Meta-Analysis of Death and Myocardial Infarction in the DEFINE-FLAIR and iFR-SWEDEHEART Trials
2017; Lippincott Williams & Wilkins; Volume: 136; Issue: 24 Linguagem: Inglês
10.1161/circulationaha.117.030430
ISSN1524-4539
AutoresColin Berry, John McClure, Keith G. Oldroyd,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculationVol. 136, No. 24Meta-Analysis of Death and Myocardial Infarction in the DEFINE-FLAIR and iFR-SWEDEHEART Trials Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBMeta-Analysis of Death and Myocardial Infarction in the DEFINE-FLAIR and iFR-SWEDEHEART Trials Colin Berry, MBChB, PhD, John D. McClure, PhD and Keith G. Oldroyd, MD(Hons) Colin BerryColin Berry British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (C.B., J.B.M.) West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, United Kingdom (C.B., K.G.O.). , John D. McClureJohn D. McClure British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (C.B., J.B.M.) and Keith G. OldroydKeith G. Oldroyd West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, United Kingdom (C.B., K.G.O.). Originally published28 Sep 2017https://doi.org/10.1161/CIRCULATIONAHA.117.030430Circulation. 2017;136:2389–2391Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 In patients with coronary heart disease, revascularization can improve symptoms and, in certain high-risk subgroups, may improve prognosis. Coronary angiography provides anatomic information, and the physiological significance of a stenosis can be determined using fractional flow reserve (FFR). Decisions on the need for and mode of revascularization can be optimized using FFR. However, this process involves administering adenosine to induce hyperemia. Generally, this is well tolerated, but in some healthcare systems, adenosine is either not licensed, unavailable, or expensive, limiting the use of FFR-guided management.Recently, alternative approaches to FFR have emerged, including resting indices such as Pd/Pa and instantaneous wave free ratio (iFR).1,2 Hybrid algorithms incorporating a resting index reduce the need for adenosine by ≈50% or a hybrid algorithm utilizing contrast FFR reduces adenosine use even further (~65%).3 These diagnostic approaches represent clinically useful advances provided health outcomes are not compromised.The DEFINE-FLAIR trial (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation)1 and the iFR-SWEDE-HEART trial (Instantaneous Wave-free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome)2 compared iFR- versus FFR-guided management using binary cutoff values in both groups. The primary composite outcome of death, myocardial infarction (MI), and urgent revascularization at 12 months and the noninferiority designs were consistent across both trials. Overall, an iFR-guided strategy was associated with a lower use of revascularization, and the primary end point results of both trials met the prespecified noninferiority criteria. The numerically dominant component of the primary outcome was unplanned revascularization. The rationale of our study was to assess the risk of death and MI between the iFR- and FFR-guided groups in a pooled analysis of these trials.Our objective was to undertake a meta-analysis of the pooled events for death and MI in the DEFINE-FLAIR and iFR-SWEDE-HEART trials. The principal summary measure was the risk ratio (95% confidence interval [CI] and P value) calculated for each study. Meta-analysis estimates were calculated from a random effects model using the REML method. Fixed effects analyses using the Cochrane-Mantel-Haenzel method produced near identical results (not shown). I2 was used to measure the consistency of the meta-analysis. The analysis was conducted with R (version 3.10) using the metaphor (https://CRAN.R-project.org/package=metafor) and rmeta (https://CRAN.R-project.org/package=rmeta) packages.The study characteristics and results are summarized in the Table. In