Comparison of Major Adverse Cardiac Events Between Instantaneous Wave-Free Ratio and Fractional Flow Reserve-Guided Strategy in Patients With or Without Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial

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 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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Joo Myung Lee received a research grant from St Jude Medical (Abbott Vascular) and Philips Volcano. Dr Bon-Kwon Koo received an institutional research grant from St Jude Medical (Abbott Vascular) and Philips Volcano. Dr Al-Lamee reports personal fees from Philips Volcano outside the submitted work. Dr Baptista reports grants and consulting fees from Abbott and personal fees from Boston Scientific, Philips Volcano, and Opsens Medical outside the submitted work. Dr Cook reports personal fees from Philips Volcano outside the submitted work. Dr Davies reports grants and personal fees from Volcano Corporation and personal fees from Imperial College during the conduct of the study, as well as grants and personal fees from Medtronic and ReCor Medical and grants from AstraZeneca outside the submitted work. In addition, Dr Davies has patents WO2011110817 A2, US9339348 B2, WO2015013134 A3, EP3021741 A2, and US20150025330 A1 issued to Imperial College/LICENSED to Volcano Corporation. Dr Di Mario reports personal fees from Philips Volcano outside the submitted work. Dr Escaned reports personal fees from Philips Volcano, Boston Scientific, and Abbott/St Jude Medical outside the submitted work. Dr Jeremias reports personal fees from St Jude Medical and Philips Volcano outside the submitted work. Dr Khashaba reports other support from Volcano Corporation and personal fees from Philips Volcano during the conduct of the study. Dr Laine reports grants from Imperial College London during the conduct of the study. Dr Nijjer reports grants from Medical Research Council and personal fees and nonfinancial support from Volcano Corporation during the conduct of the study. Dr Patel reports grants and personal fees from Volcano during the conduct of the study as well as grants and personal fees from AstraZeneca and Janssen and personal fees from Bayer outside the submitted work. Dr Petraco reports personal fees from Philips Volcano outside the submitted work. Dr Piek reports grants and personal fees from Abbott Vascular, Philips Volcano, and Miracor outside the submitted work. Dr Sen reports grants from Volcano Corporation during the conduct of the study as well as grants and personal fees from Philips and grants from Medtronic outside the submitted work. Dr Serruys reports personal fees from Abbott, AstraZeneca, Biotronik, Cardialysis, GLG Research, Medtronic, Sinomedical, Société Europa Digital and Publishing, Stentys, Svelte, Philips Volcano, St Jude Medical, Qualimed, and Xeltis outside the submitted work. Dr Seto reports grants from Volcano Corporation during the conduct of the study. Dr Sharp reports personal fees from Philips Volcano outside the submitted work. Dr Singh reports personal fees from Volcano Corporation during the conduct of the study as well as personal fees from Volcano Corporation outside the submitted work. Dr Tanaka reports personal fees from Volcano Corporation (Japan), St Jude Medical, and Boston Scientific outside the submitted work. Dr Van Belle reports personal fees from Philips Volcano and St Jude Medical outside the submitted work. Dr van Royen reports grants and personal fees from Volcano Corporation and St Jude Medical outside the submitted work. Dr Vinhas reports personal fees from Volcano Corporation outside the submitted work. Dr Samuel reports consultant/speaker’s fee from Philips Medical and Abbott Vascular outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Flow

This study was a post hoc analysis of the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR) trial. From the total trial population (2492 patients), 2465 patients (98.9% of trial population) were included for the analysis. FFR indicates fractional flow reserve; iFR, instantaneous wave-free ratio.

Figure 2.. Comparison of Major Adverse Cardiac Events (MACE) Between Instantaneous Wave-Free Ratio (iFR)–Guided and Fractional Flow Reserve (FFR)–Guided Strategy According to Type 2 Diabetes

Kaplan-Meier curves are shown for the comparison of 1-year rates of MACE between iFR-guided and FFR-guided strategy groups in the nondiabetes population (A) or diabetes population (B). HR indicates hazard ratio.

Figure 3.. Deferred Population Outcome Between Instantaneous Wave-Free Ratio (iFR)–Guided and Fractional Flow Reserve (FFR)–Guided Strategy, According to Type 2 Diabetes

Kaplan-Meier curves are shown for the comparison of 1-year major adverse cardiac event (MACE), defined as a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization, rates of deferred population between iFR and FFR-guided strategy groups in the nondiabetes population (A) or diabetes population (B). HR indicates hazard ratio.