Clinical trials at the ESC Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher Cannon MD Cardiologist Brigham and Women’s Hospital Boston, Massachusetts James Ferguson MD Associate Director Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, Texas Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, New York

Trials at the ESC RAVEL WARIS II HERO-2 ASSENT 3 GUSTO V Studies

RAndomized, double-blind sirolimus (Rapamune)-eluting Bx VELocity balloon- expandable stent in the treatment of patients with de novo native coronary lesions “These results are spectacular… a revolution in the future of intervention.” Trials at the ESC RAVEL Morice M-C, et al. ESC 2001 [abstract 2624] Valentin Fuster Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York

Trials at the ESC RAVEL design 120 patients randomized to a sirolimus- coated stent 118 patients randomized to a bare, uncoated stent follow-up: 6 months common antithrombotic therapy used in all patients

group endpointsirolimuscontrolp value late loss (mm) –0.01   0.53 < restenosis (%)0%26%< no MACE (%)96.7%72.9%< Comparison of sirolimus-coated and untreated stents Trials at the ESC RAVEL results

Trials at the ESC RAVEL: a revolution What do you think of the spectacular outcome? It changes everything. We will have to revisit our approach to every aspect of coronary artery disease management. In terms of how to manage multivessel disease, now that stents may have no restenosis, could this tilt in favor of PCI vs CABG? Cannon

Trials at the ESC RAVEL: restenosis Do we still need to look at trials exploring other therapies to prevent restenosis? Trial has to be put in perspective. Only 238 patients were enrolled. The therapy shows significant improvement in restenosis in a preliminary study. “This is really a victory for vascular biology…but I honestly would be a little bit surprised that, if we continue to follow those people out, that the incidence of restenosis is still honestly and truly zero.” Ferguson

SIRIUS, a large-scale US trial, has just completed enrollment and is now entering the angiographic follow-up phase “We will have the opportunity to corroborate the very exciting RAVEL results with larger numbers of patients.” Trials at the ESC RAVEL: further study James Ferguson Associate Director Cardiology Texas Heart Institute Houston, Texas

How long does the rapamycin work for? It works very rapidly and does not have a long half-life The lesion created with angioplasty is covered by endothelium after 3 weeks, despite the rapamycin. Trials at the ESC RAVEL: rapamycin Gallo R, et al. Circulation 1999;99: Fuster

Will radiation be less important in the near future? Radiation is directed at instent restenosis. “If the problem of instent restenosis goes away, then radiation goes away.” Radiation is an interesting delivery technique to modify the biology of the vessel wall, but it is cumbersome and difficult. “I think that radiation will probably have a shelf life of about 2-3 years before we find a better technique, or before we find out whether rapamycin is the drug we need to be using.” Ferguson Trials at the ESC RAVEL: radiation

Decrease in white cells and platelets seen with rapamycin taken orally in renal transplantation. Trials at the ESC RAVEL: side effects “That’s the beauty about loading it onto a stent.” The question is, are there other creative ways to deliver rapamycin into the vessel wall? Fuster Ferguson

Second Warfarin-Aspirin ReInfarction Study Trials at the ESC WARIS-II Arnesen H, et al. ESC 2001

3630 MI patients randomized to either  aspirin alone, 160 mg per day  warfarin alone, target INR 2.8 to 4.2  aspirin 75 mg/day + warfarin target INR 2.0 to 2.5 follow-up: 4 years Trials at the ESC WARIS-II design

Trials at the ESC WARIS-II : primary endpoint endpoint aspirin alone warfarin alone aspirin+ warfarin death, nonfatal recurrent MI, TE stroke 241 (20.0%) 203 (16.7%) 181 (15.0%)

Trials at the ESC WARIS-II: bleeding bleeding endpoint aspirin alone (% per year) warfarin alone (% per year) aspirin+ warfarin (% per year) major7 (0.15%) 28 (0.58%) 25 (0.52%) minor39 (0.81%) 105 (2.16%) 133 (2.75%)

“It looks like combining either clopidogrel or warfarin is better than aspirin alone. When we think about secondary prevention, we really have to start thinking about more than just aspirin.” Cannon Trials at the ESC WARIS-II: better than aspirin “We can do substantially better than aspirin alone.” Ferguson

In terms of practical fallout, this seems to be a very good strategy, but the actual use and implementation of warfarin is more complicated. Clopidogrel, as well as warfarin, will be the message for 2001, setting the stage for other anticoagulant therapies for long-term secondary prevention. Trials at the ESC WARIS-II: in practice Cannon

Should aspirin plus clopidogrel or Coumadin become a standard of care? “The message for me is that, particularly in high- risk individuals, I would add something above and beyond aspirin therapy.” Coumadin data are substantial, but they need to be broken out by the individual endpoints, Clopidogrel data suggests benefit to long-term therapy, but more follow-up needed. Ferguson Trials at the ESC WARIS-II: standard of care

Hirulog Early Reperfusion/Occlusion Trials at the ESC HERO-2 White HD, et al. ESC 2001

AMI patients randomized to unfractionated heparin or bivalirudin, given 3 minutes before streptokinase administration Trials at the ESC HERO-2 design

endpointbivalirudinheparinp value 30-day unadjusted mortality 10.8%10.9% day mortality/MI* 12.6%13.6% day reinfarction* 2.8%3.6% hour reinfarction* 1.6%2.3%<0.001 *adjudicated Trials at the ESC HERO-2: major efficacy results

