*Preliminary Review of APPROVe data --*

*Background package for February, 2005 AC meeting.*

*IND 46,894 -- Vioxx*

*Sponsor: Merck*

*Reviewer: Lourdes Villalba, M.D., MO, HFD-550*

*Jim Witter, M.D., Ph.D., Team Leader, HFD-550*

***1. Background**:*

*Merck withdrew Vioxx from the market on September 30, 2004, upon the
ESMB (external safety monitoring board), review of the interim analysis
of study 122, also known as APPROVe. The full name of this protocol is:
"A multicenter, randomized, parallel-group, placebo-controlled, double
blind study to determine the effect of 156 weeks of treatment with
MK-0966 on the recurrence of neoplastic polyps of the large bowel in
patients with a history of colorectal adenomas"). Preliminary analyses
from APPROVe were presented to FDA on September 28, 2004. The cut-off
date for these analyses was 8/16/04. The final report from APPROVe has
not been submitted to FDA.*

***2. Results of APPROVe as presented to FDA on September 28, 2004***

*APPROVe compared Rofecoxib 25mg* vs. *Placebo in approximately 2600
patients with a history of colonic polyps. It had a 3-Year on-drug
Treatment Period with a one-year follow up period. Colonoscopies were
done at screening, 1 year and 3 years on-drug, with a follow up
colonoscopy at year 4 (1 year off-therapy) to assess rebound. The mean
age of patients was 59 years (30% \>65 years) and 60% were male. Of
note, 15% were taking low dose aspirin for cardiovascular prophylaxis.
The study had an ESMB that met regularly every 6 months. Cardiovascular
adverse events were referred to an independent CV adjudication committee
that evaluated the cases in a blinded manner. At the September 17, 2004
ESMB meeting, based on the imbalance in the number of cardiovascular
thrombotic events, the ESMB recommended stopping the trial (Tables 1 2
and 3). The definition of confirmed APTC (Anti-Platelet Trialists
Collaboration) events and CV/T (cardiovascular thrombotic events) are
the same as used in prior Merck trials: APTC includes cardiovascular
deaths, non-fatal myocardial infarction and non fatal stroke; CV/T
includes APTC events plus unstable angina, transient ischemic attack and
peripheral events, while excludes hemorrhagic strokes.*

*Table 1. Confirmed CV thrombotic events in APPROVe*

![](media/image1.png){width="4.416666666666667in" height="3.0in"}

*Table 2. Confirmed CV/thrombotic endpoints by aspirin use*

![](media/image2.png){width="3.997916666666667in" height="2.18125in"}

*Table 3. APTC composite endpoints by aspirin use*

![](media/image3.png){width="3.872916666666667in"
height="2.0631944444444446in"}

*It is unclear why the denominator is different for Tables 2 and 3.
Clarification is pending.*

*Figure 1. Time to Event Plot. Confirmed CV/Thrombotic events in
APPROVe*

![](media/image4.png){width="4.499305555555556in"
height="2.9993055555555554in"}

*A- placebo; B- rofecoxib 25 mg*

*There was approximately twice the number of cardiovascular thrombotic
events in patients receiving rofecoxib 25 mg as compared to placebo.
Results were consistent in any way one looked at them: all investigator
reported CV/T events (data not shown), confirmed CV/T events (Table 1
and 2) or APTC events (Table 3). As per Figure 1., the hazard ratio for
CV/T events for rofecoxib and placebo increased after 18 months of
exposure, however, it is unclear whether the rate in rofecoxib increased
over time or the rate in placebo made a plateau. (Analyses of risk over
time are pending at the time of this review.)*

Reviewer's comments:

-   These results are consistent with VIGOR (rofecoxib 50 mg as compared
    to naproxen) in the overall number of CV/T events (twice on
    rofecoxib), the number of cardiovascular deaths (no difference
    between groups) and the number of MI (an excess on rofecoxib as
    compared to the comparator), although in VIGOR the difference
    between rofecoxib and naproxen was observed much earlier (starting
    at approximately 6 weeks, with more marked separation after 6-8
    months). It is unclear why this difference in risk between rofecoxib
    and naproxen occurs earlier. It might be related to a different
    mechanism or to the fact that rofecoxib was used at twice the dose
    used in APPROVe.

