Effect of PCSK9 InhibitorS On Calcific Aortic Valve DiseasE (EPISODE)

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

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.

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.

Patients in experimental group were treated with 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(Atorvastatin 40-80mg or Rosuvastatin 20-40mg or Atorvastatin 20mg+ Ezetimibe 10mg or Rosuvastatin 10mg+ Ezetimibe 10mg).

The proprotein convertase subtilisin/kexin type 9 inhibitor, Hydroxymethylglutaryl-Coenzyme A Reductase inhibitor

Patients in experimental group were treated with 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(Atorvastatin 40-80mg or Rosuvastatin 20-40mg or Atorvastatin 20mg+ Ezetimibe 10mg or Rosuvastatin 10mg+ Ezetimibe 10mg).

MACEs including all-cause death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure (HF).

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.

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