Those are the bold two-year results from the FAME-2 study, but investigators stress that such conclusions include important caveats, the most signficant being that PCI is superior to medical therapy as along as fractional flow reserve (FFR) is used to guide treatment decisions. The second caveat depends on the definition of hard clinical outcomes. In FAME-2, FFR-guided PCI reduced the composite of death from any cause, nonfatal MI, or urgent revascularization by 61%, and this reduction was driven by the need for revascularization.
"PCI, or at least an invasive strategy, is the preferred way in acute coronary syndromes, but PCI has never been shown to reduce 'hard end points,' and I put that in quotation marks because hard end points is a very relative term in stable coronary artery disease," said lead investigator Dr Bernard De Bruyne (Cardiovascular Center, Aalst, Belgium) during a press conference here at the European Society of Cardiology (ESC) 2014 Congress .
Speaking with the media, De Bruyne noted that it's fair to say that when FFR is used to guide PCI in stable patients, the invasive approach cuts the risk of death, MI, or revascularization in half compared with medical therapy alone. In stable patients where ischemia is unable to be induced, "these patients do very well with medical therapy alone," he said. "This is also an important message of the study."
The results of FAME-2 were released to the press today and will be formally presented Tuesday; they were published simultaneously in the New England Journal of Medicine.
The FAME-2 Study
FAME-2 included 1220 patients with stable coronary disease scheduled for PCI with second-generation drug-eluting stents for one-, two-, or three-vessel disease. All patients underwent FFR testing prior to randomization. Patients who had at least one stenosis with an FFR <0.80 were randomized to PCI or optimal medical therapy while individuals with an FFR >0.80 were placed in a registry and treated with optimal medical therapy. "One result that is already important and striking is that in one-quarter of the patients scheduled for PCI we didn't find any hemodynamically significant stenosis," said De Bruyne.
The primary composite end point of death, MI, or revascularization was significantly lower among patients randomized to FFR-guided PCI when compared with those treated with medical therapy alone (8.1% vs 19.5%; p<0.001). The reduction in the primary end point was driven by a 77% reduction in the need for urgent revascularization.
Clinical end points in FAME-2
|End point||PCI (n=447)||Medical therapy (n=441)||Hazard ratio|
|Primary composite of death, MI, or urgent revascularization||8.1||19.5||0.39 (0.26–0.57)|
|Death from any cause||1.3||1.8||0.74 (0.26–2.14)|
|Urgent revascularization||4.0||16.3||0.23 (0.14–0.38)|
|Death or MI||6.5||8.2||0.79 (0.49–1.29)|
Given the higher number of primary events in the PCI group between randomization and day 7, including more periprocedural MIs, the researchers conducted a landmark analysis between day 8 and two years looking at death and MI rates alone. In this analysis, there was a significant 44% reduction in the composite of death/MI compared with medical therapy alone.
"This is the first time that death or MI shows some kind of difference in stable patients after PCI," said De Bruyne.
The researchers also attempted to determine the reasons for urgent revascularization underlying the PCI advantage, noting that revascularization was triggered by MI in 31% of patients, unstable angina with ischemic changes on ECG in 20% of patients, and clinical features only in 49% of patients (including a large proportion of patients with class 4 angina).
Getting a Handle on FAME
Dr François Schiele (University Hospital of Besançon, France), who moderated the press conference but was not affiliated with the trial, said his center saw the use of FFR increase 20% after seven-month data from FAME-2 first emerged at EuroPCR in 2012. "Before FAME-2, we just used FFR to avoid unnecessary PCIs, but now with this study and with the two-year confirmation using hard end points, we know that we have to recognize patients where the lesion might not appear significant by angiogram." He said that clinicians are now using FFR to check whether there is ischemia behind intermediate-risk lesions because these data suggest that these stable patients will fare better with PCI.
"The first development of FFR was to decrease the number of revascularizations," said Schiele. "With FAME-2, we have the opposite side. We know that with patients with ischemia detected by FFR, we have to revascularize." De Bruyne agreed, suggesting this is particularly true with large vessels, such as left main, that supply a large territory of the heart.
Speaking with heartwire , Dr Patrick O'Gara (Brigham and Women's Hospital, Boston, MA), the president of the American College of Cardiology and chair of the ACC/American Heart Association STEMI guidelines, said the FAME investigators should be praised for highlighting the importance of physiologic or functional significance of a stenosis.
"I think looking at these particular results, where there was a composite end point, it's directionally consistent with what we've known from other trials of this type," said O'Gara. "It's reasonable to point out that the composite was driven by a need for urgent revascularization across these groups." Given the subjective nature of this end point, there will be individuals who question the results, especially since when death/MI were examined alone the study didn't show a benefit with PCI.
