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Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry’†, by D.-Y. Kang et al., on page 1610. Slave to the traffic light Traffic lights represent a type of decision common to many aspects of medicine: do (green), don’t (red), or maybe (yellow). While traffic lights remain a powerful guideline for driving safely, we have on rare occasion stopped at a green light (when a child ran into the intersection) or ran a red light (when racing to the hospital for an emergency at 2 o’clock in the morning). And how do we react to a yellow light? While perhaps befuddling to novice drivers (the formal rule demands that we stop unless unable to ‘stop safely’), with experience we all reach a common, practical answer: it depends. Wet roads, late for work, fast speed, or vehicle on your tail? Go! Lazy weekend, unfamiliar city, slow speed, or police car nearby? Stop! Fittingly, cardiology guidelines1 have now taken to coding their recommendations using a traffic light colour scheme: class I (recommended, green), class III (not recommended, red), and class II (with divisions IIa = should consider, yellow; and IIb = may consider, orange). Much of clinical medicine focuses on a narrow application of the guidelines in class I and class III scenarios, while—perhaps befuddling to trainees—with experience we all reach a pragmatic answer for class II options: patient preference (coupled with education and informed consent) and clinical judgement. With this analogy in mind, we turn to the article by Kang et al. in the current issue of the European Heart Journal.2 Their manuscript addresses the so-called ‘grey zone’ of fractional flow reserve (FFR), denoting values between 0.75–0.80. While the initial DEFER trial3 used an FFR < 0.75 threshold for revascularization based on a unique multi-test validation before and after revascularization,4 the subsequent FAME family of studies,5–7 and other trials8 moved to an FFR ≤ 0.80 threshold in a desire to avoid undertreatment. Because FFR = 0.75–0.80 values occur in approximately 15% of lesions (about one in seven patients),9 their optimal treatment deserves further examination. IRIS-FFR registry Using a large, prospective Korean registry, the authors analysed a total of 1334 de novo coronary lesions in the grey zone from 1334 patients, representing the largest such cohort to date.2 About half of the lesions underwent revascularization in non-randomized fashion based on unspecified and unknowable clinical factors. The revascularized patients had more frequent multivessel disease and acute coronary syndrome presentations, as well as angiographically more severe and complex lesions. During a median follow-up of 2.9 years, no statistically significant difference in outcomes [composite of all-cause mortality, target vessel myocardial infarction, and target vessel revascularization (TVR)] existed between the deferred and revascularized lesions. However, a significant increase in myocardial infarction occurred in the revascularized group, mainly due to an increase in periprocedural infarction. These results persisted even after adjustment for several potential confounders. The authors deserve compliments for a rigorous analysis. Particular strengths include its prospective design, large size, event adjudication by an independent committee, adjustment for potential confounders, and vessel-level outcomes. The unanswerable question remains why some lesions were revascularized and why some were deferred despite similar FFR values. Unfortunately, the authors did not report baseline symptoms, an important contributor to decision making. How abnormal were upstream stress tests? Were lesions in the revascularized group more focal and therefore more suitable for percutaneous coronary intervention (PCI)? Finally, the remarkably low rate of spontaneous myocardial infarction in the IRIS-FFR registry (<1% during 3 years of follow-up) implies some combination of a very low-risk population, excellent medical therapy, and/or insufficient ascertainment of events. Synthesis of existing literature In addition to the new results from Korea,2 several non-randomized, observational studies have examined revascularization vs. deferral for grey zone FFR lesions in cohorts varying from 97 to 453 patients.10–14 While we urge caution when combining observational data using a ‘back-of-the-envelope’ meta-analysis, what can we learn from a synthesis of the literature? First, death and myocardial infarction remain uncommon in the FFR grey zone. Among the 2357 patients from all publications, less than 100 hard events were observed during an average 2.5 years of follow-up (4.4% or 50 of 1129 treated conservatively, and 3.3% or 41 of 1228 treated with revascularization).2,10–14 A random effects meta-analysis suggests that the difference does not reach significance (risk ratio 1.86, 95% confidence interval 0.92–3.75, P=0.08). When accounting for the length of follow-up, these numbers imply an approximate 1.5% per year rate of death or myocardial infarction. Only two of the six studies found significant differences in hard endpoints but were mutually inconsistent: one study in favour2 and one study against10 