Author + information
- aDivision of Cardiovascular Medicine and Cardiovascular Institute, Stanford University, Stanford, California
- bCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium
- cDepartment of Cardiology, Catharina Hospital, Eindhoven, the Netherlands
- ↵∗Reprint requests and correspondence:
Dr. William F. Fearon, Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University, 300 Pasteur Drive, H2103, Stanford, California 94305.
The clinical utility of measuring fractional flow reserve (FFR) in the cardiac catheterization laboratory to guide the decision regarding coronary revascularization is now well established. In particular, multiple studies have demonstrated the safety of deferring revascularization of coronary lesions with FFR values above 0.75 to 0.80 (1,2). Medical treatment of these lesions avoids the inherent acute and late risks of percutaneous coronary intervention (PCI) and results in equally low if not lower rates of major adverse cardiac events (MACE) during long-term follow-up. Conversely, PCI for stenoses with FFR values ≤0.80 improves outcomes compared with medical therapy (3). To date, most of these data are derived from patients with stable ischemic heart disease (SIHD).
In patients presenting with an acute coronary syndrome (ACS), variable degrees of transient microvascular dysfunction can occur, particularly in the culprit vessel of a patient with ST-segment elevation myocardial infarction (STEMI), due to embolization of ruptured plaque and thrombus, as well as in situ thrombosis, inflammation, and vasoconstriction. The derivation of FFR assumes that microvascular resistance is minimized and stable, which often is not the case in recently infarcted myocardium (4). For this reason, FFR measurement is not recommended in the culprit vessel in the acute setting of STEMI (2). However, data suggest that measurement of FFR in nonculprit vessels of patients with STEMI, where less (if any) transient microvascular dysfunction is expected to occur, is reliable and can be used to guide revascularization decisions (5,6).
In patients with non–ST-segment elevation ACS (NSTE-ACS), less transient microvascular dysfunction is expected in the culprit vessel than in patients with STEMI. For example, one study showed that the index of microcirculatory resistance, a coronary pressure wire-based method for assessing microvascular dysfunction at the time of FFR measurement, in the culprit vessels of NSTE-ACS patients did not differ from those in SIHD patients and was significantly lower than in the culprit vessels of STEMI patients (7). These data imply that measuring FFR in both the culprit and the nonculprit vessels of patients with NSTE-ACS may be as reliable as in SIHD patients.
However, a theoretical concern regarding the safety of deferring PCI in culprit lesions with nonischemic FFR values in patients with NSTE-ACS does exist. In particular, one could envision plaque rupture occurring at the site of a moderate stenosis, which would result in NSTE-ACS, but after spontaneous dissolution of the associated thrombus, the stenosis might become less flow-limiting, resulting in a less significant pressure gradient when FFR was measured. Medical therapy for these biologically active plaques may be less effective than for a stable plaque with a similar nonischemic FFR value.
Despite this concern, studies have shown the utility of FFR-guided PCI in patients with NSTE-ACS. For example, in a substudy of the FAME (Fractional Flow Reserve versus Angiography for Multi-vessel Evaluation) trial, 328 patients with multivessel coronary artery disease and NSTE-ACS were randomized to either FFR-guided PCI or angiography-guided PCI, and were found to have a similar reduction in MACE at 2-year follow-up, when FFR was routinely measured to guide revascularization, as seen in the 677 SIHD patients included in the study (8). Importantly, there was no increase in rates of death, myocardial infarction (MI), or revascularization in the NSTE-ACS patients who had PCI deferred on the basis of an FFR cutoff value >0.80. Of note, most patients with NSTE-ACS in the FFR-guided arm of the FAME study received at least 1 stent, presumably to the culprit lesion.
More recently, in the FAMOUS (Fractional flow reserve vs. angiography in guiding management to optimize outcomes)-NSTEMI trial, 350 patients with non–ST-segment elevation MI were randomized to either FFR-guided PCI or angiography-guided PCI (9). In the 23% of patients randomized to FFR-guided PCI who did not undergo revascularization of any vessel at the time of presentation, the MACE rate at 1-year follow-up was not higher than that in patients in the angiography-guided group who had PCI performed, suggesting that medical therapy of lesions with an FFR >0.80 is safe in patients with NSTE-ACS. However, as in the FAME trial, most of the FFR-guided patients in the FAMOUS-NSTEMI trial received at least 1 stent, presumably to the culprit vessel. Therefore, current data support the safety and effectiveness of deferring PCI in lesions with FFR >0.80 in nonculprit vessels of patients with NSTE-ACS, but there are few data regarding medical treatment of similar culprit lesions.
Given this background, it is interesting to read the paper in this issue of the Journal by Hakeem et al. (10) comparing 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 SIHD patients. Specifically, this was a single-center, retrospective study conducted at a Veterans Affairs medical center comparing the MI and target vessel revascularization (TVR) rates at an average 3.4-year follow-up in 206 NSTE-ACS patients in 262 intermediate lesions in which PCI was deferred because the FFR value was >0.75 to those in 370 SIHD patients with 528 lesions in which PCI was deferred on the basis of the same FFR cutoff value. The investigators used propensity score matching in an attempt to account for baseline differences between the 2 groups.
