ASPIRIN IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASE

Transcription

1 Annu. Rev. Public Health :37 49 Copyright c 1997 by Annual Reviews Inc. All rights reserved ASPIRIN IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASE Charles H. Hennekens Departments of Medicine and Ambulatory Care and Prevention, Harvard Medical School, and Division of Preventive Medicine, Brigham and Women s Hospital, Boston, Massachusetts KEY WORDS: antiplatelet therapy, myocardial infarction, occlusive vascular disease, stroke. ABSTRACT Aspirin irreversibly inhibits cyclooxygenase in platelets for their entire lifespan, raising the possibility of clinical benefits by decreasing risks of occlusive vascular events. In secondary prevention among patients with a wide range of prior occlusive vascular events, including myocardial infarction (MI), stroke, transient ischemic attacks (TIAs), as well as unstable and chronic stable angina, aspirin therapy is associated with a reduction in risks of subsequent MI, stroke, and vascular deaths. In acute MI, aspirin also confers clear benefits on subsequent MI, stroke, and vascular deaths. In primary prevention, the available randomized trial data, which to date are limited to men, indicate a clear reduction in risk of a first MI; the current data are inconclusive concerning aspirin s effect on stroke and total vascular mortality. A currently ongoing trial among 40,000 apparently healthy women will provide reliable data concerning the balance of benefits and risks of aspirin in primary prevention. INTRODUCTION In the fifth century BC, Hippocrates found that an extract made from willow bark had analgesic properties. The pain-relieving action was due to salicin, a naturally occurring chemical that closely resembles today s aspirin. Aspirin was synthesized in the late nineteenth century, and became one of the most widely used drugs in the world in the twentieth century. Only in recent decades, however, has attention focused on the role of aspirin in the treatment and prevention of occlusive vascular disease /97/ $

2 38 HENNEKENS MECHANISMS OF ACTION The most plausible mechanism for a cardioprotective effect of aspirin derives from its ability to decrease platelet aggregation and thereby reduce the risk of thrombotic vascular events. Platelets, platelet products, and thrombosis play important roles in the occurrence of acute occlusive vascular events, including myocardial infarction (MI) and ischemic stroke. The disruption of plateletand fibrin-rich atherosclerotic plaque may be followed by aggressive platelet deposition and, ultimately, the development of a thrombus that can precipitate an acute occlusive event. Nobel prize-winning basic research indicated that, in platelets, small amounts of aspirin irreversibly acetylate the active site of cyclooxygenase, required for the production of thromboxane A2, a powerful promoter of aggregation (24). This effect of aspirin is so pronounced that higher doses do not appear to yield additional benefit. In fact, it has been suggested that far higher doses might even reverse this tendency, due to activation of vessel wall enzymes. OBSERVATIONAL EPIDEMIOLOGIC STUDIES Several observational epidemiologic studies have explored whether individuals who self-select aspirin use have lowered risks of cardiovascular disease. Two case-control studies of nonfatal MI, one in men and women and the other in men only, have found decreased risks associated with aspirin use (5, 20). In contrast, a third case-control study of aspirin use and coronary death found no significant association between aspirin use and fatal coronary disease in men (17). Three prospective cohort studies have evaluated this question. In the Nurses Health Study, which followed more than 87,000 US women over six years, those who reported taking one to six aspirin tablets per week experienced a significant 25% decreased risk of MI compared with women who took none (23). In contrast, however, two other prospective cohort studies found no association between regular aspirin use and risk of MI in men and women (11, 25). Not surprisingly, the observational evidence on this question is not entirely consistent. This is because when searching for small- to moderate-sized benefits, as is the case with aspirin, observational studies are simply unable to control adequately for the possible effect of unmeasured or unknown confounding variables, whose magnitude could be as great as the most plausible benefits. Randomized trials of sufficient sample size, therefore, which are able to control for both known and unknown confounding variables, are the only reliable study design for detecting the postulated small-to-moderate benefits of aspirin on occlusive cardiovascular disease. Randomized trials have now been carried out testing aspirin in a broad range of individuals with and without prior manifestations of cardiovascular disease.

