FAME 2: A "Positive" or a "Negative" Trial?
Despite the widely accepted benefit of percutaneous coronary interventions (PCI) in the treatment of acute coronary syndromes (ACS), the role of PCI in patients with stable ischemic heart disease (SIHD) is controversial. The debate revolves around the fact that, although effective for the relief of angina due to demand-induced ischemia, percutaneous revascularization has not been shown to reduce the rate of myocardial infarction (MI) or death due to a cardiac cause. Indeed, the two most recent major trials addressing this issue (COURAGE and BARI 2D) showed no significant differences in favor of PCI compared to optimal medical therapy on cardiovascular outcomes.1-2 In addition, the use of PCI in patients with stable forms of coronary artery disease (CAD) has recently been under increasing scrutiny, particularly owing to the report of an important minority of procedures being performed without appropriate documentation of their need.3 The usefulness of fractional flow reserve (FFR) to limit PCI with stent placement to coronary lesions that are hemodynamically significant—and therefore responsible for the occurrence of myocardial ischemia—was demonstrated in the original FAME trial4. FAME documented the benefit of FFR-guided (over angiography-guided) PCI for the composite endpoint of death, nonfatal MI, and repeat revascularization. However, FAME did not include a comparison between PCI and optimal medical therapy to establish the best initial treatment strategy in patients with SIHD. Hence, FAME 2 was conducted to determine whether FFR-guided PCI with drug eluting stents was superior to optimal medical therapy without revascularization in these patients.5
FAME 2 included stable patients with angiographically-documented CAD and a FFR index ≤ 0.80 in at least one coronary artery. Patients were randomized in an unblinded fashion to FFR-guided PCI plus optimal medical therapy or optimal medical therapy without PCI. All lesions with FFR ≤ 0.80 were treated with drug-eluting stents. Patients with CAD and no lesion with FFR ≤ 0.80 were not randomized but were followed as part of a registry. The planned follow-up was two years and the primary endpoint was the composite of death, MI, or unplanned hospitalization leading to urgent revascularization. Secondary endpoints were the individual components of the primary endpoint and angina class. Revascularization was considered to be urgent when the patient was admitted to the hospital for persistent or increasing chest pain (with or without ECG changes or cardiac biomarker elevation) and revascularization was performed during the same hospitalization. The study design contemplated the recruitment of 816 patients in each group in order to achieve > 84% power to detect a relative risk reduction of 30% with PCI.
Patient recruitment was terminated prematurely at the recommendation of the independent data and safety monitoring board due to the detection of a highly significant difference in the incidence rate of the primary endpoint in favor of PCI. At the point of stoppage, 888 of the planned 1,632 patients had been recruited (447 randomized to PCI plus medical therapy and 441 to medical therapy alone). In addition, 332 patients without FFR ≤ 0.80 were included into the registry, of whom a random 50% (or 166 patients) were followed in the same manner as the randomized patients. The proportion of patients with a primary endpoint event was 4.3% in the PCI group vs. 12.7% in the medical therapy group (p<0.001). However, neither the rate of death from any cause nor the rate of nonfatal MI was significantly different between the two groups. Thus, the difference in the incident rates of the primary endpoint was solely related to a higher rate of urgent revascularization among the patients randomized to medical therapy alone compared to those randomized to FFR-guided PCI (11.1% vs. 1.6%, respectively; hazard ratio with PCI: 0.13; 95% CI 0.06 to 0.30; p<0.001). Among the 56 patients requiring urgent revascularization (seven in the PCI group and 49 in the medical therapy group), 29 patients (52%) had unstable angina without documented ECG or cardiac biomarkers changes. A pre-specified analysis using a landmark point at seven days after randomization showed a greater benefit of PCI after the first week post-procedure. Of note, the benefit of PCI appeared to be greater among patients with FFR index <0.65, compared to those with values between 0.65 and 0.80. The proportion of patients with angina class II to IV was markedly reduced during follow-up in both groups, but this reduction was greater among patients randomized to PCI than among those randomized to medical therapy alone.
Based on these results, the authors conclude that, among patients with stable CAD and hemodynamically significant stenoses, a strategy of FFR-guided PCI plus optimal medical therapy reduces the rate of urgent revascularization compared to optimal medical therapy alone.
