1) The study aimed to determine if incomplete inhibition of platelet thromboxane production by aspirin (ASA), as measured by urinary 11-dehydro thromboxane B2 levels, was associated with increased cardiovascular risk in patients in the CHARISMA trial. 2) Urinary 11-dehydro thromboxane B2 levels were measured in 3261 patients to identify determinants of thromboxane production and whether clopidogrel added to ASA could reduce thromboxane biosynthesis. 3) Baseline characteristics and outcomes were compared between patients who did and did not experience a primary endpoint of stroke, MI or cardiovascular death during follow-up. Determinants of urinary 11-dehydro throm

1. Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid Determinants and Effect on Cardiovascular Risk CHARISMA OCTOBER 2008 CIRCULATION John W. Eikelboom, FRACP, FRCPA; Graeme J. Hankey, MD, FRACP, FRCP; Jim Thom, MSc; Deepak L. Bhatt, MD; P. Gabriel Steg, MD; Gilles Montalescot, MD, PhD; S. Claiborne Johnston, MD, PhD; Steven R. Steinhubl, MD; Koon-Hou Mak, MD, FRCP; J. Donald Easton, MD; Christian Hamm, MD; Tingfei Hu, MS; Keith A.A. Fox, MB, ChB, FRCP, FESC; Eric J. Topol, MD, on behalf of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators

16. Baseline Characteristics All Patients * (n=15 603) Stroke, MI, or CV Death (n=144) No Stroke, MI, or CV Death (n=3117) Age, median, y 64.0 69.0 64.0 Female sex, n (%) 4644 (29.8) 39 (27.1) 870 (27.9) BMI, kg/m 2 Mean (SD) 27.9 (5.1) 27.6 (4.8) 28.7 (5.2) Median 27.1 27.9 Inclusion subgroup, n (%) Documented vascular disease 12 153 (77.9) 117 (81.3) 2349 (75.4) Multiple risk factors 3284 (21.0) 26 (18.1) 747 (24.0) Smoking status, n (%) Current 3155 (20.2) 26 (18.1) 632 (20.3) Former 7613 (48.8) 76 (52.8) 1547 (49.6) Hypertension, n (%) 11 483 (73.6) 108 (75.0) 2285 (73.3) Hypercholesterolemia, n (%) 11 535 (73.9) 107 (74.3) 2415 (77.5) Diabetes mellitus, n (%) 6556 (42.0) 73 (50.7) 1381 (44.3) Past medical history, n (%) MI 5397 (34.6) 52 (36.1) 1082 (34.7) TIA 1864 (11.9) 17 (11.8) 303 (9.7) Stroke 3837 (24.6) 57 (39.6) 749 (24.0) PAD 3531 (22.6) 38 (26.4) 670 (21.5) PCI 3554 (22.8) 30 (20.8) 748 (24.0) CABG surgery 3079 (19.7) 34 (23.6) 568 (18.2) Carotid endarterectomy 825 (5.3) 12 (8.3) 140 (4.5) Angioplasty / bypass 1737 (11.1) 20 (13.9) 322 (10.3) CV indicates cardiovascular; BMI, body mass index; TIA, transient ischemic attack; PAD, peripheral arterial disease; and PCI, percutaneous coronary intervention. *Includes all patients randomized in the CHARISMA trial.

17. Baseline Characteristics All Patients * (n=15 603) Stroke, MI, or CV Death (n=144) No Stroke, MI, or CV Death (n=3117) Age, median, y 64.0 69.0 64.0 Female sex, n (%) 4644 (29.8) 39 (27.1) 870 (27.9) BMI, kg/m 2 Mean (SD) 27.9 (5.1) 27.6 (4.8) 28.7 (5.2) Median 27.1 27.9 Inclusion subgroup, n (%) Documented vascular disease 12 153 (77.9) 117 (81.3) 2349 (75.4) Multiple risk factors 3284 (21.0) 26 (18.1) 747 (24.0) Smoking status, n (%) Current 3155 (20.2) 26 (18.1) 632 (20.3) Former 7613 (48.8) 76 (52.8) 1547 (49.6) Hypertension, n (%) 11 483 (73.6) 108 (75.0) 2285 (73.3) Hypercholesterolemia, n (%) 11 535 (73.9) 107 (74.3) 2415 (77.5) Diabetes mellitus, n (%) 6556 (42.0) 73 (50.7) 1381 (44.3) Past medical history, n (%)

18. MI 5397 (34.6) 52 (36.1) 1082 (34.7) TIA 1864 (11.9) 17 (11.8) 303 (9.7) Stroke 3837 (24.6) 57 (39.6) 749 (24.0) PAD 3531 (22.6) 38 (26.4) 670 (21.5) PCI 3554 (22.8) 30 (20.8) 748 (24.0) CABG surgery 3079 (19.7) 34 (23.6) 568 (18.2) Carotid endarterectomy 825 (5.3) 12 (8.3) 140 (4.5) Angioplasty / bypass 1737 (11.1) 20 (13.9) 322 (10.3)

