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. N=16,588 Patients: ST ­, Sxs < 6 hours
GUSTO V
Study design
N=16,588 Patients: ST ­, Sxs < 6 hours
Randomization
Standard-Dose Reteplase
( U Double Bolus)
Abciximab +
Low-Dose Reteplase
(5 + 5 U Double Bolus)
Heparin: U
1000 U/hr (800 U/hr for <70 kg)
Heparin: 60 U/kg (max 5000 U)
7 U/kg-hr

3. Endpoints Primary Secondary GUSTO V mortality (all-cause) by 30 days
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 < 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 % for control mortality rates ranging from 5 - 9%

5. Primary endpoint GUSTO V Non-inferiority Upper bound of 95% boundary
confidence interval = 1.076
Odds Ratio = 0.948
( )
p = 0.43
Relative Risk
& 95% CI
Reteplase
Better
Abciximab +

6. GUSTO V
Reinfarction
p <

7. GUSTO V
Revascularization
All p-values <

8. Non-fatal complications
GUSTO V
Non-fatal complications
“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 (%)
Pulmonary (%)
Cardiac (%)
Retroperitoneal (%)
Genitourinary (%)
Sheath Site (%)
Gastrointestinal (%)
Other Puncture Site (%)
Surgical (%) 14

10. Doubts on non-inferiority
GUSTO V
Doubts on non-inferiority
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. GUSTO V
Beyond 30 days
“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
An entirely new strategy
“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
Mortality results are biased?
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 Europe 9712 Americas 4194 Other 2682 GUSTO V
Belgium 181
Finland 107
France 404
Germany 2511
Great Britain 1253
Ireland 12
Italy 1181
Netherlands 1310
Norway 143
Poland 1770
Portugal 88
Spain 618
Sweden 84
Switzerland 50
Americas 4194
Argentina 36
Canada 1240
United States 2918
Other 2682
Australia 509
Israel 1973
South Africa 200

15. GUSTO V
The wrong lytic?
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
Non-fatal MI questions
Accusation: The non-fatal MI wasn’t 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 5 CURE Death 5.9 5.6 0.95 5.5 5.1 0.92
GUSTO V
CURE trial comparison
GUSTO 5
CURE
Reteplase + Aspirin + Reteplase Abciximab RR Aspirin Clopidogrel RR
Death MI
Stroke
Transfusion > 2U

18. Importance of reinfarction
GUSTO V
Importance of reinfarction
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. GUSTO V
Transfusions
"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. GUSTO V
Bleeding
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
Problems with the trial
The lack of mortality reduction was disappointing.
GUSTO I reduced mortality by > 14% and some still said we didn't reduce mortality.
There are always nay-sayers for any large trial.
Topol

22. GUSTO V
Time will tell
"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. GUSTO V
Embracing the results
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. GUSTO V
Apply it to practice?
“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
Cooking up the cocktail.
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 Patients with significant MIs
GUSTO V
Who to treat
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. GUSTO V
ASSENT III
Assent III should offer some supporting evidence. Not as large a trial, but it should shed further light on the question.
Califf

28. GUSTO V
Faster treatment
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. GUSTO V
Reservations
“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. GUSTO V
Other combinations
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
Intracranial hemorrhage
Abciximab + Reteplase
Odds Ratio & 95% CI
Reteplase
Intracranial hemorrhage rate
0.6%
0.6%
Age
0.045
< 45
0.2%
0.1%
0.021
>
0.3%
0.1%
>
0.4%
0.4%
>
1.0%
0.8%
> 75
1.1%
2.1%
0.1 1 10
Abciximab + Reteplase Better
Reteplase Better 1

32. GUSTO V
Lack of progress on ICH
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
Compared to other trials
ICH Rates
N = 18,495 15,059 16,949 15,078 16,588

34. GUSTO V
The naysayers
"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. GUSTO V
Stepwise progress
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 aren’t always possible.
Topol

36. Fast track publication
GUSTO V
Fast track publication
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
Importance of non-inferiority
“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 don’t 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."