FAME 2 has received significant criticism6-7 primarily because the demonstrated benefit of PCI over medical therapy is limited to the "soft" endpoint of urgent revascularization without affecting the incidence of the more meaningful clinical outcomes (i.e., cardiovascular mortality or nonfatal MI, both of which occurred at a very low rate). Further, more than half of the unplanned revascularizations were performed solely on the basis of clinical features (without supporting evidence from cardiac markers or ECG). In the context of a non-blinded trial, there is concern that decisions regarding interventions during follow-up may have been biased by the knowledge of the previous treatment assignment. Finally, the reduced length of follow-up (average seven months) does not address the concerns about the longevity of the PCI benefit regarding need for subsequent revascularization.
The fact that such an important investigative effort leaves critical questions unanswered raises the issue of whether revascularization (planned or unplanned) should indeed be a valid endpoint in a trial of PCI vs. medical therapy. In principle, when one performs a procedure on an individual patient, it is only expected that the need to perform the same procedure during follow-up would be reduced compared to not doing it in the first place. Hence, the question should be: does the initial avoidance of the procedure confer a higher risk to the patient? The appropriate metric for that risk should not be the performance of the same procedure during follow-up, but rather the occurrence of adverse clinical outcomes. In the case of FAME 2, the reduction in the incidence rate of revascularization during follow-up (even if unplanned) does not appear as a meaningful benefit of PCI, because it was not accompanied by a decreased rate of death or MI. In fact, if one assessed FAME 2 as a trial of pre-emptive vs. clinically-driven PCI in patients with FFR ≤0.80, one would conclude that, in the clinically-driven arm, the need for PCI was reduced by about 90% without detriment to the patients in terms of increased death or MI. Others have referred to this as the paradigm of "intervening in all patients to avoid the need to intervene in a few."7
So, what do we tell our patients after FAME 2? Is it better to perform or to defer PCI until it is needed on clinical grounds when we detect a hemodynamically significant lesion by FFR in the catheterization laboratory? From a number of perspectives, it appears more sound to defer, because it would lead to reductions in 1) the risk of peri-procedural MI and other complications; 2) the requirement for dual anti-platelet therapy (which may be beneficial in case of need for non-cardiac surgical procedures); and 3) the costs associated with the procedure.
Also noteworthy from the FAME 2 trial is the efficacy of medical treatment in the relief of angina. Specifically, 296 of 440 pts (67%) randomized to medical therapy had angina class II to IV at baseline. This proportion decreased to 119/412 (29%) at 30 days, to 46/239 (19%) at six months, and to 6/37 (16%) at 12 months. Further, most patients did not have prior non-invasive stress testing. Considering these two previous points, one may conclude that most patients enrolled in FAME 2 underwent coronary angiography and FFR before thorough non-invasive assessment or full treatment of their symptoms.
Hence, a broader issue that merits discussion is related to the appropriate evaluation and treatment of stable patients with chest pain prior to the documentation of CAD (and its hemodynamic significance) by invasive angiography. This topic is highlighted in the accompanying case challenge. When should patients with chronic angina and without previously known CAD undergo coronary angiography?
- When they first present with symptoms?
- Only after non-invasive evaluation of ischemia?
- Only after a trial of medical therapy?
- Only if noninvasive CT angiography shows certain or probable disease of proximal vessels?
A number of ongoing trials will help answer these important questions.8-10 For now, the recently published guidelines recommend the performance of coronary angiography as an initial strategy to assess risk only in patients who survive a cardiac arrest or a life-threatening arrhythmia, or present with symptoms and signs of heart failure.11
- Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503-16.
- BARI 2D Study Group. Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009; 360:2503-15.
- Chan PS, Patel MR, Klein LW, et al. Appropriateness of percutaneous coronary intervention. JAMA 2011; 306:53-61.
- Tonino PAL, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009; 360:213-24.
- De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012; 367:991-1001.
- Boden WE. Which is more enduring – FAME or COURAGE? [Editorial]. N Engl J Med 2012;367:1059-61.
- Fractional flow-reserve-guided PCI in stable coronary disease [Correspondence]. N Engl J Med 2012; 367:2355-6.
- PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain; clinicaltrials.gov identifier NCT01174550).
- RESCUE (Randomized Evaluation of Patients with Stable Angina Comparing Diagnostic Examinations; clinicaltrials.gov identifier NCT01262625).
- ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; clinicaltrials.gov identifier NCT01471522).
- Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012; 60:2564-603.
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