Do Bolus Thrombolytics Carry a Higher Risk of Intracranial Hemorrhages

1
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 Womens 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

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

3
RAVEL
Trials at the ESC

• 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 spectaculara revolution in
  the future of intervention.

Valentin FusterDirector, Cardiovascular
Institute Mount Sinai Medical Center New York,
New York
Morice M-C, et al. ESC 2001 abstract 2624
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RAVEL design
Trials at the ESC
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
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RAVEL results
Trials at the ESC
Comparison of sirolimus-coated and untreated
stents
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RAVEL a revolution
Trials at the ESC
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
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RAVEL restenosis
Trials at the ESC
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
biologybut 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
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RAVEL further study
Trials at the ESC

• 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.

James FergusonAssociate Director
CardiologyTexas Heart InstituteHouston, Texas
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RAVEL rapamycin
Trials at the ESC

• 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.

Fuster
Gallo R, et al. Circulation 1999992164-2170
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RAVEL radiation
Trials at the ESC

• 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

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RAVEL side effects
Trials at the ESC

• Decrease in white cells and platelets seen with
  rapamycin taken orally in renal transplantation.
  

Fuster
Thats the beauty about loading it onto a
stent. The question is, are there other creative
ways to deliver rapamycin into the vessel wall?
Ferguson
12
WARIS-II
Trials at the ESC

• Second Warfarin-AspirinReInfarction Study

Arnesen H, et al. ESC 2001
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WARIS-II design
Trials at the ESC

• 3630 MI patients randomized to either
• aspirin alone , 160 mg per day
• warfarin alone , target INR2.8 to 4.2
• aspirin 75 mg/day warfarin target INR 2.0 to
  2.5
• follow-up 4 years

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WARIS-II primary endpoint
Trials at the ESC
15
WARIS-II bleeding
Trials at the ESC
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WARIS-II better than aspirin
Trials at the ESC

• 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

We can do substantially better than aspirin
alone. Ferguson
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WARIS-II in practice
Trials at the ESC

• 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.

Cannon
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WARIS-II standard of care
Trials at the ESC

• 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

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HERO-2
Trials at the ESC

• Hirulog Early Reperfusion/Occlusion

White HD, et al. ESC 2001
20
HERO-2 design
Trials at the ESC

• 17 073 AMI patients
• randomized to unfractionated heparin or
  bivalirudin, given 3 minutes before streptokinase
  administration

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HERO-2 major efficacy results
Trials at the ESC
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HERO-2 mortality
Trials at the ESC

• Mortality in an MI trialis 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.

Ferguson
They actually turned out to have plenty of
power, given the sample size. The drug just
didnt reduce mortality. Its difficult to
reduce mortality early on. It is not just early
reperfusion, but a lot of other factors that
impact on mortality.
Cannon
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HERO-2 combined endpoint
Trials at the ESC

• 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

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HERO-2 antithrombins
Trials at the ESC

• 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.
  

I think that the drug was not properly
controlled.
Cannon
Fuster
25
ASSENT-3
Trials at the ESC

• ASsessment of the Safety and Efficacy of a New
  Thrombolytic
• Low-molecular-weight heparin worked extremely
  good vs heparin when added to enoxaparin.

Valentin FusterDirector, Cardiovascular
InstituteMount Sinai Medical CenterNew York,
New York
The ASSENT-3 Investigators. Lancet
2001358605-613
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ASSENT-3 design
Trials at the ESC

• n6095 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

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ASSENT-3 results
Trials at the ESC

• 30-day mortality/in-hospital reinfarction or
  refractory ischemia/in-hospital ICH or other
  major bleeds

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ASSENT-3 better therapy
Trials at the ESC
Confirms previous experience with low-molecular
weight heparins and thrombolytic therapy. The
short answer is that its a better form of
therapy than unfractionated heparin. Fergus
on
It really is a better form of
heparin. Cannon
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ASSENT-3 cath lab issues
Trials at the ESC
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.

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ASSENT-3 long-term use
Trials at the ESC
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
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ASSENT-3 prehospital treatment
Trials at the ESC
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
Womens HospitalBoston, Massachusetts
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GUSTO V
Trials at the ESC

• 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

Topol EJ, et al. Lancet 20013571905-1914
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GUSTO V results
Trials at the ESC

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

• 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

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MI scenario
Trials at the ESC

• 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
Womens HospitalBoston, Massachusetts
37
MI scenario
Trials at the ESC

• 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

James FergusonAssociate Director
CardiologyTexas Heart InstituteHouston, Texas
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Conclusion
Trials at the ESC

• 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