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

N=16,588 Patients: ST ­, Sxs < 6 hours GUSTO V Study design N=16,588 Patients: ST ­, Sxs < 6 hours 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 <70 kg) Heparin: 60 U/kg (max 5000 U) 7 U/kg-hr

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

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 endpoint GUSTO V Non-inferiority Upper bound of 95% boundary confidence interval = 1.076 Odds Ratio = 0.948 (0.832 - 1.081) p = 0.43 Relative Risk & 95% CI Reteplase Better Abciximab +

GUSTO V Reinfarction p < 0.0001

GUSTO V Revascularization All p-values < 0.0001

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

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 14

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

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

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

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

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

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

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

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 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 > 2U 3.7 5.0 1.38 2.2 2.8 1.28

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

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

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

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

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

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

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

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

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

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 Califf Professor 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

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 > 45 - 55 0.3% 0.1% > 55 - 65 0.4% 0.4% > 65 - 75 1.0% 0.8% > 75 1.1% 2.1% 0.1 1 10 Abciximab + Reteplase Better Reteplase Better 1

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

Compared to other trials GUSTO V Compared to other trials ICH Rates N = 18,495 15,059 16,949 15,078 16,588

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

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

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

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."

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

GUSTO V trial review GUSTO V Dr Robert Califf Two thumbs up "A somewhat biased two thumbs up on both accounts."