ROME – Early administration of high-dose N-acetylcysteine and low-dose glyceryl trinitrate in ST-segment elevation acute myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) achieved a 30% reduction in myocardial infarct size, compared with placebo in a randomized, double-blind, multicenter clinical trial, Sivabaskari Pasupathy reported at the annual congress of the European Society of Cardiology.

The adjunctive regimen also resulted in a doubling of myocardial salvage, the secondary endpoint in the NACIAM (N-acetylcysteine in acute myocardial infarction) trial, said Ms. Pasupathy of the University of Adelaide, Australia.

NACIAM, which she stressed was a pilot study, included 75 randomized STEMI patients with follow-up cardiac MRIs obtained at about 5 days post-PCI, most of whom had another MRI at about 8 months.

All participants received IV glycerol trinitrate at a rate of 25 mcg/min for 48 hours starting in the emergency department. Patients in the active treatment arm received IV N-acetylcysteine (NAC) at 20 mg/min for the first hour and 10 mg/min for the next 47 hours. Controls got placebo at 40 mL/hour for the first hour and 20 mL/hour thereafter.

Cardiac MRI at 5 days showed a myocardial infarct size of 16.5% in the control group and 11% with active treatment. This absolute 5.5% reduction in infarct size in NAC recipients was achieved despite no difference between the two groups in myocardial area at risk by MRI, which was roughly 24%. Nor did the groups differ in rates of anterior MI or microvascular obstruction. The myocardial salvage rate was 60% in the NAC group and just 27% in controls.

Creatine kinase levels, measured hourly during the first 24 hours of hospitalization, were consistently lower in the NAC group, although the difference didn’t reach statistical significance.

In-hospital rates of hypotension, bleeding, or renal dysfunction were similar in the two study arms. However, at 2 years of follow-up the composite rate of death or cardiac rehospitalization was 27% in the control group, compared with 6% in patients who got NAC.

A key to the demonstrable success of the adjunctive NAC/nitrate treatment strategy was that it began early, in the emergency department, when patients initially presented with STEMI. The mean total ischemia time for study participants was 2.4 hours, and the shorter the duration of ischemia, the larger the reduction seen in infarct size, according to Ms. Pasupathy.

The rationale for this therapy is that NAC is thought to reduce oxidative stress by scavenging reactive oxygen species and inhibiting their release, thereby minimizing reperfusion injury. The Australian investigators also believe that NAC potentiates the effects of glycerol trinitrate in improving tissue reperfusion through enhanced vasodilation, inhibition of platelet aggregation, and dampening of inflammation. A reduction in reperfusion injury accompanied by increased tissue reperfusion could result in reduced infarct size, she explained.

John F. Beltrame, MD, lead investigator in the NACIAM study, noted that infarct size and myocardial salvage are surrogate endpoints. The investigators plan to conduct a larger trial with hard clinical outcomes.

“The key thing we need to do before we start using this in widespread fashion and changing practice guidelines is to look at clinical endpoints,” said Dr. Beltrame, professor of medicine at the University of Adelaide.

Nonetheless, he added, this therapy is given routinely in the setting of primary PCI for STEMI where he practices. That has been the case for 20 years because he and colleagues in his department did some of the early studies suggesting NAC was beneficial.

“Hospitals have different practices, and this is one of our particular practices,” the cardiologist said.

It all sounded pretty good to Jorge A. Belardi, MD, who co-chaired a press conference devoted to the NACIAM trial and other hotline presentations.

“It’s a very benign combination of medicines to use. So why not use it? We already use it to prevent contrast nephropathy. And there are no contraindications, to my knowledge,” said Dr. Belardi, director of the department of cardiology at the Buenos Aires Cardiovascular Institute.

Michel Ovize, MD, of the University of Lyon (France), the formal discussant designated for NACIAM, took a more flinty eyed view, noting that the study was small and previous studies of NAC during the past 2 decades have yielded conflicting results.

Ms. Pasupathy responded that a likely explanation for the disparate results is the fact that other investigators didn’t start NAC at the soonest possible time in the ED.

The NACIAM trial was funded by the Australian National Heart Foundation. Ms. Pasupathy and Dr. Beltrame reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

Novel treatment strategy to reduce infarct size in STEMI