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Preoperative Statin Therapy Is Not Associated with a Reduced Incidence of Postoperative Acute Kidney Injury After Cardiac Surgery

Argalious, Maged MD, MBA*; Xu, Meng MS; Sun, Zhiyuan MS; Smedira, Nicholas MD; Koch, Colleen G. MD, MS§

doi: 10.1213/ANE.0b013e3181d8a078
Cardiovascular Anesthesiology: Research Reports

BACKGROUND: Our objective was to examine the association between preoperative statin therapy and the prevalence of postoperative acute kidney injury (AKI) in patients undergoing cardiac surgery with the use of cardiopulmonary bypass.

METHODS: We performed a retrospective investigation of 10,648 consecutive patients undergoing coronary artery bypass grafting using cardiopulmonary bypass and/or valve surgery between January 2002 and December 2006. Patients were divided into 2 groups depending on preoperative therapy with statin drugs. The primary outcome was postoperative AKI based on the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria. Secondary outcomes included requirement for postoperative dialysis and hospital mortality. Multivariable logistic regression models were developed for the primary and secondary outcomes. To control for selection bias related to statin therapy, a propensity score was developed using a greedy matching technique.

RESULTS: The incidence of AKI was 12.1% (n = 1286). AKI occurred in 13.31% of patients receiving preoperative statins (819 of 6152 patients) versus 10.41% in the no statin group (467 of 4487 patients) (P < 0.001). The incidence of postoperative dialysis was 1.71% (n = 182). Postoperative dialysis was needed in 1.75% of patients in the statin group (108 of 6157 patients) compared with 1.65% of patients (74 of 4491 patients) in the no statin group (P = 0.68). Hospital mortality after surgery occurred in 1.71% (n = 182) of patients. The incidence of mortality for patients in the statin group was 1.71% (105 of 6157 patients) and this was not different from mortality in the no statin group of 1.71% (77 of 4491 patients) (P = 0.97). In multivariate logistic regression analysis, statin therapy was not associated with AKI (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.84–1.12; P = 0.68), postoperative dialysis (OR 0.80, 95% CI 0.55–118; P = 0.23), or hospital mortality (OR 0.803, 95% CI 0.56–1.16; P = 0.24). In 2646 propensity-matched pairs, the incidence of AKI was 12.0% in the statin group versus 12.8% in the no statin group (P = 0.38). The statin group had a 1.63% incidence of postoperative dialysis versus 2.08% in the no statin group (P = 0.22). In the same propensity-matched population, hospital mortality occurred in 1.63% of patients in the statin group compared with 2.1% in the no statin group (P = 0.19).

CONCLUSION: These results suggest that previously reported reductions in perioperative mortality for patients taking preoperative statins and undergoing cardiac surgery is likely not mediated through a reduction in postoperative AKI.

Published ahead of print July 7, 2010

From the Departments of *General Anesthesiology, Quantitative Health Sciences, Thoracic and Cardiovascular Surgery, and §Cardiothoracic Anesthesia, Cleveland Clinic, Cleveland, Ohio.

Address correspondence and reprint requests to Maged Argalious, MD, MBA, Department of General Anesthesiology, Cleveland Clinic, 9500 Euclid Ave./G30, Cleveland, OH 44195. Address e-mail to argalim@ccf.org.

Accepted January 28, 2010

Acute kidney injury (AKI) occurs in 7% to 30% of patients after cardiac surgery14 with 1% to 3% of patients requiring hemodialysis in the postoperative period.2,4 Associated consequences of AKI include prolonged intensive care unit and hospital length of stay5 and increased mortality.69 AKI after cardiac surgery may have multiple causes including embolism or a reduction in perfusion of the superficial renal cortex during cardiopulmonary bypass (CPB).10,11 Furthermore, AKI may result from ischemia-reperfusion injury that is exacerbated by the systemic inflammatory response from surgery and CPB.10,12 This inflammatory response may exacerbate renal hypoperfusion because of a reduction in nitric oxide concentrations leading to renal arteriolar vasoconstriction and altered intrarenal distribution of perfusion.11

Although controversial,13 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statin) therapy has been reported to favorably influence cardiovascular morbidity and mortality after cardiac surgery.14,15 Besides their lipid- decreasing properties, statins reduce endothelin secretion, have antioxidant effects, and have antiinflammatory properties that may confer protection against CPB-related AKI.1618 In one investigation, patients receiving preoperative atorvastatin therapy had lower interleukin-6 and -8 levels 4 hours after cardiac surgery compared with placebo.17 There is further evidence demonstrating reduced postischemic, angiotensin II–mediated acute renal failure with statin therapy.18,19 We therefore sought to investigate the effect of preoperative statin therapy on postoperative AKI and mortality in patients undergoing cardiac surgery requiring CPB.

