PCSK9 Inhibitors in the Treatment of Calcific Aortic Stenosis

Summary

Calcific aortic stenosis (CAS) can cause severe adverse cardiac events, but there are currently no effective drugs that can prevent or delay the progression of the disease. Our trial aims to investigate the effect of PCSK9 inhibitors on preventing or delaying the progression of CAS.

Timeline

Start

2026-04-01

Primary completion

2028-12-31

Completion

2029-01-31

Publications

• Background Leopold JA. PCSK9 and Calcific Aortic Valve Stenosis: Moving Beyond Lipids. JACC Basic Transl Sci. 2020 Jul 27;5(7):662-664. doi: 10.1016/j.jacbts.2020.06.004. eCollection 2020 Jul.
• Background O'Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Ceska R, Ezhov MV, Jukema JW, Jensen HK, Tokgozoglu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019 Mar 19;139(12):1483-1492. doi: 10.1161/CIRCULATIONAHA.118.037184.
• Background Langsted A, Nordestgaard BG, Benn M, Tybjaerg-Hansen A, Kamstrup PR. PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis. J Clin Endocrinol Metab. 2016 Sep;101(9):3281-7. doi: 10.1210/jc.2016-1206. Epub 2016 May 24.
• Background Mateos N, Gomez M, Homar A, Garcia-Elias A, Yanez L, Tajes M, Molina L, Ble M, Cladellas M, Roqueta C, Benito B. Plasmatic PCSK9 Levels Are Associated with Very Fast Progression of Asymptomatic Degenerative Aortic Stenosis. J Cardiovasc Transl Res. 2022 Feb;15(1):5-14. doi: 10.1007/s12265-021-10138-4. Epub 2021 Aug 2.
• Background Poggio P, Songia P, Cavallotti L, Barbieri SS, Zanotti I, Arsenault BJ, Valerio V, Ferri N, Capoulade R, Camera M. PCSK9 Involvement in Aortic Valve Calcification. J Am Coll Cardiol. 2018 Dec 18;72(24):3225-3227. doi: 10.1016/j.jacc.2018.09.063. No abstract available.
• Background Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014 Apr 8;63(13):1278-1288. doi: 10.1016/j.jacc.2014.01.006. Epub 2014 Feb 5.
• Background Bergmark BA, O'Donoghue ML, Murphy SA, Kuder JF, Ezhov MV, Ceska R, Gouni-Berthold I, Jensen HK, Tokgozoglu SL, Mach F, Huber K, Gaciong Z, Lewis BS, Schiele F, Jukema JW, Pedersen TR, Giugliano RP, Sabatine MS. An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial. JAMA Cardiol. 2020 Jun 1;5(6):709-713. doi: 10.1001/jamacardio.2020.0728.
• Background Capoulade R, Yeang C, Chan KL, Pibarot P, Tsimikas S. Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2018 Dec 1;3(12):1212-1217. doi: 10.1001/jamacardio.2018.3798.
• Background Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil JG, Tam JW, Teo KK, Mahmut A, Yang X, Witztum JL, Arsenault BJ, Despres JP, Pibarot P, Tsimikas S. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2015 Sep 15;66(11):1236-1246. doi: 10.1016/j.jacc.2015.07.020.
• Background Zheng KH, Tsimikas S, Pawade T, Kroon J, Jenkins WSA, Doris MK, White AC, Timmers NKLM, Hjortnaes J, Rogers MA, Aikawa E, Arsenault BJ, Witztum JL, Newby DE, Koschinsky ML, Fayad ZA, Stroes ESG, Boekholdt SM, Dweck MR. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. J Am Coll Cardiol. 2019 May 7;73(17):2150-2162. doi: 10.1016/j.jacc.2019.01.070.
