Aspirin prophylaxis in patients at low risk for cardiovascular disease: A systematic review of all-cause mortality

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Original Research

Aspirin prophylaxis in patients at low risk for cardiovascular disease: A systematic review of all-cause mortality

J Fam Pract. 2002 August;51(8):700-704

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References

1. Fuster V, Dyken M, Vokonas P, Hennekens C. Aspirin as a therapeutic agent in cardiovascular disease. Circulation 1993;87:659-75.

2. Weiss H, Aledort L. Impaired platelet/connective tissue reaction in man after aspirin ingestion. Lancet 1967;2:495-7.

3. Preston F, Whipps S, Jackson C, et al. Inhibition of prostacyclin and platelet thromboxane A2 after low dose aspirin. N Engl J Med 1981;304:76-9.

4. Hankey GJ. One year after CAPRIE, IST, and ESPS 2. Cerebrovasc Dis 1998;8(suppl 5):1-7.

5. Buring J, Hennekens C. Prevention of cardiovascular disease: risks and benefits of aspirin. J Gen Intern Med 1990;5(suppl 5):S54-7.

6. Sivenius J, Laakso M, Penttila IM, et al. The European Stroke Prevention Study: results according to sex. Neurology 1991;41:1189-92.

7. Lewis H, Davis J, Archibald D, Steinke W, Smitherman T. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983;309:396-403.

8. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of anti platelet therapy. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106.

9. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from metaanalysis of randomised trials. Heart 2001;85:265-71.

10. The Salt Collaborative Group. Swedish Aspirin Low dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischemic events. Lancet 1991;338:1345-9.

11. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62.

12. The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998;351:233-41.

13. Gum PA, Thamilarasan M, Watanabe J, Blackstone EH, Lauer MS. Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease. JAMA 2001;286:1187-94.

14. Havranek EP. Primary Prevention of CHD: nine ways to reduce risk. Am Fam Phys 1999;59:1455-63-1466.

15. National Cholesterol Education Program. Third Report on the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Washington, DC: US Department of Health and Human Services; 2001. NIH Publication 01-3305.

16. Primary Prevention of Cardiovascular Disordersn, Clinical Evidence. London: British Medical Journal; 2001;64-5.

17. Jadad AR, Moore A, Corroll D, et al. Assessing the quality of reports of randomized clinical trials: is binding necessary? Control Clin Trials 1996;17:1-12.

18. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for Meta-Analysis in Medical Research. New York: John Wiley & Sons; 2000;42-5,64-72.

19. StatXact 4 for Windows [computer program]. Cambridge, MA: CYTEL Software Corp; 2000.

20. Steering Committee of the Physician’s Health Study Research Study Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321:129-35.

21. Peto R, Gray R, Collins R, et al. Randomized trial of prophylactic daily aspirin in British male doctors. BMJ 1988;296:313-6.

22. Manson J, Stampfer M, Colditz G, et al. A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA 1991;266:521-7.

23. Silagy C, McNeil J, Donnan G, et al. The Pace Pilot Study: 12 month results and implications for future primary prevention trials in the elderly. J Am Geriatr Soc 1994;42:643-7.

24. Manson J, Buring J, Satterfield S, Hennekens C. Baseline characteristics of participants in the Physicians Health Study: a randomized trial of aspirin and beta carotene in U.S. physicians. Am J Prev Med 1991;7:150-4.

25. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.

26. Thun M, Namboodiri M, Heath C. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991;325:1593-6.

27. Hennekens C, Buring J. Aspirin in the primary prevention of cardiovascular disease. Cardiol Clin 1994;12:443-50.

28. Hennekens CH, Jonas MA, Buring JE. Antiplatelet therapy and risk of stroke. Ann Epidemiol 1993;3:568-70.

29. Iso H, Hennekens C, Stampfer M, et al. Prospective study of aspirin use and risk of stroke in women. Stroke 1999;30:1764-71.

30. Kronmal RA, Hart R, Manolio T, et al. Aspirin use and incident stroke in the cardiovascular study. Stroke 1998;29:887-94.

31. Paganini-Hill A, Chao A, Ross RK, Henderson B. Aspirin use and chronic diseases: a cohort study of the elderly. BMJ 1989;299:1247-50.

32. Silagy C, McNeil J, Donnan G, et al. Adverse effects of low dose aspirin in a healthy population. Clin Pharmacol Ther 1993;54:84-9.

In the British Doctors Study (BDS), 66% of patients were randomized to take aspirin once daily and 33% were to avoid aspirin.²¹ More than half of the subjects were at least 60 years old. Physicians with stroke, myocardial infarction, ulcer disease, or currently taking any aspirin products were excluded. Six percent of the subjects had a history of heart disease other than myocardial infarction, 10% had hypertension, and 75% of participants were currently smoking or had a history of smoking. No significant differences were noted between groups for myocardial infarction or total mortality. By the end of the study, 44% of the aspirin group had discontinued aspirin secondary to side effects, the most common being dyspepsia. Of the control group, 2% per year started using aspirin because they developed risk factors such as vascular disease or for primary prevention. Low-risk individuals were not evaluated separately.

