Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury | Acute Kidney Injury | JAMA Internal Medicine | JAMA Network
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Figure.  Forest Plots for Mortality Associated With Angiotensin-Converting Enzyme Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB) Use in Patients Stratified by the Presence of Proteinuria, Baseline Renal Function, and the Presence of Comorbidities
Forest Plots for Mortality Associated With Angiotensin-Converting Enzyme Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB) Use in Patients Stratified by the Presence of Proteinuria, Baseline Renal Function, and the Presence of Comorbidities

Error bars indicates 95% CIs. eGFR indicates estimated glomerular filtration rate; HR, hazard ratio.

Table 1.  Baseline Characteristics of ACEI or ARB Users and Nonusersa
Baseline Characteristics of ACEI or ARB Users and Nonusersa
Table 2.  Survival, Hospitalization for a Renal Cause, ESRD, and Composite Outcome of ESRD and Sustained Doubling of SCr Concentration Associated With ACEI or ARB Use in Propensity Score–Matched Patients
Survival, Hospitalization for a Renal Cause, ESRD, and Composite Outcome of ESRD and Sustained Doubling of SCr Concentration Associated With ACEI or ARB Use in Propensity Score–Matched Patients
Table 3.  Outcomes Associated With No Previous Use, New Use, Prior Use, and Continued Use of an ACEI or ARB
Outcomes Associated With No Previous Use, New Use, Prior Use, and Continued Use of an ACEI or ARB
Table 4.  Outcomes for ACEI or ARB Use in Patients Given a Prescription Within the First 90 Days After Discharge vs After 90 Days After Discharge
Outcomes for ACEI or ARB Use in Patients Given a Prescription Within the First 90 Days After Discharge vs After 90 Days After Discharge
1.
Chertow  GM, Burdick  E, Honour  M, Bonventre  JV, Bates  DW.  Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.  J Am Soc Nephrol. 2005;16(11):3365-3370. doi:10.1681/ASN.2004090740PubMedGoogle ScholarCrossref
2.
Liangos  O, Wald  R, O’Bell  JW, Price  L, Pereira  BJ, Jaber  BL.  Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey.  Clin J Am Soc Nephrol. 2006;1(1):43-51. doi:10.2215/CJN.00220605PubMedGoogle ScholarCrossref
3.
Wald  R, Quinn  RR, Luo  J,  et al; University of Toronto Acute Kidney Injury Research Group.  Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.  JAMA. 2009;302(11):1179-1185. doi:10.1001/jama.2009.1322PubMedGoogle ScholarCrossref
4.
Ishani  A, Xue  JL, Himmelfarb  J,  et al.  Acute kidney injury increases risk of ESRD among elderly.  J Am Soc Nephrol. 2009;20(1):223-228. doi:10.1681/ASN.2007080837PubMedGoogle ScholarCrossref
5.
Ishani  A, Nelson  D, Clothier  B,  et al.  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(3):226-233. doi:10.1001/archinternmed.2010.514PubMedGoogle ScholarCrossref
6.
Coca  SG, Yusuf  B, Shlipak  MG, Garg  AX, Parikh  CR.  Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis.  Am J Kidney Dis. 2009;53(6):961-973. doi:10.1053/j.ajkd.2008.11.034PubMedGoogle ScholarCrossref
7.
Lo  LJ, Go  AS, Chertow  GM,  et al.  Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.  Kidney Int. 2009;76(8):893-899. doi:10.1038/ki.2009.289PubMedGoogle ScholarCrossref
8.
Amdur  RL, Chawla  LS, Amodeo  S, Kimmel  PL, Palant  CE.  Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.  Kidney Int. 2009;76(10):1089-1097. doi:10.1038/ki.2009.332PubMedGoogle ScholarCrossref
9.
Lai  C-F, Wu  V-C, Huang  T-M,  et al; National Taiwan University Hospital Study Group on Acute Renal Failure (NSARF).  Kidney function decline after a non-dialysis-requiring acute kidney injury is associated with higher long-term mortality in critically ill survivors.  Crit Care. 2012;16(4):R123. doi:10.1186/cc11419PubMedGoogle ScholarCrossref
10.
Newsome  BB, Warnock  DG, McClellan  WM,  et al.  Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction.  Arch Intern Med. 2008;168(6):609-616. doi:10.1001/archinte.168.6.609PubMedGoogle ScholarCrossref
11.
Heung  M, Steffick  DE, Zivin  K,  et al; Centers for Disease Control and Prevention CKD Surveillance Team.  Acute kidney injury recovery pattern and subsequent risk of CKD: an analysis of Veterans Health Administration data.  Am J Kidney Dis. 2016;67(5):742-752. doi:10.1053/j.ajkd.2015.10.019PubMedGoogle ScholarCrossref
12.
Lafrance  JP, Miller  DR.  Acute kidney injury associates with increased long-term mortality.  J Am Soc Nephrol. 2010;21(2):345-352. doi:10.1681/ASN.2009060636PubMedGoogle ScholarCrossref
13.
Hsu  CY, Hsu  RK, Yang  J, Ordonez  JD, Zheng  S, Go  AS.  Elevated BP after AKI.  J Am Soc Nephrol. 2016;27(3):914-923. doi:10.1681/ASN.2014111114PubMedGoogle ScholarCrossref
14.
Wu  V-C, Wu  C-H, Huang  T-M,  et al; NSARF Group.  Long-term risk of coronary events after AKI.  J Am Soc Nephrol. 2014;25(3):595-605. doi:10.1681/ASN.2013060610PubMedGoogle ScholarCrossref
15.
Harel  Z, Wald  R, Bargman  JM,  et al.  Nephrologist follow-up improves all-cause mortality of severe acute kidney injury survivors.  Kidney Int. 2013;83(5):901-908. doi:10.1038/ki.2012.451PubMedGoogle ScholarCrossref
16.
Balamuthusamy  S, Srinivasan  L, Verma  M,  et al.  Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis.  Am Heart J. 2008;155(5):791-805. doi:10.1016/j.ahj.2008.01.031PubMedGoogle ScholarCrossref
17.
Fink  HA, Ishani  A, Taylor  BC,  et al.  Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline.  Ann Intern Med. 2012;156(8):570-581. doi:10.7326/0003-4819-156-8-201204170-00008PubMedGoogle ScholarCrossref
18.
Hemmelgarn  BR, Clement  F, Manns  BJ,  et al.  Overview of the Alberta Kidney Disease Network.  BMC Nephrol. 2009;10:30. doi:10.1186/1471-2369-10-30PubMedGoogle ScholarCrossref
19.
Quan  H, Khan  N, Hemmelgarn  BR,  et al; Hypertension Outcome and Surveillance Team of the Canadian Hypertension Education Programs.  Validation of a case definition to define hypertension using administrative data.  Hypertension. 2009;54(6):1423-1428. doi:10.1161/HYPERTENSIONAHA.109.139279PubMedGoogle ScholarCrossref
20.
