Joo Myung Lee1, Ki Hong Choi1, Bon-Kwon Koo2, Hakim-Moulay Dehbi3, Joon-Hyung Doh4, Chang-Wook Nam5, Eun-Seok Shin6, Christopher M Cook7, Rasha Al-Lamee7, Ricardo Petraco7, Sayan Sen7, Iqbal S Malik7, Sukhjinder S Nijjer7, Hernán Mejía-Rentería8, Eduardo Alegria-Barrero9, Ali Alghamdi10, John Altman11, Sérgio B Baptista12, Ravinay Bhindi13, Waldemar Bojara14, Salvatore Brugaletta15, Pedro Canas Silva16, Carlo Di Mario17,18, Andrejs Erglis19, Robert T Gerber20, Olaf Going21, Tobias Härle22, Farrel Hellig23, Ciro Indolfi24, Luc Janssens25, Allen Jeremias26, Rajesh K Kharbanda27, Ahmed Khashaba28, Yuetsu Kikuta29, Florian Krackhardt30, Mika Laine31, Sam J Lehman32, Hitoshi Matsuo33, Martijin Meuwissen34, Giampaolo Niccoli35, Jan J Piek36, Flavo Ribichini37, Habib Samady38, James Sapontis39, Arnold H Seto40, Murat Sezer41, Andrew S P Sharp42,43, Jasvindar Singh44, Hiroaki Takashima45, Suneel Talwar46, Nobuhiro Tanaka47, Kare Tang48,49, Eric Van Belle50,51, Niels van Royen52, Hugo Vinhas53, Christiaan J Vrints54, Darren Walters55, Hiroyoshi Yokoi56, Bruce Samuels57, Chris Buller58, Manesh R Patel59, Patrick Serruys7, Javier Escaned8, Justin E Davies7. 1. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 2. Seoul National University Hospital and Institute on Aging, Seoul National University, Seoul, South Korea. 3. Cancer Research UK and University College London Cancer Trials Centre, University College London, London, England. 4. Inje University Ilsan Paik Hospital, Daehwa-Dong, South Korea. 5. Keimyung University Dongsan Medical Center, Daegu, South Korea. 6. Ulsan Hospital, Ulsan, South Korea and Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea. 7. Hammersmith Hospital, Imperial College London, London, England. 8. Hospital Clínico San Carlos, IDISSC and Universidad Complutense de Madrid, Madrid, Spain. 9. Hospital Universitario de Torrejón, Universidad Francisco de Vitoria, Madrid, Spain. 10. King Abdulaziz Medical City Cardiac Center, Riyadh, Saudi Arabia. 11. Colorado Heart and Vascular, Lakewood, Colorado. 12. Hospital Prof Doutor Fernando Fonseca, Amadora, Portugal. 13. Royal North Shore Hospital, Sydney, Australia. 14. Gemeinschaftsklinikum Mittelrhein, Kemperhof Koblenz, Koblenz, Germany. 15. Cardiovascular Institute, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. 16. Hospital Santa Maria, Lisbon, Portugal. 17. Royal Brompton Hospital, Imperial College London, London, England. 18. University of Florence, Florence, Italy. 19. Pauls Stradins Clinical University Hospital, Riga, Latvia. 20. Conquest Hospital, St Leonards-on-Sea, England. 21. Sana Klinikum Lichtenberg, Lichtenberg, Germany. 22. Klinikum Oldenburg, European Medical School, Carl von Ossietzky University, Oldenburg, Germany. 23. Sunninghill Hospital, Johannesburg, South Africa. 24. University Magna Graecia, Catanzaro, Italy. 25. Imelda Hospital, Bonheiden, Belgium. 26. Stony Brook University Medical Center, New York, New York. 27. John Radcliffe Hospital, Oxford University Hospitals Foundation Trust, Oxford, England. 28. Ain Shams University, Cairo, Egypt. 29. Fukuyama Cardiovascular Hospital, Fukuyama, Japan. 30. Charite Campus Virchow Klinikum, Universitaetsmedizin, Berlin, Germany. 31. Helsinki University Hospital, Helsinki, Finland. 32. Flinders University, Adelaide, South Australia, Australia. 33. Gifu Heart Center, Gifu, Japan. 34. Amphia Hospital, Breda, the Netherlands. 35. Catholic University of the Sacred Heart, Rome, Italy. 36. AMC Heart Center, Academic Medical Center, Amsterdam, the Netherlands. 37. University Hospital Verona, Verona, Italy. 38. Emory University, Atlanta, Georgia. 39. Monash Heart, Monash University, Melbourne, Victoria, Australia. 40. Veterans Affairs Long Beach Healthcare System, Long Beach, California. 41. Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey. 42. Royal Devon and Exeter Hospital, Exeter, England. 43. University of Exeter, Exeter, England. 44. Washington University School of Medicine in St Louis, St Louis, Missouri. 45. Aichi Medical University Hospital, Aichi, Japan. 46. Royal Bournemouth General Hospital, Bournemouth, England. 47. Tokyo Medical University, Tokyo, Japan. 48. Essex Cardiothoracic Centre, Basildon, England. 49. Anglia Ruskin University, Chelmsford, England. 50. Institut Coeur Poumon, Lille University Hospital, Lille, France. 51. INSERM Unité 1011, Lille, France. 52. VU University Medical Center, Amsterdam, the Netherlands. 53. Hospital Garcia de Horta, Lisbon, Portugal. 54. Antwerp University Hospital, Antwerp, Belgium. 55. Prince Charles Hospital, Brisbane, Queensland, Australia. 56. Fukuoka Sannou Hospital, Fukuoka, Japan. 57. Cedars-Sinai Heart Institute, Los Angeles, California. 58. St Michaels Hospital, Toronto, Ontario, Canada. 59. Duke University, Durham, North Carolina.
