and duration of use, use of concomitant
medication, increasing age, co-morbid conditions, presence of *H.
pylori* infections, and prior history of ulcers or stomach irritation
\[[^82], [^83]\].

In addition to GI bleeding, endoscopic studies have implicated ASA use
in the development of acute superficial lesions suggestive of mucosal
injury \[[^84], [^85]\]. However, the clinical significance of these
superficial lesions is uncertain, and no correlation to clinical outcome
has been demonstrated. Specifically, acute endoscopic changes have not
been shown to correlate with risk of bleeding, ulceration, or other
untoward effects As such, endoscopic findings have very limited value in
predicting the frequency or severity of chronic gastric ulcers or
gastrointestinal bleeding. In fact, endoscopic findings were not
accepted as a meaningful predictor of GI events when the FDA reviewed
the approval of COX-2 inhibitors \[[^86]\].

#### GI Data From Controlled Trials

Data relevant to the GI side effects of ASA derived from the five
primary prevention trials are summarized in Table 14.

[]{#__RefHeading___Toc55791516 .anchor}Table 14: Major Gastrointestinal
Events in Primary Prevention Trials[^87]

+----+--------------+-------+--------+-------------+----------------+
|    | **Type of    | **%   |        | **Sig       | **Events       |
|    | Event**      | sub   |        | nificance** | caused per     |
|    |              | jects |        |             | 1000 patients  |
|    |              | with  |        |             | treated with   |
|    |              | ev    |        |             | ASA per yr**   |
|    |              | ent** |        |             |                |
|    |              |       |        |             |                |
|    |              | **(n  |        |             |                |
|    |              | umber |        |             |                |
|    |              | of    |        |             |                |
|    |              | fat   |        |             |                |
|    |              | aliti |        |             |                |
|    |              | es)** |        |             |                |
+----+--------------+-------+--------+-------------+----------------+
|    |              | ASA   | c      |             |                |
|    |              |       | ontrol |             |                |
+----+--------------+-------+--------+-------------+----------------+
| P  | Upper GI     | 1.5   | 1.3    | p=0.08      | 0.4            |
| HS | ulcer        | (1)   | (0)    |             |                |
+----+--------------+-------+--------+-------------+----------------+
| B  | Peptic ulcer | 2.6   | 1.6    | P\<0.05     | 1.7            |
| DT |              | (3)   | (3)    |             |                |
+----+--------------+-------+--------+-------------+----------------+
| T  | Serious GI   | 1.7   | 0.8    | Not         | 1.3            |
| PT | bleeding     | (0)   | (1)    | significant |                |
+----+--------------+-------+--------+-------------+----------------+
| H  | Major GI     | 0.8   | 0.4    | Not         | 1.1            |
| OT | bleeding     | (5)   | (3)    | reported    |                |
+----+--------------+-------+--------+-------------+----------------+
| P  | Severe GI    | 0.8   | 0.2    | Not         | 1.5            |
| PP | bleeding     | (0)   | (0)    | reported    |                |
+----+--------------+-------+--------+-------------+----------------+

Types of events captured and reported for each trial are different, but
are the best estimates available for estimating overall gastrointestinal
safety in this Low Risk population. Nonetheless, the much larger
secondary prevention database provides more precise estimates of the
hazards (summarized below).

#### GI Data from Meta-Analyses

In the meta-analysis conducted by Hayden and colleagues \[[^88]\] of the
Low Risk studies, the focus was on major extracranial bleeding. An odds
ratio for ASA therapy was estimated to be 1.7 (CI 1.4 to 2.1), or an
excess risk for major (mostly gastrointestinal) bleeding events of 0.7
(CI, 0.4 to 0.9) per 1000 patient-years. The estimates regarding excess
GI bleeding events per 1,000 patients treated per year ranged from 0.4
(Physicians' Health Study) to 1.7 (British Doctors' Trial). The total
numbers of fatal GI bleeding events across the studies were few; 9 in
the ASA groups and 7 in the control group across the trials.

[]{#__RefHeading___Toc55791517 .anchor}Table 15: Estimates of the Role
of ASA in Gastrointestinal Bleeding\*

+--------+-----------+-------+-------+-----+-------+-------+-------+
| *      | *Type of  | *     |       | *P  | *E    | *     |       |
| Trial* | Gastroi   | Cumul |       | Val | xcess | Fatal |       |
|        | ntestinal | ative |       | ue* | Ble   | G     |       |
| *      | Bleeding* | Incid |       |     | eding | astro |       |
| (Refer |           | ence* |       |     | E     | intes |       |
| ence)* |           |       |       |     | vents | tinal |       |
|        |           | *As   |       |     | per   | Ble   |       |
|        |           | pirin |       |     | 1000  | eding |       |
|        |           | Con   |       |     | Pat   | Ev    |       |
|        |           | trol* |       |     | ients | ents* |       |
|        |           |       |       |     | Tr    |       |       |
|        |           | *     |       |     | eated | *As   |       |
|        |           | Group |       |     | per   | pirin |       |
|        |           | G     |       |     | Year* | Con   |       |
|        |           | roup* |       |     |       | trol* |       |
|        |           |       |       |     |       |       |       |
|        |           | *%*   |       |     |       | *     |       |
|        |           |       |       |     |       | Group |       |
|        |           |       |       |     |       | G     |       |
|        |           |       |       |     |       | roup* |       |
|        |           |       |       |     |       |       |       |
|        |           |       |       |     |       | *n*   |       |
+--------+-----------+-------+-------+-----+-------+-------+-------+
| BDT    | Self      | 2.6   | 1.6   | \<0 | 1.7   | 3     | 3     |
| (5)    | -reported |       |       | .05 |       |       |       |
|        | peptic    |       |       |     |       |       |       |
|        | ulcer     |       |       |     |       |       |       |
|        | disease   |       |       |     |       |       |       |
+--------+-----------+-------+-------+-----+-------+-------+-------+
| PHS    | Upper     | 1.5   | 1.3   | 0   | 0.4   | 1     | 0     |
| (4)    | gastroi   |       |       | .08 |       |       |       |
|        | ntestinal |       |       |     |       |       |       |
|        | ulcers    |       |       |     |       |       |       |
+--------+-----------+-------+-------+-----+-------+-------+-------+
| TPT    | Major or  | 1.7   | 0.8   | NR  | 1.3   | 0     | 1     |
| (7)    | int       |       |       |     |       |       |       |
|        | ermediate |       |       |     |       |       |       |
|        | bleeding† |       |       |     |       |       |       |
+--------+-----------+-------+-------+-----+-------+-------+-------+
| HOT    | Fatal and | 0.8   | 0.4   | NR  | 1.1   | 5     | 3     |
| (8)    | nonfatal  |       |       |     |       |       |       |
|        | major     |       |       |     |       |       |       |
|        | gastroi   |       |       |     |       |       |       |
|        | ntestinal |       |       |     |       |       |       |
|        | bleeding  |       |       |     |       |       |       |
|        | events‡   |       |       |     |       |       |       |
+--------+-----------+-------+-------+-----+-------+-------+-------+
| PPP    | Gastroi   | 0.8   | 0.2   | NR  | 1.5   | 0     | 0     |
| (9)    | ntestinal |       |       |     |       |       |       |
|        | bleeding§ |       |       |     |       |       |       |
+--------+-----------+-------+-------+-----+-------+-------+-------+

\*BDT = British Male Doctors' Trial; HOT= Hypertension Optimal Treatment
Trial; NR = not reported; PHS = Physicians Health Study; PPP = Primary
Prevention Project; TPT = Thrombosis Prevention Trial

†Major bleeding included fatal and life-threatening hemorrhages that
required transfusion, surgery, or both. Intermediate episodes were
bleeding events that prompted patients to notify research coodinators
separately from routine questionnaires

‡Major bleeding was not defined.

§Described as severe but nonfatal.

