Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis

Official title

A Randomized Trial of PCSK9 Inhibitors in Calcific Aortic Valve Stenosis

Overview

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 Echocardiography and computer tomography were performed and blood samples were withdrawn at baseline, at 2 years visit, and before withdrawal from the study.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

Interventions

• 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).
• 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).

Primary outcome measures

• The average annual change in peak aortic jet velocity [Time frame: Up to 24 months]

Secondary outcome measures (4)

• The average annual change in aortic valve area [Time frame: Up to 24 months]
• The average annual change in aortic valve calcification score [Time frame: Up to 24 months]
• Heart valve surgery [Time frame: Up to 24 months]
• Change in quality-of-life scores [Time frame: Up to 24 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Beijing Anzhen Hospital, Capital Medical University — Beijing

Publications

• Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, Pibarot P. Calcific aortic stenosis. Nat Rev Dis Primers. 2016 Mar 3;2:16006. doi: 10.1038/nrdp.2016.6. PMID 27188578
• Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O'Brien KD, Schoen FJ, Towler DA, Yoganathan AP, Otto CM. Calcific aortic valve disease: not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2 PMID 22007101
• Smith JG, Luk K, Schulz CA, Engert JC, Do R, Hindy G, Rukh G, Dufresne L, Almgren P, Owens DS, Harris TB, Peloso GM, Kerr KF, Wong Q, Smith AV, Budoff MJ, Rotter JI, Cupples LA, Rich S, Kathiresan S, Orho-Melander M, Gudnason V, O'Donnell CJ, Post WS, Thanassoulis G; Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary Calcium Working Group. Association of low-densit PMID 25344734
• Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, Harris TB, Malhotra R, O'Brien KD, Kamstrup PR, Nordestgaard BG, Tybjaerg-Hansen A, Allison MA, Aspelund T, Criqui MH, Heckbert SR, Hwang SJ, Liu Y, Sjogren M, van der Pals J, Kalsch H, Muhleisen TW, Nothen MM, Cupples LA, Caslake M, Di Angelantonio E, Danesh J, Rotter JI, Sigurdsson S, Wong Q, PMID 23388002
• Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, Singh RJ, Stone NJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002 Jun 4;105(22):2660-5. doi: 10.1161/01.cir.0000017435.87463.72. PMID 12045173
• Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation. 2006 Nov 7;114(19):2065-9. doi: 10.1161/CIRCULATIONAHA.106.634139. Epub 2006 Oct 30. PMID 17075015
• Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, Boon NA; Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005 Jun 9;352(23):2389-97. doi: 10.1056/NEJMoa043876. PMID 15944423
• Chan KL, Teo K, Dumesnil JG, Ni A, Tam J; ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010 Jan 19;121(2):306-14. doi: 10.1161/CIRCULATIONAHA.109.900027. Epub 2010 Jan 4. PMID 20048204

Identifiers

NCT: NCT04968509 · EPISODE · 2022-2-1052

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