6 Study (N) Azmus [77] (397) Boccalandro [81] (179) Briguori [82] (183) Kay [79] (200) Marenzi [78] (354) Webb [80] (487) Cardiology Research and Practice Table 4: Studies comparing acetylcysteine administration to control arm in patients undergoing coronary angiography. CIN deﬁnition ≥25% or ≥0.5 mg/dL, increase in SCr at 48 hours ≥0.5 mg/dL increase in SCr at 48 hours ≥25% increase in Scr at 48 hours ≥25% increase in SCr at 48 hours ≥25% increase in SCr at 72 hours >5 mL/min decrease in CrCl Acetylcysteine 7.1 13 65 4 15 versus 8a 23.3 Control 8.4 12 11 12 30 20.7 P value .62 .84 .22 .03 <.001 .57 CIN, contrast-induced nephropathy; CrCl. Creatinine clearance; IV, intravenous; SCr, serum creatinine, dd, double dose aThree arm study: standard dose versus high dose versus placebo. acetylcysteine was investigated by Baker et al. in their RAP- PID trial [84]. They randomised 80 patients with stable renal dysfunction undergoing cardiac catheterization/intervention to a rapid protocol of IV NAC (150 mg/kg over 30 minutes immediately before contrast followed by 50 mg/kg over 4 hours) or IV ﬂuid administration (1 mL/kg/h N/saline for 12 hours pre- and postcontrast) and followed them prospectively for development of Radiocontrast-induced nephropathy. Even though NAC infusion was ceased after the bolus in three patients (7%) due to ﬂushing, itching, or a transient rash, overall, the trial showed a signiﬁcantly lower incidence of CIN in treated patients as compared with controls (5% versus 21%; P 1/4 0.04). Therefore, IV NAC emerged as a reasonable option in all patients at risk of CIN before contrast exposure when time constraints preclude adequate oral prophylaxis, provided that the patient is able to tolerate this degree of volume loading [84]. A meta-analysis of twenty trials involving 2195 patients showed summary risk ratio for contrast-related nephropathy to be 0.73 (95% conﬁdence interval: 0.52 to 1.0; P = .08), a nonsigniﬁcant trend towards beneﬁt in patients treated with acetylcysteine [85]. Meta-analyses generally conclude that there may be some beneﬁt of NAC in reducing CIN [85, 86]. These trials were, however, very heterogeneous with inconsistent results. High-quality, large clinical trials that are needed before acetylcysteine use in this indication can be recommended universally. Moreover, recent studies have assessed combined eﬃcacy of two most important preventive interventions, use of NAC and bicarbonate [62, 63]. These included the REMEDIAL trial that showed the strategy of volume supplementation by sodium bicarbonate plus NAC to be superior to the combination of normal saline with NAC alone or with the addition of ascorbic acid in preventing CIN in patients at medium-to-high risk [62]. However, Maioli et al. had contradicting results in their prospective single center study including 502 patients with renal dysfunction with no advantage of NAC and Sodium Bicarbonate to NAC and Saline administration [87]. 8.3. Statins. Statins have also been studied as potential agents to prevent CIN in patients undergoing PCI, primarily by means of their beneﬁcial eﬀects on endothelial function and oxidative stress. This is very promising as most patients undergoing PCI are already on this class of drugs. Patti et al. showed that Statin-treated patients had a signiﬁcantly lower incidence of CIN (3% versus 27%, P < .0001; 90% risk decrease) and had better postprocedural creatinine clearance (80 ± 20 versus 65 ± 16 mL/min, P < .0001). Beneﬁt of statin before treatment was observed in all subgroups, except in patients with a preexisting creatinine clearance <40 mL/min [88]. Similar results were obtained in two other large retrospective studies [89, 90]. However, in the prospective, randomized, double-blind, placebo-controlled, 2-center PROMISS trial, involving 247 consecutive patients, Simvastatin pretreatment for short term at high dose did not prevent renal function deterioration after administration of contrast medium in patients with baseline renal insuﬃciency undergoing coronary angiography. Another prospective, randomized, placebo control trial, involving 304 patients with baseline Chronic Kidney Disease, did not demonstrate any additional beneﬁt of 80 mg Atorvastatin pretreatment for the prevention of CIN in these patients [91]. However, a prospective randomized trial showed favourable results while using high dose Simvastatin (80 mg) pretreatment instead of low dose (20 mg) to prevent CIN [92]. Overall, strong evidence is not present to support the use of statins, especially in patients where it is not otherwise indicated. 8.4. Other Interventions. Numerous other interventions have been studied to assess their eﬃcacy in preventing CIN. Over- all, results have either been ambiguous or unsatisfactory. A list of these potential management strategies and the existing data is summarized in Table 5. 9. Gadolinium Gadolinium is often used as an alternative to iodinated contrast in patients at increased risk of CIN. Overall, the trials show conﬂicting results about whether gadolinium is better than iodinated contrast in its risk of CIN (Table 6). The safety of gadolinium in patients at increased risk of CIN has not been established yet. In their systemic review of 17 studies, Boyden et al. reported both favourable and negative results with regard to the association of gadolinium and CIN. The diﬀerences in the results appeared to be dose related. When gadolinium was used in doses of 0.4 mmol/kg or higher, there appeared to be an increased incidence of ARF particularly in patients with preexisting renal insuﬃciency [116]. Furthermore, the risk of precipitating