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New Studies Find RIPC Ineffective


NEW YORK - The theory that heart surgery can be made safer by periodically cutting off blood flow to an arm has been called into serious question.

Two large randomized studies, published online by the New England Journal of Medicine and presented on Oct. 5 at the European Society of Intensive Care Medicine Congress in Berlin, show that the technique, known as remote ischemic preconditioning (RIPC), made no difference in terms of the risk of death, heart attack, or kidney failure after surgery.

"The conclusions from both trials are definitive: remote ischemic preconditioning is ineffective in adults undergoing on-pump cardiac surgery," wrote Dr. Michael Zaugg and Dr. Eliana Lucchinetti of the University of Alberta in Edmonton, Canada, in a Journal editorial.

But the chief author of one of the studies, Dr. Patrick Meybohm of University Hospital Frankfurt in Germany, said research on the technique will likely continue because propofol was used as an anesthetic, which may have muted the effect, and patients who were excluded because of recent heart attack or severe liver or kidney disease might benefit.

"Other RIPC protocols (e.g., involving lower-limb RIPC, a longer duration of ischemia, or more cycles) may still be protective. Thus future studies should focus on these confounders," he said by email.

Evidence supporting the technique has been mixed, although tests that have looked at serum cardiac and renal biomarkers have suggested that cutting off flow to an extremity during on-pump surgery might offer better outcomes.

"The underlying hypothesis is that RIPC may attenuate organ injury by releasing various molecules such as damage-associated molecular patterns, adenosin, etc. etc., and that the body's own mediators may then induce natural defenses such as bioenergetic down-regulation and temporary cell-cycle arrest," Meybohm said. "These defenses, once engaged, can then protect the organs during subsequent inflammatory or ischemic stress."

The two studies, known as ERICCA and the RIPHeart, both included a sham group so the surgeons would not know which of the unconscious patients were getting their arm circulation cut off by a blood pressure cuff during the operation. Virtually all the patients were sedated with intravenous propofol.

ERICCA, the larger of the two, was conducted in the UK at 30 cardiac surgery centers on people undergoing coronary artery bypass graft surgery with or without valve replacement.

In the active treatment group, the blood was cut off from the arm for five minutes and restored for five minutes. The cycle was repeated three more times. In the control group, the inflation valve was left open.

Ultimately, 26.5% of the 801 patients in the test group died from cardiovascular causes, experienced a myocardial infarction, required coronary revascularization or experienced a stroke 12 months after randomization. The rate was 27.7% for the 811 in the control group (p=0.58).

There were no significant differences for those individual measures, nor on secondary measures such as the rate of acute kidney injury, troponin levels, length of stay in the ICU, or amount of time spent in the hospital.

The research team, led by Dr. Derek Hausenloy of University College in London, did not find any evidence that preconditioning produced serious side effects.

The RIPHeart study, conducted at 14 German hospitals by Dr. Meybohm and colleagues, randomized 1,403 patients and used a composite endpoint of death, heart attack, stroke, or acute renal failure up to the time of hospital discharge or a maximum of 14 days. A secondary analysis followed the volunteers for three months.

To disguise which patients were receiving preconditioning and which were not, cuffs were placed on each patient's arm and on a dummy arm, both covered by surgical drapes. Only one cuff was inflated.

Again, the endpoint rates in the two groups were the same - 14.3% with preconditioning and 14.6% with sham preconditioning. Analyzing the individual elements of the composite endpoint also show no advantage either way.

No significant differences were seen "in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium," the team concluded.

"In addition, no significant differences between treatment groups were found at the 30-day and 90-day follow-up," they wrote.

They also saw no adverse events. In their editorial, Drs. Zaugg and Lucchinetti speculated that the technique might be risky in patients with highly unstable coronary plaques because there was a small, albeit nonsignificant, increase in deaths from cardiovascular causes in one of the two studies.

Dr. Meybohm said he didn't think that speculation was warranted.

"Current data do not strongly support the hypothesis that RIPC may do more harm than good," he said. "There are preliminary results from about two-three studies, but there are also nearly a hundred studies demonstrating reduced biomarkers of organ ischemia/reperfusion injury, and positive/neutral effects."

The ERICCA study was funded by the Efficacy and Evaluation Program and the British Heart Foundation; the RIPHeart study was funded by the German Research Foundation.

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