induced nephropathy %=percent; CI=confidence interval; N=sample size; NAC=N-acetylcysteine; NaHCO3=sodium bicarbonate; p=p-value; RR=risk ratio 32 Table 5. Summary of the strength of evidence: N-acetylcysteine plus IV saline versus sodium bicarbonate Outcome Study Design: No. Studies (N) Study Limitations Directness Consistency Precision Strength of Evidence Summary of Key Outcomes Development of CIN, short-term RCT: 7 (930) Medium Direct Inconsistent Imprecise Insufficient Insufficient strength of evidence to determine whether NAC plus IV saline differs from IV sodium bicarbonate in preventing CIN Need for RRT RCT: 4 (710) Medium Direct Consistent Imprecise Insufficient Insufficient strength of evidence to determine whether NAC plus IV saline differs from IV sodium bicarbonate in preventing the need for RRT Cardiac events RCT: 3 (613) Medium Direct Consistent Imprecise Insufficient Insufficient strength of evidence to determine whether NAC plus IV saline differs from IV sodium bicarbonate in preventing cardiac events Mortality RCT: 2 (442) Medium Direct Consistent Imprecise Insufficient Insufficient strength of evidence to determine whether NAC plus IV saline differs from IV sodium bicarbonate in preventing mortality CIN=contrast-induced nephropathy; IV=IV; N=sample size; RCT=randomized controlled trial; RRT=renal replacement therapy 33 Statins In addition to decreasing low density lipoprotein cholesterol, statins have cholesterolindependent functionalities that play a growing role in various clinical contexts, including the prevention of both myocardial damage during percutaneous coronary intervention134 and atrial fibrillation after cardiac surgery.135 The proposed mechanism related to the prevention of CIN is that statins act as stabilizers of the endothelium and as free radical scavengers in a model of ischemic nephropathy.136 Given the demonstrated pleiotropic nature of statins in clinical settings, it is important to evaluate the effect of statins on CIN as well as their effects on other outcomes. Study Characteristics Our search identified 19 RCTs137-150 and one observational study on statins (Appendix E, Evidence Tables E-1, E-3, E-19).151 The 19 RCTs included 10,574 participants. Eight studies compared statins with placebo,138,139,144,145,152-155 one compared statin plus N-acetylcysteine plus sodium bicarbonate with N-acetylcysteine plus sodium bicarbonate,137 and four compared statin plus N-acetylcysteine plus saline with N-acetylcysteine plus saline.141,142,146,156 The remainder of the studies compared statin with statin,143,148,149 statin plus saline with saline and chronic statin plus saline,140 low-dose statin plus probucol with high-dose statin plus probucol,150 and statin to statin plus probucol147. Contrast media used included iodixanol,137,142-146 iopromide,138,148 iobitridol,139 iohexol,140,143 and iopamidol.141,147,150 Contrast media were administered intraarterially in all studies. These studies were completed between 1997 and 2015 and were conducted in Italyand Egypt.156 In all of the RCTs, the mean age of patients ranged from 54 to 76 years. The percentage of patients with chronic kidney disease at baseline ranged from 4 percent to 100 percent and the percent of patients with diabetes mellitus ranged from 15 percent to 100 percent). The observational study,151 with a study population of 28,871, compared statin therapy prior to the procedure with the absence of statin therapy. The contrast media used were not specified but all were administered intra-arterially. This study was completed between 1997 and 2003 and was conducted in the United States. In this study, the mean age of patients was 64. The percentage of patients with chronic kidney disease was not specified, while the percentage of patients with diabetes mellitus was 30 percent . Contrast-Induced Nephropathy We conducted two separate meta-analyses on the studies of statins to reduce the incidence of CIN in patients receiving intra-arterial contrast. One included eight studies on statin-naïve patients that compared statin plus IV saline with IV saline alone. The other included five studies: four compared statins plus N-acetylcysteine plus IV saline with Nacetylcysteine plus IV saline, and one compared statins plus N-acetylcysteine plus IV sodium bicarbonate with N-acetylcysteine plus IV sodium bicarbonate.137 The remaining six studies were not included in the meta-analyses; they either included comparisons that were not similar enough to analyze143,147-150 or did not include a CIN outcome.140(Appendix E, Evidence Table E-20). When evaluating the efficacy of prophylactic statin administration compared with IV fluids alone in the prevention of CIN, four studies138,139,145,154 found both a statistically significant and 34 clinically important reduction in CIN (above our 25% threshold for a minimally important difference) in the intervention arm. One study found a borderline clinically important difference.144 Three studies did not show either a clinically or a statistically significant reduction.