Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis

NCT04968509 | Recruiting Phase 3 DMC

• 2 other identifiers: EPISODE2022-2-1052
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 1

Brief 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. In fact, aortic valve replacement remains the only treatment option. CAS has been shown to be associated with Lp(a), LDL-C and PCSK9. Several observational studies indicated that the use of statins to decrease LDL-C levels was associated with the reduced incidence of CAS, but no randomized controlled trials (RCTs) showd that statins had any benefit on the progression of CAS. This may be related to the limited reduction of LDL-C by statin therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a new lipid-lowering drug. On the basis of statin therapy, PCSK9 inhibitors can further reduce LDL-C and Lp(a) levels by 50% to 60% and 20% to 30%, respectively. Some studies reported that elevated plasma PCSK9 levels were related to CAS and PCSK9 R46L loss-of-function mutation was associated with lower rates of CAS, and importantly, some observational studies found that PCSK9 inhibitors could reduce the incidence of CAS. Our trial aims to investigate the effect of PCSK9 inhibitors on preventing or delaying the progression of CAS. A total of 160 patients with mild or moderate CAS or asymptomatic severe AS will be randomly assigned to receive either statins or PCSK9 inhibitors+statins. All patients will be followed for at least 2 years at 3, 6,9,12,15,18,21,24 months after randomization. Quality of life (EQ-5D-3L including the EUROQOL visual analogue scale) questionnaires were gathered during each visit. Echocardiography and computer tomography were performed and blood samples were withdrawn at baseline, at 2 years visit, and before withdrawal from the study. The primary endpoint is the average annual change in peak aortic jet velocity on echocardiography. The secondary endpoints include average annual change in aortic valve area on echocardiography, average annual change in aortic valve calcification score on cardiac non-contrast computer tomography, heart valve surgery, change in quality-of-life scores, and average annual change in aortic and coronary artery calcification. Safety endpoints include all-cause death and cardiovascular events. The results of this trial will provide a new idea for the treatment of patients with CAS.

Conditions

Aortic Stenosis

Keywords

PCSK9 Inhibitors; Calcific Aortic Stenosis

Outcome Measures

Primary Outcomes (1)

• The average annual change in peak aortic jet velocity

  The peak aortic jet velocity is measured by echocardiography.

  Up to 24 months

Secondary Outcomes (4)

• The average annual change in aortic valve area

  Up to 24 months

• The average annual change in aortic valve calcification score

  Up to 24 months

• Heart valve surgery

  Up to 24 months

• Change in quality-of-life scores

  Up to 24 months

Other Outcomes (1)

• Safety endpoints

  Up to 24 months

Study Arms (2)

Treatment with PCSK9 inhibitors and conventional lipid-lowering therapy based on statins

EXPERIMENTAL

Patients in experimental group are treated with PCSK9 inhibitors (140mg with Evolocumab or 75mg with Alirocumab or 150mg with Tafolecimab subcutaneously every two weeks) and conventional lipid-lowering therapy based on statins (atorvastatin 20-40mg qd with or without ezetimibe 10mg qd, or rosuvastatin 10-20mg qd with or without ezetimibe 10mg qd).

Drug: PCSK9 inhibitors and statins with or without ezetimibe

Treatment with only conventional lipid-lowering therapy based on statins

OTHER

Patients in control group are only treated with conventional lipid-lowering therapy based on statins (atorvastatin 20-40mg qd with or without ezetimibe 10mg qd, or rosuvastatin 10-20mg qd with or without ezetimibe 10mg qd).

Drug: Statins with or without ezetimibe

Interventions

PCSK9 inhibitors and statins with or without ezetimibe DRUG

Patients in experimental group are treated with PCSK9 inhibitors (140mg with Evolocumab or 75mg with Alirocumab or 150mg with Tafolecimab subcutaneously every two weeks) and conventional lipid-lowering therapy based on statins (atorvastatin 20-40mg qd with or without ezetimibe 10mg qd, or rosuvastatin 10-20mg qd with or without ezetimibe 10mg qd).