-   The results are not consistent with those of the Alzheimer's studies
    (078 + 091) as presented in the March 30, 2004 submission to NDA
    21-042), of rofecoxib 25 mg as compared to placebo for up to 36
    months. In this database there was no difference in the number of
    total CV/T events and MI but there was half the number of
    cerebrovascular events in rofecoxib as compared to placebo. Of note,
    in the Alzheimer's studies, total cause mortality and CV/T mortality
    were higher on rofecoxib as compared to placebo (see Medical Officer
    review dated 12/18/04). Information on total cause mortality in
    APPROVe is not available at present.

-   The rate of CV events is different in different studies. For
    instance, the percentage of MI was 0.5 and 0.1% for rofecoxib 50 mg
    and naproxen, respectively in VIGOR (in patients with RA); it was
    1.3 and 1.3 % on rofecoxib 25 mg and placebo, respectively in the
    Alzheimer's studies and 1.6 and 0.6 % for rofecoxib 25 mg and
    placebo, respectively in APPROVe (patients with a history of colonic
    polyps). Different populations seem to have a different background
    rate of MI. These studies also had different duration and doses of
    rofecoxib. It is unclear which would be the best population to
    address CV issues with the selective and non-selective NSAIDs.
    Should these studies use placebo or naproxen as the active
    comparator? And what dose should be used (the highest dose
    recommended for chronic use or a higher dose)? What is clear from
    these data is that a study that would address CV safety needs to
    allow sufficiently long exposure, of at least 2 or 3 years.

-   The mechanism for this excess in CV/T events on rofecoxib (and
    potentially for other selective and non-selective NSAIDs) is
    uncertain. There may be more than one mechanism, one of which could
    be the effect of rofecoxib on blood pressure (BP). Analyses of CV/T
    events in relationship to BP changes in APPROVe (see section 3.2 of
    this memo) have not demonstrated so far that that is the sole
    explanation for the findings.

-   Of note, 3 shows that relative risk of APTC events is smaller in the
    subgroup of patients taking low dose aspirin as compared to those
    not taking low dose aspirin, although the risk is still higher for
    rofecoxib as compared to placebo (RR= 1.29). This observation is
    consistent with that of TARGET (lumiracoxib vs. naproxen and
    lumiracoxib vs. ibuprofen) and may be due to the fact that low dose
    aspirin might prevent cardiovascular thrombotic events. It is also
    possible that the number of patients is too small to detect
    differences in APTC events between groups.

> Some cardiologists have criticized FDA and suggested that a clinical
> trial to address cardiovascular issues with COX-2 selective agents
> should have been conducted in patients at high cardiovascular risk.
> However, such population with 100% use of low dose aspirin could
> potentially require huge number of patients in studies of longer
> duration in order to observe significant differences in cardiovascular
> events between treatment groups.

3.  ***October 8, 2004 submission***

> *Review of analyses of CV/T events in relation to BP changes in
> APPROVe.*
>
> *The Sponsor conducted several analyses of CV/T events in relation to
> BP. Some of these analyses are included in this review. As seen in
> Table 4. CV/T events are more common among those patients with
> baseline blood pressure above DBP of 90 or SBP of 140 mmHg. However,
> the relative risk of CV/T events for Vioxx as compared to placebo, is
> consistently elevated among those patients with normal and even low
> baseline blood pressure (RR = 1.5 to 3.5).*
>
> *Table 4. Patients with investigator reported thromboembolic or APTC
> events (excluding non-CV deaths) by baseline BP in APPROVe.*

