Multivessel disease occurs in 40 to 65% of patients with acute myocardial infarction [1]. As a consequence, angina despite successful PCI of culprit lesions is frequent and incomplete revascularization has been associated with an increased risk of adverse clinical outcomes [1, 17, 18]. In an effort to correctly identify potentially ischemia-inducing non-culprit lesions, a number of studies investigated whether hemodynamic assessment might provide benefits. Wire-based technologies have consistently shown to reduce the number of non-culprit lesions (and patients) referred to PCI [13, 14, 19], and in the FAMOUS-NSTEMI, FRAME-MI, and FIRE trials, use of physiology-based assessment was also associated with an improved prognosis [2,3,4]. Despite this evidence, a number of reasons limit the use of physiology-based assessments in the setting of ACS. These include cost concerns and device availability, (perceived) lack of conclusive evidence, and a discussion regarding the stability of the boundary conditions (recruitability of the microcirculation) in ACS. More practically, considerations that limit the use of these methods in daily routine include the unwillingness/impossibility to prolong procedural times in the acute setting and detection of additional intermediate lesions only upon revision of the angiogram. QFR might represent an alternative to the gold standard (wire-based) fractional flow reserve with the theoretical advantage of not requiring additional catheterization laboratory time in the acute setting and allowing post hoc analysis after the primary PCI is completed and the patient is discharged from the catheterization laboratory [8, 11]. A recent large trial in an all-comer setting showed that QFR leads to a change in the clinical decision in about 20% of the patients, followed by improved outcomes as shown by a reduction in myocardial infarction and unplanned PCI [20]. In the ACS setting, QFR has been shown provide reproducible and accurate results [6,7,8,9,10,11], but its impact on deferral rate and outcomes has not been definitely demonstrated. Our randomized trial tested the hypothesis that QFR, as compared to angiography, would reduce the rate of patients referred for non-culprit PCI while also improving their 1-year outcomes.

Regarding the physiological endpoint, the expected reduction in the rate of patients referred to PCI for non-culprit lesions was not observed in the current trial. Of note, the proportion of patients assigned to medical therapy in our QFR group was in line with that reported in the fractional flow reserve group in previous trials [4, 13]; in contrast, this proportion was higher in our angiography-guided group as compared to what was observed in previous studies.

Similar considerations apply to the clinical endpoint. In the current study, the incidence of death, myocardial infarction, and unplanned revascularization was similar in both groups and comparable to that seen in the fractional flow reserve group of FRAME-MI and FLOWER-MI. The rate of events was also lower than that observed in the angiography group in the FLOWER-MI [4, 13]. These observations appear to suggest that a more conservative approach (lower rate of non-culprit PCIs, whether QFR- or angiography-guided), as applied in both patients groups in the current study, might improve outcomes in ACS patients. This notion appears to be confirmed by a recent post hoc analysis of FRAME-MI in which the incidence of follow-up events was lowest in patients who did not receive staged PCI as compared to those who underwent both appropriate (QFR < 0.80) and inappropriate (QFR > 0.80) PCI [21].

Although powered for endpoints used in FORZA and FAME, this was a small trial. Notably, patients with non-focal non-culprit lesions (residual QFR < 0.80) were not enrolled to reduce this potential source of confounders, thus allowing a smaller sample size.

To test the use of QFR in clinical practice, we analyzed a broad range of lesions (30–90% by QCA), including the whole spectrum in which fractional flow reserve is known to lead to a reclassification of stenosis severity and a consequent improvement in 1-year outcomes [2, 22]. A very similar range was used in multiple other studies testing similar endpoints [10, 15, 23].

In order to compare QFR with routine practice, we did not introduce a wire-based assessment arm. This comparison would have been interesting.

Our conclusions contrast with those of FAVOR III [24]. Importantly, QFR requires adherence of a specific protocol of image acquisition. In previous trials, angiography was performed after randomization and images were acquired according to these requirements in the QFR group. In clinical routine of ACS, however, focus is set on the treatment of culprit lesions; often, any discussion on the treatment of intermediate lesions is undertaken after the patient’s discharge from the catheterization laboratory and is based on standard-quality images. To reflect clinical practice in the setting of ACS, our study tested the hypothesis that QFR may offer an advantage over angiography based on an analysis of standard images not acquired for the specific purpose of QFR.

Finally, patients with STEMI, NSTEMI, and unstable angina were enrolled in this study. Patients with unstable angina were less than 20% of the total, and sensitivity analyses excluding this group did not yield different results.

In this two-center, blinded, randomized study with external adjudication of events, QFR does not appear superior to angiography in guiding complete revascularization in multivessel disease patients with ACS.