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METHODS

After IRB approval, data from 10,648 consecutive patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery between January 2002 and December 2006 were analyzed, using the Cardiothoracic Anesthesia Patient Registry. The registry is a database containing demographic and perioperative clinical information on patients undergoing cardiac surgery. Patient data are primarily obtained through a prospective daily review of medical history, medication history, physical assessment, anesthesia records, and clinical care notes. This information is collected by full-time database research assistants. Supplemental demographic and clinical data in other institutional databases are imported into the registry either manually or through computer interfaces. Data validations are built into the registry to ensure the quality of data. Additional validations are performed quarterly to identify any quality issues (e.g., incomplete data) that may not have been identified by automated validations.

Patients who underwent cardiac surgery without the use of CPB and those with end-stage renal disease as defined by the requirement for dialysis therapy preoperatively were excluded from the analysis. Four hundred thirty patients were excluded from the multivariable analysis because of missing data mainly related to absence of preoperative albumin values in 397 patients. Patients received an intraoperative infusion of ε-aminocaproic acid according to our institutional protocol; no patients received aprotinin or tranexamic acid.

Patients were divided into 2 groups depending on whether they were taking preoperative statins. Data on statin use was obtained from the Cleveland Clinic's cardiovascular information registry, which tracks and maintains preoperative patient medication use. The primary outcome was the occurrence of postoperative AKI as defined by the RIFLE (Risk, Injury, Failure, Loss, End-stage) criteria.20 The RIFLE criteria were used to categorize patients into 3 groups: (1) those at risk of renal injury (as defined by a maximal postoperative creatinine [mg/dL] ≥1.5 but <2 times preoperative creatinine), (2) those with renal injury (maximal postoperative creatinine [mg/dL] >2 but <3 times preoperative creatinine), and (3) those with renal failure (maximal preoperative creatinine [mg/dL] ≥3 times preoperative creatinine or a maximal postoperative creatinine of >4 mg/dL in the setting of a postoperative serum creatinine increase of ≥0.5 mg/dL).20 Secondary outcomes included the requirement for postoperative dialysis and hospital mortality. The preoperative estimated glomerular filtration rate (eGFR) was calculated based on the following equation:

The equation does not require weight or height variables because the results are reported normalized to 1.73 m2 body surface area.21 A multivariable logistic regression model was developed for the primary and secondary outcomes with a backward selection procedure to test the association between preoperative statin therapy and postoperative outcomes after adjusting for the significant covariates. All variables in Figure 1were considered in the multivariable logistic model, and preoperative statin therapy was forced into the final model. Variables with a P value >0.05 were removed from the model. The reduced model was then successively refitted and the same rule applied until all remaining variables had a P value <0.05.

Propensity methodology was also used to assess the effect of statin therapy on outcomes. Demographics, comorbidity, operative, and transfusion variables noted in Figure 1 were used for the development of the propensity score. The propensity score, in logit units, was obtained by calculating the predicted value for each observation from a logistic model on the use of preoperative statin therapy.22 Greedy matching techniques were then used to select patients who received statin therapy with those who did not by choosing the patients with the nearest propensity score.23 A standardized difference plot was generated before and after matching,24 and comparisons of outcomes were made between the propensity-matched pairs with a generalized estimating equations model to account for the interclass correlation.

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RESULTS

Patient demographic and perioperative variables are listed in Table 1. The incidence of AKI was 12.1% (n = 1286). AKI occurred in 13.31% of patients receiving preoperative statins (819 of 6152 patients) versus 10.41% in the no statin group (467 of 4487 patients) (P < 0.001). In the univariate analysis, patients with AKI were more likely to be males, be older, and have a higher body mass index compared with patients without AKI. Furthermore, they were more likely to have preoperative hypertension and congestive heart failure and were taking more preoperative medications compared with patients without AKI. Patients with AKI were more likely to have a lower preoperative eGFR, lower preoperative hematocrit, and higher blood glucose values on admission to the intensive care unit. They were also more likely to have longer duration of CPB and aortic cross-clamping and to receive more red blood cell and platelet transfusions compared with patients without AKI.

The results of the multivariate logistic regression analysis are shown in Table 2. These results demonstrated that statin therapy was not associated with AKI (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.84–1.12; P = 0.68). Variables independently associated with AKI included male sex, history of congestive heart failure, hypertension, vascular disease, low left ventricular function, high body mass index, low preoperative eGFR, and a low preoperative hematocrit. Emergency surgery, use of preoperative diuretics and calcium channel blockers, use of perioperative red blood cell transfusion, a prolonged CPB, and increased blood glucose on admission to the intensive care unit were also significantly associated with a higher odds ratio of developing postoperative AKI.

The overall incidence of postoperative dialysis was 1.71% (n = 182). Postoperative dialysis was needed in 1.75% of patients in the statin group (108 of 6157 patients) compared with 1.65% of patients (74 of 4491 patients) in the no statin group (P = 0.68). In further multivariate logistic regression analysis, preoperative statin therapy was not associated with a reduction in postoperative dialysis (OR 0.80, 95% CI 0.55–118; P = 0.23), as shown in Table 3. Hospital mortality after surgery occurred in 1.71% (n = 182) of patients. The incidence of mortality for patients in the statin group was 1.71% (105 of 6157 patients) and this was not different from mortality in the no statin group of 1.71% (77 of 4491 patients) (P = 0.97). In the multivariable logistic regression analysis, preoperative statin therapy was not associated with a reduction in hospital mortality (OR 0.803, 95% CI 0.56–1.16; P = 0.24) (Table 4).

Propensity score matching results are listed in Table 5. Two thousand six hundred forty-six matched pairs of patients were identified. Figure 1 shows a plot of standardized mean differences of statin versus no statin groups before and after matching. In the propensity-matched patient population, the incidence of postoperative AKI was 12.4% (n = 657). Patients taking preoperative statins had a 12.0% (318 of 2646 patients) incidence of postoperative AKI, compared with an incidence of 12.8% (339 of 2646 patients) in patients not taking preoperative statins (P = 0.38). The incidence of postoperative dialysis in the propensity-matched population was 1.85% (n = 98). Patients taking preoperative statins had a 1.63% incidence of postoperative dialysis versus an incidence of 2.08% in patients not taking preoperative statins (P = 0.22). In the same propensity-matched population, hospital mortality occurred in 1.87% of patients. Patients taking statins had a 1.63% hospital mortality compared with an incidence of 2.1% in patients not taking preoperative statin therapy (P = 0.19).

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DISCUSSION

We found that preoperative statin therapy was not associated with a reduced prevalence of postoperative AKI, postoperative dialysis, or hospital mortality. The role of statin therapy in the reduction of CPB-induced AKI was postulated based on a number of factors including the finding that statin therapy was associated with a reduction in the incidence of contrast nephropathy in a large retrospective trial,25,26 a condition that shares similar pathologic mechanisms of injury as those caused by CPB. In addition, 2 large retrospective studies demonstrated an association between preoperative statin therapy and a reduction in postoperative mortality in patients undergoing cardiac surgery.14,15

Statins, in addition to their low-density lipoprotein-decreasing effect, have been shown to improve endothelial function by decreasing superoxide formation, upregulating the expression of nitric oxide synthase, and inhibiting the expression of angiotensin II and endothelin.2729 Pretreatment with statins in patients undergoing cardiac surgery significantly reduced the systemic inflammatory response to CPB as evidenced by reduced cytokine release and neutrophil adhesion to the venous endothelium.17 Atherosclerosis of the ascending aorta, through an increase in renal embolus burden, has been shown to be an important predictor of renal dysfunction after cardiac surgery,30 and statins decrease the thrombogenic response to plaque rupture by reducing platelet aggregation and promoting fibrinolysis through enhanced tissue plasminogen activator synthesis.16,17,27 These pleiotropic effects of statins would plausibly reduce CPB-induced AKI through reduction in ischemia-reperfusion injury, systemic inflammatory response, and a reduction in renal emboli through plaque stabilization.

Statin therapy is interrupted during and immediately after surgery because it is currently available only in oral formulation. One possible explanation for the lack of renoprotective effect of statins in our study is that the serum concentrations of statins are reduced because of hemodilution from CPB. Indeed, Verma et al.27 demonstrated an attenuation in cell injury with pravastatin only above certain serum concentrations (10 μM). Other drugs with renoprotective effects demonstrated outside of cardiac surgery failed to show renoprotective properties in patients undergoing cardiac surgery. For example, N-acetylcysteine showed a reduction of contrast-induced nephropathy in patients undergoing coronary angiography31 but failed to reduce the incidence of AKI in high-risk patients undergoing on-pump CABG surgery.

