Processing FAME II: Enrollment Halted After Positive Results Observed for OMT Plus FFR-guided PCI

Issue: March/April 2012

The Data Safety Monitoring Board has recommended investigators of the FAME II trial stop patient enrollment after an interim analysis revealed an increased risk in MACE among patients with CAD treated with optimal medical therapy alone vs. fractional flow reserve-guided PCI and optimal medical therapy, according to a press release.

In what many are calling a landmark trial, FAME II revealed that patients treated with PCI guided by FFR measurement devices (PressureWire Aeris and PressureWire Certus, St. Jude Medical) and optimal medical therapy (OMT) had a highly statistically significant reduction in the need for hospital readmission and urgent revascularization when compared with optimal medical therapy alone; no differences were observed in rates of death or MI. These findings led the Data Safety Monitoring Board (DSMB) to deem continued randomization of patients to OMT alone unethical.

The FAME II trial will continue to follow presently enrolled patients according to study protocol, but will not enroll any new patients. Currently, the trial has randomly assigned 1,219 patients with stable CAD throughout 28 centers in the United States, Europe and Canada.

To further understand the implications of this trial, Cardiology Today Intervention spoke with Bernard De Bruyne, MD, PhD, principal investigator for the FAME II trial, and William E. Boden, MD, principal investigator for the COURAGE trial, who each offered their interpretation of the findings.

Bernard De Bruyne, MD, PhD


	Bernard De Bruyne

There has been a lot of discussion about the FAME II trial, but much of it is highly speculative. All that we know for sure is that the primary endpoint is significantly different between the two groups, and there was no significant difference between death and MI. At present, we must wait for further data analysis. However, the recommendation of the DSMB was very firm and was discussed at length.

It is important to consider that FAME II studied patients with stable CAD, similar to COURAGE. However, the FAME II trial design was completely different. Beyond sharing the similarity of studying patients with stable CAD, the FAME II trial further stratified patients based upon the results of FFR measurement. With the FFR measurements, FAME II investigators were able to study PCI plus OMT vs. OMT alone in patients who were most likely to benefit from revascularization. All randomized patients were ischemic and very often had extensive and profound ischemia; so we are dealing with what is likely a very different population at much higher risk than COURAGE patients. By first utilizing FFR and intervening only on patients with physiologic evidence of ischemia, the FAME II trial may have markedly different results. In addition, it will be important to analyze the patients that had negative FFR results (FFR >0.80) and were treated with OMT alone in cohort B of the study.

In terms of the use of hospital readmission and urgent revascularization as a surrogate for death and MI, I don’t believe this can be considered an issue when we take into account that all the patients had proven ischemia and urgent revascularization. It is well known that patients with proven ischemia needing urgent revascularization have a poor prognosis if left untreated. All urgent revascularization events were adjudicated by an independent clinical events committee. These adjudicated events were then further reviewed by the DSMB prior to their recommendation to stop enrollment in the trial. So the patients in whom we said had urgent revascularization, I can say confidently they were truly urgent. On top of that, we have a number of patients who had non-urgent revascularization and we were very strict in the criteria to split both groups.

Since hospital readmission with urgent revascularization is a significant driver of cost to health care systems, FAME II offers hope that with appropriate use of FFR in patients like those studied in FAME II, we may be able to provide better outcomes and reduce the financial burden on health care systems. We have significant analysis to conduct to understand the implications of FAME II completely, and we look forward to presenting and publishing the data in the near future.

Disclosure: Dr. De Bruyne is a consultant for St. Jude Medical but does not receive any financial gain; all fees are paid to the Cardiovascular Research Center, Aalst, Belgium, a nonprofit organization.

William E. Boden, MD


	William E. Boden

First off, I congratulate the FAME II investigators for conducting an important trial that further addresses the important issue of how best to manage patients with stable ischemic heart disease. As we all know, optimal treatment is an iterative process that evolves over time and incorporates both new technology and pharmacotherapy as part of how we continue to define “optimal” in the context of contemporary management.

I do, however, have some comments and concerns about FAME II — both in terms of how it relates to the COURAGE trial and the upcoming ISCHEMIA trial (there are both similarities and differences). In the COURAGE trial, the primary endpoint was death or MI during long-term follow-up (mean, 4.6 years). During the first 2 to 3 years of follow-up, the OMT group fared better than the PCI plus OMT group, yet, despite this early advantage, the COURAGE DSMB appropriately “stayed the course” and let the study go to full completion. As I understand it, death or MI was part of the composite primary endpoint for FAME II, yet the DSMB decided to stop the study on the basis of the “softer” endpoints of hospital readmission and urgent revascularization.

I strongly take issue with the comment in the press release that the component endpoints of “hospital readmission and urgent revascularization can be considered a surrogate for a repeat heart attack or death.” This is a statement made completely in the absence of scientific evidence — as no one can rightly consider such a softer endpoint, particularly hospital readmission, as being a proxy for death or MI in an unblinded trial where the potential threshold (and clinical decision) to undertake urgent revascularization in an patient given OMT could have been driven, in part, by bias. While I respect the mission of the DSMB to safeguard patient safety in the context of a clinical research trial, the decision to stop the study when an interim analysis demonstrated a benefit for the FFR-guided PCI strategy could be viewed with some concern and suspicion, especially when the press release likewise noted that there were no significant between-group differences in death or MI.

Similar to COURAGE, all FAME II patients had their coronary anatomy defined prior to randomization, so it is unclear whether patients with very proximal coronary artery stenoses were excluded because of selection bias. We also do not have information as to the presence or severity of myocardial ischemia in FAME II. An abnormal FFR is a physiologic marker for a flow-limiting coronary stenosis, but we do not know if this correlates with ischemic myocardial segments subtending the flow-limiting stenosis. Other factors, such as coronary collaterals, could be at play, which could provide additional myocardial tissue perfusion distal to a flow-limiting stenosis. These are notable differences between FAME II and the ISCHEMIA trial, in which all enrolled patients must have moderate to severe myocardial ischemia documented by perfusion imaging or dobutamine stress echo at trial entry and will be randomized prior to coronary angiography. Also, the primary endpoint for ISCHEMIA will be the composite of CV death or MI during long-term follow-up.

Thus, while FAME II shows an apparent significant reduction in hospital readmissions and urgent revascularization in the patients randomly assigned to FFR-guided PCI as compared with OMT alone, a number of questions remain unanswered. Until a more definitive analysis is completed and the main results are published in a peer-reviewed journal, we must await further interpretation of these preliminary results in order to place them in the proper therapeutic context once we have all the facts in hand.

Disclosure:

Dr. Boden reports no relevant financial disclosures.