1. Case Presentation A 62 year old woman asks whether she should take aspirin to prevent a heart attack and stroke, and if so how much? She is on hydrochlorothiazide for hypertension. She has a history of a bleeding “stomach ulcer”. She smokes cigarettes. Framingham CV risk score, based also on her cholesterol and HDL, is 11% over the next 10 years. Her exam is normal (BP 130/84).

2. Aspirin in Primary Prevention of Cardiovascular Diseases AHA/ACC: AHA/ACC: Additional data in primary prevention are needed for complete assessment of aspirin’s benefit-to-risk ratio in apparently healthy persons. The use of aspirin in primary prevention of MI should remain an individual clinical judgement. Aspirin therapy should always be an adjunct, not an alternative, to management of other risk factors. (Circulation 96: 2751 - 2753, 1997) USPSTF: USPSTF: Clinicians should discuss aspirin chemoprevention with adults who are at increased risk for coronary heart disease. Discussions with patients should address both the potential benefits and harms of aspirin therapy. (Ann Int Med 136:157 - 160, 2002) BAYER Citizen’s Petition BAYER Citizen’s Petition: Requested in 12/03 FDA approval to market low-dose aspirin to physicians for patients at high CV risk (Framingham risk of 10%/10 years or higher). Based on several studies in 55,000 patients.

3. Primary Prevention Trials British Doctor’s Trial Physician’s Health Study Hypertension Optimal Treatment (HOT) Thrombosis Prvention Trial Primary Prevention Project

4. PRIMARY PREVENTION PROJECT Low dose ASA (100 mg/d) for 1° CV prevention in people with  1 CV risk factor(s). Lancet 357:89-95, 2001 PRIMARY PREVENTION PROJECT Low dose ASA (100 mg/d) for 1° CV prevention in people with  1 CV risk factor(s). Lancet 357:89-95, 2001 AspirinNo Aspirin Risk (n=2,226)(n=2,269) Ratio Total Deaths62 77 0.8 (NS) CV Deaths18 32 0.6 (SIG) Combined CV Endpoint *45 64 0.7 (NS) Severe Bleeding: 24 6 4.1(SIG) GI 17 5 Intracranial 2 0 Other 5 1 *

5. FDA Cardiovascular and Renal Drugs Advisory Committee Met 12/8/03 to consider Bayer petition Voted 11 to 3 against new indication for the reduction of the risk of a first MI in patients with CHD risk of  10% over 10 years –consistent reduction in nonfatal MI –not consistent reduction in fatal MI and CV deaths and a possible increase in strokes –only 12% of patients were “high risk”, and there were very few women in the studies

6. Secondary CV Prevention (Federal Register 63, No. 205, 10/23/98) No rec. No change

7. New data comparing aspirin doses (since 1998) Randomized controlled clinical trial in 1999 involving 4 aspirin doses (ACE) Non-randomized clinical trials involving very large data bases and multiple aspirin doses ( 2003) –CURE –BRAVO Meta-analyses on efficacy and on toxicity of various doses (2002, 2003)

8. ACE trial. CV outcomes in 2,849 patients (Lancet 353: 2179, 1999) * No difference between 709 pts. taking 81 mg versus 708 pts. taking 325 mg/day * P = 0.03 (Low doses) (High doses)

9. Dosing data from CURE trial 12,539Clopidogrel in Unstable angina to prevent Recurrent Events (CURE; 12,539 patients). Clopidogrel 75 mg/day or placebo PLUS ASA 75 to 325 mg/day. ASA dose was up to the treating physician. [Peters et al. Circulation 108: 1682-1687,2003)]

10. CURE in ACS. CV Endpoint

11. Dosing data from BRAVO trial Blockade of the GP II b/ III a Receptor to Avoid Vascular Occlusion (BRAVO; 9,190 patients). Lotrafiban (30 mg bid or 50 mg bid) or placebo PLUS ASA 75-325 mg/day. ASA dose up to physician. [Topol et al. Circulation 108:399-406, 2003]

