What Are the PROSPECTs and Clinical Implications of Vulnerable Plaque?

Rasha Al-Lamee; Gary S. Mintz


Eur Heart J. 2021;42(45):4680-4682. 

Graphical Abstract: Timeline of development and future directions for clinical trials in coronary vulnerable plaque (VP).

Despite the fact that it has been three decades since James Muller and his colleagues first proposed the concept of vulnerable plaque[1] and 18 years since Naghavi et al. published their consensus document summarizing the concepts behind vulnerable patients and vulnerable plaques, including classifications for clinical and pathological evaluation,[2,3] we still have much to learn about the clinical implications of vulnerable plaque (Graphical Abstract).

Feasibility of vulnerable plaque detection in clinical practice was the initial clinical hurdle. In 2011, the first landmark natural history study of rupture-prone vulnerable plaques, PROSPECT, used three-vessel virtual histology–intravascular ultrasound to study patients presenting with an acute coronary syndrome.[4] After PROSPECT, there remained a gap in major natural history studies until LRP (patients with suspected coronary artery disease who underwent cardiac catheterization with possible ad hoc percutaneous coronary intervention), CLIMA (proximal left anterior descending arteries in unselected patients), and PROSPECT II (patients with a myocardial infarction within 4 weeks) were published from 2019 to 2021.[4–7] Although enrolment criteria and imaging technologies and protocols varied among these four studies, they established the feasibility of vulnerable plaque detection using intravascular imaging. However, and once detected, what were the clinical sequelae of vulnerable plaque? The association between vulnerable plaque and events was harder to study. With an annualized death and myocardial infarction rate of <1% to 2%, events in these studies were driven mainly by revascularizations or readmission for progressive angina. The prevalence and positive predictive values of vulnerable plaques were typically <10%, and half of the lesion-causing events were missed irrespective of the specific imaging protocols.

The next important step was the exploration of options for the treatment of vulnerable plaque. Serial optical coherence tomography (OCT) studies showed that lipid lowering led to plaque stabilization, with increased thickness of the fibrous cap proportional to the reduction in LDL cholesterol with statin therapy,[8] resulting in plaques that were less prone to rupture and thrombosis. However, even experienced investigators continued to disagree on the OCT assessment of lipid and fibrous cap thickness, the cornerstones of OCT diagnosis of vulnerable, rupture-prone plaque.[9,10] With no consensus on the classification of vulnerable plaque, clinical translation has remained a problem.

Who should be targeted for vulnerable plaque detection? Studies using cardiac computed tomography have reported that a high calcium score (>400) even in patients without known coronary artery disease[11] or a low attenuation plaque burden in patients with stable symptoms[12] predicted death and/or myocardial infarction, especially when risk factors such as diabetes mellitus were integrated. These findings may be explained by the presence of vulnerable plaque, and these patients should be treated with aggressive risk factor modification including high intensity lipid-lowering therapy to potentially stabilize plaque and reduce cardiovascular events.

Diabetes mellitus has become epidemic. According to the World Health Organization, the number of people with diabetes mellitus rose from 108 million in 1980 to 422 million in 2014; and diabetic patients have a two-fold increased risk of myocardial infarction.[13] However, even in patients with diabetes mellitus that were enrolled in COMBINE OCT-FFR (published in this issue of the European Heart Journal[14]), hard events were rare. The COMBINE OCT-FFR investigators recruited patients with diabetes mellitus and at least one angiographic lesion with fractional flow reserve (FFR) >0.80. Thin-cap fibroatheroma (TCFA) was detected using OCT; and in 390 patients with FFR-negative lesions, patients were divided into those with vs. those without the presence of a TCFA. Despite no myocardial ischaemia, patients with TCFA were five times more likely than those patients with no evidence of vulnerable plaque to have major adverse cardiac events during an 18-month follow-up. However, this finding was driven by events that were mostly target lesion revascularizations or readmission for progressive angina—similar to PROSPECT, LRP, CLIMA, and PROSPECT II. While these endpoints are known to be susceptible to bias in unblinded trials, the investigators and patients in this trial were blinded to the results of OCT analysis and the presence of TCFA to minimize the impact of knowledge of vulnerable plaque on future clinical events.

Why is it so difficult to link vulnerable plaque to hard events? Autopsy studies have highlighted that most plaques rupture asymptomatically and contribute to disease progression rather than causing an acute myocardial infarction.[15] This helps to explain the observation that most events in PROSPECT, LRP, CLIMA, PROSPECT II, and COMBINE OCT-FFR were revascularization or rehospitalization for progressive angina rather than death/myocardial infarction.

Perhaps the most interesting conclusion from COMBINE OCT-FFR is that, in a post-ISCHEMIA world,[16] we have more evidence that plaque composition and stability and cardiovascular events may not be tightly linked to myocardial ischaemia. Events can occur in the absence of ischaemia, and we need further exploration of factors that lead to plaque vulnerability. Treatment options for the future need to focus on plaque stabilization and regression, even in mild lesions that are not flow limiting, in order to improve clinical outcomes for our patients. We may need to move away from the concept that ischaemia is the major driver of events and consider that it is only a surrogate for the burden of atherosclerosis. The contribution of plaque morphology to future events needs to be considered. More study is needed to direct its detection, and effective treatment strategies need to be developed.