Preprocedural statin administration may reduce contrast-induced acute kidney injury (CI-AKI), but current evidence is controversial. Randomized controlled trials (RCTs) comparing preprocedural statin administration before coronary catheterization with standard strategies were searched in MEDLINE/PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, and ScienceDirect databases. The outcome of interest was the incidence of postprocedural CI-AKI. Prespecified subgroup analyses were performed according to baseline glomerular filtration rate (GFR), statin type, and N-acetylcysteine use. Eight RCTs were included for a total of 4,984 patients. The incidence of CI-AKI was 3.91% in the statin group (n = 2,480) and 6.98% in the control group (n = 2,504). In the pooled analysis using a random-effects model, patients receiving statins had 46% lower relative risk (RR) of CI-AKI compared with the control group (RR 0.54, 95% confidence interval [CI] 0.38 to 0.78, p = 0.001). A moderate degree of non-significant heterogeneity was present (I 2 = 41.9%, chi-square = 12.500, p = 0.099, τ² = 0.100). In the subanalysis based on GFR, the pooled RR indicated a persistent benefit with statins in patients with GFR <60 ml/min (RR 0.67, 95% CI 0.45 to 1.00, p = 0.050) and a highly significant benefit in patients with GFR ≥60 ml/min (RR 0.40, 95% CI 0.27 to 0.61, p <0.0001). Statin type and N-acetylcysteine or hydration did not significantly influence the results. In conclusion, preprocedural statin use leads to a significant reduction in the pooled RR of CI-AKI.
In the last years, several protocols have been applied for reducing contrast-induced acute kidney injury (CI-AKI), but there is still no agreement on the optimal prevention strategy. Current guidelines highly recommend periprocedural intravenous hydration, whereas the recommendation for adjunctive measures such as N-acetylcysteine (NAC) or sodium bicarbonate is low. Statins exert pleiotropic effects beyond being cholesterol-lowering drugs, influencing inflammation response, oxidative stress, endothelial function, plaque stability, thrombus formation, and apoptotic pathways. All these effects concur in decreasing the risk of cardiovascular disease events. Several randomized controlled trials (RCTs) and observational studies investigated the effectiveness of statin pretreatment in reducing the incidence of CI-AKI with mixed results. Therefore, we aimed at performing a comprehensive meta-analysis of RCTs evaluating the nephron-protective role of statins to assess whether their administration before coronary angiography or percutaneous coronary intervention (PCI) can reduce the incidence of CI-AKI in patients exposed to contrast media administration.
Methods
The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The MEDLINE/PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, and ScienceDirect electronic databases were searched with the following keywords: “statin,” “3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor,” “HMG-CoA,” “CI AKI,” “CI-AKI,” “contrast induced acute kidney injury,” “CIN,” “contrast induced nephropathy,” “contrast nephropathy,” “AKI,” “acute kidney injury,” “ARF,” “acute renal failure,” “contrast media,” and “contrast agent.” Tangential electronic examination of related reports using links to related references and extensive hand searches of bibliographies of relevant reviews were also performed. No language, filter, or publication date restrictions were applied. Only published reports were considered. The last search was performed on February 10, 2014. The retrieved items were first screened at the title and abstract levels by 2 investigators (DG and PA). Screened citations that were clearly not pertinent were discarded. The inclusion criteria were the following: (1) RCTs of patients who were statin-naïve or not who did not consume statins in the 30 days before coronary angiography or PCI; (2) control group consisting of patients who did not consume statins and received placebo or standard therapy, defined as saline solution or NAC and/or sodium bicarbonate (other drugs were excluded); (3) CI-AKI reported and defined as serum creatinine increase from baseline ≥25% or ≥0.5 mg/dl within the first 48 to 72 hours; and (4) studies investigating statin use in patients undergoing coronary