3 ASPIRIN AND CARDIOVASCULAR DISEASE 39 RANDOMIZED TRIALS Secondary Prevention Early randomized trials of aspirin were conducted among patients with prior cardiovascular disease. By 1987, 25 trials enrolling a total of 29,000 patients had been conducted testing aspirin or other antiplatelet agents in the treatment or secondary prevention of cardiovascular disease. Of these, 10 were conducted among those with prior myocardial infarction (MI), 13 were among patients with a history of stroke or transient cerebral ischemia, and 2 were among those with unstable angina pectoris. The trials tested aspirin, dipyridamole, or sulfinpyrazone, either alone or in combination. Although the results of most of the trials were compatible with benefits of antiplatelet therapy, most trials were too small individually in sample size to achieve statistical significance. In such circumstances, one approach is to perform an overview, or meta-analysis. In an overview, the results of several trials are considered in aggregate, with statistical weight given to each trial according to its size. By including larger numbers of subjects, overviews can diminish the role of chance in interpreting the findings and can, thereby, provide a more statistically stable estimate (12). In 1988, with the collaboration of investigators who had conducted randomized trials of antiplatelet therapy, an overview was published of the 25 completed trials in secondary prevention (Table 1) (1). Overall, antiplatelet therapy was associated with a 32% reduction in subsequent nonfatal MI, a 27% decrease in nonfatal stroke, and a 15% decrease in total vascular mortality. The overview also evaluated a combined endpoint, termed important vascular events, which included nonfatal MI, nonfatal stroke, and vascular death. Antiplatelet therapy was associated with a 25% decrease in important vascular events. All of these reductions were statistically significant. The trials were also evaluated separately according to patient entry criteria. In these analyses, in the ten trials of survivors of MI there were statistically significant decreases in risk of 31% for nonfatal reinfarction, 42% for nonfatal stroke, 13% for vascular death, and 22% for important vascular events. In the 13 trials of patients with cerebrovascular disease [stroke or transient ischemic attacks (TIA)], there were statistically significant reductions of 35% for nonfatal MI, 22% for subsequent nonfatal stroke, 15% for vascular death, and 22% for important vascular events. Finally, in the two trials of unstable angina patients, there were statistically significant decreases of 35% in nonfatal MI, 37% in vascular death, and 36% in any vascular event. There were too few strokes in these trials to permit meaningful analyses of the effect of antiplatelet therapy on this outcome. With respect to the different antiplatelet agents tested, there was no clear evidence that aspirin plus dipyridamole was any more effective than aspirin alone.

4 40 HENNEKENS Table 1 Overview of 25 trials of antiplatelet therapy in the secondary prevention of cardiovascular disease Reduction (% ± SD) among those assigned antiplatelet therapy All Cerebrovascular 1 MI 2 Unstable Angina 3 Endpoint (25 trials) (13 trials) (10 trials) (2 trials) Nonfatal MI 32 ± 5 35±12 31 ± 5 35±17 Nonfatal stroke 27 ± 6 22±7 42±11 4 Total vascular mortality 15 ± 4 15 ± 7 13 ± 5 37±19 Important vascular events 25 ± 3 22 ± 5 22 ± 4 36±13 1 Trials of patients with prior stroke or transient ischemic attacks. 2 Trials of patients with prior MI. 3 Trials of patients with prior unstable angina. 4 Too few events reported to permit reliable assessment. The indirect comparison between the two risk reductions was not significant, and the overview of the direct comparisons indicated no difference whatsoever. In addition, there was no evidence that daily aspirin doses of mg were any more effective in reducing vascular events than 300 mg, the lowest dose tested. Although the overview provided reliable evidence of the benefit of aspirin therapy in patients with prior MI, stroke, TIA, or unstable angina, it did not address directly whether such treatment would benefit other patients at increased risk for occlusive vascular disease, including those with chronic stable angina, peripheral vascular disease, or patients undergoing revascularization procedures. The 1988 overview also did not address the question of aspirin s benefit in certain subgroups of high-risk patients, such as women or the elderly, or those with hypertension or diabetes. In order to provide reliable data on these questions, the Antiplatelet Trialists Collaboration has published an updated overview, including data from trials enrolling a much broader range of high-risk patients (2). The updated overview utilizes the results of 133 trials of antiplatelet therapy conducted among over 53,000 patients with prior cardiovascular disease. The findings among patients with prior MI, stroke and TIA, and unstable angina were similar to those of the original 1988 overview. The updated report, however, also includes the experience of approximately 22,000 patients at high risk for occlusive vascular events due to atrial fibrillation, valve surgery, peripheral vascular disease, chronic stable angina, and coronary revascularization (either coronary artery bypass graft or percutaneous transluminal coronary angioplasty). When analyzed separately according to patient entry criteria,

