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Observational Study
. 2025 Feb;18(2):e014667.
doi: 10.1161/CIRCINTERVENTIONS.124.014667. Epub 2025 Jan 22.

FFR-Negative Nonculprit High-Risk Plaques and Clinical Outcomes in High-Risk Populations: An Individual Patient-Data Pooled Analysis From COMBINE (OCT-FFR) and PECTUS-obs

Rick H J A Volleberg  1 , Andi Rroku  2   3 , Jan-Quinten Mol  1 , Renicus S Hermanides  4 , Maarten van Leeuwen  4 , Balázs Berta  4   5 , Martijn Meuwissen  6 , Fernando Alfonso  7 , Wojciech Wojakowski  8 , Anouar Belkacemi  9 , Tomasz Roleder  10 , Elvin Kedhi #  11 , Niels van Royen #  1 ; COMBINE (OCT-FFR) and PECTUS-obs investigators
Collaborators, Affiliations
Observational Study

FFR-Negative Nonculprit High-Risk Plaques and Clinical Outcomes in High-Risk Populations: An Individual Patient-Data Pooled Analysis From COMBINE (OCT-FFR) and PECTUS-obs

Rick H J A Volleberg et al. Circ Cardiovasc Interv. 2025 Feb.

Abstract

Background: Despite fractional flow reserve (FFR)-guided deferral of revascularization, recurrent events in patients with diabetes or after myocardial infarction remain common. This study aimed to assess the association between FFR-negative but high-risk nonculprit lesions and clinical outcomes.

Methods: This is a patient-level pooled analysis of the prospective natural-history COMBINE (OCT-FFR) study (Optical Coherence Tomography Morphologic and Fractional Flow Reserve Assessment in Diabetes Mellitus Patients) and PECTUS-obs study (Identification of Risk Factors for Acute Coronary Events by OCT After STEMI and NSTEMI Patients With Residual Non- Flow Limiting Lesions). Optical coherence tomography was performed on all FFR-negative (FFR >0.80) native nonculprit lesions. Patients or lesions with a high-risk plaque were compared with those without a high-risk plaque. A high-risk plaque was defined in the presence of at least 2 prespecified criteria: (1) lipid arc ≥90o, (2) minimum fibrous cap thickness <65 µm, and (3) presence of either plaque rupture or thrombus. The primary end points were native major adverse cardiovascular events (composite of all-cause mortality, nonfatal myocardial infarction, or unplanned revascularization excluding stent-failure-related events and nonattributable events) and target lesion failure (composite of cardiac death, target vessel myocardial infarction, or target lesion revascularization).

Results: Among 810 patients, 450 (55.6%) had a history of diabetes and 482 (59.5%) presented with myocardial infarction. At least 1 high-risk plaque was identified in 271 (33.5%) patients and 287 (30.6%) lesions. Over a median follow-up of 761 (interquartile range, 731-1175) days, the presence of a high-risk plaque was associated with patient-level native major adverse cardiovascular events (hazard ratio, 2.127 [95% CI, 1.451-3.120]; P<0.001) and lesion-level target lesion failure (hazard ratio, 2.623 [95% CI, 1.559-4.414]; P<0.001). The risk of adverse outcomes increased with the copresence of multiple high-risk features.

Conclusions: FFR-negative but high-risk nonculprit lesions are associated with adverse patient- and lesion-level clinical outcomes. These findings emphasize the additional value of intracoronary imaging in patients with FFR-negative nonculprit lesions.

Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02989740; Unique identifier: NCT03857971.

Keywords: acute coronary syndrome; atherosclerosis; fractional flow reserve, myocardial; myocardial infarction; plaque, atherosclerotic.

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Conflict of interest statement

Dr Hermanides reports speaker honoraria from Amgen, Novartis, Edwards Lifesciences, and Angiocare. Dr van Leeuwen reports research grants from Abbott and TOP Medical Consultancy B.V.; consulting fees from Terumo, Daiichi Sankyo, and Abbott; and speaker honoraria from Abbott. Dr Belkacemi reports speaker honoraria from Daiichi Sankyo, travel fees from Novo Nordisk, and stock from Pfizer. Dr Kedhi reports institutional research grants from Abbott and Medtronic, Inc, and proctorship honoraria from Abbott. Dr van Royen reports institutional research grants from Abbott, Health~Holland, Koninklijke Philips NV, Biotronik, and Medtronic, Inc, and speaker honoraria from MicroPort, Bayer AG, and RainMed Medical. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
Examples of high-risk plaques. Optical coherence tomography images meeting the criteria for a high-risk plaque based on (A) minimum fibrous cap thickness <65 µm (arrow) and lipid arc ≥90°, (B) lipid arc ≥90° and plaque rupture (arrowhead), and (C) minimum fibrous cap thickness <65 µm (arrow), lipid arc ≥90°, and thrombus (arrowhead).
Figure 2.
Figure 2.
Study flowchart. COMBINE (OCT-FFR) indicates Optical Coherence Tomography Morphologic and Fractional Flow Reserve Assessment in Diabetes Mellitus Patients; FFR, fractional flow reserve; NC, nonculprit; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; and PECTUS-obs, Identification of Risk Factors for Acute Coronary Events by OCT After STEMI and NSTEMI Patients With Residual Non-Flow Limiting Lesions.
Figure 3.
Figure 3.
Cumulative incidences of the composite end points. Cumulative incidence curve for the cumulative end points of native major adverse cardiovascular event (MACE; A), target lesion failure (TLF; B), and attributable TLF (aTLF; C) truncated at 1500 days.
Figure 4.
Figure 4.
High-risk plaque components and major adverse cardiovascular events (MACE). A, Association between individual high-risk plaque features and native MACE. B, Association between the number of high-risk plaque features and native MACE, in which the presence of plaque rupture and thrombus is considered 1 high-risk plaque feature. *Considering that all lesions with a minimum fibrous cap thickness (FCT) <65 µm had a lipid arc ≥90°, all these lesions are qualified as a thin-cap fibroatheroma. HR indicates hazard ratio.
Figure 5.
Figure 5.
High-risk plaque components and target lesion failure (TLF). A, Association between individual high-risk plaque features and TLF. B, Association between the number of high-risk plaque features and TLF, in which the presence of plaque rupture and thrombus is considered 1 high-risk plaque feature. *Considering that all lesions with a minimum fibrous cap thickness (FCT) <65 µm had a lipid arc ≥90°, all these lesions are qualified as a thin-cap fibroatheroma. HR indicates hazard ratio.
See this image and copyright information in PMC

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