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Preventive PCI vs Optimal Medical Therapy Alone for the Treatment of Vulnerable Atherosclerotic Coronary Plaques
TAKE-HOME MESSAGE
- The PREVENT trial, conducted at 15 research hospitals in four countries, evaluated whether preventive PCI in 1606 patients with non–flow-limiting vulnerable plaques improved outcomes compared with optimal medical therapy alone. Patients were randomly assigned to PCI plus medical therapy or medical therapy alone. At the 2-year follow-up period, the primary outcome (a composite of cardiac death, target-vessel myocardial infarction, ischaemia-driven target-vessel revascularisation, and hospitalisation for unstable angina) occurred less in the PCI group (0.4%) than the medical therapy group (3.4%).
- The results of the PREVENT trial suggest that PCI may reduce the rate of adverse cardiac events owing to high-risk vulnerable plaques.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Acute coronary syndrome and sudden cardiac death are often caused by rupture and thrombosis of lipid-rich atherosclerotic coronary plaques (known as vulnerable plaques), many of which are non-flow-limiting. The safety and effectiveness of focal preventive therapy with percutaneous coronary intervention of vulnerable plaques in reducing adverse cardiac events are unknown. We aimed to assess whether preventive percutaneous coronary intervention of non-flow-limiting vulnerable plaques improves clinical outcomes compared with optimal medical therapy alone.
METHODS
PREVENT was a multicentre, open-label, randomised controlled trial done at 15 research hospitals in four countries (South Korea, Japan, Taiwan, and New Zealand). Patients aged 18 years or older with non-flow-limiting (fractional flow reserve >0·80) vulnerable coronary plaques identified by intracoronary imaging were randomly assigned (1:1) to either percutaneous coronary intervention plus optimal medical therapy or optimal medical therapy alone, in block sizes of 4 or 6, stratified by diabetes status and the performance of percutaneous coronary intervention in a non-study target vessel. Follow-up continued annually in all enrolled patients until the last enrolled patient reached 2 years after randomisation. The primary outcome was a composite of death from cardiac causes, target-vessel myocardial infarction, ischaemia-driven target-vessel revascularisation, or hospitalisation for unstable or progressive angina, assessed in the intention-to-treat population at 2 years. Time-to-first-event estimates were calculated with the Kaplan-Meier method and were compared with the log-rank test. This report is the principal analysis from the trial and includes all long-term analysed data. The trial is registered at ClinicalTrials.gov, NCT02316886, and is complete.
FINDINGS
Between Sept 23, 2015, and Sept 29, 2021, 5627 patients were screened for eligibility, 1606 of whom were enrolled and randomly assigned to percutaneous coronary intervention (n=803) or optimal medical therapy alone (n=803). 1177 (73%) patients were men and 429 (27%) were women. 2-year follow-up for the primary outcome assessment was completed in 1556 (97%) patients (percutaneous coronary intervention group n=780; optimal medical therapy group n=776). At 2 years, the primary outcome occurred in three (0·4%) patients in the percutaneous coronary intervention group and in 27 (3·4%) patients in the medical therapy group (absolute difference -3·0 percentage points [95% CI -4·4 to -1·8]; p=0·0003). The effect of preventive percutaneous coronary intervention was directionally consistent for each component of the primary composite outcome. Serious clinical or adverse events did not differ between the percutaneous coronary intervention group and the medical therapy group: at 2 years, four (0·5%) versus ten (1·3%) patients died (absolute difference -0·8 percentage points [95% CI -1·7 to 0·2]) and nine (1·1%) versus 13 (1·7%) patients had myocardial infarction (absolute difference -0·5 percentage points [-1·7 to 0·6]).
INTERPRETATION
In patients with non-flow-limiting vulnerable coronary plaques, preventive percutaneous coronary intervention reduced major adverse cardiac events arising from high-risk vulnerable plaques, compared with optimal medical therapy alone. Given that PREVENT is the first large trial to show the potential effect of the focal treatment for vulnerable plaques, these findings support consideration to expand indications for percutaneous coronary intervention to include non-flow-limiting, high-risk vulnerable plaques.
FUNDING
The CardioVascular Research Foundation, Abbott, Yuhan Corp, CAH-Cordis, Philips, and Infraredx, a Nipro company.