5 ASPIRIN AND CARDIOVASCULAR DISEASE 41 most comparisons of antiplatelet therapy and control failed to achieve statistical significance, due to the small numbers of patients in each patient category. However, when the trials of these various high-risk patients were considered in aggregate, antiplatelet therapy was associated with a statistically significant 32% decrease in vascular events. The updated overview also provides reliable data that antiplatelet treatment produces vascular event reductions of similar size in various subgroups of highrisk patients. Separate data for men and women were available from 29 trials conducted among approximately 40,000 men and 10,000 women. There were comparable benefits on vascular events, with reductions per 1000 patients treated of 37 events for men (SD 4, p < ) and 33 events for women (SD 7, p < ). The data from these 29 trials also demonstrate comparable reductions in vascular events for middle-aged as well as older patients, in hypertensives and normotensives; and in diabetics and nondiabetics. The updated overview includes trials testing aspirin doses ranging from 75 to 1500 mg per day. As in the 1988 report, there was no evidence that higher doses were any more effective in reducing risks of occlusive vascular events than lower doses were. While 300 mg was the lowest daily dose tested in trials in the original overview, the updated analysis includes approximately 5000 patients randomized in trials testing 75 mg of aspirin per day. When analyzed separately, the trials testing daily doses of 75 mg demonstrated a statistically significant 29% reduction in vascular events associated with aspirin (p < ), indicating that daily doses this low are effective in long-term secondary prevention. It has been postulated that doses even lower than 75 mg may confer greater benefit by inhibiting platelet aggregation without blocking the synthesis of prostacyclin, an enzyme with antiplatelet and vasodilative properties. However, even very low daily doses appear to depress prostacyclin biosynthesis (8). One strategy that has been proposed to enhance the biochemical selectivity of aspirin for thromboxane A2, while sparing prostacyclin, is the use of a controlled-release aspirin preparation. A small trial has compared a controlledrelease 75-mg aspirin preparation with a conventional immediate-release 75-mg preparation, and indicated that this new formulation can inhibit thromboxane A2 production while decreasing basal prostacyclin biosynthesis only slightly (8). A large-scale trial comparing such a preparation with conventional aspirin will be necessary to determine the clinical relevance, if any, of prostacyclin sparing. In addition to aspirin, dipyridamole, and sulfinpyrazone, which were tested in trials included in the original overview, the updated analysis also includes three trials that compared the antiplatelet drug ticlopidine to aspirin. As in the original overview, the updated analysis demonstrates no significant differences in effectiveness of the various antiplatelet agents. Any differences between

6 42 HENNEKENS antiplatelet agents, however, will be much smaller than that between antiplatelet therapy and no treatment, so the results of the overview cannot reliably exclude the possibility of a small advantage of one type of agent. Finally, with respect to the optimal duration of treatment in secondary prevention, there is no direct evidence on this question, since none of the large-scale randomized trials compared different durations of treatment. However, for trials of patients with prior MI, stroke, or TIA that provided individual patient data, information is available on events occurring in the first, second, and subsequent years of scheduled treatment. Results of these trials indicate an apparent trend toward greater effect during the earlier years. However, there are difficulties in drawing firm conclusions from these data, as noncompliance with treatment tends to increase with time, with some in the treatment group stopping antiplatelet therapy and others in the control group initiating such treatment. The underestimation of the effect of actual treatment, therefore, will tend to increase over time. In addition, even with no further divergence in event rates after the first few years, continued aspirin therapy may be preventing survival and event rate curves from converging. For this reason, in the absence of direct evidence from randomized comparisons of different durations of treatment, and absent the development of a contraindication to its use in individual patients, it may be advisable to continue aspirin therapy indefinitely in those patients considered to be at high risk of occlusive vascular events. Acute Evolving Myocardial Infarction Because aspirin therapy reduces cardiovascular risks among individuals with a prior history of MI or those with unstable angina, it was hypothesized that a benefit might also result if the drug were administered within the first 24 hours following onset of symptoms of MI. One large-scale placebo-controlled trial tested the effects of aspirin during the acute phases of MI. The Second International Study of Infarct Survival (ISIS-2), a randomized double-blind, placebo-controlled trial, utilized a 2 2 factorial design in order to assess simultaneously the effects of the thrombolytic drug streptokinase and aspirin in suspected acute MI. ISIS-2 randomized 17,187 patients admitted for suspected evolving MI within 24 hours of symptom onset to either a single intravenous infusion of 1.5 million units of streptokinase over one hour, mg of oral aspirin daily for one month, both active treatments, or both placebos (19). After five weeks, aspirin was associated with a 23% reduction in vascular death, a 49% reduction in nonfatal reinfarction, and a 46% reduction in stroke (Table 2). All of these reductions were statistically significant and provide strong evidence of the benefit of aspirin for the vast majority of patients with suspected evolving MI. There were no significant differences seen between men

