Rest in peace, remote ischemic preconditioning
PARIS – Remote ischemic condition, long viewed as the best hope for the next breakthrough in improved clinical outcomes in acute MI, is now dead as a broad therapeutic strategy as a result of the resoundingly negative results of the CONDI-2/ERIC-PPCI trial, Hans Erik Bøtker, MD, PhD, declared at the annual congress of the European Society of Cardiology.
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Dr. Hans Erik Bøtker
“I would not be quite honest if I did not admit that we were somewhat disappointed in these results, given the promising results we have seen in the majority of the proof-of-concept studies,” added Dr. Bøtker, professor of cardiovascular medicine and interventional cardiology at Aarhus (Denmark) University.
Remote ischemic conditioning entails imposing brief cycles of ischemia and reperfusion on an arm or leg prior to or during reperfusion of an occluded artery in the setting of acute MI in order to provide cardioprotection against reperfusion injury. In the small proof-of-concept studies, it reduced infarct size and suggested the possibility of better clinical outcomes. But the four-country, prospective, single-blind, randomized CONDI-2/ERIC-PPCI trial, involving 5,401 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI), showed nary a glimmer of the hoped-for clinical benefits from four cycles of 5 minutes of ischemia and 5 minutes of deflation of an automated arm-cuff device.
The primary outcome, a composite of the 12-month rate of cardiac death or heart failure hospitalization, occurred in 9.4% of the remote ischemic conditioning group, which wasn’t significantly different from the 8.6% rate in controls. Nor were there any significant between-group differences in infarct size at 48 hours based upon high-sensitivity troponin T measurement or any of the other prespecified secondary study endpoints.
Discussant Bernard J. Gersh, MB, ChB, PhD, a long-time fervent advocate of remote ischemic conditioning as an important potential advance in MI care, wasn’t an investigator in CONDI-2/ERIC-PPCI, which he characterized as “very well executed, large, and pivotal.”
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Dr. Bernard J. Gersh
“The results of this trial are emphatic, and there would appear to be no role for routine remote ischemic conditioning in the management of most – and I would emphasize ‘most,’ perhaps not all, but most – patients with STEMI undergoing primary PCI. The results may not be what we’d hoped to hear, and I share Dr. Bøtker’s disappointment, but the data appear to be conclusive in regard to the majority of the primary PCI population. It is what it is. The only remaining questions are why the result were almost completely universally neutral in CONDI-2/ERIC-PPCI after so many positive experimental models and proof-of-concept studies, and whether are there other patient subsets who might benefit,” according to Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
Pointing to the 30-day cardiac death rate of about 2% in the trial, he commented that the management of STEMI has gotten so good that it becomes very difficult to demonstrate a difference with remote ischemic conditioning, even if a small benefit is actually present.
“I think that’s the era that we now live in,” Dr. Gersh said.
However, he is not ready to throw the final shovelful of dirt on the grave of remote ischemic conditioning.
“There is a group where perhaps there may be a therapeutic benefit: STEMI patients presenting with cardiogenic shock and no cardiac arrest,” he said.
He was a coauthor of a study analyzing the impact of an American Heart Association quality improvement project involving nearly 24,000 STEMI patients. Those with cardiogenic shock but no cardiac arrest had a 23.4% in-hospital mortality (JACC Cardiovasc Interv. 2018 Sep 24;11[18]:1824-33).
“We know that cardiogenic shock is an evolving process, and with this 23% mortality, perhaps myocardial salvage may still make a difference,” Dr. Gersh said.
The full results of CONDI-2/ERIC-PPCI have been published in the Lancet (2019 Oct 19;394[10207]:1415-24). In an accompanying editorial entitled “The Broken Promise of Remote Ischemic Conditioning,” Andrew Peter Vanezis, MD, of Royal Alexandra Hospital in Edmonton, Alta., said that “the role of remote ischemic conditioning in improving the lives of patients with STEMI has been thrown sharply into question. ... It might be time to abandon this form of cardioprotection in favor of more effective therapies” (Lancet. 2019 Oct 19;394:1389-90).
The CONDI-2/ERIC-PPCI study was funded by the British Heart Foundation, University College London, the Danish Innovation Foundation, the Novo Nordisk Foundation, and TrygFonden. Dr. Bøtker reported a financial relationship with CellAegis.