Levey  AS, Stevens  LA, Schmid  CH,  et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).  A new equation to estimate glomerular filtration rate.  Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-200905050-00006PubMedGoogle ScholarCrossref
21.
KDIGO Work Group.  KDIGO clinical practice guideline for acute kidney injury.  Kidney Int Suppl. 2012;2(1):1-138.Google ScholarCrossref
22.
Waikar  SS, Wald  R, Chertow  GM,  et al.  Validity of International Classification of Diseases, Ninth Revision, Clinical Modification codes for acute renal failure.  J Am Soc Nephrol. 2006;17(6):1688-1694. doi:10.1681/ASN.2006010073PubMedGoogle ScholarCrossref
23.
Government of Alberta. Pharmaceutical Information Network (PIN). 2017. http://www.albertanetcare.ca/learningcentre/Pharmaceutical-Information-Network.htm. Accessed April 16, 2017.
24.
Tonelli  M, Wiebe  N, Fortin  M,  et al; Alberta Kidney Disease Network.  Methods for identifying 30 chronic conditions: application to administrative data.  BMC Med Inform Decis Mak. 2015;15:31. doi:10.1186/s12911-015-0155-5PubMedGoogle ScholarCrossref
25.
Sarnecki  L, Gordon  L.  Analysis of acuity trends using resource intensity weights via the CIHI portal.  Stud Health Technol Inform. 2009;143:42-46.PubMedGoogle Scholar
26.
Jacobs  P, Yim  R.  Using Canadian Administrative Databases to Economic Data for Health Technology Assessments. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health; 2009.
27.
Wilson  PW, D’Agostino  RB, Levy  D, Belanger  AM, Silbershatz  H, Kannel  WB.  Prediction of coronary heart disease using risk factor categories.  Circulation. 1998;97(18):1837-1847. doi:10.1161/01.CIR.97.18.1837PubMedGoogle ScholarCrossref
28.
Quan  H, Sundararajan  V, Halfon  P,  et al.  Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.  Med Care. 2005;43(11):1130-1139. doi:10.1097/01.mlr.0000182534.19832.83PubMedGoogle ScholarCrossref
29.
Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161. doi:10.1002/pst.433PubMedGoogle ScholarCrossref
30.
Austin  PC.  Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement.  J Thorac Cardiovasc Surg. 2007;134(5):1128-1135. doi:10.1016/j.jtcvs.2007.07.021PubMedGoogle ScholarCrossref
31.
Wu  V-C, Wu  P-C, Wu  C-H,  et al; National Taiwan University Study Group on Acute Renal Failure (NSARF) Group.  The impact of acute kidney injury on the long-term risk of stroke.  J Am Heart Assoc. 2014;3(4):e000933. doi:10.1161/JAHA.114.000933PubMedGoogle ScholarCrossref
32.
Chawla  LS, Amdur  RL, Shaw  AD, Faselis  C, Palant  CE, Kimmel  PL.  Association between AKI and long-term renal and cardiovascular outcomes in United States veterans.  Clin J Am Soc Nephrol. 2014;9(3):448-456. doi:10.2215/CJN.02440213PubMedGoogle ScholarCrossref
33.
Omotoso  BA, Abdel-Rahman  EM, Xin  W,  et al.  Dialysis requirement, long-term major adverse cardiovascular events (MACE) and all-cause mortality in hospital acquired acute kidney injury (AKI): a propensity-matched cohort study.  J Nephrol. 2016;29(6):847-855. doi:10.1007/s40620-016-0321-6PubMedGoogle ScholarCrossref
34.
Ozrazgat-Baslanti  T, Thottakkara  P, Huber  M,  et al.  Acute and chronic kidney disease and cardiovascular mortality after major surgery.  Ann Surg. 2016;264(6):987-996. doi:10.1097/SLA.0000000000001582PubMedGoogle ScholarCrossref
35.
Huber  M, Ozrazgat-Baslanti  T, Thottakkara  P, Scali  S, Bihorac  A, Hobson  C.  Cardiovascular-specific mortality and kidney disease in patients undergoing vascular surgery.  JAMA Surg. 2016;151(5):441-450. doi:10.1001/jamasurg.2015.4526PubMedGoogle ScholarCrossref
36.
Ambrosioni  E, Borghi  C, Magnani  B; The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators.  The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction.  N Engl J Med. 1995;332(2):80-85. doi:10.1056/NEJM199501123320203PubMedGoogle ScholarCrossref
37.
Swedberg  K, Held  P, Kjekshus  J, Rasmussen  K, Rydén  L, Wedel  H.  Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II).  N Engl J Med. 1992;327(10):678-684. doi:10.1056/NEJM199209033271002PubMedGoogle ScholarCrossref
38.
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.  Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.  Lancet. 1993;342(8875):821-828.PubMedGoogle Scholar
39.
Køber  L, Torp-Pedersen  C, Carlsen  JE,  et al; Trandolapril Cardiac Evaluation (TRACE) Study Group.  A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.  N Engl J Med. 1995;333(25):1670-1676. doi:10.1056/NEJM199512213332503PubMedGoogle ScholarCrossref
40.
Pfeffer  MA, Braunwald  E, Moyé  LA,  et al; The SAVE Investigators.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial.  N Engl J Med. 1992;327(10):669-677. doi:10.1056/NEJM199209033271001PubMedGoogle ScholarCrossref
41.
Pfeffer  MA, McMurray  JJ, Velazquez  EJ,  et al; Valsartan in Acute Myocardial Infarction Trial Investigators.  Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.  N Engl J Med. 2003;349(20):1893-1906. doi:10.1056/NEJMoa032292PubMedGoogle ScholarCrossref
42.
Liaño  F, Pascual  J; Madrid Acute Renal Failure Study Group.  Epidemiology of acute renal failure: a prospective, multicenter, community-based study.  Kidney Int. 1996;50(3):811-818. doi:10.1038/ki.1996.380PubMedGoogle ScholarCrossref
43.
Alabdan  N, Gosmanova  EO, Tran  NQT,  et al.  Acute kidney injury in patients continued on renin-angiotensin system blockers during hospitalization.  Am J Med Sci. 2017;353(2):172-177. doi:10.1016/j.amjms.2016.09.012PubMedGoogle ScholarCrossref
44.
Lapi  F, Azoulay  L, Yin  H, Nessim  SJ, Suissa  S.  Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.  BMJ. 2013;346:e8525. doi:10.1136/bmj.e8525PubMedGoogle ScholarCrossref
45.
Bhandari  S, Ives  N, Brettell  EA,  et al.  Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease: the STOP-ACEi trial.  Nephrol Dial Transplant. 2016;31(2):255-261.PubMedGoogle Scholar
46.
Pannu  N, James  M, Hemmelgarn  B, Klarenbach  S, Network  AKD; Alberta Kidney Disease Network.  Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge.  Clin J Am Soc Nephrol. 2013;8(2):194-202. doi:10.2215/CJN.06480612PubMedGoogle ScholarCrossref
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    Original Investigation
    December 2018

    Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury

    Author Affiliations
    • 1Department of Nephrology, University of Toronto, Toronto, Ontario, Canada
    • 2Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
    • 3Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada
    • 4Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
    • 5Institute of Health Economics, Edmonton, Alberta, Canada
    JAMA Intern Med. 2018;178(12):1681-1690. doi:10.1001/jamainternmed.2018.4749
    Key Points

    Question  Is angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use associated with better outcomes after hospitalization in patients with acute kidney injury?

    Findings  In this cohort study of 46 253 adults with an episode of acute kidney injury during hospitalization, postdischarge angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use was associated with lower mortality. There was a higher risk of hospitalization for renal causes.

    Meaning  Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use may improve postdischarge outcomes in patients with acute kidney injury, but cautious monitoring for renal-specific complications may be warranted.

    Abstract

    Importance  Patients with acute kidney injury (AKI) are at an increased long-term risk of death. Effective strategies that improve long-term outcomes in patients with AKI are unknown.

    Objective  To evaluate whether the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) after hospital discharge is associated with better outcomes in patients with AKI.

    Design, Setting, and Participants  This retrospective cohort study used data from the Alberta Kidney Disease Network population database to evaluate 46 253 adults 18 years or older with an episode of AKI during a hospitalization between July 1, 2008, and March 31, 2015, in Alberta, Canada. All patients who survived to hospital discharge were followed up for a minimum of 2 years.

    Exposures  Use of an ACEI or ARB within 6 months after hospital discharge.

    Main Outcomes and Measures  The primary outcome was mortality; secondary outcomes included hospitalization for a renal cause, end-stage renal disease (ESRD), and a composite outcome of ESRD or sustained doubling of serum creatinine concentration. An AKI was defined as a 50% increase between prehospital and peak in-hospital serum creatinine concentrations. Propensity scores were used to construct a matched-pairs cohort of patients who did and did not have a prescription for an ACEI or ARB within 6 months after hospital discharge.

    Results  The study evaluated 46 253 adults (mean [SD] age, 68.6 [16.4] years; 24 436 [52.8%] male). Within 6 months of discharge, 22 193 (48.0%) of the participants were prescribed an ACEI or ARB. After adjustment for comorbidities, ACEI or ARB use before admission, demographics, baseline kidney function, other factors related to index hospitalization, and prior health care services, ACEI or ARB use was associated with lower mortality in patients with AKI after 2 years (adjusted hazard ratio, 0.85; 95% CI, 0.81-0.89). However, patients who received an ACEI or ARB had a higher risk of hospitalization for a renal cause (adjusted hazard ratio, 1.28; 95% CI, 1.12-1.46). No association was found between ACEI or ARB use and progression to ESRD.

    Conclusions and Relevance  Among patients with AKI, ACEI or ARB therapy appeared to be associated with lower mortality but a higher risk of hospitalization for a renal cause. These results suggest a potential benefit of ACEI or ARB use after AKI, but cautious monitoring for renal-specific complications may be warranted.

    Introduction

    Acute kidney injury (AKI) is a common complication in hospitalized patients and has been consistently associated with increased long-term risk of death, de novo or worsening chronic kidney disease (CKD), and end-stage renal disease (ESRD).1-11 Patients discharged after an episode of AKI have a 40% increased risk of death in the 2 years after hospitalization12 compared with patients who do not develop AKI. Increased risk of mortality in these patients may be driven by higher rates of hypertension13 and cardiovascular events14 after AKI. There are currently no known effective therapies for AKI. Although recent data suggest that nephrologist follow-up was associated with a 24% reduction in risk of death after hospitalization in patients with severe AKI requiring dialysis,15 little is known about the specific processes of care that modify outcomes after episodes of AKI. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective for reducing cardiovascular events and mortality in patients with CKD.16,17 We sought to evaluate whether the use of an ACEI or ARB was associated with better outcomes after hospitalization in patients with AKI.

    Methods
    Study Population and Data Sources

    We used the Alberta Kidney Disease Network population-based database, which has been described in detail elsewhere.18 The study cohort, which has been previously described, comprised adults 18 years or older residing in Alberta who were admitted to the hospital between July 1, 2008, and March 31, 2013, and had an episode of AKI during hospitalization.19 To be eligible for inclusion, patients had to have at least 1 outpatient serum creatinine measurement within 180 days before hospitalization to establish baseline kidney function and 1 or more measurements during the hospitalization to establish AKI. If participants had more than 1 hospitalization during this period, only the first was considered (index hospitalization). Participants who died or whose condition progressed to ESRD (estimated glomerular filtration rate [eGFR]<15 mL/min/1.73 m2, long-term dialysis, prior kidney transplant) before or during the index hospitalization were excluded. All patients were followed up from the discharge date of their index hospitalization until March 31, 2015, with a minimum follow-up of 2 years. The study was reviewed and approved by the Health Research Ethics Board at the University of Alberta and the Conjoint Health Research Ethics Board at the University of Calgary, which determined that patient consent was not required. The details of the data (how they were linked and deidentified) are summarized in the article by Hemmelgarn et al.18

    Assessment of Baseline Kidney Function

    The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate the eGFR.20 Baseline kidney function was defined as the mean outpatient serum creatinine concentration in the 180 days before the index hospitalization.

