N- acetylcysteine and Intravenous Sodium Bicarbonate Infusion in the Prevention of Contrast Associated Kidney Injury: A Cautionary Tale Strategies to Reduce Acute Kidney Injury and Improve Clinical Outcomes Following Percutaneous Coronary Intervention: A Subgroup Analysis of the PRESERVE Trial

A study published in JACC Cardiovascular Interventions has shown that among patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI), there was no benefit of IV sodium bicarbonate over IV sodium chloride or of acetylcysteine over placebo for the prevention of contrast-associated acute kidney injury (CAAKI) or intermediate-term adverse outcomes.

It was a known fact that periprocedural administration of acetylcysteine and IV sodium bicarbonate was commonly used to prevent CAAKI in clinical practice. Although N- acetylcysteine and intravenous sodium bicarbonate infusion are 2 treatments that have been extensively studied for contrast-induced acute kidney injury (CI-AKI) prevention, the published research has evolved to confirm that these therapies are ineffective, a process that was slow and unnecessarily confusing. As data were conflicting on the optimal strategy to reduce CAAKI and related complications after percutaneous coronary intervention (PCI), Dr. Santiago Garcia,  Minneapolis Heart Institute, Minnesota and his colleagues aimed to compare intravenous (IV) sodium bicarbonate with IV sodium chloride and oral acetylcysteine with placebo for the prevention of contrast-associated acute kidney injury (CAAKI) and intermediate-term adverse outcomes. The PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial used a 2 by 2 factorial design to randomize 5,177 patients with stage III or IV chronic kidney disease undergoing angiography to IV 1.26% sodium bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or placebo. A subgroup analysis was conducted of the efficacy of these interventions in patients who underwent PCI during the study angiographic examination. The primary endpoint was a composite of death, need for dialysis, or persistent kidney impairment at 90 days; CAAKI was a secondary endpoint.

The investigators found that a total of 1,161 PRESERVE patients (mean age 69) underwent PCI. The median estimated glomerular filtration rate was 50.7 ml/min/1.73 m2 (interquartile range: 41.7 to 60.1 ml/min/1.73 m2), and 952 patients (82%) had diabetes mellitus. The primary endpoint occurred in 15 of 568 patients (2.6%) in the IV sodium bicarbonate group and 24 of 593 patients (4.0%) in the IV sodium chloride group (odds ratio: 0.64; 95% confidence interval: 0.33 to 1.24; p for interaction ¼ 0.41) and in 23 of 598 patients (3.8%) in the acetylcysteine group and 16 of 563 patients (2.8%) in the placebo group (odds ratio: 1.37; 95% confidence interval: 0.71 to 2.62; p for interaction ¼ 0.29). There were no significant between-group differences in the rates of CAAKI.

Therefore, in the present subgroup analysis of more than 1,150 patients with chronic kidney disease undergoing PCI, the investigators concluded that neither IV sodium bicarbonate (compared with IV sodium chloride) nor oral acetylcysteine (compared with placebo) was superior in reducing serious adverse 90-day events or CAAKI. Speaking of the next step, the investigators claimed, “Our results support a discontinuation in the use of these interventions in the catheterization laboratory. Intravascular volume expansion with isotonic sodium chloride should be considered the standard of care for the prevention of adverse renal outcomes.” In an accompanying editorial titled ‘The Arc of the Research Universe Is Long, But it Bends Toward the Truth,’ Dr. Somjot S. Brar remarked, “The PRESERVE trial was born out of considerable confusion in published medical research regarding the effectiveness of sodium bicarbonate and N-acetylcysteine. Much of the purported benefit was reinforced by the publication of serial meta-analyses that included numerous small trials, emphasized statistically significant summary estimates, and often downplayed or disregarded the observed high levels of heterogeneity among trials. Careful assessment of heterogeneity should provide greater insight into the results, increase the scientific value of the report, and lessen the likelihood of erroneous conclusions. There is more to a meta-analysis than simply producing a single estimate of effect. The PRESERVE trial closes the lengthy chapter on N-acetylcysteine and sodium bicarbonate for CI-AKI prevention almost 2 decades after it began. The arc of the research universe can be long, but it bends toward the truth.”