CHEMOPROPHYLAXIS AND IMMUNIZATIONS Prevention of Cardiovascular Disease: Risks and Benefits of Aspirin JULIE E. BURING, ScD, CHARLES H. HENNEKENS, AdD, DrPH
Aspirin has been testedf o r its benefit in preventing cardiovascular disease in randomized trials in three categories o f patients. In secondary preventton among those with a history o f myocardial infarction (MI), stroke or transient cerebral ischemia, or unstable angina pectori& 25 randomized trials demonstrated significant reductions f r o m aspirin o f 25 %f o r the occurrence o f an "~mportant vascular event" (nonfatal MI, nonfatal stroke, or vascular death), 32% f o r nonfatal MI, 27% f o r nonfa#a! stroke, and 15% f o r vascular mortality. Among those evolving an M1, t h e Second International Study o f Infarct Survival (ISIS-2) s h o w e d a significant reduction o f 23% in five-week vascular mortality among those started on a one-month r e g i m e n o f daily aspirin within 24 hours o f the onset o f symptoms o f suspected MI. Aspirin also significantly reduced reinfarction, nonfatal stroke, and important vascular events. Finally, in primary prevention, the US Physicians" Health Study (PHS) showed a significant 44% reduction in t h e occurrence o f a first MI among apparently healthy male physicians; numbers o f strokes and vascular deaths w e r e insud~cient to permit conclusions f o r these endpoints. Thus, aspirin is o f clear benefit in reducing MI, stroke, and vascular death in secondary prevention and among t h o s e evolving an MI. It is also beneficial in the primary prevention o f MI a m o n g m e n over 40, but data concerning its effects on stroke and vascular death remain inconclusive. Key w o r d s : a s p / r / n ; cardiovascular disease; prevention,. myocardial infarction~ J GEN INTERN MED 1990; 5 ( s u p p l ) : S 5 4 - $57.
THE POTENTIALof low-dose aspirin to r e d u c e risks of cardiovascular disease is derived from basic research, observational analytic studies, and randomized trials. In platelets, small amounts o f aspirin irreversibly acetylate the active site of cyclooxygenase, w h i c h is req u i r e d for the p r o d u c t i o n of t h r o m b o x a n e A2, a powerful p r o m o t e r of aggregation.t Observational cohort and c a s e - control studies 2, 3 indicate that aspirin may have the potential to r e d u c e risks of cardiovascular disease by about 20%. However, since the size o f uncontrolled confounding in observational designs is about as large as the magnitude of the small to moderate effects being sought, the only reli-
Received from the Departments of Medicine and Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts. Presented at the conference, Frontiers in Disease Prevention, Johns Hopkins University, June 5 - 6 , 1989. Address correspondence and reprint requests to Dr. Buring: 55 Pond Avenue, Brooldine, MA 02146.
able study design for detecting such small to moderate effects is the randomized trial. 4 Data from randomized trials of aspirin in three categories of individuals are n o w available. They include: 1) survivors of myocardial infarction (MI), stroke, or unstable angina pectoris; 2) those evolving an MI; and 3) apparently healthy individuals.
SURVIVORS OF PREVIOUS CARDIOVASCULAR E V E N T S The Anti-Platelet Trialists (APT), representing the investigators w o r l d w i d e involved in randomized trials of antiplatelet therapy among individuals with a history of cardiovascular disease, have collaborated in a comprehensive overview, or meta-analysis, of all completed trials involving aspirin or two other antiplatelet agents, dipyridamole and sulfinpyrazone. 5 A total of 25 c o m p l e t e d randomized trials of aspirin, dipyridamole, or sulfinpyrazone, either alone or in combination, were identified. The study populations for these trials inc l u d e d nearly 2 9 , 0 0 0 individuals with a history of myocardial infarction, stroke, transient ischemic attack, or unstable angina. While the results of virtually all these trials w e r e in the direction of a benefit for low-dose aspirin, most were too small in sample size individually to achieve statistical significance. The overview, however, found a statistically significant 25 % reduction in risk o f developing what was termed a n " important vascular event," a category that c o m b i n e d nonfatal MI, nonfatal stroke, and vascular death. For nonfatal MI, w h e n all available trials were considered, there was a statistically significant 32% reduction in risk, while for nonfatal stroke, there was a statistically significant 27% reduction in risk. Finally, with respect to total vascular mortality, there was a statistically significant 15% reduction. When the trials were g r o u p e d according to patiententry criteria, there were significant reductions for each endpoint among the three categories of trials (MI, cerebrovascular, and unstable angina), with the exception of the trials among unstable angina patients, in w h i c h there were too few subsequent strokes to allow for reliable estimates of the effect of aspirin on this endpoint.
