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

Selected in European Heart Journal by M. Pighi , S. Brugaletta , S. Fezzi

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.

Reviewers

Michele Pighi

@PighiMichele

Interventional cardiologist / cardiologist

University of Verona - Verona, Italy

Salvatore Brugaletta

@sbrugaletta

Interventional cardiologist / Cardiologist

Barcelona, Spain

Simone Fezzi

@FezziSimone

Interventional cardiologist / Cardiologist

University of Verona - Verona, Italy

Our Comment

Why this study? – the rationale/objective

According to the updated international revascularization guidelines, Fractional flow reserve (FFR) is proposed as the standard of care for ischemia detection in guiding percutaneous coronary intervention (PCI) of intermediate coronary stenosis.

Retrospective studies suggested the existence of a positive relationship between ischaemic FFR values and the presence of Thin-cap Fibroatheromas (TCFAs), supporting the safety of deferring the treatment of FFR-negative lesions. However, in some high-risk categories such as acute coronary syndromes (ACS) and diabetes mellitus (DM), the FFR-based decision process seems to be related to a higher risk of MACE. To date, the natural history of TCFA lesions in patients with fast-progressing atherosclerotic disease has not been studied in a powered and prospective fashion.

The objective of this analysis was to prospectively investigate the clinical impact of vulnerable plaques (OCT-detected TCFA) in a DM population with intermediate, non-ischaemic (FFR-negative) lesions deemed to be managed by optimal medical therapy.

How was it executed? – the methodology

• This is a prospective, double-blind, multi-centre, international, natural history study including 550 DM patients.
• Patients underwent coronary angiography for stable CAD (>70%) or ACS with detection of the angiography-defined intermediate lesions (40-80% by visual estimation). In the case of ACS, the culprit-lesion was revascularized first.
• All the lesions included were investigated with FFR. Patients with FFR-negative lesions (n=423) underwent OCT analysis and were further treated by OMT.
• The comparison at 18-month follow-up was performed between “FFR-negative/TCFA-negative” (group A; n=292) and “FFR-negative/TCFA-positive” (group B; n=98) patients.
• Patients with FFR-positive lesions (n=112) underwent revascularization and were classified as group C.
• OCT analysis was performed in a corelab, with OCT findings blinded to the patients, the operators, and the team that performed clinical follow-up.
• MACE was defined as a composite of cardiac death, target-vessel MI, clinically driven target lesion revascularization or, hospitalization due to unstable angina.
• The primary endpoint was the per-patient MACE incidence at 18-month follow-up between group A and group B.

What is the main result?

• The primary endpoint occurred in 13.3% of FFR-negative/TCFA-positive as compared to 3.1% of FFR-negative/TCFA-negative patients (HR 4.65; 95%CI 1.99-10.89, p<0.001), driven by a significantly higher incidence of target vessel MI (4.1% vs 0%; p<0.001), clinically driven TLR (11.2% vs 1.4%; p<0.001) and unstable angina (6.1% vs 1.7%; p<0.001).
• At the Cox multivariable analysis, TCFA positivity was the strongest predictor for the primary endpoint (HR 5.12; 95%CI 2.12-12.34; p<0.001), together with MI at presentation (HR 2.77; 95% CI 1.04–7.35, P=0.04) as well as a smaller MLA (HR 2.29; 95% confidence interval 1.11–4.69, P=0.04).

Critical reading and the relevance for clinical practice

This report represents the first prospective study evaluating the impact of OCT-detected vulnerable plaque, with negative FFR values, on clinical outcomes in a high-risk population with DM. Among DM patients, TFCA represents 25% of FFR-negative lesions, with a 5-fold higher rate of adverse events (MI and TLR) at follow-up, being responsible for >80% of MACE.

