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• W2015672635 abstract "Acute kidney injury (AKI) is a serious complication of cardiovascular surgery. Although some nonexperimental studies suggest that statin use may reduce postsurgical AKI, methodologic differences in study designs leave uncertainty regarding the reality or magnitude of the effect. The aim of this study was to estimate the effect of preoperative statin initiation on AKI after coronary artery bypass grafting (CABG) using an epidemiologic approach more closely simulating a randomized controlled trial in a large CABG patient population. Health care claims from large, employer-based and Medicare insurance databases for 2000 to 2010 were used. To minimize healthy user bias, patients were identified who underwent nonemergent CABG who either newly initiated a statin <20 days before surgery or were unexposed for ≥200 days before CABG. AKI was identified <15 days after CABG. Multivariate-adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using Poisson regression. Analyses were repeated using propensity score methods adjusted for clinical and health care utilization variables. A total of 17,077 CABG patients were identified. Post-CABG AKI developed in 3.4% of statin initiators and 6.2% of noninitiators. After adjustment, a protective effect of statin initiation on AKI was observed (RR 0.78, 95% CI 0.63 to 0.96). This effect differed by age, with an RR of 0.91 (95% CI 0.68 to 1.20) for patients aged ≥65 years and an RR of 0.62 (95% CI 0.45 to 0.86) for those aged <65 years, although AKI was more common in the older group (7.7% vs 4.0%). In conclusion, statin initiation immediately before CABG may modestly reduce the risk for postoperative AKI, particularly in younger CABG patients. Acute kidney injury (AKI) is a serious complication of cardiovascular surgery. Although some nonexperimental studies suggest that statin use may reduce postsurgical AKI, methodologic differences in study designs leave uncertainty regarding the reality or magnitude of the effect. The aim of this study was to estimate the effect of preoperative statin initiation on AKI after coronary artery bypass grafting (CABG) using an epidemiologic approach more closely simulating a randomized controlled trial in a large CABG patient population. Health care claims from large, employer-based and Medicare insurance databases for 2000 to 2010 were used. To minimize healthy user bias, patients were identified who underwent nonemergent CABG who either newly initiated a statin <20 days before surgery or were unexposed for ≥200 days before CABG. AKI was identified <15 days after CABG. Multivariate-adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using Poisson regression. Analyses were repeated using propensity score methods adjusted for clinical and health care utilization variables. A total of 17,077 CABG patients were identified. Post-CABG AKI developed in 3.4% of statin initiators and 6.2% of noninitiators. After adjustment, a protective effect of statin initiation on AKI was observed (RR 0.78, 95% CI 0.63 to 0.96). This effect differed by age, with an RR of 0.91 (95% CI 0.68 to 1.20) for patients aged ≥65 years and an RR of 0.62 (95% CI 0.45 to 0.86) for those aged <65 years, although AKI was more common in the older group (7.7% vs 4.0%). In conclusion, statin initiation immediately before CABG may modestly reduce the risk for postoperative AKI, particularly in younger CABG patients. Statins may have anti-inflammatory1Chello M. Patti G. Candura D. Mastrobuoni S. Di Sciascio G. Agro F. Carassiti M. Covino E. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (198) Google Scholar and endothelial stabilizing2Giusti-Paiva A. Martinez M.R. Felix J.V. da Rocha M.J. Carnio E.C. Elias L.L. Antunes-Rodrigues J. Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats.Shock. 2004; 21: 271-275Crossref PubMed Scopus (103) Google Scholar pleiotropic effects with potential benefits on kidney function,3Mithani S. Kuskowski M. Slinin Y. Ishani A. McFalls E. Adabag S. Dose-dependent effect of statins on the incidence of acute kidney injury after cardiac surgery.Ann Thorac Surg. 2011; 91: 520-525Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar motivating investigation into protective effects against postsurgical kidney injury.3Mithani S. Kuskowski M. Slinin Y. Ishani A. McFalls E. Adabag S. Dose-dependent effect of statins on the incidence of acute kidney injury after cardiac surgery.Ann Thorac Surg. 2011; 91: 520-525Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 4Argalious M. Xu M. Sun Z. Smedira N. Koch C.G. Preoperative statin therapy is not associated with a reduced incidence of postoperative acute kidney injury after cardiac surgery.Anesth Analg. 