total, 160 deaths or MI events occurred in 4345 participants during the 12 months after randomization. Of these events, 90 occurred in the iFR group (n=2159), and 70 events occurred in the FFR group (n=2186) (hazard ratio, 1.30; 95% CI, 0.96−1.77; P=0.09). Considering the hazard ratio for death or MI, the lower CI limit crosses unity. The upper CI limit indicates that the risk of this adverse outcome could be ≤77% greater for iFR guidance compared with FFR guidance. No evidence of heterogeneity was found between the 2 studies (I2 was 0% and χ2P>0.5 for all analyses and unplanned revascularizations were I2=16% and χ2P=0.28). We identified a risk of bias in these trials because any coronary revascularization after 60 days was defined as unplanned, but this procedure (a primary outcome event) was ordered by a physician who may have had knowledge of the treatment group assignment because of the open-label trial design (DEFINE-FLAIR attempted to blind the treating clinician to whether iFR or FFR was performed, but this was not done in iFR-SWEDE-HEART).In the DEFINE-FLAIR and iFR-SWEDE-HEART trials, we observed a numeric excess of death or MI events in the iFR compared with the FFR groups. Directional consistency exists for this outcome in both trials and also when considering death and MI as separate outcomes. Both trials have relevant design limitations. First, because of the concordance between iFR and FFR in 80% of patients, the randomized strategy could only influence outcome in 20% of trial participants, diluting the power of both studies to detect a clinically meaningful difference in outcomes. Second, in the context of other evidence, the discordance between iFR and FFR is greatest in stenoses of the left main and proximal coronary arteries,4,5 which is where revascularization may confer a survival advantage. The distribution of coronary disease in the trial participants has not been reported. Finally, the populations studied in both trials were at relatively low cardiovascular risk, with incidence of death, MI, and repeat revascularization at 1 year ≈50% of what was observed in the FAME trial (Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention), highlighting the limited power for detecting any difference in clinically important health outcomes between the 2 strategies in the current trials.In conclusion, in a pooled meta-analysis of the DEFINE-FLAIR and iFR-SWEDE-HEART trials, a numeric excess of death and MI events occurred in the iFR group that is not statistically significant and, therefore, hypothesis generating. Considering death and MI, iFR-guided management may not be noninferior to FFR-guided management. Further research seems warranted.Table. Unplanned Revascularization and Spontaneous Adverse Outcomes at 12 Months in DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome) TrialsiFR n (%)FFR n (%)Risk Ratio95% CIP ValueUnplanned revascularization DEFINE-FLAIR46 (4.0)63 (5.3)0.75(0.52−1.09)0.13 iFR-SWEDEHEART47 (4.6)46 (4.6)1.02(0.68−1.51)0.94 Overall0.87(0.65−1.16)0.34Test for heterogeneity: χ2 = 1.18 df=1 (P=0.277), I2 = 15.6%Nonfatal myocardial infarction DEFINE-FLAIR31 (2.7)28 (2.4)1.14(0.69−1.89)0.61 iFR-SWEDEHEART22 (2.2)17 (1.7)1.29(0.69−2.41)0.43 Overall1.20(0.81−1.77)0.37Test for heterogeneity: χ2 = 0.09 df=1 (P=0.767), I2 = 0%Death DEFINE-FLAIR22 (1.9)13 (1.1)1.74(0.88−3.44)0.11 iFR-SWEDEHEART15 (1.5)12 (1.2)1.24(0.59−2.64)0.57 Overall1.50(0.90−2.48)0.12Test for heterogeneity: χ2 = 0.42 df=1 (P=0.516), I2 = 0%Death or myocardial infarction DEFINE-FLAIR53 (4.6)41 (3.5)1.33(0.89−1.98)0.16 iFR-SWEDEHEART37 (3.7)29 (2.9)1.27(0.79−2.05)0.33 Overall1.30(0.96−1.77)0.09The DEFINE-FLAIR trial (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) randomized 2492 participants, and primary outcome data were presented for 2330 (93%) (iFR group, n=1148, and FFR group, n=1182, respectively). Ninety-five participants in the iFR group were