Periprocedural effects of statins on the incidence of contrast-induced acute kidney injury: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: The reports on the efficacy of statins for the prevention of contrast-induced acute kidney injury (CIAKI) remain controversial. The objective of this meta-analysis was to assess the effect of statins for the prevention of CIAKI. Methods: Comprehensive literature searches for randomized controlled trials (RCTs) of periprocedural statin treatment for prevention of CIAKI were performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials Systematic Reviews and clinicaltrials.gov from inception until May 2014. The primary outcome was the incidence of CIAKI. Results: Thirteen prospective RCTs were included in our analysis. Of 5803 patients with contrast exposures, 304 patients (5.2%) had CIAKI. Patients in the statin group had an overall lower incidence of CIAKI (3.6%) compared to the control group (6.9%). Intravenous (IV) fluid hydration was used in both groups of all included studies for prevention of CIAKI. There was a significant protective effect of periprocedural statins on the incidence of CIAKI when compared to the control group [risk ratios (RRs): 0.49; 95% CI: 0.37–0.66, I² of 25%]. Conclusions: Our study demonstrates a statistically significant protective effect of statin treatment during procedures with contrast exposures. This finding suggests the use of statins in addition to standard IV crystalloid hydration may be beneficial in the prevention of CIAKI.

• Acute kidney injury
• contrast-induced acute kidney injury
• contrast-induced nephropathy
• meta-analysis
• statins

Introduction

Contrast-induced nephropathy or contrast-induced acute kidney injury (CIAKI) is a well-recognized complication of radiological interventions, cardiac catheterization or minimally invasive procedures that require iodinated contrast administration. It is a common cause of acute kidney injury (AKI) in an inpatient setting.1 Despite current prophylactic strategies with hydration and low contrast volume, the incidence of CIAKI has been reported from 2% in the general population without risk factors to more than 40% in high-risk patients.2–7 The overall incidence of CIAKI is approximately 150,000 patients each year worldwide.8 Patients with CIAKI have also been demonstrated to have longer hospitalizations and higher long-term adverse event and mortality rates.2^,9

In addition to the improvement of lipid profiles and cardiovascular effects, statins ameliorate endothelial function and reduce oxidative stress and inflammation which underlies the pathogenesis of CIAKI.10^,11 However, the beneficial effects of statins on prevention of CIAKI are still controversial. Several studies have demonstrated a protective effect of statins for CIAKI prevention.12–20 Conversely, a few studies showed no significant beneficial effect of statins for prevention of CIAKI.21–28

To assess whether statins had beneficial effects on prevention of CIAKI, we performed this meta-analysis to investigate the effect of statins on the incidence of CIAKI between statin and control groups.

Methods

Search strategy

Two investigators (WC and CT) independently searched published RCTs indexed in MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials Systematic Reviews and clinicaltrials.gov from inception to May 2014 using the search strategy described in Appendix. A manual search for additional relevant studies using references from retrieved articles was also performed. Conference abstracts and unpublished studies were excluded.

Inclusion criteria

The inclusion criteria was as follows: (1) RCTs published as original studies to evaluate the effect of periprocedural statins for the prevention of CIAKI in patients undergoing elective cardiac catheterization or any radiological procedures with contrast exposures, (2) data for analysis for relative risks, hazard ratios, standardized incidence ratio with 95% confidence intervals (CI) were provided, (3) reference groups composed of participants who were not prescribed statins or used lower dose of statins compared to interventional group and (4) only studies in humans.

Study eligibility was independently determined by the two investigators noted above. Differing opinions were resolved by mutual consensus. The quality of each study was independently evaluated by each investigator using Jadad quality assessment scale.29 The studies with Jadad quality assessment scale ≥2 were included in the analysis for the validity of our study results.

Data extraction

A standardized data collection form was used to extract the following information: last name of the first author, study design, year of study, country of origin, year of publication, sample size, characteristics of included participants, randomization techniques, blinding status, statin dose, type of statin, type of contrast, definition of CIAKI, outcome ascertainment and relative risk with 95% CI. The two investigators mentioned above independently performed this data extraction.