The findings by Hayden and colleagues were similar to the findings of
the meta-analyses of secondary prevention trials conducted by Roderick
and colleagues \[Error: Reference source not found\]. They conducted an
overview analysis of 21 placebo-controlled, randomized clinical trials,
representing 70,000 person years of ASA exposure and found that ASA
increased the pooled odds ratio for gastrointestinal bleeding (including
non major bleeding, e.g., melena) (OE 1.5 to 2.0). The risk of
subjective gastrointestinal symptoms was reported to be 1.7 and peptic
ulcer 1.3 \[[^89]\].

The risk of gastrointestinal hemorrhage with long-term use of ASA across
a variety of uses (including both Low Risk and High Risk patient
populations) was assessed in a meta-analysis by Derry and Loke
\[[^90]\]. They evaluated 24 randomized, controlled trials with almost
66,000 participants comparing ASA with placebo or no treatment for a
minimum of 1 year. As expected, gastrointestinal hemorrhage occurred in
2.47% of patients taking ASA compared with 1.42% taking placebo (odds
ratio 1.68; 95% CI 1.51 - 1.88). At doses below 163 mg/day,
gastrointestinal hemorrhage occurred in 2.30% of patients taking ASA
compared with 1.45% taking placebo (1.59; 1.40 - 1.81). Meta-regression
showed no correlation between gastrointestinal hemorrhage and dose. For
modified release formulations of ASA the odds ratio was 1.93 (1.15 -
3.23). According to the authors, these data suggest a number needed to
harm of 248 per year.

Weisman and Graham evaluated the gastrointestinal risks of low dose ASA
([\<]{.underline} 325 mg/d) when used in FDA-approved secondary
prevention of cardiovascular events \[Error: Reference source not
found\]. Using a computerized literature technique, the investigators
reviewed the worldwide published literature to perform a meta-analysis
of 6 trials (6300 patients) using ASA in approved secondary prevention
indications. The investigators reported that GI bleeding was a rare
finding with only 58 reports across the 6 studies (41 in the ASA groups;
17 in the placebo groups). Only about half of the cases of GI bleeding
were deemed severe enough to require treatment withdrawal. There were no
reported deaths related to GI bleeding and GI bleeding led to almost no
permanent morbidity (i.e., morbidity reported by the investigators of
the studies). Only one report, the United Kingdom Transient Ischemic
Attack (UK-TIA) trial \[[^91]\] demonstrated a statistically significant
increased risk of GI bleeding as a result of ASA intake. An analysis of
GI bleeding across all studies suggests a common risk ratio of 2.5 (95%
CI, 1.4-4.7; P=.001). Calculation revealed an absolute risk range for GI
bleeding of 0% to 2.0% [+]{.underline}1.4% (52-month follow-up).

The Antithrombotic Trialists' Primary Prevention Group also conducted a
comprehensive meta-analysis based on individual patient data from the
five available Low Risk primary prevention trials \[Error: Reference
source not found\]. In their analysis, ASA use was associated with a
nonstatistically significant increased risk of major bleeds (67%),
suggesting that ASA might cause 4 - 5 major extracranial bleeds per 1000
patients treated for 5 years.

#### Labeling for GI Warnings

The professional labeling for ASA includes the following warning
information associated with the risk of adverse GI effects in
susceptible individuals. As the rate of adverse GI events are similar in
the low risk studies, this warning should be sufficient to include the
risks associated with broadened labeling.

  -----------------------------------------------------------------------
  ***GI Side Effects:*** GI side effects include stomach pain, heartburn,
  nausea, vomiting, and gross GI bleeding. Although minor upper GI
  symptoms, such as dyspepsia, are common and can occur anytime during
  therapy, physicians should remain alert for signs of ulceration and
  bleeding, even in the absence of previous GI symptoms. Physicians
  should inform patients about the signs and symptoms of GI side effects
  and what steps to take if they occur.

  -----------------------------------------------------------------------

### Intracerebral Bleeding (Hemorrhagic Stroke)

### Overall Rate of Intracerebral Bleeding

Based upon the available evidence, a reasonable approximation of the
risk of hemorrhagic stroke associated with the use of ASA therapy in Low
Risk patients is 0.2 events per 1000 patient-years. That is, for every
1000 patients treated for a 5-year period, ASA therapy would be expected
to result in 1 excess hemorrhagic stroke.

#### Intracerebral Bleeding Data from Controlled Trials

Data relevant to hemorrhagic stroke from all five trials in Low Risk
patients are summarized in the following Table:

[]{#__RefHeading___Toc55791518 .anchor}Table 16: Hemorrhagic Stroke /
Intracranial Hemorrhage in Primary Prevention Trials[^92]

  ------ ---------- --------- --------------------- -----------------------
         **%                  **Odds ratio          **Events caused (or
         patients             (95%CI)**             avoided) per 1000
         with                                       patients treated with
         event**                                    ASA per year**

         ASA        Control                         

  PHS    0.21       0.11      1.92 (0.95 -- 3.86)   0.20

  BDT    0.38       0.35      1.08 (0.41 -- 2.85)   0.05

  TPT    0.24       0.16      1.51 (0.25 -- 9.03)   0.12

  HOT    0.15       0.16      0.93 (0.45 -- 1.93)   (0.03)

  PPP    0.09       0.13      0.67 (NR)             (0.12)
  ------ ---------- --------- --------------------- -----------------------

The estimates of the role of ASA in hemorrhagic stroke and intracranial
haemorrhage showed 0.05, 0.12 and 0.2 approximate excess bleeding events
per 1,000 patients treated per year in the British Doctors\' Trial, the
Thrombosis Prevention Trial and the Physicians\' Health Study,
respec­tively. In the Hypertension Optimal Treatment Trial and the
Primary Prevention Project, the approximate bleeding events avoided per
1,000 patients treated per year were 0.03 and 0.12, respectively. These
adverse event rates in the primary prevention trials do not differ
appreciably from those seen in the secondary prevention trials,
suggesting that the much larger database should be used in developing
the Contraindications and Warnings sections of the professional label.

The effect of blood pressure on the occurrence of hemorrhagic stroke was
not consistently demonstrated in these trials. Interestingly, in the HOT
trial, where blood pressure was controlled, no difference in the
occurrence of hemorrhagic stroke between the treatment and control
groups was seen. In all studies, the difference in the percent of
patients experiencing a hemorrhagic stroke or intracranial bleed (ASA
vs. placebo) did not reach statistical significance, due to the very
rare occurrence of these events.

#### Intracerebral Bleeding Data from Meta-Analyses

A number of meta-analyses have examined the effect of ASA on the
incidence of hemorrhagic stroke in Low Risk patients \[[^93], Error:
Reference source not found, [^94]\].

Hart and colleagues pooled the results of the first four Low Risk
studies (excluding PPP) and estimated that the relative risk for
hemorrhagic stroke due to long-term ASA use was 1.36 (95% CI = 0.88 --
0.21). Sudlow's analysis reached a similar estimate (OR = 1.4; 95% CI =
0.9 to 2.0). Eidelman and colleagues calculated a slightly higher
statistically non-significant elevated relative risk for hemorrhagic
stroke (RR = 1.56; 95% CI = 0.99 -- 2.46).

A comprehensive meta-analysis of hemorrhagic stroke has been conducted
by He and colleagues (1998) across a wide variety of trials (including
two Low Risk populations) \[Error: Reference source not found\]. These
investigators performed a meta-analysis of 16 trials (including 14
secondary prevention trials) that reported stroke subtypes involving
more than 55,000 participants. The summary RR for hemorrhagic stroke
with ASA use was 1.84 (CI, 1.24-2.74), or an increased absolute risk of
12 events (CI, 5-20) per 10,000 persons over about 3 years, or about 0.4
excess event per 1000 users annually (p\<0.001). The number needed to
cause 1 excess hemorrhagic stroke event was 833.

Finally, the Antithrombotic Trialists' Primary Prevention Group
meta-analysis based on individual patient data from the five available
primary prevention trials found that ASA use was associated with a 32%
non-statistically significant increased risk of hemorrhagic stroke.

#### Labeling for Intracerebral Bleeding Warnings

The professional labeling for ASA includes the following adverse
reaction information associated with the risk of intracerebral bleeding.

+-----------------------------------------------------------------------+
| **ADVERSE REACTIONS**                                                 |
|                                                                       |
| Many adverse reactions due to aspirin ingestion are dose-related. The |
| following is a list of adverse reactions that have been reported in   |
| the literature. (See **Warnings.**)                                   |
|                                                                       |
| ***Central Nervous System:*** Agitation, cerebral edema, coma,        |
| confusion, dizziness, headache, subdural or intracranial hemorrhage,  |
| lethargy, seizures.                                                   |
+-----------------------------------------------------------------------+

### Renal Effects

### Overall Rate of Renal Effects

The risk of analgesic-induced renal toxicity is low; however, some
pre-existing conditions may increase the risk. Patients with diabetes
\[[^95]\], concomitant diuretic therapy, renal or hepatic impairment,
cardiac failure, or old age, should use caution with non-prescription
analgesic self-therapy. Elevations in blood urea nitrogen or serum
creatinine levels have been reported with long-term high dose ASA
\[[^96]\], as well as short-term use in patients with underlying renal
impairment \[[^97]\]. Cessation of ASA use, however, typically results
in a reversal of drug-induced effects on renal function \[Error:
Reference source not found, Error: Reference source not found\].

Analgesic nephropathy, a unique type of renal toxicity, has been
reported with ASA; however, such toxicity occurs most often only after
years of exposure to high therapeutic doses or mixtures containing at
least two analgesics with caffeine or codeine \[[^98]\]. Additionally,
many early reports of analgesic nephropathy were reported in patients
taking large amounts of products containing phenacetin \[Error:
Reference source not found\], an ingredient that has been taken off the
U.S. market due to toxicity.

#### Labeling for Renal Warnings

The professional labeling for ASA includes the following precaution
information associated with the renal effects.

  -----------------------------------------------------------------------
  ***Renal Failure:*** Avoid aspirin in patients with severe renal
  failure (glomerular filtration rate less than 10 mL/minute).

  -----------------------------------------------------------------------

## ASA Drug Interactions

### Interactions with prescription medications

While ASA has been implicated in a number of drug interactions,
physicians consider only a few such interactions to be clinically
significant. Among the noteworthy drug interactions with ASA are those
associated with concomitant oral anticoagulant, thrombolytic, uricosuric
agent, sulfonylurea, corticosteroid, or methotrexate use \[[^99]\].

[]{#__RefHeading___Toc55791519 .anchor}Table 17: Drug-Drug Interactions
with ASA that Warrant Caution

  -----------------------------------------------------------------------
  **Prescription Drug**                                    **ASA**
  -------------------------------------------------------- --------------
  Oral Anticoagulants and Heparin                          +\*

  Anti-thrombotics                                         \+

  Anti-convulsants                                         \+

  Uricosuric Agents                                        \+

  Corticosteroids                                          \+

  Methotrexate                                             \+^\*\*^

  Sulfonylureas                                            \+^\*\*\*^
  -----------------------------------------------------------------------

\+ = Drug-drug interaction requires caution due to inherent risk of
adverse event

^\*^Despite the interaction between ASA and heparin use, the American
College of Cardiology and American Heart Association promotes the use of
ASA and heparin for management of patients with acute coronary syndrome
(unstable angina) (Ryan, 1999)

^\*\*^ASA administration to patients receiving low dose methotrexate
therapy for treatment of rheumatic conditions is of little safety
concern (Haas, 1999).

^\*\*\*^Despite potential interactions between some anti-diabetic drugs
and ASA, the American Diabetes Association (ADA) advocates the benefits
of ASA, particularly for use as a primary prevention strategy in men and
women with diabetes who are at high risk for cardiovascular events
(American Diabetes Association, 2002).

### Interactions with other Analgesics

Concomitant use of ASA with other OTC analgesic ingredients, including
the NSAIDs, may increase risk of gastrointestinal \[[^100], [^101]\] or
renal disorders \[Error: Reference source not found\]. The potential
increased risk for GI and renal adverse events warrant caution with
concomitant use of ASA with ibuprofen, naproxen sodium or ketoprofen.

Importantly, the efficacy of low-dose ASA used for cardiovascular
benefit may be compromised by concomitant use of ASA with other NSAIDs.
Treatment with ibuprofen in patients with increased cardiovascular risk
may limit the cardio-protective effects of ASA \[[^102]\].

## Post Market Surveillance

### Published ASA Safety Evaluations

It is important to evaluate ASA's safety profile from a postmarketing
perspective. A review of reported adverse effects can assist in the
development of warnings and contraindications for use, as well as areas
for further investigation.

A number of published case analyses have specifically evaluated the
gastrointestinal tolerability of chronic low dose ASA for cardiovascular
prophylaxis and are instructive in assessing the potential hazards of
broader ASA use. These analyses are based on findings from observational
studies of a variety of types, and hence have differing degrees of
reliability. Nonetheless, to provide the Committees with a complete
understanding of the overall safety picture of ASA they are included
herein for completeness.

Three relevant case-control observational studies have also been
conducted \[[^103], [^104], [^105]\]. These three studies specifically
evaluated hospitalization for gastrointestinal bleeding and evaluated
the effects of ASA.

Weil and Colleagues \[Error: Reference source not found\] evaluated
hospitalization for bleeding peptic ulcer with prophylactic ASA regimens
of 300 mg or less per day. This case control study was conducted with
1121 patients presenting with gastric or duodenal ulcer bleeding and age
and gender matched hospital and community controls (989 subjects). Prior
drug use was assessed by questioning patients who were admitted to
selected hospitals in the UK with a report of hematemesis or melena
secondary to gastric or duodenal ulcer. Only patients 60 or older were
included in this evaluation. The number of cases reporting exposure to
any dose of ASA at any time during the month before admission was 126
compared to 60 for the hospital and 57 for the community controls
respectively, resulting in an odds ratio of 4.0 (2.8 -- 5.8 CI). Rates
varied appreciably by formulation.

Kelly \[Error: Reference source not found\] evaluated 550 incident cases
admitted to 28 Massachusetts hospitals because of acute upper
gastrointestinal bleeding. Cases as well as 1202 population controls
were interviewed regarding their use of ASA and other nonsteroidal
anti-inflammatory drugs during the seven days before presenting with a
bleed. The odds-ratios for risk of bleeding varied between 2.6 and 3.1
based on various demographic groupings.

The study by de Abajo \[Error: Reference source not found\] represents a
retrospective, population-based case control evaluation. Identified
incident cases of upper gastrointestinal bleeding or perforation were
from the General Practice Research Database (UK). Controls were randomly
selected from the source population. A total of 2105 cases and 11500
controls were selected. Among them, 287 (13.6%) cases and 837 (7.3%)
controls were exposed to ASA, resulting in a relative risk of 2.0 (1.7
--2.3).

### Bayer Sponsored Post Marketing Study

To further evaluate the tolerability of low dose ASA, Bayer HealthCare
conducted an open label post marketing surveillance study enrolling 2739
patients recruited from 577 physician practices. Patients were
prescribed 100 mg enteric-coated aspirin tablets for prevention of
cardiovascular or cerebrovascular events and followed for a period of
two years, with 8 visits scheduled over this period. The mean age of
participants was 65.4 years (23-97), 40.6% were women, and 57.3% were
previously taking another ASA containing product. Interestingly, the
main reason many entered the study was because of previous
gastrointestinal complaints (42.2%) or heartburn (19.5%) with previously
used ASA formulations.

The mean duration of treatment was 30.2 months. At baseline and at
3-month intervals, patients were evaluated by questionnaire regarding 8
gastrointestinal symptoms (heartburn, sensation of fullness,
gastrointestinal complaints, nausea, vomiting, constipation, diarrhea,
melena). In addition, bleeding events and other adverse events were
collected.

