renal replacement therapy, only seven reported p-values and one reported a statistically insignificant, and clinically non-significant difference between groups (risk ratio: 0.87; 95% CI: 0.17-4.35).69 The remaining studies reporting on the need for renal replacement therapy did not report statistics. One study, Marenzi et al.,2006,81 reported a statistically significant and clinically important difference in mortality between the placebo arm and the N-acetylcysteine arms, with more in-hospital deaths in the placebo arm (placebo: 13/119 (11%); standard dose N-acetylcysteine: 5/115 (4%); high-dose Nacetylcysteine: 3/118 (3%), p=0.007).81 Two studies reported significant findings for length of 18 hospitalization. Hsu et al., 200771 showed a statistically significant and clinically important reduction in length of hospitalization in the N-acetylcysteine arm (placebo: mean 8.1 days, standard deviation (SD) 4.1); low-dose N-acetylcysteine arm (mean 5.2 days, SD 1.5); p=0.04)).71 Kay et al., 200347 also showed a statistically significant reduction in length of hospitalization in the N-acetylcysteine arm, but the difference was not clinically important (placebo: mean 3.9 days, SD 2.0); low-dose N-acetylcysteine: mean 3.4 days, SD 0.9: p=0.02).47 No clinically important or statistically significant differences were reported for cardiac events. Overall, the strength of evidence was low that N-acetylcysteine plus IV saline did not differ from IV saline without N-acetylcysteine in the need for renal replacement therapy, cardiac events, or the length of hospitalization. (Table 3; Appendix E, Evidence Table E-8; see Appendix G for study limitations). Most of the studies addressing these outcomes had at least one important study limitation (frequently lacking documentation of allocation concealment or blinding of participants and personnel). The results generally were consistent in the direction of impact of N-acetylcysteine. However, the effect estimates were imprecise. The studies addressing mortality had insufficient strength of evidence to support a conclusion because they had important study limitations, with inconsistent and imprecise effect estimates. 19 Figure 3. Meta-analysis of high-dose* N-acetylcysteine plus IV saline versus IV saline with or without placebo for the prevention of contrast-induced nephropathy %=percent; 1/2NS=0.45% saline; CI=confidence interval; CIN=contrast induced nephropathy; DM=diabetes mellitus; ER=emergency room; IA=intra-arterial; IV=intravenous; N=sample size; NAC=N-acetylcysteine; NS=normal saline (0.9%); p=p-value; RR=risk ratio *High-dose N-acetylcysteine refers to studies that administered more than 1200mg N-acetylcysteine daily to participants. 20 Figure 4. Meta-analysis of low-dose* N-acetylcysteine plus IV saline versus IV saline with or without placebo for the prevention of contrast-induced nephropathy %=percent; 1/2NS=0.45% saline; ACS=acute coronary syndrome; CAD=coronary artery disease; CI=confidence interval; CIN=contrast induced nephropathy; CKD=chronic kidney disease; ER=emergency room; IA=intra-arterial; IV=intravenous; N=sample size; NAC=N-acetylcysteine; NS=normal saline (0.9%); p=p-value; RR=risk ratio *Low-dose N-acetylcysteine refers to studies that administered 1200mg or less of N-acetylcysteine daily to participants. 21 Figure 5. Meta-analysis of N-acetylcysteine plus IV saline versus IV saline with or without placebo for the prevention of contrast-induced nephropathy when low-osmolar contrast is used %=percent; CAD=coronary artery disease; CI=confidence interval; CIN=contrast induced nephropathy; CKD=chronic kidney disease; ER=emergency room; N=sample size; NAC=N-acetylcysteine; p=p-value; RR=risk ratio 22 Figure 6. Meta-analysis of N-acetylcysteine plus IV saline versus IV saline with or without placebo for the prevention of contrast-induced nephropathy when iso-osmolar contrast is used %=percent; CAD=coronary artery disease; CI=confidence interval; CIN=contrast induced nephropathy; DM=diabetes mellitus; N=sample size; NAC=N-acetylcysteine; p=p-value; RR=risk ratio; NS=normal saline (0.9%); 1/2NS=0.45% saline 23 Figure 7. Meta-analysis of oral and IV route of N-acetylcysteine plus IV saline versus IV saline with or without placebo for the prevention of contrast-induced nephropathy %=percent; ACS=acute coronary syndrome; CAD=coronary artery disease; CI=confidence interval; CIN=contrast induced nephropathy; DM=diabetes mellitus; ER=emergency room; IV/Oral=intravenous or oral NAC administration; IV=intravenous; N=sample size; NAC=N-acetylcysteine; p=p-value; RR=risk ratio 24 Table 3. Summary of the strength of evidence: N-acetylcysteine plus IV saline versus IV saline with or without placebo Outcome Study Design: No. Studies (N) Study Limitations Directness Consistency Precision Strength of Evidence Summary of Outcomes Development of CIN (high-dose NAC) RCT: 18 (4336) Medium Direct Inconsistent Precise Low Low strength of evidence that highdose NAC with IV saline has a small clinically unimportant benefit in preventing CIN compared with IV saline without NAC Development of CIN (low-dose NAC) RCT: 36 (5217) Medium Direct Inconsistent Precise Low Low strength of evidence that low-dose NAC with IV saline has a small clinically unimportant benefit in preventing CIN compared with IV saline without NAC Development of CIN (in patients