Additional Info
Disclosure statements are available on the authors' profiles:
Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT): a multicentre, open-label, randomised controlled trial
Lancet 2024 Apr 04;[EPub Ahead of Print], SJ Park, JM Ahn, DY Kang, SC Yun, YK Ahn, WJ Kim, CW Nam, JO Jeong, IH Chae, H Shiomi, HL Kao, JY Hahn, SH Her, BK Lee, TH Ahn, KY Chang, JK Chae, D Smyth, GS Mintz, GW Stone, DW ParkFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The PREVENT trial encompassed 1606 participants (mean age, 64 years; women, 27%) across 15 centers spanning four nations. The inclusion criteria involved individuals with non–flow-limiting coronary plaques (>50% stenosis) and negative fractional flow reserve (FFR, >0.80), indicative of vulnerability. Vulnerable plaques met two or more of the following criteria: a minimal lumen area ≤4.0 mm² via intravascular ultrasound (IVUS) or optical coherence tomography (OCT), a plaque burden >70% via intravascular imaging, the detection of thin-cap fibroatheroma by OCT or radiofrequency IVUS, and the identification of a lipid-rich plaque by near-infrared spectroscopy (NIRS; maximal lipid core burden index in a 4-mm segment, >315). Grayscale intravascular imaging was predominantly employed (95%) over newer modalities such as OCT/NIRS. Participants were randomized to receive PCI plus optimal medical therapy (OMT) or OMT alone. The median count of vulnerable plaques (target lesions) in both arms was one (IQR, 1–1). Initially intended to utilize bioresorbable scaffolds (BRS), PCI shifted to cobalt–chromium everolimus-eluting metallic stents (DES) due to BRS withdrawal, with DES adoption in 67% and BRS in 33% of the PCI group. Intravascular imaging guided all interventions for stent or scaffold optimization. During follow-up, over 50% of the participants in both groups received high- or moderate-intensity statins plus ezetimibe, resulting in mean LDL-C levels of 64 mg/dL by the last follow-up, down from respective baselines (preventive PCI, 83 mg/dL; OMT, 93 mg/dL). At 2 years, the primary outcome incidence was 0.4% in the preventive PCI group and 3.4% in the OMT group (HR, 0.11; 95% CI, 0.03–0.36). Over extended follow-up, the preventive PCI group exhibited lower primary outcome rates than the OMT group (6.5% vs 9.4%; HR, 0.54; 95% CI, 0.33–0.87), with a sustained 3% absolute difference through 7 years (median, 4.4 years). The NNT to prevent one primary outcome event over 2 years was 45.4 in the preventive PCI group, with an NNT of 87.7 for one cardiac death or target-vessel myocardial infarction (MI).1
The trial outcomes suggest that combining preventive PCI, targeting focal non–FFR-positive plaques with >50% visual diameter stenosis on angiography and evidence of vulnerability on intravascular imaging, with OMT yields superior clinical results compared with OMT alone over a 2-year follow-up period in patients predominantly afflicted by stable ischemic heart disease. The primary benefit predominantly stemmed from a reduction in the risk of subsequent revascularization, including ischemia-driven target lesion revascularization, and this advantage persisted over 7 years of observation. These findings are significant and likely to provoke substantial discourse. Establishing a precise definition of vulnerable plaque and determining the optimal modality for its assessment will be crucial moving forward. Notably, while periprocedural MI was part of the MI definition within the primary composite endpoints, there was no mention of the incidence of periprocedural MI in patients treated with BRS or DES.
IVUS-derived FFR and OCT-derived FFR have shown excellent sensitivity and diagnostic accuracy with wire-based FFR as a gold standard, obviating the necessity for two procedures and distinct instrumentations.2,3 Looking ahead, amalgamating high-resolution intravascular imaging with imaging-derived physiology holds promise for synergistically discerning and managing vulnerable versus nonvulnerable lesions. This approach may lead to the consideration of leaving potentially nonvulnerable lesions with non–physiologically significant features to OMT alone. Well-powered trials combining morphological and physiological assessments could demonstrate their efficacy in enhancing clinical outcomes. Although the trial's eligibility criteria focused on non–flow-limiting vulnerable coronary plaques with >50% stenosis based on visual assessment, there is a dearth of trials investigating the role of preventive PCI in patients with stenosis <50%.
The lingering question pertains to the precise definition of a "vulnerable" plaque. The study categorized patients as having vulnerable plaques primarily (89%) based on two features: a minimal lumen area <4 mm² and plaque burden >70%, predominantly assessed using grayscale IVUS in 95% of the cases. Presently, advanced imaging modalities with superior resolution, such as optical frequency domain imaging and DeepOCT–NIRS, offer enhanced capabilities for characterizing vulnerable plaques and warrant exploration in future investigations.
