Chicago, IL - Results from a Japanese study presented today at the American Heart Association 2006 Scientific Sessions showed that carperitide, a recombinant form of human atrial natriuretic peptide (ANP), reduced infarct size and increased ejection fraction in patients with acute MI undergoing PCI [1]. In addition to reducing infarct size, investigators report that carperitide decreased cardiovascular death and hospitalizations for heart failure.

"Reduction of infarct size is kind of a dream for cardiologists because there are currently no drugs that reduce it," Dr Masafumi Kitakaze (National Cardiovascular Center, Suita, Japan), lead investigator of the Japan Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Damage by ANP or Nicorandil (J-WIND) study, said during a briefing for the media. Kitakaze said the reduction in infarct size and the increase in ejection fraction translated into clinical benefit by decreasing cardiac death and heart-failure hospitalizations and suggested the findings could alter the current treatment of acute MI.

Dr Robert Harrington (Duke University Medical Center, Durham, NC), who commented on the study during the late-breaking clinical-trials session, cautioned that the results must be verified in larger clinical trials, especially the way improvements in infarct size and ejection fraction translate into clinical outcomes. Harrington pointed out that the scientific literature is filled with promising adjunctive therapies that have been tested, most of which have proven to have limited clinical benefit.

"Despite great biological belief and promise in preclinical work that suggested there was upward of a 50% reduction in infarct size in animal models, and then in early human studies, absolutely no benefit in clinical trials enrolling more than 100 000 patients of these agents has ever been seen," said Harrington.

Testing the benefits of carperitide and nicorandil

During the morning briefing, Kitakaze said that human ANP is currently used in Japan to treat heart failure. The drug possesses potent diuretic, natriuretic, and vasodilatory activity and is known to inhibit the renin-aldosterone and sympathetic nervous systems. The J-WIND study was a randomized, prospective, placebo-controlled trial enrolling 1216 patients at 65 medical centers in Japan. Investigators sought to test human ANP and nicorandil (a potassium-channel activator used in the treatment of angina) as possible adjuncts to therapy in ST-segment-elevation myocardial infarction (STEMI) patients undergoing PCI, evaluating both agents separately and comparing them with placebo. Patients treated with carperitide received an infusion of 0.025 µg/kg per minute for three days. Those treated with nicorandil received an initial bolus followed by a 1.67-µg/kg-per-minute infusion for 24 hours. The primary end points were infarct size (estimated by the area under the curve of creatine kinase) and chronic left ventricular function (assessed by left ventriculography).

Investigators report that treatment with carperitide decreased infarct size 14.7%, compared with patients treated with placebo. Ejection fraction among those treated with carperitide was also positively affected, increasing 5.1% compared with placebo-treated controls. Nicorandil, on the other hand, did not affect infarct size or left ventricular ejection fraction.

Presenting data on secondary end points, Kitakaze noted that reperfusion injury was significantly lower (by 25.6%) than in controls; nicorandil had no effect on this end point. Overall, there was no reduction with either agent on the composite end point of death, acute coronary syndrome, rehospitalization for heart failure, or revascularization, although carperitide significantly reduced (by 73.3%) the incidence of cardiac death and rehospitalization for heart failure. In a small subset of patients treated with nicorandil during the chronic phase of treatment, the drug improved left ventricular ejection fraction and resulted in less revascularization of nonculprit lesions, suggesting that both drugs could be used for acute and delayed left ventricular salvage.

"ANP is able to reduce infarct size and improve ejection fraction [and is] followed by improvements in some cardiovascular events," Kitakaze told heartwire. "ANP is definitely good for patients with acute myocardial infarction. It does not affect the coronary artery, nor does it decrease the incidence of revascularization of nonculprit lesions. But when you administer nicorandil over two or three years, it appears to reduce the incidence of PCI. It might be possible that it is beneficial to administer nicorandil or ANP, both early, continuing nicorandil longer term."

Clinical benefit and infarct size

Commenting on the findings, Harrington praised the investigators for tackling the issue, noting that death and heart failure remain one of the current limitations in the treatment of STEMI. However, in interpreting these data, Harrington said that there were a variety of techniques to assess therapeutic benefit in STEMI treatment—angiography, continuous ST monitoring, various cardiac markers, SPECT imaging, and MRI—that were not used in this study, making it difficult to assess the true benefit of carperitide.

Harrington commented that the best way to make a "difference in myocardial infarction is to prevent [it] from occurring" through the management of common cardiovascular risk factors. As shown in the INTERHEART study, previously reported by heartwire, nearly all of the population-attributable risk for first-time MI is contained in nine common risk factors, including smoking, obesity, diabetes, and hypertension. Changes in the delivery of care, by ensuring more patients get to the catheterization laboratory in a timely manner, are also important. Harrington hopes that other agents coming along at the molecular level will be able to target problems in the microcirculation and assist in the issue of reperfusion injury, as well as restore function and potentially promote cell growth.