Atherosclerotic Coronary Plaque Regression and Risk of Adverse Cardiovascular Events: A Systematic Review and Updated Meta-Regression Analysis

Abstract

Importance: The association between changes in atherosclerotic plaque induced by lipid-lowering therapies (LLTs) and reduction in major adverse cardiovascular events (MACEs) remains controversial.

Objective: To evaluate the association between coronary plaque regression assessed by intravascular ultrasound (IVUS) and MACEs.

Data sources: A comprehensive, systematic search of publications in PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was performed.

Study selection: Clinical prospective studies of LLTs reporting change in percent atheroma volume (PAV) assessed by IVUS and describing MACE components were selected.

Data extraction and synthesis: Reporting was performed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The association between mean change in PAV and MACEs was analyzed by meta-regression using mixed-effects, 2-level binomial logistic regression models, unadjusted and adjusted for clinical covariates, including mean age, baseline PAV, baseline low-density lipoprotein cholesterol level, and study duration.

Main outcome and measures: Mean PAV change and MACE in intervention and comparator arms were assessed in an updated systematic review and meta-regression analysis of IVUS trials of LLTs that also reported MACEs.

Results: This meta-analysis included 23 studies published between July 2001 and July 2022, including 7407 patients and trial durations ranging from 11 to 104 weeks. Mean (SD) patient age ranged from 55.8 (9.8) to 70.2 (7.6) years, and the number of male patients from 245 of 507 (48.3%) to 24 of 26 (92.3%). Change in PAV across 46 study arms ranged from -5.6% to 3.1%. The number of MACEs ranged from 0 to 72 per study arm (17 groups [37%] reported no events, 9 [20%] reported 1-2 events, and 20 [43%] reported ≥3 events). In unadjusted analysis, a 1% decrease in mean PAV was associated with 17% reduced odds of MACEs (unadjusted OR, 0.83; 95% CI, 0.71-0.98; P = .03), and with a 14% reduction in MACEs in adjusted analysis (adjusted OR, 0.86; 95% CI, 0.75-1.00; P = .050). Further adjustment for cardiovascular risk factors showed a 19% reduced risk (adjusted OR, 0.81; 95% CI, 0.68-0.96; P = .01) per 1% decrease in PAV. A 1% reduction of PAV change between intervention and comparator arms within studies was also associated with a significant 25% reduction in MACEs (OR, 0.75; 95% CI, 0.56-1.00; P = .046).

Conclusions and relevance: In this meta-analysis, regression of atherosclerotic plaque by 1% was associated with a 25% reduction in the odds of MACEs. These findings suggest that change in PAV could be a surrogate marker for MACEs, but given the heterogeneity in the outcomes, additional data are needed.

Figure 1.. Flowchart of Literature Search and Selection

IVUS indicates intravascular ultrasound; MACE, major adverse cardiovascular event.

Figure 2.. Association of Percent Atheroma Volume (PAV) With Odds of Major Adverse Cardiovascular Events (MACEs)

A, Each circle represents a single study group. The size of the circle is proportional to the sample size of that study group. The MACE proportion was converted to log odds, and a constant 0.5 was added to 0 counts to allow the conversion of log odds. The regression line is based on the adjusted mixed-effects logistic regression model with follow-up at 52 weeks, age fixed at a mean of 62 years, baseline low-density lipoprotein cholesterol fixed at a mean of 123 mg/dL (to convert to mmol/L, multiply by 0.0259), and baseline PAV fixed at a mean of 45%. B, The black line indicates the regression line; shaded area, 95% CI; light blue circles, observed log(odds ratio [OR]) between the intervention and high-intensity statin arm and the comparator or reference arm for the change in PAV; size of circles, size of study (ie, total number of patients in each study); and brown circles, studies for which the log(OR) was calculated with addition of a non-0 constant (0.1) to 0 events to allow conversion of log odds.

Figure 3.. Evaluation of Heterogeneity of Observed Major Adverse Cardiovascular Events (MACEs) by Study Group

Included are only study groups with active lipid-lowering therapy. The MACEs are presented for each study group as total counts and as the proportion of patients with a MACE. For 0 MACE counts, the lower CI was set as 0 and the upper CI as [1 – 0.05^(1/n)], where n is the sample size in the study group. For non-0 MACE counts, the CI was obtained from the log odds and then converted back to proportions. EPA indicates eicosapentaenoic acid.

Figure 4.. Sensitivity Analysis of Major Adverse Cardiovascular Events (MACEs) per 1% Reduction in Mean Percent Atheroma Volume (PAV)

The odds ratios (ORs) and 95% CIs are shown after exclusion of 1 trial at a time, nonrandomized studies, studies performed in patients with acute coronary syndrome (ACS), studies of mixed ACS and stable coronary artery disease (CAD), and studies of stable CAD exclusively.