angiography or PCI. Studies not satisfying the aforementioned criteria were excluded. Eligibility assessment and data extraction were performed by 2 investigators (DG and PA), and discordances were solved by consensus. Participants of any age, with or without chronic kidney disease, undergoing coronary angiography or PCI were considered. No statin type and dosage limitations were imposed. CI-AKI was prespecified as the outcome of interest. Planned subanalyses included stratification based on baseline renal function (glomerular filtration rate [GFR] <60 ml/min or ≥60 ml/min), statin type (lipophilic or hydrophilic), and type of adjunctive treatment (saline solution or NAC). Statistical analysis was performed using the Comprehensive Meta-Analysis (version 2.2.064; Biostat Inc., Englewood, New Jersey). A DerSimonian-Laird random-effects model was used. The primary end point measure was quantified and reported as pooled relative risk (RR) ratio with 95% confidence interval (CI). The influence of removal of 1 study each time on RR was measured to establish the impact of each individual trial on the pooled effect size. Additional analyses were performed to identify the relative weight of each trial and to describe the pooled RR trend over time. Heterogeneity was graded using the I 2 statistic with I 2 <25%, 25% to 50%, and I 2 >50% representing mild, moderate, and severe inconsistencies, respectively. The extent of publication bias was assessed by visual inspection of funnel plots. Additionally, Egger’s regression asymmetry test was performed to explore the potential publication bias and Orwin’s fail-safe N formula was used to evaluate whether the entire effect was a bias-driven artifact. To quantify the potential impact of bias on the pooled RR, Duval and Tweedie’s trim and fill method was used.
Results
The search strategy retrieved a total of 95 citations. After duplicates were removed, 46 reports remained. Of these, 38 were discarded after full text reading because they were not pertinent or did not meet the eligibility criteria ( Figure 1 ). A total of 8 RCTs investigating the effect of preprocedural statin intake in reducing CI-AKI in 4,984 patients were included. The main characteristics of the included RCTs are reported in Table 1 and Table 2 . All studies included patients with baseline renal impairment. The main results of the meta-analysis are illustrated in Figure 2 . In the forest plot each square indicates the effect of the corresponding study, while the pooled RR is visually quantified by the red diamond. The incidence of CI-AKI spanned from 3.0% to 16.1% across studies. In the largest study TRACK-D (Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes) the incidence of CI-AKI was 3.1%. Overall, the incidence of CI-AKI was 3.91% in the statin group (n = 2,480) and 6.98% in the control group (n = 2,504). Using a random-effects model, patients receiving statins had 46% lower RR of CI-AKI compared with the control group (RR 0.54, 95% CI 0.38 to 0.78, p = 0.001). A moderate degree of non-significant heterogeneity was present (I 2 = 41.9%). The relative weight of each study on the pooled RR was found acceptable ( Figure 2 ). Visual estimation of the funnel plot ( Figure 3 ) suggested a minimal asymmetry, which was quantified to be statistically non-significant by means of Egger’s regression intercept (−1.39, 95% confidence interval −1.08 to 3.86, t = 1.37, p = 0.218). Orwin’s fail-safe N was 205, suggesting that >200 studies with a mean RR of 1.0 would need to be added to the analysis before the cumulative effect become trivial (defined as RR = 0.98). Using a random-effects model, the Duval and Tweedie’s trim and fill method suggested no asymmetry on the left of the mean and 2 studies on the right of the mean, which, if trimmed, would change the RR from 0.53 to 0.66. The risk of bias was assessed according to the Cochrane recommendations and summarized in Figure 4 . The effect of removal of individual studies on the pooled RR using a random-effects model was assessed using a forest plot, showing that statin use was associated at each step with a significant reduction of CI-AKI risk ( Figure 5 ). A cumulative analysis was performed with studies organized in chronological order to describe the change of RR from the earliest to latest RCT ( Figure 6 ).
