Drug Safety 6 (3): 166-170, 1991 0114-5916/91/0005-0166/$02.50/0 © Adis International Limited. All rights reserved. DRS111A
Treatment and Prevention of Cardiovascular Disease by Aspirin Charles H. Hennekens Departments of Medicine and Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, Brookline, Massachusetts, USA
The most plausible mechanism of the action of aspirin in reducing the risk of cardiovascular disease is found in basic research findings (Moncada & Vane 1979) that, in platelets, small amounts of aspirin irreversibly acetylate the active site of cyclooxygenase, which is required for the production of thromboxane A2, a powerful promoter of aggregation. This tendency is so profound that higher aspirin doses provide no additional benefit. In fact, it has been speculated that very much higher doses might even reverse this tendency, due to activation of vessel wall enzymes. Further evidence suggesting the possibility of a beneficial effect of aspirin has emerged over the last 20 years from observational epidemiological studies, which have raised the question whether aspirin may reduce the risk of cardiovascular disease by about 20% (Hammond & Garfinkel 1975; Hennekens et al. 1978). However, unlike basic research, epidemiology is crude and inexact since observations on free-living humans can rarely take place under the rigidly controlled conditions possible in the laboratory. In a search for 20 to 30% effects, the size of uncontrolled confounding in casecontrol and cohort study designs might easily be as large as the magnitude of the benefits or risks the study is trying to detect. As a result, the most reliable study design for detecting such small to moderate effects is a randomised trial of sufficiently large sample size (Hennekens & Buring 1987).
1. Secondary Prevention Trials Of 25 secondary prevention trials of antiplatelet therapy conducted among 29 000 patients, 10 were conducted among patients with myocardial infarction, 13 among patients with stroke or transient cerebral ischaemia, and 2 among those with unstable angina pectoris. These trials tested aspirin, dipyridamole or sulfinpyrazone, either alone or in combination. While most of the trials seemed compatible with a benefit, they were usually too small in sample size to provide reliable results. In such circumstances, one method to diminish the play of chance is to perform an overview (Hennekens et al. 1988); this showed there was a 32% reduction in subsequent myocardial infarction associated with antiplatelet therapy (table I) [Antiplatelet Trialists' Collaboration 1988]. For nonfatal stroke there was a 27% decrease in risk, and for total vascular mortality the reduction was 15%. Finally, for all important vascular events, a combined end-point of nonfatal myocardial infarction, nonfatal stroke and vascular death, the overview demonstrated a 25% decrease. All these reductions were statistically significant. When the trials are considered separately according to patient entry criteria, the studies of survivors of myocardial infarction demonstrated statistically significant decreases in risk of 31 % for nonfatal reinfarction, 42% for nonfatal stroke, 13%
Treatment of Cardiovascular Disease by Aspirin
Table I. Overview of 25 trials of anti platelet therapy in the secondary prevention of cardiovascular disease End-point
Mean (± SO) reduction (%) all 8 (25 trials)
cerebrovascular8 (13 trials)
myocardial infarction 8 (10 trials)
unstable anginaa (2 trials)
Nonfatal myocardial infarction
32 ± 5
35 ± 12
31 ± 5
35 ± 17
27 ± 6
22 ± 7
42 ± 11
Total cardiovascular death
15 ± 4
15 ± 7
13 ± 5
37 ± 19
Any vascular event
25 ± 3
22 ± 5
22 ± 4
36 ± 13
Entry criterion. Too few events reported to allow for meaningful results.
for vascular death and 22% for any vascular event. The trials of patients with cerebrovascular disease demonstrated statistically significant reductions of 35% for myocardial infarction, 22% for subsequent nonfatal stroke, 15% for vascular death and 22% for any vascular event. Finally, for unstable angina, there were statistically significant decreases of 35% in nonfatal myocardial infarction 37% in vascular death and 36% in any vascular event, but too few strokes to provide meaningful data. As regards the different anti platelet agents tested, there was no clear evidence that aspirin plus dypridamole was any more effective than aspirin alone, because the indirect comparison between the 2 risk reductions was not significant, and the overview of the direct comparisons indicated no difference whatsoever (table II).
2. Evolving Myocardial Infarction Because aspirin therapy reduced subsequent cardiovascular risks among individuals with a history of myocardial infarction or unstable angina, it seemed reasonable to hypothesise a similar benefit if the drug were administered within the first few hours following the onset of symptoms of the former. Only I trial has been completed to date that tested the effects of aspirin in evolving myocardial infarction, the Second International Study of Infarct Survival (ISIS-2) [ISIS-2 Collaborative Group 1988]. ISIS-2 was a randomised, double-blind, placebo-controlled trial that used a 2 x 2 factorial de-
sign to assess the effects of streptokinase and aspirin in suspected acute myocardial infarction. It randomised over 17 000 patients admitted for suspected evolving myocardial infarction to either a single intravenous infusion of streptokinase 1.5MU over I hour, or aspirin 162 mgjday for I month, or both, or neither. The aspirin results 5 weeks after randomisation indicated reductions of 49% in nonfatal reinfarction, 46% in stroke, 23% in vascular death and 28% in any vascular event. All of these reductions were statistically significant.
Table II. Direct and indirect comparisons between various antiplatelet therapies from the overview for important vascular events (Antiplatelet Trialists' Collaboration 1988). Values are mean (± SO) Comparison
favour of aspirin (%)
Direct (total events/patients) Aspirin vs sulfinpyrazone
28 ± 17
(54/346 vs 74/357) Aspirin vs aspirin + dipyridamole (275/1597 vs 279/1597) Indirect (vs nil) Aspirin 0.9-1.5 g/day Aspirin 0.3 g/day Sulfinpyrazone Aspirin + dipyridamole
1 ± 9
23 24 17 31
± 4 ± 8 ± 8 ± 5
Drug Safety 6 (3) 1991
Table III. Aspirin in primary prevention: US Physicians' Health Study (PHS) and British Doctors Trial (BDT). Values are mean (± SD) End-point
Reduction (%) PHS
Nonfatal myocardial infarction Nonfatal stroke Total cardiovascular death Any vascular event
39 ± 9 119 ± 15 2 ± 15 18 ± 7
BDT 3 ± 19 113 ± 24 7 ± 14 4 ± 12
overview 32 ± 8 118 ± 13 5 ± 10 13 ± 6
Key: 1 = nonsignificant increased risk of stroke among subjects receiving aspirin.
3. Primary Prevention Trials Two randomised trials of aspirin in primary prevention have been completed (Peto et al. 1988; Steering Committee of the Physicians' Health Study Research Group 1989) [table III], both among male physicians. The US trial randomised 22 071 male physicians, aged 40 to 84, and tested aspirin 325mg on alternate days, using a double-blind, placebocontrolled, 2 X 2 factorial design, which allowed for the independent testing of the effects of (3carotene supplementation on the risks of cancer. The aspirin group had a 44% reduction in risk of myocardial infarction, with significant benefits on fatal and nonfatal events. For the latter the reduction was 39%. For all important vascular events, there was a statistically significant 18% reduction in the aspirin group. There were insufficient numbers of strokes on which to draw firm conclusions, but the available data did not suggest any reduction in the incidence of stroke. There was, in fact, an apparent 19% increase in nonfatal stroke, but this did not achieve statistical significance. In the subgroup with haemorrhagic strokes, although the numbers were small and did not achieve statistical significance, there was a suggestion of a possible increase. The British Doctors' Trial (Peto et al. 1988) randomised 5 139 male physicians, aged 50 to 78, and tested a daily dose of aspirin 500mg, with the control group simply asked to avoid aspirin or any
aspirin-containing compounds. The subjects were aware of their assignment, but the investigators remained blinded. In the British trial, there were no significant differences for nonfatal myocardial infarction, nonfatal stroke, vascular death or all important vascular events. In this trial it was not possible to distinguish between thrombotic and haemorrhagic strokes. Because the US trial was so much larger, an overview of both studies (Hennekens et al. 1988) demonstrated a highly significant 32% reduction in the risk of nonfatal myocardial infarction. For stroke and vascular death the number of end-points was too small to permit firm conclusions. The available data showed a nonsignificant 18% apparent increase in nonfatal stroke and nonsignificant 5% reduction in cardiovascular mortality. The wide confidence limits around these estimates indicate that the data on primary prevention of stroke and cardiovascular death are insufficient for meaningful inferences to be drawn.
4. Side Effects The UK-TIA trial, which tested 2 daily dosages of aspirin, provides the most informative data regarding side effects. This trial (among 2 345 patients with a history of transient ischaemic attacks) tested aspirin 300 and 1200 mg/day against placebo. For each category of symptom, including indigestion, nausea or heartburn; constipation; total gastrointestinal bleed; and serious gastrointestinal bleed, the percentage of participants reporting it was lowest in the placebo group, somewhat higher in the group receiving aspirin 300 mg/day and highest among those receiving aspirin 1200 mg/day. In the ISIS-2 trial of evolving myocardial infarction, which tested a dosage of aspirin 162 mg/day, there were no significant differences between the aspirin and placebo groups for major bleeds, and only a small increase in minor bleeds associated with the drug. Finally, in primary prevention, in the larger, placebo-controlled US trial, the alternate-day aspirin 325mg regimen was associated with a slight but nonsignificant increase in gastrointestinal symptoms.
