Clinical trial NCT02080299: Protection by Remote Ischemic Preconditioning During Transcatheter Aortic Valve Implantation
Official title: Protection of Heart, Brain and Kidney by Remote Ischemic Preconditioning in Patients Undergoing Transcatheter Aortic Valve Implantation - a Randomized, Single-blind Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Aortic Valve Stenosis
Lead sponsor: University Hospital, Essen
Sponsor class: OTHER
Collaborators: name: Koblenz University of Applied Science
First posted: 2014-03-06
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Extent of periinterventional myocardial injury as reflected by the geometric mean of the area under the curve (AUC) for troponin I serum concentrations
timeFrame: 72 hours postinterventionally after TAVI
Secondary outcomes:
measure: Periprocedural myocardial infarction according to current Valve Academic Research Consortium (VARC-2) criteria
timeFrame: 72 hours postinterventionally after TAVI
measure: Incidence of new wall abnormalities and deterioration of overall left ventricular function as assessed by postinterventional transthoracic echocardiography
timeFrame: Within the first week after TAVI
measure: Incidence of new-onset cardiac arrhythmias including the necessity of defibrillation or transient/permanent pacemaker implantation as assessed by continuous ECG-monitoring
timeFrame: Within the first week after TAVI
measure: Prevalence and volume of delayed gadolinium enhancement
timeFrame: Within the first week after TAVI
measure: Maximum elevation of serum creatinine concentration
timeFrame: Until 72 hours after TAVI
measure: Maximum decrease of estimated glomerular filtration rate
timeFrame: Until 72 hours after TAVI
measure: Incidence of VARC-2 defined acute kidney injury
timeFrame: Until 72 hours after TAVI and until discharge
measure: Total and median per patient number as well as total and median per patient volume of new foci of restricted diffusion
timeFrame: Within the first week after TAVI
measure: Cardioprotective factor release into circulating blood
timeFrame: Day of intervention
measure: All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) at 30 days
timeFrame: Within the first 30 days after TAVI
measure: All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) at 1 year
timeFrame: Within the first year after TAVI
measure: All cause mortality and major adverse cardiac and cerebrovascular events (MACCE) after 3 months
timeFrame: Until 3 months after TAVI
measure: VARC-2 defined combined early TAVI safety endpoint at 30 days
timeFrame: Until 30 days after TAVI
Other outcomes:
Locations:
city: Essen
country: Germany
facility: Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen
Study officials:
affiliation: Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen
name: Philipp Kahlert, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Duisburg-Essen
name: Matthias Thielmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Pathophysiology, University Duisburg-Essen
name: Petra Kleinbongard, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinic for Anesthesiology and Intensive Care Medicine, University Duisburg-Essen
name: Eva Kottenberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinic for Anesthesiology and Intensive Care Medicine, University Duisburg-Essen
name: Jürgen Peters, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Duisburg-Essen
name: Heinz Jakob, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen
name: Raimund Erbel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Pathophysiology, University Duisburg-Essen
name: Gerd Heusch, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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. Epub 2010 May 21.
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. Epub 2011 Nov 21.
citation: 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.
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. Epub 2013 Mar 1.
citation: 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.
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. No abstract available.
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.
citation: 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.