JOURNALOFGENERALINTERNALMEDICINE,Volume S (Sep£ember/October Supplement), 1990
The overview also demonstrated that aspirin, the safest, least expensive, and most convenient type of antiplatelet therapy, is at least as effective as dipyridamole or sulfinpyrazone. Moreover, a lower daily dose, 325 mg, or one standard tablet, is no less effective in reducing risks than higher doses of 1 to 1.5 grams daily. In fact, pharmacologic studies suggest that the optimal dosage m a y b e even lower than 80 rag, w h i c h is roughly the equivalent of taking one tablet of baby aspirin. The importance of this finding is underscored by the results from the recently c o m p l e t e d UK-TIA trial. 6 Since two dosage levels of aspirin as well as placebo were tested in this randomized, double-blind, placebo-controlled trial, the investigators were able to assess w h e t h e r reported GI side effects were dose-related. For each side effect, the percentage reporting it in the group receiving 300 mg of aspirin dailywas higher than the percentage in the placebo group but lower than that in the group receiving 1,200 mg of aspirin daily. Moreover, for symptoms of GI distress, including indigestion, nausea, and heartburn, as well as for GI bleed, the differences b e t w e e n the low- and high-dose groups achieved statistical significance. Because aspirin appears to confer a moderate degree of protection against the d e v e l o p m e n t of cardiovascular endpoints among individuals with a previous history of stroke, MI, or angina, it seemed reasonable to hypothesize a similar benefit if this agent w e r e given during the first several hours following the onset of symptoms of MI.
PATIENTS EVOLVING MYOCARDIAL INFARCTION To test the hypothesis that low-dose aspirin decreases risks in patients with evolving MI, as well as to assess the role of intravenous streptokinase in treating acute MI, a 2 X 2 factorial design was utilized to conduct ISIS-2, the Second International Study of Infarct Survival. 7 Due to the outstanding efforts of collaborators from more than 400 hospitals in 16 different countries, 17,187 patients were randomized to taking either 160 mg of aspirin or placebo daily for 30 days, beginning immediately u p o n hospital admission for evolving MI. Patients w e r e also randomized to receiving a single dose of either 1.5 million units of streptokinase or placebo intravenously over 60 minutes. As regards the aspirin findings, the data on mortality five weeks after randomization indicated a statistically significant 23% reduction among those assigned to this agent. For the c o m b i n e d endpoint of all important vascular events, those receiving aspirin had a significant reduction of 28%. As regards other vascular events during hospitalization, there were no differences between the aspirin and placebo groups for major bleeds or cardiac ruptures. However, for cardiac arrest, those on aspirin experie n c e d significantly fewer events. With respect to rein-
farction, there were 156 events in the aspirin group c o m p a r e d with 284 among those on placebo. This reduction was highly statistically significant. And, finally, for stroke, 47 events were e x p e r i e n c e d in the aspirin group compared with 81 on placebo, a reduction that was also statistically significant.
APPARENTLY HEALTHY INDIVIDUALS The third category of patients in w h o m trials of aspirin have been c o n d u c t e d is apparently healthy individuals at usual risk for cardiovascular disease. Two primary prevention trials of aspirin have been carried out, one among 22,071 male U.S. physicians 8 and the other among 5,139 male British physicians. 9 In December 1987, after an average follow-up of approximately five years, the Data Monitoring Board in the U.S. trial took the unusual step of r e c o m m e n d i n g that the randomized aspirin c o m p o n e n t of the trial be terminated early. The principal basis for this recommendation was the observation of a highly statistically significant 47% reduction in risk of total MI, w h i c h reflected significant benefits of aspirin in reducing both nonfatal and fatal events. The final report from the trial, 1° which considered additional events not confirmed at the time of the preliminary report, indicates a 44% reduction in MI. For total stroke, the relative risk among those receiving aspirin was 1.21, but this finding was not significant ( p = 0.15). When strokes were subdivided by w h e t h e r the event was ischemic or hemorrhagic, there was an apparent increase in hemorrhagic stroke that was of borderline statistical significance ( R R = 2 . 1 4 , p = O . 