The majority of patients were treated for stable CAD, without difference among the two groups. At discharge, TCFA-positive patients had a lower statin usage, which did not impact the primary endpoint, while in the same group, P2Y12 inhibitors usage was higher. Furthermore, despite superimposable FFR values (0.88± 0.05 vs. 0.88±0.05, P=0.66), TCFA-positive lesions tended to be longer, with smaller MLA and with higher prevalence of macrophage, cholesterol clefts, and neovascularization. On the other hand, TCFA-negative lesions presented a higher degree of calcium arc and protruding calcifications. TCFA-positive patients tended to present more frequently multi-vessel disease, reflecting a generalized, more aggressive atherosclerotic disease. As stressed by the authors, the study was underpowered for the detection of differences in low incidence endpoints such as cardiac mortality. However, interestingly, TCFA presence was strictly related to both acute plaque destabilization with ACS and progressive plaque progression leading to angina.

According to the PROSPECT study, the vast majority of vulnerable plaques are stable and seldomnly cause of ACS, with only about 5% of IVUS-detected TCFA related to MACEs at a median follow-up of 3.4 years. Of note, while the PROSPECT study enrolled a high-risk ACS population, TCFA in lower-risk patients may cause even fewer events. The consequences of a plaque rupture, in fact, depend not only on plaque morphology but also on the interplay between pro-/anti-thrombotic factors, leading to the well-known phenomenon of plaque healing.

That been said, the impact of vulnerable plaques on adverse events seems to be strongest in the setting of high-risk patients (ACS, DM) or high-risk vulnerable plaques. A sub-analysis on DM patients from the PROSPECT study, showed those with ≥1 TCFA had a 3-fold higher rate of MACE at 3 years. In the CLIMA registry, the combination of multiple OCT high-risk plaque features (MLA<3.5 mm2, FCT<75 µm, macrophages and lipid arch>180°) that were present in a small subgroup of patients was a strong predictor of TV-MI and cardiac death at 12 months.

In the PROSPECT II trial, following recent ACS, the detection with IVUS/NIRS, in the non-culprit lesions, of a plaque burden more than 70% and a LCBI >324 were independent predictors of MACE. In FLOWER-MI, the use of FFR in the non-culprit lesion showed to be disadvantageous in patients with STEMI possibly due to the consequent systemic inflammatory syndrome and plaque vulnerability.

To date, despite the recent PROSPECT II-ABSORB pilot trial suggested PCI of plaques with high-risk “vulnerable” characteristics was safe and effective in enlarging luminal dimensions and providing a neo cap of intimal hyperplasia, clinical trials have failed to show a clear clinical benefit of PCI in this setting. Further data are warranted to support the best management of vulnerable intermediate plaque, with the central role of optimal medical therapy on plaque modification and regression and of PCI.

References

1. Lee JM, Choi KH, Koo BK et al. Prognosis of deferred non-culprit lesions according to fractional flow reserve in patients with the acute coronary syndrome. EuroIntervention. 2017;13:e1112–9
2. Prati F, Romagnoli E, Gatto L, et al. (2020) Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: The CLIMA study. Eur Heart J 41:383–391. https://doi.org/10.1093/eurheartj/ehz520
3. Erlinge D, Maehara A, Ben-Yehuda O et al. Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study. Lancet. 2021;397:985–95
4. Kedhi E, Kennedy MW, Maehara A, et al. (2017) Impact of TCFA on Unanticipated Ischemic Events in Medically Treated Diabetes Mellitus: Insights From the PROSPECT Study. JACC Cardiovasc Imaging 10:451–458. https://doi.org/10.1016/j.jcmg.2015.12.023
5. Stone GW, Maehara A, Lansky AJ, et al. (2011) A prospective natural-history study of coronary atherosclerosis. N Engl J Med 364:226–235. https://doi.org/10.1056/NEJMoa1002358
6. Stone GW, Maehara A, Ali Z, et al. (2020) Percutaneous Coronary Intervention for Vulnerable Coronary Atherosclerotic Plaque. JACC Cardiovasc Interv 76:2289–2301. https://doi.org/10.1016/j.jacc.2020.09.547