A total of 460 (16.8%) patients did not complete the study. Reasons were
lack of compliance, death (none related to study medication),
non-medical reasons and others. Only thirty-four patients (1%)
discontinued study medication due to intolerance.

Adverse events (Table 18) were largely (2.3%) non-specific
gastrointestinal complaints. Gastrointestinal hemorrhage and gastric
ulcer were reported in 0.2% and 0.6% respectively. Overall 10.6% of
patients reported at least one adverse event.

[]{#__RefHeading___Toc55791520 .anchor}Table 18: Adverse Event Rates in
Post Marketing Surveillance Study

+--------------+-------------+-------------+-------------+-------------+
| Adverse      | Patients    | Patients    | Number of   | \% Of Total |
| Effect       |             |             | Events      | Number      |
|              | \(n\)       | (%)         |             |             |
+--------------+-------------+-------------+-------------+-------------+
| GI           | 64          | 2.3         | 68          | 19.2        |
| Complaints   |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| Micr         | 2           | 0.1         | 2           | 0.6         |
| o-hemorrhage |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| GI           | 6           | 0.2         | 6           | 1.7         |
| hemorrhage   |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| Gastric      | 17          | 0.6         | 17          | 4.8         |
| Ulcer        |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| Nausea       | 5           | 0.2         | 5           | 1.4         |
+--------------+-------------+-------------+-------------+-------------+
| Vomiting     | 2           | 0.1         | 2           | 0.6         |
+--------------+-------------+-------------+-------------+-------------+
| Diarrhea     | 3           | 0.1         | 3           | 0.9         |
+--------------+-------------+-------------+-------------+-------------+
| Hype         | 2           | 0.1         | 2           | 0.6         |
| rsensitivity |             |             |             |             |
| Reactions    |             |             |             |             |
+--------------+-------------+-------------+-------------+-------------+
| Other        | 190         | 6.9         | 249         | 70.3        |
+--------------+-------------+-------------+-------------+-------------+
| TOTAL        | 291         | 10.6        | 354         | 100         |
+--------------+-------------+-------------+-------------+-------------+

### Bayer Post Marketing Experience

All U.S. serious adverse events reported to Bayer HealthCare for ASA are
captured in the Bayer Global Drug Safety database. Data in this database
from 1999-mid 2003 was searched for all U.S. cases where a serious
gastrointestinal event or a serious bleeding event was reported while
the patient was using aspirin. Importantly, during this time period, 10
billion Bayer aspirin tablets were sold in the U.S.

A total 79 cases meeting these criteria were identified. Forty cases
(50%) were reported by consumers, sixteen (20%) were from clinical
trials, seven (9%) were found in the scientific literature and four (5%)
were reported by healthcare professionals. Fifty-six reports (71%)
involved the gastrointestinal body system. Forty-three cases (54%)
involved daily aspirin doses greater than 325 mg, including 12 cases
from a clinical trial using 650 mg daily. Twenty-six reports (33%)
involved doses between 325 and 81mg, and ten (13%) involved aspirin
doses of less than or equal to 81 mg daily. Fifty (63%) of the patients
identified in these cases were female, and the average patient age was
62 years. Approximately 58% of patients were taking ASA for
cardiovascular prevention, which corresponds to estimates of the percent
of total ASA sales in the U.S. for cardiovascular use.

Using sales volume as a surrogate for exposure, one can calculate a
reporting rate for combined serious GI and bleeding events at 0.008 per
million tablets sold, demonstrating that reports of these events are
exceedingly rare.

### FDA Office of Drug Safety Postmarketing Safety Review

The FDA Office of Drug Safety conducted a review of the postmarketing
experience of ASA-containing products relating to gastrointestinal
hemorrhage, ulceration, or perforation to better understand the
circumstances that may result in these events. The review was conducted
for the NDAC review of OTC analgesics September 2002. The review was
limited to events reported to the FDA from January 1, 1998 through
December 31, 2001 \[[^106]\].

The analysis was based on the review of 541 cases of GI hemorrhage,
ulceration or perforation reported for ASA-containing products. Most
reports did not contain complete information related to the patients'
prior medical history, medication use, and course of the GI event. The
majority of patients in this analysis were taking low dose ASA (less
than or equal to 325 mg per day) for cardio- or cerebrovascular
indications. Use for cardiovascular disease prophylaxis was specifically
mentioned in 181 of the cases. Use of multiple preparations containing
aspirin was reported in only 10 cases (1.9%).

The mean age of patients in this analysis was 69.3 years. For the subset
for which gender was reported, 63% (319/503) of the cases were male. The
duration of aspirin use, while not reported in the majority of the
cases, ranged from less than 1 day (after one dose) to 25 years. The
median duration, for those cases reporting duration, was 42 days. The
median daily dose and the dose most commonly reported was 325 mg per
day.

Eighty six percent of the reports (468) involved hospitalization and 5%
(29) died. Medical treatment was indicated in most of the reports, with
only 24 patients requiring surgical intervention.

[]{#__RefHeading___Toc55791521 .anchor}Table 19: Number of GI Events

  ----------------------------------- -----------------------------------
  GI Event or Finding                 Number

  Bleed                               361

  Ulceration                          197

  Perforation                         9

  Melena                              101

  Hematemesis                         52

  Gastritis                           29

  Hematochezia                        20

  Erosion                             10

  Duodenitis                          6

  Esophagitis                         5

  Colitis                             3

  Other GI                            4

  TOTAL                               797
  ----------------------------------- -----------------------------------

Remarkably, 485 patients (approximately 90%) had one or more risk
factors or other possible causes for their GI event. Risk factors
included a significant GI medical history (111 cases), concurrent
medication that may have increased risk of a GI bleed (366 cases), a
concurrent smoking or drinking history that may have increased risk (75
cases). Sixty-seven percent of the 347 patients listed age greater than
65 as the only risk factor. Additionally, although not quantified, many
patients had other significant intercurrent illness or past medical
history that might put them at increased risk of a GI event. These
findings are suggestive that with appropriate warnings and effective
physician evaluation the benefit-to-risk relationship for aspirin can be
enhanced.

##  Conclusion

The safety profile of ASA is well characterized, and toxicity is
generally dose-related and adverse events are extremely rare, especially
at lower doses. Based upon the data, the most important adverse events
due to ASA when used for cardiovascular therapy, include the GI effects
and intracerebral hemorrhage.

# patients can be identified for whom the cardiovascular benefits of aspirin outweigh the risks

## Overview of the Risk/Benefit Analysis

ASA has clear therapeutic benefits in the prevention of MI in patients
in a variety of underlying risk categories ranging from Low Risk to High
Risk as summarized in Section 3. However, ASA is also associated with
specific, well-defined risks (summarized in Section 4) that must be
taken into account before a clear recommendation for ASA therapy can be
made in any given individual.

In patients with high underlying cardiovascular risk (i.e., patients
with a greater than 20% 10 year CHD risk), the benefits of ASA therapy
clearly outweigh the risks for prevention of MI and therefore ASA has
been recommended by numerous professional bodies for treatment in this
population. However, the current FDA approvals for ASA limit its use to
patients who have suffered a previous event (a High Risk group), failing
to recognize that many individuals may be at sufficient risk of MI to
warrant treatment in spite of not having had a previous event (a
Moderate Risk group). The available data also clearly demonstrate that
the benefits of ASA in the prevention of MI can be appropriately
extended to individuals at Moderate Risk (i.e., individuals with a
greater than 10% risk of CHD over 10 years). A clear understanding of
the number of MIs that can be prevented in this population can be easily
determined by applying the proportional risk reductions observed across
the risk continuum to the underlying 10% 10 year risk. The known hazards
of chronic low dose ASA can then be compared to these benefits to
demonstrate that a favorable benefit to risk relationship can be
achieved. In fact, in the Moderate Risk population, 2-3 CHD events can
be prevented for every adverse event caused.

