Effect of PCSK9 InhibitorS On Calcific Aortic Valve DiseasE

• Status: Recruiting
• Trial end date: 2024-01-01
• Target enrollment: 0
• Participant gender: All

Summary

Calcific Aortic Stenosis (CAS) can cause severe adverse cardiac events, but there is currently no effective drug that can prevent or delay the progression of the disease, aortic valve replacement is still the only therapy.

The epidemiology of CAS shows that it is related with level of Lp(a)、LDL-C and PCSK9. Several observational studies indicate that the use of statins to decrease the level of LDL-C is associated with the reduced incidence of CAS, but no Randomized Control Trials(RCTs) show that statins have any benefit on the progression or clinical outcome of CAS，so the investigators speculated that this may be related to the limited reduction of LDL-C by statins therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has emerged as a new lipid-lowing drug. On the basis of statin treatment, it can further reduces LDL-C and Lp(a) concentrations by 50% to 60% and 20% to 30%,respectively. Some studies report that elevated plasma PCSK9 levels are related to CAS and PCSK9 R46L loss-of-function mutation are associated with lower rates of CAS, and other observational studies found that PCSK9 inhibitors can reduce the incidence of CAS.

The research, on the basis of statins therapy, intends to study the effect of PCSK9 inhibitors on delaying or preventing patients with CAS. 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. All of the patients were followed at 4 weeks、24 weeks 、48 weeks and 96 weeks for a minimum of 2 years. 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). The outcomes of the study will provide new ideas for the treatment of patients with CAS, and will also provide an important theoretical basis for the expansion of the clinical indications of PCSK9 inhibitors and the exploration their extra-lipid-lowering effects.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Beijing Anzhen Hospital
• Treatments: Hydroxymethylglutaryl-CoA Reductase Inhibitors

Criteria

Inclusion Criteria:

• 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, and the patient has no symptoms and/or signs related to aortic valve stenosis and the exercise treadmill test is negative.

• Patients with moderate to very high cardiovascular risk require long-term use of statins and after 2 weeks of conventional intensive lipid-lowering therapy , the level of LDL-C is still≥1.8mmol/L and/or L(a)>50mg/dL.

Exclusion Criteria:

• Cannot maintain the use of PCSK9 inhibitors for about 12 months

• Child-bearing potential without contraception

• Active or chronic liver disease

• 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%),

• Planned aortic-valve replacement

• Intolerance of statins or PCSK9 inhibitors

• The presence of a permanent pacemaker or cardiodefibrillator.