7 ASPIRIN AND CARDIOVASCULAR DISEASE 43 Table 2 Results from the Second International Study of Infarct Survival (ISIS-2): vascular events in the first five weeks after suspected acute MI Endpoint Reduction (% ± SD) among those assigned aspirin Nonfatal reinfarction 49 ± 9 Nonfatal stroke 46 ± 17 Total vascular mortality 23 ± 4 and women in the benefits of aspirin. There was no increase in hemorrhagic stroke or major bleeding associated with aspirin, and only a slight increase in minor bleeding. Streptokinase-treated patients experienced a comparable statistically significant 25% reduction in vascular mortality, but a nonsignificant excess of nonfatal reinfarction and no apparent effect on overall nonfatal stroke, although there was a significant excess of confirmed cerebral hemorrhage. The effect of combined treatment with aspirin and streptokinase was largely additive, with patients receiving both drugs experiencing a significant 42% decrease in vascular mortality. About 48 hours are required to achieve maximal inhibition of serum thromboxane B2 with a daily dose of 75 mg of aspirin. For this reason, while doses in this range appear to be as efficacious as higher doses for use in long-term secondary prevention, to achieve a rapid clinical antithrombotic effect in the setting of acute MI, an initial loading dose of at least mg aspirin should be used. Despite the clear benefits of aspirin in acute MI, this therapy remains underutilized. A survey of treatment patterns in the United States before and after publication of the ISIS-2 findings indicated that use of aspirin in acute MI increased substantially, from about 39% of all patients to approximately 72% of those admitted for acute evolving MI (21). Although the ISIS-2 results, therefore, appear to have had an appreciable impact on clinical practice, aspirin could, in fact, be given to nearly all patients with acute MI, as the benefits on fatal and nonfatal vascular events are substantial, and the bleeding risks appear to be minimal among this population of high-risk patients. From a public health standpoint, with approximately 1.2 million patients admitted to US hospitals each year with acute MI, increasing the use of aspirin in this setting from 72% of patients to virtually all acute MI patients would avoid nearly 8000 premature deaths each year (16).

8 44 HENNEKENS Primary Prevention The evidence from secondary prevention trials and the ISIS-2 trial in acute MI does not address directly the possibility that aspirin may also be of benefit in primary prevention among healthy individuals. Two primary prevention trials of aspirin have been completed, both among male physicians (Table 3). The US Physicians Health Study utilized a 2 2 factorial design to test simultaneously the effects of aspirin in reducing risks of cardiovascular disease and beta-carotene in the prevention of cancer (15). A total of 22,071 male physicians, aged 40 to 84, were randomized to either 325 mg aspirin on alternate days (Bufferin, provided by Bristol-Myers Products), 50 mg beta- carotene on alternate days (Lurotin, provided by BASF Corp.), both agents, or both placebos. The aspirin component of the trial was terminated early, in 1988, after an average treatment and follow-up of 60.2 months, due primarily to the emergence of a statistically extreme benefit on risk of MI. Aspirin was associated with a 44% reduction in risk of a first MI, with significant benefits on both fatal and nonfatal events (28). With respect to stroke, there were insufficient numbers of events upon which to draw firm conclusions. However, the available data did not suggest any reduction in stroke, and there was, in fact, a nonsignificant 19% increase in nonfatal stroke. Because of aspirin s effect on platelet aggregation, a particular concern with long-term use is an increase in hemorrhagic stroke. For this small subgroup of strokes in the Physicians Health Study, although the findings are inconclusive, there was a suggestion of a possible increase in the aspirin group (23 vs 12 events, p = 0.06). The other completed primary prevention trial of aspirin was conducted among 5139 male physicians, aged 50 78, in Great Britain. The British trial tested a daily dose of 500 mg aspirin, with the control group simply asked to avoid Table 3 Aspirin in primary prevention: US Physicians Health Study and British Doctors Trial Reduction (% ± SD) among those assigned aspirin US Physicians British Endpoint Health Study Doctors Trial Overview Nonfatal MI 39 ± 9 3±19 32 ± 8 Nonfatal stroke 19 ± ± ± 13 Total vascular mortality 2 ± 15 7 ± 14 5 ± 10 Important vascular events 18 ± 7 4 ± ± 6 = Nonsignificant increased risk among aspirin-allocated subjects.