Of course, for individuals with a 10-year risk that is \<10% (a Low Risk
individual), the absolute number of coronary heart disease events that
would be avoided in treating 1000 patients over a 5 year period, is 4
(1 - 12), compared to the absolute number of hemorrhagic strokes 1 (0 -
2) and major GI bleeding events 3 (2 - 4) that would be caused. Because
this differential is not great, the risk-benefit analysis might reject
the recommendation of ASA for cardiovascular disease prevention in these
individuals. Of course, the severity of the risk (i.e., GI bleeds) must
also be weighed in relation to the magnitude of the benefit (i.e.,
preventing a potentially life-threatening MI).

### Extrapolation to Broad Patient Groups is Appropriate

A comprehensive cardiovascular risk assessment is of critical importance
in assessing whether an individual patient should be considered a
candidate for treatment, as it determines the goals of therapy and the
intensity of the intervention. As in all areas of medical practice, the
risk assessment guides the clinical judgement of the physician as it
relates to the management of the individual patient. Today, the
physician can draw on many resources to make informed decisions
regarding treatment options. These include a large body of evidence from
epidemiological studies and from prospective clinical trials toguide
therapeutic decision-making.

With respect to ASA, the database is large and robust and provides
significant insight regarding the benefits and hazards of preventative
therapy that exceed other therapeutic interventions. Nonetheless, in
spite of its size, the ASA database does not include every single
permutation of the risk continuum and therefore requires an
understanding of the pathophysiology of the underlying disease process
and the pharmacology of the agent to make appropriate extrapolations
relative to a decision regarding a specific patient.

Importantly, an appropriate risk evaluation is necessary in the
selection of the appropriate type and intensity of treatment, including
whether or not drug treatment is appropriate. Such an assessment will
identify those patients in which the risk of an event is significantly
great enough to necessitate intervention.

[]{#__RefHeading___Toc55791528 .anchor}Figure 6: Vascular Event Risk

There is no question that risk is enhanced as a consequence of having
suffered a previous serious vascular event. As highlighted in Figure 6
above, persons experiencing an acute, evolving MI are at greatest risk
of a nonfatal or fatal vascular event. Those with unstable angina, a
history of prior MI, stroke, TIA, chronic stable angina or atrial
fibrillation, as well as patients undergoing a revascularization
procedure or haemodialysis, are also at substantially elevated risks of
occlusive vascular events. However, those without clinically evident
vascular disease, but with underlying pathology/multiple risk factors
(including high cholesterol level, high blood pressure, diabetes or a
history of smoking) are at intermediate risk, a group referred to in
this document as Moderate Risk. And, finally, those without overt
manifestations of vascular disease or risk factors are at much lower
risk.

If one considers cardiovascular risk as a continuum, with individuals
who experienced a previous cardiovascular event at one end (i.e., the
group with the highest underlying risk) and those with underlying risk
factors who are otherwise "healthy" at the other end (i.e., the group
with lower underlying risk) a logical risk model can be established. Of
course, healthy individuals with no underlying risk factors would be the
group with the lowest underlying risk. The expected benefits of an
intervention along this continuum depend on the risk/benefit analysis,
with the clearest benefit being conferred to those at the higher levels
of underlying risk.

Today ASA is indicated in individuals who have suffered a previous
vascular event (MI, TIA, stroke, angina). The suggestion that many
patients exist who could benefit from ASA in spite of the fact that they
have not experienced a previous event necessitates revision of the
labeling to include those at elevated risk (Moderate Risk), defined as
those with a 10% or greater risk of a CHD event over the next 10 years
(or 1% per annum). Risk-based strategies are currently recognized as
effective in selecting patients for a variety of interventions,
including cholesterol and blood pressure lowering agents.

### Risk Assessment Can be Guided With Appropriate Tools

There is a large gap between which evidence-based interventions are
recommended and what is actually carried out in clinical practice. The
challenge for healthcare professionals is to engage greater numbers of
patients at an earlier stage of their disease, so that many more
individuals may realize the benefits that primary prevention can
provide. Guidelines, even when based on the best available evidence from
randomized, controlled trials, cannot be successfully implemented
without broad understanding by the healthcare team. In other words, a
physician-patient partnership must be forged. As part of this
partnership, the physician must assess and effectively communicate to
the patient information pertaining to underlying CHD risk as well as
benefits and risks of therapy and must develop, with the patient, a plan
of preventive action.

Risk for future CHD events can be predicted from coronary risk
algorithms. Factors used to estimate risk include sex, age, blood
pressure, serum total cholesterol level, diabetes mellitus and cigarette
smoking. These established risk factors allow physicians to accurately
assess an individual patient's 10-year risk of having a cardiovascular
event, allowing the determination as to the appropriateness of a variety
of interventions. Several easy-to-use risk assessment tools, most based
on risk equations derived from the Framingham Heart Study, are available
and can be used to facilitate clinical decision-making. Framingham data
have recently been shown to generalize adequately to other populations.

The natural response when confronted with the utility of tools to assist
in clinical decision-making is to ask whether they have been adequately
validated. While a reasonable question, it is clear that these are only
tools to assist physicians in their clinical evaluation and should not
be viewed as definitive "diagnostic tests" requiring specific
performance standards. As there are not fine lines between patient
groups who should be treated and those who should not, such precision is
not required.

Based upon the available risk calculators and working backwards,
Moderate Risk for CHD can be defined as an individual that meets any one
of the following four criteria:

1.  presence of one risk factor of severe degree sufficient to warrant
    intervention (e.g., a middle aged man who smokes a pack a day);

2.  presence of two risk factors of moderate degree (e.g., a middle aged
    man with a plasma cholesterol of 200-300 mg/dL plus HDL-cholesterol
    less than 40 mg/dL or obesity);

3.  a quantitative risk assessment that exceeds 1% per year; or

4.  presence of type 1 or type 2 diabetes mellitus without microvascular
    complications.

In quantitative terms, a High Risk individual presents with a CHD risk
of 2% per annum or greater (i.e., 20% over 10 years). In contrast, a Low
Risk individual would have less than 1% per annum risk (i.e., 10% over
10 years). The Moderate Risk individual falls in between these two
extremes.

To provide a sense of the ease in which global risk can be evaluated,
the following examples are presented below.

***Example 1. Solitary elevated LDL-cholesterol (180 mg/dL)***

A 45 year-old man with systolic blood pressure 130 mmHg, HDL-cholesterol
49 mg/dL, triglycerides 90 mg/dL, LDL-cholesterol 180 mg/dL, total
cholesterol 247 mg/dL, smoker, non-diabetic. *This patient's CHD risk is
13% over 10 years, i.e. "moderate risk".*

***Example 2. Multiple risk factors including elevated LDL-cholesterol
(180 mg/dL)***

A 45 year-old man with systolic blood pressure 180 mmHg, HDL-cholesterol
30 mg/dL, triglycerides 250 mg/dL, LDL-cholesterol 180 mg/dL, total
cholesterol 260 mg/dL, smoker, non-diabetic. *This patient's CHD risk is
31% over 10 years, putting him in the highest risk group.*

***Example 3. Multiple risk factors, normal LDL-cholesterol (100
mg/dL)***

A 45 year-old man with systolic blood pressure 180 mmHg, HDL-cholesterol
30 mg/dL, triglycerides 250 mg/dL, LDL-cholesterol 100 mg/dL, total
cholesterol 180 mg/dL, smoker, non-diabetic. *This patient's CHD risk,
despite the normal LDL-cholesterol level is 20% over 10 years, also
putting him in the highest group.*

As the available evidence strongly supports the effectiveness of ASA in
reducing the MI risk in both Low Risk and High Risks groups, it is
intuitive that it would also be of benefit in Moderate Risk individuals.
It is also logical and appropriate to conclude that the absolute benefit
would be proportionate to the underlying risk and therefore greater in
Moderate Risk patients than in Low Risk patients. To make an appropriate
decision as to whether ASA is appropriate in this Moderate Risk group
one needs to understand the hazards of treatment as well. With this
information, the risk-benefit relationship can be established.

