http://bmj.com/cgi/content/full/324/7330/167
BMJ 2002;324:167 ( 19 January )
Letters
Article makes simple errors and could cause unnecessary deaths
The
worldwide meta-analysis of antiplatelet trials shows that low dose aspirin (or
some other effective antiplatelet regimen) reduces non-fatal
myocardial infarction, non-fatal stroke, and vascular death in a
wide range of patients who are at high risk of occlusive vascular
disease.1
A paper disputing this was published concurrently in the For Debate
section of the journal,2
but the arguments in it (some of which the author also published on
the same date in an editorial in the Lancet)3 depend
strongly on quite simple mistakes about the randomised evidence and
could cause unnecessary deaths.
Consider, for example, the ISIS-2 trial of short term antiplatelet therapy,
in which 17 187 patients with suspected acute myocardial
infarction were randomised, half to active aspirin and half to
placebo.4
This trial showed a clear reduction in five week all cause mortality
(811/8587 (9.4%) aspirin v 1030/8600 (12.0%) placebo deaths,
2P<0.00001).5
Bizarrely, in a section entitled "Trials do not show that
aspirin saves lives," the For Debate paper attempts to dismiss
the ISIS-2 findings by suggesting that "all patients lost to
follow up in the active group should be considered to have died and
none of those in the control arm. Such an analysis would neutralise
the benefit observed in one of the few seemingly convincingly
positive studies of aspirin, the ISIS-2 trial."2
This is not even arithmetically correct, and such a statement should not be
part of any serious debate in the BMJ. The five week follow
up was 97% complete when this trial was first reported,4 and
99% complete when further follow up was reported in the BMJ.5 This
slightly greater completeness yielded, in fact, only 13 extra deaths
(6 in the aspirin group, 7 in the placebo), and the even slighter
incompleteness that remains cannot, of course, be of any material
relevance (especially since most of the few still untraced at five
weeks are known to have been discharged alive from hospital: for
only 0.2% of the patients given aspirin and 0.2% of those given
placebo is there no follow up at all).
Likewise, among about 20 000 patients in the 12 trials of long
term (mean two years) antiplatelet therapy among patients with a
history of previous myocardial infarction, the odds of having a
non-fatal reinfarction were reduced by 30% (SE 6; 2P<0.00001), with
no significant heterogeneity between the results in different studies.1 The For
Debate paper purports to account for this 30% reduction by
suggesting (without good evidence of any such effect) that the
proportion of non-fatal infarctions that would be reported might be
70% with aspirin and 75% without. Again, however, this argument is
arithmetically wrong, for 70 v 75 would represent a
reduction of only 7%, not 30%.
Furthermore, having suggested earlier that it is only analyses of all cause
mortality that can be trusted, the paper then goes on to elaborate a
curious theory that involves trusting the somewhat arbitrary distinction
between mortality attributed to sudden death and to other cardiac
causes. From this it eventually concludes that aspirin could be
producing "an increased risk of sudden death among concealed,
and therefore untreated, events."2 But,
there is no good evidence that this is true.
More importantly, in the worldwide meta-analysis, vascular mortalitywhich
is highly significantly reducedalready
included both sudden death and death from unknown causes (as well as
death from any type of stroke).1 In the
12 trials of long term antiplatelet therapy during the years
after myocardial infarction the reduction in vascular mortality was
15% (SE 5; 2P=0.002) again with no significant heterogeneity between
the effects in different antiplatelet trials (or 17%; 2P<0.0010),
with even less heterogeneity, if the imbalance in prognostic
features in the AMIS trial is appropriately allowed for).6 Moreover,
all cause mortality was also reduced, as there was no significant
excess of non-vascular deaths in this category of patient, or in any
of the other four main categories of patients at high risk. Indeed,
taking the 135 000 patients in all five categories together,
non-vascular mortality was 1.1% with antiplatelet therapy and 1.2%
without, which looks pretty safe. Thus, there is no good evidence
from these trials that non-vascular mortality offsets the highly
significant reduction in vascular death or in non-fatal myocardial
infarction or stroke among high risk patients.
A recent study of the costs of the secondary prevention of such vascular
events by aspirin is cited in the For Debate paper as concluding
that the cost per event prevented would be over £3000. If true, this
could be money well spent, but it is included in a section
misleadingly entitled "Neither safe nor cheap."2 (No
other cost estimates in that section are relevant to secondary prevention.)
The author also suggests that "the greatest potential detriment
of aspirin on health care, however, is that it diverts attention
away from treatments that are of unequivocal benefit." No good
evidence for this assertion is provided and, moreover, there is no
good reason why other effective treatments (such as angiotensin
converting enzyme inhibitors, 
blockers,
and statins) should not be used in addition to aspirin, conferring
additional benefit.7
There are several other errors of judgment, partly from failure to
understand the proper role of meta-analysis in the interpretation of
randomised evidence. Given this, none of the substantive points in
the For Debate article is of material relevance (except, perhaps, as
a warning about the power of prejudice), and the chief ones have
been dealt with adequately in the current or previous antiplatelet reports.
In retrospect, it would perhaps have been better for the BMJ
to have sought review of the paper from, among others, those whose
work it criticises. This would have given the journal the
opportunity to avoid publication of arguments and conclusions that are
wrong for trivial reasons and potentially damaging to patients.
Colin Baigent
colin.baigent@ctsu.ox.ac.uk
Rory Collins
Richard Peto
Radcliffe Infirmary, Oxford OX2 6HE
|
1. |
Antithrombotic Trialists' Collaboration. Collaborative
meta-analysis of randomised trials of antiplatelet therapy for prevention of
death, myocardial infarction and stroke in high risk patients. BMJ
2002; 324: 71-86 |
|
2. |
Cleland JGF. For debate: Preventing atherosclerotic events
with aspirin. BMJ 2002; 324: 103-105 |
|
3. |
Cleland JGF. No reduction in cardiovascular risk with
NSAIDS |
|
4. |
ISIS-2 Collaborative Group. Randomised trial of
intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases
of suspected acute myocardial infarction. Lancet 1988; ii: 349-360 |
|
5. |
Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto
R, on behalf of the ISIS-2 Collaborative Group. ISIS-2: 10-year survival
among patients with suspected acute myocardial infarction in randomised
comparison of intravenous streptokinase, oral aspirin, both, or neither. BMJ
1998; 316: 1337-1343 |
|
6. |
Antiplatelet Trialists' Collaboration. Secondary
prevention of vascular disease by prolonged antiplatelet treatment. BMJ
1988; 296: 320-331 |
|
7. |
Flather MD, Yusuf S, Køber L, Pfeffer M, Hall A, Murray G,
et al. Long-term ACE-inhibitor therapy in patients with heart failure or left
ventricular dysfunction: a systematic overview of data from individual
patients. Lancet 2000; 355: 1575-1581 |
|
Other related articles in
BMJ:
PAPERS
Collaborative meta-analysis of randomised trials of antiplatelet
therapy for prevention of death, myocardial infarction, and stroke in high risk
patients.
BMJ 2002 324: 71-86.
ALL INFORMATION, DATA,
AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION
PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR
OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING
MEDICAL OR LEGAL ADVICE. THE DECISION WHETHER OR NOT TO VACCINATE IS AN
IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN
CONSULTATION WITH YOUR HEALTH CARE PROVIDER.