9 ASPIRIN AND CARDIOVASCULAR DISEASE 45 aspirin or any aspirin-containing compounds. After six years of treatment, there were no significant differences between groups for nonfatal MI, nonfatal stroke, or vascular death (26). It was not possible to distinguish reliably between thrombotic and hemorrhagic strokes. There was, however, an increase of borderline statistical significance (p = 0.05) in the aspirin group of the subgroup of strokes self-reported as disabling. It is difficult to know, however, whether this reflects a real increase in such events, which might be more likely to be hemorrhagic in etiology than less disabling events, or is the result of bias in the self-reporting of residual impairment due to the study s open design. There were several design differences between the two primary prevention trials. With respect to dose, while the US trial tested 325 mg on alternate days, the British study used a daily dose of 500 mg. The US trial was doubleblind and placebo controlled, whereas the British trial was single-blind and had open control. The most striking difference, however, and the most important in interpreting the findings of the two trials, is in sample size, with the US trial more than four times as large. In order to consider the available primary prevention trial data in aggregate, an overview was performed of the US and British primary prevention trials (18). Because the US study was so much larger, the overview demonstrated a highly significant 32% reduction in risk of nonfatal MI. For stroke and vascular death, even when the trials were considered together there were too few endpoints upon which to base firm conclusions. Findings from basic research on aspirin have largely supported an acute effect on platelet aggregation as the principal mechanism for its benefit on occlusive vascular disease. However, it has also been suggested that platelet adhesion to damaged endothelium may lead to plaque formation, raising the possibility that aspirin might also play a role in inhibiting the long-term process of atherosclerosis. In such a case, aspirin might be expected to decrease the risk of developing angina the clinical manifestation of atherosclerotic progression as well as confer greater benefit with longer use. Data from the Physicians Health Study, however, do not support this hypothesis, as participants assigned to aspirin and placebo experienced similar rates of development of angina during the five-year treatment and follow-up period (22). In addition, with respect to duration of treatment, the magnitude of benefit of aspirin on MI was as great at six months as at the end of five years. SIDE EFFECTS Although aspirin s benefits in reducing occlusive vascular events may be approximately equal over the wide dose range tested in trials to date, the principal side effects of the drug appear to be strongly dose related.

10 46 HENNEKENS The UK-TIA trial, which tested two daily dosages of aspirin as well as placebo, provides a direct comparison of the side effects of different aspirin dosages (29). This trial among 2345 patients with a history of transient ischemic attacks tested aspirin doses of 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 300 mg/day, and highest among those receiving 1200 mg daily. In acute MI, in the ISIS-2 trial, which tested 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 aspirin. Finally, in primary prevention, in the larger, placebo-controlled US Physicians Health Study, the alternate day 325 mg aspirin regimen was associated with an excess in ulcer (1.5 vs 1.3%, p = 0.08) and bleeding problems (27.0 vs 20.4%, p < ). Rates of gastrointestinal symptoms other than ulcer were similar (34.8 vs 34.2%). This latter finding may have been due partially to the low dose and alternate day schedule used in the trial, as well as to a prerandomization run-in period, which eliminated before formal assignment to study groups those physicians who reported intolerance to aspirin. CONCLUSIONS The totality of evidence has provided a rational basis for clinical and policy recommendations concerning the use of aspirin to decrease risks of occlusive cardiovascular disease. In secondary prevention, there are clear benefits of aspirin for patients with prior cardiovascular disease. The 1994 update of the earlier overview of antiplatelet trials in secondary prevention indicates that these benefits extend to a broad range of patients, with significant benefits accruing not only to patients with prior MI, stroke, TIA, or unstable angina, but also to those with peripheral vascular disease, atrial fibrillation, chronic stable angina, valvular disease, and patients undergoing revascularization procedures. Among this wide range of patients, aspirin therapy reduces by about one quarter the risk of subsequent occlusive vascular events, with comparable reductions in men and women. Based on the available data in 1980, the US Food and Drug Administration (FDA) approved the prescription labeling of aspirin for treatment of men with prior TIAs (3), and in 1985, this approval was extended to men and women with a prior MI or unstable angina (4). Currently available evidence strongly supports the extension of the labeling for TIA for women, as well as the extension of the labeling to include men and women with prior stroke, chronic stable angina, coronary revascularization procedures, and other conditions implying an increased risk of occlusive vascular events.