• Background Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, Harris TB, Malhotra R, O'Brien KD, Kamstrup PR, Nordestgaard BG, Tybjaerg-Hansen A, Allison MA, Aspelund T, Criqui MH, Heckbert SR, Hwang SJ, Liu Y, Sjogren M, van der Pals J, Kalsch H, Muhleisen TW, Nothen MM, Cupples LA, Caslake M, Di Angelantonio E, Danesh J, Rotter JI, Sigurdsson S, Wong Q, Erbel R, Kathiresan S, Melander O, Gudnason V, O'Donnell CJ, Post WS; CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013 Feb 7;368(6):503-12. doi: 10.1056/NEJMoa1109034.
• Background Perrot N, Valerio V, Moschetta D, Boekholdt SM, Dina C, Chen HY, Abner E, Martinsson A, Manikpurage HD, Rigade S, Capoulade R, Mass E, Clavel MA, Le Tourneau T, Messika-Zeitoun D, Wareham NJ, Engert JC, Polvani G, Pibarot P, Esko T, Smith JG, Mathieu P, Thanassoulis G, Schott JJ, Bosse Y, Camera M, Theriault S, Poggio P, Arsenault BJ. Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis. JACC Basic Transl Sci. 2020 Jul 1;5(7):649-661. doi: 10.1016/j.jacbts.2020.05.004. eCollection 2020 Jul.
• Background Guddeti RR, Patil S, Ahmed A, Sharma A, Aboeata A, Lavie CJ, Alla VM. Lipoprotein(a) and calcific aortic valve stenosis: A systematic review. Prog Cardiovasc Dis. 2020 Jul-Aug;63(4):496-502. doi: 10.1016/j.pcad.2020.06.002. Epub 2020 Jun 8.
• Background Youssef A, Clark JR, Koschinsky ML, Boffa MB. Lipoprotein(a): Expanding our knowledge of aortic valve narrowing. Trends Cardiovasc Med. 2021 Jul;31(5):305-311. doi: 10.1016/j.tcm.2020.06.001. Epub 2020 Jun 7.
• Background Capoulade R, Cariou B. Editorial commentary: Lp(a) and calcific aortic valve stenosis: Direct LPA targeting or PCSK9-Lowering therapy? Trends Cardiovasc Med. 2021 Jul;31(5):312-314. doi: 10.1016/j.tcm.2020.06.009. Epub 2020 Jul 2. No abstract available.
• Background Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov 7.
• Background Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.
• Background Seidah NG, Prat A. The Multifaceted Biology of PCSK9. Endocr Rev. 2022 May 12;43(3):558-582. doi: 10.1210/endrev/bnab035.
• Background Punch E, Klein J, Diaba-Nuhoho P, Morawietz H, Garelnabi M. Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis. J Am Heart Assoc. 2022 Feb;11(3):e023328. doi: 10.1161/JAHA.121.023328. Epub 2022 Jan 20.
• Background Writing Committee Members; Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F, Jneid H, Krieger EV, Mack M, McLeod C, O'Gara PT, Rigolin VH, Sundt TM 3rd, Thompson A, Toly C. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2021 Feb 2;77(4):e25-e197. doi: 10.1016/j.jacc.2020.11.018. Epub 2020 Dec 17. No abstract available.
• Background Dichtl W, Alber HF, Feuchtner GM, Hintringer F, Reinthaler M, Bartel T, Sussenbacher A, Grander W, Ulmer H, Pachinger O, Muller S. Prognosis and risk factors in patients with asymptomatic aortic stenosis and their modulation by atorvastatin (20 mg). Am J Cardiol. 2008 Sep 15;102(6):743-8. doi: 10.1016/j.amjcard.2008.04.060. Epub 2008 Jul 2.
• Background van der Linde D, Yap SC, van Dijk AP, Budts W, Pieper PG, van der Burgh PH, Mulder BJ, Witsenburg M, Cuypers JA, Lindemans J, Takkenberg JJ, Roos-Hesselink JW. Effects of rosuvastatin on progression of stenosis in adult patients with congenital aortic stenosis (PROCAS Trial). Am J Cardiol. 2011 Jul 15;108(2):265-71. doi: 10.1016/j.amjcard.2011.03.032. Epub 2011 May 10.
