Renoprotective Effect of Preoperative Statins in Coronary Artery Bypass Grafting

Renoprotective Effect of Preoperative Statins in Coronary Artery Bypass Grafting Minoru Tabata, MD, MPH*, Zain Khalpey, MD, PhD, Paul A. Pirundini, MD, M. Letti Byrne, MPH, Lawrence H. Cohn, MD, and James D. Rawn, MD The renoprotective effect of preoperative statin use in coronary artery bypass grafting remains poorly defined. A retrospective review of 1,802 consecutive patients who underwent isolated coronary artery bypass grafting from January 2002 to October 2005 was performed. Of those, 1,039 patients were receiving statins preoperatively, and 763 patients were not. Two propensity score–matched cohorts each of 641 patients (statin and nonstatin groups) were constructed. Multivariate logistic regression analyses for matched patients and all patients were performed to investigate whether preoperative statin use was associated with the incidence of new renal insufficiency. In a matched analysis, the statin group had a lower incidence of new renal insufficiency than the nonstatin group (1.6% vs 3.9%, odds ratio 0.39, 95% confidential interval 0.18 to 0.82, p ⴝ 0.01). Multivariate logistic regression analysis including all patients also showed that preoperative statin use (odds ratio 0.54, 95% confidence interval 0.30 to 0.99, p ⴝ 0.047) was significantly associated with low incidence of new postoperative renal insufficiency. In conclusion, preoperative statin use may be renoprotective after coronary artery bypass grafting. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:442– 444) Retrospective studies have shown that preoperative statin use reduces mortality and morbidity after coronary artery bypass grafting (CABG).1–3 The potential renoprotective effect of preoperative statins in patients who undergo CABG has not been well investigated. The aim of this study was to assess whether the preoperative use of statins was associated with the incidence of postoperative renal insufficiency after CABG. We hypothesized that the preoperative use of statins would reduce the incidence of postoperative renal insufficiency. Methods and Results We conducted a retrospective cohort study reviewing 1,802 patients who underwent isolated CABG from January 2002 to October 2005. We excluded patients who underwent off-pump CABG and patients undergoing long-term dialysis from this study. The preoperative use of statins was defined as being on any statin medication 1 day before surgery. By this definition, we found 1,039 patients who were taking statins before surgery and 763 patients who were not. The classes and doses of statins given are listed in Table 1. As preoperative management, we prescribed statins until the day before CABG and did not start statins for patients who were not receiving statins at the time of admission. We started statins for all patients after CABG unless there was a contraindication. All variables were defined on the basis of the definitions provided in the Society of Thoracic Surgery Adult Cardiac Database version 2.52. Preoperative renal insufficiency was defined as a documented history of renal insufficiency Division of Cardiac Surgery, Brigham and Women’s Hospital, Boston, Massachusetts. Manuscript received January 24, 2007; revised manuscript received and accepted March 6, 2007. *Corresponding author: Tel: 617-732-7678; fax: 617-975-0848. E-mail address: [email protected] (M. Tabata). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.03.071

Table 1 Preoperative statins and doses Statin Class and Dose (mg) Atorvastatin 5–10 15–20 30–50 60–80 Simvastatin 5–10 20 30–40 60–80 Pravastatin 10 20–25 30–40 60–80

No. of Patients

Statin Class and Dose (mg)

No. of Patients

559 174 190 102 93 406 39 173 135 59 41 4 17 16 4

Lovastatin 10 20 40 Fluvastatin 20 40 80 Rosuvastatin 10 20 40

12 1 5 6 11 2 4 5 10 4 5 1

and/or a history of creatinine ⬎2.0 mg/dl. Renal transplant patients with post-transplantation creatinine levels of ⱕ2.0 mg/dl were not included in the preoperative renal insufficiency category. Preoperative creatinine was defined as the serum creatinine level measured most recently before surgery. Postoperative renal insufficiency was defined as an increase in the serum creatinine to ⬎2.0 mg/dl and 2 times the most recent preoperative creatinine level and/or a new requirement for dialysis postoperatively. All data were collected from the Brigham and Women’s Hospital cardiac surgery database and medical records. This study was approved by the institutional review board of Brigham and Women’s Hospital. Patients’ demographic and clinical characteristics were compared between the statin and nonstatin groups. We used www.AJConline.org

Coronary Artery Disease/Renoprotective Effect of Statins in CABG

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Table 2 Preoperative characteristics of all patients Characteristic

Statin (n ⫽ 1,039)

Nonstatin (n ⫽ 763)

p Value

Age (yrs) Men Body mass index (kg/m2) Current smoking Family history of coronary artery disease Diabetes Renal insufficiency Preoperative creatinine (mg/dl) Hypertension Chronic obstructive pulmonary disease Peripheral vascular disease Cerebrovascular disease Acute myocardial infarction (within 24 h) Previous myocardial infarction (1–7 d) Previous myocardial infarction (8–21 d) Previous myocardial infarction (⬎21 d) Unstable angina pectoris New York Heart Association class III/IV History of congestive heart failure Left main coronary artery disease Triple-vessel coronary artery disease Preoperative intra-aortic balloon pump Nonelective surgery Previous coronary artery bypass surgery Previous percutaneous coronary intervention Previous noncoronary cardiac surgery ␤ blockers Angiotensin-converting enzyme inhibitors

65.8 ⫾ 10.2 796 (76.6%) 28.8 ⫾ 5.4 126 (12.1%) 322 (31.0%) 403 (38.8%) 74 (7.1%) 1.2 ⫾ 0.7 829 (79.8%) 107 (10.3%) 184 (17.7%) 141 (13.6%) 35 (3.4%) 185 (17.8%) 55 (5.3%) 229 (22.0%) 745 (71.7%) 318 (30.6%) 237 (22.8%) 402 (38.7%) 762 (73.3%) 89 (8.6%) 611 (58.8%) 38 (3.7%) 256 (24.6%) 12 (1.2%) 557 (53.6%) 269 (25.9%)

