Novel Peptide During Primary PCI Helps Limit Reperfusion Injury

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As an adjunct to primary percutaneous coronary intervention (PCI), the experimental agent exenatide increases myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI), according to findings from a small randomized study published online September 14, 2011, ahead of print in the European Heart Journal.

Results from the study were previously presented May 19, 2011, at EuroPCR in Paris, France.

Exenatide, a glucagon-like peptide-1, is the active substance in the diabetes drug Byetta (Amylin Pharmaceuticals, San Diego, CA; Eli Lilly, Indianapolis, IN). Preclinical research has demonstrated the agent to be cardioprotective during reperfusion in rodents.

Early Signs of Efficacy

In a proof-of-concept study, Jacob Lønborg, MD, of Rigshospitalet (Copenhagen, Denmark), and colleagues randomized 172 STEMI patients who presented within 12 hours of symptom onset and had thrombolysis in myocardial infarction (TIMI) flow 0/1 to intravenous (IV) exenatide (n = 85) or saline as placebo (n = 87). In the exenatide group, plasma levels were maintained at 0.03 to 0.3 nmol/L. Adjunctive treatment began 15 minutes before primary PCI and lasted until 6 hours after the procedure.

Based on sequential cardiac magnetic resonance (CMR) evaluations, the researchers calculated salvage index at 3 months, the study’s primary endpoint. Patients treated with exenatide had larger salvage index at follow-up than those given placebo. Infarct size in relation to myocardial area at risk (AAR), meanwhile, was smaller in the exenatide group, with a trend toward reduced final infarct size (table 1).

Table 1. Outcomes at 3 Months

 

Exenatide
(n = 85)

Placebo
(n = 87)

P Value

Salvage Index

0.71 ± 0.13

0.62 ± 0.16

0.003

Infarct Size/AAR

0.30 ± 0.15

0.39 ± 0.15

0.003

Final Infarct Size, g

13 ± 9

17 ± 14

0.11


Differences in salvage index and the ratio of infarct size to AAR were apparent regardless of whether the infarct location was anterior or nonanterior, though exenatide’s effect was more pronounced among patients with anterior infarcts.

However, the benefits of exenatide did not extend to 3-month LVEF, which was equivalent between the exenatide and placebo groups. And in an intention-to-treat analysis, peak troponin T levels were similar for both arms, as were 30-day clinical outcomes.

Promising, But Clinical Value Remains to Be Seen

When asked by TCTMD whether the evidence backing exenatide is persuasive despite the drug’s failure to affect clinical outcomes, Dr. Lønborg made no promises.

“Myocardial salvage index has been related to outcome in STEMI patients,” he said in an e-mail communication. “It is, however, not possible to say anything about whether the cardioprotection by exenatide observed in our study will translate into improved clinical outcome. A large-scale clinical study is warranted in order to address the question.” Planning for such a study is underway, he noted.

Other issues to be resolved are the optimal dose and administration route. As such, “the present study should be considered as proof of concept,” Dr. Lønborg cautioned.

According to the paper, exenatide’s mechanism also needs clarification. The drug, “acting on GLP-1 receptors, may exert its cardioprotective actions through a number of pathways encompassing metabolic, contractility, and antiapoptotic effects,” the investigators write.

Regardless, the treatment would be easy to integrate into clinical practice, Dr. Lønborg confirmed. “Exenatide administration was without any interactions, side effects, or complications,” he reported. “The drug was handled by a nurse, which allowed the PCI operator to be focused on the patients. Thus, the procedure was not delayed by exenatide administration.”

Other Options Still Being Explored

Dr. Lønborg mentioned other possibilities for cardioprotection, including ischemic postconditioning and remote ischemic conditioning, as well as cyclosporine, an immunosuppressant drug given transplant patients.

The field is moving toward a pharmacologic approach, he said, because postconditioning “is hampered by the introduction of thrombus aspiration in STEMI patients. Cyclosporine is another interesting drug that has proven to be cardioprotective, but there [are] no comparative data between exenatide and cyclosporine. Remote conditioning and hypothermia are both promising methods, but whether the effect with exenatide is additive or competitive remains to be solved.”

Study Details

CMR imaging was initially performed during the index admission (≤ 1 week of PCI) in order to determine AAR, then repeated 90 ± 21 days later in order to measure final infarct size. Baseline characteristics including AAR were similar between the 2 groups, although anterior infarcts were slightly more common among the placebo patients.

Patients were pretreated with aspirin (300 mg orally or 500 mg IV), clopidogrel (600 mg orally), and heparin (10,000 U IV). Ischemic postconditioning was prohibited, and glycoprotein IIb/IIIa inhibitors were given when not contraindicated. After PCI, patients received 75 mg clopidogrel daily for 12 months and 75 mg aspirin indefinitely.

 


Source:
Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2011;Epub ahead of print.

 

 

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Disclosures
  • The study was supported by Danielsen’s Foundation, the Danish Heart Foundation, Danish National Research Foundation for Heart Arrhythmia, the Novo Nordisk Foundation, and Rigshospitalet’s Research Foundation.
  • Dr. Lønborg reports no relevant conflicts of interest.

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