| Study Design | N | Age ∗ | Diabetes (%) | Baseline Renal Function | Presentation (%) | Contrast Agent Osmolarity | |||
|---|---|---|---|---|---|---|---|---|---|
| DB | OL | GFR (ml/min) | Creatinine (mg/ml) | ||||||
| PROMISS | + | – | 236 | 65 ± 9/66 ± 8 | 26 | ≤60 | ≥1.1 | — | Iso |
| Toso et al | + | – | 304 | 75 ± 8/76 ± 7 | 21 | <60 | — | Stable CAD | Iso |
| Özhan et al | – | + | 130 | 54 ± 10/55 ± 8 | 16 | >70 ∗ | <1.5 | — | Low |
| ARMYDA-CIN | + | – | 241 | 65 ± 11/66 ± 10 | 28 | — | <3 | NSTE-ACS | Low |
| Li et al | + | – | 161 | 66 ± 7/66 ± 7 | 28 | — | — | STEMI | Iso |
| NAPLES II | – | + | 410 | 70 ± 6/70 ± 8 | 41 | <60 ∗ | — | Stable CAD † | Iso |
| PRATO-ACS | – | + | 504 | 66 ± 12/66 ± 14 | 21 | — | <3 | NSTE-ACS | Iso |
| TRACK-D | – | + | 2998 | 61 ± 9/62 ± 9 | 100 | 30–90 ∗ | — | Stable CAD/NSTE-ACS | Iso |
† The presentation distribution is not described in the NAPLES II subanalysis investigating statins effects in CI-AKI prevention; however, the main analysis of the study presented a 97.6% prevalence of stable coronary ischemic disease in both groups.
| Statin Type | Statin Dose (mg) | Additive Treatment ∗ | CI-AKI Definition | Timepoint (hours) | |
|---|---|---|---|---|---|
| PROMISS | Simvastatin | 80 | NaCl | Cr ≥0.5 mg/dl or ≥25% | 48 |
| Toso et al | Atorvastatin | 80 | NAC | Cr ≥0.5 mg/dl and ≥25% | 120 |
| Özhan et al | Atorvastatin | 80 | NAC | Cr >0.5 mg/dl or >25% | 48 |
| ARMYDA-CIN | Atorvastatin | 40 | NaCl | Cr ≥0.5 mg/dl or >25% | 48 |
| Li et al | Atorvastatin | 80 | NaCl | Cr >0.5 mg/dl or >25% | 72 |
| NAPLES II | Atorvastatin | 80 | NAC + NaHCO 3 | Cr ≥0.5 mg/dl and ≥25% | 48 |
| PRATO-ACS | Rosuvastatin | 40 | NAC | Cr ≥0.5 mg/dl or ≥25% | 72 |
| TRACK-D | Rosuvastatin | 10 | NaCl | Cr ≥0.5 mg/dl or ≥25% | 72 |
∗ Patients assigned to statin group received the drug plus the same therapy of control group.
The prespecified subanalysis comparing only patients with GFR <60 ml/min or patients with GFR ≥60 ml/min is illustrated in Figure 7 . In patients with GFR <60 ml/min, the pooled RR indicated a persistent borderline benefit from preprocedural administration of statins. In patients with GFR ≥60 ml/min, the pooled RR indicated a highly significant benefit in the statins group. The second prespecified subanalysis is illustrated in Figure 7 . The upper comparison pooled 5 studies investigating atorvastatin and 1 study using simvastatin (lipophilic statins). The pooled RR was significantly reduced in the lipophilic statins group. The lower comparison consists of 2 studies using rosuvastatin (hydrophilic statin). The pooled RR showed a significant reduction to a similar extent to non-rosuvastatin studies. The third prespecified subanalysis is reported in Figure 7 . Patients were stratified based on the adjunctive control therapy. The upper evaluation compared statin and NAC, and the lower evaluation compared statin and hydration. In both evaluations, the pooled RR was similarly reduced but only in the NAC subgroup it was found to be statistically significant.
