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The PREVENT Trial: Vulnerable Plaque is Back

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The concept of treating a vulnerable plaque to reduce the risk of future adverse cardiovascular events has been an elusive goal in the field of interventional cardiology since its description in the 1980s. The majority of acute coronary syndromes (ACS) arise from lesions less than 50% stenosed, and these lesions typically have a thin fibrous cap, large lipid core, and increased inflammatory cell content. Over the years, the emphasis has switched from treating the vulnerable plaque to optimizing medical therapy for the vulnerable patient. However, the presentation of the PREVENT trial at the American College of Cardiology Annual Meeting this April in Atlanta, with simultaneous publication in the Lancet, put the vulnerable plaque back in the crosshairs.

The Preventive Coronary Intervention on Stenosis with Functionally Insignificant Vulnerable Plaque (PREVENT) trial was a multicenter, open-label, randomized controlled trial conducted at 15 hospitals in South Korea, Japan, Taiwan, and New Zealand. The study screened 5,627 patients undergoing coronary angiography for either stable coronary artery disease (CAD) or ACS with intermediate stenoses, of whom 2,065 underwent percutaneous coronary intervention (PCI) for hemodynamically significant stenosis with fractional flow reserve (FFR) value ≤0.80 and were excluded. The study excluded additional patients with prior coronary bypass surgery, in-stent restenosis, arteries with multiple lesions, heavily calcified or angulated lesions, or bifurcation lesions. The remaining 3,562 patients with lesions with diameter >50% with FFR value >0.80 underwent intravascular ultrasound (IVUS), a combination of IVUS and near-infrared spectroscopy, or optical coherence tomography (OCT) to assess for features of vulnerable plaque. The intermediate stenosis was considered a vulnerable plaque if it had at least two of the following four features: minimal luminal area <4.0 mm2, plaque burden of >70%, lipid-rich plaque by near-infrared spectroscopy (defined as maximum lipid core burden index >315 within any 4 mm pullback length), or a thin-cap fibroatheroma. 

The study included 1,606 patients, randomizing 803 patients with 831 lesions to preventive PCI plus optimal medical therapy and 803 patients with 841 lesions to optimal medical therapy alone. Baseline characteristics were similar between the groups, with 84% of patients with stable CAD, 12% with unstable angina, and 4% with recent myocardial infarction. Most patients underwent IVUS to assess vulnerable plaques, while 42% underwent near-infrared spectroscopy, and only 5% underwent OCT imaging. The vast majority of vulnerable plaques had minimal luminal area <4.0 mm2 and a plaque burden of >70% (97% and 96%, respectively). Only 11% had lipid-rich plaque by near-infrared spectroscopy, and 55% had a thin-cap fibroatheroma. Given the growing data regarding the risk for scaffold thrombosis from bioresorbable vascular scaffolds during the study enrollment, 33% of patients in the preventive PCI group received bioresorbable vascular scaffolds, while 67% underwent PCI with placement of cobalt-chromium everolimus-eluting metallic stents. The patients were followed for a median of 4.4 years.

The primary composite outcome of cardiovascular death, target-vessel MI, ischemia-driven target-vessel revascularization, and hospitalization for unstable angina occurred in three (0.4%) patients in the preventive PCI group and 27 (3.4%) patients in the optimal medical therapy groups (-3% absolute difference [95% CI -4.4 to -1.8], p=0.0003). Concerning the hard endpoints, post-hoc analysis demonstrated preventive PCI significantly reduced the risk of cardiovascular death or target-vessel MI compared with optimal medical therapy (two [0.3%] patients versus 11 [1.4%] patients, respectively). Preventive PCI also remained superior to optimal medical therapy throughout the entire study follow-up period. Interestingly, the primary endpoint was driven by a reduction of revascularization, in particular ischemia-driven revascularization (HR 0.66, 0.25-0.77). Furthermore, there was a significant 81% relative risk reduction of hospitalizations for angina. For this study, the treatment of approximately 45 patients with vulnerable plaque with preventive PCI would prevent one primary outcome event compared with optimal medical therapy at a two-year follow-up. Post-hoc analysis demonstrated preventive PCI with cobalt-chromium everolimus-eluting metallic stents were superior to the use of bioresorbable vascular scaffolds.

The PREVENT trial has numerous and powerful implications for managing patients with CAD. This trial supports PCI for treating patients with intermediate stenoses with features consistent with vulnerable plaque. The findings of these studies are reliant on incorporating intravascular imaging to better characterize atherosclerotic plaque in the setting of coronary angiography. We expect the results of the PREVENT trial will further increase the incorporation of intravascular imaging into coronary angiography and routine PCI, an increasing trend with the management of heavily calcified lesions and fueled by data demonstrating improved cardiovascular outcomes with imaging-guided PCI. Furthermore, these results may warrant continuing education and improved proficiency with IVUS and other modalities to identify vulnerable plaque. It will also be interesting to see if high-risk features identifiable in coronary CTA are also applicable to the findings of this study. The implication that intermediate stenoses with features of vulnerable plaque are best managed with PCI and stenting also raises the potential for abuse, and it will be important that best practices are employed uniformly across the field of interventional cardiology to avoid unnecessary or inappropriate PCI. Nonetheless, the significant reduction in hospitalization for angina highlights the known superiority of PCI over medical therapy for angina relief, although, in this case, in physiologically non-significant lesions. Another question is how and when treatment of vulnerable plaques with stenosis ≥50% can be realistically applied to practice, as current guidelines recommend against the treatment of these lesions with PCI. Interestingly, signals of this were not seen through decades of randomized trials that support deferring PCI in patients with hemodynamically “insignificant” lesions. We expect additional randomized trials will be necessary to test the portability of the PREVENT trial findings before adoption into accepted practice. We eagerly await to see the impact of this landmark trial on the field of cardiology with the hope of PREVENT-ing cardiovascular death and MI in patients with vulnerable plaque.

Drs. Lipinski, Baker, and Escarcega have no conflicts of interest to report.

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