PCSK9 Inhibitors in the Treatment of Calcific Aortic 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 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 not currently requiring valve replacement therapy will be enrolled and randomized (stratified by center) in a 1:1 ratio to two groups, the PCSK9 inhibitor treatment group (test group) or the no PCSK9 inhibitor group (control group). All patients will be followed for at least 2 years after randomization. After enrollment, telephone follow-ups will be conducted in the first month and every three months to collect data including medication use, quality-of-life scores, and clinical endpoint events. Doppler echocardiography will be collected at baseline, the 1-year visit, the 2-year visit, and before study withdrawal. Blood samples and aortic computed tomography angiography (CTA) will be collected at baseline, the 2-year visit, and before study withdrawal. The primary endpoint is the annualized mean change in peak aortic jet velocity over the 24-month follow-up period. Secondary endpoints include the annualized mean change in aortic valve area by echocardiography, the annualized mean change in aortic valve calcium score by aortic CTA, the incidence of cardiac valve surgery, and changes in quality-of-life scores. The safety endpoint is a composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. The results of this trial will provide new insights into the treatment of CAS patients.

Blood samples should be tested for serological indicators, including blood routine, C-reactive protein (CRP), biochemical, coagulation function, brain natriuretic peptide (BNP), markers of myocardial injury, glycosylated hemoglobin, erythrocyte sedimentation rate, cytokines (12 items).

• Treatment with PCSK9 inhibitors (Drug), also known as Treatment with Proprotein convertase subtilisin/kexin type 9 inhibitors: Patients in experimental group are treated with PCSK9 inhibitors (Tafolecimab subcutaneously every two weeks) plus guideline-directed management in cardiovascular primary or secondary prevention.
• Treatment without PCSK9 inhibitors (Other), also known as Treatment without Proprotein convertase subtilisin/kexin type 9 inhibitors: Patients in control group only receive guideline-directed management in cardiovascular primary or secondary prevention without PCSK9 inhibitor treatment.

Primary outcomes

• The annualized mean change in peak aortic jet velocity [Up to 24 months]: The peak aortic jet velocity is measured by echocardiography.

Secondary outcomes

• The annualized mean change in aortic valve area [Up to 24 months]: The aortic valve area is measured by echocardiography.
• The annualized mean change in aortic valve calcium score [Up to 24 months]: The aortic valve calcification score is measured by aortic computed tomography angiography.
• Cardiac valve surgery [Up to 24 months]: Transcatheter aortic valve implantation or surgical aortic valve replacement
• Change in quality-of-life scores [Up to 24 months]: Change in quality-of-life scores is assessed with the use of the EQ-5D-3L scale

Other outcomes

• Safety endpoint [Up to 24 months]: The safety endpoint is a composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke.

Sex: All, ages: 18 Years to 85 Years

Inclusion Criteria:

1. Aged 18-85 years old, clinically diagnosed with mild or moderate CAVS (echocardiography shows ejection fraction > 50%; valve orifice area > 1.0 cm²; left ventricular stroke volume index > 35 ml/m²; flow velocity ≥ 2 m/s and < 4 m/s, or mean transvalvular pressure gradient < 40 mmHg) and currently not requiring valve replacement therapy;
2. LDL-C ≥ 2.6 and < 4.9 mmol/L, or Lp(a) ≥ 30 mg/dL, or receiving statin therapy due to a clinical diagnosis of hypercholesterolemia/hyperlipidemia;
3. Patients who can understand the purpose of the trial, voluntarily participate, sign the informed consent form, and are willing to undergo clinical follow-up in accordance with the trial requirements.

   * The position and method of measurement have been further clarified in ultrasonic measurement to ensure comparability among all enrolled patients, as follows: Aortic valve peak flow velocity, aortic valve mean pressure gradient, and valve orifice area (select images of at least 3 consecutive cardiac cycles with stable heart rate; for atrial fibrillation, select images of more than 5 consecutive cardiac cycles; obtain the peak blood flow velocity of the aortic valve orifice using continuous wave Doppler in the apical 5-chamber view; calculate the instantaneous aortic valve pressure gradient using the simplified Bernoulli equation, and calculate the standardized aortic valve orifice area using the continuity equation; all participating sonographers will receive unified training, perform measurements in fixed views and retain images, which will then be reviewed by two experienced sonographers who are blinded to the trial in the core laboratory).

Exclusion Criteria:

1. Any previous treatment with PCSK9 inhibitors;
2. Patients must be treated with PCSK9 inhibitors by physician's judgment;
3. Patients who cannot maintain PCSK9 inhibitor use for 24 months;
4. Contraindications or hypersensitivity to PCSK9 inhibitors;
5. Suspected or confirmed familial hypercholesterolemia;
6. Fasting triglycerides (TG) >400 mg/dL (4.5 mmol/L) at baseline screening;
7. Thyroid hypofunction;
8. Active or chronic liver disease;
9. Severe renal insufficiency (eGFR <30 mL/min/1.73 m²);
10. History of intracranial hemorrhage;
11. History of alcohol or drug abuse；
12. Known active infection, or severe hematologic, metabolic, or endocrine dysfunction;
13. Systemic corticosteroid or cyclosporine therapy within the past 3 months;
14. Active malignancy;
15. Any life-threatening condition with life expectancy less than 12 months;
16. Rheumatic aortic stenosis;
17. Severe mitral stenosis (mitral valve area <1 cm²);
18. Severe mitral or aortic regurgitation;
19. Planned cardiac valve surgery;
20. Left ventricular ejection fraction < 30% or severe heart failure (NYHA class III or IV);
21. Implanted permanent pacemaker or cardioverter-defibrillator;
22. Drug-refractory arrhythmias;
23. Pregnancy, lactation, or planned pregnancy.

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• Zhijian Wang, Study chair, Beijing Anzhen Hospital
• Xiaoteng Ma, Principal investigator, Beijing Anzhen Hospital