0 6 ) . For the c o m b i n e d e n d p o i n t of nonfatal MI, nonfatal stroke, and cardiovascular death, there was a highly significant 18% reduction in risk among those allocated to the aspirin group. As regards cardiovascular mortality, there was no difference, but too few cardiovascular deaths were reported to permit an informative test of this hypothesis. The U.K. trial did not show a reduction in MI, stroke, or total vascular mortality, though the 95% confidence intervals were wide. An overview was c o n d u c t e d that considered the preliminary report from the U.S. study and the final report of the British trial. Because the U.S. study was so m u c h larger, the overview demonstrated an overall 33% reduction in nonfatal MI, w h i c h was highly statistically significant, n These analyses were repeated using data from the final aspirin report of the U.S. trial and yielded a virtually identical 32% reduction in nonfatal MI. With respect to subgroups of participants in the U.S. trial, analyses indicate that there are no significant modifications of the effects of aspirin across various strata of individuals with the differing risk factors of cigarette smoking, systolic and diastolic blood pressure elevations, levels of physical exercise, diabetes, parental history of MI, alcohol use, and b o d y mass index. However, aspirin's effect on MI risk was modified by
Buring, Hennekens, ASPIRIN AND CARDIOVASCULARDISEASE
two v a r i a b l e s - - age and b l o o d cholesterol level. As regards age, the reduction in MI risk associated w i t h aspirin was a p p a r e n t o n l y a m o n g those 50 years o f age or older. This m a y reflect a true effect o f aspirin that is present o n l y in those aged 50 or older, or it m a y s i m p l y result f r o m the fact that there w e r e very f e w MIs a m o n g doctors 4 0 - 4 9 years old in the trial, and the absolute risks in the age range are very low. For cholesterol, there was a benefit of aspirin at all levels, but this was even greater for those w i t h l o w e r levels. As regards gastrointestinal discomfort in the U.S. trial, this was r e p o r t e d b y 26.1% of the aspirin g r o u p and 25.6% of the p l a c e b o group, leaving only 0.5% of such s y m p t o m s attributable to aspirin. This very l o w rate of GI discomfort from an alternate-day dose of 325 m g is consistent w i t h the findings of the UK-TIA6 and ISIS-27 investigations, w h i c h indicate t h a t the side effects f r o m aspirin are strongly dose-dependent. A buffered aspirin preparation, as was used in the US trial, m a y h e l p to m i n i m i z e GI symptoms, as m i g h t the use of an enteric-coated aspirin formulation.
CURRENT KNOWLEDGE OF THE EFFECTS OF ASPIRIN ON CARDIOVASCULAR DISEASE In secondary p r e v e n t i o n a m o n g patients w i t h previous MI, stroke, or unstable angina, aspirin definitely reduces the incidences of s u b s e q u e n t MI, stroke, and cardiovascular death, and in 1985 the US Food and Drug Administration a p p r o v e d the p r e s c r i p t i o n labeling of aspirin for the treatment of patients w i t h a previous MI or unstable angina. Similarly, for the t r e a t m e n t o f s u s p e c t e d evolving MI, a conclusive benefit is seen for all three cardiovascular endpoints. As regards prim a r y prevention, there is a conclusive reduction in risk of a first MI. This v i e w is s u p p o r t e d b y the recent r e p o r t of the U.S. Preventive Services Task Force, w h i c h states, "Low-dose aspirin therapy should be considered for m e n aged 40 and over w h o are at significantly increased risk for myocardial infarction and w h o lack contraindications to the d r u g . " ~2 As regards aspirin's p r i m a r y prevention role in stroke and vascular mortality, this remains uncertain d u e to inadequate n u m b e r s o f e n d p o i n t s in the U.S. and British doctors' trials. This should, however, not divert attention from aspirin's firmly established value in secondary prevention. While aspirin's benefits in secondary p r e v e n t i o n and a m o n g those evolving an infarction have b e e n demonstrated for b o t h m e n and w o m e n , there are no prim a r y p r e v e n t i o n data on aspirin in w o m e n . While it m a y be reasonable to assume that there is a p r i m a r y preventive effect o f aspirin for s o m e categories of w o m e n , it is uncertain w h e t h e r the magnitude of such benefits w o u l d be the same in w o m e n as in m e n , or w h e t h e r the net benefits m i g h t b e different in s o m e subgroups of w o m e n . For e x a m p l e , since coronary risks in w o m e n u n d e r 60 are m u c h l o w e r than those in m e n u n d e r 60, the risk-to-benefit ratio for such w o m e n