2010; 111: 324-330Crossref PubMed Scopus (66) Google Scholar, 5Pan W. Pintar T. Anton J. Lee V.V. Vaughn W.K. Collard C.D. Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery.Circulation. 2004; 110: II45-II49PubMed Google Scholar, 6Clark L.L. Ikonomidis J.S. Crawford Jr., F.A. Crumbley III, A. Kratz J.M. Stroud M.R. Woolson R.F. Bruce J.J. Nicholas J.S. Lackland D.T. Zile M.R. Spinale F.G. Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: an 8-year retrospective cohort study.J Thorac Cardiovasc Surg. 2006; 131: 679-685Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 7Le Manach Y. Ibanez Esteves C. Bertrand M. Goarin J.P. Fleron M.H. Coriat P. Koskas F. Riou B. Landais P. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing vascular surgery.Anesthesiology. 2011; 114: 98-104Crossref PubMed Scopus (58) Google Scholar, 8Virani S.S. Nambi V. Polsani V.R. Lee V.V. Elayda M. Kohsaka S. Pan W. Reul R.M. Wilson J.M. Petersen L.A. Willerson J.T. Ballantyne C.M. Preoperative statin therapy decreases risk of postoperative renal insufficiency.Cardiovasc Ther. 2010; 28: 80-86Crossref PubMed Scopus (36) Google Scholar, 9Welten G.M. Chonchol M. Schouten O. Hoeks S. Bax J.J. van Domburg R.T. van Sambeek M. Poldermans D. Statin use is associated with early recovery of kidney injury after vascular surgery and improved long-term outcome.Nephrol Dial Transplant. 2008; 23: 3867-3873Crossref PubMed Scopus (62) Google Scholar, 10Prowle J.R. Calzavacca P. Licari E. Ligabo E.V. Echeverri J.E. Haase M. Haase-Fielitz A. Bagshaw S.M. Devarajan P. Bellomo R. Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery.Nephrology (Carlton). 2012; 17: 215-224Crossref PubMed Scopus (62) Google Scholar, 11Huffmyer J.L. Mauermann W.J. Thiele R.H. Ma J.Z. Nemergut E.C. Preoperative statin administration is associated with lower mortality and decreased need for postoperative hemodialysis in patients undergoing coronary artery bypass graft surgery.J Cardiothorac Vasc Anesth. 2009; 23: 468-473Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 12Tabata M. Khalpey Z. Pirundini P.A. Byrne M.L. Cohn L.H. Rawn J.D. Renoprotective effect of preoperative statins in coronary artery bypass grafting.Am J Cardiol. 2007; 100: 442-444Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 13Kor D.J. Brown M.J. Iscimen R. Brown D.R. Whalen F.X. Roy T.K. Keegan M.T. Perioperative statin therapy and renal outcomes after major vascular surgery: a propensity-based analysis.J Cardiothorac Vasc Anesth. 2008; 22: 210-216Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 14Molnar A.O. Coca S.G. Devereaux P.J. Jain A.K. Kitchlu A. Luo J. Parikh C.R. Paterson J.M. Siddiqui N. Wald R. Walsh M. Garg A.X. Statin use associates with a lower incidence of acute kidney injury after major elective surgery.J Am Soc Nephrol. 2011; 22: 939-946Crossref PubMed Scopus (94) Google Scholar, 15Brunelli S.M. Waikar S.S. Bateman B.T. Chang T.I. Lii J. Garg A.X. Winkelmayer W.C. Choudhry N.K. Preoperative statin use and postoperative acute kidney injury.Am J Med. 2012; 125: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar However, studies have used widely varying definitions of preoperative statin use, including prescribed statin use at the time of surgery,4Argalious M. Xu M. Sun Z. Smedira N. Koch C.G. Preoperative statin therapy is not associated with a reduced incidence of postoperative acute kidney injury after cardiac surgery.Anesth Analg. 2010; 111: 324-330Crossref PubMed Scopus (66) Google Scholar, 5Pan W. Pintar T. Anton J. Lee V.V. Vaughn W.K. Collard C.D. Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery.Circulation. 2004; 110: II45-II49PubMed Google Scholar, 6Clark L.L. Ikonomidis J.S. Crawford Jr., F.A. Crumbley III, A. Kratz J.M. Stroud M.R. Woolson R.F. Bruce J.J. Nicholas J.S. Lackland D.T. Zile M.R. Spinale F.G. Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: an 8-year retrospective cohort study.J Thorac Cardiovasc Surg. 2006; 131: 679-685Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 8Virani S.S. Nambi V. Polsani V.R. Lee V.V. Elayda M. Kohsaka S. Pan W. Reul R.M. Wilson J.M. Petersen L.A. Willerson J.T. Ballantyne C.M. Preoperative statin therapy decreases risk of postoperative renal insufficiency.Cardiovasc Ther. 2010; 28: 80-86Crossref PubMed Scopus (36) Google Scholar administration the day of or the day before surgery,11Huffmyer J.L. Mauermann W.J. Thiele R.H. Ma J.Z. Nemergut E.C. Preoperative statin administration is associated with lower mortality and decreased need for postoperative hemodialysis in patients undergoing coronary artery bypass graft surgery.J Cardiothorac Vasc Anesth. 2009; 23: 468-473Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 12Tabata M. Khalpey Z. Pirundini P.A. Byrne M.L. Cohn L.H. Rawn J.D. Renoprotective effect of preoperative statins in coronary artery bypass grafting.Am J Cardiol. 2007; 100: 442-444Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Brunelli S.M. Waikar S.S. Bateman B.T. Chang T.I. Lii J. Garg A.X. Winkelmayer W.C. Choudhry N.K. Preoperative statin use and postoperative acute kidney injury.Am J Med. 2012; 125: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar and pharmacy dispensing <90 days before coronary artery bypass grafting (CABG).14Molnar A.O. Coca S.G. Devereaux P.J. Jain A.K. Kitchlu A. Luo J. Parikh C.R. Paterson J.M. Siddiqui N. Wald R. Walsh M. Garg A.X. Statin use associates with a lower incidence of acute kidney injury after major elective surgery.J Am Soc Nephrol. 2011; 22: 939-946Crossref PubMed Scopus (94) Google Scholar Many of these definitions fail to consider the history or duration of statin use, which may introduce bias due to the healthy user effect,16Brookhart M.A. Patrick A.R. Dormuth C. Avorn J. Shrank W. Cadarette S.M. Solomon D.H. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect.Am J Epidemiol. 2007; 166: 348-354Crossref PubMed Scopus (313) Google Scholar whereby differences in healthy behaviors between long-term medication users and nonusers may lead to exaggerated estimates of the benefits of preventive medications. These important methodologic concerns limit the ability to distinguish whether observed results are a direct beneficial effect of statins or are caused by unmeasured behavioral differences in long-term users of statins. Yet acute kidney injury (AKI) remains a serious complication of CABG, resulting in short- and long-term consequences, including chronic kidney disease (CKD), end-stage renal disease, and death.17Ishani A. Nelson D. Clothier B. Schult T. Nugent S. Greer N. Slinin Y. Ensrud K.E. The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (299) Google Scholar Understanding the effect of preoperative statin use could allow clinicians to modify the risk for an outcome for which there are currently no proved interventions. In a cohort of patients who underwent planned CABG, we compared postsurgical AKI risk among those initiating statin therapy immediately before surgery with risk among those not initiating statins using a modern epidemiologic study design and analysis aimed at minimizing confounding bias. Patients who underwent CABG surgery from 2000 to 2010 were identified in the MarketScan Commercial Claims and Encounters database and the MarketScan Medicare Supplemental and Coordination of Benefits database (Thomson Reuters, New York, New York). These databases are compilations of insurance billing data for employees, dependents, and retirees from across the United States with employer-based primary insurance (ages 18–64 years) or Medicare supplemental insurance coverage (aged ≥65 years). Adjudicated, paid inpatient, outpatient, and pharmacy claims, as well as enrollment information, are included in the databases. This study was exempted from further review by the University of North Carolina institutional review board. All patients aged ≥18 years with inpatient procedure claims for CABG, with 200 days of continuous plan enrollment before hospital admission for CABG, were identified. If a patient had multiple eligible CABG procedures, only the first was considered. The 20 days immediately before the date of hospital admission were considered the exposure window, during which statin initiation was assessed. The 180 days before the exposure window were considered the washout period, during which the absence of any statin prescription was required (see Figure 1). We required ≥1 pharmacy claim for any nonstatin medication during the washout period to ensure pharmacy benefit utilization. Patients with inpatient or outpatient diagnosis codes for AKI, unspecified renal failure, or end-stage renal disease in the 200 days before CABG were excluded. To restrict to planned CABG procedures by removing patients with emergency surgeries, we excluded patients with inpatient claims for myocardial infarction or unstable angina during the 20-day exposure period, CABG occurring after the fifth day of hospitalization, or angiographic studies in the 3 days before CABG. Statin initiation was defined as having a pharmacy dispensing claim for any statin during the exposure window, without any statin claims during the preceding baseline period. Nonusers had no observable statin use during the exposure or baseline windows and were required to have an outpatient physician's office visit during the exposure window to ensure health care utilization. Baseline covariates for multivariate regression and propensity score (PS) models included claims for diagnoses, procedures, prevalent