There are theoretical concerns regarding the utility of FFR-guided decision making in patients with non-ST segment elevation (NSTE) –ACS because of global microcirculatory dysfunction. In a prospective study, resistance reserve ratio, which is a measure of the ability to achieve maximal hyperemia, of 50 patients with NSTEMI were compared to those of 50 patients with stable angina and 40 patients with STEMI [3]. There was no significant difference between non-culprit vessels instable angina (2.9 [2.3 − 3.9]) and either culprit vessels in stable angina (2.8 [1.7 − 4.8], p = 0.75) or culprit vessels in NSTEMI (2.46 [1.6 − 3.9], p = 0.61). As expected, IMR was greater in NSTEMI compared with the non-culprit vessels instable angina (22.7 ± 11.36 vs. 16.9 ± 9.06, p = 0.015). These data imply that, in selected patients with NSTEMI, microcirculation can dilate sufficiently to enable maximal hyperemia and measuring FFR in both culprit and the non-culprit vessels may be as reliable as in stable angina. The FAME study included 328 patients with unstable angina (UA) or NSTEMI, of whom 178 were randomized to angiographically guided PCI and 150 to FFR-guided PCI [22]. FFR to guide PCI resulted in similar risk reductions of major adverse cardiac events and its components in patients with UA or NSTEMI, compared with patients with chronic stable angina (absolute risk reduction of 5.1% vs. 3.7%, respectively, p = 0.92). The benefit of using FFR to guide PCI in MVD does not differ between patients with UA or NSTEMI, compared with patients with chronic stable angina. However, this was a secondary analysis of original FAME study [23], and these patients were generally stable prior to the study. Therefore, it is hard to apply this study to general NSTEMI population and should be confirmed in a prospective trial. Carrick et al. tested clinical utility of using FFR to guide decision making in NSTEMI in a retrospective analysis [24]. Five interventional cardiologists independently reviewed the clinical history and coronary angiogram of 100 patients and then made a treatment decision. Following FFR disclosure, the same cardiologists were asked to reevaluate their initial decisions. Cardiologists changed their initial treatment plans in 46% of patients (p = 0.0016). The use of FFR led to increase of medical therapy (24%, p = 0.0016). In a French FFR registry (1075 patients, 19% with recent ACS), FFR disclosure was associated with reclassification of their treatment decision in 43% of the patient [25]. In the RCT, Lessar et al. demonstrated FFR-guided decision making in 70 patients with recent UA or NSTEMI markedly reduces the duration and cost of hospitalization compared with stress perfusion scintigraphy [26]. However, patients in this study were medically stable for 48 h or more, and thereby this was not genuine NSTE-ACS population. The FAMOUS-NSTEMI trial is a prospective multicenter RCT which is designed to assess whether management decisions guided by routine FFR measurement in patients with NSTEMI would be feasible and safe, and would optimize clinical outcome compared with angiography-guided standard care [27]. All patients were to obtain FFR measurement to each vessel containing at least 30% stenosis, but only in the FFR-guided arm was the result revealed to the operators. This study demonstrated that the proportion of patients that were assigned to medical therapy was significantly higher in the FFR-guided group than in the angiography-guided group (22.7% vs. 13.2%, difference 95% (95% CI: 1.4–17.7%), p = 0.022). FFR disclosure resulted in a change in management decision in 38 (21.6%) patients. In terms of clinical outcome, revascularization remained lower in the FFR-guided group (79.0 vs. 86.8%, difference 7.8% (−0.2%, 15.8%), p = 0.054) at 12 months.

The other concern is that whether using contemporary threshold for FFR is safe for deferring PCI in the culprit lesions in patients with NSTE-ACS. In an all-comer ACS population including NSTEMI and STEMI, Potvin et al. demonstrated 201 unselected patients with non-flow-limiting lesions (FFR threshold ≤0.75) had 7.5% cardiac events related to the deferred coronary lesion [28]. Although it seems to be safe to allow deferral of PCI, the use of FFR was neither blinded nor randomized. In particular, plaque rupture can occur at the site of a moderate stenosis with less flow-limiting lesion after thrombus resolution in NSTE-ACS. In case, the stenosis might result in a less significant pressure gradient and higher FFR. Therefore, there is a concern that medical therapy for deferred biologically active plaque may not be effective to prevent ischemic events compared to stable plaque with a similar nonischemic FFR value in stable angina. Although FAME substudy and FAMOUS-NSTEMI trial support the safety and effectiveness of deferring PCI in lesion with FFR >0.80 in non-culprit vessels of patients with NSTE-ACS, there are few data regarding medical treatment of similar culprit lesions. Hakeem et al. compared outcomes in NSTE-ACS patients who did not undergo PCI of any lesion on the basis of FFR to those in a similar group of patients with stable angina [29]. The long-term major adverse cardiovascular events were higher in ACS group than in the stable angina group (25% versus 12%, p < 0.0001). Best cutoffs to predict accuracy for major adverse cardiovascular events is less than 0.84 for ACS and less than 0.81 for stable angina. The 2015 ESC guidelines for the management of NSTE-ACS addressed that the role of FFR in NSTE-ACS still needs to be defined (Table 28.3).

In NSTE-ACS, it can often be difficult to discriminate IRA if there is no locating electrocardiographic sign, no regional wall motion abnormality on 2D-echocardiogram, or no typical angiographic feature such as haziness, luminal irregularity, and filling defect. Invasive image such as intravascular ultrasound, optical coherence tomography may be helpful to identify plaque rupture or dissection. However, these lesions may not be culprit lesion in terms of FFR if there is no flow limitation. Therefore, FFR has the ability to identify the vessel with physiologically reduced flow and hemodynamic instability. As mentioned above, FFR of non-culprit coronary stenoses during PCI has also reliability as those of STEMI [3, 19].