Abstract
Importance: Invasive physiologic indices such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are used in clinical practice. Nevertheless, comparative prognostic outcomes of iFR-guided and FFR-guided treatment in patients with type 2 diabetes have not yet been fully investigated. Objective: To compare 1-year clinical outcomes of iFR-guided or FFR-guided treatment in patients with and without diabetes in the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization (DEFINE-FLAIR) trial. Design, Setting, and Participants: The DEFINE-FLAIR trial is a multicenter, international, randomized, double-blinded trial that randomly assigned 2492 patients in a 1:1 ratio to undergo eitheriFR-guided or FFR-guided coronary revascularization. Patients were eligible for trial inclusion if they had intermediate coronary artery disease (40%-70% diameter stenosis) in at least 1 native coronary artery. Data were analyzed between January 2014 and December 2015. Interventions: According to the study protocol, iFR of 0.89 or less and FFR of 0.80 or less were used as criteria for revascularization. When iFR or FFR was higher than the prespecified threshold, revascularization was deferred. Main Outcomes and Measures: The primary end point was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. The incidence of MACE was compared according to the presence of diabetes in iFR-guided and FFR-guided groups. Results: Among the total trial population (2492 patients), 758 patients (30.4%) had diabetes. Mean age of the patients was 66 years, 76% were men (1868 of 2465), and 80% of patients presented with stable angina (1983 of 2465). In the nondiabetes population (68.5%; 1707 patients), iFR guidance was associated with a significantly higher rate of deferral of revascularization than the FFR-guided group (56.5% [n = 477 of 844] vs 46.6% [n = 402 of 863]; P < .001). However, it was not different between the 2 groups in the diabetes population (42.1% [n = 161 of 382] vs 47.1% [n = 177 of 376]; P = .15). At 1 year, the diabetes population showed a significantly higher rate of MACE than the nondiabetes population (8.6% vs 5.6%; adjusted hazard ratio [HR], 1.88; 95% CI, 1.28-2.64; P < .001). However, there was no significant difference in MACE rates between iFR-guided and FFR-guided groups in both the diabetes (10.0% vs 7.2%; adjusted HR, 1.33; 95% CI, 0.78-2.25; P = .30) and nondiabetes population (4.7% vs 6.4%; HR, 0.83; 95% CI, 0.51-1.35; P = .45) (interaction P = .25). Conclusions and Relevance: The diabetes population showed significantly higher risk of MACE than the nondiabetes population, even with the iFR-guided or FFR-guided treatment. The iFR-guided and FFR-guided treatment showed comparable risk of MACE and provided equal safety in selecting revascularization target among patients with diabetes. Trial Registration: ClinicalTrials.gov identifier: NCT02053038.
RCT Entities:
Importance: Invasive physiologic indices such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are used in clinical practice. Nevertheless, comparative prognostic outcomes of iFR-guided and FFR-guided treatment in patients with type 2 diabetes have not yet been fully investigated. Objective: To compare 1-year clinical outcomes of iFR-guided or FFR-guided treatment in patients with and without diabetes in the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization (DEFINE-FLAIR) trial. Design, Setting, and Participants: The DEFINE-FLAIR trial is a multicenter, international, randomized, double-blinded trial that randomly assigned 2492 patients in a 1:1 ratio to undergo either iFR-guided or FFR-guided coronary revascularization. Patients were eligible for trial inclusion if they had intermediate coronary artery disease (40%-70% diameter stenosis) in at least 1 native coronary artery. Data were analyzed between January 2014 and December 2015. Interventions: According to the study protocol, iFR of 0.89 or less and FFR of 0.80 or less were used as criteria for revascularization. When iFR or FFR was higher than the prespecified threshold, revascularization was deferred. Main Outcomes and Measures: The primary end point was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. The incidence of MACE was compared according to the presence of diabetes in iFR-guided and FFR-guided groups. Results: Among the total trial population (2492 patients), 758 patients (30.4%) had diabetes. Mean age of the patients was 66 years, 76% were men (1868 of 2465), and 80% of patients presented with stable angina (1983 of 2465). In the nondiabetes population (68.5%; 1707 patients), iFR guidance was associated with a significantly higher rate of deferral of revascularization than the FFR-guided group (56.5% [n = 477 of 844] vs 46.6% [n = 402 of 863]; P < .001). However, it was not different between the 2 groups in the diabetes population (42.1% [n = 161 of 382] vs 47.1% [n = 177 of 376]; P = .15). At 1 year, the diabetes population showed a significantly higher rate of MACE than the nondiabetes population (8.6% vs 5.6%; adjusted hazard ratio [HR], 1.88; 95% CI, 1.28-2.64; P < .001). However, there was no significant difference in MACE rates between iFR-guided and FFR-guided groups in both the diabetes (10.0% vs 7.2%; adjusted HR, 1.33; 95% CI, 0.78-2.25; P = .30) and nondiabetes population (4.7% vs 6.4%; HR, 0.83; 95% CI, 0.51-1.35; P = .45) (interaction P = .25). Conclusions and Relevance: The diabetes population showed significantly higher risk of MACE than the nondiabetes population, even with the iFR-guided or FFR-guided treatment. The iFR-guided and FFR-guided treatment showed comparable risk of MACE and provided equal safety in selecting revascularization target among patients with diabetes. Trial Registration: ClinicalTrials.gov identifier: NCT02053038.
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