Multiple Small Feedings of the Mind WV ACP Chapter Meeting 2008

1. Multiple Small Feedings of the MindWV ACP Chapter Meeting 2008 Laura Davisson, MD, MPH Assistant Professor West Virginia University Dept. of Medicine Clinic Director, Center of Excellence in Women’s Health

2. Clinical Question When should aspirin be used for primary prevention in women?

3. Aspirin and cardiovascular disease • Benefits in known cardiovascular disease well-established • Is it beneficial in primary prevention? • Is there a gender difference in effects of aspirin in primary prevention?

4. Aspirin primary prevention trials prior to 2005 • Physicians Health Study (PHS), NEJM 1989 • British Male Doctors Trial (BMD), BMJ 1988 • Thrombosis Prevention Trial (TPT), Lancet 1998 • Hypertension Optimal Treatment (HOT) Trial, Lancet 1998 • Primary Prevention Project (PPP), Lancet 2001

5. Characteristics of these primary prevention trials • Mostly men older than 50. • Only 2 (HOT and PPP) included women. • ~1/5 of ~50,000 patients in the 5 trials were women. • Aspirin given 4-7 years, from 75-500 mg qd. • Study quality: fair to good. • Primarily addressed CHD.

6. Meta-analysis of the primary prevention trials Annals of Internal Medicine 2002;136:16172.

7. Benefits and Harms from the primary prevention trials Annals of Internal Medicine 2002;136:16172.

8. HOT trial subgroup analysis by gender J Hypertension 2000;18:629-42.

9. PPP Trial Results in Women • Investigators noted women had same CHD reduction benefit as men. • Specific data not presented.

10. Guidelines: Aspirin for primary prevention

11. United States Preventive Services Task Force (USPSTF) http://www.ahrq.gov/clinic/uspstfix.htm

12. USPSTF grades strength of evidence • A-Strongly recommends • B-Recommends • C-No recommendation for or against • D-Recommends against • I-Insufficient evidence to recommend for or against

13. USPSTF 2002 recommendations • Strongly recommends discussingaspirin chemoprevention with adults at increased risk for CHD. • Discussions should address potential benefits and harms. • An “A” recommendation.

14. USPSTF 2002 recommendations • Risk/benefit balance of aspirin most favorable in patients at high risk of CHD • Definition of high risk of CHD: 5 year risk 3%, 10 year risk 6%* *Risk calculator: http://hp2010.nhlbihin.net/atpIII/calculator.asp?usertype=prof

15. USPSTF 2002 recommendations • Optimum aspirin dose not known • 75 mg daily, 100 mg daily, 325 mg every other day likely all beneficial.

16. AHA http://www.americanheart.org/presenter.jhtml?identifier=3003999

17. AHA Recommendations 2002 • Use aspirin if 10% 10-year CHD risk. • Dose 75-160 mg daily. • No distinction based on sex. • Based on studies done primarily in men, results may not apply equally to women. Circulation. 2002;106:388. Circulation. 1997;96:2751-3.

18. “Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women” • High-risk: use aspirin unless contraindicated. • Intermediate-risk: consider if blood pressure controlled and benefit likely to outweigh risk of GI side effects. • Lower-risk: use not recommended pending results of ongoing trials. Circulation. 2004;109:672-693.

19. Women’s Health Study A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women Paul M Ridker, M.D., Nancy R. Cook, Sc.D., I-Min Lee, M.B., B.S., David Gordon, M.A., J. Michael Gaziano, M.D., JoAnn E. Manson, M.D., Charles H. Hennekens, M.D. and Julie E. Buring, Sc.D.

20. Women’s Health Study Methods • 100 mg aspirin every other day vs. placebo in 2x2 factorial design. • ~40,000 apparently healthy women followed for 10 years. • Mean age: 54.6 years. • End point data obtained by questionnaire and medical records. NEJM 2005;352:1293-304

21. Women’s Health Study Methods • Primary end point: combination of major cardiovascular events. • Designed for power 86% to detect 25% reduction in primary end point. • Analyzed on intention to treat basis. • Cox proportional hazards models used to calculate relative risks after adjustments. NEJM 2005;352:1293-304

22. Women’s Health Study Results *Primary end point NEJM 2005;352:1293-1304

23. Women’s Health Study Significant Subgroup Analysis Results NEJM 2005;352:1293-304

24. Women’s Health Study Conclusions • Aspirin lowered risk of stroke in women. • No effect on risk of MI or death from cardiovascular causes except women >65. • Benefit offset by increased risk of GI bleeding. • Overall, non-significant finding for primary endpoint. • Limitation: low dosage of aspirin. NEJM 2005;352:1293-1304

25. Answer to question • Minimal evidence of benefit. • Probably not sufficient to recommend to most women. • If recommend, would be primarily for stroke prevention. • Findings opposite to what was found in men. When should aspirin be used for primary prevention in women?

26. References • Physicians Health Study I, NEJM. 1989;321:129-35. • British Male Doctors Trial, BMJ. 1988;296:313-6. • Thrombosis Prevention Trial, Lancet. 1998;351:233-41. • Hypertension Optimal Treatment (HOT) Trial, Lancet. 1998;351:1755-62. • Primary Prevention Project (PPP), Lancet. 2001;357:89-95. • Aspirin for the primary prevention of cardiovascular events: A summary of the evidence for the U.S. Preventive Services Task Force. Annals of Internal Medicine 2002;136:16172.

27. References • Influence of gender and age on preventing cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT study. J Hypertension 2000;18:629-42. • US Preventive Services Task Force. Guide to clinical preventive services, 3rd ed. Washington, DC: Agency for healthcare research and quality, 2002. • AHA guidelines: Circulation. 2002;106:388. • AHA guidelines: Circulation. 1997;96:2751-3. • Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women, AHA. Circulation. 2004;109:672-693. • Women’s Health Study, NEJM 2005;352:1293-304.