Protection by Remote Ischemic Preconditioning During Transcatheter Aortic Valve Implantation

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Procedure: Remote ischemic preconditioning (RIPC)
* Procedure: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Remote ischemic preconditioning (RIPC)<br>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)<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* Prior to TAVI-procedure, the blood pressure cuff remains uninflated for 30 min.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |