Characterising patients and lesions with plaque progression despite high-intensity LDL-C-lowering therapy: a multimodality serial intracoronary imaging study from the IBIS-4 and PACMAN-AMI trials

Background/Introduction Even with intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapies, a subset of patients show plaque progression (non-responders). The relative contribution of on-treatment LDL-C levels, non-LDL-C-related residual risk, or the heterogeneity of plaque phenotypes remains unclear. Phenotyping non-responders would aid optimising secondary prevention therapy. Purpose To characterise non-responders and identify clinical and imaging predictors of plaque progression. Methods We analysed pooled data from the IBIS-4 and PACMAN-AMI trials. Patients presenting with acute myocardial infarction (AMI) and non-obstructive lesions in non-infarct-related arteries (non-IRAs) underwent intracoronary imaging at baseline and at 52 weeks, including intravascular ultrasound (IVUS) and optical coherence tomography (OCT) in both cohorts, and near-infrared spectroscopy (NIRS) in the PACMAN-AMI cohort. All patients received high-intensity statin therapy; in PACMAN-AMI, patients were additionally randomised to alirocumab or placebo. Non-responders were defined as patients showing an increase in IVUS-derived percent atheroma volume (PAV) from baseline to follow-up. Clinical characteristics, biomarkers, and imaging findings were compared between responders and non-responders. Results The proportion of non-responders was 27% (94/347 patients) overall and 15% (20/130) among PACMAN-AMI patients randomised to alirocumab. Age, sex, risk factors (hypertension, diabetes, chronic kidney disease), and baseline high-sensitivity C-reactive protein (hsCRP) levels did not differ between groups. Compared with responders, non-responders were more frequently on prior statin therapy at baseline (18.9% vs 9.5%, P = 0.025) and had lower baseline LDL-C levels (Figure 1). At follow-up, non-responders had higher LDL-C, lower high-density lipoprotein cholesterol, higher lipoprotein(a), higher apolipoprotein B, and no difference in hsCRP levels (Figure 1). At the lesion level, 742 lesions were evaluated by serial IVUS, and 175 (24%) were classified as non-responder lesions. Non-responder lesions more frequently exhibited lipid-rich plaque on OCT and by NIRS (maximum lipid core burden index within 4 mm > 215) at baseline (Figure 2). Independent predictors of non-responder lesions were lipid-rich plaque by OCT or NIRS (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.28–3.30), lower baseline PAV (OR 0.94, 95% CI 0.90–0.98), and absence of alirocumab use (OR 0.34, 95% CI 0.20–0.57). Conclusions One-quarter of AMI patients exhibit plaque progression in non-IRAs despite intensive LDL-C-lowering therapy. Prior statin use, higher on-treatment LDL-C, and absence of PCSK9 inhibitor therapy, but not factors unrelated to LDL-C, were associated with non-responder patients. Lipid-rich lesions were associated with an increased risk of plaque volume progression.Figure 1Figure 2