    Identification of AKI

    An AKI event was identified by changes between baseline (prehospital) and peak in-hospital serum creatinine concentration. An AKI was defined as an increase in serum creatinine concentration of 50% or greater during hospitalization or of 0.3 mg/dL (to convert to micromoles per liter, multiply by 88.4) within 48 hours and/or a need for dialysis during the index hospitalization. Severity of the AKI was determined using the consensus criteria for AKI staging from the Kidney Disease Improving Global Outcomes (KDIGO) AKI guidelines.21 Need for short-term dialysis for AKI was determined using a validated approach based on diagnosis and procedural administrative codes.22

    Assessment of Medication Use After Discharge

    Prescription drug information was obtained from the Pharmaceutical Information Network database. Community pharmacies in Alberta, Canada, are mandated to contribute drug-dispensing data to the Pharmaceutical Information Network database, and approximately 96% of drugs dispensed from community pharmacies are available in this system.23 For the primary analysis, ACEI or ARB users were defined as patients who received at least 1 prescription within 6 months after discharge. For the secondary analysis, we classified ACEI or ARB exposure into the following groups: no use (no prescription in the 6 months before or 6 months after the index hospitalization), new use (at least 1 prescription within 6 months after discharge from the index hospitalization, with no prescriptions in the 6 months before admission), prior use (at least 1 prescription in the 6 months before admission), and continued use. Patients were classified in the continuing use group if they had at least 1 prescription in the 6 months before admission and at least 1 prescription within 6 months after discharge.

    Assessment of Comorbid Conditions

    Relevant demographic characteristics, preexisting comorbid conditions (defined using validated algorithms),19,24 hospitalizations and outpatient physician visits (general practitioner and specialist visits), details of the index hospitalization (including primary admission diagnosis), and intensive care unit stay were obtained using hospitalization data, claims files, and ambulatory care classification system files. We obtained primary International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and used these to classify primary admission diagnoses using a previously published approach.24 Resource intensity weight, similar to diagnostic related group weight, was used to categorize acuity and severity of illness.25,26 Cholesterol level was defined as the mean outpatient total cholesterol concentration in the 1 year before the index hospitalization. The cholesterol levels were classified into 5 risk categories according to the Framingham Coronary Heart Disease Risk Score.27 Patients who did not have a cholesterol measurement during this period were classified as an unknown group.

    Outcomes

    The primary outcome was all-cause mortality; secondary outcomes included hospitalization for a renal cause, ESRD, and a composite outcome of ESRD or sustained doubling of serum creatinine concentration. All-cause mortality was identified using provincial vital statistics. Hospitalization for a renal cause was defined as any hospitalization after the index hospitalization discharge date until March 31, 2015, with a most responsible diagnosis code of acute renal failure, congestive heart failure, hypervolemia, hyperkalemia, or malignant hypertension (eTable 1 in the Supplement).22,28 If multiple hospitalizations occurred, only the first one was included. Transfers among hospitals were excluded from the hospitalization for a renal cause outcome. End-stage renal disease was defined as a sustained eGFR less than 15 mL/min/1.73 m2, which was at least 2 consecutive eGFR measurements of less than 15 mL/min/1.73 m2 until the end of the study follow-up period. Sustained doubling of the serum creatinine concentration was defined as a 2-fold increase from the baseline outpatient serum creatinine concentration (determined within 180 days before the index hospitalization) until the end of the study follow-up period provided that all subsequent outpatient serum creatinine concentrations during the follow-up period remained at least twice as high compared with baseline.

    Statistical Analysis

    Continuous variables were described using mean (SD) or median (interquartile range [IQR]) as appropriate. Categorical variables were described as proportions. Baseline differences between ACEI or ARB users and nonusers were addressed using a propensity score approach. Differences between groups were also compared using χ2 tests for categorical variables and t tests for all continuous variables. Statistical significance was defined as P < .05.

    A multivariable logistic regression model that included age, sex, neighborhood income quintile, aboriginal race, location of residency, health care use preceding the index hospitalization, Canadian Institute for Health Information resource intensity weight, intensive care unit admission during the index hospitalization, primary diagnostic code for hospitalization, procedures associated with AKI (cardiac catheterization, cardiac and abdominal aortic surgery), comorbid conditions, baseline kidney function (based on eGFR), cholesterol concentration (Table 1), and statin, ACEI, ARB, and β-blocker use in the 6 months before admission and after discharge was used to estimate the probability of being treated with an ACEI or ARB. We used 1-to-1 matching on the logit of the propensity score without replacement and a caliper width of 0.2 of the SD of the logit of the propensity score.29 We assessed the balance in baseline covariates before and after matching using the standardized mean difference, for which an absolute value of standardized mean difference of 10% or less indicated a high degree of similarity of the distribution of both groups.30

    Multivariable Cox proportional hazards regression models were used to estimate the association between use of ACEI or ARB after index hospitalization and all-cause mortality, hospitalization for a renal cause, ESRD, and ESRD or sustained doubling of serum creatinine concentration. Use of an ACEI or ARB was treated as a time-varying covariate. In these time-varying models, a person who was prescribed an ACEI or ARB would contribute person-time to the no ACEI or ARB use exposure group before the first ACEI or ARB was prescribed and contribute person-time to the ACEI or ARB use group after the first ACEI or ARB was prescribed. The adjusted factors included all the covariates used to estimate propensity score to minimize confounding. For the outcomes with low event rates, the adjusted models only included age and sex. Patients were censored if they moved out of the province or reached the end of the study date (March 31, 2015) for all outcomes. For the secondary outcomes, cause-specific Cox proportional hazards regression models were used in which patients were censored on the day they died. The proportional hazards assumption was evaluated and satisfied by examining plots of the log-negative log, within-group survivorship functions vs log time.

    Analyses were repeated after further categorizing ACEI or ARB users into the following groups: no previous use, new use after discharge, prior use (stopping use of a prehospital admission prescription), and continued use (continuing use of a previous prescription within 6 months after discharge). No use was the control group. Given that there are a number of potential indications for ACEI or ARB use, subgroup analyses were performed in patients stratified by those with and without proteinuria, baseline eGFR of 60 mL/min/1.73 m2 or greater vs less than 60 mL/min/1.73 m2, and the presence or absence of comorbidities, including diabetes, hypertension, chronic heart failure, or cardiovascular disease (myocardial infarction or stroke), to test statistical interactions and to determine whether similar associations were present for ACEI or ARB use across other stratifications.

