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BMJ. 2002 January 12; 324(7329): 103–105. | PMCID: PMC1121995 |
Preventing atherosclerotic events with aspirin John G F Cleland, professor Department of Cardiology, Castle Hill Hospital, University of Hull, Kingston upon Hull HU16 5JQ On p  71 we publish the latest in a series of meta-analyses
from the Antithrombotic Trialists' Collaboration. Here John Cleland
argues that, despite the vast size of these meta-analyses, the evidence
in support of aspirin preventing atherosclerotic events is still
inconclusive. One adverse effect of the belief that aspirin is more
effective than it is, he argues, is the neglect of more effective drugs
for preventing heart disease and stroke. The third meta-analysis from the Antithrombotic Trialists'
Collaboration, published in this issue, contains data on over 100 000
patients at high risk of atherosclerotic events, representing more than
250 000 patient years of follow up. 1 This meta-analysis
and its predecessors form the major argument for the current widespread
fashion of prescribing aspirin to such patients. 2,3 It is
an enormous body of research and the collaboration is to be
congratulated for having gathered so much data. However, quality as
well as quantity matters. And the quality is such that the results can
only be inconclusive.
Summary points - The series of meta-analyses on the antiplatelet activity of
aspirin overvalues aspirin's effectiveness and safety
- All the large long term trials of aspirin after myocardial infarction
show no effect on mortality
- Aspirin may change the way vascular events present rather than prevent
them
- This may lead to a “cosmetic” reduction in non-fatal events and an
increase in sudden death
- Data on the safety and cost-benefit of aspirin are inadequate
- Advocating the use of aspirin for preventing atherosclerotic events
diverts attention from other, more effective, drugs
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Trials do not show that aspirin saves lives Meta-analysis is increasingly viewed either as a way of verifying
that the outcome of an individual trial is consistent with the rest of
the known data or as a way of generating a hypothesis. However, in the
absence of a definitively positive trial, many consider meta-analysis
inadequate evidence for clinical decision making. The series of
meta-analyses from the trialists' collaboration contains serious
additional flaws. 3–6 Since the benefit from treatment
with antiplatelet agents is small, these flaws could lead to erroneous
conclusions. It is remarkable—and probably statistically significant—how seldom
trials of antiplatelet agents have shown benefit on their selected
primary outcome. The choice of the primary endpoint by the
Antithrombotic Trialists' Collaboration is arbitrary and suspect.
Antiplatelet agents seem to be substantially more effective in reducing
the incidence of non-fatal events than in reducing death. Indeed, among
large long term trials after myocardial infarction there is no evidence
that aspirin saves lives. An intervention can reduce non-fatal events in three ways: by genuinely
reducing them, by concealing them, or by converting non-fatal events
into fatal ones. The failure of aspirin to reduce mortality despite a
reduction in non-fatal events in many studies suggests that aspirin may
conceal, rather than prevent, vascular events. 6
Epidemiological data suggest that 25% of non-fatal myocardial
infarctions are silent. 4,5 As aspirin, even at low doses,
is an analgesic and because it may provoke dyspepsia, which may create
confusion about the cause of chest pain, it is not difficult to believe
that aspirin could increase the proportion of silent events from 25%
to 30%. This could explain all the benefits of antiplatelet agents on
non-fatal myocardial in the meta-analysis. Aspirin increased the risk of sudden death in every long term study
after myocardial infarction that reported such events. This increase
was from 4.4% on placebo to 5.6% on aspirin in the persantine-aspirin
reinfarction (PARIS) study (n=2026) 7; from 2.0% to 2.7%
in the aspirin myocardial infarction study (AMIS)
(n=4524) 8; and from 2.0% to 2.4% in the
persantine-aspirin reinfarction study (PARIS-II)
(n=3128). 9 This could reflect an increased risk of sudden
death among concealed, and therefore untreated, events. Another
possible mechanism by which aspirin may convert non-fatal events into
fatal ones is by increasing the risk of haemorrhagic conversion of
cerebral and myocardial infarctions. All cause mortality and, arguably,
disabling stroke are the only robust markers of benefit with an
antiplatelet agent. It is not clear that antiplatelet agents reduce the
risk of either .
All the meta-analyses from the Antithrombotic Trialists' Collaboration
are incomplete. Large long term trials after myocardial infarction
were consistently neutral; small trials were consistently positive; and
there were no small negative trials. 4–6 This almost
certainly reflects publication bias: small negative trials may not be
reported by investigators or accepted for publication by editors. Also
some trials that were included lost more than a quarter of their
patients to follow up. 10 In similar circumstances, with
other agents, it has been suggested that all patients lost to follow up
in the active treatment 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. 11The Antithrombotic Trialists' Collaboration shows bias in the
analysis and interpretation of their results. We are given scant detail
on how the numbers of events credited to each trial changed between
meta-analyses. 2,3 Trials were retrospectively reanalysed,
resulting in resurrection of a number of apparently dead patients and
the discovery of a number of new deaths. This inadequately blinded
exercise resulted in a substantial bias in favour of aspirin.
