1. PPP and Complement Inhibition Clinical Trial Commentary Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

2. Where we are now PPP Aspirin has been shown to be quite effective in secondary prevention, but there has been significant controversy about primary prevention Physicians’ Health Study – stopped early, substantial reduction in non-fatal MI but an excess of hemorrhagic strokes (non- significant trend) British study – did not show dramatic difference in primary prevention

3. Primary Prevention Project Innovative approach: recruiting from daily practice Open 22 factorial design in 4495 people with one or more major cardiovascular risk factor (hypertension, hypercholesterolemia, diabetes, obesity, family history of premature myocardial infarction, or old age) but no prior events or symptomatic angina The PPP trial evaluated low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in a randomized, non-blinded study PPP

4. Results PPP Aspirin (n=2226) No aspirin (n=2269) Relative risk (95% CI) Total cardiovascular events 6.3%8.2%0.77 (0.62–0.95) Total mortality2.8%3.4%0.81 (0.58-1.13) Cardiovascular mortality 0.8%1.4%0.56 (0.31–0.99) All stroke0.7%1.1%0.67 (0.36–1.27) Roncaglioni et al. Lancet 2001; 357:89-95

5. Design “The ability to inexpensively randomize a large number of patients and get a result that’s this dramatic not only is an important finding for clinical practice, but also, I think, points the way to a system that we might use to more rapidly evaluate the effectiveness of simple interventions in primary care practice.” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University PPP

6. Issues with the trial Primary endpoint not significant CV death, non-fatal MI, non-fatal stroke Relative risk = 0.71 (0.48–1.04) Trial stopped early enrolled 4495 instead of the projected 7500 patients owing to the results of other trials that may not be germane PPP

7. Choice of endpoint Does total mortality trump a primary endpoint? Should you pull out cardiovascular mortality? Do partial studies weaken the implications of secondary endpoints? PPP

8. Available dose 100-mg dose isn’t available in the US Effectiveness of 80-mg dose seems to have been corroborated by several studies Hypertension may be a contraindication for aspirin use (Hypertension Optimal Treatment trial) PPP

9. Optimal dose The optimal dose remains unresolved Currently anywhere from 80 mg to 325 mg has been validated in one way or another Correct dose of aspirin could be more effective for developing countries than the latest drug A simple dose-comparison study is being proposed PPP

10. Conclusions Califf PPP and HOT push him to recommend aspirin as primary prevention Topol Aspirin shows implications in many diseases other than cardiology This is convincing, but would be more convincing if the trial had gone to completion PPP

11. Pexelizumab (Alexion/Procter & Gamble): An anti-inflammatory C5 inhibitor monoclonal antibody fragment 914 patients scheduled for CABG surgery, or CABG plus valve replacement enrolled, randomized to: placebo pexelizumab in a 2.0 mg/kg bolus pexelizumab in a 2.0 mg/kg bolus followed by a 24-hour infusion of pexelizumab at 0.05 mg/kg/h Complement inhibition Pexelizumab study

12. Results 30-day safety and efficacy follow-up Results only available from a press release CABG-only group (n=796)PexelizumabPlacebo Death0.4%1.9% Non-Q-wave MI (CK-MB >100 ng/mL) 2.7%8.0% Death or MI (non-Q-wave or Q-wave) 7.8%13.2% Complement inhibition Press release, Jan 26, 2001: Alexion Pharmaceuticals, Inc.

13. Perioperative MI An area that has not been sufficiently studied C5 inhibition may reduce perioperative MI The mechanism is still unclear Will it be verified? What were the changing definitions of MI? Complement inhibition

14. “I think it is important for cardiologists to be aware that there’s tremendous activity right now on the issue of preventing necrosis in the setting of bypass surgery, [because] the complexity of the operation and the morbidity is still quite high. This is despite clear improvements in the technology and the skill of the surgeons and the operating teams. But they’re just operating on very high-risk patients as we all know. So there’s a real niche for this type of therapy if it really works.” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University Complement inhibition Preventing necrosis

15. Defining myocardial necrosis Cardioplegia makes EKGs very unreliable because the majority of patients have some elevation of markers of necrosis Where do you define the threshold? How much necrosis do you need to prevent? CARDINAL trials: direct angioplasty and thrombolysis, should add to the picture There are multiple methods of inhibiting complement that are under investigation Complement inhibition

16. Future of CABG Bypass has been neglected for development of therapeutics and adjunctive medications The dangers of periprocedural MI during CABG need to be examined, it isn’t revered enough We may see a resurgence of CABG as technology allows for less severe patients to be operated on Complement inhibition

17. Cognitive decline Percentage of patients who suffered a decline of 20% or more in cognitive function from pre-CABG baseline Complement inhibition Time framePatients suffering decline Discharge53% 6 weeks36% 6 months24% 5 years42% Newman M, et. al. N Engl J Med 2001; 344(6):395-402

18. Cognitive decline questions Is this all related to bypass surgery, or is it associated with severe athereosclerosis? How much is due to the bypass machine? Does off-pump surgery prevent cognitive decline? Does complement inhibition help? What genetic markers may indicate risk? Complement inhibition