Remote Ischemic Preconditioning in Elective Cardiac Surgery: Long-Term Overall Survival Benefit in a Single-Center Randomized Double-Blinded Controlled Trial

Objectives: Remote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion can reduce myocardial injury and improve patients’ prognosis following cardiac surgery in proof-of-concept and smaller randomized controlled trials (RCT), while two recent large Phase III RCTs were neutral for troponin release and outcome after 90 days and 1 year.

Methods: Between April 2008 and August 2018, a total of 1,204 patients scheduled for elective cardiac surgery with the use of isoflurane anesthesia, cardiopulmonary bypass, and crystalloid cardioplegic arrest were allocated to receive either RIPC (n = 607; three cycles of 5-min transient left upper arm ischemia with 5-min reperfusion after induction of anesthesia) or served as controls (n = 597).

Results: Patient characteristics and intraoperative data did not differ between the two groups. The primary short-term endpoint was myocardial injury following surgery as reflected by the perioperative cardiac troponin (cTn) serum concentration over 72 hours and its area under the curve (AUC). The mean troponin AUC profiles in the RIPC group were lower (geometric mean [confidence interval, CI]: 137.97 [122.26; 155.71] for controls vs. 131.60 [116.55; 148.60] for RIPC group; ratio [CI] 0.95 [0.80; 1.13], but did not reach statistical significance, neither in the intention-to-treat (ITT; p = 0.589) nor in the per-protocol (PP) analysis (p = 0.482). The primary long-term endpoint was all-cause mortality, and the secondary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCE). In the ITT analysis, there were 111 deaths in the control group and 85 in the RIPC group (p = 0.031), but 80 deaths in the control group versus 71 in the RIPC group in the PP analysis (p = 0.252) over a total follow-up of 4.0 ± 2.5 years. The Kaplan–Meier overall survival in the ITT analysis was superior with RIPC (p = 0.024), but did not reach statistical significance in the PP analysis (p = 0.234), whereas MACCE rate was superior with RIPC in the ITT (p = 0.040) as well as in the PP analysis (p = 0.045).

Conclusion: Our extended RCT confirms that RIPC provides no significant difference in perioperative cardiac troponin AUC profiles, but demonstrates a continued robust prognostic benefit with superior survival and MACCE rate in patients undergoing elective cardiac surgery with isoflurane anesthesia, cardiopulmonary bypass, and crystalloid cardioplegic arrest.

No conflict of interest has been declared by the author(s).