"The addition of revascularization leaves something open to interpretation," said O'Gara.
The FAMOUS ACS Patient
In the British Heart Foundation (BHF) FAMOUS study, investigators shifted their attention to patients with non–ST-segment-elevation MI (NSTEMI) to see if the use of FFR had an impact on the management of patients. The study, led by Dr Jamie Layland (University of Glasgow, Scotland) and presented at an ESC hot-line session by senior investigator Dr Colin Berry (University of Glasgow), included 350 patients with NSTEMI, all of whom who underwent coronary angiography and had at least one stenosis amenable to revascularization.
FFR was measured in all 350 patients. For 176 patients, the results of the FFR measurement were disclosed to the operator after a visual assessment of the lesion to determine whether the measurement shifted treatment for revascularization to medical therapy. In 174 patients, the results of the FFR were not disclosed to the treating physician.
Of the 704 lesions measured with FFR, 61% were considered physiologically significant (FFR <0.80). In examining treatment in the two study arms, the investigators revealed that more patients were treated by medical therapy when FFR was disclosed to the operator. In total, 22.7% of patients in the FFR-guided arm were treated medically compared with 13.2% in the angiography-guided arm.
"Bear in mind that the majority of patients in our study were treated with stents," Berry told heartwire . "It's a clear message that the standard of care for patients with non-STEMI is a stent for the culprit lesion. But in non-STEMI patients there can be multiple lesions and even the culprit lesion might not be severe. There is a diagnostic dilemma as to what to do with mild culprit lesions and a diagnostic dilemma about what to do with multiple narrowings."
In terms of the changes in treatment, FFR altered the initial treatment decision in 38 of 176 of cases (21.6%). "Let's say there were three different narrowings in three different arteries," said Berry. "If the FFR value in one or two of these arteries was negative, that would change the treatment plan of the patient from bypass surgery to a single-stent procedure. We even had some patients go from bypass surgery to medical therapy. I think that's quite impactful, especially on an individual patient basis."
To heartwire , Berry said a recent analysis showed that just 2.8% of acute-MI patients in the UK underwent FFR measurements prior to treatment. In FAMOUS, there were two dissections with the pressure wire in 706 lesions crossed and no issues with adenosine.
At 12 months, the researchers reported similar health outcomes and costs with the FFR- and angiography-guided treatment. The data suggested a reduction in procedure-related MIs in the FFR-guided arm compared with angiography-guided PCI and a slight trend toward higher major adverse cardiac events in the FFR group. Berry stressed, though, that FAMOUS was not powered to make any real conclusions about clinical end points. "We really need a 3500-patient study to answer this question," he said. "I'm working on it."
FFR for the ACS Patient: Many Unknowns
Dr Douglas Weaver (Henry Ford Health System, Detroit, MI), past-president of the ACC, told heartwire there is a big difference using FFR in stable coronary heart disease and ACS patients. "In patients with stable angina, we think the plaques are mostly stable and fibrous," he said. "In unstable angina, the plaques are soft, ruptured, and irregular. One of the basic methodological issues is how do we know that 0.80 means anything in this kind of plaque. We don't know right now."
In an editorial in the European Heart Journal, which published the FAMOUS study to coincide with the ESC presentation, De Bruyne, the lead investigator of FAME-2, and colleague Julien Adjedj (Cardiovascular Center, Aalst, Belgium) point out that the microvascular dysfunction associated with an ACS might differ in the acute phase from the dysfunction observed in the hours, days, or weeks after the event. Given that the patients in FAMOUS were treated an average of three days after the index event, they might represent a more stabilized unstable patient.
The editorialists point out there is a growing expectation of transforming the cath lab into a "one-stop shop" for ACS patients. To ensure a comprehensive and quality procedure, this includes "a left ventricular angiogram and left ventricular pressure recordings, a coronary angiogram, and a complete functional analysis of the coronary circulation. This approach provides all the elements for a complete diagnosis, optimal treatment, and thorough risk stratification," they write.
FAME-2 was sponsored by St Jude Medical. De Bruyne reports research contracts and consulting fees directly with St Jude Medical. The company also provided the pressure wires to the six hospitals in the FAMOUS study. Berry reports consulting for St Jude Medical and Volcano Corp.
Heartwire from Medscape © 2014
Cite this: FAME-2 and FAMOUS: FFR Impressive in Stable CAD and ACS - Medscape - Sep 01, 2014.