Clinical Trial Commentary

1
Clinical Trial Commentary
GUSTO V

• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic
• Dr Robert Califf
• Professor of Cardiology
• Associate Vice Chancellor for
• Clinical Research at Duke University

2
Study design
GUSTO V
Randomization
Standard-Dose Reteplase (10 10 U Double Bolus)
Abciximab Low-Dose Reteplase (5 5 U Double
Bolus)
Heparin 5000 U 1000 U/hr (800 U/hr for lt70 kg)
Heparin 60 U/kg (max 5000 U) 7 U/kg-hr
3
Endpoints
GUSTO V

• Primary
• mortality (all-cause) by 30 days
• Secondary
• mortality (30-day) or non-fatal disabling stroke
  (in-hospital or 7-day)
• hemorrhagic stroke (in-hospital or 7-day)
• mortality by 1 year
• reinfarction
• coronary revascularization
• other prespecified complications of MI

4
Statistical methods
GUSTO V
Superiority Testing one-sided Type I error lt
2.5 for control mortality rates ranging from 5 -
9. approximately 80 power to detect 15
reduction if control mortality rate
7.4 Non-Inferiority Testing less than 10
relative increase in mortality - upper bound of
95 CI for relative risk 1.10 one-sided Type I
error ranges from 2.051 - 2.627 for control
mortality rates ranging from 5 - 9
5
Primary endpoint
GUSTO V
Non-inferiority boundary
Upper bound of 95 confidence interval 1.076
6
Reinfarction
GUSTO V
7
Revascularization
GUSTO V
8
Non-fatal complications
GUSTO V

• It looked like, if one starts to consider the
  whole gestalt of non-fatal complications, that
  there was a very consistent and important
  reduction of these endpoints for the
  combination.
• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic

9
Bleeding
GUSTO V
Abciximab Reteplase Reteplase N 8260
N 8328 EENT () 0.1 0.6 Pulmonary
() 0.1 0.3 Cardiac () 0.1 0.1 Retroperitoneal
() 0.1 0.1 Genitourinary () 0.1 0.4 Sheath Site
() 0.7 0.4 Gastrointestinal () 0.4 1.9 Other
Puncture Site () 0.3 0.6 Surgical () 0.4 0.3
10
Doubts on non-inferiority
GUSTO V

• Accusation We just cooked up this
  non-inferiority thing, mortality reduction is all
  that counts.
• Califf
• Rebuttal The overall mortality was extremely
  low, and the improvement in the combination arm
  was flanked by other improvements.
• Topol

11
Beyond 30 days
GUSTO V

• We have to start getting beyond just life or
  death at 30 days. The SHOCK trial taught us
  a big lesson, that you don't always see the
  benefit of an aggressive strategy for cardiogenic
  shock at 30 days, in fact you see a lot more
  impact of this at 1 year. I think we may well
  see the same thing as far as 1 year mortality in
  GUSTO V.
• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic

12
An entirely new strategy
GUSTO V

• We did do what we had hypothesized we could do.
  Which is develop an entirely new strategy, not
  one that was red clot dissolving, to achieve a
  very impressive endpoint of mortality at 30 days,
  and beyond that.
• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic

13
Mortality results are biased?
GUSTO V

• Accusation The smart doctors just siphoned off
  the high-risk patients for direct angioplasty.
• Califf
• Rebuttal Many of the patients were outside the
  US, where cath-based reperfusion isn't the
  standard mode. But there doesn't seem to be a
  tendency towards low-risk patients in the trial.
• Topol

14
Final enrollment
GUSTO V
15
The wrong lytic?
GUSTO V

• Accusation Reteplase is a weak lytic and was a
  bad choice for the trial.
• Califf
• Rebuttal We have no head-to-head comparative
  data. Without the head-to-head it's too much
  speculation.
• Topol

16
Non-fatal MI questions
GUSTO V

• Accusation The non-fatal MI wasnt strictly
  defined and isn't useful. How can you have a big
  difference in MI but not mortality?
• Califf
• Rebuttal After mortality, death of heart tissue
  is the most important thing. These were major
  clinical events linked to other complications
  seen in the trial.
• That it was only day 7 and non-blinded data are
  legitimate critiques.
• Topol

17
CURE trial comparison
GUSTO V
GUSTO 5
CURE
Reteplase Aspirin Reteplase Abciximab RR
Aspirin Clopidogrel RR Death 5.9 5.6 0.95 5.5 5.1
0.92 MI 3.5 2.3 0.67 6.7 5.2 0.77 Stroke 0.3 0.2
0.76 1.4 1.2 0.85 Transfusion gt
2U 3.7 5.0 1.38 2.2 2.8 1.28
18
Importance of reinfarction
GUSTO V

• GUSTO I and III showed a marked difference in 1
  year survival for those who had no reinfarction
  in 30 days vs those who did.
• More reason to suspect we should see an even
  stronger difference in mortality at 1 year.
• Topol

19
Transfusions
GUSTO V

• "But the question is death of heart tissue or
  death of patient vs a transfusion. When you look
  at the net there that maybe you're better off
  reducing the death of the patient or the death of
  heart tissue and you have to bite the bullet with
  transfusion.
• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic

20
Bleeding
GUSTO V

• Bleeding is clustered in the elderly, female, and
  light-weight patients.
• Different anti-coagulants may lower this bleeding
  even further.
• Topol

21
Problems with the trial
GUSTO V

• The lack of mortality reduction was
  disappointing.
• GUSTO I reduced mortality by gt 14 and some still
  said we didn't reduce mortality.
• There are always nay-sayers for any large trial.
• Topol

22
Time will tell
GUSTO V

• "The only way to know what you've done, is
  how the trial's data are adopted in practice.
• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic

23
Embracing the results
GUSTO V

• The costs of the combination therapy should not
  be very different from the standard so that isn't
  fueling the controversy.
• I would think it should be viewed as a good
  thing
• reduced non-fatal endpoints
• discriminates the population at risk of
  bleeding
• Bleeding didn't override the clinical benefits
• This should be embraced for certain patients.
• Topol

24
Apply it to practice?
GUSTO V

• I'd like to see any better data on how to treat
  patients today.
• There's a cath-lab strategy, but often there is a
  delay, and most places don't have it available.
• It may not be for all patients. (Tough to
  advocate for patients with small MIs)
• Topol

25
Cooking up the cocktail.
GUSTO V

• Reteplase currently comes in two vials. So you
  use just one with the abciximab.
• Costs about 300 more than reteplase or
  tenecteplase alone.
• There are several hospitals that have done it for
  the last year, even withou the GUSTO V data.
• Topol

26
Who to treat
GUSTO V

• Patients with significant MIs
• Patients 75 years old or younger
• If it is a relatively small MI, I probably would
  NOT bother using combination therapy.
• Topol

27
ASSENT III
GUSTO V

• Assent III should offer some supporting evidence.
  Not as large a trial, but it should shed further
  light on the question.
• Califf

28
Faster treatment
GUSTO V

• The 90 minute to 2 hour delay getting to cath lab
  is the big question. Would we be better off
  having drugs working en route?
• Topol
• The great hope is that we can organize things to
  treat people quickly and open the artery and the
  cath-lab is proving where you want to be in the
  long run.
• Califf

29
Reservations
GUSTO V

• I think it's a matter of getting organized and
  absorbing the data some more and seeing whether
  ASSENT 3 confirms it. I think it is so close
  temporally that I'm not quite ready to jump on it
  at this point."
• Dr Robert Califf
• Professor of Cardiology
• Associate Vice Chancellor for
• Clinical Research at Duke University

30
Other combinations
GUSTO V

• All combinations are possible, but you can't
  adopt any combination until you have some solid
  evidence with a large-scale trial.
• GUSTO V is favorable on balance, but it is
  tenuous, a small difference.
• Strong data is needed on other combinations
  before we can advocate them.
• Califf

31
Intracranial hemorrhage
GUSTO V
Abciximab Reteplase
Reteplase
Odds Ratio 95 CI
Intracranialhemorrhage rate
0.6
0.6
Age
0.045
lt 45
0.2
0.1
0.021
gt 45 - 55
0.3
0.1
gt 55 - 65
0.4
0.4
gt 65 - 75
1.0
0.8
1.1
2.1
gt 75
0.1
1
10
ReteplaseBetter
Abciximab Reteplase Better
32
Lack of progress on ICH
GUSTO V

• Trial didn't show any increase in ICH overall.
  But it remains a problem with the elderly. It
  doesn't look like a great strategy for the
  elderly.
• Topol
• Most frustrating to me is that we have made no
  progress on ICH. We still don't know how to pick
  out people at risk.
• Califf

33
Compared to other trials
GUSTO V
ICH Rates
N 18,495 15,059 16,949 15,078 16,588
34
The naysayers
GUSTO V

• "The most frustrating thing is to see that no
  matter what trial you do, no matter what the
  findings are, they are very harshly criticized by
  some. And after a while it makes you not want to
  be engaged in clinical trials. "
• Dr Eric Topol
• Provost and Chief Academic Officer
• Chairman and Professor, Department of Cardiology
• Cleveland Clinic

35
Stepwise progress
GUSTO V

• We need to remember that AMI is still the
  developed world's number 1 cause of death and
  disability.
• Anything we do to chip away at the problem is a
  step-wise advance.
• Huge reductions in mortality arent always
  possible.
• Topol

36
Fast track publication
GUSTO V

• With the agents already available, getting the
  information out to the medical community quickly
  and accurately was important.
• Topol
• Making sure things get published before all the
  rumors start flying around is a laudable goal.
• Califf

37
GUSTO V trial review
GUSTO V

• Dr Eric Topol
• Two thumbs up
• I'm not saying that's what the findings
  necessarily support but I think in terms of the
  design."

38
Importance of non-inferiority
GUSTO V

• We want to have therapies that have fewer side
  effects, or are easier to give, or cheaper.
  Hopefully a combination of all of those. In many
  cases you may not have a reduction in mortality
  but you sure want to make sure that you dont
  create an excess mortality."
• Dr Robert Califf
• Professor of Cardiology
• Associate Vice Chancellor for
• Clinical Research at Duke University

39
GUSTO V trial review
GUSTO V

• Dr Robert Califf
• Two thumbs up
• "A somewhat biased two thumbs up on both
  accounts."