Favourable aspects of trials published after 1997, which were excluded
from the meta-analysis, are none the less reported in the text, but
inconvenient trials 12 and details, such as the significant
excess in non-fatal and fatal coronary events in the Pulmonary Embolism
Prevention (PEP) trial, 13 were ignored. Most interventions probably help some people some of the time and harm
others some of the time. A small benefit could reflect a small overall
benefit in a large population or a substantial benefit in some patients
and harm in others. Aspirin could exert a short term benefit followed
by long term harm, in which case the benefits and safety of aspirin
could be increased by using only a short term course of
therapy. 14 Aspirin may be harmful in patients with
coronary disease and heart failure. 5,6,12 The evidence
for an adverse interaction between aspirin and angiotensin converting
enzyme inhibitors observed in the SOLVD (studies of left ventricular
function) and HOPE (heart outcomes prevention evaluation) trials is
also a matter for concern. 6,12 These are important issues
that have not been adequately addressed. Many believe that, even if aspirin is not effective, it is safe.
Aspirin does appear to be relatively safe for the patients included in
clinical trials, but as these studies excluded by design patients at
risk of adverse events with aspirin and tended to include younger
patients with lower multiple morbidity it is likely that aspirin is not
as safe as suggested. Low dose aspirin for cardiovascular prophylaxis
may account for more than 30% of all major gastrointestinal
haemorrhage in patients aged over 6, 4,6,15 and may also
be associated with an increased risk of renal failure. Finally, there is a widespread view that aspirin is cheap. However,
when evaluating the costs of treatment the amount and type of benefit
and the costs of managing adverse effects also need to be evaluated.
Very few economic appraisals of aspirin have been done. One such
analysis, recently commissioned by the chief scientist's office
in Scotland, suggested it may cost more than £80 000 to prevent one
event with aspirin for primary prevention and more than £3000 for
secondary prevention. 16 These analyses have assumed that
aspirin is as effective as the meta-analyses suggest, which may not be
true. Perhaps the greatest potential detriment of aspirin on health
care, however, is that it diverts attention away from treatments that
are of unequivocal benefit to many groups of patients, such as
angiotensin converting enzyme inhibitors, β blockers, and statins,
and creates a potentially false gold standard for good medical
care. The reader should not accept the conclusions of the
Antithrombotic Trialists' Collaboration uncritically but rather read
the original papers on which their conclusions are based. Editorial
by Fitzgerald Papers
p 711. Antithrombotic Trialists' Collaboration. Prevention of death, myocardial infarction and stroke by antiplatelet therapy in high-risk patients. BMJ. 2001;323:71–86. [PubMed] 2. The antiplatelet trialists' collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ. 1988;296:320–331. [PubMed] 3. The antiplatelet trialists' collaboration. Collaborative overview of randomised trials of antiplatelet therapy - 1:Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106. [PubMed] 4. Cleland JGF, Bulpitt CJ, Falk RH, Findlay IN, Oakley CM, Murray G, et al. Is aspirin safe for patients with heart failure? Br Heart J. 1995;74:215–219. [PubMed] 5. Cleland JGF. Anticoagulant and antiplatelet therapy in heart failure. Curr Opinion Cardiol. 1997;12:276–287. [PubMed] 6. Cleland JGF, John J, Houghton T. Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors in hypertension or heart failure? Curr Opin Nephrol Hypertens. 2001;10:625–631. [PubMed] 7. The Persantine-Aspirin Reinfarction Study (PARIS) Research Group. Persantine and aspirin in coronary heart disease. Circulation. 1980;62:449–462. 8. The Aspirin Myocardial Infarction Study Research Group. The aspirin myocardial infarction study: final results. Circulation. 1980;62:V79–V84. [PubMed] 9. Klimit CR, Knatterud GL, Stamler J, Meier P. Persantine-aspirin reinfarction study. Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol. 1986;7:251–269. [PubMed] 10. Breddin K, Loew D, Uberla KK, Walter E. The German-Austrian aspirin trial: A comparison of acetylsalicylic acid, placebo and phenprocoumon in secondary prevention of myocardial infarction. Circulation. 1980;62:V63–V71. [PubMed] 11. 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. 12. Jones CG, Cleland JGF. Meeting report - LIDO, HOPE, MOXCON and
WASH Studies. Eur J Heart Failure 1999;425-31. 13. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000;355:1295–1302. [PubMed] 14. Lewis HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE, et al. Protective effects of aspirin against acute mycardial infarction and death in men with unstable angina. N Engl J Med. 1983;309:396–403. [PubMed] 15. Weil J, Langman MJS, Wainwright P, Lawson DH, Rawlins M, Logan RFA, et al. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs. Gut. 2000;46:27–31. [PubMed] 16. McMahon AD, MacDonald TM, Davey PG, Cleland JGF. Edinburgh: Chief Scientist Office; 2001. The impact of low-dose aspirin prescribing on upper gastrointestinal toxicity, renal toxicity and healthcare resource utilisation; p. 1.
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Competing interests: JC is a member of the
steering committee for the WATCH (warfarin antiplatelet therapy in
chronic heart failure) trial that compares the effects of warfarin,
aspirin, and clopidogrel on outcome of 4500 patients with heart
failure. This trial is being conducted by the US Veterans
Administration and is partly financed by Sanofi.