Author + information
- Petra Kleinbongard, PhD,
- Jürgen Peters, MD,
- Heinz Jakob, MD,
- Gerd Heusch, MD and
- Matthias Thielmann, MD∗ ()
- ↵∗Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center Essen, University of Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany
Our single-center, randomized, double-blind, controlled trial included patients undergoing coronary artery bypass graft (CABG) surgery under cardiopulmonary bypass and ischemic cardioplegic arrest. Remote ischemic preconditioning (RIPC) by 3 cycles of 5-min blood pressure cuff inflation and 5-min deflation on the left upper arm reduced myocardial injury, as reflected by troponin release, and improved short-term outcome (i.e., reduced all-cause mortality, major adverse cardiac and cerebrovascular events, and repeat revascularization) over a mean follow-up of 1.54 ± 1.22 years (1).
Short-term and more long-term protection by RIPC in patients undergoing cardiovascular surgery was confirmed in a retrospective analysis of several, but not all, studies. Two prospective, large Phase III trials (ERICCA [Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Surgery] and RIPHeart [Remote Ischemic Preconditioning for Heart Surgery]) of RIPC in patients undergoing cardiovascular surgery were neutral for troponin release and outcome after 1 year (2). In both studies, however, patients were anesthetized with propofol, and propofol abrogates the protection by RIPC (3,4). In our trial, in contrast, propofol was not used; anesthesia was induced with the opioid sufentanil and etomidate, and it was maintained with isoflurane (1). The number of events in our follow-up analysis was small (all-cause mortality: 3 for RIPC vs. 11 for control), and thus the protection by RIPC could have been a false-positive finding. We have therefore now repeated a follow-up analysis after an additional 5 years.
This follow-up was performed between August 14, 2017, and August 24, 2017, by telephone call and written request to the patients or the local resident registration offices, respectively; the response rate was 100%. Survival functions were estimated with the Kaplan-Meier method and compared by using Cox’s proportional hazards regression. After a follow-up of 5.82 ± 1.93 years, all-cause mortality in the intention-to-treat cohort was still lower in the RIPC group (n = 23; 14.2%) than in the control group (n = 39; 23.4%) (p = 0.028) (Figure 1A). A separate per-protocol analysis was performed without protocol violators, as done in the initial analysis (1), and a sustained better long-term survival after RIPC was confirmed (Figure 1B).
To the best of our knowledge, the present single-center, randomized, double-blind, controlled trial is the first to show that RIPC under opioid/isoflurane anesthesia provides prognostic benefit for up to 9 years of follow-up in patients undergoing CABG surgery. In fact, a survival benefit persisted for so long after the procedure that the all-cause mortality rate in our control group was comparable to that in a contemporary CABG cohort (5). The survival curves diverged immediately, and this effect persisted, supporting the notion that RIPC attenuates the acute injury.
Our study has limitations. It was a retrospective analysis of a single-center trial that was powered only for the primary endpoint of the area under the curve of troponin I as a surrogate marker for cardioprotection. Due to the retrospective nature of our analysis and the long time between the procedure and follow-up, there were no reliable data on the causes of death, and we therefore report only all-cause mortality.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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