GUSTO V

Clinical Trial Commentary

Dr Eric TopolProvost and Chief Academic OfficerChairman and Professor, Department of CardiologyCleveland Clinic

Dr Robert CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Study design GUSTO V

RandomizationRandomization

N=16,588 Patients: ST , Sxs < 6 hours N=16,588 Patients: ST , Sxs < 6 hours

Standard-Dose Reteplase(10 + 10 U Double Bolus)Standard-Dose Reteplase(10 + 10 U Double Bolus)

Heparin: 5000 U1000 U/hr (800 U/hr for <70

kg)

Abciximab +Low-Dose Reteplase

(5 + 5 U Double Bolus)

Abciximab +Low-Dose Reteplase

(5 + 5 U Double Bolus)

Heparin: 60 U/kg (max 5000 U)

7 U/kg-hr

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

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 2.051 - 2.627% for control mortality rates ranging from 5 - 9%

Primary endpointGUSTO V

Reteplase

(n = 8260)

Reteplase

(n = 8260)

Abciximab+ Reteplase(n = 8328)

Abciximab+ Reteplase(n = 8328)

00

22

44

66

8830-Day Mortality (%)30-Day Mortality (%)

5.915.915.625.62

Odds Ratio = 0.948(0.832 - 1.081)

p = 0.43

Non-inferiorityboundaryUpper bound of 95%

confidence interval = 1.076

0.80.8

0.90.9

11

1.11.1

Relative Risk& 95% CI

ReteplaseBetter

Abciximab+

ReteplaseBetter

AnyAny Q-WaveQ-Wave EnzymaticEnzymatic Ischemic ST Change

Ischemic ST Change

00

11

22

33

44Myocardial Reinfarction (%)Myocardial Reinfarction (%)

3.53.5

2.32.3

0.50.5 0.20.2

1.61.61.21.2

2.72.7

1.71.7

Reteplase

Abciximab + Reteplase

p < 0.0001

GUSTO V

Reinfarction

Revascularization

< 6 Hours< 6 Hours < 12 Hours< 12 Hours < 24 Hours< 24 Hours < 7 Days< 7 Days00

55

1010

1515

2020

2525

3030

3535Revascularization (% of Patients)Revascularization (% of Patients)

8.78.75.75.7

9.99.96.76.7

11.911.98.68.6

31.231.228.228.2

Reteplase

Abciximab + Reteplase

All p-values < 0.0001

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 TopolProvost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic

Non-fatal complicationsGUSTO V

Bleeding

AbciximabReteplase

+ Reteplase N = 8260

N = 8328

EENT (%) 0.10.6Pulmonary (%) 0.10.3Cardiac (%) 0.10.1Retroperitoneal (%) 0.10.1Genitourinary (%) 0.10.4Sheath Site (%) 0.70.4Gastrointestinal (%) 0.41.9Other Puncture Site (%) 0.30.6Surgical (%) 0.40.3

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

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 TopolProvost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic

Beyond 30 daysGUSTO 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 TopolProvost and Chief Academic Officer Chairman and Professor, Department of

Cardiology Cleveland Clinic

An entirely new strategyGUSTO 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

GUSTO V

Final enrollment

Europe 9712

Belgium 181Finland 107France 404Germany 2511Great Britain 1253Ireland 12Italy 1181Netherlands 1310Norway 143Poland 1770Portugal 88Spain 618Sweden 84Switzerland 50

Americas 4194

Argentina 36Canada 1240United States 2918

Other 2682

Australia 509Israel 1973South Africa 200

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

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

GUSTO V

CURE trial comparisonGUSTO V

Reteplase + Aspirin +Reteplase Abciximab RR Aspirin Clopidogrel

RR

Death 5.9 5.6 0.95 5.5 5.10.92

MI 3.5 2.3 0.67 6.7 5.20.77

Stroke 0.3 0.2 0.76 1.4 1.20.85

Transfusion > 2U 3.7 5.0 1.38 2.2 2.81.28

GUSTO 5 CURE

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

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 TopolProvost and Chief Academic Officer Chairman and Professor, Department of

Cardiology Cleveland Clinic

TransfusionsGUSTO V

Bleeding

Bleeding is clustered in the elderly, female, and light-weight patients.

Different anti-coagulants may lower this bleeding even further.

Topol

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

GUSTO V

"The only way to know what you've done, […] is how the trial's data are adopted in practice.

Dr Eric TopolProvost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic

Time will tellGUSTO 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

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

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

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

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

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

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 CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

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

GUSTO V

ReteplaseBetter

Abciximab +Reteplase

Better

> 45 - 55 0.3%

ReteplaseAbciximab +

Reteplase

0.1%

< 45 0.2% 0.1%

0.1 1 10

1.1% 2.1%

1.0% 0.8%

> 75

> 65 - 75

Intracranial hemorrhage

Odds Ratio & 95% CI

0.045

0.021

Intracranialhemorrhage rate 0.6% 0.6%

0.4% 0.4%> 55 - 65

Age

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

GUSTO V

GUSTO IGUSTO I GUSTO 3GUSTO 3 ASSENT 2ASSENT 2 INTIME IIINTIME II GUSTO 5GUSTO 50.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

1.21.2

1.41.4

0.540.54

0.720.72

0.870.87 0.910.91 0.940.94 0.930.93

0.640.64

1.121.12

0.600.60 0.600.60

PercentPercent

tPA

SK

TNK

RPA + Abciximab

RPA

NPA

N = 18,495 15,059 16,949 15,07816,588

ICH Rates

Compared to other trialsGUSTO 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 TopolProvost and Chief Academic Officer Chairman and Professor, Department of Cardiology Cleveland Clinic

The naysayersGUSTO 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

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

GUSTO V

GUSTO V trial review

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."

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 CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

GUSTO V

GUSTO V trial review

Dr Robert Califf

Two thumbs up

"A somewhat biased two thumbs up on both accounts."

GUSTO V