DENVER, CO — PCI guided by fractional flow reserve (FFR) measurement plus medical therapy improved long-term outcomes for a majority of patients with stable coronary artery disease compared with medical therapy alone, a new trial shows[1], and at 3 years of follow-up, the cumulative costs of care for PCI patients equaled that of patients managed with drugs alone.
In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME 2) trial, the 3-year rate of a composite end point of major adverse cardiovascular events (MACE), consisting of death, MI, and or need for urgent revascularization was 10.1% for patients randomized to PCI and medical therapy, compared with 22% for patients assigned to medical therapy (P<0.001), reported Dr William F Fearon on behalf of coinvestigators.
“Previous studies such as COURAGE have suggested no improvement in angina relief, outcomes, or quality of life and higher costs with PCI. However, those studies were limited by including patients with minimal or no myocardial ischemia and used older PCI techniques,” Fearon said at a briefing prior to presentation of the data in a late-breaking abstracts session at TCT 2017 here. FAME 2 results were also published online in Circulation.
“We now know that measuring fractional flow reserve in the cath lab identifies lesions responsible for ischemia in patients who benefit from PCI,” he said.
The results to some degree contradict those of the ORBITA trial, also reported at TCT 2017, which showed that single-vessel PCI was no better than a sham procedure at improving exercise capacity or relieving symptoms in patients with stable angina, including those with severe coronary stenosis.
FFR First for All Comers
The FAME 2 investigators screened 1220 patients with stable CAD who were scheduled for one-, two-, or three-vessel PCI with FFR in all target lesions. Those patients who had FFR >0.80 across all lesions (332, or 27% of the total population) were not randomized, although 50% of this group were randomly assigned to a registry for clinical follow-up.
The remaining 888 patients, who had at least one stenosis with an FFR of <0.80 were randomly assigned to PCI with medical therapy or medical therapy alone, with follow-up scheduled for 1 and 6 months and 1,2, 3 and 5 years.
Patients assigned to undergo PCI received a 600-mg loading dose of clopidogrel and aspirin immediately before the procedure if they were not already taking these drugs. All stenoses with an FFR of 0.80 or less were treated with second-generation drug-eluting stents (DES). All patients in this trial arm also received clopidogrel 75 mg daily for at least 12 months, in addition to the best available medical therapy.
As noted above, the rate of MACE at 3 years for patients in the PCI arm was less than half that of patients managed with medical therapy alone (10.1 vs 22%). For purposes of comparison, the MACE rate at 3 years in the registry patients was 12.7%.
The advantage for PCI was accounted for largely by a significantly lower rate of urgent revascularizations (4.3% vs 17.2%, P<0.001). Rates of MI and death were numerically but not significantly lower among patients in the PCI arm as well.
Changes in quality-adjusted life-years (QALY), assessed by the EuroQuol 5D health survey at baseline and during follow-up, showed that that PCI/medical therapy was associated with significantly lower numbers of patients with class 2–4 angina at every time point.
Percentage of Patients With Class 2–4 Angina by Study Time Point
| Time point | PC plus medical therapy (%) | Medical therapy only (%) | P |
|---|---|---|---|
| Baseline | 70.2 | 67.7 | 0.42 |
| 1 mo | 10.2 | 28.5 | <0.001 |
| 6 mo | 7.5 | 18.4 | <0.001 |
| 1 y | 5.9 | 15.2 | <0.001 |
| 2 y | 5.9 | 12 | 0.002 |
| 3 y | 5.2 | 9.7 | 0.015 |
The investigators also compared costs of the two treatment options by prospectively measuring the use of healthcare resources associated with the index hospitalization and with follow-up outpatient visits, diagnostic tests, medications, adverse events, and hospitalizations. This included the use of guiding catheters, coronary guidewires, balloon catheters, stents, medication, cardiac catheterization laboratory time, and hospital days for each patient, as well as pharmacy costs for cardiac drugs.
Costs for the PCI group were double that of the medical therapy group at baseline ($9944 vs $4439), 1 year ($13,372 vs $11,499) and 2 years ($15,280 vs $14,485). But by year 3, the cumulative costs of PCI with medical therapy and medical therapy were only $55 apart ($16,792 vs $16,737).
In addition, the analysis showed that at 1, 2, and 3 years the annual follow-up costs for the PCI option were, respectively, 51%, 37%, and 33% of the costs of medical therapy.
At 2 years, the incremental cost-effectiveness ratio (ICER) for was $17,300 per quality-adjusted life-year (QALY). By 3 years, however, the ICER for PCI had plummeted to just $1600 per QALY.
“These results were robust in a variety of sensitivity analyses, including eliminating the cost of the initial angiogram and FFR for the medical therapy,” Fearon said.
Placebo Effect in Doubt
Data from the FAME 2 trial indicate that patients who received FFR-guided therapy “are probably, just by virtue of that assessment, going to be those patients who benefit at least more from an ischemia-reduction standpoint, and that looks like what we’re seeing in these results,” commented Dr Robert W Yeh (Beth Israel Deaconess Medical Center, Boston), a discussant at the briefing.
“We’re seeing reduction in, principally, urgent revascularization, but actually directional benefit for all the end points,” he said.
Yeh added that it would have been interesting to see what the results had been had the FAME 2 trial included a sham PCI arm, similar to that used in ORBITA.
Fearon acknowledged that there is likely a placebo effect associated with PCI procedures. He pointed out, however, that when FFR assessments of all patients assigned to medical therapy in FAME 2, including those in the registry or who were not randomized, were grouped and divided into quintiles, “we notice this very impressive and clear separation of event rates based on the FFR value.”
“It really points to the fact that the degree of ischemia correlates very highly with outcomes,” he said.
Dr Martin Leon (Columbia University Medical Center, New York City), who also attended the briefing, remarked that “you could also argue here that the end points chosen were less subjective to placebo influence.”
“I’m talking about a directional effect on mortality, directional effect on target-vessel MI, and a dramatic effect on the need for urgent revascularization. That may be somewhat affected, but it’s hard to imagine that the consistency of those three categories would be overwhelmed by placebo effects,” he said.
“This is an excellent trial and really helps us as interventionalists,” remarked Dr Molly Szerlip (Heart Hospital Baylor Plano, TX). “It’s a pretty good thing to feel comfortable that revascularization is the way to go if you have FFRs that are significant.”
FAME 2 is supported by St Jude Medical. Fearon reports institutional research support from Medtronic, Abbott Vascular, ACIST Medical, CathWorks, and Edwards Lifesciences, and minor stock options with HeartFlow. Disclosures for the coauthors are listed in the paper. Yeh disclosed grant/research support from Abiomed and Boston Scientific, and consultant fees/honoraria from Abbott Vascular, Boston Scientific and Medtronic. Leon disclosed grant support from St Jude Medical and others, as well as consultant fees/honoraria and intellectual property rights with the Boston Scientific and others. Szerlip reported consultant fees/honoraria from Abbott Vascular, Edwards Lifesciences, and Medtronic.
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