The DES controversy and DREAM

1. The DES controversy and DREAM Eric J Topol MDProfessor of GeneticsCase Western Reserve University Cleveland, OH Robert M Califf MDProfessor of MedicineAssociate Vice Chancellor for Clinical ResearchDirector, Duke Clinical Research InstituteDuke University Medical CenterDurham, NC

2. Evolution of stent technology • Two problems with angioplasty technology • Abrupt thrombosis at the time of the procedure • Restenosis • Better anticoagulation and the advent of bare-metal stents helped resolve both problems • Bare-metal stents reduced symptomatic restenosis by 50% to 75% Califf

3. Drug-eluting stents • Regulatory approval and marketing of drug-eluting stents were based on short-term trials with a straightforward population that excluded more difficult PCI patients • The evidence was overwhelming • No effect on risk of death or nonfatal MI in the 6- to 12-month timeframe • Additional 70% reduction in restenosis • Two main types of drug-eluting stents • Sirolimus-eluting (Cypher) stents • Paclitaxel-eluting (Taxus) stents Califf

4. Fantastic data . . . on the surface • The data looked fantastic • "Who wouldn't want to sign up for one?" • Renu Virmani (Cardiovascular Pathology, Gaithersburg, MD) predicted that there would be a catastrophic problem with the failure to cover the stent with endothelium in a certain percentage of cases • Fairly early on there were publications of small series or case reports of late thrombosis • But the evidence seemed to indicate that it was not much of a problem Califf

5. PREMIER Registry • Funded by a company developing a drug to treat angina • People who prematurely stopped clopidogrel had a ninefold increase in the risk of stent thrombosis • All acute-coronary-syndrome patients • Much higher-risk patients than those studied in clinical trials Califf Spertus JA, et al. Circulation 2006; 113(24):2803-2809.

6. BASKET-LATE • Swiss government–run trial • Results were "very concerning, almost frightening" • After everyone had stopped taking clopidogrel, there was a significant increase in death and MI in patients randomized to drug-eluting stents vs those randomized to bare-metal stents Califf Pfisterer ME. American College of Cardiology Annual Scientific Session 2006; March 14, 2006; Atlanta GA.

7. Signals from Barcelona • The possibility that there is a relatively linear but consistent-over-time incremental risk with drug-eluting stents compared with bare-metal stents • The additive effect over two to five years might be highly significant, both clinically and statistically • None of the studies were definitive, but they all point in the same direction • Dr Salim Yusuf concluded that if we stop putting stents in people who don't need them, this would not be much of a problem Califf

8. SIRTAX • Examining rates of early and late stent thrombosis • More than 8000 patients • By three years, the rate of stent thrombosis with drug-eluting stents was almost 3% Topol Wenaweser P. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Presentation 1012.

9. RAVEL: Five-year follow-up • Pristine from the standpoint of restenosis • More death with the Cypher stent than with the bare-metal stent: 11.1% vs 7% • Not statistically significant, but unexpected Topol RAVEL: SerruysPW. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain.

10. Meta-analysis • A significant excess of late thrombosis with Cypher stents vs bare-metal stents: 6.3% vs 3.9% • Results are consistent with predictions from BASKET • "I think it's a pretty significant concern" Topol Camenzind E. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Hotline I.

11. Courses of action • What advice would you give to a patient who shows up in the cardiologist's office? Califf

12. Not time to panic • Late thrombosis a very-low-frequency event • We don't know about the long-term safety of drug-eluting stents in some individuals • We can't predict who is going to have a late clotting risk • Some patients never endothelialize the strut of the stent because the drug is so effective • Some patients have a propensity for thrombosis • Tell patients that there is a small risk over extended follow-up Topol

13. Restenosis: A trade-off • The trade-off: the low risk of stent clotting and fatality vs the chance of having a repeat procedure • Risk of a repeat procedure is higher with a bare-metal stent • Restenosis is generally viewed as benign; this might not be entirely true • We don't have good data from large, multiyear, randomized trials comparing bare-metal and drug-eluting stents Topol

14. Genomics? • Weren't you arguing just last year that we could do small trials with genomics and not have to do large trials? Califf

15. Genomics: The way of the future • If we had DNA for patients who had stent thrombosis and for suitable controls, we could identify the genes involved • Stent thrombosis doesn't appear to be a mechanical issue (eg, stent apposition) • Patients are either not endothelializing well or are prone to thrombosis • Eventually, genomics will allow us to get a handle on the problem, but we haven't even started this work yet Topol