    We performed a sensitivity analysis that compared outcomes in those patients who started taking an ACEI or ARB within 90 days of discharge vs after 90 days (3-6 months after discharge) to determine whether patients had worse outcomes when use of these medications was started earlier after an episode of AKI. Patients who used an ACEI or ARB within 90 days of discharge were matched to patients who used an ACEI or ARB after 90 days after discharge. To achieve balanced distribution of the pretreatment covariates, 1-to-1 matching was used as described above.

    Results
    Patient Characteristics

    Between July 1, 2008, and March 31, 2013, a total of 59 951 patients 18 years or older who resided in Alberta, Canada, were hospitalized with an episode of AKI (eFigure 1 in the Supplement). The study cohort included 46 253 patients (mean [SD] age, 68.6 [16.4] years; 24 436 [52.8%] male; 39 738 [85.9%] living in an urban location) who survived to discharge without developing ESRD before or during the index hospitalization (Table 1). A total of 23 407 (50.6%) of the cohort had prior CKD. The mean number of hospitalizations during the 3 years preceding the index hospitalization was 1.4 (IQR, 0-2), and 7848 (17.0%) of the cohort had a cardiovascular diagnostic code as the diagnosis most responsible for the index hospitalization. Most of the participants had hypertension (35 104 [75.9%]), and a large number had diabetes (17 657 [38.2%]), chronic heart failure (13 499 [29.2%]), and history of stroke or transient ischemic attack (9 690 [20.9%]). Of these patients, 9456 (42.6%) were matched 1:1 to similar patients who had no dispensed ACEI or ARB prescription within 6 months after discharge, resulting in a final study cohort of 18 912 patients. Before propensity score matching, there was moderate imbalance in the distribution of some covariates by ACEI or ARB use. After propensity score matching, balance was achieved across all included covariates (eTable 2 in the Supplement).

    Primary Outcomes

    A total of 25 211 patients (54.5%) were using an ACEI or ARB within 6 months before their index hospitalization and 22 193 (48.0%), 6 months after discharge. A large portion (17 852 [38.6%]) of the cohort never used an ACEI or ARB, whereas 3190 (6.9%) received a new prescription within 6 months after discharge. A total of 19 003 (41.1%) continued using an ACEI or ARB within 6 months after hospital discharge, and 6208 (13.4%) of previous users did not restart use of an ACEI or ARB after hospital discharge.

    In the matched analysis, the adjusted hazard ratio (HR) for mortality associated with ACEI or ARB use after hospital discharge, compared with no ACEI or ARB use, was 0.85 (95% CI, 0.81-0.89) (Table 2). Use of an ACEI or ARB after hospitalization, however, was associated with a higher risk of hospitalization for a renal cause (HR, 1.28; 95% CI, 1.12-1.46), mainly acute renal failure, congestive heart failure, and hyperkalemia. No association was found between ACEI or ARB use and progression to ESRD or between ACEI or ARB use and the composite of progression to ESRD or sustained doubling of serum creatinine concentration.

    Both new ACEI or ARB use (HR, 0.85; 95% CI, 0.78-0.93) and continued use (HR, 0.77; 95% CI, 0.73-0.80) after hospital discharge were associated with lower mortality compared with no ACEI or ARB use (Table 3). However, stopping use of an ACEI or ARB prescribed before hospital admission was associated with increased mortality (HR, 1.23; 95% CI, 1.17-1.30). Higher rates of hospitalization for a renal cause were found in patients who were given a new ACEI or ARB prescription or continued use of a previous ACEI or ARB prescription after hospital discharge compared with no ACEI or ARB use.

    Tests for interaction in matched patients showed that use of an ACEI or ARB in participants with an eGFR less than 60 mL/min/1.73 m2 (HR, 0.89; 95% CI, 0.84-0.9) compared with those with an eGFR of 60 mL/min/1.73 m2 or greater (HR, 0.81; 95% CI, 0.75-0.87; P = .03) and patients without hypertension (HR, 1.10; 95% CI, 0.94-1.28) compared with those with hypertension (HR, 0.84; 95% CI, 0.80-0.88; P  = .001) had less survival benefit (ACEI) (Figure and eFigure 2 in the Supplement). Participants with an eGFR less than 60 mL/min/1.73 m2 (HR, 1.01; 95% CI, 0.90-1.12) compared with those with an eGFR of 60 mL/min/1.73 m2 or greater (HR, 0.75; 95% CI, 0.58-0.96; P = .03) more likely had conditions that progressed to ESRD (eFigure 3 in the Supplement). Participants with myocardial infarction or stroke (HR, 1.03; 95% CI, 0.91-1.18) compared with those with no myocardial infarction or stroke (HR, 0.87; 95% CI, 0.79-0.96; P = .04) more likely had conditions that progressed to ESRD or doubling of serum creatinine concentrations (eFigure 4 in the Supplement).

    Sensitivity Analysis

    When survival was compared in patients who started taking an ACEI or ARB within 90 days after discharge from the index hospitalization vs after 90 days, there was an increased risk of mortality (HR, 1.15; 95% CI, 1.03-1.28) (Table 4). No significant differences in hospitalization for a renal cause (HR, 1.28; 95% CI, 0.99-1.65), ESRD (HR, 1.18; 95% CI, 0.96-1.47), and ESRD or sustained doubling of serum creatinine concentration (HR, 1.07; 95% CI, 0.91-1.27) were found.

    Discussion

    Using a large population-based cohort, we characterized ACEI or ARB use in patients with AKI. A large portion of the cohort (38.6%) was never prescribed an ACEI or ARB, and 13.4% of the cohort did not continue taking an ACEI or ARB after discharge. During a follow-up period of at least 2 years after discharge, patients with AKI dispensed an ACEI or ARB after the index hospitalization (new or continued use) had a lower risk of death compared with those with no ACEI or ARB use. However, ACEI or ARB use was also associated with an increased risk of hospitalization for a renal cause, mainly acute renal failure and hyperkalemia; no difference was found for ESRD.

