1. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Direct coronary intervention for ST-elevation MI Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, Ohio Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, North Carolina

2. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI DANAMI-2 and C-PORT DANAMI-2 DANish Multicenter Trial in Acute Myocardial Infarction 2 C-PORT Atlantic Cardiovascular Patient Outcomes Research Team

3. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI DANAMI-2: Setup 1572 patients randomized to fibrinolysis (100 mg front loaded tPA) or PCI + stent Primary endpoint: Death, reinfarction, or disabling stroke in 30 days 5 PCI centers and 24 referral hospitals which served 62% of Danish population Patients arriving at a referral center who were randomized to PCI were transferred to the nearest PCI center

4. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI DANAMI-2: Stratification Patients arriving at referral hospitals: 1100 planned/1129 enrolled Received either tPA or ambulance transfer to PCI center for PCI Patients arriving at PCI centers: 800 planned/443 enrolled Received either tPA or PCI

5. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI DANAMI-2: Pre-treatment Inclusion criteria: ST-elevation 4 mm Symptoms  12 hrs at randomization Transfer time of  3 hrs Few complications in transport

6. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI DANAMI-2: Time to treatment Time to hospital: < 1-hr transport by ambulance from referral center to PCI center 120 minutes from onset of symptoms to hospital Door-to-needle time < 1 hr Door-to-balloon time did not differ much between patients arriving at referral hospitals or PCI centers

7. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI ACC 2002 DANAMI-2: Events by hospital type p=0.0003 p=0.002 p=0.048 8.0 13.7 8.5 14.2 6.7 12.3

8. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI ACC 2002 DANAMI-2: Event rate p=0.0003 p<0.0001 p=0.15 p=0.35 8.0 13.7 1.6 6.3 1.1 2.0 6.6 7.6

9. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI C-PORT: Setup 451 AMI patients randomized to tPA (n=226) or primary PCI (n=225) Primary endpoint: Death, reinfarction, and stroke in 6 months; median hospital length of stay 11 community hospitals without on-site cardiac surgery were turned into PCI centers Door-to-balloon time: 101 minutes

10. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI C-PORT: Original plan Trial was planned with 2550 patients but was stopped in June 1999 due to poor funding "So it's almost 3 years before the trial findings are seeing the light of day." Topol

11. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Aversano T et al. JAMA 2002;287:1943-51 C-PORT: Combined endpoint p=0.03 10.7 17.7 12.4 19.9

12. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI C-PORT: Interpretation The trial data get more weight when put in context with DANAMI-2 "The big problem of course is how do you interpret this in terms of 'are there new recommendations for practice'?" I don't know if C-PORT and DANAMI- 2 justify making lytic therapy an obsolete strategy Topol

13. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Effects on mortality "In fact there's never been, and there still is not, one single trial that shows survival improvement. And that's been our standard in acute MI." Topol Some of the 21 studies Cannon cites did not show superiority, somewhere along the way he's not counting right

14. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Issues with the PCI trials There are problems with the PCI trials Lytic trials of over 200 000 patients These PCI trials are open trials, not blinded There are less than 10 000 patients in these randomized PCI trials DANAMI-2 had only 2.5% rate of rescue PCI and a high ST-segment elevation entry criteria Topol

15. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Counterarguments "Let me respond to the whole barrage of fibrinolytic propaganda." There is a trend in most of these trials We can't blind PCI (How to do device trials in acute MI is a general issue that needs to be discussed) Califf

16. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Small inferior MI "Would I rather expose that person to a cardiac cath (which they are probably are going to need anyway) or to a 1-2% risk of intracranial hemorrhage?" Califf "I don't know it gets up that high unless you're talking about greater than age 75." Topol

17. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Refuting PCI for everyone "I want to cut through the hyperbole about PCI for everyone and every hospital now should be made into a PCI center. I don't think that the data necessarily support that." "I think PCI is superior to lytics -- in the right place at the right time." Topol

18. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Refuting PCI for everyone "I'm just trying to fast-forward to St Elsewhere hospital with an operator that's never done a PCI who takes these trials and says, 'You know what? I'm going to start doing angioplasty in acute MI because these trials support that.' " Topol

19. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Ideals and reality "I think you would agree with me that the ideal now would be if you could organize hospitals into MI centers and have an efficient, effective transportation system where patients could get to the right place at the right time." Califf "Well that sounds really good, but you know what? In reality it's not going to work so easily." Califf

20. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI A force fit "I would like to know that it works; that you can really do streamlined transfer of patients, that you can really get operator proficiency before we adapt cities around our country into a forced fit." Topol Cannot throw out the current therapy on just these trials, it is premature

21. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI "I'd hate to see these two trials reshape public health policy on acute MI." Topol These trials are best-case scenarios: not enough rescue angioplasty was done in DANAMI-2 and C-PORT is an aborted trial Reshaping policy

22. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI DANAMI-2 site DANAMI-2: 12-hour window

23. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Door-to-balloon time Intuitively, the shorter the door-to- balloon time, the better Ideally, I would want it between 60-90 minutes. Even 2 hours is too long I would take lytics within 45 minutes of hitting the ER over direct PCI in 2 hours without question Topol

24. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI One size does not fit all You can't make blanket statements about what to do in all MIs A patient with anterior MI aged <75, little risk of ICH – I would be comfortable using a GUSTO V-type regimen In a patient with a high risk for ICH it would make sense to accept a longer transport time to get direct PCI Topol

25. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Hub-and-spoke model All evidence points to an advantage in creating MI centers with experienced personnel Califf But the delays in transfer are so long that you cannot abandon lytics Topol

26. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Time to PCI The door-to-balloon time should be as short as possible DANAMI doesn't have enough data to support 3 hours as acceptable That transfer time was used to prepare the cath-team in the PCI center to receive the patient "I don't know that our system, in most places, is so well conditioned like that." Topol

27. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Unskilled practitioners "This whole idea […] that coronary intervention is so safe now with stents, IIb/IIIa inhibitors, and other adjunctive therapy that we don't need bypass surgery backup? I think this is overstepping the data we have available today?" Topol Many cardiologists in the US don't have adequate volume in elective PCI, let alone AMI

28. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Adequate proficiency in PCI Must exceed the AHA/ACC minimums >100 interventions per year > 25 acute interventions per year "Those are so remarkably low threshold to me for this sort of decision." Topol

29. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Community MI centers A community would be well-served to centralize its MI care if it could assure efficient transfer from outlying hospitals Califf: Up to 3 hrs would be acceptable Topol: 1.5-hour limit to mechanical reperfusion – 3 hrs only if you also give lytics during the wait

30. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Next trials The next set of trials that should be done is to randomize patients who will be transported to either get chemical reperfusion en route or not Califf Is the difference between the "bland" infarct from coronary intervention vs the hemorrhagic infarct from the drugs important in the end result? Topol

31. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Pitfalls "There's some real pitfalls of these two trials. That unless you tune into the details you might just dismiss lytics which have, I would say, an exceptional track record of having gone through rigorous trials and large numbers of patients." Topol

32. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI When to move on "I'm a big fan of lytics as you know, and both of us have spent a good part of our careers developing them, but I would also say at some point if something better comes along you've gotta give it up." Califf

33. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Mandated health strategy "When you roll out a strategy all across the country and you start to make that a mandate and its really a contrived sort of thing without the data to back it up […] I think there's a lot of uncertainties here." Topol We must beware of overextrapolation from the results

34. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Establishing standards Communities who do want to implement this direct-PCI strategy Should have good records of actual transport times The outside limit of time delay is still unclear and needs to be determined

35. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Mortality benefit Is this 1% absolute benefit in PCI not about salvage? Is it just patency that's important? Topol After 3 hours after symptoms, the wavefront may well be done. So beyond 3 hours it may be just a question of the open artery Califf

36. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Device approval What should the criteria be for approving a device for AMI? The FDA and device community have rejected a randomized mortality trial as being unfeasible Califf

37. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI "The only problem they had is they were too good, it may not be generalizable to most countries and communities." Califf Califf: 2 thumbs up for DANAMI-2

38. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Califf: 1 up/1 down for C-PORT "It was an innovative study but it obviously didn't achieve its objective in terms of enrollment and left a lot of questions unanswered." Califf

39. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Topol: 1 up/1 down for C-PORT "By not having done the experiment as planned it suffers from some concerns about the conclusions." Topol

40. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Topol: 2 thumbs up for DANAMI-2 "I wish they had been more permissive with rescue intervention […] But to do that in only 2.5% of patients seemed like it loaded the deck unnecessarily for the mechanical strategy." Topol

41. Thumbs up/Thumbs down – May 2002 Direct coronary intervention for MI Califf: Final thoughts "It's a topic we shouldn't get complacent about. It's still the leading cause of death in the developed world and something that every percent reduction in mortality is very important." Califf