The concept that lipid lowering can alter characteristics of atherosclerotic plaques associated with their disruption and thrombotic complications arose from animal experiments conducted in the 1990s.1 The clinical translatability of these laboratory investigations has remained largely speculative. By the time humans present with atherosclerotic complications, the plaques have usually percolated for many years and have often become more fibrotic and calcified than lesions typically produced in experimental animals. The concept that lipid lowering could reduce the volume of human atherosclerotic plaques derived support from several intravascular imaging studies.2 The PACMAN-AMI trial has extended these results by testing the hypothesis that initiation of profound lowering of low-density lipoprotein cholesterol (LDL-C) by stacking statins and PCSK9 inhibitors could improve characteristics of plaques associated with thrombotic complications in patients with acute coronary syndrome (ACS).3 This study used a suite of intravascular imaging modalities: intravascular ultrasound (well validated for quantitative analysis of plaque volume), optical coherence tomography (apt for assessing the thickness of the plaque’s protective fibrous cap), and near-infrared spectroscopic assessment (reported to reflect lipid content). The study enrolled 300 individuals with ACS who underwent primary stenting and characterized plaques by interrogating the non–infarct-related arteries. The subjects underwent repeat examination with the trio of intravascular tests after 1 year of treatment with an anti–PCSK9 antibody on the background of statin treatment.
The study showed significantly greater reduction in atheroma volume, increase in fibrous cap thickness, and lipid content in the combination therapy group, which achieved an LDL-C of 24 mg/dL versus 75 mg/dL in patients treated with a statin alone. As in previous studies, even in the aggressive lipid-lowering group, the actual percent reduction in atheroma volume was modest indeed at about 2%. The enrolled population had only about 12% statin use at baseline. The large proportion of statin-naïve participants offered an excellent opportunity to test the effects of steep LDL-C lowering on plaque characteristics. A reinforced fibrous cap should render a plaque less likely to rupture, but only a small minority of thin-capped plaques will actually provoke a clinical event.4 We should also bear in mind that up to a third of ACS result from plaque erosion rather than rupture.5 Erosion-related events may depend less on lipid content than those due to fissured fibrous caps.
The results of this study extend the clinical translation of the concept of plaque “stabilization” to profound LDL lowering in patients in the throes of an acute myocardial infarction.6 This study was not powered for clinical outcomes. Roughly half of recurrent events in survivors of ACS arise from non-culprit lesions, indicating that the regimen employed in the PACMAN-AMI trial could confer clinical benefit. The results of this study indicate that, if cost and parenteral administration were not barriers, patients with ACS should be treated not only with statins but also with a PCSK9 inhibitor. We know that adoption or persistence with prescribed statin therapy following ACS falls far short of ideal. In that regard, the availability of the small-interfering RNA PCSK9 inhibitor inclisiran suggests a management strategy that would involve administration of a first dose within the first day of presentation with ACS. This approach could produce these potentially favorable changes in plaques during the particularly vulnerable first year following ACS, with one injection administered in the hospital. Implementing this strategy would be an attractive subject for future clinical outcome trials.