might be less favorable than that for a similarly aged g r o u p of men. These uncertainties underscore the n e e d for a r a n d o m i z e d triaI o f aspirin in healthy w o m e n in order to p r o v i d e definitive data on this question. The w i d e s p r e a d use of nonsteroidal antiinflammatory drugs (NSAIDs), w h i c h have antiplatelet properties, has p r o m p t e d the question of w h e t h e r patients taking such agents for various indications are also receiving antiplatelet effects c o m m e n s u r a t e w i t h those of aspirin. While such agents have b e e n d e m o n s t r a t e d to inhibit platelet aggregation, this effect appears to be restricted to the t i m e the drug is actually present in bloodstream. Aspirin, on the other hand, inhibits aggregation for the life of the platelet. It is i m p o r t a n t to v i e w the results c o n c e r n i n g aspirin in the context of w h a t w e already k n o w a b o u t modification of risk factors to decrease risks of cardiovascular disease. Specifically, as regards b l o o d cholesterol, a 10% decrease c o r r e s p o n d s to r o u g h l y a 20% decrease in incidence of coronary heart disease. 13 For b l o o d pressure, a 6 - m m Hg decrease in diastolic pressure a m o n g those w i t h hypertension results in a b o u t a 10% l o w e r risk of coronary heart disease, as well as a reduction in risk of a p p r o x i m a t e l y 40% for stroke. 14, 15 Finally, in middle age, cessation of cigarette smoking yields about a 37% decrease in risk of coronary heart disease even within a matter of months. ~6 While the p r e s e n c e of cardiovascular risk factors may generally w e i g h in favor of a decision to prescribe p r o p h y l a c t i c aspirin, caution must be exercised in assessing w h i c h patients m a y benefit f r o m aspirin. For e x a m p l e , w h i l e a middle-aged man w i t h elevated cholesterol may b e a suitable candidate for p r o p h y l a c t i c aspirin, the use of aspirin m i g h t b e contraindicated in a w o m a n in her forties w i t h u n c o n t r o l l e d hypertension, w h o is at relatively l o w risk of MI but p e r h a p s at higher risk for h e m o r r h a g i c stroke. Thus, aspirin should b e v i e w e d as a possible adjunct, not an alternative, to comp r e h e n s i v e risk factor m a n a g e m e n t , w h i c h should be p r e s c r i b e d only by a physician or other p r i m a r y health care provider. 17 The clinical decision for the individual patient should include consideration of that p a t i e n t ' s specific cardiovascular risk profile, the k n o w n side effects of the drug, and the d e m o n s t r a t e d benefits of aspirin in different categories of patients.
REFERENCES 1. Moncada S, VaneJR. Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N EnglJ Med. 1979;300:1142-7. 2. Hennekens CH, Karlson LA, Rosner B. A case-control study of regular aspirin use and coronary deaths. Circulation. 1978; 58:35-8. 3. Hammond EC, Garfinkel L. Aspirin and coronary heart disease: findings of a prospective study. Br MedJ. 1975;2:269. 4. Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little, Brown, 1987. 5. Anti-Platelet Trialists Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet therapy. Br Med J. 1988;296:320-31.
JOURNALOFGENERALINTERNALMEDICINE, Volume5 (September/OctoberSupplement), 1990 6. UK-TIAStudy Group. United Kingdom transient ischaemic attack
9. 10. 11. 12.
(UK-TIA) aspirin trial interim results. Br Med J. 1988; 296:316-20. ISIS-2(SecondInternationalStudyofInfarctSurvival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;II:349-59. Steering Committee of the Physicians' Health Study Research Group. Preliminary Report: Findings from the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1988;318:262-4. Peto R, Gray R, Collins R, et al. A randomised trial of the effects of prophylactic daily aspirin among male British doctors. Br MedJ. 1988;296:313-6. 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. 1989;321:129-35. Hennekens CH, Peto R, Hutchison GB, Doll R. An overview of the British and American aspirin studies. N Engl J Med. 1988; 318:923-4. Report of the U.S. Preventive Services Task Force. Clinical Guide
to Preventive Services. US Department of Health and Human Services, 1989. Peto R, Yusuf S, Collins R. Cholesterol-lowering trial results in their epidemiologic context. Circulation. 1985;72(suppl III):451. Hebert PR, Fiebach NH, Eberlein KA, TaylorJO, Hennekens CH. The community-based randomized trials of pharmacologic treatment of mild-to-moderate hypertension. Am J Epidemiol. 1988;127:581-90. Collins R, Peto R, MacMahon S, et al. Effects of drug treatment for hypertension on the risks of stroke and of coronary heart disease: evidence from an overview of randomised controlled trials considered in the context of observational epidemiology. Lancet. 1990;335:827-38. Hennekens CH, Buring JE, Mayrent S. Smoking, aging and coronary heart disease. In: Bosse R, ed. Smoking and aging. Lexington, MA: D. C. Heath, 1984. Hennekens CH, Buring JE, Sandercook P, Collins R, Peto R. Aspirin in the secondary and primary prevention of cardiovascular diseases. Circulation. 1989;80:749-56.
