Patients with familial hypercholesterolemia (FH) without previous clinical atherosclerotic cardiovascular disease (ASCVD) who receive alirocumab in addition to high-intensity statin therapy have a significant decrease in coronary atherosclerotic burden, investigators reported in Circulation.
The phase IV, open-label, single-arm ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition; ClinicalTrials.gov Identifier: NCT05465278) trial assessed the effect of alirocumab at 78 weeks on coronary atherosclerotic plaque burden and its characteristics in patients with molecularly determined FH without clinical ASCVD. The participants were enrolled at 18 hospitals in Spain for the Spanish Familial Hypercholesterolemia Cohort Study (SAFEHEART) registry and received optimized and stable treatment with maximum tolerated doses of statins with or without ezetimibe in clinical practice conditions.
Participants were eligible for the study if they did not achieve low-density lipoprotein cholesterol (LDL-C) levels of less than 100 mg/dL, they had a global coronary plaque burden of more than 30% at baseline, and their treating physician prescribed alirocumab. All patients received a coronary computed tomographic angiography (CTA) at baseline and at 78 weeks and also received 150-mg alirocumab subcutaneously every 14 days.
The analysis included 104 patients (median age, 53.3 [IQR, 46.2-59.4] years; 52% women) enrolled from June 2018 to October 2019. Their median LDL-C was 138.9 (IQR, 117.5-175.3) mg/dL at entry and 45.0 (IQR, 36.0-65.0) mg/dL at follow-up (P <.001). This was a 67.6% median relative percentage decrease.
The participants who were treated with alirocumab had significantly greater decreases in triglycerides, lipoprotein (a), and high-sensitivity C-reactive protein. The median 10-year cardiovascular risk based on the SAFEHEART risk equation was 0.68% (IQR, 0.35%-1.02%) at enrollment and 0.22% (IQR, 0.09%-0.35%) after follow-up (P <.001).
The analyzed coronary tree length was 330.6 (IQR, 229.6-403.8) mm at entry vs 336.8 (IQR, 252.9-432.8) mm at follow-up (P =.209). The total plaque volume was 1028.6 (IQR, 721.3-1238.5) mm3 at entry and 819.4 (IQR, 618.5-1016.6) mm3 at follow-up (P <.001).
The global coronary plaque burden changed from 34.6% (IQR, 32.5%-36.8%) at study entry to 30.4% (IQR, 27.4%-33.4%) at follow-up, which was a -4.6% (IQR, -7.7% to -1.9%) statistically significant regression (P <.001). LDL-C decrease and plaque burden regression were not related in univariate linear regression analysis (B: 0.004 [95% CI, -0.014 to 0.021]; P =.662).
The characteristics of coronary atherosclerosis changed significantly at the end of follow-up. The proportion of calcified (+0.3%; P <.001) and mainly fibrous (+6.2 %; P <.001) plaque increased. The percentage of fibro-fatty (-3.9%; P <.001) and necrotic plaque (-0.6%; P <.001) decreased.
Adverse events related to treatment administration were reported in 25 patients (14%), although none of the events was severe. The most common events were mild and transient myalgia (6 patients) and mild and transient allergic reactions (5 patients).
The main study limitation is that it was not a randomized clinical trial, but rather each patient was evaluated individually before and after a therapeutic intervention. The study lacked a comparison group and was open-label. Also, the follow-up was relatively short, and a direct correlation was not established with either clinical events or biochemical parameters. Other limitations are the premature termination of the study owing to operational reasons and the median age of patients, which may have implications for external validity.
“…treatment with PCSK9 inhibitor alirocumab, in addition to high-intensity statin therapy, resulted in significant regression of coronary PB [plaque burden] and plaque stabilization on coronary CTA over 78 weeks in patients with FH without clinical ASCVD,” the researchers wrote. “Further studies in this high-risk population are needed to demonstrate the hypothesis raised by our results.”
Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Pérez de Isla L, Díaz-Díaz JL, Romero MJ, et al; on behalf of the SAFEHEART study group. Alirocumab and coronary atherosclerosis in asymptomatic patients with familial hypercholesterolemia: the ARCHITECT study. Circulation. Published online April 3, 2023. doi: 10.1161/CIRCULATIONAHA.122.062557