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Ischemic Preconditioning 'Ineffective' Before Cardiac Surgery

— Two trials turn up "definitive" negative results, one with a signal for possible harm

Last Updated October 6, 2015
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This article is a collaboration between 51˶ and:

Cycles of upper arm ischemic preconditioning before heart surgery did no good and were possibly harmful, two well-powered clinical trials showed.

In the ERICCA (the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Surgery) trial, remote ischemic preconditioning with four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm had no impact on the composite primary endpoint of death from cardiovascular causes, nonfatal myocardial infarction (MI), coronary revascularization, or stroke.

Action Points

  • Upper-arm remote ischemic preconditioning (RIPC) before heart surgery requiring cardiopulmonary bypass provided no benefits according two well-powered, randomized clinical trials showed.
  • The RIPC protocol consisted of four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm.

The rate at 12 months was 26.5% compared with 27.7% among patients who got sham preconditioning before on-pump CABG (P=0.58), , of University College London, and colleagues found.

In the RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) trial, the same preconditioning protocol had no impact on the primary composite endpoint of death, MI, stroke, or acute renal failure up to the time of hospital discharge compared with sham conditioning before elective cardiac surgery requiring cardiopulmonary bypass (14.3% versus 14.6%, P=0.89), , of University Hospital Frankfurt, and colleagues reported.

Neither trial showed significant advantages for any secondary endpoints, ranging from ICU stay duration to quality of life and acute kidney injury, according to findings published online in the in conjunction with presentation at the in Berlin.

"The conclusions from both trials are definitive: remote ischemic preconditioning is ineffective in adults undergoing on-pump cardiac surgery," editorialists , and , both of the University of Alberta in Edmonton, concluded.

Moreover, ERICCA showed what they called "a worrisome observation."

While underpowered to detect a difference in individual endpoints, "the number of deaths from cardiovascular causes was higher in the group of patients undergoing remote ischemic preconditioning than in the group undergoing sham treatment (although the difference was not significant [P=0.08]), yet there were fewer cases of non-lethal MI in the remote ischemic- preconditioning group," they wrote.

"These puzzling data suggest a shift in the complication profile from non-lethal MI to lethal cardiovascular complications in the remote ischemic-preconditioning group and confirm similar observations in two other recent studies," they added.

"In view of these concerns and despite the fact that remote ischemic preconditioning has been praised as safe and has been heavily promoted as the 'future of cardioprotection' by some advocates, its safety as a cardioprotective strategy should be carefully investigated in additional, adequately powered studies, specifically in patients undergoing nonsurgical interventions, even if it is applied only at a distance," Zaugg and Lucchinetti concluded. "As for every drug and therapy, the principle of Paracelsus, dosis sola venenum facit (the dose alone makes the poison), applies to remote ischemic preconditioning. Unfortunately, we do not know the right dose of ischemia to deliver."

The RIPHeart study included 1,385 patients with a fairly low average EuroSCORE cardiac operative risk score (4.2 on the scale that ranges up to 39 for a 65-year-old man). While the trial included patients scheduled for any elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol, most were getting CABG, some with valve or ascending-aorta replacement or combined procedures.

The ERICCA trial included 1,612 patients with a EuroSCORE of 5 or higher (median 6) who were getting on-pump CABG with or without valve surgery.

"Possible explanations for the divergent results of the trials are that most of the positive trials used surrogate end points, were conducted at a single center, used a single-blind design, had a small sample size, included mostly patients undergoing isolated CABG, or were not standardized with respect to the anesthesia regimen," Meybohm's group suggested.

The RIPHeart investigators, though, acknowledged that their negative findings didn't rule out a possible benefit from other remote ischemic preconditioning protocols, such as those done on lower limbs, with a longer duration of ischemia, or more cycles of preconditioning.

Disclosures

The ERICCA trial was supported by a Medical Research Council and National Institute of Health Research partnership and by the British Heart Foundation.

The RIPHeart trial was funded by the German Research Foundation.

Hausenloy, Zaugg, and Lucchinetti disclosed having no conflicts of interest to report.

Meybohm disclosed support from the German Research Foundation.

Primary Source

New England Journal of Medicine

Source Reference: Meybohm P, et al "A multicenter trial of remote ischemic preconditioning for heart surgery" N Engl J Med 2015; DOI: 10.1056/NEJMoa1413579.

Secondary Source

New England Journal of Medicine

Source Reference: Hausenloy DJ, et al "Remote ischemic preconditioning and outcomes of cardiac surgery" N Engl J Med 2015; DOI: 10.1056/NEJMoa1413534.

Additional Source

New England Journal of Medicine

Source Reference: Zaugg M, Lucchinetti E "Remote ischemic preconditioning in cardiac surgery -- ineffective and risky?" N Engl J Med 2015; DOI: 10.1056/NEJMe1510338.