    Recent studies have found that AKI is an independent risk factor for subsequent development of hypertension,18 stroke,31 and long-term cardiovascular events.14,32-35 To date, no studies have examined the consequences of long-term use of ACEI or ARB after an AKI episode. The association between ACEI or ARB use and survival in our study may be secondary to a reduction in cardiovascular events. Multiple previous randomized clinical trials have found that ACEI or ARB therapy is associated with a reduction in mortality in patients with cardiovascular disease, including myocardial infarctions and heart failure.36-41 A large portion of our cohort had known cardiovascular risk factors, including hypertension, diabetes, previous myocardial infarction, and chronic heart failure. In addition, more than half of the cohort had prior CKD, which is another risk factor for cardiovascular disease.

    Conservative population-based estimates of AKI incidence in hospitalized adults are in the range of 3000 per 100 000 person-years,42 and most of these patients will survive to hospital discharge. Recent KDIGO guidelines recommended that patients be followed up 3 months after an AKI episode to assess for CKD21; however, information is lacking to guide the care that these patients should receive. On the basis of our results, patients with AKI may benefit from ACEI or ARB therapy after discharge, an intervention that does not require specialized care and could be readily implemented with appropriate monitoring. In our study, only 48.0% of the cohort was dispensed an ACEI or ARB within 6 months of the index hospitalization. We also observed better survival in the subgroup of patients who were given a new ACEI or ARB prescription compared with those who did not receive an ACEI or ARB prescription. These findings suggest that there is an opportunity to improve postdischarge care in patients with AKI.

    Our findings also highlight that use of an ACEI or ARB to reduce mortality in patients with AKI may be accompanied by a tradeoff in higher rates of hospitalization for a renal cause. Use of an ACEI or ARB is known to lead to the development of AKI in hospitalized patients with hypotension, those undergoing surgery,43 or those using a combination of nonsteroidal anti-inflammatory drugs and diuretics.44 It is also unclear whether ACEI or ARB use should be continued in patients with low kidney function.45 Patients with AKI using an ACEI or ARB may require close monitoring for potential complications, such as, stopping use of an ACEI or ARB in a patient with an acute illness to prevent additional AKI events or minimizing use of other medications that may cause hyperkalemia. It is possible that the advantage of nephrologist follow-up seen in another study15 was attributable to increased surveillance of renal complications of ACEI or ARB medications.

    A previous study17 found that ACEI or ARB use slows progression of CKD and reduces risk of ESRD, particularly in those with proteinuria. Our results did not indicate any improvement in the risk of ESRD; however, the low event rate and short follow-up period may have been insufficient to detect an association with this outcome. There is a concern that prescribing an ACEI or ARB too soon after an episode of AKI can lead to deterioration in renal function. We did not see higher rates of ESRD or doubling of serum creatinine concentrations in patients who were given an ACEI or ARB in the first 90 days compared with those who received these medications after the first 90 days. It is possible that slowing the progression of CKD was offset by hemodynamic consequences of ACEI or ARB on eGFR and increased rates of acute renal failure, leading to hospitalizations. However, we found an increased risk of mortality when ACEI or ARB therapy was started within 90 days after hospital discharge, suggesting that it may be better to start use of these medications after the first 90 days.

    Strengths and Limitations

    Our study has several strengths, including a population-based design, a large cohort size, comprehensive data on community prescribing, and the ability to adjust for many important confounders. Nonetheless, there are some limitations to our analysis, related primarily to the retrospective use of administrative and laboratory data and observational design. First, entry into the cohort was limited to patients who had 1 or more outpatient serum creatinine measurements within 180 days before hospitalization and more than 1 inpatient serum creatinine measurement performed as part of hospital care in Alberta, Canada. However, additional measurements of serum creatinine levels are common in patients hospitalized for short-term medical and surgical problems. Based on prior work,46 patients who do not have serum creatinine levels measured after hospitalization have outcomes similar to those who do not have AKI; therefore, it is likely that we were able to identify all patients with AKI at high risk for poor outcomes after discharge. Second, we were unable to obtain measures of some potentially important covariates, such as blood pressure, urine output, nutritional status, and deconditioning after hospitalization with AKI, which may influence outcomes. Third, because patients were not randomized to different processes of care, there is potential for treatment × indication bias, whereby certain patient characteristics prompt differences in prescription of an ACEI or ARB thereby introducing confounding. However, using propensity score matching, we were able to balance the distribution of pretreatment covariates, thereby minimizing this risk. It is also possible that ACEI or ARB use was a marker of better follow-up or access to care. Fourth, our exposure was defined as a dispensed prescription, and the rate of adherence among patients in the ACEI or ARB group was likely not 100%.

    Conclusions

    We found that the use of an ACEI or ARB in patients with AKI after hospital discharge was associated with lower mortality but a higher rate of hospitalization for a renal cause. This observation requires further evaluation in prospective studies evaluating postdischarge care strategies for patients with AKI. In particular, our results suggest a need for a trial to evaluate treatment with an ACEI or ARB in patients with AKI to determine whether this intervention improves long-term outcomes in high-risk patients.

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    Article Information

    Accepted for Publication: July 24, 2018.

    Corresponding Author: Neesh Pannu, MD, SM, Department of Medicine, University of Alberta, 11-107 CSB, 8440-112 St, Edmonton, Alberta T6G 2G3, Canada (npannu@ualberta.ca).

    Published Online: October 27, 2018. doi:10.1001/jamainternmed.2018.4749

    Author Contributions: Drs Ye and Pannu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Brar, Ye, James, Klarenbach, Pannu.

    Acquisition, analysis, or interpretation of data: Brar, Ye, James, Hemmelgarn, Pannu.

    Drafting of the manuscript: Brar, Ye.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Brar, Ye, James, Hemmelgarn.

    Obtained funding: James, Pannu.

    Administrative, technical, or material support: Pannu.

    Supervision: Pannu.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was funded through an operating grant from the Canadian Institute of Health Research (Dr Pannu). Dr James was supported by a Canadian Institute for Health Research New Investigator Award. The Interdisciplinary Chronic Disease Collaboration is funded through a Collaborative Research and Innovation Opportunities Team Grant from Alberta Innovates–Health Solutions.

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

    Group Members: The Interdisciplinary Chronic Disease Collaboration members are Brenda Hemmelgarn, MD, Braden Manns, MD, and Marcello Tonelli, MD.