Our study results support the findings of others who reported that preoperative statin therapy is not associated with a reduction in postoperative AKI.32,33 Huffmyer et al.32 demonstrated a lack of association between preoperative statins and acute renal failure in patients undergoing on-pump CABG surgery. However, they found, unlike our results, a reduction in hospital mortality and renal replacement therapy in patients receiving preoperative statins. This difference in the study results might be explained by their inclusion of patients undergoing CABG surgery with CPB and not patients undergoing valvular surgery as in our study. Moreover, their different definition of acute renal failure (reduction of eGFR of >50%) excluded patients with risk of renal dysfunction (according to the RIFLE criteria) from their analysis. Most importantly, preoperative risk factors such as diabetes mellitus, preoperative left ventricular ejection fraction, and other preoperative medications (β-blockers, calcium channel blockers, aspirin, and angiotensin-converting enzyme inhibitors) known to influence the incidence of AKI were not included in their analysis, which may have confounded their results. Huffmyer et al.32 found no reduction in mortality in the subset of patients requiring renal replacement therapy who received preoperative statins. This finding, in addition to the lack of association between preoperative statin use and acute renal failure in their report, makes a renal-specific benefit of statins unlikely. Indeed, the authors explain the need for renal replacement therapy after CABG as a possible marker of patient systemic injury.

Our study results contrast with other trials that have shown an association between preoperative statin therapy and a reduction in hospital mortality in patients undergoing cardiac surgery with CPB.14,15,33 In our study, there was no consistent protocol for resumption of statin drugs after surgery. It may be that any potential protective effects of statin therapy on mortality are reduced by the delayed postoperative reinstitution of statins in some patients. The deleterious effects of postoperative statin withdrawal on mortality have been reported.34,35 Another explanation, albeit speculative, may be that preoperative statin use is a marker of better overall preoperative health care. Ali and Buth,36 in a retrospective report of 2886 patients undergoing cardiac surgery with CPB, showed similar mortality findings to this report: a lack of association between preoperative statin and in-hospital mortality.

Our risk-adjusted model identified several variables associated with an increased risk for postoperative AKI. Several of these variables such as preoperative renal insufficiency, heart failure, reduced left ventricular function, and emergency surgery have been identified in a validated scoring system for predicting acute renal failure after cardiac surgery.37 Red blood cell transfusion was also found to be associated with an increased risk for postoperative AKI, which is consistent with other studies.2,9,38 The association between a prolonged CPB time and postoperative AKI in our study has also been reported.8,9

Our study has several limitations. In this retrospective cohort study design, the specific formulation, dose, and duration for preoperative statin therapy were not considered. Kourliouros et al.39 recently reported a dose-related effect of statins on atrial fibrillation incidence after cardiac surgery. In their study, high-dose statins had the greatest preventative effect, whereas low-dose statins did not influence postoperative atrial fibrillation, suggesting that the pleiotropic effects of statins may also be dose related. We used serum creatinine as a surrogate for renal function in this study; calculated creatinine clearance has been shown to be more sensitive in the estimation of renal reserve and the need for renal replacement therapy in the postoperative period.40

This study did not show a statistically significant difference in any of the 3 outcomes of AKI, postoperative dialysis, or hospital mortality. These findings could either be because statin therapy truly does not affect the frequency of these outcomes or because the sample size of this study was not large enough to detect a difference between the 2 groups. A post hoc sample size calculation suggests that approximately 27,000 patients per group would be necessary to exclude a type II error in assessing the effects of statin therapy on the frequency of AKI. Furthermore, 15,000 patients per group would be needed to find a reduction in the frequency of postoperative dialysis or hospital mortality with statin versus no statin therapy. Even if found to have a beneficial effect on renal outcomes and mortality after cardiac surgery with a larger patient population, the magnitude of renoprotection by statins is likely to be low.

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CONCLUSION

Although statins' pleiotropic effects offered a biologically plausible mechanism for a potential renoprotective effect in cardiac surgical patients, preoperative statin therapy was not associated with a reduction in the incidence of AKI, postoperative dialysis, or hospital mortality in patients undergoing cardiac surgery.

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