medication use, and preoperative initiation of other, nonstatin medications. Included covariates are listed in Table 1. Baseline diagnoses and procedures were assessed in the 200 days before hospital admission for CABG and during the hospitalization up to the day of surgery and included age, gender, year of surgery, number of grafts in surgery, diagnoses of cardiovascular conditions, indicators of cardiovascular disease management, acute cardiovascular events and procedures, evidence of renal conditions, number of emergency department visits, and number of hospitalizations. Claims for medications during the washout period were considered prevalent medication use. If the medications were newly initiated during the exposure window without use during the washout period, the medications were considered newly initiated and considered separately in the analysis.Table 1Baseline demographics and clinical characteristics by statin initiation statusVariableStatin Noninitiators (n = 13,992)Statin Initiators (n = 3,085)Male10,394 (74.3%)2,453 (79.5%)Age (yrs)65.4 ± 11.062.5 ± 10.0MarketScan database Commercial Claims and Encounters7,135 (51.0%)1,978 (64.1%) Medicare Supplemental and Coordination of Benefits6,857 (49.0%)1,107 (35.9%)Health care utilization Day of hospitalization on which CABG was performed0.88 ± 1.260.49 ± 0.99 Number of lipid tests∗Occurring <200 days before admission for CABG.0.68 ± 1.110.84 ± 1.12 Number of creatinine measurements∗Occurring <200 days before admission for CABG.0.04 ± 0.370.03 ± 0.25 Number of hospitalizations∗Occurring <200 days before admission for CABG.0.67 ± 0.760.47 ± 0.70 Number of emergency department visits∗Occurring <200 days before admission for CABG.0.14 ± 0.490.11 ± 0.43Cardiovascular disease management Angiography performed10,492 (75.0%)2,634 (85.4%) Cardiac stress test performed8,381 (59.9%)2,166 (70.2%) Echocardiography performed8,030 (57.4%)1,723 (55.9%)Cardiovascular and co-morbid conditions Number of vessels bypassed during surgery1 or 25,265 (37.6%)951 (30.8%)3–57,565 (54.1%)1,779 (57.7%)≥6862 (6.2%)259 (8.4%) Diabetes mellitus4,170 (29.8%)813 (26.4%) CKD109 (0.8%)13 (0.4%) Other kidney disease Proteinuria70 (0.5%)13 (0.4%) Hypertension7,208 (51.5%)1,596 (51.7%) Hyperlipidemia4,550 (32.5%)1,283 (41.6%) Other ischemic heart disease12,811 (91.6%)2,972 (96.3%) Atrial fibrillation1,422 (10.2%)163 (5.3%)Acute events in previous 6 months Recent myocardial infarction†Not including events that occurred in the 20 days before hospital admission for CABG, because those patients were excluded.484 (3.5%)108 (3.5%) History of myocardial infarction364 (2.6%)83 (2.7%) Unstable angina†Not including events that occurred in the 20 days before hospital admission for CABG, because those patients were excluded.1,743 (12.5%)464 (15.0%) Stroke3,723 (26.6%)746 (24.2%) Insertion of a coronary stent236 (1.7%)51 (1.7%) Angioplasty228 (1.6%)50 (1.6%)Prevalent medication use during baseline Angiotensin-converting enzyme inhibitors4,349 (31.1%)916 (29.7%) Angiotensin receptor blockers2,212 (15.8%)434 (14.1%) β blockers4,981 (35.6%)982 (31.8%) Calcium channel blockers3,219 (23.0%)607 (19.7%) Antiplatelet agents1,497 (10.7%)231 (7.5%) α blockers1,324 (9.5%)200 (6.5%) Thiazide diuretics3,215 (23.0%)675 (21.9%) Potassium-sparing diuretics880 (6.3%)124 (4.0%) Loop diuretics1,794 (12.8%)210 (6.8%) Niacin250 (1.8%)36 (1.2%) Fibrates976 (7.0%)150 (4.9%) Ezetimibe637 (4.6%)85 (2.8%) Anticoagulants1,031 (7.4%)106 (3.4%) Nonsteroidal anti-inflammatory drugs2,612 (18.7%)562 (18.2%)Medications initiated during exposure window Angiotensin-converting enzyme inhibitors1,410 (10.1%)606 (19.6%) Angiotensin receptor blockers573 (4.1%)189 (6.1%) β blockers2,832 (20.2%)1,498 (48.6%) Calcium channel blockers928 (6.6%)306 (9.9%) Antiplatelet agents549 (3.9%)253 (8.2%) α blockers546 (3.9%)248 (8.0%) Thiazide diuretics839 (6.0%)246 (8.0%) Potassium-sparing diuretics249 (1.8%)52 (1.7%) Loop diuretics634 (4.5%)106 (3.4%) Niacin69 (0.5%)49 (1.6%) Fibrates264 (1.9%)57 (1.9%) Ezetimibe143 (1.0%)176 (5.7%) Anticoagulants308 (2.2%)47 (1.5%) Nonsteroidal anti-inflammatory drugs456 (3.3%)78 (2.5%)Data are expressed as mean ± SD or as number (percentage).∗ Occurring <200 days before admission for CABG.† Not including events that occurred in the 20 days before hospital admission for CABG, because those patients were excluded. Open table in a new tab Data are expressed as mean ± SD or as number (percentage). Inpatient claims in the 15 days after CABG were searched for International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for AKI (584.5 to 584.9). Sensitivity analyses were performed using a broader definition of kidney failure (any of the following diagnosis codes: acute renal failure [584.5 to 584.9], end-stage renal disease [585.6], or unspecified renal failure [586]). We estimated the association between statin initiation and AKI using multivariate Poisson regression, resulting in adjusted risk ratios (RRs) and 95% confidence intervals (CIs).18Zou G. A modified Poisson regression approach to prospective studies with binary data.Am J Epidemiol. 