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.
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
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.
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
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
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.
Dr. Boden reports no relevant