16. Clopidogrel or not clopidogrel? • With drug-eluting stents, people are potentially committed to dual antiplatelet therapy for the rest of their lives • The risk of bleeding • The expense • The possibility of having to stop clopidogrel because of events such as significant dental work, orthopedic procedures, other surgical procedures • There are anecdotes of patients developing stent thrombosis days after stopping dual antiplatelet treatment Topol

17. Practical advice • If you get a drug-eluting stent, stay on clopidogrel until this is sorted out • If you have a patient you don't think can stay on clopidogrel, try not to use a drug-eluting stent Califf

18. Weighing the risk • Bare-metal stents are preferable for the following people: • Those who don't take medication reliably • Those who have issues with the cost • Those who might require another significant procedure • Until we have data from large, real-world, multiyear trials, we must weigh the risk of restenosis and its complications against the risk of late thrombosis Topol

19. FDA reform • The Future of Drug Safety: Promoting and Protecting the Health of the Public • A report on postmarketing FDA issues published by the Institute of Medicine (IOM) Califf

20. Hard-hitting report • A 255-page report that really slammed the FDA • The recommendations are extraordinary • The IOM got paid $3 million to do it • "I think the FDA would rather get its money back." • It takes on problems with drug-safety leadership Topol

21. FDA takes action • The problem with drug-eluting stents is a postmarketing issue • There were grounds for their approval • The need for monitoring and proper clinical trials is addressed in the report • The FDA is convening a special panel to review this issue before year-end Topol

22. The genie's out of the bottle • Drug-eluting stents have been on the market for a number of years • They're used in 90% or more of stent procedures in the US • Boston Scientific announced today that the use of drug-eluting stents has diminished in recent weeks • "It may be that the interventional community is a little spooked about this late thrombosis thing." Topol

23. First responders • "I'd have to say the interventional community is one of the most sensitive on earth to clinical-trial findings and clinical-research statements" • In some other fields, it takes 15 years to integrate results into clinical practice Califf

24. News travels • There wasn't a very good showing of interventional cardiologists from the US at the meetings in Barcelona • But it did seem to be the story that was highlighted Topol

25. Too many PCIs? • Salim Yusuf's research group (McMaster University, Hamilton ON) continues to turn out trials that are interesting and worthwhile • I don't think we are doing too many PCIs, although we might be doing them in the wrong people • "I think it's a procedure that has a lot of benefit." Califf

26. Attitudes in the US • In the interventional world, no one is allowed to have ischemia, even if they're asymptomatic • Yusuf believes that stable angina with occasional angina or even a stress-induced functional test is acceptable • As long as there has been balloon angioplasty, the attitude has been to stamp out all ischemia • Is there a financial incentive to do this? Topol

27. Financial incentive • As long as PCI is rewarded above other activities, people are going to do it when it's a toss-up • In this country, the big money's in imaging, it's not in PCI anymore • I don't think it's the only factor, but it is part of the culture • When you hear there's a blockage and you can open it up, it feels like a good thing Califf

28. The debate continues • Drug-eluting stents became commonplace because they got rid of the reoccurrence of blockages • "It's a very blockage-centric world we live in in the US." • There are no data to show that PCI in stable angina benefits patients, but they do show that it is beneficial in ischemia • Echo and nuclear imaging are going to be emphasized with the CT angiography that's popular now Topol

29. Worth watching • The FDA hearing will be something worth watching as it goes through these data • People should look at the FDA reform report Califf

30. The search for a cure for "diabesity" • People are gaining weight and developing diabetes at relatively young ages and suffering the consequences thereof • The pharmaceutical industry has been searching for drugs to prevent the development of diabetes in people who are at risk Califf

31. DPP trial • The Diabetes Prevention Program (DPP) trial • Looking at whether either diet and exercise or the oral diabetes drug metformin (Glucophage) prevent or delay the onset of type 2 diabetes in people with impaired glucose tolerance • Results • An intensive exercise and diet regimen reduces the time to onset of diabetes diabetes by 60% to 70% Califf

32. ACE inhibitors reduce diabetes • In populations studied for other reasons, ACE inhibitors have been shown to reduce the frequency of diabetes • These studies weren't looking specifically at the diabetes end point in a rigorous fashion Califf

