Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial

Elvin Kedhi*, Balazs Berta, Tomasz Roleder, Renicus S. Hermanides, Enrico Fabris, Alexander J.J. IJsselmuiden, Floris Kauer, Fernando Alfonso, Clemens von Birgelen, Javier Escaned, Cyril Camaro, Mark W. Kennedy, Bruno Pereira, Michael Magro, Holger Nef, Sebastian Reith, Arif Al Nooryani, Fernando Rivero, Krzysztof Malinowski, Giuseppe De LucaHector Garcia Garcia, Juan F. Granada, Wojciech Wojakowski

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

50 Citations (Scopus)


Aims The aim of this study was to understand the impact of optical coherence tomography (OCT)-detected thin-cap fibroatheroma (TCFA) on clinical outcomes of diabetes mellitus (DM) patients with fractional flow reserve (FFR)-negative lesions. Methods and results COMBINE OCT-FFR study was a prospective, double-blind, international, natural history study. After FFR assessment, and revascularization of FFR-positive lesions, patients with ≥1 FFR-negative lesions (target lesions) were classified in two groups based on the presence or absence of ≥1 TCFA lesion. The primary endpoint compared FFR-negative TCFA-positive patients with FFR-negative TCFA-negative patients for a composite of cardiac mortality, target vessel myocardial infarction, clinically driven target lesion revascularization or unstable angina requiring hospitalization at 18 months. Among 550 patients enrolled, 390 (81%) patients had ≥1 FFR-negative lesions. Among FFR-negative patients, 98 (25%) were TCFA positive and 292 (75%) were TCFA negative. The incidence of the primary endpoint was 13.3% and 3.1% in TCFA-positive vs. TCFA-negative groups, respectively (hazard ratio 4.65; 95% confidence interval, 1.99-10.89; P < 0.001). The Cox regression multivariable analysis identified TCFA as the strongest predictor of major adverse clinical events (MACE) (hazard ratio 5.12; 95% confidence interval 2.12-12.34; P < 0.001). Conclusions Among DM patients with ≥1 FFR-negative lesions, TCFA-positive patients represented 25% of this population and were associated with a five-fold higher rate of MACE despite the absence of ischaemia. This discrepancy between the impact of vulnerable plaque and ischaemia on future adverse events may represent a paradigm shift for coronary artery disease risk stratification in DM patients.

Original languageEnglish
Pages (from-to)4671-4679
Number of pages9
JournalEuropean heart journal
Issue number45
Early online date29 Jul 2021
Publication statusPublished - 1 Dec 2021


  • Coronary artery disease
  • Diabetes mellitus
  • Fractional flow reserve
  • Optical coherence tomography
  • Thin-cap fibroatheroma
  • Vulnerable plaque
  • n/a OA procedure


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