12. BRAVO patients had symptomatic CAD or cerebrovasc. disease, or had “double bed” vascular disease. CV endpts (placebo arm): N=2,410N= 2,179

13. Meta-analysis of 65 studies. Antithrombotic Trialists’ Collaboration (ATC). BMJ 324: 71, 2002

14. Why should CV outcomes tend to be higher with higher aspirin doses? TXA 2 is a potent platelet aggregator/vasoconstrictor –platelet thromboxane production is maximally inhibited at 75mg/day and above, and no further benefit is achieved at higher doses PGI 2 is a potent platelet inhibitor and vasodilator –some endothelial cell (EC) production of PGI 2 (prostacyclin) is preserved at 75-81 mg/ day but is abolished at higher aspirin doses; this may be because aspirin is COX-1 selective at lower doses Vessel wall EC 1 2

15. ACE trial: bleeding complications LOW DOSESHIGH DOSES

16. CURE. Major bleeding

17. CURE. Life-threatening bleeding

18. BRAVO. Major bleeding

19. BRAVO. Need for transfusion

20. Sites of bleeding in BRAVO (placebo arm: aspirin alone) GI4.0% Epistaxis3.7% GU/hematuria2.0% Oral/gum1.4% Hematoma1.4% Menstrual/vaginal0.5% Ocular0.4% Hemoptysis0.3% Intracerebral0.2% Retroperitoneal0.04% 1 in 25 1 in 27 1 in 50 1 in 71 1 in 200 1 in 250 1 in 333 1 in 500 1 in 2500

21. Meta-analysis of numerous trials, involving > 300,000 patients (Serebruany et al. American J. Hematology, in press)

22. My take and recommendations There is insufficient evidence supporting use of aspirin for primary CV prevention in patients with CV risk factors. There is no strong reason to recommend aspirin doses higher than 75 or 81 mg per day for secondary prevention of MI, CVA, or TIA –same or higher efficacy –less toxicity –equal or lower cost

23. Do we ever need to use aspirin doses > 81 mg/day Acute MI –162-162.5 mg/day for first 30 days (ISIS-2) Revascularization procedures (Fed.Register, ‘98) –CABG: 325 mg 6 hr postop, and for one year –PTCA: 325 mg 2 hr pre-procedure and maintenance of 160-325 mg/day indefinitely –CEA: 80-650 mg bid (160-1300 mg/day) beginning preop and continued indefinitely (should change post ACE trial)

24. Can we use < 81 mg daily or less than daily aspirin doses? DUTCH TIA GROUP: –30 vs. 283 mg/day in 3,131 patients with TIA or minor stroke –CV EFFICACY: 14.7 vs 15.2% com- bined endpoint (NS) –BLEEDING: minor in 49 vs 89 (SIG) major in 40 vs. 53 (NS) (NEJM 325: 1261-6,1991) Rx for 1 month (Feldman et al, 2001. Clinical and Applied Thrombosis/Hemostasis)

25. Prevention of recurrent complicated peptic ulcers from low-dose ASA in patients at high CV risk 123 patients at high CV risk, with complicated GU  DU associated with chronic low-dose ASA use H. pylori infection in all Ulcers and H.pylori Rx’d with LAC for 7d PLUS famotidine 20 bid for 35d ASA 100 mg/day then restarted for a year, PLUS lansoprazole 30 mg/d or placebo. Recurrent ulcer compli- cations in 10 : Placebo: 9/61(14.8%) Lansoprazole:1/63 (1.6%) Risk ratio with lanso- prazole = 0.11 (p<0.05) (KC Lai et a. NEJM 346: 2033-2038,2002)

26. Approach to Use of Low Dose Aspirin Low GI Bleed Risk No ASA ASA 81 mg/day 2º CV Prev1º CV Prev High GI Bleed Risk No aspirin ASA + PPI (± Antibiotics) 2º CV Prev1º CV Prev Hp 