## The Risk-Benefit Relationship of ASA in Moderate Risk Patients

### Benefits of ASA Treatment in Moderate Risk Patients

There is compelling evidence that ASA reduces the risk of a first MI
appreciably in Low Risk patients. The analysis by Eidelman, *et. al.*
\[56\], which was published in the September 2003 issue of *Archives of
Internal Medicine* and serves as the basis of our petition, demonstrates
a highly significant 32% risk reduction in nonfatal MI. The USPSTF
systematic review of the pooled data from the five primary prevention
studies came up with a comparable estimate, concluding that ASA therapy
reduced the risk of coronary heart disease by 28% (summary odds ratio
0.72, 95% CI 0.60 to 0.87) \[1\], as did the Antithrombotic Trialist
Primary Prevention Group that found a 23% risk reduction. While these
estimates appear different, because of slight variations in how the data
were handled, they are suggestive of the same clinical impact.

In light of the clear and consistent evidence that ASA reduces the risk
of MI in Low and High Risk trials combined with the fact that these two
databases represent a homogeneous group of patients with the same
underlying pathologic basis for cardiovascular events, it is reasonable
and appropriate to use these data to develop an integrated model for the
expected relative and absolute benefits in MI. As the absolute benefits
in terms of MI reduction increase as one moves from a healthy to a more
"at risk" population, there is no question that the benefits of ASA
therapy will be enhanced.

In patients at particularly High Risk of vascular events, the benefits
of antiplatelet therapy are evident. For example, among 1,000 patients
with acute MI who are given one month of ASA (ASA) and then continue to
take low-dose ASA for some years, about 40 would avoid a serious
vascular event during the first month and a roughly equivalent number of
patients would avoid a vascular event in the next couple of years. Even
in patient populations at a 2-3% annual risk of serious occlusive
vascular events (e.g., patients with stable angina who have not had a
previous vascular event), antiplatelet therapy for one to two years
would be expected to prevent about 10-15 vascular events for every 1,000
patients treated. As a consequence, there is no question that if
underlying risk of MI is sufficiently high, the benefits increase,
regardless of the intervention.

### Risks of ASA in Moderate Risk Patients

To fairly assess whether a patient at a certain cardiovascular risk
should be considered a candidate for ASA therapy, it is important to
know the "cost" of the benefit (in terms of side effects). It is
possible to address this question by evaluating the totality of safety
evidence derived from a variety of sources. As the hazards of treatment
are not expected to be affected by underlying cardiovascular risk (if
anything, candidates for primary prevention would presumably be
healthier and therefore at a lower risk of adverse bleeding events), it
is prudent to be conservative and assume that the same risks accrue to
all chronic users of ASA. By doing so, it is possible to utilize the
complete ASA database, including high-risk studies and post marketing
experience to address the hazard side of the risk benefit analysis.

The side-effect profile of ASA has been well established. Much is known
about the pharmacology of ASA and its anticipated adverse effects from
over 100 years of use as well as hundreds of controlled clinical trials.
As specified in the safety summary (Section 4), the primary safety
concerns associated with chronic ASA use are GI bleeding and hemorrhagic
stroke. As expected, the safety data demonstrate that adverse event
rates are constant across the cardiovascular risk strata and suggest
that the risk of injury can be projected to be the same in patient
groups not necessarily included in the current database.

The findings with respect to the adverse effects of greatest interest
suggest that chronic low dose ASA use can increase the risk of GI
bleeding 2-3 fold and hemorrhagic stroke risk by about one-third. This
would result in approximately 1 excess major extracranial bleed for
every 1000 patients and 1 hemorrhagic stroke for every 10,000 patients
exposed to ASA. Such risks would be expected to be equivalent whether
one evaluates Low, Moderate, or High Risk patients.

### The Benefit to Risk Relationship is Favorable in Moderate Risk Patients

The benefit to risk evaluation with respect to the use of ASA in
Moderate Risk patients must therefore compare the expected absolute
benefits and risks of treatment. As outlined above, the risks of
treatment across the cardiovascular risk continuum are well established.
Likewise, the benefits of treatment in reducing the risk of MI across
the continuum are supported by equivalent proportional risk reductions
in both the low and high-risk databases. The only additional variables
that affect the risk-benefit analysis are the clarity of understanding
of an individual\'s underlying cardiovascular risk profile and an
appreciation of individual history that may alter the risk, such as a
history of gastric ulcer.

Clinicians can effectively assess cardiovascular risk and counsel
patients with respect to the benefits and risks of treatment options.
This, coupled with clear and consistent evidence that significant
benefits can be achieved, safely mandates the need for broader labeling
to include patients at Moderate Risk of CHD. The broader use in this
population would be expected to prevent 2-3 CHD events for every
extracranial bleed. As highlighted in the Safety section, the vast
majority of bleeds are not life threatening and are appropriately
managed through standard medical care. A therapeutic margin of this
magnitude is consistent with other interventions of this type and should
therefore lead to more broad scale appropriate use.

## Recommendations

To ensure that appropriate candidates are not denied the benefits of
ASA, while ensuring an appropriate therapeutic margin, numerous
guidelines have been developed that have specifically set the point at
which ASA therapy is appropriate at an underlying risk level that is
higher than that in the five studies that comprise the primary
prevention database. Our proposal to include individuals at Moderate
Risk of MI in the professional labeling for ASA is consistent with the
views of these major public health organizations, which have
independently reviewed the evidence in development of guidelines for
reducing the burden of cardiovascular disease in this country. The
promulgation of guidelines by the United States Preventive Services Task
Force and the American Heart Association highlights that significant
scientific consensus exists regarding the public health importance of
broadening the aspirin labeling to include patients "at risk" who have
not suffered a previous cardiovascular event.

### The U.S. Preventive Services Task Force Recommendations

The favorable benefit to risk relationship for the use of ASA in
Moderate Risk patients is clearly demonstrated by the recent U.S.
Preventive Services Task Force recommendations (2002) \[1\].
Furthermore, the taskforce acknowledges the importance of global risk
assessment, including asking about the presence and severity of the
following risk factors: age, sex, diabetes, elevated total cholesterol
levels, low levels of high-density lipoprotein cholesterol, elevated
blood pressure, family history (in younger adults), and smoking in
determining whether an individual patient should be a candidate for ASA
therapy.

The taskforce estimated the benefits and harms of ASA administered for 5
years to 1000 persons with various levels of baseline risk for coronary
heart disease, basing their estimates on a clearly supportable relative
risk reduction of 28% for coronary heart disease events in ASA-treated
patients derived from the five primary prevention studies in Table 20
below. For comparison purposes, it is important to note that the USPSTF
estimates are based on 5-year event rates rather than the 10-year rates
included in our submission and the recommendations of the American Heart
Association.

[]{#__RefHeading___Toc55791522 .anchor}Table 20: Estimates of Benefits
and Harms of Aspirin Given for 5 years to 1000 Persons with Various
Levels of Baseline Risk for Coronary Heart Disease\*

  ---------------------------- ---------- ------------- --------------- -------------
  Benefits and Harms           Baseline                                 
                               Risks for                                
                               Coronary                                 
                               Heart                                    
                               Disease                                  
                               over 10                                  
                               Years †                                  

                                          Low Risk      Moderate Risk   High Risk
                                          (\<10%)       (10%)           (20%)

  Coronary heart disease                  3 - 8\        14 (6--20)      20+
  events, n                               (1 -- 12)     avoided         avoided\*\*
                                          avoided                       

  Hemorrhagic strokes, n‡                 1 (0 -- 2)    1 (0 -- 2)      1 (0 -- 2)
                                          caused        caused          caused

  Major gastrointestinal                  3 (2 -- 4)    3 (2 -- 4)      3 (2 -- 4)
  bleeding events, n§                     caused        caused          caused
  ---------------------------- ---------- ------------- --------------- -------------

\*Estimates are based on a relative risk reduction of 28% for coronary
heart disease events in aspirin-treated patients and assume that risk
reductions do not vary significantly by age.