33. Another class of drug • Thiazolidinediones • Affect the PPAR system (nuclear-receptor hormones) • Are widely used without any real outcome data on their effect, other than lowering blood sugar • Triglitazone showed a dramatic reduction in time to onset of diabetes • Unfortunately, it caused liver damage Califf

34. The DREAM trial • Factorial randomized design • 1/4 got rosiglitazone • 1/4 got ramipril • 1/4 got both rosiglitazone and ramipril • 1/4 got placebo • Patients had impaired fasting glucose levels or impaired glucose tolerance but no diabetes • The population was relatively young and at low risk for cardiovascular events • DREAM was powered to show a reduction in the onset of diabetes Califf

35. DREAM: The ramipril arm • Reduction (about 1%) in onset of diabetes was not statistically significant • Fasting glucose levels and the proportion of patients who returned to normal glucose tolerance significantly favored ramipril • No significant differences in clinical events • Absolutely no difference for the first couple of years, then the curves began to separate but didn't reach significance • It could be argued that this was a delayed effect Califf DREAM trial investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355.

36. DREAM: The rosiglitazone arm • Results with rosiglitazone • A 60% reduction in the onset of diabetes • Lower blood pressure • A 2.4-kg increase in weight • An increase in heart failure • A trend toward an increase in vascular events Califf DREAM trial investigators. Effect of rosiglitazone on the frequency of diabetes In patients with impaired glucose tolerance or impaired fasting glucose: A Randomised controlled trial. Lancet 2006.

37. A conundrum • ACE inhibitors work but have a much smaller effect than expected • Thiazolidinediones clearly reduce diabetes but have an uncertain negative trend in terms of vascular events Califf

38. Why didn't ramipril work? • The ramipril results were really surprising • Ramipril worked well in the HOPE trial • Other trials of ACE inhibitors showed a pretty consistent reduction in the incidence of diabetes • Of course, the DREAM patients didn't have cardiovascular disease Topol

39. DREAM population • The DREAM patients were younger than the HOPE population and not as sick • Ramipril did work in the sense that glucose levels were lower, it was just a very weak effect Califf

40. Very weak results • For primary outcomes over the 3.5 years, the event curves (combined end point of diabetes and death) are totally superimposable • Are you impressed that there was a consistent reduction in the incidence of diabetes with ACE inhibitors in older patients with cardiovascular disease? Topol

41. More practical advice • "It's likely that that's true, but there's no way to know for sure." • I wouldn't prescribe ramipril just to prevent diabetes, but if I had a reason to give an antihypertensive medicine to someone in a prediabetic state, "it would be a minor additional factor to make me lean in that direction." Califf

42. Surprising results • The fact that rosiglitazone was effective for the combined end point (diabetes and death) was a surprise • I knew that there would likely be some increase in heart failure, as has been seen with the other glitazones, but I didn't expect it to be as marked Topol

43. Drugs doing what they should • "I thought that this would work." • These drugs were designed to treat diabetes, so it would be shocking if there wasn't a reduction Califf

44. No benefit • For the clinical outcomes, when mortality was compared with the new incidence of confirmed heart failure, there was no benefit Topol

45. The heart-failure issue • There is likely harm from the thiazolidinediones that comes from fluid retention and a proinflammatory state in some patients • We've known about the heart-failure issue for a long time Califf

46. Why two papers? • Rosiglitazone might even be somewhat worse than PYA or other agents in this class • Why were these results not incorporated into one paper? Topol

47. Two for one • I presume that one of the advantages of a factorial design is you get two trials for the price of one Califf

48. Two thumbs up • This trial asked a legitimate question • "The results are disappointing in that it doesn't really change my view of prescribing ramipril." • It's a great drug for hypertension and LV dysfunction • Ramipril probably somewhat reduced coronary-disease events, but I wouldn't prescribe it just to prevent diabetes • Rosiglitazone does show that if you have a drug that's highly effective, you might make a dent in the long-term issue of diabetes Califf

49. Is it worth the trade-off? • The adverse effects weren't significant, but they weren't far from being significant • By inhibiting the development of diabetes, you invite other adverse outcomes Topol

50. Needed data on its way • Until we have more outcome data, we should not be prescribing thiazolidinediones to prevent diabetes • The good news is that there are several major cardiovascular trials under way that will provide answers Califf