Exenatide Only Cardioprotective in STEMI Patients Treated Quickly

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As an adjunct to primary percutaneous coronary intervention (PCI), the experimental agent exenatide is cardioprotective in patients with ST-segment elevation myocardial infarction (STEMI)—but only in those without lengthy system delays. The findings, from a post-hoc analysis of a randomized clinical trial, were published online April 10, 2012, ahead of print in Circulation: Cardiovascular Interventions.

Exenatide is a glucagon-like peptide-1 (GLP-1) marketed as Byetta (Amylin Pharmaceuticals, San Diego, CA) for the treatment of type 2 diabetes. It has been shown to decrease infarct size by approximately 40% in animal models.

For the earlier study, researchers led by Jacob Lønborg, MD, of Rigshospitalet (Copenhagen, Denmark), randomized 387 STEMI patients who presented within 12 hours of symptom onset and had TIMI flow 0/1 to intravenous exenatide (25 µg in 250 mL saline, with plasma levels then maintained at 0.03 to 0.3 nmol/L) or placebo (saline). Adjunctive treatment began at least 15 minutes before primary PCI and lasted until 6 hours after the procedure.

Sequential cardiac MRI demonstrated significantly higher myocardial salvage index from baseline to 3 months but only a trend toward smaller infarct size with exenatide.

Time Matters for Myocardium

For the current analysis, Dr. Lønborg and colleagues looked at 148 patients who had complete imaging data (n = 77 exenatide and n = 71 placebo). The researchers stratified patients according to whether they fell above or below the median system delay (time from first medical contact to balloon) of 132 minutes.

Patients treated within 132 minutes fared better with exenatide than placebo at 3-month follow-up. But among those who exceeded the system delay cutoff, there was no difference in final infarct size or myocardial salvage index between the 2 study arms (table 1).

Table 1. Median 3-Month Outcomes on MRI Stratified by System Delay

There was a significant interaction between system delay and treatment allocation for infarct size (P = 0.018). Moreover, exenatide continued to show benefit in patients treated within 132 minutes even after exclusion of those with multivessel disease, who might have inadvertently experienced ischemic preconditioning in myocardium located near the stenotic vessels.

Stratifying by system delay above or below 90 minutes showed a trend toward reduced infarct size (P = 0.07) and improved myocardial salvage index (P = 0.09) in patients treated more quickly but not in those who exceeded the cutoff. But raising the bar to 150 minutes again showed a significant benefit among patients with shorter delays in terms of infarct size and myocardial salvage index (P = 0.008 for both). Exenatide did not appear to influence outcomes in patients treated beyond 150 minutes.

Clinical Relevance Unclear

In an e-mail communication with TCTMD, Dr. Lønborg acknowledged that while no published data have specified what makes for a clinically meaningful difference in final infarct size, the approximately 30% relative difference observed here “among the patients with short system delay is great; and if this finding holds true, it may very likely be translated into an improved clinical outcome.”

Moreover, the researchers did not observe any side effects from exenatide treatment, he reported.

According to Dr. Lønborg, there may be 2 reasons why patients treated quickly were the only ones to derive benefit. They “have more viable myocardium at the time of reperfusion, and thus more myocardium exposed to [possible] reperfusion injury,” he explained, adding that longer durations of ischemia lead to more severe changes in mitochondrial membrane potential. Therefore, these cells are more resistant to cardioprotection and experience irreversible damage.

It is still unknown whether it is worth using the drug in conjunction with longer delays. “There may be other potential benefits not related to infarct size,” Dr. Lønborg noted. And because it is unclear whether the cutoff is exact or whether the relationship exists on a continuum, he said he would err on the side of giving the drug to all patients referred for primary PCI, though not until the clinical effects of exenatide are confirmed.

Beyond this, Dr. Lønborg advised, future research needs to explore the optimal timing, dose, and administration route of exenatide as well as whether other GLP-1 analogues such as liraglutide (Victoza; Novo Nordisk, Bagsværk, Denmark) also have cardioprotective effects.

 

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Source:
Lønborg J, Kelbæk H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment elevation myocardial infarction and short duration of ischemia. Circ Cardiovasc Intv. 2012;Epub ahead of print.

 

 

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