May 18th, 2012
FAME II: Another Study Abides in Infamy
In FAME II, a prospective study conducted at 28 centers in Europe and the United States, >1200 patients with ischemia (as determined by fractional flow reserve [FFR]) were randomly assigned to receive (a) PCI (with a DES) and optimal medical therapy (OMT) or (b) OMT alone. The primary endpoint was a composite of death, myocardial infarction (MI), and unplanned hospitalization leading to urgent revascularization within 24 months of randomization.
Patients were considered to have urgent revascularization if they (a) entered the hospital through the emergency department and their revascularization procedures were performed during the same hospitalization, or (b) presented to clinic with increased angina symptoms.
The study was halted prematurely by the data safety monitoring board (DSMB) because of a difference in the incidence of urgent revascularization in the two study arms; the rates of death or MI were similar. In other words, urgent revascularization was performed for symptom relief, not MI. According to results presented at EuroPCR, the rate of unplanned revascularization within 6 months in the OMT and PCI+OMT groups was 12% and 2%, respectively.
These data can be interpreted in one of two ways. One can conclude that because urgent revascularization was required about 11 times more often in the OMT group than in the PCI+OMT group, PCI in patients with abnormal FFR results in an improved outcome. Alternatively, one can conclude that almost 90% of patients in the OMT+PCI group had an unnecessary (and costly) PCI.
The fact that the DSMB prematurely stopped this trial is troubling for several reasons.
1) Fewer than 40% of the patients had been followed for 2 months or longer before the study was stopped.
2) The trial was discontinued on the basis of a “soft endpoint” (i.e., symptom-prompted revascularization). Participants who did not undergo PCI experienced no “real” harm (i.e., death or MI).
3) Randomizing patients with ischemia to OMT alone is problematic. Because of the perception — held by both physicians and patients — that ischemic myocardium should be revascularized, PCI is almost always performed in such patients. In these individuals, any symptom becomes angina or an anginal equivalent and, as a result, PCI is indicated.
It is well known that trials that are stopped early because of an apparent treatment difference are prone to exaggerate the true effect of the intervention. They often stop on a “random high,” whereas the observed difference might well have regressed to the true effect if they had been continued for a longer time period.
Would you have considered it unethical to continue this trial, or would you have allowed it to continue?