Statistical analysis

Review Manager 5.2 software from the Cochrane Collaboration was used for data analysis. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird.30 Given the high likelihood of between study variances, we used a random-effect model rather than a fixed-effect model. Statistical heterogeneity was assessed using the Cochran's Q test. This statistic is complemented with the I² statistic, which quantifies the proportion of the total variation across studies that is due to heterogeneity rather than chance. A value of I² of 0–25% represents insignificant heterogeneity, 26–50% low heterogeneity, 51–75% moderate heterogeneity and > 75% high heterogeneity.31 The presence of publication bias was assessed by funnel plots of the logarithm of odds ratios versus their standard errors.32

Results

Our search strategy yielded 102 potentially relevant articles. Eighty-seven articles were excluded based on title and abstract for clearly not fulfilling inclusion criteria on the basis of the type of article, study design, population or outcome of interest. Eighteen articles underwent full-length-article review. Five articles were subsequently excluded (three articles were not RCTs or Jadad quality assessment scale <2 and two articles were conference abstracts with preliminary results). Thirteen prospective RCTs were identified and included in the data analysis.14^,16–20^,22–28 Figure 1 outlines our search methodology and selection process. Table 1 describes the detailed characteristics and quality assessment of the included studies.

Figure 1. Studies identification. Outline of our search methodology.

Table 1. Main characteristics of the studies included in this meta-analysis.