The Nurses Health Study (NHS) was a cohort study of women who were free of diagnosed coronary heart disease, stroke, and cancer at the start of the study. However, 29% of the women smoked and 15% had hypertension.²² The mean age was 46.0 years, and the follow-up was 96.7% of total potential person years. The study respondents were asked how many aspirin tablets they took per week: 0, 1 to 3, 4 to 6, 7 to 14, or 15+. Those who smoked or were overweight were more likely to take aspirin. No separate analysis of low-risk subjects was performed. Mortality from aspirin use was clearly dose dependent. For study participants taking 1 to 6 aspirin tablets each week, mortality was 0.84% (OR, 1.51; 95% confidence interval [CI], 1.26–1.82); for those taking 7 to 14 aspirin tablets, mortality was 0.99% (OR, 1.80; CI, 1.39–2.33); and for those taking 15+ aspirin tablets, mortality was 1.82% (OR, 3.32; CI, 2.62–4.21). Rates of myocardial infarction and stroke also were higher for all groups taking aspirin (see Table 2). When combined, the USPHS and the BDS demonstrated no significant difference in mortality between aspirin and placebo groups, whereas the NHS found increased mortality from aspirin (Figure).

TABLE 1

Characteristics of aspirin studies that included low-risk subjects

	USPHS	BDS	NHS
Trial	Steering Committee²⁰	Peto et al²¹	Manson et al²²
Study population	Healthy US physicians	Healthy UK physicians	Healthy US nurses
Study type	Randomized controlled trial	Randomized controlled trial	Cohort
Subjects in aspirin group	11,037	3429	35,048
Subjects in control group	11,034	1710	52,630
Treatment	325 mg aspirin every other day	500 mg/d aspirin	1–15 aspirin tablets/wk
Comparison	Placebo	No aspirin	None
Follow-up time (y)	5	6	6
Jadad score
Randomization^†	1	2	NA*
Blinding ‡	1	0	NA
Withdrawals §	1	0	NA
Total	3	2	NA
Significant difference in mortality	No	No	Yes in favor of no aspirin
*The Jadad scale does not apply to cohort studies.
^†Two points maximum.
^‡Two points maximum.
^§One point maximum.
BDS, British Doctors Study; NA, not applicable; NHS, Nurses Health Study; USPHS, US Physicians Health Study.

TABLE 2

Rates of myocardial infarction, stroke, total cardiovascular mortality, and total mortality in studies of aspirin vs no aspirin that included low-risk patients

	Study
Outcome	USPHS (5 y)	BDS (6 y)	NHS (6 y)
Myocardial infarction
Aspirin, n (%)	139 (1.26)	169 (4.93)	244 (0.70)
No aspirin, n (%)	239 (2.17)	88 (5.15)	157 (0.30)
OR (CI)	0.58 (0.47–0.71)	0.96 (0.73–1.24)	2.34 (1.92–2.86)*
Stroke
Aspirin, n (%)	119 (1.08)	91 (2.65)	109 (0.31)
No aspirin, n (%)	98 (0.89)	39 (2.28)	89 (0.17)
OR (CI)	1.22 (0.93–1.59)	1.17 (0.80–1.71)	1.84 (1.39–2.44)*
Total cardiovascular mortality
Aspirin, n (%)	81 (0.73)	148 (4.32)	68 (0.19)
No aspirin, n (%)	83 (0.75)	79 (4.62)	62 (0.12)
OR (CI)	0.98 (0.72–1.33)	0.93 (0.70–1.23)	1.65 (1.17–2.33)*
Total mortality
Aspirin, n (%)	217 (1.97)	270 (7.87)	354 (1.01)
No aspirin, n (%)	227 (2.06)	151 (8.83)	292 (0.55)
OR (CI)	0.95 (0.79–1.15)	0.88 (0.72–1.09)	1.83 (1.57–2.14)*
*OR significant at the .05 level.
BDS, British Doctors Study; CI, 95% confidence interval; n (%), number (percentage) of patients taking or not taking aspirin; NHS, Nurses Health Study; OR, odds ratio; USPHS, US Physicians Health Study.

FIGURE Forest plot of mortality in healthy patients on aspirin

Discussion

To date, there has been no study of aspirin for primary prevention that included a separate analysis of patients who were free of cardiovascular risk factors. Each of the 3 studies that included low-risk subjects grouped them with subjects at higher risk, those known to benefit from aspirin.^9,11,12 Even so, none of those studies demonstrated a statistically significant decrease in all-cause mortality. Even when combined, the BDS and the USPHS demonstrated no significant improvement in mortality. Mortality in the BDS was nearly 4 times greater than that in the USPHS. This finding is likely due to the higher baseline rate of smoking and other risk factors in the British doctors. In contrast to the BDS, the USPHS demonstrated significantly decreased rates for fatal and nonfatal myocardial infarction. Our analysis of the NHS associated aspirin with increased mortality, fatal myocardial infarction, and nonfatal myocardial infarction at any dose. The nurses on average had lower risk than the doctors, fewer smoked, and they were younger.

Many studies have clearly demonstrated the benefits of aspirin for primary prevention in high-risk subjects.^10-12,25 There may be other benefits to taking prophylactic aspirin. In the Cancer Prevention Study II, aspirin use was associated with decreased death rates from colon cancer.²⁶ Unfortunately, that study did not measure all-cause mortality.