2004; 159: 702-706Crossref PubMed Scopus (6136) Google Scholar We also performed regression analyses using stabilized inverse probability of treatment weighting.19Cole S.R. Hernan M.A. Constructing inverse probability weights for marginal structural models.Am J Epidemiol. 2008; 168: 656-664Crossref PubMed Scopus (1620) Google Scholar Multivariate logistic regression was used to estimate the predicted probability of initiating a statin, or PS, for each patient in the sample using the prespecified covariates described previously. To exclude patients treated contrary to prediction, as their extreme weights may disproportionately influence the effect measure estimate,20Sturmer T. Rothman K.J. Avorn J. Glynn R.J. Treatment effects in the presence of unmeasured confounding: dealing with observations in the tails of the propensity score distribution–a simulation study.Am J Epidemiol. 2010; 172: 843-854Crossref PubMed Scopus (296) Google Scholar we trimmed patients with PS less than the 1st percentile of the treated or greater than the 99th percentile of the untreated. The PS was then used to calculate the inverse probability of treatment weighting in the remaining patients, and the weights were applied to a Poisson regression model. Last, we performed 1-to-1 PS matching using a greedy matching algorithm21Parsons L.S. Reducing Bias in a Propensity Score Matched-Pair Sample Using Greedy Matching Techniques. SAS Institute Inc., Cary, North Carolina2001Google Scholar whereby nonusers were matched to statin initiators by PS to the fifth decimal place, if possible. We then estimated RRs using regression models in the remaining matched patients. Models were run separately in the 2 databases: commercial insurance (ages 40 to 64 years) and Medicare supplementary insurance (ages ≥65 years). We also repeated the analyses in prespecified subgroups: by gender and in those without CKD. Analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). Sensitivity analyses were performed by varying the length of the exposure window before CABG (10 to 30 days) to observe if the effect may be dependent on the length of time on statin before CABG. To estimate the extent to which medication initiation is simply a proxy for better presurgical care, the entire analysis was repeated considering β-blocker initiation as a negative control exposure22Brookhart M.A. Patrick A.R. Shrank W.H. Dormuth C.R. Validating studies of adherence through the use of control outcomes and exposures.Am J Hypertens. 2010; 23: 110Crossref PubMed Scopus (6) Google Scholar rather than statin initiation. Beta blockers are preventive cardiovascular medications with a similar behavioral profile and user population as statins, but they are not thought to confer a protective effect against postoperative AKI. Therefore, if a protective effect was observed among the β-blocker initiators, it could be assumed that our study design did not adequately address the healthy user effect and other sources of confounding bias. We identified 149,696 patients with CABG procedures with 200 days of baseline enrollment. After applying exclusion criteria, our sample consisted of 17,077 patients, 3,085 of whom newly initiated statins <20 days before CABG admission and 13,992 of whom were free of any statin use. For the distribution of day of statin initiation before CABG among the initiators, see Figure 2. Distributions of demographic and clinical variables by statin status are listed in Table 1. The sample was predominantly male. Statin initiators were predominantly commercially insured, whereas statin noninitiators were as likely to be covered by Medicare or commercial insurance. Variables were generally well balanced across treatment groups, with the notable exceptions that initiators underwent more cardiac stress tests or angiographic studies, had more diagnoses of hyperlipidemia and ischemic heart disease, and coinitiated more other cardiovascular medications. Although these characteristics may be associated with increased CVD risk, in claims data, all of these factors may also be seen as markers of better disease management, preventive health care utilization, or preoperative care. Post-CABG AKI codes occurred in 871 noninitiators (6.2%) and 104 initiators (3.4%). Unadjusted regression models yielded a highly protective effect measure estimate, but adjustment attenuated the estimate to an RR of 0.78 (95% CI 0.63 to 0.96; Table 2). When the analysis was repeated with trimmed inverse probability of treatment weighting models and PS matching, the results were very similar (see Table 2).Table 2Effect of statin initiation on acute kidney injury and any renal failure after coronary artery bypass graftingModelTreatment GroupnAKIAny Renal FailureEventsRR(95% CI)EventsRR(95% CI)—Nonusers13,992871 (6.2%)——998 (7.1%)——CrudeStatin initiators3,085104 (3.4%)0.54(0.44–0.66)111 (3.6%)0.50(0.41–0.61)Multivariate adjusted0.78(0.63–0.96)0.73(0.59–0.90)Inverse probability of treatment weightingNonusers13,347777 (5.8%)——885 (6.6%)——Statin initiators2,866101 (3.5%)0.80(0.62–1.04)107 (3.7%)0.76(0.59–0.98)PS matchedNonusers2,812134 (4.8%)——147 (5.2%)——Statin initiators2,812102 (3.6%)0.76(0.59–0.98)108 (3.8%)0.73(0.57–0.94) Open table in a new tab However, when stratifying the effect measure estimates by age, the relative protective effect was more pronounced in patients aged <65 years than in older patients (see Table 3). AKI was much more common in the older age group (7.7%) than the younger age group (4.0%). No differences were seen in other subgroups.Table 3The effect of statin initiation on acute kidney injury after coronary artery bypass grafting by age groupModelTreatment GroupAge <64 YrsAge ≥65 YrsnEventsRR(95% CI)nEventsRR(95% CI)—Noninitiators7,201325 (4.5%)——6,791546 (8.0%)——CrudeStatin initiators1,99446 (2.3%)0.51(0.38–0.70)1,09158 (5.3%)0.66(0.50–0.87)Multivariate adjusted0.62(0.48–0.86)0.91(0.69–1.20) Open table in a new tab When the length of exposure window before CABG was varied, the effect measure estimate remained constant. Additionally, when a wider definition of kidney failure was used, the results remained essentially unchanged (see Table 2). When the analysis was repeated considering β-blocker initiation in the place of statin initiation, we observed no protective effect of β-blocker initiation against post-CABG AKI, with multivariate-adjusted models yielding an RR of 0.96 (95% CI 0.84 to 1.10) and inverse probability of treatment weighting models yielding an RR of 1.02 (95% CI 0.87 to 1.19). In this cohort study of >17,000 patients, we found that the initiation of a statin before nonemergent CABG was associated with reduced risk for postsurgical AKI. The results were robust throughout sensitivity analyses and estimation methods. We observed effect measure modification by age. The protective effect was much more pronounced in younger patients. However, those <65 years of age experienced many fewer post-CABG AKI events overall, suggesting that the absolute benefit of statin treatment may not be as large as the RR suggests.23Rothman K.J. Poole C. A strengthening programme for weak associations.Int J Epidemiol. 1988; 17: 955-959Crossref PubMed Scopus (101) Google Scholar Statins lower low-density lipoprotein cholesterol, reducing the risk for cardiovascular disease. Randomized trials have also demonstrated that perioperative statin use is associated with decreased myocardial ischemia24Schouten O. Boersma E. Hoeks S.E. Benner R. van Urk H. van Sambeek M.R. Verhagen H.J. Khan N.A. Dunkelgrun M. Bax J.J. Poldermans D. Fluvastatin and perioperative events in patients undergoing vascular surgery.N Engl J Med. 2009; 361: 980-989Crossref PubMed Scopus (324) Google Scholar and atrial fibrillation,25Patti G. Chello M. Candura D. Pasceri V. D'Ambrosio A. Covino E. Di Sciascio G. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery) study.Circulation. 2006; 114: 1455-1461Crossref PubMed Scopus (547) Google Scholar which could indirectly benefit kidney function by maintaining renal perfusion during and immediately after surgery. However, the elderly are at higher AKI risk for a variety of reasons,26Rao M.K. Anderson S. The kidney in aging.in: Greenberg A. Primer on Kidney Diseases. Saunders Elsevier, Philadelphia, Pennsylvania2009: 413-419Crossref Scopus (3) Google Scholar and statins' benefit may be diluted in such an at-risk population. Other estimates of the effect of perioperative statin use on postoperative AKI have ranged from strongly protective8Virani S.S. Nambi V. Polsani V.R. Lee V.V. Elayda M. Kohsaka S. Pan W. Reul R.M. Wilson J.M. Petersen L.A. Willerson J.T. Ballantyne C.M. Preoperative statin therapy decreases risk of postoperative renal insufficiency.Cardiovasc Ther. 2010; 28: 80-86Crossref PubMed Scopus (36) Google Scholar to null.4Argalious M. Xu M. Sun Z. Smedira N. Koch C.G. Preoperative statin therapy is not associated with a reduced incidence of postoperative acute kidney injury after cardiac surgery.Anesth Analg. 2010; 111: 324-330Crossref PubMed Scopus (66) Google Scholar, 10Prowle J.R. Calzavacca P. Licari E. Ligabo E.V. Echeverri J.E. Haase M. Haase-Fielitz A. Bagshaw S.M. Devarajan P. Bellomo R. Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery.Nephrology (Carlton). 2012; 17: 215-224Crossref PubMed Scopus (62) Google Scholar, 13Kor D.J. Brown M.J. Iscimen R. Brown D.R. Whalen F.X. Roy T.K. Keegan M.T. Perioperative statin therapy and renal outcomes after major vascular surgery: a propensity-based analysis.J Cardiothorac Vasc Anesth. 2008; 22: 210-216Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Our estimate is comparable to those of other studies of the subject3Mithani S. Kuskowski M. Slinin Y. Ishani A. McFalls E. Adabag S. Dose-dependent effect of statins on the incidence of acute kidney injury after cardiac surgery.Ann Thorac Surg. 2011; 91: 520-525Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 14Molnar A.O. Coca S.G. Devereaux P.J. Jain A.K. Kitchlu A. Luo J. Parikh C.R. Paterson J.M. Siddiqui N. Wald R. Walsh M. Garg A.X. Statin use associates with a lower incidence of acute kidney injury after major elective surgery.J Am Soc Nephrol. 2011; 22: 939-946Crossref PubMed Scopus (94) Google Scholar but differs from the null result of a recent, small randomized trial10Prowle J.R. Calzavacca P. Licari E. Ligabo E.V. Echeverri J.E. Haase M. Haase-Fielitz A. Bagshaw S.M. Devarajan P. Bellomo R. Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery.Nephrology (Carlton). 2012; 17: 215-224Crossref PubMed Scopus (62) Google Scholar restricted to patients at high AKI risk. We saw little protective effect in older patients but observed the protective effect primarily in the younger, low-risk patients, which could explain the difference in results. Nonrandomized studies of preventive medications are potentially subject to bias, which can inflate protective effect measure estimates. Yet through the implementation of a rigorous method, our study helps more accurately quantify the potential benefit of statins in 4 ways. First, we adopted a design explicitly aimed at minimizing the healthy user effect, a potentially important bias in nonexperimental statin studies. We restricted our study to new users who initiated statins immediately before surgery and compared these with patients not initiating statins, removing bias created by comparing long-term, adherent users to nonusers. Second, we excluded emergency CABG procedures, resulting in a relatively homogenous patient population of those with planned CABG procedures. We speculated that statin initiation in these patients would be more dependent on physician preference or protocol than clinical factors or patient characteristics. Third, we adjusted for a wide array of clinical characteristics, including the complexity of surgery. Prevalent medication use and concurrent medication initiation were considered separate covariates. Prevalent medication use was very similar between the 2 treatment groups, but statin initiators tended to coinitiate other medications more frequently. Although statin initiation immediately before surgery may be indicative of more aggressive disease management or access to care, considering other perioperative medication initiation allowed us to more accurately assess preoperative care and adjust for differences that may exist between the treatment groups. Last, we examined the effect of β-blocker initiation on post-CABG AKI as a negative control. Beta-blocker initiation was not associated with a reduced AKI risk, suggesting that the observed effect estimate among the statin users may be a real effect, not simply unmeasured behavioral or clinical factors for which any medication initiation serves as a proxy.27Patrick A.R. Shrank W.H. Glynn R.J. Solomon D.H. Dormuth C.R. Avorn J. Cadarette S.M. Mogun H. Brookhart M.A. The association between statin use and outcomes potentially attributable to an unhealthy lifestyle in older adults.Value Health. 2011; 14: 513-520Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Nevertheless, these study findings should be interpreted in the context of the following limitations. First, despite our attempts to create comparable treatment groups, we observed differences (e.g., more health care utilization, cardiovascular disease management, and concurrent medication initiation) among the statin users, which may indicate better health status, or health care quality and access, and thus potentially better outcomes among statin users. Although we controlled for these observed factors in our analysis, the potential for unmeasured confounding remains. For example, measures of baseline glomerular function are unavailable in claims; diagnosis codes for CKD and the number of procedure claims for measures of glomerular function were used as proxies, but they may not fully capture baseline renal impairment, which is a strong risk factor for AKI.28Charytan D.M. Yang S.S. McGurk S. Rawn J. Long and short-term outcomes following coronary artery bypass grafting in patients with and without chronic kidney disease.Nephrol Dial Transplant. 