Remote Preconditioning Prior to PCI Demonstrates Long-term Ischemic Benefits

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New evidence suggests that the reduction in major adverse events seen for patients undergoing elective percutaneous coronary intervention (PCI) with remote ischemic preconditioning is maintained out to 6 years. But the long-term data, from a study published online May 21, 2013, ahead of print in Circulation: Cardiovascular Interventions, also suggest that diabetic patients are unlikely to benefit from the therapy.

For the CRISP Stent (Cardiac Remote Ischemic Preconditioning in Coronary Stenting) study, Stephen P. Hoole, MA, of Papworth Hospital (Cambridge, United Kingdom), and colleagues randomized 202 patients undergoing elective PCI between July 2006 and November 2007 to remote ischemic preconditioning via inflation and deflation of a blood pressure cuff (n = 104) or control therapy (n = 98), in which the cuff was placed around the upper arm but not inflated. Preconditioning was performed about 1 hour prior to PCI; the cuff was inflated to a pressure of 200 mm Hg for 5 minutes, followed by 5 minutes of deflation to allow reperfusion. This sequence was repeated 2 more times.

In 6-month data published in Circulation in 2009, there was a lower risk of MACCE (defined as all-cause mortality, stroke or TIA, nonfatal MI, ACS, and left ventricular failure requiring hospital admission) with preconditioning vs. control (HR 0.28; 95% CI 0.12-0.82; P = 0.018), a difference predominately driven by ACS/nonfatal MI.

The current report details mean long-term follow-up of 1,579.7 ± 603.6 days in 192 patients from the original cohort.

Confirmation of Earlier Findings

The overall rate of MACCE was 30.7% (59 events) during the follow up period. Patients who experienced MACCE had longer cuff-to-balloon times than those who did not (76.6 ± 34.0 min vs. 58.9 ± 23.5 min; P = 0.024) as well as higher cardiac troponin I values within 24 hours after PCI (2.07 ± 6.99 ng/mL vs. 0.91 ± 2.07 ng/mL; P = 0.05).

Similar to the 6-month data, the MACCE rate at 6 years was lower in the preconditioning group. There were 23 events with preconditioning and 36 with control treatment (HR 0.58; 95% CI 0.35-0.97; P = 0.039). The number needed to treat to prevent 1 MACCE at 6 years was 8, and the absolute risk reduction was 0.13.

Five deaths occurred in the control group vs. 1 in the preconditioning group. When the MACCE definition included only cardiovascular death, rather than all-cause death, the preconditioning group faired even better than controls at 6 years (HR 0.54; 95% CI 0.31-0.94; P = 0.029).

Although the overall MACCE rate was similar between patients with and without diabetes (28.2% vs. 31.5%; P = 0.718), diabetic patients who underwent preconditioning did not appear to derive any detectable long-term advantage.

While nondiabetic patients experienced fewer events after preconditioning than did nondiabetic controls (17 vs. 29 events; P = 0.045), this was not the case for diabetic patients, who saw similar MACCE rates whether they underwent preconditioning or not (6 vs. 7 events; P = 0.54). Irrespective of whether they did or did not experience MACCE, diabetic patients randomized to preconditioning had similar levels of procedural blood glucose (120.6 ± 9.0 mg/dL vs. 149.4 ± 45.0 mg/dL; P = 0.14) and hemoglobin A1C (7.9 ± 1.7% vs. 7.9±1.1%; P = 0.99).

Elective PCI Patients Should be Candidates

Mr. Hoole and colleagues note that remote ischemic preconditioning was first shown to provide cardioprotection in the early 1990s. Since then, the technique has been found to reduce the incidence of procedure-related cardiac troponin I release not only in the setting of primary PCI but also in pediatric cardiac surgery, adult bypass surgery, and abdominal aortic aneurysm repair.

Patients undergoing elective PCI should be considered for preconditioning, "in an attempt to reduce postprocedural troponin release and thus abrogate MACCE at both short- and long-term follow-up," they conclude, adding that delays in cuff-to-balloon time should be minimized to ensure that patients achieve the full effect.

Although the exact mechanism by which remote ischemic preconditioning provides benefit is unclear, Robert A. Kloner, MD, PhD, of Good Samaritan Hospital (Los Angeles, CA), told TCTMD in a telephone interview that there are several theories. Dr. Kloner coauthored the1993 paper that first broached the concept.

One possibility is that by preconditioning 1 organ "you are releasing some kind of humeral factor, which some studies suggest is a low-molecular weight substance and others suggest adenosine is involved," he reported. Another is that it stimulates neural reflexes. But many researchers, he added, believe the process is actually multifactorial in nature, involving both mechanisms and potentially others as well.

"The exciting thing about this paper is that not only are they showing that preconditioning with simple brachial artery pump inflation reduced infarct size, it also significantly reduced a pretty robust set of adverse events," Dr. Kloner said. "I don’t think any other group has followed patients [receiving remote ischemic preconditioning] as far as they have."

Accumulating evidence to date by this group and others suggests that the benefit somehow continues in the years after PCI and may stem from improved endothelial dysfunction and/or reduction of arrhythmias, he said.

Comorbidities May Be a Hindrance

The answer as to why diabetic patients failed to gain cardioprotection is unknown.

The study authors point out that none of the diabetic patients were taking glibenclamide, an ATP-dependent potassium channel blocker known to attenuate the effect of conditioning. However, diabetic resistance to conditioning has been documented previously and "may be attributable to hyperglycemia, exacerbating the ischemia reperfusion injury," they add. At least 2 studies have suggested that the conditioning threshold required to protect myocardium may be higher in this patient subset because of alterations in diabetic mitochondrial ATP-sensitive potassium channels.

Dr. Kloner noted that the lack of effect in diabetic patients is not surprising since some previous laboratory studies have suggested that certain comorbidities may compromise the ability to achieve optimal preconditioning. He agreed with the study authors that it may be possible to increase dosing—and thereby improve the odds of success—in diabetic patients, but emphasized that the theory remains untested.

Davies WR, Brown AJ, Watson W, et al. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: The CRISP stent trial long-term follow-up. Circ Cardiovasc Interv. 2013;Epub ahead of print.

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