Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study

Abstract

BACKGROUND: The effect of alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, on coronary plaque burden in patients with familial hypercholesterolemia has not been addressed. Our aim was to assess changes in coronary plaque burden and its characteristics after treatment with alirocumab by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of a noninvasive analysis of coronary computed tomographic angiography in asymptomatic subjects with familial hypercholesterolemia receiving optimized and stable treatment with maximum tolerated statin dose with or without ezetimibe. METHODS: This study is a phase IV, open-label, multicenter, single-arm clinical trial to assess changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent an initial coronary computed tomographic angiography at baseline and another at 78 weeks. Every patient received 150 mg of alirocumab subcutaneiously every 14 days in addition to high-intensity statin therapy. The main outcome was the change on coronary plaque burden and its characteristics by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of analysis of coronary computed tomographic angiography. RESULTS: The study was completed by 104 patients. The median age was 53.3 (46.2–59.4) years. Of these patients, 54 were women (51.9%). Median low-density lipoprotein cholesterol was 138.9 (117.5–175.3) mg/dL at entry and 45.0 (36.0–65.0) mg/dL at follow-up ( P <0.001). Coronary plaque burden changed from 34.6% (32.5%–36.8%) at entry to 30.4% (27.4%–33.4%) at follow-up ( P <0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%; P <0.001) and mainly fibrous (+6.2%; P <0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (–3.9%; P <0.001) and necrotic plaque (–0.6%; P <0.001). CONCLUSIONS: Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in these groups of patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) could link and explain ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) results. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05465278

Letter by Aldana-Bitar et al Regarding Article, “Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study”

“…The study found that alirocumab led to reduced total plaque volume and total plaque burden and increased calcified and fibrous plaque, as well as reduced fibrofatty and necrotic plaque. 1 These are significant findings as familial hypercholesterolemia patients are at a very high risk for cardiac events.…”

Eradicating Atherosclerotic Events by Targeting Early Subclinical Disease: It Is Time to Retire the Therapeutic Paradigm of Too Much, Too Late

“…For example, after extensive improvements in the plasma lipoprotein profile, cholesterol crystals and areas of necrosis within the arterial wall diminish, but slowly and often incompletely. 15,[57][58][59][60][61] Without adequate management, the progressing plaque expresses two key enzymes, SMase (sphingomyelinase) and LpL (lipoprotein lipase), that synergistically accelerate further retention and aggregation of apoB-lipoproteins onto arterial PGs (proteoglycans). [62][63][64][65] In an end-stage atheroma, MMPs (matrix metalloproteinases) weaken the fibrous cap, thereby rendering the plaque susceptible to rupture or erosion.…”

Letter by Long and Jiang Regarding Article, “Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study”

“…We read with interest the study by Pérez de Isla et al 1 assessing changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease, which demonstrated that alirocumab resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. After reading this article carefully, we have some suggestions to point out as follows.…”