N-Acetylcysteine for Cardiac Protection During Coronary Artery Reperfusion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Coronary artery reperfusion is essential for the management of symptoms in the patients with myocardial ischemia. However, the benefit of reperfusion often comes at an expense of paradoxical injury, which contributes to the adverse events, and sometimes heart failure. Reperfusion is known to increase the production of reactive oxygen species (ROS). We address whether N-acetylcysteine (NAC) reduces the ROS and alleviates reperfusion injury by improving the clinical outcomes. A literature search for the randomized controlled trials (RCTs) was carried out in the five biomedical databases for testing the effects of NAC in patients undergoing coronary artery reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft. Of 787 publications reviewed, 28 RCTs were identified, with a summary of 2,174 patients. A meta-analysis using the random effects model indicated that NAC administration during or prior to the reperfusion procedures resulted in a trend toward a reduction in the level of serum cardiac troponin (cTn) [95% CI, standardized mean difference (SMD) -0.80 (-1.75; 0.15), p = 0.088, n = 262 for control, 277 for NAC group], and in the incidence of postoperative atrial fibrillation [95% CI, relative risk (RR) 0.57 (0.30; 1.06), p = 0.071, n = 484 for control, 490 for NAC group]. The left ventricular ejection fraction or the measures of length of stay in intensive care unit (ICU) or in hospital displayed a positive trend that was not statistically significant. Among the nine trials that measured ROS, seven showed a correlation between the reduction of lipid peroxidation and improved clinical outcomes. These lines of evidence support the potential benefit of NAC as an adjuvant therapy for cardiac protection against reperfusion injury.

Keywords: N-acetylcysteine; acute coronary syndrome; antioxidants; atrial fibrillation; coronary artery bypass; percutaneous coronary intervention; reactive oxygen species; stable angina.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. The numbers document the literature search results.

Figure 2

Risk of bias of 28 included trials. The plus sign in green (+) shows “low risk” for bias and the question or exclamation mark in yellow (?/!) shows “some concerns” for bias. None of the trials show high risk for bias per RoB2 analyses.

Figure 3

Forest plots of random effects model meta-analysis with 95% confidence interval (CI) comparing NAcetylcysteine (NAC) group vs. control group. The plots are showing standard mean difference (SMD) for continuous variables along with standard deviations (SD) or risk ratio (RR) for binary variables along with events for (A) serum troponin levels at 24 h after procedure. Shafiei et al. (25) measured cTnI in ng/ml, Nozari et al. (33) measured high sensitivity TnT (hs-TnT) in ng/dl, Talasaz et al. (32, 34) measured hs-TnT (unit not available, inquires not answered), Kurian et al. (40) measured cTnI in ng/ml, Karahan et al. (49) measured cTnT in ng/ml, Prabhu et al. (42) measured cTnI in ng/ml, Peker et al. (46) measured cTnT in ng/ml, and El-Hamamsy et al. (47) measured cTnT in ng/l (per response to inquires). (B) Serum CK-MB levels, (C) left ventricular ejection fraction (LVEF), (D) post-operative atrial fibrillation (POAF), (E) length of stay (LOS) in intensive care unit (ICU), and (F) LOS in hospital.