Clinical trials at the ESC

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Christopher Cannon MDCardiologistBrigham and Women’s HospitalBoston, Massachusetts

James Ferguson MDAssociate Director CardiologySt Luke's Episcopal Hospital and Texas Heart InstituteHouston, Texas

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, 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 FusterDirector, Cardiovascular InstituteMount Sinai Medical CenterNew 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

endpoint sirolimus control p value

late loss (mm) –0.01 0.330.8 0.53 <0.0001

restenosis (%) 0% 26% <0.0001

no MACE (%) 96.7% 72.9% <0.0001

Comparison of sirolimus-coated and untreated stents

Trials at the ESC

RAVEL results

Trials at the ESC

RAVEL: a revolutionWhat 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: restenosisDo 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 FergusonAssociate Director CardiologyTexas Heart InstituteHouston, 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;99:2164-2170

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-AspirinReInfarction 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

endpointaspirin 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

aspirinalone

(% per year)

warfarinalone

(% per year)

aspirin+ warfarin

(% per year)

major 7(0.15%)

28(0.58%)

25(0.52%)

minor 39(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

17 073 AMI patients

randomized to unfractionated heparin or bivalirudin, given 3 minutes before streptokinase administration

Trials at the ESC

HERO-2 design

endpoint bivalirudin heparin p value

30-day unadjusted mortality

10.8% 10.9% 0.876

30-day mortality/MI*

12.6% 13.6% 0.067

30-day reinfarction*

2.8% 3.6% 0.004

96-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;358:605-613

Valentin FusterDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Trials at the ESC

ASSENT-3 designn=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

enoxaparin abciximab heparin p 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 CannonCardiologist Brigham and Women’s HospitalBoston, 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;357:1905-1914

Trials at the ESC

GUSTO V: results

efficacy endpoints*reteplase (n=8260)

combination (n=8328) OR

p value

death at 30 days 5.9% 5.6% 0.95 0.43

death/nonfatal disabling stroke

6.2% 5.9% 0.94 0.36

death/nonfatal reinfarction

8.8% 7.4% 0.83 0.001

PCI 27.9% 25.4% 0.88 0.0001

death/reinfarction/urgent PCI

20.6% 16.2% 0.75 0.0001

*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 CannonCardiologist Brigham and Women’s HospitalBoston, 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 FergusonAssociate Director CardiologyTexas Heart InstituteHouston, 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 FusterDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York