ERICCA: Remote Ischemic Preconditioning Fails to Improve Long-Term Outcomes After CABG
SAN DIEGO, CA—Remote ischemic conditioning prior to on-pump CABG in high-risk patients fails to reduce long-term adverse events, according to results presented March 16, 2015, at the American College of Cardiology/i2 Scientific Session.
For the ERICCA trial, Derek J. Hausenloy, MD, PhD, of University College London Hospitals (London, England), and colleagues randomized 1,612 patients (mean age 76 years; 70.8% male) undergoing on-pump CABG to receive remote ischemic preconditioning (n = 801) or a sham procedure (n = 811) at 29 hospitals in the United Kingdom.
Preconditioning was performed using intermittent arm ischemia via 4 cycles of 5-minute inflation followed by 5-minute deflation of a standard blood-pressure cuff after anesthesia induction but before surgical incision. Perioperative myocardial injury was measured by the area under the curve of high-sensitivity troponin T at 6, 12, 24, 48, and 72 hours.
Mean additive EuroSCORE was 6.7, and one-quarter of patients had diabetes. About half underwent either valve repair or replacement in addition to CABG, and many were on concomitant medications including volatile anesthetics (40.0%), propofol (88.5%), IV nitrates (28.7%), fentanyl (81.8%), and morphine (29.6%).
Reduction in Myocardial Injury Seen
At 1 year, there was no difference in the primary endpoint of MACCE (cardiovascular death, MI, stroke, and coronary revascularization) or any of its individual outcomes between the study and control groups (table 1).
Preconditioning reduced perioperative myocardial injury by about 10% (P = .039). However, Dr. Hausenloy said, “an important caveat to this is that only about half of patients distributed equally between the 2 treatment groups had the full dataset.” Additionally, there were no differences in inotrope score, ICU or hospital lengths of stay, or acute kidney injury between the study arms.
Researcher Outlines Possible Reasons for Failure
According to Dr. Hausenloy, there are many reasons why remote ischemic preconditioning failed to reduce adverse outcomes.
“Many of the preclincial studies that have looked at [the intervention] have focused on its cardioprotective effect in terms of limiting acute ischemia reperfusion injury,” he said. “However…, there are multiple causes of injury during surgery, which include not only ischemia reperfusion injury but also coronary microembolization, inflammation as the patient is put on and off bypass, but also direct injury to the heart.”
Previous studies have shown that diabetes and hypertension can impact the efficacy of preconditioning, Dr. Hausenloy explained, adding that, given ERICCA’s high-risk population, this interaction could have played a role. “It is important to bear in mind that not all proof-of-concept studies have shown a positive effect of [preconditioning],” he said. “This will suggest that in the setting of cardiac bypass surgery, the cardioprotective effect exhibited by [preconditioning] may be affected by factors during surgery.”
That the reduction in perioperative myocardial injury did not translate into improved clinical outcomes raises uncertainty about its use “as a surrogate marker for cardiac protection,” suggested Dr. Hausenloy.
Panelist Bernard J. Gersh, MBChB, DPhil, of the Mayo Clinic (Rochester, MN), countered that perioperative myocardial injury is still “a reasonable measure, but what you’ve got is competing risks. Reperfusion injury may be overpowered by the effect of all the other comorbidities and age and everything.”
Preconditioning Mechanism Still Unclear
Discussing the study, panelist Alice K. Jacobs, MD, of Boston University Medical Center (Boston, MA), suggested that the reason no clinical effect was seen could perhaps be related to the injuries being “too small in this model despite the fact that the patients were such high risk.”
Additionally, she questioned the high rate of propofol use in ERICCA, noting that recent studies implicate the drug in mitigating the effects of preconditioning.
Dr. Hausenloy explained that the propofol studies were published after the original study design of ERICCA was set but acknowledged the possibility “that concomitant medication interfered with the cardioprotective effect.”
Although the underlying mechanism for benefit with preconditioning “still remains unclear,” he explained, “[i]t is believed to be due to a circulating factor that's produced into the bloodstream in response to the blood pressure cuff remote ischemic conditioning. To complicate things, it requires an intact neuropathway to the limb.”
Even though preconditioning failed to change post-CABG outcomes in ERICCA, Dr. Hausenloy said, it still merits further research. There may be other settings involving reperfusion injury, such as primary PCI for STEMI or organ transplantation, in which the intervention could be more beneficial, he noted.
Hausenloy DJ. Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery: a multi-center randomized controlled clinical trial. Presented at: American College of Cardiology/i2 Scientific Session; March 16, 2015; San Diego, CA.
- Dr. Hausenloy reports no relevant conflicts of interest.
- Dr. Jacobs reports receiving research grants from Abbott Vascular, Boston Scientific, Bristol-Myers Squibb/Sanofi-Aventis, Eli Lilly/Daiichi Sankyo, and Medtronic Vascular and having other conflicts with Acetylon.
- Dr. Gersh reports receiving consulting fees/honoraria from Merck and Ortho-McNeil Janssen; serving on data and safety monitoring boards for Baxter Healthcare, Medtronic, and Teva; and having other conflicts with Boston Scientific and St. Jude Medical.