Response by Pasupathy et al to Letters Regarding Article, “Early Use of N-acetylcysteine (NAC) With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Reduces Myocardial Infarct Size (The NACIAM Trial [ <i>N</i> -Acetylcysteine in Acute Myocardial Infarction])”
Authors: Sivabaskari Pasupathy, Rosanna Tavella, John F. Beltrame
Journal: Circulation (2018)

In Response:We appreciate the correspondence concerning the NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction), 1 which focused on the study analytical methods and potential mechanisms contributing to the benefits of N-acetylcysteine (NAC)/ nitroglycerin use in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.Ye et al commented on the study analytical methods, raising concerns as to whether (1) propensity score matching between study groups is required, (2) repeated measures ANOVA should be undertaken in the chest pain and creatine kinase (CK) analyses, and (3) a curvilinear relationship exists between infarct size and the predictive clinical variables so that a generalized linear model analysis would be more appropriate.First, concerning study group matching, the groups were balanced in this randomized controlled trial of consecutive eligible patients so that propensity analysis is not required, particularly in light of the limitations of this analytic approach. 2Second, repeated measures ANOVA is appropriate and was conducted for the chest pain analysis, but the CK analysis required a standard trapezoidal method 3 because the area under the curve was assessed.Third, analysis of the raw data demonstrates a linear and not a curvilinear relationship between infarct size and clinical predictors so that the analysis performed was appropriate.The more intriguing question arising from the correspondence is the mechanisms responsible for the observed clinical benefits.Potential mechanisms responsible for the reduced infarct size and preserved left ventricular function include (1) prompt alleviation of myocardial ischemia, (2) reduced reperfusion injury, and (3) improved left ventricular modeling.Unfortunately, the study design of the NA-CIAM trial does not provide conclusive evidence as to the relative contribution of these mechanisms.Thus, hypotheses and prompt future mechanistic studies should be considered.Mansour et al explored whether the ability of NAC to enhance thrombolysis by disrupting von Willebrand multimers could play a role in rapidly restoring arterial patency and thereby promptly alleviate myocardial ischemia.However, they concluded that the NAC concentrations required for this effect would not have been achieved during the early NAC/nitroglycerin treatment.Consistent with this conclusion, arterial patency was similar between the NACIAM trial study groups, although the trial was not powered to examine infarct-related artery patency.Whether NAC improves residual microcirculatory ischemia by potentiating the antiplatelet and vasodilating effects of nitroglycerin after the restoration of coronary artery patency with percutaneous coronary intervention is open to speculation.This possible benefit in combination with NAC's free radical scavenging properties would reduce reperfusion injury and thus minimize infarct size.