Impact of Evinacumab on coronary plaques in patients with Homozygous Familial Hypercholesterolemia: Protocol of the "EVOLVE-HoFH" study (EValuation of atherOma pLaque Volume after Evinacumab in HOmozygous Familial Hypercholesterolemia)
EVOLVE-HoFH Study Protocol
Copyright (c) 2025 European Atherosclerosis Journal
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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Published: December 31, 2025
Abstract
Background: Homozygous Familial Hypercholesterolemia (HoFH) is a rare and severe genetic disorder characterized by markedly elevated low-density lipoprotein-cholesterol (LDL-C) levels from birth onwards, leading to accelerated and premature atherosclerotic cardiovascular disease (ASCVD). Evinacumab, a monoclonal antibody targeting angiopoietin-like protein 3 (ANGPTL3), has been shown to effectively reduce LDL-C in this population. However, its direct impact on coronary atherosclerotic plaque burden remains to be established. Given the rarity of the condition, randomized placebo-controlled clinical trials on major adverse cardiovascular events (MACE) are unfeasible.
Aim and Methods: This document describes the methodology of the EVOLVE-HoFH study, a real-world, observational, multicenter, international study (prospective and retrospective) designed to assess whether intensification of lipid-lowering therapy (LLT) with Evinacumab leads to regression or stabilization of the coronary atherosclerotic plaque burden as well as altered composition in patients with HoFH. The study will use Coronary Computed Tomography Angiography (CCTA), a validated surrogate risk marker, to compare changes in plaque volume in a group of patients initiating treatment with Evinacumab ("intensified treatment group") with a "conventional treatment comparator group." The primary endpoint is the difference in change in percent non-calcified plaque volume (%NCPV), a key indicator of plaque instability, between baseline and 18-24 months follow-up.
Conclusion: This pragmatic methodological approach is designed to overcome the barriers of research in rare diseases, allowing for the evaluation of a clinically relevant and mechanistically informative surrogate efficacy endpoint. The results will provide the first evidence of the beneficial impact of Evinacumab on coronary atherosclerosis, filling an important knowledge gap.
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References
- Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J 2023;44:2277–2291. doi: https://doi.org/10.1093/eurheartj/ehad197
- Belanger AM, Akioyamen L, Alothman L, Genest J. Evidence for improved survival with treatment of homozygous familial hypercholesterolemia. Curr Opin Lipidol 2020;31:176–181. doi: https://doi.org/10.1097/MOL.0000000000000686
- Tromp TR, Hartgers ML, Hovingh GK, Vallejo-Vaz AJ, Ray KK, Soran H, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet 2022;399:719–728. doi: https://doi.org/10.1016/S0140-6736(21)02001-8
- Reeskamp LF, Millar JS, Wu L, Jansen H, van Harskamp D, Schierbeek H, et al. ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report. Arterioscler Thromb Vasc Biol 2021;41:1753–1759. doi: https://doi.org/10.1161/ATVBAHA.120.315204
- Rosenson RS, Burgess LJ, Ebenbichler CF, Baum SJ, Stroes ESG, Ali S, et al. Evinacumab in Patients with Refractory Hypercholesterolemia. N Engl J Med 2020;383:2307–2319. doi: https://doi.org/10.1056/NEJMoa2031049
- Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med 2020;383:711–720. doi: https://doi.org/10.1056/NEJMoa2004215
- Gaudet D, Gipe DA, Pordy R, Ahmad Z, Cuchel M, Shah PK, et al. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. N Engl J Med 2017;377:296–297. doi: https://doi.org/10.1056/NEJMc1705994
- Schonck WAM, Reijman MD, Wiegman A, Ibrahim S, Corpeleijn WE, Planken RN, et al. Decreased LDL-Cholesterol Exposure Following ANGPTL3 Inhibition Reduces Coronary Plaque Development in Homozygous Familial Hypercholesterolemia. JACC Cardiovasc Imaging 2024;17:1258–1260. doi: https://doi.org/10.1016/j.jcmg.2024.05.005
- Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA 2016;316:2373–2384. doi: https://doi.org/10.1001/jama.2016.16951
- Raber L, Ueki Y, Otsuka T, Losdat S, Haner JD, Lonborg J, et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA 2022;327:1771–1781.
- doi: https://doi.org/10.1001/jama.2022.5218
- Han D, Tzolos E, Park R, Gransar H, Hyun MC, Friedman JD, et al. Effects of Evolocumab on Coronary Atherosclerotic Plaque Composition and Microcalcification Activity by Coronary Pet-Ct Angiography: Results of the Prospective Evolve Study. JACC 2024;83: (13_Supplement) 1396. https://doi.org/10.1016/S0735-1097(24)03386-2
- Perez de Isla L, Diaz-Diaz JL, Romero MJ, Muniz-Grijalvo O, Mediavilla JD, Argueso R, et al. Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study. Circulation 2023;147:1436–1443.
- doi: https://doi.org/10.1161/CIRCULATIONAHA.122.062557
- Nurmohamed NS, Bom MJ, Jukema RA, de Groot RJ, Driessen RS, van Diemen PA, et al. AI-Guided Quantitative Plaque Staging Predicts Long-Term Cardiovascular Outcomes in Patients at Risk for Atherosclerotic CVD. JACC Cardiovasc Imaging 2023;17:269–280. doi: https://doi.org/10.1016/j.jcmg.2023.05.020
- Nurmohamed NS, Danad I, Jukema RA, de Winter RW, de Groot RJ, Driessen RS, et al. Development and Validation of a Quantitative Coronary CT Angiography Model for Diagnosis of Vessel-Specific Coronary Ischemia. JACC Cardiovasc Imaging 2024;17:894–906. doi: https://doi.org/10.1016/j.jcmg.2024.01.007
- Nurmohamed NS, Min JK, Anthopolos R, Reynolds HR, Earls JP, Crabtree T, et al. Atherosclerosis quantification and cardiovascular risk: the ISCHEMIA trial. Eur Heart J 2024;45:3735–3747. doi: https://doi.org/10.1093/eurheartj/ehae471
- Iraqi N, Mortensen MB, Sand NPR, Busk M, Grove EL, Dey D, et al. Interscan reproducibility of computed tomography derived coronary plaque volume measurements. J Cardiovasc Comput Tomogr 2024;18:583–592. doi: https://doi.org/10.1016/j.jcct.2024.09.009
- Bernardo R, Nurmohamed NS, Bom MJ, Jukema R, de Winter RW, Sprengers R, et al. Diagnostic accuracy in coronary CT angiography analysis: artificial intelligence versus human assessment. Open Heart 2025;12. doi: https://doi.org/10.1136/openhrt-2024-003115
- Griffin WF, Choi AD, Riess JS, Marques H, Chang HJ, Choi JH, et al. AI Evaluation of Stenosis on Coronary CTA, Comparison With Quantitative Coronary Angiography and Fractional Flow Reserve: A CREDENCE Trial Substudy. JACC Cardiovasc Imaging 2023;16:193–205.
- doi: https://doi.org/10.1016/j.jcmg.2021.10.020