Photon-counting CCTA, representing a significant advancement, offers a remarkable resolution of 120 microns. This technology has demonstrated the capacity to identify vulnerable plaque features on par with or even surpassing intravascular imaging modalities.4 It can identify vulnerable plaques that could be ideal therapeutic targets for DES or newer iterations of BRS in the future. Furthermore, in a patient with nonobstructive coronary artery disease, CCTA can be used as a diagnostic "one-stop shop" (anatomy, physiological significance of a lesion [FFRCT], tissue composition, finite element analysis, wall shear stress and axial plaque stress, and perivascular fat attenuation index) to individualize treatment decisions (OMT vs PCI).5-7
The EMERALD study showed that combining CCTA-based assessment of noninvasive hemodynamic assessments (FFRCT, change in FFRCT across the lesion, wall shear stress, and axial plaque stress) with the assessment for adverse plaque characteristics (low-attenuation plaque, positive remodeling, napkin-ring sign, and spotty calcification) may improve the identification of culprit lesions for future acute coronary syndromes.8 Future trials in addition to the criteria used in the PREVENT trial should incorporate adverse hemodynamic characteristics and adverse plaque characteristics to decide between OMT or PCI.
It was interesting to see that, the mean LDL-C level in both groups was 64 mg/dL, and only 54.6% of participants in the preventive PCI group were on a high-intensity statin or moderate-intensity statin plus ezetimibe therapy.1 In FOURIER-OLE, 1604 patients (24%) achieved LDL-C levels of <20 mg/dL.9 There was a monotonic relationship between lower achieved LDL-C levels — down to very low levels <20 mg/dL — and a lower risk of the primary efficacy endpoint (composite of cardiovascular death, MI, stroke, hospital admission for unstable angina, and coronary revascularization).9 Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up period of 8.6 years, with no significant safety concerns — reinforcing the fact that LDL-C levels “as low as achievable” should be the goal, especially in patients with vulnerable plaque features.9 The Yellow III randomized controlled trial showed that (results presented at the American College of Cardiology/World Congress of Cardiology meeting in New Orleans in March 2023), in angiographically nonobstructive lesions, a 26-week regimen of evolocumab (a PCSK9 inhibitor) resulted in a significant increase in the minimum fibrous cap thickness as assessed on OCT, reduction in lipid core burden index at the maximal 4-mm segment as assessed on near-infrared spectroscopy, and reduction in atheroma volume as assessed on IVUS. The VICTORION PLAQUE study (NCT05360446) is an ongoing CCTA study assessing the effect of inclisiran in addition to maximally tolerated statin therapy on atherosclerotic plaque progression, plaque composition, and atheroma volume in participants with a diagnosis of nonobstructive CAD without previous cardiovascular events.
Although on long-term follow-up in the PREVENT trial the DES performed better than BRS, there are currently newer iterations. Recently, Haude et al have shown that the new-generation magnesium scaffold has a late loss of 0.24 mm at 1 year compared with the respective late losses of the first three generations of 1 mm, 0.77 mm, and 0.44 mm.10 The current late loss may well compete with the best metallic DES. Purer and more crystalline magnesium, with small grains and anti-corrosion coating layers, has rendered this technology much more efficacious. Furthermore, it is well-established that magnesium is not thrombogenic and has a strong “anticoagulant” effect. As an alternative to BRS, will drug-coated balloons fulfill the dream to “leave nothing behind” and supersede BRS — and even compromise their return? This remains to be seen.11
The decade of 2020 to 2030 will probably witness the emergence and combination of metabolic and anti-inflammatory interventions targeting PCSK9, lipoprotein(a), IL-1, IL-6, inflammasome, and many other molecular pathways, thereby curbing the need for mechanical revascularization. A single infusion of a CRISPR-based gene-editing therapy significantly reduced LDL-C and PCSK9 levels in patients with heterozygous familial hypercholesterolemia, based on findings from the VERVE-101 trial presented on November 12 at American Heart Association's Scientific Sessions 2023. During the next 5 decades, we should not be surprised if PCI and CABG are replaced by an intelligent primordial prevention guided by the early detection of the ominous omics, which, combined with noninvasive imaging, will identify the early stage of the diseased phenotype. It is then that the era of “imagomics” will have arrived. Time will tell.12
References