conservative treatment. The other cohorts did not observe a significant difference, probably due to lack of power in small populations.11–14 Second, subsequent TVR takes place in a small minority of stenoses with FFR values in the grey zone. Although numerically greater in conservatively treated lesions (8.0% or 90 of 1129 treated conservatively, and 5.9% or 72 of 1228 treated with revascularization), a random effects meta-analysis did not reach statistical significance (risk ratio 1.55, 95% confidence interval 0.91–2.65, P=0.11). Scaling for the average 2.5 years of follow-up implies an approximate 2–3% per year rate of TVR. It is important to realize that most studies discount initial revascularizations in the PCI group. Indeed, TVR would be much higher in the PCI arm if those procedures were counted. TVR for grey zone FFR lesions will always be lower with a strategy of initial medical therapy because 100% of the revascularization group receives an immediate TVR. As a counterargument, initial revascularization may prevent the need for a second procedure and its accompanying burden, highlighting the importance of patient preference, especially in the presence of limiting symptoms. Similarly, composite major adverse cardiac events, although somewhat heterogeneously defined among the studies, reached every possible conclusion: neutral in the two largest series,2,10 favouring revascularization,11–13 and favouring conservative treatment.14 Stop or go? Take home figure summarizes the clinical factors and randomized literature organized using the traffic light analogy for grey zone FFR. Several aspects warrant specific comment. First, we know already from the FFR risk continuum9 that lesions with a value 0.75–0.80 have a worse natural history than those >0.80. Therefore, the relevant clinical question must focus on medical therapy vs. revascularization for lesions within the 0.75–0.80 range, not how these grey zone stenoses fare in relation to different stenoses with higher or lower FFR values. Second, all published studies employed observational designs,2,10–14 whereby treatment was determined by the physician, thereby creating the serious potential for allocation bias. The awaited GzFFR results (clinicaltrials.gov NCT02425969) will be the first to randomize lesions within the specific FFR range 0.75–0.82, with its 108-subject sample size powered for angina status as the primary outcome. Take home figure View largeDownload slide Traffic light analogy for fractional flow reserve (FFR). When confronted with an FFR value above 0.80 (red traffic light), the usual response should be to avoid revascularization (stop!). Conversely, a lesion whose FFR value falls below 0.75 (green traffic light) should most often be revascularized (go!). In between falls the FFR ‘grey zone’—much like a yellow traffic light—where patient preference and clinical judgement decide. Take home figure View largeDownload slide Traffic light analogy for fractional flow reserve (FFR). When confronted with an FFR value above 0.80 (red traffic light), the usual response should be to avoid revascularization (stop!). Conversely, a lesion whose FFR value falls below 0.75 (green traffic light) should most often be revascularized (go!). In between falls the FFR ‘grey zone’—much like a yellow traffic light—where patient preference and clinical judgement decide. Third, the existing observational literature—with its important caveat regarding potential bias—does not indicate a consistent adverse signal for hard endpoints of death or myocardial infarction. Given the low lesion-related event rates in the FFR grey zone coupled with its 15% prevalence,9 an enormous (and perhaps prohibitive) number of subjects would need to be screened for a properly powered randomized controlled trial. Fourth, because even best-generation drug-eluting stents still carry a 1-year risk of target lesion death or myocardial infarction around 4–8% and clinically driven repeat revascularization of 2%,15 the natural history of a grey zone FFR lesion would need to be sufficiently greater to offer a reasonable trade-off. In conclusion, when approaching a grey zone FFR value—or yellow traffic light—we should not always stop or always go. Rather, we must incorporate patient preference and our clinical judgement to make the decision. Although it may not always seem like it, we thankfully have more time in the catheterization laboratory to weigh the options than when hurtling towards an intersection! Conflict of interest: N.P.J. received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; has an institutional licensing and consulting agreement with Boston Scientific for the smart minimum FFR algorithm; has received significant institutional research support from St. Jude Medical (CONTRAST, NCT02184117) and Volcano/Philips Corporation (DEFINE-FLOW, NCT02328820) for studies using intracoronary pressure and flow sensors; and has a patent pending on quantification of aortic valve stenosis. F.M.Z. reports no support or industry relationships. 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European Heart Journal – Oxford University Press
Published: Mar 22, 2018
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