withdrawn from the study before or at 1 year, and 71 participants were withdrawn in the FFR group. The iFR-SWEDEHEART trial (Instantaneous Wave-free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome) randomized 2037 participants, and primary outcome data were available for 2019 (99%) (iFR group, n=1012, and FFR group, n=1007, respectively). Test for heterogeneity: χ2 = 0.02 df=1 (P=0.886), I2 = 0%.Sources of FundingThis work was supported by the University of Glasgow and the British Heart Foundation (RE/13/5/30177, PG/14/97/31263). The funders had no involvement in the analysis.DisclosuresDr Berry received a significant research grant and modest honoraria; and, based on an institutional agreement with the University of Glasgow, acted as a consultant to Abbott Vascular. The company had no involvement in any aspect of the manuscript. Dr Oldroyd received modest honoraria and has acted as a consultant to Abbott Vascular. Dr McClure reports no conflicts of interest.Footnotes*Drs Berry and McClure contributed equally.Circulation is available at http://circ.ahajournals.org.Correspondence to: Colin Berry, MBChB, PhD, British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126 University Place, University of Glasgow, Glasgow, G12 8TA, Scotland, United Kingdom. E-mail [email protected]References1. Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, Bhindi R, Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khashaba A, Laine M, Van Belle E, Krackhardt F, Bojara W, Going O, Härle T, Indolfi C, Niccoli G, Ribichini F, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista SB, Alghamdi A, Hellig F, Koo BK, Nam CW, Shin ES, Doh JH, Brugaletta S, Alegria-Barrero E, Meuwissen M, Piek JJ, van Royen N, Sezer M, Di Mario C, Gerber RT, Malik IS, Sharp ASP, Talwar S, Tang K, Samady H, Altman J, Seto AH, Singh J, Jeremias A, Matsuo H, Kharbanda RK, Patel MR, Serruys P, Escaned J. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI.N Engl J Med. 2017; 376:1824–1834. doi: 10.1056/NEJMoa1700445.CrossrefMedlineGoogle Scholar2. Götberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, Jakobsen L, Olsson SE, Öhagen P, Olsson H, Omerovic E, Calais F, Lindroos P, Maeng M, Tödt T, Venetsanos D, James SK, Kåregren A, Nilsson M, Carlsson J, Hauer D, Jensen J, Karlsson AC, Panayi G, Erlinge D, Fröbert O; iFR-SWEDEHEART Investigators. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI.N Engl J Med. 2017; 376:1813–1823. doi: 10.1056/NEJMoa1616540.CrossrefMedlineGoogle Scholar3. Johnson NP, Jeremias A, Zimmermann FM, Adjedj J, Witt N, Hennigan B, Koo BK, Maehara A, Matsumura M, Barbato E, Esposito G, Trimarco B, Rioufol G, Park SJ, Yang HM, Baptista SB, Chrysant GS, Leone AM, Berry C, De Bruyne B, Gould KL, Kirkeeide RL, Oldroyd KG, Pijls NHJ, Fearon WF. Continuum of vasodilator stress from rest to contrast medium to adenosine hyperemia for fractional flow reserve assessment.JACC Cardiovasc Interv. 2016; 9:757–767. doi: 10.1016/j.jcin.2015.12.273.CrossrefMedlineGoogle Scholar4. Kobayashi Y, Johnson NP, Berry C, De Bruyne B, Gould KL, Jeremias A, Oldroyd KG, Pijls NHJ, Fearon WF; CONTRAST Study Investigators. The influence of lesion location on the diagnostic accuracy of adenosine-free coronary pressure wire measurements.JACC Cardiovasc Interv. 2016; 9:2390–2399. doi: 10.1016/j.jcin.2016.08.041.CrossrefMedlineGoogle Scholar5. Hennigan B, Oldroyd KG, Berry C, Johnson N, McClure J, McCartney P, McEntegart MB, Eteiba H, Petrie MC, Rocchiccioli P, Good R, Lindsay MM, Hood S, Watkins S. Discordance between resting and hyperemic indices of coronary stenosis severity: the VERIFY 2 study (A Comparative Study of Resting Coronary Pressure Gradient, Instantaneous Wave-Free Ratio and Fractional Flow Reserve in an Unselected Population Referred for Invasive Angiography).Circ Cardiovasc Interv. 2016; 9:e004016. doi: 10.1161/CIRCINTERVENTIONS.116.004016.