2010; 25: 3654-3663Crossref PubMed Scopus (48) Google Scholar However, although glomerular function is a strong predictor of AKI, it is not obviously a predictor of statin initiation and therefore may not be a strong confounder of the association. Second, some of the included variables have been shown to have poor validity, such as CKD,29Vlasschaert M.E. Bejaimal S.A. Hackam D.G. Quinn R. Cuerden M.S. Oliver M.J. Iansavichus A. Sultan N. Mills A. Garg A.X. Validity of administrative database coding for kidney disease: a systematic review.Am J Kidney Dis. 2011; 57: 29-43Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar which would allow some residual confounding by baseline renal impairment to remain. Similarly, the sensitivity of AKI billing codes has been shown to be very poor, yet the specificity is very high.29Vlasschaert M.E. Bejaimal S.A. Hackam D.G. Quinn R. Cuerden M.S. Oliver M.J. Iansavichus A. Sultan N. Mills A. Garg A.X. Validity of administrative database coding for kidney disease: a systematic review.Am J Kidney Dis. 2011; 57: 29-43Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Although the insensitive AKI definition may underestimate true AKI occurrence, under the assumption of nondifferential misclassification of the outcome between the treatment groups, relative effect measures, such as the RRs calculated in this study, should be unbiased.30Greenland S. Lash T.L. Bias analysis.in: Rothman K.J. Greenland S. Lash T.L. Modern Epidemiology. Lippincott Williams & Wilkins, Philadelphia, Pennsylvania2008Google Scholar Third, these results may not be generalizable to all CABG patients. Most patients who underwent CABG were prevalent statin users, and many others had urgent or emergency surgeries, thus not meeting our inclusion criteria. However, emergency CABG patients likely do not have time to initiate statins before surgery. The resulting patients are those of most interest: it is among statin-naive patients that statin intervention is possible and the potential benefits of initiation need to be determined. As researchers continue to investigate and suggest additional protective and beneficial statin effects, careful consideration must be given to the designs of nonexperimental studies to ensure that they are not subject to common biases in studies of preventive medications. After considering the timing of statin initiation, observing the entire length of statin treatment, measuring important markers of preclinical care such as medication initiation, and matching nonusers to users on health care utilization, our study supports the hypothesis that prescribing a statin before CABG in those not already receiving statin therapy may modestly attenuate the incidence of post-CABG AKI, particularly among younger patients. Although many CABG patients will already be receiving statin therapy, those not yet receiving it may benefit from initiation before surgery. Dr. Layton has no conflicts of interest to declare. Dr. Kshirsagar receives investigator-initiated research funding and support as a co-investigator from the Agency for Healthcare Research and Quality. Dr. Simpson has received research support from Merck, and honoraria from Merck and Pfizer. Ms. Pate has no conflicts of interest to declare. Dr. Jonsson Funk receives investigator-initiated research funding and support as Principal Investigator from the Agency for Healthcare Research and Quality and as Co-Investigator from the Patient Centered Outcomes Research Institute. She also receives salary support through an unrestricted educational grant from the Center for Pharmacoepidemiology in the Department of Epidemiology at the University of North Carolina. Dr. Stürmer receives investigator-initiated research funding and support as Principal Investigator (RO1 AG023178) and Co-Investigator (RO1 AG018833) from the National Institute on Aging at the National Institutes of Health. He also receives research funding as Principal Investigator of the UNC-DEcIDE center from the Agency for Healthcare Research and Quality. Dr. Stürmer does not accept personal compensation of any kind from any pharmaceutical company, though he receives salary support from the Center for Pharmacoepidemiology in the Department of Epidemiology at the University of North Carolina and from unrestricted research grants from pharmaceutical companies to UNC. Dr. Brookhart has served on scientific advisory boards for Pfizer, with honoraria either donated to charity or received by UNC." @default.
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