1. PHYSICIANS' HEALTH STUDY A randomized, double-blind, placebo controlled trial designed to test the effects of low-dose aspirin and beta- carotene in the primary prevention of CVD and cancer among 22,071 US male physicians, aged 40 to 84 at baseline in 1982. Baseline blood specimens were collected and frozen for later analyses from 14,916 participants. Using a 2x2 factorial design: 325 mg of aspirin (Bufferin, supplied by Bristol-Myers Products on alternate days) 50 mg of beta-carotene (Lurotin, supplied by BASF AG on alternate days)

2. PHYSICIANS' HEALTH STUDY Randomized aspirin component terminated early, on 1/25/88 Randomized beta carotene component ended, as scheduled, on 12/21/95 After an average duration of beta carotene treatment and follow-up of 12 years:  Fewer than 1% of participants were lost to morbidity and mortality follow-up  Compliance with pill-taking was > 80%

3. Rationale for Choosing Physicians Ability to give true informed consent Knowledge of possible side effects Accuracy and completeness of information Ease of follow-up Opportunity to conduct trial by mail

4. Personal history of Myocardial infarction Stroke or TIA Cancer (except nonmelanoma skin cancer) Current liver or kidney disease Peptic ulcer or gout Contraindication to aspirin use Current use of aspirin or other drugs affecting platelet function Current use of vitamin A or beta-carotene supplement Exclusion Criteria PHYSICIANS' HEALTH STUDY

5. Total cancer Prostate cancer Cardiovascular disease Eye disease ä Cataract ä Macular degeneration Primary Endpoints

6. PHYSICIANS’ HEALTH STUDY 261,248 U.S. male MD’s, aged 40-84 112,528 respondents to questionnaires 59,285 willing to participate Population Hierarchy

7. 33,223 willing and eligible MDs enrolled in run-in (18 weeks on active aspirin and beta-carotene placebo) 22,071 randomized PHYSICIANS’ HEALTH STUDY Run-in Phase

8. Randomization Scheme PHYSICIANS' HEALTH STUDY 22,071 Randomized 11,037 Aspirin 11,037 Aspirin placebo 5,517 Beta-carotene 5,520 Beta-carotene placebo 5,519 Beta-carotene 5,515 Beta-carotene placebo

9. Baseline Characteristics AssignmentASA + BCASA + PLPL + BCPL + PL (n = 5,517)(n = 5,520)(n = 5,519)(n = 5,515) Demographic Mean age (years)53.2±9.553.3±9.653.2±9.553.2±9.5 Geographic region Northeast 27.8 27.9 27.3 28.8 Midwest 22.4 21.9 22.1 20.3 South or Southwest 26.8 26.1 27.0 27.9 Mountain or Far West 22.0 23.3 22.8 22.1 Other 1.0 0.9 0.7 0.9 PHYSICIANS' HEALTH STUDY I

10. Baseline Characteristics AssignmentASA + BCASA + PLPL + BCPL + PL Medical history Reported hypertension 11.8 11.8 12.4 11.5 Mean systolic BP 126.0±11.9126.3±12.1126.1±11.7126.1±11.7 Mean diastolic BP 78.8±7.6 78.9±7.5 78.9±7.5 78.7±7.5 High cholesterol 7.9 7.5 8.0 8.0 Mean cholesterol mg/dl)211.7±43.9212.3±45.0212.7±46.5211.4±44.8 Diabetes mellitus 2.1 2.5 2.2 2.2 Mean BMI 24.9±3.1 24.9±3.0 24.9±3.0 24.9±3.0 Overweight 13.5 14.0 13.6 13.6 History of angina pectoris 1.2 1.4 1.1 1.2 Parental history of Ml 12.7 13.3 12.7 13.6 PHYSICIANS' HEALTH STUDY I

11. Baseline Characteristics AssignmentASA + BCASA + PLPL + BCPL + PL Health habits Cigarette smoking Never 49.8 48.8 49.6 50.1 Past only 39.3 40.1 39.1 39.0 Current 10.9 11.1 11.4 10.9 Mean cigarettes/day21.7±13.022.1±12.922.4±13.722.8±13.5 <15 (of current smokers) 28.8 27.4 27.3 24.6 15-24 (of current smokers) 32.5 33.7 34.7 35.4 25+ (of current smokers) 38.7 38.8 37.9 40.0 Current cigar smoking 4.7 4.2 4.3 4.3 Current pipe smoking 8.8 7.7 8.2 8.0 PHYSICIANS' HEALTH STUDY I

12. Baseline Characteristics AssignmentASA + BCASA + PLPL + BCPL + PL Health habits Alcohol use Mean drinks/week3.5±3.23.5±3.23.5±3.23.5±3.3 Daily 24.8 24.9 24.7 25.2 Rarely or never 14.8 14.6 14.7 15.4 Exercise frequency Mean times/month10.2±8.59.8±8.310.0±8.610.0±8.6 Rarely or never 12.8 14.2 14.0 13.5 PHYSICIANS' HEALTH STUDY I