No Benefit From Ischemic Preconditioning at Cardiac Surgery in Two Major Trials

Pam Harrison

October 06, 2015

BERLIN, GERMANY — The use of remote ischemic preconditioning (RIPC) in the setting of CABG and other cardiac surgeries with cardiopulmonary bypass (CBP) support does not protect patients from adverse clinical outcomes, according to two separate large-scale, double-blind studies published October 5, 2015 in the New England Journal of Medicine[1,2] to coincide with the presentation of the first one at the European Society of Intensive Care Medicine 2015 Annual Meeting.

In that one, the RIPHeart Study, with about 1400 randomized patients, there was no significant difference in the primary end point of death from any cause, nonfatal MI, new stroke, or acute renal failure out to 14 days or in its components out to 3 months. The 14-day rate was just over 14% in both groups.

In the other trial, the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in CABG Surgery (ERICCA), 26.5% of patients who received RIPC had a major adverse cardiac or cerebral event after 1 year, compared with a statistically similar 27.7% for the control group. The results of ERICCA had been presented at the American College of Cardiology 2015 Scientific Sessions and reported by heartwire from Medscape at the time.

"There is a small group of RIPC experts who focus on experimental studies showing benefits in surrogate parameters from RIPC again and again," Dr Patrick Meybohm (University Hospital Frankfurt, Germany) told heartwire in written correspondence. But until now, he said, there have been no large clinical trials in the setting of cardiac surgery with CBP support. Meybohm is first author on the RIPHeart paper.

"Future studies," he added, "should take into account well-known confounders and try to elucidate potential RIPC effects in other cohorts, such as patients undergoing urgent surgery, and explore other RIPC protocols—such as those involving lower-limb RIPC, a longer duration of ischemia, or more cycles—which may still be protective."

Dr Robert Kloner (Huntington Medical Research Institute, Pasadena, CA), who wasn't involved in either study, noted for heartwire that there have been several previous clinical studies showing that remote ischemic conditioning does not add additional protection in cardiac surgery. "Hence, I am not surprised by the findings" in the two current studies, he said in written correspondence.

He added, "It is hard to show additional protection on top of the cardioprotection that these patients are already receiving, such as hypothermia, opioids, anesthetics, and even the nociceptive conditioning that may occur with a skin incision."

The RIPHeart Study

The investigators randomized 1403 patients who were undergoing elective cardiac surgery requiring CBP support to undergo RIPC or a sham RIPC procedure. Patients were given total anesthesia with intravenous propofol.

RIPC was induced by four cycles of upper-limb ischemia delivered at 5-minute intervals by inflating a blood-pressure cuff to ≥200 mm Hg or at least 15 mm Hg higher than the patient's actual systolic blood pressure, followed by 5 minutes of cuff deflation. To preserve double-blinding, a dummy arm was used for patients assigned to sham RIPC with similar cycles of inflation and deflation.

The primary end point occurred in 14.3% of the RIPC group vs 14.6% in the sham-RIPC group in the full data-set analysis. There were also no significant differences in the rate of any of components in the primary end point in the full data-set analysis.

Adjusted End-Point Analyses

Outcome RIPC, n=692 (%)
Sham RIPC, n=693 (%)
Adjusted odds ratio (95% CI)
Death 1.3 0.6 0.46 (0.14–1.54)
MI 6.8 9.1 1.37 (0.92–2.03)
Stroke 2 2.2 1.10 (0.53–2.31)
Acute renal failure 6.% 5.1 0.83 (0.52–1.34)

The rate of event-free survival was the same, 85%, at both 30 and 90 days after surgery.

The ERICCA Study

As copublished by Dr Derek Hausenloy (University College London, UK) and colleagues, ERICCA enrolled 1612 patients at 30 cardiac surgery centers in the UK. Patients were at increased surgical risk and were undergoing on-pump CABG with or without valve surgery with blood cardioplegia.

Anesthetic management and perioperative care were not standardized in the ERICCA study as they were in RIPHeart, but the RIPC strategy and sham procedure were similar in the two trials.

In ERICCA, the primary end point was death from cardiovascular causes, nonfatal MI, coronary revascularization, or stroke 12 months after randomization. It was reached by 26.5% patients who received RIPC and 27.7% of controls. There were no significant differences between the RIPC group and sham controls in any of the individual components of the primary end point, as investigators note.

Other Factors "Masking" RIPC Effects

In an accompanying editorial[3], Drs Michael Zaugg and Eliana Lucchinetti (University of Alberta, Edmonton) agreed that prior positive reports in which clinical benefits have been found from application of RIPC were mainly from single-center, single-blind studies using surrogate markers of myocardial damage. Moreover, preclinical studies strongly suggested the strategy would work.

So why doesn't it now work in the setting of CBP-supported cardiac surgery? they ask. First, since cardiopulmonary bypass itself, as well as hypothermia and cardioplegia, are known to be protective against ischemic and reperfusion injury, perhaps further protection is impossible to achieve, propose Zaugg and Lucchinetti.

"Importantly, concomitant medications, specifically anesthetics, may interfere with remote ischemic preconditioning," they add. Indeed, propofol, used prevalently for anesthesia in both trials, and opioids—also used in both trials—are known to diminish or ablate the effects of ischemia-induced cardioprotection, including RIPC.

"Hence, the most obvious explanation for the negative results in these two clinical trials is that other cardioprotective pharmacologic agents may have masked the effect of remote ischemic preconditioning or rendered it redundant," they write.

Kloner proposed that with the addition of these two negative studies to the literature, it will no longer be worth pursuing remote ischemic preconditioning specifically for cardioprotection in CBP-supported cardiac surgery.

"The concept of remote conditioning still shows great promise, but not for improving organs that are already well protected, as in the setting of cardiac surgery," Kloner concluded.

On the other hand, he noted, several studies have shown that remote conditioning improves myocardial salvage in the setting of acute MI, and other promising areas include reduction of contrast-induced nephropathy.

The RIPHeart study was funded by the German Research Foundation. The ERICCA study was supported by grants from the Efficacy and Mechanism Evaluation Program and the British Heart Foundation. Meybohm reports no relevant financial relationships; disclosures for the coauthors are listed in the article. Hausenloy reports no relevant financial relationships; disclosures for the coauthors are listed on the journal website. Zaugg and Lucchinetti has no relevant financial relationships. Kloner had no relevant financial relationships.

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