	Jo et al.22	Zhou et al.23	Wang et al.24	Xinwei et al.14	Toso et al.25
Country	Korea	China	China	China	Italy
Year	2008	2009	2009	2009	2010
Total number	236	100	196	228	304
Patients	Patients undergoing elective CAG ± PCI, with renal dysfunction (SCr > 1.1 or CrCl < 60)	Patients undergoing nonemergency CAG ± PCI (relatively normal kidney function at baseline, normal or SCr <1.7)	Patients (relatively normal kidney function at baseline, normal SCr) undergoing cerebral artery intervention.	Patients undergoing PCI for ACS	Patients undergoing elective CAG ± PCI, with CrCl < 60
Randomization	1:1 by computer-generated permuted block of 6	1:1 with blocking	Yes but not described	1:1 by computer-generated permuted block of 8	Computerized open-label assignment in blinded envelopes, no blocking
Blinding	Double-blind	Single-blind	single-blind	No	No
Statin type	Simvastatin	Atorvastatin	Atorvastatin	Simvastatin	Atorvastatin
Statin dose, duration (total dose)	80 mg before, 80 mg after procedure (160 mg)	High dose: 80 mg at 1 day before, 10 mg for 6 days after procedure (140 mg)	80 mg for 3 days before procedure (240 mg)	80 mg/ before (80 mg), then 20 mg/d after procedure	80 mg/d for 2 days before, 80 mg/d for 2 days after procedure (320 mg)
Control arm	Placebo	Atorvastatin low dose: 10 mg qd for 7 days (70 mg)	Placebo	Simvastatin 20 mg/d before (20 mg), then 20 mg/d after procedure	Placebo
Other interventions	Hydration with 0.45% NaCl, no oral NAC use	Hydration with 0.9% NaCl	Hydration with 0.9% NaCl	Hydration with 0.9% NaCl, No oral NAC use	Hydration with 0.9% NaCl, oral NAC
Contrast agent	Iso-osmolar, nonionic contrast (Iodixanol)	Nonionic, low-osmolar iodinated contrast (Iopamidol)	Nonionic, low-osmolar iodinated contrast (Iohexol)	Iso-osmolar, nonionic contrast Iodixanol for CKD patients; low-osmolar iodinated contrast iohexol for non-CKD patients	Iso-osmolar, nonionic contrast (Iodixanol)
Contrast-induced nephropathy definition	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 48 h after contrast exposure	An increase in serum creatinine ≥0.5 mg/dL within 48 h of contrast exposure	An increase in serum creatinine of 0.5 mg/dL within 48 h of contrast exposure.	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 48 h after contrast exposure	≥0.5 mg/dL increase in baseline SCr within 5 days after contrast exposure
Outcome ascertainment	SCr were measured 24 and 48 h after procedure	Serum creatinine measurement performed 24 and 48 h after catheterization.	Serum creatinine were collected day 1 and day 2 following radiological procedures.	SCr were measured 24 and 48 h after procedure	SCr were measured on day 1, 2, 3 and 5 after procedure
Relative risk	0.75 (0.17–3.28)	0.14 (0.01–2.70)	0.83 (0.26–2.64)	0.34 (0.14–0.82)	0.94 (0.48–1.83)
Jadad quality assessment scale29	Five out of five	Three out of five –No double blind	Two out of five – No report in randomization procedure – No double blind	Three out of five – No double blind	Three out of five – No double blind
	Ozhan et al.26	Acikel et al.28	Patti et al.18	de Oliveira et al.27	Quintavalle et al.19
Country	Turkey	Turkey	Italy	Brazil	Italy
Year	2010	2010	2011	2012	2012
Total number	130	160	241	135	410
Patients	Patients undergoing CAG ± PCI. Patients with SCr > 1.5 or CrCl < 70 mL/min were excluded	Patients undergoing elective CAG with LDL-C ≥ 70 mg/dL	Patients undergoing non-emergency PCI for ACS	Patients undergoing elective PCI	Patients undergoing elective CAG ± PCI with eGFR < 60 mL/min/1.73 m^2
Randomization	Yes but not described	1:1 using a simple randomization method	1:1 with blocking	Yes but not described	1:1 with computer-generated random number
Blinding	No	No	Double blind	No	No
Statin type	Atorvastatin	Atorvastatin	Atorvastatin	Rosuvastatin	Atorvastatin
Statin dose, duration (total dose)	80 mg before, 80 mg for 2 days after procedure (240 mg)	40 mg/d for 3 days before, and for 2 days after procedure	80 mg 12 h before, then another 40 mg^2 hours before procedure (120 mg), then 40 mg/d after procedure	40 mg 2–6 hours prior to PCI.	80 mg within 24 h before procedure
Control arm	No placebo	No placebo	Placebo, then atorvastatin 40 mg/d after procedure	No placebo	No placebo
Other interventions	Hydration with 0.9% NaCl, Oral NAC	Hydration with 0.9% NaCl, No oral NAC use	Hydration with 0.9% NaCl in CKD patients, Oral NAC use not specified.	Hydration (0.9% saline, 1 mL/kg/h in the case of normal left ventricular function or 0.5 mL/kg/hour in the case of left ventricular dysfunction) for at least six hours before and 12 h after PCI	Hydration with isotonic NaHCO3, Oral NAC use
Contrast agent	Nonionic, low-osmolar iodinated contrast (Iopamidol)	Nonionic low-osmolar (Iohexol)	Low-osmolar nonionic iodinated contrast	High and Low osmolar contrast	Iso-osmolar, nonionic contrast (Iodixanol)
Contrast-induced nephropathy definition	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 48 h after contrast exposure	Increase in SCr ≥ 0.5 mg/dL or ≥ 25% over baseline within 48 h after contrast exposure	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 48 h after contrast exposure	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 24 h after contrast exposure	Increase in SCr ≥ 0.5 mg/dL or ≥ 25% over baseline 48 h after contrast exposure
Outcome ascertainment	SCr were measured 24 and 48 h after procedure	SCr were measured 48 h after procedure	SCr were measured 24 and 48 h after procedure	SCr were measured 48 h after procedure.	Cystatin C and SCr were measured 24 and 48 h after procedure
Relative risk	0.35 (0.08–1.65)	0.33 (0.01–8.06)	0.38 (0.15–0.93)	1.22 (0.39–3.38)	0.25 (0.12–0.51)
Jadad quality assessment scale29	Two out of five No report in randomization procedure No double blind	Three out of five No double blind	Five out of five	Two out of five -No report in randomization procedure -No double blind	Three out of five No double blind
	Li et al.20	Han et al.16	Leoncini et al.16
Country	China	China	Italy
Year	2012	2014	2014
Total number	161	2998	504
Patients	STEMI undergoing emergency coronary angiography and/or PCI	Patients undergoing CAG ± PCI, peripheral artery angiography, left ventriculography, with DM and CKD stage 2 and 3	Patients undergoing non-emergency PCI for ACS
Randomization	1:1 with computer-generated random number	1:1 by computerized open-label assignment with blocks of 6	1:1 by computerized open-label assignment with blocks of 50
Blinding	Double blind	No	No
Statin type	Atorvastatin	Rosuvastatin	Rosuvastatin
Statin dose, duration (total dose)	80 mg loading, followed by 40 mg/d postprocedure.	10 mg for 2 days before, then 10 mg for 3 days after procedure (50 mg)	40 mg on admission, followed by 20 mg/d
Control arm	Placebo	No placebo but started statin medication 3 days after procedure	No placebo but received atorvastatin 40 mg/d at discharge
Other interventions	IV 0.9%NaCl (1 mL/kg/h) 12 h before and after the procedure	Hydration with 0.9% NaCl at physician's discretion	Hydration with 0.9% NaCl, Oral NAC
Contrast agent	Nonionic, low-osmolar iodinated contrast (Iopromide)	Nonionic, iso-osmolar contrast (Iodixanol)	Nonionic, iso-osmolar contrast (Iodixanol)
Contrast-induced nephropathy definition	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 48 h after contrast exposure	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 72 h after contrast exposure	≥25% or ≥ 0.5 mg/dL increase in baseline SCr within 72 h after contrast exposure
Outcome ascertainment	SCr were measured 48 and 72 h after procedure	SCr were measured 48 and 72 h after procedure	SCr were measured 24, 48 and 72 h after procedure
Relative risk	0.16 (0.04–0.70)	0.59 (0.39–0.89)	0.45 (0.26–0.77)
Jadad quality assessment scale29	Five out of five	Three of five due to – No double blind	Three of five due to – No double blind