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kasturi S (2022) Left Main Coronary Artery Disease: Current Updates on CABG versus PCI Coronary Artery Bypass Surgery [Working Title], 10.5772/intechopen.104755 Gabara L, Hinton J, Gilpin T and Curzen N (2021) Fractional flow reserve derived from coronary computed tomography: where are we now and where are we heading?, Future Cardiology, 10.2217/fca-2020-0058, 17:4, (723-741), Online publication date: 1-Jul-2021. Leone A, Arioti M, Cialdella P, Vergallo R, Zimbardo G, Migliaro S, Anastasia G, Di Giusto F, Galante D, Basile E, Pepe F, Ierardi C, D'Amario D, Burzotta F, Aurigemma C, Niccoli G, Trani C and Crea F (2021) Prognostic impact of FFR/contrast FFR discordance, International Journal of Cardiology, 10.1016/j.ijcard.2020.11.011, 327, (40-44), Online publication date: 1-Mar-2021. Tomaniak M, Masdjedi K, Zandvoort L, Neleman T, Tovar Forero M, Vermaire A, Kochman J, Kardys I, Dekker W, Wilschut J, Diletti R, Jaegere P, Van Mieghem N, Zijlstra F and Daemen J (2020) Correlation between 3D‐QCA based FFR and quantitative lumen assessment by IVUS for left main coronary artery stenoses, Catheterization and Cardiovascular Interventions, 10.1002/ccd.29151, 97:4, Online publication date: 1-Mar-2021. Modi B and Perera D (2021) How to select patients requiring coronary revascularisation using coronary physiology, JRSM Cardiovascular Disease, 10.1177/2048004020979476, 10, (204800402097947), Online publication date: 1-Jan-2021. Driessen R, de Waard G, Stuijfzand W, Raijmakers P, Danad I, Bom M, Min J, Leipsic J, Ahmadi A, van de Ven P, Knuuti J, van Rossum A, Davies J, van Royen N, Narula J and Knaapen P (2020) Adverse Plaque Characteristics Relate More Strongly With Hyperemic Fractional Flow Reserve and Instantaneous Wave-Free Ratio Than With Resting Instantaneous Wave-Free Ratio, JACC: Cardiovascular Imaging, 10.1016/j.jcmg.2019.06.013, 13:3, (746-756), Online publication date: 1-Mar-2020. Chernyak A, Dzeshka M, Snezhitskiy V, Yanushka A and Maksimchik A (2020) PERCUTANEOUS CORONARY INTERVENTIONS: INTRAVASCULAR IMAGING AND ASSESSMENT OF INTRACORONARY HAEMODYNAMICS, Journal of the Grodno State Medical University, 10.25298/2221-8785-2020-18-5-513-522, 18:5, (513-522), . Bae J, Corban M, Seo Y, Kim T, Lee G, Kwon T, Kim K, Song I, Lee M, Rihal C and Lerman A (2020) Ten-year clinical outcomes of an intermediate coronary lesion; prognosis and predictors of major adverse cardiovascular events, International Journal of Cardiology, 10.1016/j.ijcard.2019.06.076, 299, (26-30), Online publication date: 1-Jan-2020. Dérimay F, Johnson N, Zimmermann F, Adjedj J, Witt N, Hennigan B, Koo B, Barbato E, Esposito G, Trimarco B, Rioufol G, Park S, Baptista S, Chrysant G, Leone A, Jeremias A, Berry C, De Bruyne B, Oldroyd K, Pijls N and Fearon W (2019) Predictive factors of discordance between the instantaneous wave‐free ratio and fractional flow reserve, Catheterization and Cardiovascular Interventions, 10.1002/ccd.28116, 94:3, (356-363), Online publication date: 1-Sep-2019. Modi B, Rahman H, Arri S, Ellis H, Mills M, Williams R, Asrress K, Clapp B, Redwood S and Perera D (2019) Resting Coronary Flow Varies With Normal Cardiac Catheter Laboratory Stimuli, Cardiovascular Revascularization Medicine, 10.1016/j.carrev.2018.10.010, 20:8, (669-673), Online publication date: 1-Aug-2019. Kern M, Berry C, deBruyne B, Fearon W, Jeremias A, Johnson N, Kandzari D, Kirtane A, Moses J, Krucoff M and Stone G (2019) Conversation in cardiology: Is there a need for clinical trials for the nonhyperemic pressure ratios?, Catheterization and Cardiovascular Interventions, 10.1002/ccd.28336, 94:2, (227-232), Online publication date: 1-Aug-2019. Cabrales J, del Portillo J and Echeverri D (2019) Flujo de reserva fraccional, relación de la presión instantánea en el periodo libre de ondas, y angiotomografía de arterias coronarias, Revista Colombiana de Cardiología, 10.1016/j.rccar.2018.11.003, 26, (190-197), Online