• Background Evangelista A, Galian-Gay L, Guala A, Teixido-Tura G, Calvo-Iglesias F, Sevilla T, Bermejo J, Mendez I, Sanchez V, Robledo Carmona JM, Alegret JM, Ferrer-Sistach E, Saura D, Ruiz-Munoz A, Dux-Santoy L, Carmona MA, Huguet M, Cuellar-Calabria H, Sao-Aviles A, Ferreira-Gonzalez I, Rodriguez-Palomares JF. Atorvastatin Effect on Aortic Dilatation and Valvular Calcification Progression in Bicuspid Aortic Valve (BICATOR): A Randomized Clinical Trial. Circulation. 2024 Jun 18;149(25):1938-1948. doi: 10.1161/CIRCULATIONAHA.123.067537. Epub 2024 May 28.
• Background Chan KL, Teo K, Dumesnil JG, Ni A, Tam J; ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010 Jan 19;121(2):306-14. doi: 10.1161/CIRCULATIONAHA.109.900027. Epub 2010 Jan 4.
• Background Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Barwolf C, Holme I, Kesaniemi YA, Malbecq W, Nienaber CA, Ray S, Skjaerpe T, Wachtell K, Willenheimer R; SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008 Sep 25;359(13):1343-56. doi: 10.1056/NEJMoa0804602. Epub 2008 Sep 2.
• Background Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, Boon NA; Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005 Jun 9;352(23):2389-97. doi: 10.1056/NEJMoa043876.
• Background Nazarzadeh M, Pinho-Gomes AC, Bidel Z, Dehghan A, Canoy D, Hassaine A, Ayala Solares JR, Salimi-Khorshidi G, Smith GD, Otto CM, Rahimi K. Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Eur Heart J. 2020 Oct 21;41(40):3913-3920. doi: 10.1093/eurheartj/ehaa070.
• Background Lincoff AM, Ray KK, Sasiela WJ, Haddad T, Nicholls SJ, Li N, Cho L, Mason D, Libby P, Goodman SG, Nissen SE. Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs. J Am Coll Cardiol. 2024 Jul 9;84(2):152-162. doi: 10.1016/j.jacc.2024.04.048.
• Background Natorska J, Kopytek M, Undas A. Aortic valvular stenosis: Novel therapeutic strategies. Eur J Clin Invest. 2021 Jul;51(7):e13527. doi: 10.1111/eci.13527. Epub 2021 Mar 13.
• Background Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O'Brien KD, Schoen FJ, Towler DA, Yoganathan AP, Otto CM. Calcific aortic valve disease: not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update. Circulation. 2011 Oct 18;124(16):1783-91. doi: 10.1161/CIRCULATIONAHA.110.006767. No abstract available.
• Background Genereux P, Stone GW, O'Gara PT, Marquis-Gravel G, Redfors B, Giustino G, Pibarot P, Bax JJ, Bonow RO, Leon MB. Natural History, Diagnostic Approaches, and Therapeutic Strategies for Patients With Asymptomatic Severe Aortic Stenosis. J Am Coll Cardiol. 2016 May 17;67(19):2263-2288. doi: 10.1016/j.jacc.2016.02.057. Epub 2016 Apr 2.
• Background Lindman BR, Dweck MR, Lancellotti P, Genereux P, Pierard LA, O'Gara PT, Bonow RO. Management of Asymptomatic Severe Aortic Stenosis: Evolving Concepts in Timing of Valve Replacement. JACC Cardiovasc Imaging. 2020 Feb;13(2 Pt 1):481-493. doi: 10.1016/j.jcmg.2019.01.036. Epub 2019 Jun 12.
• Background Yang Y, Wang Z, Chen Z, Wang X, Zhang L, Li S, Zheng C, Kang Y, Jiang L, Zhu Z, Gao R. Current status and etiology of valvular heart disease in China: a population-based survey. BMC Cardiovasc Disord. 2021 Jul 13;21(1):339. doi: 10.1186/s12872-021-02154-8.
• Background Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, Pibarot P. Calcific aortic stenosis. Nat Rev Dis Primers. 2016 Mar 3;2:16006. doi: 10.1038/nrdp.2016.6.
• Background Otto CM, Newby DE, Hillis GS. Calcific Aortic Stenosis: A Review. JAMA. 2024 Dec 17;332(23):2014-2026. doi: 10.1001/jama.2024.16477.

Drugs

Indications