Note: ACS = acute coronary syndrome, CrCl = creatinine clearance, CAG = coronary angiography, IV = intravenous, g = gram, kg = kilogram, NaCl = sodium chloride, NAC = n-acetyl cysteine, PCI = percutaneous coronary intervention, SCr = serum creatinine.

The incidence of CIAKI

Of 5803 patients who had elective cardiac catheterization or radiological procedures with contrast exposures, 304 patients (5.2%) developed CIAKI. Patients in the statin group had overall lower incidence of CIAKI (3.6%) compared to control group (6.9%).

The risk of CIAKI in statin and control groups

The pooled risk ratio (RR) of CIAKI in the periprocedural statin group versus control group was 0.49 (95% CI, 0.37–0.66). Intravenous (IV) fluid hydration was used in both groups of all included studies for prevention of CIAKI. The statistical heterogeneity was insignificant with an I² of 25%. Figure 2 shows the forest plot of the included studies.

Figure 2. Forest plot of the included studies comparing risk of CIAKI in patients who used statins and those who did not; square data markers represent risk ratios (RRs); horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest.

Evaluation for publication bias

A funnel plot to evaluate publication bias for the risk of CIAKI in patients receiving statins versus control group is summarized in Figure 3. The graph is fairly asymmetric and, thus, providing a suggestion to the presence of publication in favor of negative studies.

Figure 3. Funnel plot of 13 studies included in the meta-analysis for the risk of hypomagnesemia in patients with PPI use. The plot did not show significant publication bias of included studies. RR = risk ratio, SE = standard error.

Discussion

Our meta-analysis showed an overall incidence of CIAKI of 5.2% in patients with contrast exposures. Patients in the statin group had a lower incidence of CIAKI (3.6%) when compared to the control group (6.9%). Based on the pooled incidence of CIAKI in the statin and control groups, the number needed to treat (NNT) (the number of patients) to prevent a CIAKI event using statin is 31. Our study also demonstrated a significant protective effect of periprocedural statins on the incidence of CIAKI.

