ESC Trials: The Best And The Worst Reply

Two trials presented at the ESC this year– WOEST and IABP-SHOCK II– are great examples of the way medicine is supposed to work. Another trial, FAME 2, is an example of so many of the things that can go wrong.

WOEST and IABP-SHOCK II are remarkably similar. Both trials tested conventional wisdom and found it lacking. WOEST examined the routine use of aspirin in “triple therapy” when people already taking an anticoagulant undergo PCI and then receive an additional antiplatelet drug and aspirin. IABP-SHOCK II tested the routine use of circulatory support with intraaortic balloon counterpulsation (IABP) for patients in cardiogenic shock following MI for whom early revascularization is planned.

Despite a complete lack of evidence, both of the ideas tested in these trials had received class 1 recommendations in the guidelines and were widely used in clinical practice. And both trials provided near definitive proof that the conventional wisdom was completely and utterly wrong.

This is the way science is supposed to work: an idea gets put to a fair test. Judging from the initial response to these trials, it seems likely that the cardiology community will rapidly accept the findings of the trials, and guidelines and clinical practice likely will change in short order to reflect the new evidence base.

FAME 2

FAME 2 also addressed, or claimed to address, an important question. Although the evidence base for PCI in stable angina had always been weak or nonexistent, its popularity had undergone exponential growth for many years, until COURAGE famously put the brakes on this growth. When fractional flow reserve (FFR) first came along, it was viewed with considerable suspicion in the interventional community, since in many respects it helped confirm the findings of COURAGE by appearing to demonstrate that a significant percentage of lesions intervened upon were not ischemic and therefore almost certainly didn’t benefit the patients who had undergone PCI.

Eventually, however, the interventional cardiology community found a path to renewal with FFR. Perhaps, it reasoned, instead of being used to illustrate the lack of utility of PCI, FFR could be used to guide PCI decisions, limiting interventions to ischemic lesions that would benefit from PCI.

This is where FAME 2 comes into the picture. In the trial, patients who had at least one functionally significant lesion, as defined by FFR, were randomized to FFR-guided PCI plus medical therapy or medical therapy alone. The trial was stopped early, after only about half of the intended number of patients were enrolled, because of a significant reduction in the primary endpoint (the composite of death, MI or urgent revascularization) in the PCI group compared to the medical therapy alone group.

The FAME 2 investigators, along with many members of the interventional cardiology community, have presented the results of the trial as a definitive response to the questions about PCI raised by COURAGE. In an ESC press release, FAME 2 co-ordinator Bernard De Bruyne said:

“With this new knowledge, I believe that FFR should become the standard of care for treating most patients with stable coronary artery disease and significant coronary narrowings.”

The Society for Cardiovascular Angiography and Interventions (SCAI) was so excited about the results of FAME 2 that it rushed out an e-publication of a “President’s Page” perspective on FAME 2, written by SCAI president J. Jeffrey Marshall and interventional cardiologist Ajay Kirtane, arguing that “FAME 2 offers the best data currently available to guide” treatment. The perspective of most interventional cardiologists is probably best summarized by this headline published on TCTMD: “PCI Bests Medical Therapy in Stable Patients with Proven Ischemia.”

The sad thing about these simplistic responses to FAME 2– and the reason why I use this trial as an example of a poor model for clinical trials– is that there is no acknowledgement of the extraordinary division of opinion about this trial and its meaning. The SCAI document discusses the FAME 2 publication but does not even reference, or respond to, the issues raised in an editorial accompanying the publication of FAME 2 in the New England Journal of Medicine. That editorial, by Bill Boden, the principal investigator of the COURAGE trial, delivered a trenchant attack on the view that FAME 2 represents anything like a definitive response to COURAGE.

I summarized Boden’s points in my previous news story about FAME 2:

  • There were few “hard” events in FAME 2 and urgent revascularization could be performed without objective evidence  of ischemia or positive biomarkers.
  • Since the trial was unblinded, “investigators may have had a lower threshold for recommending revascularization” for patients in the medical group.
  • Patients in the FFR group did not have noninvasive testing demonstrating ischemia, so some may have had preserved myocardial perfusion.
  • Patients in FAME II were not at very high risk.
  • The short followup period (mean followup of 7 months) did not leave enough time for the risk of restenosis in the PCI group to fully emerge.

Boden is highly critical of the early termination of the study, writing that it leaves “more questions than answers…. but the only enduring finding of the FAME 2 trial appears to be that  of a reduced short-term rate of unplanned revascularization with FFR-guided PCI, with little evidence of long-term, incremental benefit on prognostically important clinical outcomes.”

Astonishingly, the ESC press release didn’t even mention that the ESC’s own discussant of the trial, Frans Van de Werf, concluded that FAME 2 did not provide the “final answer to the question how to treat stable CHD patients.” Over on CardioExchange, Rick Lange and David Hillis provided another deeply skeptical perspective on FAME 2, and their view received endorsements from Sanjay Kaul, David Cohen, and Harlan Krumholz.

PCI supporters are acting as if the new evidence provided by FAME 2 forges a new consensus in support of FFR-guided PCI, but only by ignoring a chorus of dissent.

It is perhaps worth noting here that WOEST and IABP-SHOCK II were investigator-driven trials in which industry played no significant role. Of course, this idyllic situation may have been possible only because no significant commercial interests were at stake in the trial. With FAME 2, by contrast, the commercial stakes– for industry, for hospitals, and for interventional cardiologists– could not be higher. Perhaps these influences have helped induce a self-interested reality distortion field.