May 18th, 2012
FAME II: Another Study Abides in Infamy
Richard A. Lange, MD, MBA and L. David Hillis, MD
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?
5 Responses to “FAME II: Another Study Abides in Infamy”
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Sounds like a medical judgement call to me. Ethical or not ethical is not the question.
Stopping rules with composite primary endpoints can be quite biased. There is always a judgement issue. In this case a high threshold for stopping for TVRs with a Bayeaian evaluation would
have been more appropriate.
More attention to stopping rules is necessary…the underlying assumptions for such rules should be spelled out in as nontechnical language as possible.
It becomes clear , medical management in any type of CAD can never be tested in real scientific manner in this hyped interventional era for various reasons.
We have a huge problem here .Premature Conclusions and judgments are made against optimal medical management .FAME 2 was contemplated to answer this perennially unanswered question .The very purpose is defeated.
I guess , may be the fear of PCI losing against OMT is one of reasons to terminate this study early.
Dr Venkatesan Sangareddi
Chennai.
India .
Please allow me to link a related article from my blog
In response to your comment #3, there are surprising yet consistent data from imaging registries that support clinical equipoise on the decision to refer a patient with at least moderate ischemia to catheterization. Despite conventional wisdom, the rate of referral to catheterization in these patients is only 35%-65% from 9 reports (5,833 patients at 51 centers). The latest data come from the NHLBI SPARC registry (JACC 2012;59;462-474). They reported the 90-day post-test rates of catheterization in 1,700 patients without a documented history of CAD and abnormal CCTA or stress nuclear perfusion imaging. Among patients with the most abnormal test results, 38% to 61% were not referred to catheterization. Furthermore, a survey of 500 cardiologists found that 80% were willing to enroll a sample patient with frequent stable angina, >10% myocardial ischemia, and normal ejection fraction into a randomized trial with a 50% chance of being conservatively managed with optimal medical therapy without cardiac catheterization (Am Heart J 2011;162:1034-1043). This is encouraging news for the ISCHEMIA trial, an NHLBI-funded trial that will compare the effectiveness of two initial management strategies – conservative (OMT alone) versus invasive (cath + revascularization + OMT) – in patients with stable ischemic heart disease and at least moderate ischemia on a stress imaging test. ISCHEMIA will begin enrolling patients this summer.
The authors’ comments highlight the problem of composite endpoints mixing objective (death, MI) and more subjective (SYMPTOM-DRIVEN revascularization leading to rehospitalization) endpoints. The latter simply cannot be reliably measured. The premature discontinuation of the trial thus will not be able to assess whether PCI + OMT improves death/MI compared to OMT alone among patients meeting ischemia criteria as defined by FFR.
Having said that, the trial clearly addressed a so-called “soft” endpoint, but important in everyday living because it has everything to do with quality of life. Depending on the perceived level of discomfort, some patients may choose death rather than hell on earth. For QOL reasons, hip/knee replacements for severe osteoarthritis are performed without clear mortality benefit that I’m aware of. If having a PCI + OMT means relief from pain without long-term adverse outcomes versus having to live with discomfort for prolonged periods, the former choice is a no-brainer if I were the patient.