Not surprisingly, the MI and TVR rates were higher in the NSTE-ACS patients than in the SIHD patients (25% vs. 12%, respectively; p < 0.0001), as demonstrated in numerous previous studies (11,12). Of particular interest in that study is that when the investigators performed receiver-operating characteristic (ROC) curve analysis, they identified the best FFR cutoff value for predicting MI or TVR of ≤0.80 in patients with SIHD, supporting current practice. However, in NSTE-ACS patients, the best cutoff value was ≤0.84, implying that transient microvascular dysfunction might be falsely elevating FFR in a portion of NSTE-ACS patients. The investigators concluded that, when measuring FFR to guide revascularization decisions in NSTE-ACS patients, one should apply the current cutoff value of ≤0.80 with caution and consider adjunctive intravascular imaging in these patients when the FFR value is between 0.80 and 0.85.
This study raises the question of whether we should apply a different FFR cutoff value for patients presenting with NSTE-ACS. There are a few points worth considering before adapting this strategy. First, it is unclear why death was not included in the composite endpoint in this study, as it is, of course, the most important outcome. One wonders if the FFR cutoff value would be closer to ≤0.80 in this cohort had death been included.
Second, there are some technical issues that might explain a higher FFR cutoff value in that study. The exact position of the pressure wire in the vessel was not described. It has been shown that if the sensor is positioned just beyond the lesion, rather than in the distal two-thirds of the vessel (where FFR should be measured), the value will be significantly higher (13). Furthermore, approximately one-half of the patients had FFR measured with intracoronary adenosine at a median dose of 130 μg of intracoronary adenosine, and some patients received only 60 μg, which might have resulted in suboptimal hyperemia and higher FFR values (14).
Third, there are some important features of the study population that should be highlighted. Because this was a select group of predominantly male veterans, it is not clear how these findings apply to the general population of NSTE-ACS patients. Along these lines, the medical therapy given to these patients appeared to be less than optimal, with 14% not receiving a statin and approximately two-thirds not receiving dual antiplatelet therapy. In addition, and perhaps most importantly, most of the high-risk NSTE-ACS patients who present to the cardiac catheterization laboratory clearly have a culprit vessel on the basis of angiographic and clinical findings, which requires PCI. FFR is typically measured in the nonculprit vessel in the case of intermediate disease. This study included only patients who had NSTE-ACS and intermediate disease (with only 20% classified as non–ST-segment elevation MI) and who did not ultimately have PCI performed in any vessel. This patient population may represent a different cohort than typically presents with NSTE-ACS; for example, perhaps these patients had elevated biomarkers or unstable symptoms from other causes than usual epicardial artery plaque rupture. To this end, it would have been interesting to know if the NSTE-ACS patients who had an MI during follow-up underwent revascularization or continued to have no obvious culprit epicardial artery lesion, which would suggest that the original NSTE-ACS presentation had nothing to do with the lesion with a nonischemic FFR.
Fourth, instead of comparing outcomes only to those patients with SIHD who also did not undergo PCI, it would have been interesting to compare event rates with those of NSTE-ACS patients who underwent PCI (on the basis of angiography and/or FFR guidance) in order to gauge at what FFR cutoff value the event rate in medically treated NSTE-ACS patients was lower than those undergoing PCI. The ideal comparator would be patients with NSTE-ACS who had FFR values >0.80 and were randomized to PCI anyway, in which case, if outcomes were improved, one could be more confident in adopting a higher FFR cutoff value in NSTE-ACS patients.
In summary, the bulk of the available data support the role of measuring FFR and applying a cutoff value of 0.80 in stable lesions, that is, in stenoses in stable patients or in nonculprit stenoses in patients presenting with an ACS. The report by Hakeem et al. (10) is actually the first to focus specifically on the clinical outcome of patients in whom the culprit lesion of a recent NSTE-ACS was deferred on the basis of an FFR value >0.80. We do not believe that a higher cutoff should be used. However, despite the limitations of the current study, we should acknowledge the signal suggesting an increased event rate associated with FFR-based deferral of PCI on lesions that are clearly responsible for a recent NSTE-ACS. Until we have more data, FFR-based decision making concerning revascularization of clear culprit stenoses of STEMI and NSTE-ACS should be discouraged (Table 1).
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Fearon has received research support from St. Jude Medical, Medtronic, and ACIST; honoraria from Medtronic; and is a consultant for Medtronic, HeartFlow, and CathWorks. Dr. De Bruyne holds equity shares in Siemens, General Electric, Bayer, Philips, HeartFlow, Edwards LifeSciences, Sanofi, and Omega Pharma; has received grant support through his institution from Abbott, Boston Scientific, Biotronik, and St. Jude Medical; and is a consultant for St. Jude Medical, Opsens, and Boston Scientific. Dr. Pijls is a consultant for St. Jude Medical, Opsens, and Boston Scientific; and holds equity in Heartflow, Philips, ASML, and General Electric.
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