11 ASPIRIN AND CARDIOVASCULAR DISEASE 47 For acute evolving MI, there are clear and conclusive benefits of aspirin on reinfarction, stroke, and vascular death. The FDA has proposed extension of the prescription labeling of aspirin to include its use in patients with acute MI, at an initial dose of 160 to mg, to be continued daily for at least 30 days (29a). In primary prevention, there is a conclusive benefit of low-dose aspirin on risk of a first MI in men. However, the evidence concerning stroke and vascular mortality remains inconclusive due to inadequate numbers of endpoints in both primary prevention trials of aspirin as well as in the overview of their findings. With respect to hemorrhagic stroke, the numbers are small but raise the possibility of some excess risk. The only data available on aspirin use in apparently healthy women derive from observational studies. The findings from these investigations are not entirely consistent, with two studies in women suggesting benefits (5, 23) and two reporting no apparent effect (11, 25). The primary concern in extrapolating findings from trial data in men is that the benefit-to-risk ratio for prophylactic aspirin use in women may differ, since their risk of MI, the principal outcome that aspirin may prevent, is lower at each age, while women have roughly comparable rates of stroke, hemorrhagic forms of which aspirin may increase. To evaluate directly the benefits and risks of low-dose aspirin among apparently healthy women as well as to provide reliable evidence on stroke and vascular mortality, for which data are lacking in both men and women a large-scale randomized trial was begun in The Women s Health Study has randomized approximately 40,000 US women, aged 45 and older, to alternate day aspirin (100 mg, provided by Bayer Corp.) or placebo (6, 7). Utilizing a 2 2 factorial design, the trial is also evaluating vitamin E (600 IU on alternate days, provided by the Natural Source Vitamin E Association) in the primary prevention of cancer and cardiovascular disease. There are presently no approved prescription indications for aspirin in primary prevention of cardiovascular disease, and any such formal policy recommendations should await the results of the Women s Health Study. In the meantime, aspirin prophylaxis may nonetheless be considered appropriate for some individuals. The recently updated guidelines from the US Preventive Services Task Force suggest that the benefit of aspirin may outweigh the harm in men with risk factors for coronary disease who lack contraindications to aspirin use (30). The American Heart Association has made similar recommendations (10). No guidelines have been issued for women. However, while awaiting definitive data from the Women s Health Study, the observational data in women, in conjunction with the definitive randomized trial data in male physicians, suggest that aspirin may also be beneficial in primary prevention for those women whose risk of MI is sufficiently high to warrant exposure to any risks of long-term administration of this drug.

