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. References 1 Windecker S , Kolh P , Alfonso F , Collet JP , Cremer J , Falk V , Filippatos G , Hamm C , Head SJ , Jüni P , Kappetein AP , Kastrati A , Knuuti J , Landmesser U , Laufer G , Neumann FJ , Richter DJ , Schauerte P , Sousa Uva M , Stefanini GG , Taggart DP , Torracca L , Valgimigli M , Wijns W , Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) . Eur Heart J 2014 ; 35 : 2541 – 2619 . Google Scholar CrossRef Search ADS PubMed 2 Kang D-Y , Ahn J-M , Lee CH , Lee PH , Park D-W , Kang S-J , Lee S-W , Kim Y-H , Lee CW , Park S-W , Park S-J. Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry . Eur Heart J 2018 ; 39 : 1610 – 1619 . 3 Zimmermann FM , Ferrara A , Johnson NP , van Nunen LX , Escaned J , Albertsson P , Erbel R , Legrand V , Gwon HC , Remkes WS , Stella PR , van Schaardenburgh P , Bech GJ , De Bruyne B , Pijls NH. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial . Eur Heart J 2015 ; 36 : 3182 – 3188 . Google Scholar CrossRef Search ADS PubMed 4 Pijls NH , De Bruyne B , Peels K , van der Voort PH , Bonnier HJ , Bartunek J , Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses . N Engl J Med 1996 ; 334 : 1703 – 1708 . Google Scholar CrossRef Search ADS PubMed 5 van Nunen LX , Zimmermann FM , Tonino PA , Barbato E , Baumbach A , Engstrøm T , Klauss V , MacCarthy PA , Manoharan G , Oldroyd KG , Ver Lee PN , van 't Veer M , Fearon WF , De Bruyne B , Pijls NH ; FAME Study Investigators . Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial . Lancet 2015 ; 386 : 1853 – 1860 . Google Scholar CrossRef Search ADS PubMed 6 Fearon WF , Nishi T , De Bruyne B , Boothroyd DB , Barbato E , Tonino P , Jüni P , Pijls NHJ , Hlatky MA ; FAME 2 Trial Investigators . Clinical outcomes and cost-effectiveness of fractional flow reserve-guided percutaneous coronary intervention in patients with stable coronary artery disease: three-year follow-up of the FAME 2 trial (Fractional flow reserve versus Angiography for Multivessel Evaluation) . Circulation 2018 ; 137 : 480 – 487 . Google Scholar CrossRef Search ADS PubMed 7 Zimmermann FM , De Bruyne B , Pijls NH , Desai M , Oldroyd KG , Park SJ , Reardon MJ , Wendler O , Woo J , Yeung AC , Fearon WF. Rationale and design of the Fractional flow reserve versus Angiography for Multivessel Evaluation (FAME) 3 trial: a comparison of fractional flow reserve-guided percutaneous coronary intervention and coronary artery bypass graft surgery in patients with multivessel coronary artery disease . Am Heart J 2015 ; 170 : 619 – 626.e2 . Google Scholar CrossRef Search ADS PubMed 8 Smits PC , Abdel-Wahab M , Neumann FJ , Boxma-de Klerk BM , Lunde K , Schotborgh CE , Piroth Z , Horak D , Wlodarczak A , Ong PJ , Hambrecht R , Angerås O , Richardt G , Omerovic E ; Compare-Acute Investigators . Fractional flow reserve-guided multivessel angioplasty in myocardial infarction . N Engl J Med 2017 ; 376 : 1234 – 1244 . Google Scholar CrossRef Search ADS PubMed 9 Johnson NP , Tóth GG , Lai D , Zhu H , Açar G , Agostoni P , Appelman Y , Arslan F , Barbato E , Chen SL , Di Serafino L , Domínguez-Franco AJ , Dupouy P , Esen AM , Esen OB , Hamilos M , Iwasaki K , Jensen LO , Jiménez-Navarro MF , Katritsis DG , Kocaman SA , Koo BK , López-Palop R , Lorin JD , Miller LH , Muller O , Nam CW , Oud N , Puymirat E , Rieber J , Rioufol G , Rodés-Cabau J , Sedlis SP , Takeishi Y , Tonino PA , Van Belle E , Verna E , Werner GS , Fearon WF , Pijls NH , De Bruyne B , Gould KL. Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes . J Am Coll Cardiol 2014 ; 64 : 1641 – 1654 . Google Scholar CrossRef Search ADS PubMed 10 Adjedj J , De Bruyne B , Floré V , Di Gioia G , Ferrara A , Pellicano M , Toth GG , Bartunek J , Vanderheyden M , Heyndrickx GR , Wijns W , Barbato E. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease . Circulation 2016 ; 133 : 502 – 508 . Google Scholar CrossRef Search ADS PubMed 11 Agarwal SK , Kasula S , Edupuganti MM , Raina S , Shailesh F , Almomani A , Payne JJ , Pothineni NV , Uretsky BF , Hakeem A. Clinical decision-making for the hemodynamic "gray zone" (FFR 0.75-0.80) and long-term outcomes . J Invasive Cardiol 2017 ; 29 : 371 – 376 . Google Scholar PubMed 12 Courtis J , Rodés-Cabau J , Larose E , Déry JP , Nguyen CM , Proulx G , Gleeton O , Roy L , Barbeau G , Noël B , DeLarochellière R , Bertrand OF. Comparison of medical treatment and coronary revascularization in patients with moderate coronary lesions and borderline fractional flow reserve measurements . Catheter Cardiovasc Interv 2008 ; 71 : 541 – 548 . Google Scholar CrossRef Search ADS PubMed 13 Li L , Li B , Xie H , Zhai CJ , Liu QW , Zhang HZ , Cui LQ. Long-term outcome of intravascular ultrasound application in patients with moderate coronary lesions and grey-zone fractional flow reserve . Coron Artery Dis 2016 ; 27 : 221 – 226 . Google Scholar CrossRef Search ADS PubMed 14 Lindstaedt M , Halilcavusogullari Y , Yazar A , Holland-Letz T , Bojara W , Mügge A , Germing A. Clinical outcome following conservative vs revascularization therapy in patients with stable coronary artery disease and borderline fractional flow reserve measurements . Clin Cardiol 2010 ; 33 : 77 – 83 . Google Scholar CrossRef Search ADS PubMed 15 Kandzari DE , Mauri L , Koolen JJ , Massaro JM , Doros G , Garcia-Garcia HM , Bennett J , Roguin A , Gharib EG , Cutlip DE , Waksman R ; BIOFLOW V Investigators . Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation (BIOFLOW V): a randomised trial . Lancet 2017 ; 390 : 1843 – 1852 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: Mar 22, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera