Impact of Chronic Statin Therapy on Postprocedural Contrast-Induced Nephropathy in Patients Undergoing Non-Emergent Percutaneous Coronary Intervention

Abstract: Background. Following percutaneous coronary intervention (PCI), elevations in serum creatinine level and declines in glomerular filtration rate are common. Prior studies have demonstrated benefit of chronic statin therapy in the prevention of contrast-induced nephropathy (CIN); however, it is unknown whether chronic statin therapy reduces the incidence of CIN in the non-emergent PCI setting. Methods. Using the 2004-2005 Cornell Angioplasty Registry, a total of 1171 consecutive patients were selected for analysis. The population was divided into two groups: (1) patients on chronic (≥30 days) statin therapy prior to PCI (n = 874); and (2) patients not on chronic statin therapy (n = 297). Results. Patients taking chronic statin therapy were more likely to have diabetes mellitus (35.7% vs 22.6%; P<.001), previous myocardial infarction (36.3% vs 20.5%; P<.001), previous PCI (38.9% vs 16.2%; P<.001), and previous coronary artery bypass graft surgery (19.5% vs 11.4%; P=.01). Statin users were also more likely to be taking long-term aspirin (77.8% vs 59.6%; P<.001) and clopidogrel therapy (29.9% vs 14.1%; P<.001). Baseline serum creatinine levels were comparable between the two groups, as were procedural characteristics. The incidence of CIN following PCI was not significantly different between patients on chronic statin therapy versus those not on chronic statin therapy (4.2% vs 5.4%; P=.42). However, after multivariate adjustment, chronic statin therapy was associated with a lower incidence of CIN (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.05-0.94; P=.04). Acute heart failure on admission and the urgency of the procedure (urgent vs elective PCI) were also independent predictors for developing CIN (OR, 3.04; 95% CI, 1.45-6.66 [P=.01] and OR, 2.80; 95% CI, 1.42-5.55 [P=.01], respectively). Long-term mortality rates were similar between those on chronic statin therapy and those not on statins. Conclusion. CIN occurred in 4.5% of patients following non-emergent PCI. Multivariate analysis demonstrated that chronic statin therapy decreased the odds of developing CIN in patients undergoing PCI.

J INVASIVE CARDIOL 2015;27(11):490-496. Epub 2015 May 15.

Key words: statin, contrast-induced nephropathy (CIN), percutaneous coronary intervention (PCI)

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Contrast-induced nephropathy (CIN) can be a major complication following the use of iodinated contrast material, resulting in increased length of stay, healthcare costs, as well as morbidity and mortality.¹ After non-emergent percutaneous coronary intervention (PCI), elevations in serum creatinine level and declines in glomerular filtration rate (GFR) occur in 2%-9% of patients.^2,3 The data suggest a three-fold increase in risk of CIN in patients presenting with acute coronary syndrome (ACS).^4,5 The benefits of statin therapy have been widely established for the prevention and treatment of cardiovascular disease.^6-8 Evidence from recent trials suggests that preprocedural high-dose statin therapy prior to contrast exposure may reduce the incidence of CIN.^3,9-11 A meta-analysis of seven such trials supported the use of short-term high-dose statin therapy for the prevention of acute kidney injury (AKI).³ It is believed that the pleiotropic properties of statins may reduce the oxidative and renal toxic effects of contrast dye.^1,12-14 The aim of this study was to examine the effect of chronic statin therapy on the incidence of postprocedural CIN in a cohort of patients undergoing non-emergent PCI in the era of drug-eluting stenting.

Methods

The methods for data collection in this study have been previously described in detail.¹⁵ All patients undergoing PCI at New York-Presbyterian Hospital/Weill Cornell Medical College (New York, New York) were enrolled in the Cornell Angioplasty Registry. A standard case report form delineating comprehensive patient demographics, preintervention clinical status, procedural findings, and in-hospital complications was completed for each PCI performed. Patient follow-up was obtained by publicly available mortality data through the Social Security Death Index and through regularly scheduled telephone contacts.¹⁶ The present study included all consecutive patients from January 1, 2004 through December 31, 2005. Only patients with normal preprocedural cardiac troponin I (cTnI) levels (<0.15 ng/mL) and normal preprocedural creatine kinase-MB (CK-MB) levels (<4.5 ng/mL) were included in the study. We excluded patients with very advanced chronic kidney disease (serum creatinine ≥4 mg/dL) and those on hemodialysis from this analysis. Patients presenting with acute myocardial infarction (MI) ≤7 days, hemodynamic instability, or shock, and those receiving thrombolytic therapy ≤7 days were also excluded. The study was approved by the institutional review board of Weill Cornell Medical College. 

Patients were considered to have been on long-term or chronic statin therapy if they reported the use of a hydroxymethylglutaryl-coenzyme A reductase inhibitor (including a statin as part of a combination pill) for ≥30 days before PCI and statins were continued after PCI (the “statin” group). Patients were included in the “no-statin” group if they did not report statin use before PCI and did not receive statin therapy immediately before PCI. Patients were excluded from the study if the timing of periprocedural statin therapy was missing. Patients on long-term statin therapy whose statin therapy was interrupted before PCI were excluded. Patients who were not on long-term statin therapy and received ≥1 statin dose before PCI were excluded from analysis. High-dose statin therapy was defined as simvastatin ≥40 mg/day, atorvastatin ≥20 mg/day, or any dose of rosuvastatin. All other statin doses were classified as low-dose statin therapy. 

Baseline patient characteristics, angiographic, and procedural data were compared in patients with versus without long-term statin therapy. The primary endpoint analyzed was an increase in serum creatinine ≥25% above baseline or an absolute increase of serum creatinine ≥0.5 mg/dL post procedure. Serum creatinine was measured in all patients 12-24 hours after PCI. Secondary endpoints included an increase in serum creatinine ≥25% above baseline alone, an absolute increase in serum creatinine ≥0.5 mg/dL alone, or an absolute increase in serum creatinine ≥1.0 mg/dL, as well as long-term all-cause mortality. Long-term mortality data were obtained for 98.5% of patients using the Social Security Death Index with a mean follow-up period of 53.2 ± 13.2 months. Multivessel disease was defined as the presence of ≥70% lesion in ≥2 major coronary arteries/branches or a left main coronary artery lesion. Multivessel PCI was defined as a coronary intervention in ≥2 major coronary arteries/branches or a left main coronary artery. Cases were classified as urgent when the patient was too ill or unstable to be discharged from the hospital without undergoing intervention, but did not meet the criteria for emergent PCI. Patients with ongoing, refractory, unrelenting cardiac compromise, with or without hemodynamic instability were defined as emergent. Cases that were neither urgent nor emergent were classified as elective. Emergent cases were excluded. Congestive heart failure (CHF) referred to New York Heart Association class III or IV heart failure during admission. Vascular injury referred to an access site complication requiring mechanical/surgical intervention. Major bleeding was defined as a decrease in hemoglobin ≥4 g/dL. Minor bleeding was defined as decreases in hemoglobin ≥2 g/dL and <4 g/dL. Angiographic success was defined as a final stenosis ≤20% of the target vessel reference diameter.

Data analysis. Data management and analyses were performed with Excel 12.2.7 (Microsoft Corporation) and SPSS Statistics 18.0 (IBM Corporation). Data were presented as mean ± standard deviation for continuous variables or proportions for dichotomous variables. Differences in prevalence between groups were compared with chi-square test or Fisher’s exact test for dichotomous variables, and mean values for continuous variables were compared with Student’s t-test. A P-value <.05 was considered statistically significant. The relation between long-term statin therapy and the risk of developing CIN after PCI was assessed with multivariable logistic regression models. Univariate associations with CIN were estimated for all clinical and procedural variables (Tables 1 and 2). To test the independence of long-term statin therapy as a predictor of CIN, chronic statin therapy was entered into the stepwise multivariate logistic regression model that also included univariate predictors of CIN (significant at a level of .10). Mortality rates were calculated and plotted according to the Kaplan-Meier method, and comparisons between the groups were performed using the log-rank statistic.

Results

During the study period, there were 3611 elective or urgent PCIs performed in 2504 consecutive patients. Of these, 1171 patients met the inclusion criteria and were included in the final analysis. A total of 874 patients (74.6%) were taking statins for ≥30 days before PCI as well as periprocedurally, while 297 patients (25.3%) were not on long-term statin therapy and did not receive statins immediately before PCI. In our study population, atorvastatin (60.9%) and simvastatin (27.1%) were the most frequently used statins, whereas pravastatin, rosuvastatin, lovastatin, and fluvastatin were used less commonly. 

The baseline characteristics of study patients are listed in Table 1. The baseline serum creatinine levels were non-significantly higher in patients on chronic statin therapy (1.13 ± 0.36 mg/dL vs 1.09 ± 0.33 mg/dL; P=.06), whereas creatinine clearance was similar in both groups (74.8 ± 31.5 mL/min vs 77.7 ± 33.9 mL/min; P=.20). A distribution of baseline serum creatinine levels in the overall cohort is illustrated in Figure 1. Patients receiving long-term statin therapy were more likely to have a history of diabetes mellitus, myocardial infarction, PCI, and coronary artery bypass graft (CABG) surgery. Statin users were also more likely to be taking long-term aspirin therapy (77.8% vs 59.6%; P<.001) and clopidogrel therapy (29.9% vs 14.1%; P<.001). Overall ejection fraction was mildly reduced in both groups (52%). A similar proportion of patients presented with unstable angina (49%). 

In-hospital outcomes. Angiographic and procedural characteristics are presented in Table 2. There was a trend toward a higher frequency of single-vessel coronary artery disease (CAD) in the no-statin therapy group, whereas multivessel or left main CAD was more prevalent in the long-term statin therapy group. Both groups had a high rate of stenting (>92%) and drug-eluting stent (>86%) placement during PCI. The volume of contrast used during the procedure was slightly lower in the statin group (224.1 ± 3.5 mL vs 237 ± 5.7 mL; P=.05). Iohexol was less frequently used in the statin group as compared to the non-statin group (88.0% vs 93.4%; P=.01), while iodixanol was more frequently used in the statin group (12.0% vs 6.6%; P=.01). There was a high rate of angiographic success (>99%) in all patients and a low rate of in-hospital adverse events (Table 3). Overall length of stay was short, with most patients staying a total of 1-2 days.

Overall, a total of 53 out of 1171 patients (4.5%) developed CIN following PCI. The CIN rate was not different between the statin and no-statin groups (4.2% vs 5.4%; P=.42), as shown in Table 3. There was also no significant difference between groups for secondary outcomes, including creatinine increase ≥25% above baseline (4.2% vs 5.4%; P=.42), an absolute increase of ≥0.5 mg/dL (1.5% vs 20%; P=.06), or an absolute increase of ≥1.0 mg/dL (0.8% vs 1.0%; P=.72). After adjustment for confounding variables with multivariate regression analysis, chronic stain therapy was independently associated with lower odds of developing CIN (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.05-0.94; P=.04) (Table 4). In addition, presentation with heart failure (OR, 3.04; 95% CI, 1.45-6.66; P=.01), previous CABG surgery (OR, 1.38; 95% CI, 0.60-3.20; P=.01), and urgent PCI as compared with elective cases (OR, 2.80; 95% CI, 1.42-5.55; P=.01) were associated with increased odds of developing CIN after PCI. 

In the subgroup analysis, there were no significant differences in outcomes when patients were stratified by urgency of procedure and presence of CHF on admission; however, the CIN rates were higher for patients undergoing urgent PCI and with CHF (Figure 2). Although the CIN rate was also increased in patients with decreased creatinine clearance, there was no significant difference between statin and non-statin therapy when subdivided for GFR ≤60 mL/min (Figure 2). 

All-cause mortality at 1-year follow-up was not significantly different between the two groups (3.4% vs 4.0%; P=.59). By the end of the follow-up period, the all-cause mortality rate was 11.7% in the overall population. The Kaplan-Meier survival rates were similar in the chronic statin therapy group versus the no-statin therapy group (88.4% vs 86.8%; log-rank P=.48).

Discussion

This retrospective analysis of patients undergoing non-emergent PCI showed that chronic statin therapy significantly reduced the odds of developing CIN after adjusting for patient-related and procedure-related factors. Although this study did not demonstrate a long-term mortality difference, renal insufficiency is known to be a marker of poor prognosis in patients with cardiovascular disease, and reductions in CIN rates have been previously shown to reduce hospital length of stay, morbidity, and mortality.⁹ 

There are several proposed mechanisms for why statin therapy may play a beneficial role in protection from kidney injury following contrast infusion. The pleiotropic effects of statins, which include anti-inflammatory, antioxidant, and antithrombotic properties, are thought to be renally protective.^1,17 Statins also have been shown to improve endothelial function by increasing nitric oxide production, aiding renal perfusion following contrast administration. At the cellular level, in vitro studies have shown that pretreatment of renal epithelial tubular cells with statins decreased apoptosis and amplified signaling pathways required for cell survival.¹⁸

Prior randomized trials examining the role of statin therapy and prevention of CIN have focused on the acute periprocedural use of statins before planned PCI, and there is a growing body of evidence to suggest that preprocedural statin loading can prevent CIN. The recent PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in Patients With Acute Coronary Syndrome) study on 504 patients found that the incidence of CIN was significantly lower (6.7% vs 15.1%; P=.01) when statin-naïve patients undergoing early invasive therapy for non-ST elevation ACS were pretreated with rosuvastatin 40 mg followed by rosuvastatin 20 mg/day.⁹ In fact, the PRATO-ACS study showed that the patients who developed CIN were at higher risk of death or non-fatal MI after 6 months of follow-up. In the smaller ARMYDA-CIN (Atorvastatin for Reduction of Myocardial Damage During Angioplasty — Contrast-Induced Nephropathy) trial of 241 statin-naïve ACS patients, a periprocedural administration of atorvastatin (80 mg at 12 hours before intervention with another preprocedure 40 mg dose) reduced the incidence of CIN from 13.2% to 5% (P=.046).¹⁹ Prospective studies have also shown that periprocedural rosuvastatin significantly reduces the risk of CIN in patients with risk factors for AKI, such as diabetes mellitus, and in patients with underlying chronic kidney disease.¹⁰ Another high-risk cohort study of patients with baseline chronic renal insufficiency found that the incidence of CIN was lower with chronic pravastatin therapy.²⁰ Multiple meta-analyses have now demonstrated that short-term preprocedure statin therapy can significantly reduce the incidence of CIN.^3,21-24

While prior investigations on this topic have largely focused on higher-risk ACS patients, our results add to the body of data supporting the importance and benefit of chronic statin therapy for the prevention of CIN, with extension to the non-emergent PCI setting. The largest of these cohorts, reported by Khanal et al in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium database, demonstrated that prior statin use similarly decreased the incidence of CIN (4.4% vs 5.9%; P<.001) as in our study (4.2% vs 5.4%), although it is unclear how long statins were used before PCI.²⁵ The similar rates and reduction in CIN is in contrast to the PRATO-ACS and ARMYDA-CIN studies, where the incidence of CIN was significantly higher, likely explained by the inclusion of ACS patients who would be at greater risk for CIN. An alternative explanation for the variances in CIN rates between studies is the lack of a standardized and uniformly accepted CIN definition, as CIN rates can vary between 3.3% to 10.2% based on the CIN definition utilized.²⁶

Limited data exist addressing the issue of whether prevention of CIN with statins would improve long-term outcomes. A prior report by Patti et al demonstrated decreased CIN rates and major adverse cardiac events with prior statin use and, importantly, improved survival at 4-year follow-up.¹⁹ Mechanisms responsible for improved long-term outcomes with statins after PCI are not completely understood. Prevention of CIN and periprocedural myocardial necrosis by statins, as well as their anti-inflammatory effects and improvement of endothelial function, may explain the reduction in long-term cardiac events. Our study did not demonstrate a mortality difference after 4 years of follow-up, likely due to small sample size, small differences in post-PCI CIN rates, and selection of a lower-risk PCI population with few long-term cardiac events. 

Study limitations. We acknowledge several limitations in this study. First, our analysis was derived from a single-center, albeit high-volume, tertiary-care population. Second, although data in the present study were collected prospectively, this is a retrospective analysis and is subject to the limitations therein (eg, differences in contrast volume and type between the two groups). Third, the type of statin, dose, or duration of treatment may have had differential effects on the results of this study. It is also unknown if different types of statins (hydrophilic vs lipophilic) would prove to be more effective in protection from CIN. Lastly, the baseline lipid status of the patients was not routinely checked during in the study period. 

Further studies are needed to demonstrate whether patients without clear indications for statins should be on statin therapy for the purpose of renal protection alone or whether periprocedural high-dose statin loading should be administered to patients already on chronic statin therapy. Given the potential benefits and minimal risks associated with periprocedural loading with statins, we suggest that preprocedural loading with a high-dose statin should be strongly considered whether or not patients are receiving chronic statin therapy. In addition, these results may not be limited to patients undergoing PCI; the benefit of chronic statin therapy might apply to patients undergoing coronary angiography and contrast administration for other radiologic procedures.

Conclusion

Contrast-induced nephropathy rates are relatively low following non-emergent PCI, but higher in select patients with higher-risk presentations such as acute heart failure. Although there was no long-term mortality benefit, chronic statin therapy was associated with a significant risk-adjusted decrease in the incidence of CIN after contemporary non-emergent PCI. 

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^*Joint first authors.

From the Greenberg Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest Dr. Feldman has consulted for and/or received speaker’s fees from Eli Lilly and Company, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, and Abbott Vascular. The remaining authors report no relevant conflicts of interest regarding the content herein.

Manuscript submitted September 4, 2014, provisional acceptance given October 27, 2014, final version accepted November 24, 2014.

Address for correspondence: Dmitriy N. Feldman, MD, Associate Professor of Medicine, New York Presbyterian Hospital, Weill Cornell Medical College, Greenberg Division of Cardiology, 520 East 70th Street, Starr-434 Pavilion, New York, NY 10021. Email: dnf9001@med.cornell.edu