Effect of PCSK9 InhibitorS On Calcific Aortic Valve DiseasE

Study Overview
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Brief Summary
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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 Echocardiography and computer tomography were performed and blood samples were withdrawn at baseline, at 2 years visit, and before withdrawal from the study.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.

Official Title
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Effect of PCSK9 Inhibitors on Calcific Aortic Valve Disease: a Prospective Randomized Controlled Trial

Conditions
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Aortic Stenosis

Intervention / Treatment
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* Drug: PCSK9 inhibitors and statins with or without ezetimibe
* Drug: Statins with or without ezetimibe


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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) Severe mitral or aortic regurgitation Patients who are scheduled to undergo heart valve surgery Left ventricular ejection fraction < 30% or severe heart failure (NYHA class III or IV) The presence of a permanent pacemaker or defibrillator Arrhythmias that are not controlled by drugs Child-bearing potential without contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment with PCSK9 inhibitors and conventional lipid-lowering therapy based on statins<br>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<br>* 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).<br>* Other names: Ezetimibe;|
| Other: Treatment with only conventional lipid-lowering therapy based on statins<br>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<br>* 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).<br>* Other names: Ezetimibe;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The average annual change in peak aortic jet velocity | The peak aortic jet velocity is measured by echocardiography. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The average annual change in aortic valve area | The aortic valve area is measured by echocardiography. | Up to 24 months | 
| The average annual change in aortic valve calcification score | The aortic valve calcification score is measured by cardiac noncontrast computer tomography. | Up to 24 months | 
| Heart valve surgery | Transcatheter aortic valve implantation or surgical aortic valve replacement | Up to 24 months | 
| Change in quality-of-life scores | Change in quality-of-life scores is assessed with the use of the EQ-5D-3L scale | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCSK9 Inhibitors, Calcific Aortic Stenosis