Protection by Remote Ischemic Preconditioning During Transcatheter Aortic Valve Implantation

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

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.

Study Overview

• Status: Unknown
• Conditions: Aortic Valve Stenosis
• Intervention / Treatment: Procedure: Remote ischemic preconditioning (RIPC); Procedure: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45122
    • Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Remote ischemic preconditioning (RIPC); RIPC-protocol before TAVI: after induction of conscious sedation/anesthesia, but prior to TAVI procedure, remote ischemic preconditioning (RIPC) protocol is performed, consisting of 3 cycles of 5 minutes left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 minutes of reperfusion, followed by a time interval between the end of the last deflation and local groin anaesthesia with subsequent skin puncture of 30 min.	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 Comparator: Placebo; Placebo protocol before TAVI: After induction of conscious sedation/anesthesia and before TAVI, the cuff is left uninflated for 30 min, followed by a further time interval of 30 min until local groin anaesthesia with subsequent skin puncture.	Procedure: Placebo; Prior to TAVI-procedure, the blood pressure cuff remains uninflated for 30 min.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Periprocedural myocardial infarction according to current Valve Academic Research Consortium (VARC-2) criteria		72 hours postinterventionally after TAVI
Incidence of new wall abnormalities and deterioration of overall left ventricular function as assessed by postinterventional transthoracic echocardiography		Within the first week after TAVI
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
Prevalence and volume of delayed gadolinium enhancement	Cardiac MRI will be performed in selected patients.	Within the first week after TAVI
Maximum elevation of serum creatinine concentration		Until 72 hours after TAVI
Maximum decrease of estimated glomerular filtration rate		Until 72 hours after TAVI
Incidence of VARC-2 defined acute kidney injury		Until 72 hours after TAVI and until discharge
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
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
All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) at 30 days		Within the first 30 days after TAVI
All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) at 1 year		Within the first year after TAVI
All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) after 3 months		Until 3 months after TAVI
VARC-2 defined combined early TAVI safety endpoint at 30 days		Until 30 days after TAVI

Collaborators and Investigators

• Sponsor: University Hospital, Essen
• Collaborators: Koblenz University of Applied Science
• Investigators: Principal Investigator: Philipp Kahlert, MD, Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen; Principal Investigator: Matthias Thielmann, MD, Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Duisburg-Essen; Principal Investigator: Petra Kleinbongard, PhD, Institute of Pathophysiology, University Duisburg-Essen; Principal Investigator: Eva Kottenberg, MD, Clinic for Anesthesiology and Intensive Care Medicine, University Duisburg-Essen; Principal Investigator: Jürgen Peters, MD, Clinic for Anesthesiology and Intensive Care Medicine, University Duisburg-Essen; Principal Investigator: Heinz Jakob, MD, Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Duisburg-Essen; Principal Investigator: Raimund Erbel, MD, Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen; Principal Investigator: Gerd Heusch, MD, PhD, Institute of Pathophysiology, University Duisburg-Essen

Publications and helpful links

General Publications

• 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.
• Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhauser 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.
• 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. Epub 2011 Nov 21.
• 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. Epub 2010 May 21.
• 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. Epub 2011 Nov 23.
• 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. Epub 2013 Mar 1.
• 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. No abstract available.
• Kahlert P, Hildebrandt HA, Patsalis PC, Al-Rashid F, Janosi RA, Nensa F, Schlosser TW, Schlamann M, Wendt D, Thielmann M, Kottenberg E, Frey U, Neuhauser M, Forsting M, Jakob HG, Rassaf T, Peters J, Heusch G, Kleinbongard P. No protection of heart, kidneys and brain by remote ischemic preconditioning before transfemoral transcatheter aortic valve implantation: Interim-analysis of a randomized single-blinded, placebo-controlled, single-center trial. Int J Cardiol. 2017 Mar 15;231:248-254. doi: 10.1016/j.ijcard.2016.12.005. Epub 2016 Dec 6.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Anticipated): August 1, 2017
• Study Completion (Anticipated): August 1, 2017

Study Registration Dates

• First Submitted: March 1, 2014
• First Submitted That Met QC Criteria: March 4, 2014
• First Posted (Estimate): March 6, 2014

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis
• Other Study ID Numbers: 135355-BO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO