Protection by Remote Ischemic Preconditioning During Transcatheter Aortic Valve Implantation

Aortic Valve Stenosis Clinical Trial

Official title:

Protection of Heart, Brain and Kidney by Remote Ischemic Preconditioning in Patients Undergoing Transcatheter Aortic Valve Implantation - a Randomized, Single-blind Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02080299
• Other study ID #: 135355-BO
• Status: Active, not recruiting
• Phase: Phase 2
• First received: March 1, 2014
• Last updated: November 1, 2016
• Start date: September 2013
• Est. completion date: August 2017

Study information

• Verified date: November 2016
• Source: University Hospital, Essen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Ethics Commission
• Study type: Interventional

Clinical Trial Summary

Transcatheter aortic valve implantation (TAVI) has rapidly been adopted into clinical practice, but concerns have been raised regarding periprocedural complications like e.g. myocardial injury, stroke or acute kidney injury. Remote ischemic preconditioning (RIPC) with upper limb ischemia/reperfusion provides perioperative myocardial protection in patients undergoing elective coronary artery bypass surgery. The present study assesses protection of heart, brain and kidney by RIPC in patients undergoing TAVI. The study also addresses safety and clinical outcome.

Description:

• On the assumption of our recent data (Thielmann et al, Lancet 2013, 382(9892):597-604), we performed a power analysis, revealing an estimated enrollment of 189 patients per group. But since no true data exist regarding RIPC and TAVI, interim analysis will be performed after 50 patients per group.

• After induction of conscious sedation or general anaesthesia, RIPC is accomplished by 3 cycles of 5 min inflation/5 min deflation of a blood pressure cuff around the left arm to 200 mm Hg. In the placebo group, the blood pressure cuff remains uninflated for 30 min.

• Blind: study coordinators, outcome assessors, operators and treating physicians except for the attending anaesthetist.

• Drugs used for conscious sedation: midazolam, remifentanil.

• Drugs used for general anaesthesia: sufentanil, etomidate, rocuronium, isoflurane.

• TAVI is performed by standard techniques using the balloon-expandable Sapien XT (Edwards Lifesciences Inc., Irvine, California, USA) and the next-generation Sapien 3 stent-valve bioprosthesis which replaces the Sapien XT prosthesis, when CE-approved.

• Arterial blood samples are obtained prior to and after RIPC-maneuver/Placebo, after aortic valve implantation and after access site closure, for biochemical analyses focussing on ligands that have been previously implicated in conditioning protocols at various organs. A bioassay system, consisting of a Langendorff-perfused isolated heart with ischemia and reperfusion will be used. This bioassay system will be exposed to the obtained arterial plasma of the patients.

• Venous blood samples are drawn before TAVI and at 1, 6, 12, 24, 48 and 72 hours after the procedure.

• Cardiac and cerebral MRI is performed in selected patients at baseline and within the first week after TAVI.

• On-site follow-up at 3±3 months, 12±3 months and yearly thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: August 2017
• Est. primary completion date: August 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult patients with severe symptomatic native aortic valve stenosis scheduled for elective TAVI due to a prohibitive or high risk for surgical aortic valve replacement as judged by the institutional heart team based on risk scores and comorbidity assessment

• Written informed consent

Exclusion Criteria:

• Life expectancy < 1 year

• Patients who are unlikely to gain improvement in their quality of life by TAVI procedure

• Unfavorable anatomy for TAVI (e.g. inadequate annulus size)

• Left-ventricular thrombus

• Active endocarditis

• Active infection

• Acute ST-segment elevation myocardial infarction

• Hemodynamic instability

• Preoperative troponin I concentration above the upper normal limit of 0.1 ng/ml

• Stroke within the last 6 weeks

• Acute or chronic hemodialysis

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Aortic Valve Stenosis

Intervention

Procedure:
• Remote ischemic preconditioning (RIPC)
3 circles of 5 min left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 min reperfusion, preceding TAVI procedure.
• Placebo
Prior to TAVI-procedure, the blood pressure cuff remains uninflated for 30 min.

