Postconditioning Ineffective in STEMI Patients Receiving Primary PCI

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Ischemic postconditioning during primary percutaneous coronary intervention (PCI) improves neither myocardial perfusion nor clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). The findings, from a large-scale randomized trial, were published online September 25, 2013, ahead of print in Circulation.

For the POST trial, a team led by Hyeon-Cheol Gwon, MD, of Samsung Medical Center (Seoul, South Korea), randomly assigned 700 patients undergoing primary PCI for STEMI within 12 hours of symptom onset to postconditioning (n = 350) or conventional treatment (n = 350).

Ischemic postconditioning, successfully performed per protocol in 323 patients (92.3%), was initiated immediately after restoration of coronary blood flow. An angioplasty balloon positioned at the culprit lesion was inflated for 1 minute followed by 1 minute of deflation, in 4 cycles.

All Outcomes Similar

Complete ST-segment resolution (primary endpoint; >70% on ECG) at 30 minutes after PCI occurred at similar levels in the postconditioning and control groups. Though the rate of resolution was higher when measured at least 4 hours after PCI, it remained equivalent between the 2 groups. Other endpoints including myocardial blush grade and TIMI flow after PCI as well as 30-day MACE (death, MI, severe heart failure, and stent thrombosis) also were similar (table 1).

Table 1. Echocardiographic, Angiographic, and Clinical Outcomes

^a Primary endpoint.

Subgroup analyses showed no variation in the likelihood of complete ST-segment resolution at 30 minutes based on age, sex, infarct-related artery, symptom onset-to-reperfusion time, or the use of thrombus aspiration, direct stenting, or glycoprotein IIb/IIIa inhibitors.

Thrombus Aspiration, Predilation May Have Blunted Effect

According to Dr. Gwon and colleagues, the negative findings may stem from the fact that thrombus aspiration, which may itself improve myocardial perfusion, was performed in nearly half of patients. Predilation was also allowed “to reflect the current standard practice pattern of primary PCI,” they add. “As a result, stents were implanted after postconditioning procedures in nearly all of the patients. Therefore, embolization due to stenting may dilute the cardioprotective effect of postconditioning.”

POST investigator Joo-Yong Hahn, MD, also of Samsung Medical Center, told TCTMD in an e-mail communication that it is still “possible that postconditioning works. However, it is unlikely that ischemic postconditioning is protective in patients undergoing primary PCI with current standard practice.”

Dr. Hahn reported that pharmacologic agents are now the most promising option for cardioprotection. “By conditioning myocardium pharmacologically, we can avoid repeated balloon occlusion after restoration of coronary reflow which can potentially aggravate ischemia or cause distal embolization,” he explained.

Large randomized trials such as CIRCUS, which aims to determine whether cyclosporine before PCI can improve clinical outcomes in STEMI patients, are needed to confirm the efficacy of such agents, the paper adds.

Better Trials Needed

In an editorial accompanying the paper, Warren K. Laskey, MD, MPH, and Alex Schevchuck, MD, both of the University of New Mexico School of Medicine (Albuquerque, NM), outline the inconsistent evidence for and against the use of postconditioning in AMI. They ask, “Is the current uncertainty regarding the presence or extent of benefit of post-conditioning in humans simply a matter of inadequately powered studies and inflated early estimates of the ‘true’ effect?”

POST does not fully put the issue to rest, Drs. Laskey and Schevchuck argue, particularly in light of the delays associated with use of adjunctive therapies such as thrombus aspiration “and the very likely possibility of mitigating, if not abrogating, activation of salvage signaling pathways.”

Overall, they conclude, “while this trial remains the largest reported attempt to identify a post-conditioning effect in patients undergoing primary PCI, further improvement in trial conduct, patient selection and clinical, non-surrogate outcomes assessment are necessary for effective translation of this still potentially clinically relevant cardioprotective phenomenon.”

POST Far from ‘Definitive’

Giuseppe Tarantini, MD, PhD, of the University of Padua (Padua, Italy), emphasized several study limitations to TCTMD in an e-mail communication.

For example, Dr. Tarantini said, ST-segment resolution is a surrogate endpoint and POST was underpowered for detecting differences in clinical outcome. The numerically higher mortality rate with postconditioning (3.7% vs. 2.9%; P = 0.53) is particularly concerning given that it has been previously observed by other studies, he noted. POST also fails to report data on biomarker assessments of infarct size and whether the presence of collateral circulation was similar between the study arms.

Dr. Tarantini agreed with the editorial authors that “use of thrombectomy and predilation prolongs significantly the time from restoration of TIMI 3 flow to the beginning of [the postconditioning] protocol beyond the effective time window to reduce reperfusion injury.”

Also in an e-mail communication with TCTMD, Robert A. Kloner, MD, PhD, of Good Samaritan Hospital (Los Angeles, CA), said that, based on his own laboratory’s experience, he is unsurprised by the POST trial’s negative results. “Nevertheless, some experimental labs have documented impressive reductions of infarct size with postconditioning and several—but not all—clinical studies suggest it works in patients with STEMI,” he said.

Importantly, POST “does not measure true myocardial infarct size. [ST resolution] is a rather soft endpoint,” Dr. Kloner said. “Area under the curve of enzymatic markers of necrosis or, better yet, MRI or SPECT imaging would have been better ways to really address the question.”

Predilation and thrombus aspiration, meanwhile, “could have caused an inadvertent conditioning phenomenon in all of the patients who received these therapies and then could have blunted any beneficial effect of postconditioning,” he noted, adding that the inclusion of patients up to 12 hours after symptom onset may also mean that the “duration of ischemia may simply be too long for any intervention to work.”

“This paper adds to the controversy over postconditioning [and] will not be definitive,” Dr. Kloner commented. “Whether postconditioning works and should be used for PCI procedures remains to be determined.”

Sources:
1. Hahn J-Y, Song YB, Kim EK, et al. Ischemic postconditioning during primary percutaneous coronary intervention: The POST randomized trial. Circulation. 2013;Epub ahead of print.

2. Laskey WK, Schevchuck A. Post-conditioning during PCI in acute myocardial infarction: Continued difficulty in translation [editorial]. Circulation. 2013;Epub ahead of print.

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