EPISODE: Effect of PCSK9 InhibitorS On Calcific Aortic Valve DiseasE
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: treatment with PCSK9 inhibitor and statin 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). |
Drug: PCSK9 inhibitor and Statin
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).
Other Names:
Drug: Statin
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).
Other Names:
|
| Other: statin-only treatment 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). |
Drug: Statin
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).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- the average annual change in aortic-jet velocity [up to 24 months]
The aortic-jet velocity was measured by Echocardiography.
Secondary Outcome Measures
- The average annual change of aortic valve calcification score [up to 24 months]
The aortic valve calcification score was measured by Computed Tomography(CT)
Other Outcome Measures
- The incidence of major adverse cardiovascular events(MACEs) [up to 24 months]
MACEs including all-cause death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure (HF).
- Change of Serological indicators [1 month、6 months、12 months and up to 24months]
The change of serum LDL-C、L(a) and CRP
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Beijing Anzhen Hospital, Capital Medical University | Beijing | Beijing | China | 100000 |
Sponsors and Collaborators
- Beijing Anzhen Hospital
Investigators
- Principal Investigator: Zhijian Wang, Beijing Anzhen Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
- Bergmark BA, O'Donoghue ML, Murphy SA, Kuder JF, Ezhov MV, Ceška R, Gouni-Berthold I, Jensen HK, Tokgozoglu SL, Mach F, Huber K, Gaciong Z, Lewis BS, Schiele F, Jukema JW, Pedersen TR, Giugliano RP, Sabatine MS. An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial. JAMA Cardiol. 2020 Jun 1;5(6):709-713. doi: 10.1001/jamacardio.2020.0728.
- Capoulade R, Cariou B. Editorial commentary: Lp(a) and calcific aortic valve stenosis: Direct LPA targeting or PCSK9-Lowering therapy? Trends Cardiovasc Med. 2021 Jul;31(5):312-314. doi: 10.1016/j.tcm.2020.06.009. Epub 2020 Jul 2.
- 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.
- 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.
- 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. Review.
- Perrot N, Valerio V, Moschetta D, Boekholdt SM, Dina C, Chen HY, Abner E, Martinsson A, Manikpurage HD, Rigade S, Capoulade R, Mass E, Clavel MA, Le Tourneau T, Messika-Zeitoun D, Wareham NJ, Engert JC, Polvani G, Pibarot P, Esko T, Smith JG, Mathieu P, Thanassoulis G, Schott JJ, Bossé Y, Camera M, Thériault S, Poggio P, Arsenault BJ. Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis. JACC Basic Transl Sci. 2020 Jul 1;5(7):649-661. doi: 10.1016/j.jacbts.2020.05.004. eCollection 2020 Jul.
- Poggio P, Songia P, Cavallotti L, Barbieri SS, Zanotti I, Arsenault BJ, Valerio V, Ferri N, Capoulade R, Camera M. PCSK9 Involvement in Aortic Valve Calcification. J Am Coll Cardiol. 2018 Dec 18;72(24):3225-3227. doi: 10.1016/j.jacc.2018.09.063.
- 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-2011 update. Circulation. 2011 Oct 18;124(16):1783-91. doi: 10.1161/CIRCULATIONAHA.110.006767. Review.
- 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.
- Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Bärwolf C, Holme I, Kesäniemi YA, Malbecq W, Nienaber CA, Ray S, Skjaerpe T, Wachtell K, Willenheimer R; SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008 Sep 25;359(13):1343-56. doi: 10.1056/NEJMoa0804602. Epub 2008 Sep 2.
- 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-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA. 2014 Nov 5;312(17):1764-71. doi: 10.1001/jama.2014.13959.
- 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, Kälsch H, Mühleisen TW, Nöthen MM, Cupples LA, Caslake M, Di Angelantonio E, Danesh J, Rotter JI, Sigurdsson S, Wong Q, Erbel R, Kathiresan S, Melander O, Gudnason V, O'Donnell CJ, Post WS; CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013 Feb 7;368(6):503-12. doi: 10.1056/NEJMoa1109034.
- 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. Epub 2006 Oct 30.
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