Treatment of Cardiovascular Disease by Aspirin
5. Clinical Implications In secondary prevention trials aspirin offers clear benefits for patients with a previous myocardial infarction, stroke, transient ischaemic attack or unstable angina. Aspirin-treated patients had significantly lower risks of subsequent myocardial infarction, stroke and vascular death. In 1985, the US Food and Drug Administration approved the prescription labelling of aspirin for the treatment of patients with a prior myocardial infarction or unstable angina (FDA Drug Bulletin 1985). For total stroke, the overview of trials of secondary prevention demonstrated a clear and statistically significant decrease. Thus, any postulated increased risk of the rare but serious haemorrhagic stroke would be outweighed by the protective effects of aspirin on the far more common strokes of thrombotic aetiology. For evolving myocardial infarction, there are clear and conclusive benefits of aspirin on reinfarction, stroke and vascular death. In primary prevention, there is a conclusive reduction in risk of first myocardial infarction associated with low dose aspirin. However, the evidence concerning stroke and vascular mortality remains inconclusive, due to inadequate numbers of end-points in both primary prevention trials of aspirin as well as in the overview. With respect to haemorrhagic stroke, the numbers are small but raise the possibility of some excess risk. The British study also raised the possibility of an increase in the subgroup 'disabling' strokes, but it remains unclear whether this represents a true increase in haemorrhagic strokes (which are typically more severe than thrombotic events) or reflects some bias due to subjective assessment of residual disability, which was done through self-reports, without placebo control. For primary prevention, prophylactic aspirin therapy should be considered for those whose risk of a first myocardial infarction is sufficiently high to warrant exposure to the adverse effects of the drug. In October 1989, the Cardiology and Renal Drugs Advisory Committee voted to recommend to the US Food and Drug Administration that the results of the US Physicians' Health Study be in-
corporated into the professional labelling of aspirin to reduce the risks of a first myocardial infarction in apparently healthy people whose risks are sufficiently high to warrant the adverse effects of long term administration of the drug. The potential benefits of aspirin should be viewed in the context of current knowledge of the modification of cardiovascular risk factors. For example, as regards blood cholesterol, a 10% decrease corresponds to a roughly 20 to 30% reduction in the risk of cardiovascular disease (Peto et al. 1985). For blood pressure, a 5 to 6mm Hg decrease in diastolic pressure among those with mild-to-moderate hypertension appears to lower the risk of coronary heart disease by 12% and stroke by about 40% (Hebert et al. 1988). Finally, stopping cigarette smoking results in a decrease of approximately 50% in coronary heart disease, perhaps even within a matter of months (Hennekens et al. 1984). Thus, aspirin should be viewed as an adjunct, not an alternative, to the control or elimination of other cardiovascular risk factors. In addition, aspirin should be initiated only on the recommendation of a physician or other primary health care provider. Such an individual judgment should consider the cardiovascular risks of the p~tient, the adverse effects of the drug, and these newly documented benefits on various manifestations of cardiovascular disease in different categories of individuals (Hennekens et al. 1989).
Acknowledgement The author is indebted to Michael Jonas for his expert editorial assistance with the manuscript.
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Hennekens CH, Buring JE, Mayrent S. Smoking, aging and coronary heart disease. In Bosse (Ed.) Smoking and aging, D.C. Heath, Lexington, 1984 Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation 80: 749756, 1989 Hennekens CH, Karlson LK, Rosner B. A case-control study of regular aspirin use and coronary deaths. Circulation 58: 35-38, 1978 Hennekens CH, Satterfield S, Hebert P. Treatment of elevated blood in use and coronary deaths. Circulation 58: 35-38, 1978 Hennekens CH, Satterfield S, Hebert P. Treatment of elevated blood pressure to prevent coronary heart disease. In Higgins & Luepker (Eds) Trends in coronary heart disease mortality: the influence of medical care, pp. 103-108, Oxford University Press, New York, 1988 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17, 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2: 349-360, 1988
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Moncada S, Vane JR. Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. New England Journal of Medicine 300: 1142-1147, 1979 Peto R, Gray R, Collins R, Wheatley K, Hennekens C, et al. A randomised trial of the effects of prophylactic daily aspirin among male British doctors. British Medical Journal 296: 313316, 1988 Peto R, Yusuf S, Collins R. Cholesterol-lowering trial results in their epidemiologic context. Circulation 72 (Suppl. III): 451, 1985 Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. New England Journal of Medicine 321: 129-135, 1989
Correspondence and reprints: Professor Charles H. Hennekens. Departments of Medicine and Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, 55 Pond Avenue, Brookline, MA 02146, USA.