+-----------------------+-----------+--------------+-----------------+
| *Baseline BP*         | *Placebo* | *Rofecoxib   | *Relative risk* |
|                       |           | 25 mg*       |                 |
|                       | *Event    |              |                 |
|                       | s/patient | *Ev          |                 |
|                       | years     | ents/patient |                 |
|                       | (rate x   | years (rate  |                 |
|                       | 100 pt    | x 100 pt     |                 |
|                       | years)*   | years)*      |                 |
+-----------------------+-----------+--------------+-----------------+
|                       | *N= 1299* | *N= 1287*    |                 |
+-----------------------+-----------+--------------+-----------------+
| *DBP≥100 or SBP≥ 160* | *5/189    | *7/176       | *1.524*         |
|                       | (2.7)*    | (4.0)*       |                 |
+-----------------------+-----------+--------------+-----------------+
| *DPB 90-99 or SBP     | *19/1026  | *26/846      | *1.660*         |
| 140-159*              | (1.9)*    | (3.1)*       |                 |
+-----------------------+-----------+--------------+-----------------+
| *DBP 85-89 or SBP     | *14/704   | *23/746      | *1.555*         |
| 130-139*              | (2.0)*    | (3.1)*       |                 |
+-----------------------+-----------+--------------+-----------------+
| *DBP 80-84 or SBP     | *4/808    | *12/705      | *3.433          |
| 120-129*              | (0.5)*    | (1.7)*       | (p\<0.05)*      |
+-----------------------+-----------+--------------+-----------------+
| *DBP \<80 and SBP     | *2/547    | *6/546       | *3.159*         |
| \<120*                | (0.4)*    | (1.1)*       |                 |
+-----------------------+-----------+--------------+-----------------+

> *(From Sponsor's Table 10.d. of October 8, 2004 submission).*
>
> Table 5. Patients with investigator reported thromboembolic or APTC
> events (excluding non CV deaths) by on-treatment Hypertension in
> APPROVe.

+-----------------------------------+----------------+-----------------+
| ***On treatment HTN***            | *Placebo*      | *Rofecoxib 25   |
|                                   |                | mg*             |
|                                   | *              |                 |
|                                   | Events/patient | *Events/patient |
|                                   | years (rate x  | years (rate x   |
|                                   | 100 pt years)* | 100 pt years)*  |
+-----------------------------------+----------------+-----------------+
| *Patients without HTN*            | *32/2510       | *35/2058 (1.7)* |
|                                   | (1.3)*         |                 |
+-----------------------------------+----------------+-----------------+
| *Patients with HTN (twice or      | *8/381 ( 2.1)* | *18/520 (3.5)*  |
| more)*                            |                |                 |
+-----------------------------------+----------------+-----------------+

> *n=events. \* Hypertension defined as patients with DBP ≥ 100 or DBP ≥
> 160 mm Hg twice or more. (From Sponsor's Table 11.d. of October 8,
> 2004 submission).*
>
> *Table 5 suggests that the rate of investigator reported CV/T or APTC
> events is greater among patients who had hypertension during the study
> (as defined by DBP ≥ 100 or DBP ≥ 160 mm Hg in two or more
> measurements) for both, the rofecoxib and placebo groups as compared
> to those who did not develop hypertension, and that more patients
> developed hypertension in the rofecoxib group as compared to placebo.
> However, the relative risk of CV/T events is greater in the rofecoxib
> group as compared to placebo, regardless of hypertension status.*
>
> Reviewer's comment: This observation suggests that while hypertension
> is important, there may be another mechanism to explain the different
> rate of CV/T events between rofecoxib and placebo in this study.
>
> Another possibility is that increase in blood pressure, even if not as
> marked as DBP ≥ 100 or SBP ≥ 160 mm Hg may have an effect in
> increasing the risk of CV/T events. Data from the Framingham Heart
> Study suggest that even high-normal blood pressure is associated with
> an increased risk of cardiovascular disease.
>
> Additional analyses in patients who develop borderline HTN (defined as
> DBP ≥ 90 or SBP ≥ 140 mm Hg) and in patients taking concomitant
> antihypertensive medications (by different categories of
> anti-hypertensive) are pending at the time of this review.