August 28, 2016

ROME, ITALY — The addition of intravenous N-acetylcysteine (NAC) to IV glyceryl trinitrate (GTN) significantly reduced infarct size by approximately one-third in STEMI patients undergoing PCI, in the NACIAM trial[1].

"Any intervention that actually reduces myocardial infarct size by approximately a third might reasonably be expected to substantially improve long-term outcomes," noted Sivabaskari Pasupathy (University of Adelaide, Australia), who presented the findings today at the European Society of Cardiology (ESC) 2016 Congress.

Principal investigator of the study, Dr John Beltrame (University of Adelaide), explained that small studies going back 20 years in their center have suggested GTN and NAC may reduce infarct size, and these drugs are used routinely in their practice now. "But this is not the case elsewhere, and we wanted to look at this again."

Sivabaskari Pasupathy

"The hypothesis is that NAC might reduce infarct size, either by potentiating the effects of GTN or via scavenging of reactive oxygen species," Pasupathy said.

In the study, 112 STEMI patients (mean age 64 years) within 12 hours of symptom onset from three Australian hospitals all received GTN and were randomized to receive either high-dose (15 g/24 hours) NAC or placebo, both drugs delivered intravenously over 48 hours and started in the emergency department.

Cardiac magnetic resonance (CMR) imaging performed within 1 week and again 3 months post-MI showed that patients who received NAC had reductions in infarct size of 33% and 50%, respectively, compared with placebo (P=0.02 for both). There was a similar but not significant trend toward reduction in creatine kinase (CK) release.

In addition, myocardial salvage, measured at 1 week, was approximately doubled in patients who received NAC (60% vs 27%, P<0.001), and there was also evidence of accelerated tissue reperfusion and hypochlorous acid "scavenging" in these patients, Pasupathy reported.

Most benefit occurred in patients treated early—within 3 hours of symptom onset.

Over 2 years of follow-up, the combination of cardiac readmissions and deaths was less frequent in NAC-treated (three vs 16 patients, P<0.01).

Safety end points, including hypotension, bleeding, and contrast-induced nephropathy, were similar in both groups.

"Intravenous NAC administration was associated with more rapid chest-pain resolution, improved myocardial salvage, a favorable in-hospital safety profile, sustained infarct size reduction at 3 months post-STEMI, and promising clinical outcomes at 2 years," concluded Pasupathy. "While the results of this study are encouraging, we would prefer to regard NACIAM as the precursor of a follow-up study, sized for clinical end points," she concluded.

Benign, Cheap Drugs

Commenting for heartwire from Medscape, cochair of the ESC press conference at which the study was discussed, Dr Stephan Gielan (Detmold Hospital, Germany), said: "If we can increase myocardial salvage by around 40% to 50%, as suggested here, this will be of enormous benefit to the patient. But I would be a bit cautious until we have clinical outcome data from a larger study. And it may be difficult to get funding for such a study, as both GTN and NAC are generic."

He added: "But it would be great to have cheap drugs like these that actually work. Both these agents have been around a long time and are very benign—hardly any side effects—so there is no harm and potentially a substantial benefit; I can understand why they are using them in Adelaide."

Discussant of the study trial at the hot-line session, Dr Michel Ovize (University of Lyon, France), who has previously led a similar studies with cyclosporine, noted that although several phase 2 studies with NAC have been performed in STEMI they have shown conflicting results.

Ovize pointed out some potential limitations of the NACIAM study—including a relatively low-risk population, with some non-LAD MI patients and a substantial proportion already having TIMI 2-3 flow at time of angiography. "This would suggest the study may have missed some of the benefit of the drug—which is aimed at reducing reperfusion injury—by giving it after reperfusion has taken place."

But Pasupathy noted that more patients in the NAC arm had an open artery at angiography, suggesting that NAC may aid reperfusion as well as reduce reperfusion injury, so giving it before reperfusion may be beneficial.

Ovize also noted that while infarct size was reduced on MRI, it wasn't reduced by CK release, and there was no improvement in LV function. "I would suggest we need more mechanistic and phase 2 studies before moving to phase 3," he said.

Expanding on the time of administration and possible effect on enhancing reperfusion at the press conference, Beltrame noted that the previous studies with cyclosporine also suggested a reduction in infarct size, but this did not translate into a clinical benefit in a larger trial.

He pointed out that cyclosporine was given later—at the time of PCI—and only to patients who had an occluded artery at that time, as an attempt to reduce reperfusion injury. "But in the NACIAM study, GTN and NAC were given in the emergency room and one-third of patients had an open artery at the time of angiography, so they wouldn't have gotten into the cyclosporine trial. We believe GTN and NAC might help open up the artery to begin with and also reduce reperfusion injury too."

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