    Disclaimer: The interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta or Alberta Health Services. Neither the Government of Alberta nor Alberta Health Services express any opinion in relation to this study.

    References
    1.
    Chertow  GM, Burdick  E, Honour  M, Bonventre  JV, Bates  DW.  Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.  J Am Soc Nephrol. 2005;16(11):3365-3370. doi:10.1681/ASN.2004090740PubMedGoogle ScholarCrossref
    2.
    Liangos  O, Wald  R, O’Bell  JW, Price  L, Pereira  BJ, Jaber  BL.  Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey.  Clin J Am Soc Nephrol. 2006;1(1):43-51. doi:10.2215/CJN.00220605PubMedGoogle ScholarCrossref
    3.
    Wald  R, Quinn  RR, Luo  J,  et al; University of Toronto Acute Kidney Injury Research Group.  Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.  JAMA. 2009;302(11):1179-1185. doi:10.1001/jama.2009.1322PubMedGoogle ScholarCrossref
    4.
    Ishani  A, Xue  JL, Himmelfarb  J,  et al.  Acute kidney injury increases risk of ESRD among elderly.  J Am Soc Nephrol. 2009;20(1):223-228. doi:10.1681/ASN.2007080837PubMedGoogle ScholarCrossref
    5.
    Ishani  A, Nelson  D, Clothier  B,  et al.  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(3):226-233. doi:10.1001/archinternmed.2010.514PubMedGoogle ScholarCrossref
    6.
    Coca  SG, Yusuf  B, Shlipak  MG, Garg  AX, Parikh  CR.  Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis.  Am J Kidney Dis. 2009;53(6):961-973. doi:10.1053/j.ajkd.2008.11.034PubMedGoogle ScholarCrossref
    7.
    Lo  LJ, Go  AS, Chertow  GM,  et al.  Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.  Kidney Int. 2009;76(8):893-899. doi:10.1038/ki.2009.289PubMedGoogle ScholarCrossref
    8.
    Amdur  RL, Chawla  LS, Amodeo  S, Kimmel  PL, Palant  CE.  Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.  Kidney Int. 2009;76(10):1089-1097. doi:10.1038/ki.2009.332PubMedGoogle ScholarCrossref
    9.
    Lai  C-F, Wu  V-C, Huang  T-M,  et al; National Taiwan University Hospital Study Group on Acute Renal Failure (NSARF).  Kidney function decline after a non-dialysis-requiring acute kidney injury is associated with higher long-term mortality in critically ill survivors.  Crit Care. 2012;16(4):R123. doi:10.1186/cc11419PubMedGoogle ScholarCrossref
    10.
    Newsome  BB, Warnock  DG, McClellan  WM,  et al.  Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction.  Arch Intern Med. 2008;168(6):609-616. doi:10.1001/archinte.168.6.609PubMedGoogle ScholarCrossref
    11.
    Heung  M, Steffick  DE, Zivin  K,  et al; Centers for Disease Control and Prevention CKD Surveillance Team.  Acute kidney injury recovery pattern and subsequent risk of CKD: an analysis of Veterans Health Administration data.  Am J Kidney Dis. 2016;67(5):742-752. doi:10.1053/j.ajkd.2015.10.019PubMedGoogle ScholarCrossref
    12.
    Lafrance  JP, Miller  DR.  Acute kidney injury associates with increased long-term mortality.  J Am Soc Nephrol. 2010;21(2):345-352. doi:10.1681/ASN.2009060636PubMedGoogle ScholarCrossref
    13.
    Hsu  CY, Hsu  RK, Yang  J, Ordonez  JD, Zheng  S, Go  AS.  Elevated BP after AKI.  J Am Soc Nephrol. 2016;27(3):914-923. doi:10.1681/ASN.2014111114PubMedGoogle ScholarCrossref
    14.
    Wu  V-C, Wu  C-H, Huang  T-M,  et al; NSARF Group.  Long-term risk of coronary events after AKI.  J Am Soc Nephrol. 2014;25(3):595-605. doi:10.1681/ASN.2013060610PubMedGoogle ScholarCrossref
    15.
    Harel  Z, Wald  R, Bargman  JM,  et al.  Nephrologist follow-up improves all-cause mortality of severe acute kidney injury survivors.  Kidney Int. 2013;83(5):901-908. doi:10.1038/ki.2012.451PubMedGoogle ScholarCrossref
    16.
    Balamuthusamy  S, Srinivasan  L, Verma  M,  et al.  Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis.  Am Heart J. 2008;155(5):791-805. doi:10.1016/j.ahj.2008.01.031PubMedGoogle ScholarCrossref
    17.
    Fink  HA, Ishani  A, Taylor  BC,  et al.  Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline.  Ann Intern Med. 2012;156(8):570-581. doi:10.7326/0003-4819-156-8-201204170-00008PubMedGoogle ScholarCrossref
    18.
    Hemmelgarn  BR, Clement  F, Manns  BJ,  et al.  Overview of the Alberta Kidney Disease Network.  BMC Nephrol. 2009;10:30. doi:10.1186/1471-2369-10-30PubMedGoogle ScholarCrossref
    19.
    Quan  H, Khan  N, Hemmelgarn  BR,  et al; Hypertension Outcome and Surveillance Team of the Canadian Hypertension Education Programs.  Validation of a case definition to define hypertension using administrative data.  Hypertension. 2009;54(6):1423-1428. doi:10.1161/HYPERTENSIONAHA.109.139279PubMedGoogle ScholarCrossref
    20.
    Levey  AS, Stevens  LA, Schmid  CH,  et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).  A new equation to estimate glomerular filtration rate.  Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-200905050-00006PubMedGoogle ScholarCrossref
    21.
    KDIGO Work Group.  KDIGO clinical practice guideline for acute kidney injury.  Kidney Int Suppl. 2012;2(1):1-138.Google ScholarCrossref
    22.
    Waikar  SS, Wald  R, Chertow  GM,  et al.  Validity of International Classification of Diseases, Ninth Revision, Clinical Modification codes for acute renal failure.  J Am Soc Nephrol. 2006;17(6):1688-1694. doi:10.1681/ASN.2006010073PubMedGoogle ScholarCrossref
    23.
    Government of Alberta. Pharmaceutical Information Network (PIN). 2017. http://www.albertanetcare.ca/learningcentre/Pharmaceutical-Information-Network.htm. Accessed April 16, 2017.
    24.
