Clinical Trial Commentary

1. Clinical Trial Commentary CURE Dr Eric Topol Provost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

2. CURE: A positive trial CURE • Trial in acute coronary syndromes (ACS): • Would adding clopidogrel to aspirin provided a clinical benefit? • Simple trial design: • Patients with active ACS (though not necessarily with positive troponin or ST-segment depression) received either 40 mg of clopidogrel or placebo, in addition to aspirin. • Variation in aspirin dosage: • Ranged between 75-325 mg.

3. Study design CURE • Major outcome: • Occurrence of death or nonfatal MI. • End point: • Median stopping point of 9 months (patients were followed from 3 to 12 months).

4. Findings CURE • Event rates between trial groups began to diverge from the first day. • Highly statistically significant (20%) reduction in deaths and nonfatal MIs. • Reductions in: need for revascularization; recurrent unstable angina. • Small increase in bleeding.

5. Other aspects of trial CURE • Despite emphasis on conservative approach in treating patients: • One third of study patients had revascularization procedures. • (All patients undergoing percutaneous intervention were switched to active clopidogrel) • CURE showed a significant benefit in the population being studied, and will probably have a major impact on clinical practice. • Califf

6. Major endpoints Main efficacy results CURE Aspirin + clopidogrel (n=6259) • Relative risk • p value • Endpoint • Aspirin (n=6303) • CV death, MI, stroke (primary endpoint) 11.47% 9.28% 0.80 0.00005 • 5.06% • N/A CV death 5.4% 0.92 5.19% 0.77 <0.001 • MI • 6.68% Stroke 1.4% 1.2% 0.85 N/A Non-CV death 0.70% 0.67% 0.96 N/A

7. Bleeding results CURE Bleeding risks Aspirin + clopidogrel (n=6259) • Relative risk • p value • Endpoint • Aspirin (n=6303) • Major bleeding 2.7% 3.6% 1.34 0.003 • 2.1% Life-threatening bleeding • N/A 1.8% 1.15 15.3% 1.78 <0.001 • Minor bleeding • 8.6% Transfusions 2.2% 2.8% 1.28 0.03

8. Points of contention CURE • No significant reductions in deaths or stroke. • Major bleeding rates and consequences thereof with clopidogrel were underestimated. • MI somewhat loosely defined in study (any change in CK-MB, troponin, or ECG). • Topol

9. The right trends CURE • Study was designed to examine an addition to an already-proven treatment regimen. • Virtually all other endpoints – not just MI – showed clopidogrel was effective to some degree. • Even a minor reduction in fatalities is noteworthy for a simple treatment. • Califf

10. Bleeding CURE • Blood transfusions in major bleeding cases are more worrisome than the bleeding itself. • Increase in bleeding in the clopidogrel group was not as great as had been expected, considering the increased antiplatelet effect. • Califf

11. Recurrent ischemia CURE • Recurrent ischemia rates between the two groups diverged in the first few hours; MI rates diverged in the first few days. • Results indicate that in the first 24-48 hours post-MI, a more potent therapy would be worthwhile. • Califf

12. MI definition in CURE CURE • CURE largely conducted in sites that favored non-aggressive therapies. • Patients were less likely to be monitored for enzyme and ECG changes than in typical US hospitals. • Events recorded as an MI in the study would likely be considered an MI in clinical practice. • Califf

13. Extrapolation to US practice CURE • Only 4% of patients in CURE were in US hospitals; the majority were in hospitals abroad, which favor non-aggressive therapies. • The results may not be transferrable to US hospitals, which typically favor aggressive therapies. • If clopidogrel is used in the ER, surgeons may be reluctant to perform on these patients immediately. • Topol

14. A conservative approach CURE • “I think if there is a soft underbelly to this study it’s that it used an approach to practice which is probably not the direction that the clinical world is going. That is, a very conservative approach.” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

15. Bleeding in the OR CURE • Past worries about excess bleeding in the OR due to antiplatelet therapies (eg aspirin, amiodarone) have proven to be exaggerated. • Califf

16. Excess bleeding concerns CURE • “Some surgeons at least, I can say the ones at the Cleveland Clinic, they want to cancel the surgery if the patient has had clopidogrel, and wait for at least 5-7 days. Now they may be going against the grain, compared to the surgeons throughout the US, but there are at least some bad experiences out there.” • Dr Eric Topol • Provost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic

17. Dual therapy CURE • “I do think it’s incumbent on the CURE investigators to produce the data about the subset of patients, no matter how small they may be, who had surgery on dual antiplatelet therapy. I don’t want to appear totally nonchalant about this; I do think it needs to be looked at […].” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

18. Excess bleeding concerns CURE • There is no way to fix the platelet issue acutely. • Physicians concerned about bleeding should wait until it is confirmed the patient won’t have emergency surgery to administer clopidogrel. • Topol

19. Cost of using clopidogrel CURE • $3 per day in the US • Given the age of the at-risk population and the lack of a Medicare drug benefit, cost will be burden on doctors and patients • Califf

20. Long term cost CURE • Advantages over ticlopidine • Once-daily dosing • Relative absence of TTP or neutropenia • Faster onset of action • Cost is 25% less • Now that the indication has moved beyond stent use to a long-term application, cost has become a significant issue. • Topol

21. Formal cost-effectiveness CURE • Haven’t yet seen formal cost-effectiveness from CURE, but they will be forthcoming. • By preventing major cardiovascular events, it should fit into benchmarks for cost-effectiveness although it will add to the overall pharmaceutical cost burden to society. • Topol

22. Individual cost burden CURE • The burden to society may be cost-neutral. • The problem will be to the individual, with no coverage to pay for these drugs, they may be too much for the elderly patient with no income outside social security. • Califf

23. Pharmacogenomics CURE • “When you think about it, we’re helping 2-3 patients per 100, 97-98 patients don’t derive the benefit. There has got to be a way, over the years ahead, to unravel this by knowing the genotypic basis of the benefit.” 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

24. Complexity CURE • “I am a little less optimistic about this than you are.” • These are complex pathways with multiple positive and negative effects. It won’t be that easy to determine what the effects of adding a pharmacological agent is. • Califf

25. Finding the responders CURE • “My hope is that we won’t have to give 5 or 6 or 7 drugs to every patient with common diseases some day.” • Dr Eric Topol • Provost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic

26. Gene-based drug trials CURE • The pharmaceutical industry doesn’t want to conduct them, they want everyone taking all the drugs. • The sample sizes might not be unmanageable, we don’t know yet how to do these trials. • We need disinterested parties to fund these trials. • Topol

27. Extrapolating to high risk patients CURE • Should clopidogrel be used past the strict lines of the CURE results? • 3 of my patients out of 12 in my clinic elected to take clopidogrel after hearing the data, risks, and costs despite being 1 year out from their events. • Given that the curves continue to diverge after 9 months, it is reasonable to use it as long as the patient is informed. • Califf

28. Extending CURE CURE • Extrapolation makes sense, but it must be decided on an individual patient basis. • Topol

29. Failure of oral GP IIb/IIIa CURE • In retrospect, we have learned that Oral GP IIb/IIIa have a paradoxical, pro-inflammatory effect. (p-selectin goes up, CD-40 ligand release, etc) • In hindsight, it may be that oral GP IIb/IIIa has a pro-inflammatory dark side. • Topol

30. CURE trial review CURE • Dr Robert Califf • Two thumbs up

31. CURE trial review CURE • Dr Eric Topol • Two thumbs up