12 48 HENNEKENS It is important to view the potential benefits of aspirin in the context of current knowledge about modification of cardiovascular risk factors. For example, a 10% decrease in blood cholesterol corresponds to a roughly 20 30% reduction in risks of cardiovascular disease (27). For blood pressure, a 5 6 mm decrease in diastolic pressure among those with mild-to-moderate hypertension appears to lower risks of coronary heart disease by 14% and stroke by 42% (9). Finally, cessation of cigarette smoking results in an approximately 60% decrease in coronary heart disease, perhaps even within a matter of months (13). Thus, aspirin should always be viewed as a possible adjunct, not an alternative, to control or elimination of other cardiovascular risk factors. Aspirin therapy should be initiated only upon the recommendation of a physician or other primary health care provider. Such a recommendation should be based on an individual clinical judgment that considers the cardiovascular risks of the patient, the adverse effects of the drug, and the documented benefits on various manifestations of cardiovascular disease in different categories of patients (14). Literature Cited 1. Antiplatelet Trialists Collaboration Secondary prevention of vascular disease by prolonged anti-platelet therapy. Br. Med. J. 296: Antiplatelet Trialists Collaboration Collaborative overview of randomized trials of antiplatelet treatment. Part I: prevention of vascular death, myocardial infarction and stroke by prolonged antiplatelet therapy in different categories of patients. Br. Med. J. 308: Aspirin for TIA s FDA Drug Bull. 10: Aspirin for heart patients FDA Drug Bull. 15: Boston Collaborative Drug Surveillance Group Regular aspirin intake and acute myocardial infarction. Br. Med. J. 1: Buring JE, Hennekens CH, for the Women s Health Study Research Group The Women s Health Study: summary of the study design. J. Myocard. Ischemia 4: Buring JE, Hennekens CH, for the Women s Health Study Research Group The Women s Health Study: rationale and background. J. Myocard. Ischemia 4:30 40 Visit the Annual Reviews home page at 8. Clarke RJ, Mayo G, Price P, FitzGerald GA Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N. Engl. J. Med. 325: Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, et al Blood pressure, stroke and coronary heart disease. Part II: effects of short-term reductions in blood pressure an overview of randomised drug trials in an epidemiological context. Lancet 335: Fuster V, Dyken ML, Vokonas PS, Hennekens CH Aspirin as a therapeutic agent in cardiovascular disease. Circulation 87: Hammond EC, Garfinkel L Aspirin and coronary heart disease: findings of a prospective study. Br. Med. J. 2: Hennekens CH, Buring JE Epidemiology in Medicine. Boston: Little, Brown & Co. 13. Hennekens CH, Buring JE, Mayrent S Smoking, aging and coronary heart disease. In Smoking and Aging, ed. R Bosse, Lexington, MA: Heath 14. Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R Aspirin and other antiplatelet agents in the secondary

13 ASPIRIN AND CARDIOVASCULAR DISEASE 49 and primary prevention of cardiovascular disease. Circulation 80: Hennekens CH, Eberlein K A randomized trial of aspirin and betacarotene among US physicians. Prev. Med. 14: Hennekens CH, Jonas MA, Buring JE The benefits of aspirin in acute myocardial infarction: still a well-kept secret in the US Arch. Int. Med. 1: Hennekens CH, Karlson LK, Rosner B A case control study of regular aspirin use and coronary deaths. Circulation 58: Hennekens CH, Peto R, Hutchison GB, Doll R An overview of the British and American aspirin studies. N. Engl. J. Med. 318: 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: Jick H, Miettinen OS Regular aspirin use and myocardial infarction. Br. Med. J. 1: Lamas GA, Pfeffer MA, Hamm P, Wertheimer J, Rouleau JL, Braunwald E Do the results of randomized clinical trials of cardiovascular drugs influence medical practice? N. Engl. J. Med. 327: Manson JE, Grobbee DE, Stampfer MJ, Taylor JO, Goldhaber SZ, et al Aspirin in the primary prevention of angina pectoris in a randomized trial of US physicians. Am. J. Med. 89: Manson JE, Stampfer MJ, Colditz GA, Willett WC, Rosner B, et al A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA 266: Moncada S, Vane JR Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N. Engl. J. Med. 300: Paganini-Hill A, Chao A, Ross RK, Henderson BE Aspirin use and chronic diseases: a cohort of the elderly. Br. Med. J. 299: 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. Br. Med. J. 296: Peto R, Yusuf S, Collins R Cholesterol-lowering trial results in their epidemiologic context. Circulation 72(Suppl. III): Steering Committee of the Physicians Health Study Research Group Final report on the aspirin component of the ongoing Physicians Health Study. N. Engl. J. Med. 321: UK-TIA Study Group United Kingdom transient ischaemic attack (UK- TIA) aspirin trial interim results. Br. Med. J. 296: a. US Food and Drug Administration Internal analgesic, antipyretic, and antirheumatic drug products for over-thecounter human use. Proposed amendment to the tentative final monograph. Federal Register : (June 13, 1996) 30. US Preventive Services Task Force Aspirin prophylaxis for the primary prevention of myocardial infarction. In Guide to Clinical Preventive Services. Baltimore, MD: Williams & Wilkins. 2nd ed.