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In patients undergoing primary percutaneous coronary intervention (PCI), postconditioning—a technique aimed at protecting intact myocardium from reperfusion injury—not only fails to reduce infarct size but may impair myocardial salvage, according to data published online August 16, 2011, ahead of print in the European Heart Journal.

To assess the impact of the experimental strategy, investigators led by Xavier Freixa, MD, of the University of Barcelona (Barcelona, Spain), looked at 79 patients who received primary or rescue PCI at their center for a first STEMI within 12 hours of symptom onset. The patients were randomized to 4 rounds of balloon inflation and deflation, each lasting 1 minute, immediately after reperfusion (n = 39) or no postconditioning (n = 40). All patients had TIMI grade flow 0-1 and no collaterals.

The 2 groups were well balanced with regard to baseline clinical characteristics and angiographic parameters.

Cardiac MR Assessment

One week and 6 months after PCI, infarct size, myocardial salvage, and LVEF were assessed by contrast-enhanced cardiac MR imaging (CMR).

At 1 week, there was no difference in infarct size (co-primary endpoint) or LVEF between the postconditioning and control groups. However, myocardial salvage and myocardial salvage index (co-primary endpoint) were both lower in patients who received postconditioning (table 1).

Table 1. CMR Results at 1 Week

At 6 months, infarct size and LVEF remained similar for the 2 arms (table 2).

Table 2. CMR Results at 6 Months

Results were consistent across several key subgroups, including patients who had:

• Symptom-to-balloon time ≤ 3 or ≤ 6 hours
• Primary PCI
• Direct stenting
• Symptom-to-balloon time ≤ 6 hours, primary PCI, and direct stenting

Importantly, a regression analysis in which the final infarct size was related to the area at risk showed no differences between the groups (P = 0.129).

In addition, post-PCI TIMI grade and myocardial blush grade, measured by angiography, as well as ECG resolution at 90 minutes, showed similar results in both groups. There was a trend toward higher troponin I peak release in the postconditioning group (299 ± 72 ng/mL vs. 148 ± 23.8 ng/mL in controls; P = 0.05), but no significant differences appeared in CK and CK-MB peak.

In terms of clinical outcomes, 1 control patient died in-hospital secondary to heart failure, while 1 postconditioning patient died due to stent thrombosis 4 months after the index event. Three other patients (1 control and 2 postconditioning) were readmitted for heart failure within 6 months.

The authors say their findings are buttressed by the fact that, unlike some earlier studies, they tried to take into account several potential confounding factors, such as the presence of collaterals, nonculprit vessel disease, and direct stenting.

Mixed Results Resolved by Better Methodology?

This is yet another small series, and results for postconditioning thus far have been variable, observed Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), in a telephone interview with TCTMD. “But here the analysis of infarct size and myocardial salvage is very well done, and CMR is very precise,” he said. “Much of the data from earlier studies were accrued with different methodologies, so we’re not comparing apples with apples.”

Moreover, “collectively, the infarct data from randomized trials using cardiac MR do not appear to differ greatly,” Giuseppe Tarantini, MD, PhD, of the University of Padua (Padua, Italy), told TCTMD in an e-mail communication. Results from his earlier CMR study, presented at EuroPCR in May 2011, parallel the current findings.

Dr. Brener noted that direct stenting is preferred to minimize the risk of distal embolization, but in this study it was performed in slightly more than half of patients. And aspiration thrombectomy was used in only about 17%. “That is not up-to-date primary angioplasty,” he commented. “We know from the TAPAS trial that when you do thrombectomy, you achieve good blush grade in a much greater proportion of patients than was achieved in this study.”

However, the authors point to a Catch-22 in the timing of thrombectomy. Performing it upfront means delaying postconditioning, which could reduce the latter’s effectiveness. On the other hand, starting with postconditioning defers the protection provided by thrombectomy.

Other factors also may blunt the response to postconditioning, observed Dr. Tarantini, such as underlying microvascular disease, which is common in STEMI patients with diabetes or left ventricular hypertrophy, and the microvascular injury associated with prolonged ischemia.

An anomaly of the study is that the myocardial area at risk is much larger than in previous trials—about 32% of the left ventricle compared with about 20%, said Dr. Brener. That may be due in part to the fact that in the current study it was calculated from an algorithm, so the actual area at risk may have been smaller, he noted. Nonetheless, the tight correlation between infarct size and area at risk “suggests that—contrary to some suggestions—postconditioning is ineffective regardless of the size of the area at risk,” he added.

Trials Should Be Put on Hold

More basic research is what is currently needed to understand exactly how postconditioning works, Dr. Brener stressed.

Dr. Tarantini agreed. “An important limitation [of this strategy] is the extreme complexity of the numerous physiological and biochemical mechanisms responsible for the beneficial effects of postconditioning in experimental models,” he said. “Extrapolation to the clinical setting is further complicated by the fact that the optimal window for the coupling of postconditioning to beneficial responses may be substantially shorter than the mean duration of ischemia in typical STEMI patients.”

Further clinical trials should probably await a more sophisticated understanding of these biological pathways and CMR datasets in experimental models, Dr. Brener said. Meanwhile, it is not surprising that postconditioning might have an adverse effect on myocardial salvage, he noted. “After all, if you don’t evoke a protective reaction [as intended], you can harm the patient because you’re occluding the artery,” he said.

Study Details

Unfractionated heparin was administered at a dose of 60 UI/kg, and a loading dose of clopidogrel (300 mg) was given at least 15 minutes before PCI. Glycoprotein IIb/IIIa receptor antagonists were routinely used if there was no contraindication.

 

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Source:
Freixa X, Bellera N, Ortiz-Pérez JT, et al. Ischemic postconditioning revisited: Lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J. 2011;Epub ahead of print.

 

 

 

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