Adult Immunizations: Are They Worth the Trouble? F. MARC LaFORCE, MD There are good data to recommend routine use o f vaccines against measles, rubella, tetanus, influenza, and pneumococcal infections in adults. An adolescent o r an adult born after 1956 is considered to be susceptible to measles unless he o r she has received two doses o f live measles vaccine o r has suffered a physician-diagnosed case o f measles. Tetanus is largely a disease o f the elderly, a n d there is a universal need f o r immunizations with tetanus toxoid. Influenza continues to be a m a j o r public health problem, a n d influenza vaccine should be given annually to the elderly a n d to those at high risk. The efficacy o f pneumococcai vaccine in American adults is still being debated. Results f r o m c a s e control studies show that the vaccine is about 60% effective in reducing the incidence o f disease due to vaccine-related strains. Its use in the elderly a n d in those at higher risk f o r pneumococcal infection is recommended. Key words: immunizations; elderly; pneumococcal vaccine; influenza vaccine; health promotion; adult health care. J GEN INTERN
MED 1990; 5(suppl):s57-S61.
VACCINESARE ONE o f t h e m o s t c o s t - e f f e c t i v e a p p r o a c h e s to i m p r o v e d h e a l t h care. C h i l d h o o d v a c c i n a t i o n s h a v e i n c r e a s e d life e x p e c t a n c y a m o n g A m e r i c a n s m o r e t h a n h a v e all i n v e s t m e n t s in t e r t i a r y care, a n d at a f r a c t i o n o f t h e cost. T h e i n c i d e n c e s o f m e a s l e s e n c e p h a l i t i s a n d t h e c o n g e n i t a l r u b e l l a s y n d r o m e are at an a l l - t i m e l o w . I n t e r e s t in a d u l t i m m u n i z a t i o n s has i n c r e a s e d o v e r t h e Received from the Department of Medicine, The Genesee Hospital and the University of Rochester School of Medicine and Dentistry, Rochester, New York. Presented at the conference, Frontiers in Disease Prevention, The Johns Hopkins University, June 5 - 6, 1989. Address correspondence and reprint requests to Dr. LaForce: The Genesee Hospital, 224 Alexander Street, Rochester, NY 14607.
TABLE 1 Routine Adult Immunization Recommendations Based on Age Age Vaccine
1 8 - 2 4 Years
2 5 - 6 4 Years
Measles Rubella Influenza Pneumococcal
65 Years or Older
*For susceptible patients.
last d e c a d e w i t h s p e c i f i c efforts to i m p r o v e v a c c i n a t i o n c o v e r a g e o f a d u l t s f r o m t h e A m e r i c a n C o l l e g e o f Physicians, t h e D i v i s i o n o f I m m u n i z a t i o n at t h e C e n t e r s f o r D i s e a s e C o n t r o l ( C D C ) , a n d t h e U.S. P r e v e n t i v e Serv i c e s Task F o r c e . D e s p i t e this r e n e w e d i n t e r e s t , signific a n t gaps in v a c c i n e c o v e r a g e o f a d u l t A m e r i c a n s remain. T a b l e 1 lists t h e r o u t i n e l y r e c o m m e n d e d v a c c i n a t i o n s f o r a d u l t s b y age. This p a p e r r e v i e w s t h e r a t i o n a l e a n d t h e e v i d e n c e in f a v o r o f t h e i r use. P n e u m o c o c c a l v a c c i n e is d i s c u s s e d in m o r e d e t a i l b e c a u s e o f t h e c o n t r o v e r s y s u r r o u n d i n g its use. R e a d e r s are r e f e r r e d to m o r e c o m p r e h e n s i v e p u b l i c a t i o n s f r o m t h e C D C Imm u n i z a t i o n D i v i s i o n , 1 r e c o m m e n d a t i o n s f r o m t h e Advisory C o m m i t t e e o n I m m u n i z a t i o n P r a c t i c e s , w h i c h are p u b l i s h e d r e g u l a r l y in M M W R a n d t h e t e x t b o o k Vacc i n e s , e d i t e d b y P l o t k i n a n d M o r t i m e r . 2 T h e U.S. Prev e n t i v e S e r v i c e s Task F o r c e f o r m a t , w h i c h i n c l u d e s b u r d e n o f suffering, t h e v a c c i n e , a n d e v i d e n c e f o r efficacy, is u s e d t o d i s c u s s e a c h v a c c i n e .