clinical trials at the esc valentin fuster md director, cardiovascular institute mount sinai medical...
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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
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
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
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