†Nonfatal acute myocardial infarction and fatal coronary heart disease.
Five-year risks of 1%, 3%, and 5%

are equivalent to 10-year risks of 2%, 6% and 10% respectively.

‡Data from secondary prevention trials suggests that increases in
hemorrhagic stroke may be offset by reduction in other types of stroke
in patients at very high risk for cardiovascular disease. (≥10% 5-year
risk).

§Rates may be two to three times higher in persons older than 70 years
of age.

\*\*Based on an analysis of secondary prevention studies

According to this analysis, estimates of the type and magnitude of
benefits and harms associated with ASA therapy vary with an individual's
underlying cardiovascular risk. The balance of benefit to risk is
clearly favorable in individuals with a 5-year risk that is greater than
3% (a 6% risk over 10 years). In this population, 4 - 12 coronary heart
disease events would be avoided, while only 0 - 2 hemorrhagic strokes
and 2 - 4 major GI bleeding events would be caused when treating 1000
patients for a 5-year period. Thus, the risk-benefit analysis clearly
works in favor of recommending ASA for cardiovascular disease prevention
in this Moderate Risk individual.

### The AHA Recommendations

Using the meta-analysis by Hayden and co-workers \[Error: Reference
source not found\] as a basis, the American Heart Association arrived at
a more conservative recommendation than the U.S. Preventive Services
Task Force \[1\]. According to the latest AHA guidelines for primary
prevention \[2\], 75 to 160 mg ASA per day should be considered for
persons at higher risk, especially those with a 10-year risk of coronary
heart disease of ≥10%. Treating such patients would further enhance the
benefit to risk relationship and prevent 14 events (range: 6 to 20), a
benefit of cardiovascular risk reduction which outweighs possible harms
estimated to result in an excess of 1 hemorrhagic stoke (range: 0 to 2)
and 3 major gastro­intestinal bleeding events (range: 2 to 4) among 1,000
persons treated over a 5-year period.

### Bayer HealthCare Recommendations

This Citizen's Petition follows the more conservative recommendation by
the American Heart Association of defining only patients at Moderate
Risk (those with a 10-year risk of coronary heart disease of ≥10%) as
eligible for treatment in order to make sure that the patients' benefit
of treatment clearly outweighs potential risks. If appropriate patients
are selected, many more heart attacks can be prevented for the small
number of adverse events caused.

## Conclusions: ASA Therapy Should Be Recommended for Those Individuals for Whom the Benefit Outweighs the Risk

The available data support the following specific guiding principles for
arriving at a risk assessment as to whether an individual patient should
be considered appropriate for ASA for the prevention of MI:

-   The risk of experiencing a first MI increases proportionally with an
    individual's overall underlying, measurable, cardiovascular risk.

-   The appropriateness of any intervention for MI (including ASA
    therapy) should be evaluated in the context of that individual's
    global risk of experiencing an MI (first MI or subsequent MI).

-   The proportional benefits and risks of ASA therapy are similar in
    individuals who are at High, Moderate, or Low Risk and are known and
    predictable

-   Because the proportional risk reductions of ASA are consistent
    across the studied Low Risk and High Risk populations, the benefits
    can reasonably be expected to extend to a Moderate Risk population
    where the absolute benefits will be greater than the benefits in the
    Low Risk population.

-   The benefits of ASA therapy should be offered to those who might
    accrue the greatest benefit.

-   A large number of patients exist who are at sufficiently high risk
    of MI to warrant intervention even if they have not had a previous
    event.

-   To maximize the benefit-risk relationship, patients at Moderate Risk
    (e.g., 10% or greater 10 year risk) where the benefit would be
    expected to far exceed the risk should be specifically included in
    the labeling.

Some might suggest that it would be inappropriate to approve the use of
ASA in Moderate Risk patients without additional study. However, this is
an overly cautious point of view. The label will clearly and
appropriately limit exposure to those at sufficiently elevated risk
(based on all the available scientific evidence) and, as set forth here,
will greatly improve the benefit-to-risk relationship. Furthermore, such
an approach validates the view that decisions are based on the totality
of the evidence, including the pathophysiology of the underlying
condition. Finally, this approach is consistent with previous precedent
in restricting access to a more limited population than specifically
studied in the pivotal clinical trials.

Based on this recommendation, the routine use of ASA by Moderate Risk
patients would be expected to result in 6 -- 20 CHD events prevented at
an appropriate level of risk of side effects per 1000 patients treated
in a 5-year period. Based on these findings ASA represents a worthwhile
intervention that should be used more broadly in this population.

# Goals of Labeling ASA for Primary Prevention

The FDA is charged with assuring that drugs are safe and effective for
their intended use and that their labeling provides adequate information
for such use and is not false or misleading. Informing physicians about
uses and necessary precautions is an important element in fulfilling
that responsibility. As new information becomes available to the agency,
the labeling of drug products should reflect the new information after
scientific and regulatory review.

Based on the body of evidence available showing a favorable benefit to
risk relationship and the issuance of the AHA and USPSTF
recommendations, along with the underutilization of ASA, it is important
to consider swift revisions to the professional labeling for ASA.

## Benefit-Risk Assessment

The labeling for a product serves as the tool to communicate the
appropriateness of therapy and necessary precautions associated with
therapy. The labeling for ASA should define the appropriateness of
therapeutic intervention based upon the evaluation of benefit-to-risk
relationship. Since the side effect profile of ASA is well established,
with the primary concerns of chronic use being GI bleeding and
hemorrhagic stroke, the focus of changes in labeling should be to
delineate the benefit to risk relationship associated with treatment of
ASA in a broader at risk population.

The currently approved professional labeling for ASA and the proposed
labeling to be considered can be found in Appendix 1. The expanded
labeling approved must adequately define the "moderate" risk population
(CHD risk of 10% over 10 years or in patients for whom there is a
positive benefit-risk as assessed by their health care provider), to
ensure a positive therapeutic margin where the benefits of treatment
would outweigh the risks. The recommended level of adverse event risk is
greater than the baseline cardiovascular risk in the Low Risk population
studies. This 10% over 10 years was conservatively chosen to ensure a
positive therapeutic margin where the benefits of treatment would
significantly outweigh the risks and is consistent with the current
guidelines of the AHA based on their evaluation of the benefit-to-risk
relationship.

## Underutilization of Treatment

A survey \[Error: Reference source not found\] was conducted to
determine the prevalence of use of ASA or other OTC analgesics to
prevent or treat CVD. The survey participants included 23,158 persons
aged 40 or over with no prior CVD and 3818 that reported prior CVD.
Results demonstrate that 10% of the respondents reported regular use of
any analgesic for primary prevention; 8% specified reporting using ASA.
Only 43% of the participants that reported prior CVD used ASA. Based
upon the results of the survey, there is a need from a public health
standpoint to address this underutilization of therapy and to ensure
appropriate product use. Professional labeling of ASA and educational
programs to support the appropriate use of ASA in a population at risk
for CVD would have a significant positive public health impact.

# EDUCATION

Directing cardiovascular health associated information to both the
patient and the physician are necessary to ensure appropriate ASA use.
The patient must be a part of the decision-making process with regard to
their health choices and must be directed to seek medical input and
advice, while the physician must have the labeling and risk assessment
tools to appropriately evaluate the patient. The process whereby this
will be achieved is through responsible educational healthcare
communications from a variety of sources, including, but not limited to
the FDA, industry, and professional organizations such as the American
Heart Association.

## Patient/Consumer Education

The importance of having the patient participate in the decision-making
process as it relates to their health is necessary from a public health
perspective. The patient needs to understand how risks associated with
cardiovascular disease (among others) impact their health, and how
behavior modification can reduce those risks. In order for this to be a
success, the public must have ready access to important healthcare
information. The responsibility for the communication of accurate
healthcare information lies with all parties concerned with public
health.