    Tonelli  M, Wiebe  N, Fortin  M,  et al; Alberta Kidney Disease Network.  Methods for identifying 30 chronic conditions: application to administrative data.  BMC Med Inform Decis Mak. 2015;15:31. doi:10.1186/s12911-015-0155-5PubMedGoogle ScholarCrossref
    25.
    Sarnecki  L, Gordon  L.  Analysis of acuity trends using resource intensity weights via the CIHI portal.  Stud Health Technol Inform. 2009;143:42-46.PubMedGoogle Scholar
    26.
    Jacobs  P, Yim  R.  Using Canadian Administrative Databases to Economic Data for Health Technology Assessments. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health; 2009.
    27.
    Wilson  PW, D’Agostino  RB, Levy  D, Belanger  AM, Silbershatz  H, Kannel  WB.  Prediction of coronary heart disease using risk factor categories.  Circulation. 1998;97(18):1837-1847. doi:10.1161/01.CIR.97.18.1837PubMedGoogle ScholarCrossref
    28.
    Quan  H, Sundararajan  V, Halfon  P,  et al.  Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.  Med Care. 2005;43(11):1130-1139. doi:10.1097/01.mlr.0000182534.19832.83PubMedGoogle ScholarCrossref
    29.
    Austin  PC.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.  Pharm Stat. 2011;10(2):150-161. doi:10.1002/pst.433PubMedGoogle ScholarCrossref
    30.
    Austin  PC.  Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement.  J Thorac Cardiovasc Surg. 2007;134(5):1128-1135. doi:10.1016/j.jtcvs.2007.07.021PubMedGoogle ScholarCrossref
    31.
    Wu  V-C, Wu  P-C, Wu  C-H,  et al; National Taiwan University Study Group on Acute Renal Failure (NSARF) Group.  The impact of acute kidney injury on the long-term risk of stroke.  J Am Heart Assoc. 2014;3(4):e000933. doi:10.1161/JAHA.114.000933PubMedGoogle ScholarCrossref
    32.
    Chawla  LS, Amdur  RL, Shaw  AD, Faselis  C, Palant  CE, Kimmel  PL.  Association between AKI and long-term renal and cardiovascular outcomes in United States veterans.  Clin J Am Soc Nephrol. 2014;9(3):448-456. doi:10.2215/CJN.02440213PubMedGoogle ScholarCrossref
    33.
    Omotoso  BA, Abdel-Rahman  EM, Xin  W,  et al.  Dialysis requirement, long-term major adverse cardiovascular events (MACE) and all-cause mortality in hospital acquired acute kidney injury (AKI): a propensity-matched cohort study.  J Nephrol. 2016;29(6):847-855. doi:10.1007/s40620-016-0321-6PubMedGoogle ScholarCrossref
    34.
    Ozrazgat-Baslanti  T, Thottakkara  P, Huber  M,  et al.  Acute and chronic kidney disease and cardiovascular mortality after major surgery.  Ann Surg. 2016;264(6):987-996. doi:10.1097/SLA.0000000000001582PubMedGoogle ScholarCrossref
    35.
    Huber  M, Ozrazgat-Baslanti  T, Thottakkara  P, Scali  S, Bihorac  A, Hobson  C.  Cardiovascular-specific mortality and kidney disease in patients undergoing vascular surgery.  JAMA Surg. 2016;151(5):441-450. doi:10.1001/jamasurg.2015.4526PubMedGoogle ScholarCrossref
    36.
    Ambrosioni  E, Borghi  C, Magnani  B; The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators.  The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction.  N Engl J Med. 1995;332(2):80-85. doi:10.1056/NEJM199501123320203PubMedGoogle ScholarCrossref
    37.
    Swedberg  K, Held  P, Kjekshus  J, Rasmussen  K, Rydén  L, Wedel  H.  Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II).  N Engl J Med. 1992;327(10):678-684. doi:10.1056/NEJM199209033271002PubMedGoogle ScholarCrossref
    38.
    The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.  Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.  Lancet. 1993;342(8875):821-828.PubMedGoogle Scholar
    39.
    Køber  L, Torp-Pedersen  C, Carlsen  JE,  et al; Trandolapril Cardiac Evaluation (TRACE) Study Group.  A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.  N Engl J Med. 1995;333(25):1670-1676. doi:10.1056/NEJM199512213332503PubMedGoogle ScholarCrossref
    40.
    Pfeffer  MA, Braunwald  E, Moyé  LA,  et al; The SAVE Investigators.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial.  N Engl J Med. 1992;327(10):669-677. doi:10.1056/NEJM199209033271001PubMedGoogle ScholarCrossref
    41.
    Pfeffer  MA, McMurray  JJ, Velazquez  EJ,  et al; Valsartan in Acute Myocardial Infarction Trial Investigators.  Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.  N Engl J Med. 2003;349(20):1893-1906. doi:10.1056/NEJMoa032292PubMedGoogle ScholarCrossref
    42.
    Liaño  F, Pascual  J; Madrid Acute Renal Failure Study Group.  Epidemiology of acute renal failure: a prospective, multicenter, community-based study.  Kidney Int. 1996;50(3):811-818. doi:10.1038/ki.1996.380PubMedGoogle ScholarCrossref
    43.
    Alabdan  N, Gosmanova  EO, Tran  NQT,  et al.  Acute kidney injury in patients continued on renin-angiotensin system blockers during hospitalization.  Am J Med Sci. 2017;353(2):172-177. doi:10.1016/j.amjms.2016.09.012PubMedGoogle ScholarCrossref
    44.
    Lapi  F, Azoulay  L, Yin  H, Nessim  SJ, Suissa  S.  Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.  BMJ. 2013;346:e8525. doi:10.1136/bmj.e8525PubMedGoogle ScholarCrossref
    45.
    Bhandari  S, Ives  N, Brettell  EA,  et al.  Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease: the STOP-ACEi trial.  Nephrol Dial Transplant. 2016;31(2):255-261.PubMedGoogle Scholar
    46.
    Pannu  N, James  M, Hemmelgarn  B, Klarenbach  S, Network  AKD; Alberta Kidney Disease Network.  Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge.  Clin J Am Soc Nephrol. 2013;8(2):194-202. doi:10.2215/CJN.06480612PubMedGoogle ScholarCrossref
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