Also known as: Proprotein convertase subtilisin/kexin type 9 inhibitors, Hydroxymethylglutaryl-Coenzyme A Reductase inhibitors, Ezetimibe

Treatment with PCSK9 inhibitors and conventional lipid-lowering therapy based on statins

Statins with or without ezetimibe DRUG

Patients in control group are only treated with conventional lipid-lowering therapy based on statins (atorvastatin 20-40mg qd with or without ezetimibe 10mg qd, or rosuvastatin 10-20mg qd with or without ezetimibe 10mg qd).

Also known as: Hydroxymethylglutaryl-Coenzyme A Reductase inhibitors, Ezetimibe

Treatment with only conventional lipid-lowering therapy based on statins

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients older than 18 years of age with mild or moderate calcific aortic stenosis (peak aortic jet velocity ≥ 2m/s and \< 4m/s or mean transvalvular gradients ≥ 20mmHg and \< 40mmHg), or asymptomatic severe aortic stenosis (peak aortic jet velocity ≥ 4m/s or mean transvalvular gradients ≥ 40mmHg and no symptoms and/or signs related to aortic stenosis and negative exercise treadmill test)
• Patients who are required to be treated with a stable statin (atorvastatin or rosuvastatin) dose for at least 4 weeks and to have an LDL-C level of 80 mg/dL or higher or between 60 and 80 mg/dL (to convert LDL-C values to mmol/L, multiply by 0.0259) with 1 major or 3 minor cardiovascular risk factors. Major risk factors include atherosclerotic cardiovascular disease, myocardial infarction or hospitalization for unstable angina in the preceding 2 years, or type 2 diabetes mellitus. Minor risk factors include current cigarette smoking, hypertension, low levels of high-density lipoprotein cholesterol, family history of premature coronary heart disease, high sensitivity C-reactive protein (hsCRP) level of 2 mg/L or higher (to convert hsCRP values to nmol/L, multiply by 9.524), or age 50 years or older for men and 55 years or older for women
• Patients agree to participate in the study by signing an informed consent form

You may not qualify if:

• Any previous treatment with PCSK9 inhibitors
• Patients who must be treated with long-term PCSK9 inhibitors
• Patients who cannot maintain statin and/or PCSK9 inhibitor use for 24 months
• Hypersensitivity to PCSK9 inhibitors and/or statin
• Fasting triglyceride (TG) levels \> 400mg/dL (4.5 mmol/L) at screening
• Thyroid hypofunction
• Active or chronic liver disease
• Severe renal dysfunction (eGFR \< 30 ml/min/1.73m2)
• History of cerebral hemorrhage
• History of alcohol or drug abuse
• Known active infection, or major hematological, metabolic, or endocrine dysfunction
• Patients who have been treated with systemic steroids or cyclosporine within the past 3 months
• Active malignant tumor
• Any life-threatening condition with life expectancy less than 12 months
• Severe mitral stenosis (valve area\<1cm2)

Sponsors & Collaborators

• Beijing Anzhen Hospital: lead
• Beijing Municipal Health Commission: collaborator

Study Sites (1)

Beijing Anzhen Hospital, Capital Medical University

Beijing, Beijing Municipality, 100000, China

RECRUITING

Related Publications (14)

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  PMID: 25344734 BACKGROUND

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• 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.

  PMID: 18765433 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.

  PMID: 32347887 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.

  PMID: 32623063 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.

  PMID: 30545459 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.

  PMID: 32760854 BACKGROUND

• Zheng Y, Li Q, Yang Y, Yang J, Liu Z, Ma X, Wang Z. Rationale and Design of the EPISODE Trial: A Randomized Controlled Trial on the Effect of PCSK9 Inhibitors in Calcific Aortic Valve Stenosis. J Am Heart Assoc. 2025 Oct 7;14(19):e042112. doi: 10.1161/JAHA.125.042112. Epub 2025 Sep 19.

  PMID: 40970544 DERIVED

MeSH Terms

Conditions

Aortic Valve Stenosis; Aortic Valve, Calcification of

Interventions

PCSK9 Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ezetimibe

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Zhijian Wang

  Beijing Anzhen Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zhijian Wang

CONTACT

+8615711057972; zjwang1975@hotmail.com

Xiaoteng Ma

CONTACT

+8618810616459; maxiaotengai@163.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 4, 2021
• First Posted: July 20, 2021
• Study Start: March 22, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: May 9, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)