publication date: 1-Jul-2019. Lehmann R (2019) iFR-Messung: Hämodynamische Relevanz von Koronarläsionen, Deutsches Ärzteblatt Online, 10.3238/PersKardio..2019.04.12.06 Younus M and Seto A (2019) Clinical Outcomes Data for Instantaneous Wave-Free Ratio-Guided Percutaneous Coronary Intervention, Interventional Cardiology Clinics, 10.1016/j.iccl.2018.11.003, 8:2, (121-129), Online publication date: 1-Apr-2019. Shah S and Pfau S (2019) Coronary Physiology in the Cardiac Catheterization Laboratory, Journal of Clinical Medicine, 10.3390/jcm8020255, 8:2, (255) Aoun J, Lahsaei S, Zahm C, Bhat T and Carrozza J (2018) Validation and comparison of non‐hyperemic pressure reserve to fractional flow reserve for assessment of coronary artery stenosis: A real world study, Catheterization and Cardiovascular Interventions, 10.1002/ccd.27834, 93:2, (250-255), Online publication date: 1-Feb-2019. Maznyczka A and Berry C (2019) Contrast fractional flow reserve: Attractive alternative to non-hyperaemic pressure ratios for coronary disease evaluation, International Journal of Cardiology, 10.1016/j.ijcard.2018.10.058, 275, (46-47), Online publication date: 1-Jan-2019. G Toth G and Wijns W (2018) Circulus vitiosus of validation , European Heart Journal, 10.1093/eurheartj/ehy724, 39:46, (4082-4085), Online publication date: 7-Dec-2018. Cesaro A, Gragnano F, Di Girolamo D, Moscarella E, Diana V, Pariggiano I, Alfieri A, Perrotta R, Golino P, Cesaro F, Mercone G, Campo G and Calabrò P (2018) Functional assessment of coronary stenosis: an overview of available techniques. Is quantitative flow ratio a step to the future?, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2018.1540303, 16:12, (951-962), Online publication date: 2-Dec-2018. Ligthart J, Masdjedi K, Witberg K, Mastik F, van Zandvoort L, Lemmert M, Wilschut J, Diletti R, de Jaegere P, Zijlstra F, Kardys I, Van Mieghem N and Daemen J (2018) Validation of Resting Diastolic Pressure Ratio Calculated by a Novel Algorithm and Its Correlation With Distal Coronary Artery Pressure to Aortic Pressure, Instantaneous Wave–Free Ratio, and Fractional Flow Reserve, Circulation: Cardiovascular Interventions, 11:12, Online publication date: 1-Dec-2018. Leone A, Lassandro Pepe F, Arioti M and Crea F (2018) Contrast Fractional Flow Reserve (cFFR): A pragmatic response to the call for simplification of invasive functional assessment, International Journal of Cardiology, 10.1016/j.ijcard.2018.04.048, 268, (45-50), Online publication date: 1-Oct-2018. Vojáček J (2018) iFR and FFR - present possibilities of establishing a functional significance of coronary stenosis, Intervenční a akutní kardiologie, 10.36290/kar.2018.038, 17:2, (62-65), Online publication date: 1-May-2018. AL-Obaidi F, Fearon W and Yong A (2018) Invasive physiological indices to determine the functional significance of coronary stenosis, IJC Heart & Vasculature, 10.1016/j.ijcha.2018.02.003, 18, (39-45), Online publication date: 1-Mar-2018. Chacko Y and Fearon W (2017) Should We Just Go With the Flow?, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2017.10.040, 10:24, (2525-2527), Online publication date: 1-Dec-2017. van't Veer M, Pijls N, Hennigan B, Watkins S, Ali Z, De Bruyne B, Zimmermann F, van Nunen L, Barbato E, Berry C and Oldroyd K (2017) Comparison of Different Diastolic Resting Indexes to iFR, Journal of the American College of Cardiology, 10.1016/j.jacc.2017.10.066, 70:25, (3088-3096), Online publication date: 1-Dec-2017. December 12, 2017Vol 136, Issue 24 Advertisement Article InformationMetrics © 2017 The Authors.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.117.030430PMID: 28972006 Originally publishedSeptember 28, 2017 Keywordsmyocardial infarctioninstantaneous wave-free ratiometa-analysisdeathfractional flow reservePDF download Advertisement SubjectsAngiographyMeta AnalysisPercutaneous Coronary InterventionPrognosisRevascularization
Referência(s)