19. Medications All Patients * (n=15 603) Stroke, MI, or CV Death (n=144) No Stroke, MI, or CV Death (n=3117) ASA ASA treatment, n (%) 15 552 (99.7) 144 (100) 3114 (99.9) ASA dose in mg, median 100.0 81.0 81.0 ASA <100 mg/d, n (%) 7269 (46.7) 90 (62.5) 1,928 (61.9) ASA 100–149 mg/d, n (%) 4984 (32.0) 28 (19.4) 737 (23.7) ASA 150 mg/d, n (%) 3299 (21.2) 26 (18.1) 449 (14.4) Clopidogrel, n (%) Study clopidogrel 7802 (50.0) 64 (44.4) 1536 (49.3) Any clopidogrel 8574 (55.0) 105 (72.9) 1683 (54.0) NSAIDS, n (%) 3378 (21.6) 42 (29.2) 749 (24.0) Statin, n (%) 11 992 (76.9) 119 (82.6) 2483 (79.7) β- Blocker, n (%) 8636 (55.3) 112 (77.8) 1733 (55.6) Diuretics, n (%) 7428 (47.6) 95 (66.0) 1419 (45.5) Calcium channel blockers, n (%) 5745 (36.8) 61 (42.4) 1205 (38.7) Ramipril, n (%) 2811 (18.0) 31 (21.5) 589 (18.9) Other ACE inhibitor, n (%) 7219 (46.3) 69 (47.9) 1441 (46.2) Other antihypertensive agent, n (%) 1934 (12.4) 24 (16.7) 347 (11.1) Oral hypoglycemic agent, n (%) 5355 (34.3) 58 (40.3) 1120 (35.9) Insulin, n (%) 2694 (17.3) 45 (31.3) 583 (18.7) ACE indicates angiotensin-converting enzyme. *Includes all patients randomized in the CHARISMA trial.

20. Treated Not Treated P Randomized clopidogrel treatment, n 1600 1661 11-Dehydro thromboxane B 2 , ng/mmol creatinine Median (Q1, Q3) 57.1 (40, 90) 58.5 (40, 92) 0.50 Minimum, maximum 0.5, 3509 7.1, 3741 Log-transformed mean (SD) 4.2 (0.76) 4.2 (0.72) Geometric mean 63.6 64.1 NSAID, n 791 2470 11-Dehydro thromboxane B 2 , ng/mmol creatinine Median (Q1, Q3) 54.1 (37, 86) 58.9 (40, 92) 0.001 Minimum, maximum 7.5, 1235 0.5, 3741 Log-transformed mean (SD) 4.1 (0.70) 4.2 (0.75) Geometric mean 58.7 65.6 Statins, n 2602 659 11-Dehydro thromboxane B 2 , ng/mmol creatinine Median (Q1, Q3) 55.5 (39, 86) 69.7 (46, 122) <0.001 Minimum, maximum 0.5, 3741 8.1, 1455 Log-transformed mean (SD) 4.1 (0.71) 4.4 (0.83) Geometric mean 60.3 80.1 Q indicates quartile.

21. ASA Dose P <100 mg/d 100–149 mg/d 150 mg/d No. of subjects 2018 765 475 11-Dehydro thromboxane B 2 , ng/mmol creatinine Median (Q1, Q3) 58.7 (40, 92) 59.8 (42, 93) 50.3 (36, 80) <0.001 Minimum, maximum 0.5, 3509 2.8, 3741 12.5, 694 Log-transformed mean (SD) 4.2 (0.75) 4.2 (0.75) 4.0 (0.66) Geometric mean 64.8 66.5 56.2 Q indicates quartile.

22. 11-Dehydro Thromboxane B 2 Stroke, MI, or CV Death (n=144) No Stroke, MI, or CV Death (n=3117) Median (Q1, Q3) 72.7 (41, 135) 57.4 (40, 90) Minimum, maximum 12, 1235 0.5, 3741 Log-transformed mean (SD) 4.4 (0.96) 4.1 (0.73) Geometric mean 84.1 63.1 CV indicates cardiovascular; Q, quartile.

24. Baseline Characteristic OR 95% CI Concomitant statin use 0.72 0.61–0.87 Hypercholesterolemia 0.74 0.63–0.88 Concomitant NSAID use 0.78 0.67–0.90 Average ASA dose (per 50 mg/d) until urine sample collected 0.78 0.71–0.87 Age, in 10-year increments 1.19 1.11–1.27 Concomitant ACE inhibitor use 1.22 1.07–1.38 Concomitant use of oral hypoglycemic drugs 1.42 1.24–1.62 Female sex 1.48 1.29–1.71 Peripheral artery angioplasty or bypass surgery 1.67 1.36–2.06 Current smoker 2.02 1.72–2.38 *Model includes age, sex, body mass index, current smoking, hypertension, hypercholesterolemia, diabetes, past history of MI, stroke, transient ischemic attack, peripheral artery disease, percutaneous coronary intervention, CABG surgery, endarterectomy, peripheral angioplasty/bypass, ASA dose groups, study clopidogrel, NSAIDs, statins, β- blockers, diuretics, calcium channel blockers, ACE inhibitors (ramipril or other), other blood pressure-lowering agents, oral hypoglycemic agents, and insulin. C statistic for overall model=0.62.