Locations

Country	Name	City	State
Germany	Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen	Essen

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Essen	Koblenz University of Applied Science

Country where clinical trial is conducted

Germany, 

References & Publications (7)

Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res. 2012 Jan 6;110(1):111-5. doi: 10.1161/CIRCRESAHA.111.259556. — View Citation

Kahlert P, Knipp SC, Schlamann M, Thielmann M, Al-Rashid F, Weber M, Johansson U, Wendt D, Jakob HG, Forsting M, Sack S, Erbel R, Eggebrecht H. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation. 2010 Feb 23;121(7):870-8. doi: 10.1161/CIRCULATIONAHA.109.855866. — View Citation

Kleinbongard P, Thielmann M, Jakob H, Peters J, Heusch G, Kottenberg E. Nitroglycerin does not interfere with protection by remote ischemic preconditioning in patients with surgical coronary revascularization under isoflurane anesthesia. Cardiovasc Drugs Ther. 2013 Aug;27(4):359-61. doi: 10.1007/s10557-013-6451-3. — View Citation

Kottenberg E, Musiolik J, Thielmann M, Jakob H, Peters J, Heusch G. Interference of propofol with signal transducer and activator of transcription 5 activation and cardioprotection by remote ischemic preconditioning during coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2014 Jan;147(1):376-82. doi: 10.1016/j.jtcvs.2013.01.005. — View Citation

Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand. 2012 Jan;56(1):30-8. doi: 10.1111/j.1399-6576.2011.02585.x. — View Citation

Thielmann M, Kottenberg E, Boengler K, Raffelsieper C, Neuhaeuser M, Peters J, Jakob H, Heusch G. Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol. 2010 Sep;105(5):657-64. doi: 10.1007/s00395-010-0104-5. — View Citation

Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhäuser M, Peters J, Jakob H, Heusch G. Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet. 2013 Aug 17;382(9892):597-604. doi: 10.1016/S0140-6736(13)61450-6. Erratum in: Lancet. 2013 Sep 14;382(9896):940. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Extent of periinterventional myocardial injury as reflected by the geometric mean of the area under the curve (AUC) for troponin I serum concentrations		72 hours postinterventionally after TAVI	Yes
Secondary	Periprocedural myocardial infarction according to current Valve Academic Research Consortium (VARC-2) criteria		72 hours postinterventionally after TAVI	Yes
Secondary	Incidence of new wall abnormalities and deterioration of overall left ventricular function as assessed by postinterventional transthoracic echocardiography		Within the first week after TAVI	Yes
Secondary	Incidence of new-onset cardiac arrhythmias including the necessity of defibrillation or transient/permanent pacemaker implantation as assessed by continuous ECG-monitoring		Within the first week after TAVI	Yes
Secondary	Prevalence and volume of delayed gadolinium enhancement	Cardiac MRI will be performed in selected patients.	Within the first week after TAVI	No
Secondary	Maximum elevation of serum creatinine concentration		Until 72 hours after TAVI	Yes
Secondary	Maximum decrease of estimated glomerular filtration rate		Until 72 hours after TAVI	Yes
Secondary	Incidence of VARC-2 defined acute kidney injury		Until 72 hours after TAVI and until discharge	Yes
Secondary	Total and median per patient number as well as total and median per patient volume of new foci of restricted diffusion	Cerebral MRI will be performed in selected patients.	Within the first week after TAVI	No
Secondary	Cardioprotective factor release into circulating blood	Blood samples will be collected at 4 time points: prior to and after RIPC-maneuver/Placebo, after aortic valve implantation and after access site closure. Time frame: approximately 2,5 hours.	Day of intervention	No
Secondary	All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) at 30 days		Within the first 30 days after TAVI	Yes
Secondary	All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) at 1 year		Within the first year after TAVI	Yes
Secondary	All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) after 3 months		Until 3 months after TAVI	Yes
Secondary	VARC-2 defined combined early TAVI safety endpoint at 30 days		Until 30 days after TAVI	Yes