Statins, potent lipid-lowering agents, have been widely prescribed for primary and secondary prevention of coronary artery disease. Studies have demonstrated the cholesterol-independent or “pleiotropic” effects of statins including amelioration of endothelial function, stabilization of atherosclerotic plaques, reduction of oxidative stress and inflammation and inhibition of thrombogenic process.33 Statins have also been found to up-regulate inhibitors of transforming growth factor-beta signaling and decreases renal fibrosis.34 Recently, a meta-analysis of statin use on renal function demonstrated their renoprotective effects on slow progression of chronic kidney disease (CKD) and reduction of proteinuria.35

The underlying pathogenesis of CIAKI is not completely understood. However, studies have suggested that a combination of direct tubular injury, hemodynamic changes of renal blood flow mediated by increase in free radicals and vasoconstriction might play important roles.11^,36 The pleiotropic effects of statins might potentially reduce vascular endothelial inflammation and free radicals that are caused by contrast media nephrotoxicity. Although a previous meta-analysis on this topic showed inconclusive data, it showed a trend of beneficial effects of statins in reducing the incidence of CIAKI.37 Our studies included newer studies that used lower volume of contrast media, which caused less tubular toxicities.16–20^,27 Therefore, our meta-analysis successfully reveals the benefit of statins for the prevention of CIAKI.

The strengths of our study include insignificant heterogeneity among included studies. All RCTs in this meta-analysis used the same definition of CIAKI (an increase in serum creatinine ≥0.5 mg/dL within 48–72 h of contrast exposure). Thus, this meta-analysis provides reliable results on the effects of statins for the prevention of CIAKI.

Although almost all included studies were of moderate to high quality14^,16–20^,23^,25^,28 (as evaluated by Jadad quality assessment scale), there are some limitations. Firstly, there is publication bias in favor of negative studies in this meta-analysis. Despite this, our study demonstrates the positive effect of statins for CIAKI prevention. Secondly, although all included studies used IV fluid hydration for CIAKI prevention in both statin and control groups, rate and type of IV fluid used in studies were different and these differences could potentially affect the incidence of CIAKI among included studies. In addition, the effective dose of statins for the prevention of CIAKI is still not well established. Only two included RCTs compared high dose statin to low dose statin and they showed different results. Almost all studies revealing the beneficial effect of statins, however, used moderately high dose statins (Table 1).

In summary, our study demonstrates a statistically significant protective effect of statin treatment during procedures with contrast exposures for the prevention of CIAKI. This finding suggests the use of statins in addition to standard IV crystalloids hydration may be beneficial in the prevention of CIAKI.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Appendix

Searches: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials Systematic Reviews and clinicaltrials.gov until May, 2014

1. exp hydroxymethylglutaryl-CoA Reductase Inhibitors/

2. hydroxymethylglutaryl-CoA Reductase Inhibitors$.mp

3. exp statin/

4. statin$.mp

5. simvastatin$.mp

6. pravastatin$.mp

7. lovastatin$.mp

8. atorvastatin$.mp

9. fluvastatin$.mp

10. pitavastatin$.mp

11. hydroxymethylglutaryl-coa reductase inhibitor$.mp

12. hmg coa reductase inhibitor$.mp

13. hydroxymethylglutaryl coenzyme a reductase inhibitor$.mp

14. hmg co a reductase inhibitor$.mp

15. mevinolin$.mp

16. pravachol$.mp

17. lipitor$.mp

18. zocor$.mp

19. mevacor$.mp

20. lescol$.mp

21. exp contrast nephropathy/

22. contrast nephropathy$.mp

23. exp contrast medium/

24. contrast medium$.mp.

25. exp contrast-induced nephropathy/

26. contrast-induced nephropathy$.mp.

27. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

28. 21 or 22 or 23 or 24 or 25 or 26

29. 27 and 28

30. limit 30 to humans

31. limit 31 to randomized controlled trial