“Mortality in an MI trial…is ambitious, with mortality rates continuously improving.” Unless you are just doing mortality trials in areas that have high mortality you have a problem of statistical power. Trials at the ESC HERO-2: mortality “They actually turned out to have plenty of power, given the sample size. The drug just didn’t reduce mortality.” It’s difficult to reduce mortality early on. It is not just early reperfusion, but a lot of other factors that impact on mortality. Ferguson Cannon

Recent heart failure trials, for instance Val-HeFT, needed to go to a composite endpoint to find interesting developments with the treatment. New post-MI studies being planned are also looking at reinfarction and new onset congestive heart failure. Weber Trials at the ESC HERO-2: combined endpoint

Are the antithrombins going to take off? There are a lot of other things that reduce reinfarction, for instance, LMWH is an inexpensive version of anticoagulation. “One has to balance this vs the other things that are out there.” Bleeding and stroke rates were disappointing in this trial, in contrast to previous studies. Trials at the ESC HERO-2: antithrombins “I think that the drug was not properly controlled.” Cannon Fuster

ASsessment of the Safety and Efficacy of a New Thrombolytic “Low-molecular-weight heparin worked extremely good vs heparin when added to enoxaparin.” Trials at the ESC ASSENT-3 The ASSENT-3 Investigators. Lancet 2001;358: Valentin Fuster Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York

Trials at the ESC ASSENT-3 design n=6095 patients within 6 hours of AMI onset randomized to  full-dose tenecteplase and enoxaparin every 12 hours up to 7 days  half-dose tenecteplase with low-dose unfractionated heparin infusion and a 12-hour infusion of abciximab  full-dose tenecteplase with unfractionated heparin infusion for 48 hours

30-day mortality/ in-hospital reinfarction or refractory ischemia/ in-hospital ICH or other major bleeds Trials at the ESC ASSENT-3 results enoxaparinabciximabheparinp value 13.8%14.2%17.0%0.0081

Trials at the ESC ASSENT-3: better therapy Confirms previous experience with low- molecular weight heparins and thrombolytic therapy. “The short answer is that it’s a better form of therapy than unfractionated heparin.” Ferguson “It really is a better form of heparin.” Cannon

Trials at the ESC ASSENT-3: cath lab issues The biggest thing holding everything back is the interface with the cath lab, in terms of how to manage heparinization during procedures. Cannon The 8000-patient SYNERGY trial will address this issue.

Trials at the ESC ASSENT-3: long-term use Can low-molecular-weight heparin be used as long-term post-MI treatment? Other unstable angina trials looking at prolonged administration have not shown benefit. “The whole issue of IIb/IIIa plus lytic may have to be revisited as we start using low- molecular-weight heparin instead of unfractionated heparin.” Ferguson

Trials at the ESC ASSENT-3: prehospital treatment Antithrombotic treatment could be started earlier. “By getting in early with a protocol in the ambulance you get the treatment when it can have the greatest benefit.” Christopher Cannon Cardiologist Brigham and Women’s Hospital Boston, Massachusetts

Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition Trials at the ESC GUSTO V Topol EJ, et al. Lancet 2001;357:

Trials at the ESC GUSTO V: results efficacy endpoints* reteplase (n=8260) combination (n=8328)OR p value death at 30 days5.9%5.6% death/ nonfatal disabling stroke 6.2%5.9% death/ nonfatal reinfarction 8.8%7.4% PCI27.9%25.4% death/reinfarction/ urgent PCI 20.6%16.2% *all nonfatal endpoints measured at 7 days.

Trials at the ESC GUSTO V vs ASSENT-3 Mortality in both trials would favor the abciximab plus half-dose lytic therapy if the researchers had taken a look further out. The trials are very similar in their outcomes. Antithrombotic and antiplatelet therapies keep vessels open. Weber Cannon Ferguson

How would you like to be treated if you arrived in the ER with an MI, and a cath lab was available? within 2 hours of symptom onset between 2 and 24 hours after 24 hours Trials at the ESC MI scenario

Trials at the ESC MI scenario within 2 hours  aspirin, clopidogrel, and IIb/IIIa inhibitors, and PCI 2 to 24 hours  taking one of the combinations of either TNK and enoxaparin, or half-dose TNK and abciximab, or reteplase and abciximab, and head to the cath lab early on after 24 hours  clopidogrel and aspirin as pre-PCI treatment Christopher Cannon Cardiologist Brigham and Women’s Hospital Boston, Massachusetts

within 2 hours  initiate therapy with a IIb/IIIa blocker, probably abciximab, and LMWH in the ER; bring patient forward to the cath lab; clopidogrel post-procedure between 2 and 24 hours  lytic agent plus low-molecular-weight heparin and aspirin; clopidogrel possibly not until discharge after 24 hours  bring patient forward to cath lab to define anatomy, low-molecular-weight heparin Trials at the ESC MI scenario James Ferguson Associate Director Cardiology Texas Heart Institute Houston, Texas

Trials at the ESC Conclusion “The field is becoming exciting, but at the same time complex. Regardless of what combination you are going to use… probably is going to do much better than what we had 5 years ago.” Valentin Fuster Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York