Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis (EPISODE)

May 7, 2024 updated by: Zhi Jian Wang, Beijing Anzhen Hospital

A Randomized Trial of PCSK9 Inhibitors in Calcific Aortic Valve Stenosis

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 Echocardiography and computer tomography were performed and blood samples were withdrawn at baseline, at 2 years visit, and before withdrawal from the study.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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The study is a single-center, prospective, randomized controlled study. A total of 160 patients are planned to be selected for the presence of CAS that are confirmed by echocardiography but currently do not need valve replacement, and with the diagnosis of hypercholesterolemia. Record the patient's baseline information, including risk factors, blood lipids and other indexes related to serology. The eligible patients randomly divided into two groups, namely treatment with PCSK9 inhibitor and statin (experimental group) and statin-only treatment (control group). Patients in experimental group were assigned to PCSK9 inhibitors (140mg with Evolocumab or 75mg with Alirocumab subcutaneously every two weeks ) and conventional intensive lipid-lowering therapy(Atorvastatin 40-80mg or Rosuvastatin 20-40mg or Atorvastatin 20mg+ Ezetimibe 10mg or Rosuvastatin 10mg+ Ezetimibe 10mg). Patients in control group were only treated with conventional intensive lipid-lowering therapy.

Inclusion criteria including:(1) patients older than 18 years of age with the diagnosis of calcific aortic stenosis, aortic-jet velocity≥2m/s，<4m/s or mean aortic-valve pressure gradients≥20mmHg，<40mmHg, or aortic-jet velocity≥4m/s or mean aortic-valve pressure gradients≥40mmHg on echocardiography but the patient has no symptoms and/or signs related to aortic valve stenosis, and the exercise treadmill test is negative. (2)Patients with moderate to very high cardiovascular risk require long-term use of statin and after 2 weeks of intensive lipid-lowering therapy, the level of LDL-C is still more than 1.8mmol/L and/or L(a)>50mg/dL. Exclusion criteria were expected cannot maintain the use of PCSK9 inhibitors for about 12 months, child-bearing potential without contraception, active or chronic liver disease, a history of alcohol or drug abuse, severe mitral-valve stenosis (mitral-valve area<1 cm2), severe mitral or aortic regurgitation, left ventricular dysfunction (ejection fraction<35%), a planned aortic-valve replacement, intolerance of statins or PCSK9 inhibitors, and presence of a permanent pacemaker or cardiodefibrillator.

The primary endpoint is the average annual change in aortic-jet velocity. Secondary endpoints include average annual change of aortic valve calcification score that measured by Computed Tomography and major adverse cardiovascular events (cardiovascular death, non-fatal stroke or non-fatal myocardial infarction).

Eligible patients were assessed at baseline, 4 weeks、24 weeks、48 weeks and 96 weeks for a minimum of 2 years. Clinical evaluation included assessment of functional status and adverse events, and the biochemical analysis of blood. Echocardiography and CT were performed at baseline, at 2 years visit, and before withdrawal from the study.

Study Type

Interventional

Enrollment (Estimated)

160

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Beijing
      • Beijing, Beijing, China, 100000
        • Recruiting
        • Beijing Anzhen Hospital, Capital Medical University
        • Contact:
          • Zhijian Wang

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional 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
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
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).
Other Names:
  • Ezetimibe
  • Proprotein convertase subtilisin/kexin type 9 inhibitors
  • Hydroxymethylglutaryl-Coenzyme A Reductase inhibitors
Other: Treatment with only conventional lipid-lowering therapy based on statins
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
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).
Other Names:
  • Ezetimibe
  • Hydroxymethylglutaryl-Coenzyme A Reductase inhibitors

What is the study measuring?

Primary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety endpoints
Time Frame: Up to 24 months
All-cause death or cardiovascular events
Up to 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Beijing Anzhen Hospital

Collaborators

Beijing Municipal Health Commission

Investigators

  • Principal Investigator: Zhijian Wang, Beijing Anzhen Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 22, 2024

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

January 1, 2028

Study Registration Dates

First Submitted

July 4, 2021

First Submitted That Met QC Criteria

July 8, 2021

First Posted (Actual)

July 20, 2021

Study Record Updates

Last Update Posted (Actual)

May 9, 2024

Last Update Submitted That Met QC Criteria

May 7, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EPISODE
  • 2022-2-1052 (Other Grant/Funding Number: Capital's Funds for Health Improvement and Research)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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