Cardiovascular and Renal Drugs Advisory Committee Meeting
The Cardio-Renal Advisory Committee is asked
to opine on the use of aspirin for the primary prevention of myocardial
infarction. This meeting is in response to a Citizen Petition, filed
The
British Doctors' Trial (BDT; British Medical Journal, 1988) was conducted
between 1978 and 1984 among 5139 healthy male British doctors. age 50 to 78. The comparison was between aspirin 500 mg
daily and no treatment. The primary end point was fatal or non-fatal MI,
stroke, or TIA; p=NS.
The
Physician's Health Study (PHS; New England Journal of Medicine, 1989) was
conducted between 1982 and 1987 among 22071 healthy male
The
Thrombosis Prevention Trial (TPT; Lancet, 1998) was conducted between 1984 and
1989 among 5085 British males at high risk, age 45 to 69. The comparison was
between controlled-release aspirin 75 mg daily and placebo. The primary end
point was "coronary death and fatal and non-fatal MI"; p=0.04 (p=0.07
including silent MI).
The
Hypertension Optimal Treatment study (HOT; Lancet, 1998) was conducted in 26
countries between 1992 and 1997 among 19196 men and women with mild-to-moderate
hypertension and no stroke or MI within 12 months. The comparison was between
aspirin 75 mg daily and placebo. The primary end point was cardiovascular death
and non-fatal MI or stroke; p=0.17 (p=0.03 excluding silent MI).
The
Primary Prevention Project (PPP; Lancet 2001) was conducted in
Of the 5 studies, a
study protocol and source data were reviewed only for HOT (PHS having been
previously reviewed), and the FDA review of HOT suggests a substantially weaker
result than is published. The primary end point in HOT included silent MI,
while in TPT silent MI was assessed (but it unclear whether it is included in
the reported analyses) and in the other 3 studies silent MI was, apparently,
not collected. Assessed end points in the published studies are shown in the
table below:
|
BDT |
PHS |
TPT |
PPP |
All-cause
mortality |
Ö |
Ö |
Ö |
Ö |
Cardiovascular
mortality |
Ö |
Ö |
Ö |
Ö |
CV death + MI +
stroke |
Ö |
|
|
Ö |
Fatal MI + fatal
stroke |
Ö |
|
|
|
Fatal or non-fatal
MI |
Ö |
Ö |
Ö |
Ö |
Fatal or non-fatal
stroke |
Ö |
Ö |
Ö |
Ö |
Non-fatal MI |
Ö |
Ö |
Ö |
Ö |
Non-fatal stroke |
Ö |
Ö |
Ö |
Ö |
Silent MI |
|
|
Ö |
|
1.
Are there other studies that should be
considered?
2.
In considering how to interpret these
trials with respect to primary prevention of MI, whether by formal or informal
meta-analysis, …
2.1.
…what is the significance of each of
the following?
2.1.1.
The study protocol is unavailable for
BDT, TPT, and PPP.
2.1.2.
The source data are unavailable for
BDT, TPT, and PPP.
2.1.3.
No study had primary prevention of MI
as a primary end point.
2.1.4.
Only one study appears to have shown an
effect on its pre-specified primary end point.
2.1.5.
The studies varied with respect to what
MIs were captured.
2.1.6.
The dose, regimen, and
biopharmaceutical properties of aspirin varied.
2.1.7.
The baseline risk factors varied.
2.2.
…do you conclude that a meaningful
synthesis is possible?
3.
Aspirin has a claim for secondary prevention of myocardial
infarction.
3.1.
How much, if at all, does this lower
the evidentiary burden for primary
prevention of myocardial infarction?
3.2.
Aspirin also has secondary prevention
claims related to strokes and overall cardiovascular mortality. Since effects
of aspirin on strokes and cardiovascular mortality are not evident in these
primary prevention studies, how much, if at all, does this discrepancy raise the evidentiary burden for primary
prevention of myocardial infarction?
4.
What do the available data say was the
effect of aspirin on primary prevention of myocardial infarction? If there was
an effect, …
4.1.
…is this opinion based on selected
studies or the formal meta-analysis?
4.2.
…name the effect and define what
constituted a myocardial infarction.
4.3.
…how do you explain differences in
outcome among these studies?
4.4.
…what was the effect in relevant
demographic subgroups (gender, age, and race)?
5.
What do the available data say about
the safety of aspirin in primary prevention setting? What do you know about …
5.1.
…risks in demographic subgroups
(gender, age, race)?
5.2.
...interactions with underlying
disease?
5.3.
…use with various concomitant drugs?
6.
Should professional labeling for
aspirin recommend its use for primary prevention of MI?
6.1.
If so, …
6.1.1.
…what patient population can expect to
benefit from aspirin?
6.1.2.
…what dose, regimen, and form of
aspirin should be recommended?
6.2.
If not, describe the study that would
provide compelling evidence for this indication.
7.
If aspirin were to be approved for
primary prevention of myocardial infarction, comment on the petitioner's
proposal to identify a target population using an integrated risk assessment
score.
7.1.
How confident are you that the proposed
scoring system appropriately identifies patients most likely to benefit from
aspirin?
7.2.
Can physicians use this?
7.3.
Can patients understand it?