N-Acetylcysteine: The Next Best Thing for Cardiovascular Interventions and Surgery?

Abstract

True genius resides in the capacity for evaluation of uncertain, hazardous, and conflicting information Attributed to Winston Churchill T he quest for simple, ingenious, safe, cheap, and yet effective treatments to improve outcomes for patients undergoing invasive cardiovascular procedures continues. 1 Clearly, we should always be skeptical inasmuch because, to openly quote John Ioannidis, 2 most published research findings are false or at risk of being based on type I error. The case of acetylcysteine, also labelled N-acetyl-cysteine (NAC), is a uniquely informative example of the risk of trusting potentially spurious findings at face value (Fig. 1). 3,4 For more than 20 years, clinical researchers have reported favorable trial data on the benefits of using NAC to prevent nephropathy following contrast media administration. 5,6 Although the evidence base on its comparative effectiveness for this clinical indication has substantially expanded on an almost yearly basis, the jury is still out. 6 Indeed, the relevant evidence base continues to be undermined by relatively small-sized trials, with imperfect methodological designs. 3,6 Yet, this intervention could still be considered in selected cases given its substantial safety and limited cost. 7 The rosy prophecy regarding NAC may have become even rosier today, thanks to the comprehensive meta-analysis by Gakuba and colleagues, 8 who considered the use of NAC not only for cardiac catheterization procedures but also for cardiac surgery operations. They found intriguingly that across 19 trials published between 2003 and 2018, and including 3728 patients, administration of NAC was associated with improved inhospital survival rates, as well as fewer cases of contrast-associated nephropathy. Intriguingly, there was evidence for a dose-response relationship, in the sense that higher NAC doses were associated with better outcomes. Apparently, inconsistency, heterogeneity, and small study effects (which include publication bias) were not substantial.Indeed, can we trust these results? Should we apply them in our clinical practice? Before formally addressing these questions, it is useful to remind us that NAC is a prodrug for L-cysteine, which is a precursor of the antioxidant glutathione, thus contributing to the neutralization of free radicals and reduction of oxidative stress. Although it is commonly used in case of acetaminophen/paracetamol overdose or as a mucolytic, other applications are less established. 9 Indeed, plausible pathophysiologic mechanisms underpinning the benefits of NAC in patients undergoing cardiac procedures might be, on top of antioxidant effects, antiinflammatory actions, antiplatelet activity, and vasodilation. 10 Yet, pathophysiologic premises may often lead to negative trial results, as indeed, there is often a wide translational gap, as well epitomized several years ago by the landmark Cardiac Arrhythmia Suppression Trial