Fractional flow reserve (FFR) is a wire-based technique used to measure pressure differences across a coronary stenosis and thus assess its hemodynamic relevance. It is calculated as the maximum myocardial blood flow in a stenotic territory, divided by normal maximum blood flow in that same territory.2 It is obtained by measuring the ratio of distal coronary pressure to the aortic pressure using pressure-measuring guidewires during pharmacologically induced maximal coronary artery vasodilation. It is generally accepted that a stenosis with a FFR value of less than 0.8 is physiologically significant and thus the lesion should be revascularized. Lesions with a FFR above 0.8 are regarded as physiologically non-ischemic and can be treated medically using pharmacotherapy and/or lifestyle change recommendations.
Three landmark studies have led the evolution of FFR-guided revascularization, namely the DEFER, FAME, and FAME 2 clinical trials.3–5
The DEFER (Deferral versus Performance of Percutaneous Transluminal Coronary Angioplasty in Patients Without Documented Ischaemia)3 trial enrolled 325 patients with stable chest pain scheduled for percutaneous coronary intervention (PCI) of an intermediate stenosis defined as an angiographic stenosis of >50% diameter. Its aim was to assess the outcome and safety of deferring PCI in angiographic stenoses with FFR>0.75. Patients were randomly assigned to deferral (n=91) or performance of PCI (n=90) if FFR was <0.75. At 1-year follow-up, event-free survival rates were similar in the deferral and FFR-guided PCI groups (89% versus 83%, respectively; P=0.27).3 A 5-year follow-up of DEFER patients showed that these outcomes were maintained over time.6 Event-free survival did not differ between the “Defer” and “Perform” groups (80% and 73%, respectively; P=0.52). The composite rate of cardiac death and acute myocardial infarction (AMI) in the “Defer” and “Perform” groups was not significantly different (3.3% versus 7.9%; P=0.21). These results indicate that many patients referred for PCI on the basis of an angiographic significant coronary stenosis have functionally non-significant lesions as indicated by their FFR index.
The FAME trial (Fractional Flow Reserve versus Angiography for Multivessel Evaluation)4 compared two different revascularization strategies: FFR-guided PCI (revascularization of lesions with an FFR ≤0.80) compared to angiography-guided PCI (revascularization of lesions with >50% stenosis) in 1,005 patients with stable coronary artery disease and multivessel disease.4 Results showed that at the 1-year follow-up the primary endpoint (a composite of death, myocardial infarction [MI], and repeat revascularization) was significantly reduced in the FFR-guided group compared with the angiographic-guided group (13.2% versus 18.3%; P=0.02). Further benefit of the FFR strategy was a decrease in the number of stents and the amount of contrast used. Of note, 65% of those with an angiographic stenosis of 50%–70% did not have hemodynamically significant lesions, nor did 20% of those with a stenosis of 71%–90%. This highlights the poor correlation between diameter stenosis by visual estimation versus functional relevance. Long-term follow-up at 5 years showed that major adverse cardiac events (MACE) occurred in 31% of patients in the angiography-guided group versus 28% in the FFR-guided group (relative risk 0.91; 95% CI 0.75–1.10; P=0.31).7 This study showed that FFR-guided PCI can lead to improved patient outcomes and prevent unnecessary stenting.
The FAME 2 trial (Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2) investigated the outcomes of 1,220 patients with stable angina and at least one stenosis with FFR ≤0.80, in which it compared those receiving FFR-guided PCI with patients who received optimal medical therapy alone.5 Recruitment was stopped early due to the compelling results showing that PCI using drug-eluting stent (DES) implantation decreased the primary endpoint of death, non-fatal MI, or urgent revascularization within 2 years compared with medical treatment alone (4.3% versus 12.7%; P<0.001). This was driven by a significantly lower need for urgent revascularization (1.6% versus 11.1%; hazard ratio [HR] 0.13; 95% CI 0.06–0.30; P<0.001). The benefit of FFR-guided PCI over medical therapy alone was still significant at 3 years’ follow-up (MACE 10.1% versus 22.0%; P<0.001).8 The conclusion was that hemodynamically significant lesions should be revascularized rather than treated with optimal medical therapy.
Based on the above evidence, the 2018 European Society of Cardiology (ESC) Guidelines on Myocardial Revascularization regards coronary pressure-derived FFR as the standard of care for the functional assessment of lesion severity in patients with intermediate-grade stenosis without evidence of ischemia in non-invasive testing (Class I recommendation based on Level of Evidence A), and in those with multivessel disease (Class IIa Recommendation based on Level of Evidence B).9
Another wire-based physiological index that does not require pharmacologic hyperemia is iFR. This index is based on the diastolic wave-free period. This is a time frame in the cardiac cycle during which resistance at rest is stable. Therefore, at this time the coronary flow is proportional to the ratio of the proximal and distal coronary artery pressures.2 An iFR of ≤0.89 has been found to be comparable to FFR of ≤0.80.
In the DEFINE-FLAIR trial, 2,492 patients with coronary artery disease were randomized to undergo either iFR-guided or FFR-guided coronary revascularization. The primary endpoint of MACE (composite of death from any cause, non-fatal MI, or unplanned revascularization) at 1 year occurred in 6.8% in patients randomized to iFR-guided revascularization versus 7.0% in patients randomized to FFR-guided revascularization (P<0.001 for non-inferiority; HR 0.95; 95% CI 0.68–1.33; P=0.78).10 Coronary revascularization guided by iFR was non-inferior to revascularization guided by FFR.
In the iFR-SWEDEHEART trial, 2,037 participants with stable angina or an acute coronary syndrome were randomly assigned to undergo revascularization guided by either iFR or FFR; iFR was non-inferior to FFR, with the primary endpoint of death from any cause, non-fatal MI, or unplanned revascularization occurring in 6.7% of the iFR group and 6.1% in the FFR group (P=0.007 for non-inferiority; HR 1.12; 95% CI 0.79–1.58; P=0.53).11