Bayer HealthCare takes its role seriously and has helped to educate the
public on the risks associated with cardiovascular disease and the
behaviors known to mitigate these risks, with the goal of encouraging
individuals to visit a physician and have their personal risk assessed.
Brochures have been distributed through Bayer HealthCare Consumer
Relations, physicians and in retail outlets on such topics as how to
recognize the symptoms of a heart attack, steps to better heart health
and heart health for women. In 2003, over 3 million brochures have been
distributed to consumers. In addition, Bayer has provided tools to
consumers with cardiovascular disease risk factors, such as high blood
pressure, diabetes and high cholesterol, through the sponsorship of
blood pressure kiosks, educational booklets and distribution of
information on responsible aspirin use. Individuals can also obtain
additional information by calling the toll-free number, which is listed
on all Bayer Aspirin products (1-800-331-4536), or by visiting
Bayeraspirin.com. Bayer plans to continue to expand these information
resources over time.

The broadest approach to reaching individuals at risk of a
cardiovascular event is via media (television, magazines, radio,
internet). Direct-to-Consumer (DTC) advertising has increased consumer's
knowledge about the availability of various drug products, with the
focus on speaking to their doctor. In 1999 the FDA conducted a national
telephone survey \[[^107]\] of adults (with a follow-up mail survey) to
ask their views on DTC promotion of prescription drugs. Although aspirin
is not a true "prescription" drug, the results from the FDA's survey
highlight some areas that are applicable to ASA as a drug product with
professional labeling. The FDA's Survey demonstrates that more consumers
need to consider seeing their physician. The results of the survey
showed that there were a significant group of respondents that had not
seen a doctor in more than a year (28% of those patients categorized as
not having seen a doctor in the last 3 months responded that they had
not seen a doctor for their own health condition or health concern for
"more than 1 year").

The public health impact of ASA "DTC" advertising is aimed at
communicating the importance of CV health and the importance talking to
their doctor before starting an ASA regimen.

## Physician Education 

Physicians are provided with new information from a wide variety of
sources. New information comes in numerous ways, e.g., guidelines, new
publications, new drug products, changes in drug products, CME topics,
industry detailing. The importance of keeping up with new
medical/scientific information for all drug products continues as new
information emerges. This is especially relevant to emerging information
on the cardiovascular medicine front. Physicians need to increase the
consumer/physician interactions to stem the underutilization of therapy
and behavior modification needed to treat the growing CVD problem.
Physician directed educational programs help to encourage the medical
community to recognize the importance of their role in assessment and
treatment of patients' cardiovascular risks. Bayer HealthCare has a wide
range of medical communication initiatives to inform, educate and assist
physicians and other healthcare providers implement the appropriate use
of aspirin in their patient populations. In 2003, 180,000 physician
office visits have been made and Bayer Aspirin-sponsored CME programs
have reached over 100,000 physicians and pharmacists.

In addition, Bayer has developed physician tools and patient materials
to help facilitate the discussion between doctors and their patients
about their risk for cardiovascular disease and to help determine if
aspirin therapy is right for them. Physicians can download
cardiovascular risk assessment guides by logging on to
[www.bayeraspirin.com/savinglivesASAP](http://www.bayeraspirin.com/savinglivesASAP).
Electronic versions are also being made available for physicians to
download onto their personal digital assistants (PDAs). Additionally,
copies are to be distributed to physicians via the Bayer sales force and
at major medical meetings.

## Professional Associations

To further enhance the communication of credible cardiovascular risk
reduction information, Bayer HealthCare partners with a number of
leading health authorities, such as The American Stroke Association, The
American College of Obstetricians & Gynecologists, and the American
College of Emergency Physicians. Bayer is also a major sponsor of the
American Heart Association (AHA) to help raise awareness of the risks of
cardiovascular disease and ways to help control risk factors. An AHA
partner for more than a decade, Bayer provides particular support to
initiatives supporting healthcare professional education. These AHA
initiatives include:

-   Healthcare Professional AHA Guidelines Distribution: Bayer
    HealthCare will continue to aid AHA in disseminating primary and
    secondary prevention guidelines, to provide the latest science and
    education on this topic to multiple professional audiences;

-   Underwriting of related scientific conferences on this topic;

-   Distribution of Healthcare Professional Tool Kit Materials;

Bayer has also expanded its nationwide partnership with VHA Inc, the
largest cooperative of not-for-profit hospitals in the U.S., comprising
2,200 healthcare organizations, in support of the Women's HeartAdvantage
program. The goals of this educational program are to raise
cardiovascular disease awareness among women, and to encourage and
enhance communication between physicians and patients. The program
strives to change women's heart health behavior through the prevention,
detection and treatment of risk factors. Bayer HealthCare through this
program provide more than 100 hospitals with aspirin compliance packs,
which are provided by the physician to appropriate patients upon
discharge from the hospital. The compliance packs are designed to help
patients new to an aspirin regimen follow their physician-prescribed
therapy. In 2003, 100,000 discharge kits have been distributed through
this program.

Bayer HealthCare looks forward to continuing to improve and expand its
outreach to doctors and patients through its own efforts as well as
through partnerships with organizations dedicated to improving
cardiovascular health.

# Conclusion

Bayer HealthCare has provided compelling evidence supporting the urgency
for the expanded use of ASA in a broader "at risk" population, i.e.,
moderate risk (10% 10-year CHD risk). The totality of the efficacy and
safety evidence supports the utility of ASA in preventing MI in this
population. Based on this evidence, regulatory action is necessary to
align the FDA approved ASA labeling with current practice guidelines
that define the current appropriateness of therapeutic intervention
based upon the evaluation of benefit-to-risk in all patients at
increased risk for CHD.

# List of Appendices

Appendix 1. Aspirin Professional Labeling / Proposed Labeling

Appendix 2. Aspirin Worldwide Cardiovascular Indications

Appendix 3. Coronary Disease Risk Prediction Score Sheets for Women and
Men Based on Total Cholesterol Level

Appendix 4. British Doctors' trial (BDT): Peto, R.; Gray, R.; Collins,
R.; Wheatley, K.; Hennekens, C.; Jamrozik, K.; Warlow, C.; Hafner, B.;
Thompson, E.; Norton, S.; Gilliland, J.; Doll, R. Randomised trial of
prophylactic daily aspi­rin in British male doctors. BMJ 1988; 296:
313-316.

Appendix 5. Hypertension Optimal Treatment trial (HOT): Hansson, L.;
Zanchetti, A.; Carruthers, S.G.; Dahlöf, B.; Elmfeldt, D.; Julius, S.;
Ménard, J.; Rahn, K.H.; Wedel, H.; Westerling, S. Effects of intensive
blood-pressure lowering and low-dose aspirin in patients with
hypertension: principal results of the Hypertension Optimal Treatment
(HOT) randomised trial. Lancet 1998; 351: 1755-1762.

Appendix 6. Physicians' Health Study (PHS): Steering Committee of the
Physicians\' Health Study Research Group. Final report on the aspirin
component of the ongoing Physicians\' Health Study. N.Engl.J.Med. 1989;
321: 129-135.

Appendix 7. Primary Prevention Project (PPP): Collaborative Group of the
Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in
people at cardiovascular risk: a randomised trial in general practice.
Lancet 2001; 357: 89-95.

Appendix 8. Thrombosis Prevention Trial (TPT): Medical Research
Council\'s General Practice Research Framework. Thrombosis Prevention
Trial: randomised trial of low-intensity oral anticoagulation with
warfarin and low-dose aspirin in the primary prevention of ischemic
heart disease in men at increased risk. Lancet 1998; 351: 233-241.

Appendix 9. Eidelman, R.S.; Hebert, P.R.; Weisman, S.M.; Hennekens, C.H.
An Update on Aspirin in the Primary Prevention of Cardiovascular
Disease. Arch Intern Med. 2003; 163: 2006-10.

Appendix 10. Antithrombotic Trialists' Collaboration. Collaborative
meta-analysis of randomized trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk
patients. BMJ 2002; 324: 71-86.

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