66.5 ⫾ 10.7 573 (75.1%) 28.7 ⫾ 4.8 85 (11.1%) 193 (25.3%) 273 (35.8%) 48 (6.3%) 1.2 ⫾ 0.9 570 (74.7%) 52 (6.8%) 119 (15.6%) 80 (10.5%) 40 (5.2%) 150 (19.7%) 28 (3.7%) 113 (14.8%) 591 (77.5%) 290 (38.0%) 165 (21.6%) 307 (40.2%) 523 (68.5%) 97 (12.7%) 468 (61.3%) 27 (3.5%) 140 (18.3%) 4 (0.5%) 263 (34.5%) 109 (14.3%)

0.163 0.458 0.529 0.520 0.008 0.193 0.488 0.536 0.011 0.010 0.236 0.049 0.049 0.318 0.104 ⬍0.001 0.037 0.001 0.551 0.507 0.026 0.004 0.279 0.894 0.001 0.159 ⬍0.001 ⬍0.001

2-sample Student’s t tests for continuous variables and chisquare or Fisher’s exact tests for categorical variables. We calculated the propensity score, which showed the probability of taking preoperative statins. We included all variables listed in Table 2 in the logistic regression model for the propensity score. We did not include year of procedure or surgeon in the model because there were no significant associations between preoperative statin use and those factors. We constructed 2 propensity-matched cohorts each of 641 patients using nearest-neighbor matching within a caliper of 0.05, and we compared the incidence of renal insufficiency between 2 matched groups. Then we performed multivariate logistic regression analyses to assess whether the preoperative use of statins was associated with the incidence of postoperative renal insufficiency. We created 2 models, for matched patients (n ⫽ 1,282) and all patients (n ⫽ 1,802). We included cardiopulmonary bypass time as a covariate in the first model and included propensity score and cardiopulmonary bypass time as covariates in the other model to adjust confounding factors. Age, body mass index, and preoperative serum creatinine level were included as continuous variables and others were as binary ones. We created different propensity-score models for each subgroup. Continuous variables are expressed as mean ⫾ SD. A p value was considered statistically significant when it was ⬍0.05. Statistical analysis was performed with SPSS version 11.5 (SPSS, Inc., Chicago, Illinois).

Patient characteristics are listed in Table 2. Those in the statin group more frequently had family histories of coronary artery disease, histories of hypertension, chronic obstructive pulmonary disease, cerebrovascular disease, acute myocardial infarctions (⬍24 hours before surgery), and previous myocardial infarctions (⬎21 days before surgery); more were diagnosed with triple-vessel diseases, more had undergone previous percutaneous coronary interventions, and more had the preoperative use of ␤ blockers and angiotensin-converting enzyme inhibitors. Statin users also were less frequently diagnosed with unstable angina pectoris; fewer were in New York Heart Association class III or IV, and fewer had undergone the placement of preoperative intra-aortic balloon pumps. For matched patients, all preoperative variables were balanced well between 2 groups. The incidence of new renal insufficiency was 1.6% (10 of 641) in the statin group and 3.9% (25 of 641) in the nonstatin group. The odds ratio for new renal insufficiency was 0.39 (95% confidence interval 0.18 to 0.82, p ⫽ 0.01). A multivariate logistic regression model including all 1,802 patients also showed a significant association between preoperative statin use and postoperative new renal insufficiency (odds ratio 0.54, 95% confidence interval 0.30 to 0.99, p ⫽ 0.047). Discussion A renoprotective effect of statins has been reported.4 – 6 Although some studies investigated predictors of postoper-

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ative renal failure after cardiac surgery, the effect of preoperative statins was not assessed in those studies.7–9 Statins improve endothelial function, enhance the stability of atherosclerotic plaques, decrease oxidative stress and inflammation, and inhibit the thrombogenic response.10 Some studies have shown that preoperative statins reduce an increase in the serum level of cytokines after cardiac surgery.11,12 Those effects could attenuate the adverse effect of the surgical invasiveness and cardiopulmonary bypass on the kidneys. In an animal model of ischemia-induced renal dysfunction, statin pretreatment was found to reduce serum creatinine increases by 40%, prevent inflammatory cell infiltration, and decrease the extent of tubular necrosis.13 In this study, we have shown a significant association of preoperative statin use with a lower incidence of postoperative renal insufficiency using propensity scores and a multivariate logistic regression model. This finding is consistent with a renoprotective effect of statins in patients who undergo CABG. We did not use continuous values of creatinine or glomerular filtration rate as an outcome measure, because the indication for dialysis does not necessarily depend on those variables, and dialysis could mask the peak creatinine or reduced estimated glomerular filtration rate. A limitation of this study is its observational nature. We minimized confounding using propensity score and multivariate regression analyses, but there still could be unmeasured confounders, such as the quality of preoperative care and patients’ medical knowledge. A prospective randomized controlled study is preferred to remove all confounding factors. Clinically, this study implies that preemptive preoperative statin use may reduce postoperative renal insufficiency after CABG. We did not, however, assess the effect of duration, dose, and class of statin; we do not know when, how much, and what class of statin should be administered for maximal benefit. Furthermore, the routine use of preoperative statins may result in an increased incidence of side effects, including liver dysfunction and rhabdomyolysis. Risk and benefits need to be investigated more fully. In conclusion, the preoperative use of statins is associated with a low incidence of postoperative renal insuffi-

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