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Research Letters |

Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers and Cardiovascular Outcomes in Chronic Dialysis Patients: A Population-Based Cohort Study FREE

Ravi R. Bajaj, MD; Ron Wald, MD, MPH; Daniel G. Hackam, MD, PhD; Tara Gomes, MHSc; Jeffrey Perl, MD, SM; David N. Juurlink, MD, PhD, BPharm; Michael Manno, MSc; Amit X. Garg, MD, PhD; Abhijat Kitchlu, MD; Muhammad M. Mamdani, MPH, MA; Andrew T. Yan, MD
[+] Author Affiliations

Author Affiliations: Terrence Donnelly Heart Centre (Drs Bajaj and Yan), Division of Nephrology (Drs Wald and Perl), and Applied Health Research Centre, Li Ka Shing Knowledge Institute (Mr Mamdani), St Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine (Drs Bajaj, Wald, Perl, Juurlink, and Yan and Mr Mamdani), Leslie Dan Faculty of Pharmacy (Ms Gomes), and Department of Health Policy, Management, and Evaluation (Dr Juurlink), University of Toronto, Toronto; Divisions of Clinical Pharmacology (Dr Hackam) and Nephrology (Drs Garg and Kitchlu), Department of Medicine, and Department of Epidemiology and Biostatistics (Dr Garg), University of Western Ontario, London; and Institute for Clinical Evaluative Sciences, Toronto (Ms Gomes, Drs Juurlink and Garg, and Mr Manno).


Arch Intern Med. 2012;172(7):594-595. doi:10.1001/archinternmed.2012.139.
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Published online

Routine use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for the treatment of cardiovascular disease is well established.1,2 However, because most randomized controlled trials have excluded patients with advanced chronic kidney disease,3 the role of ACEIs/ARBs in chronic dialysis patients remains poorly defined. Our objective was to determine whether ACEI/ARB use is associated with a reduction in mortality and major adverse cardiovascular events in older chronic dialysis patients.

We conducted a retrospective, population-based cohort study using linked health care databases in Ontario, Canada. To minimize bias, we used a new-user study design.4 The study population was composed of older chronic dialysis patients in Ontario (age ≥66 years) who were newly treated with ACEIs/ARBs, calcium channel blockers (CCBs), or statins between July 1, 1991, and July 31, 2007. We selected new treatment with ACEIs/ARBs as the exposure group and new treatment with CCBs or statins-only as the comparator groups to minimize confounding by indication and because CCBs and statins have not been shown to be clearly beneficial in this population. We excluded patients with missing demographic information or incomplete drug records.

Patients were stratified into 1 of 3 mutually exclusive treatment groups (ACEI/ARB, CCB, or statin) and were prospectively observed for up to 5 years, or March 31, 2010. The primary outcome was a composite of all-cause mortality or hospitalization for myocardial infarction (MI), stroke, heart failure (HF), or coronary revascularization. Secondary end points included each component of the primary end point. We used an intention-to-treat approach. We estimated event-free survival by the Kaplan-Meier method and used the log-rank test for comparison. We used standardized differences to compare baseline characteristics in the 3 treatment groups, and Cox proportional hazards regression, adjusting for age, sex, diabetes, hypertension, coronary artery disease, HF, dialysis duration, and the Deyo-Revised Charlson Comorbidity score.57

During the study period, we identified 1950 older chronic dialysis patients in Ontario who initiated treatment with 1 of the study drug classes. There were no systematic differences in the baseline characteristics between the treatment groups (Table 1). There was no significant difference in event-free survival among the 3 groups (log-rank P = .12). In multivariable analysis, the use of ACEIs/ARBs was not independently associated with a reduction in the primary outcome (hazard ratio, 0.97; 95% CI, 0.84-1.13) or secondary outcomes compared with the CCB group (Table 2). Similar results were obtained when the ACEI/ARB group was compared with the statin-only group.

Table Graphic Jump LocationTable 1. Baseline Characteristics of Study Patients in the Different Study Groupsa

In this population-based cohort study of chronic dialysis patients older than 65 years, new use of ACEIs or ARBs was not independently associated with an overall reduction in major adverse cardiovascular events. Data from previous randomized controlled trials and observational studies have been conflicting. This study offers unique insights into the use of ACEIs/ARBs in chronic dialysis patients through its new-user study design.4 Although this new-user study design has not been used extensively in chronic dialysis patients, it allows for a less biased evaluation of the “real world” safety and effectiveness of secondary prevention therapies in such patients, in contrast to randomized controlled trials, which often recruit highly selected healthier patients.8,9

We focused on chronic dialysis patients older than 65 years, who are the most underrepresented in clinical trials.9 Despite their high baseline cardiovascular risk, as evidenced by the high event rate in our study, treatment benefit with ACEIs/ARBs was not observed. Another strength of our study was the large unselected cohort of incident dialysis patients observed for longer periods to more accurately assess the cardiovascular effects of ACEIs/ARBs.

Important limitations of our study are that drug therapy was not randomly assigned, and we analyzed classes of drugs rather than individual drugs. We selected our control groups with the expectation that these would serve as nonactive comparators. If statin or CCB use can indeed confer cardiovascular protection in chronic dialysis patients, our comparative analysis may have attenuated any observed benefit of ACEIs/ARBs.

In conclusion, our data suggest that use of ACEI or ARB therapy in chronic dialysis patients may not favorably impact cardiovascular outcomes. Compared with patients with normal kidney function, chronic dialysis patients may not derive the same cardiovascular benefit from ACEI/ARB use. Given the substantial cardiovascular morbidity and mortality in the expanding chronic dialysis patient population, a large definitive randomized controlled trial of ACEIs/ARBs is warranted.

Correspondence: Dr Yan, Division of Cardiology, St Michael's Hospital, 30 Bond St, Room 6-030 Queen, Toronto, ON M5B 1W8, Canada (yana@smh.ca).

Author Contributions:Study concept and design: Wald, Hackam, Gomes, Juurlink, Garg, Kitchlu, Mamdani, and Yan. Acquisition of data: Juurlink and Kitchlu. Analysis and interpretation of data: Bajaj, Wald, Hackam, Gomes, Perl, Manno, Kitchlu, Mamdani, and Yan. Drafting of the manuscript: Bajaj and Kitchlu. Critical revision of the manuscript for important intellectual content: Bajaj, Wald, Hackam, Gomes, Perl, Juurlink, Manno, Garg, Kitchlu, Mamdani, and Yan. Statistical analysis: Gomes, Juurlink, Manno, Kitchlu, and Mamdani. Obtained funding: Juurlink. Administrative, technical, and material support: Gomes, Kitchlu, and Mamdani. Study supervision: Wald and Yan.

Financial Disclosure: None reported.

Funding/Support: Dr Yan is supported by a New Investigator Award from the Heart and Stroke Foundation of Canada.

This article was corrected for errors on May 14, 2012.

Kushner FG, Hand M, Smith SC Jr,  et al.  2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2009;54(23):2205-2241
PubMed   |  Link to Article
Hunt SA, Abraham WT, Chin MH,  et al; American College of Cardiology Foundation; American Heart Association.  2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation.  J Am Coll Cardiol. 2009;53(15):e1-e90
PubMed   |  Link to Article
Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.  JAMA. 2006;296(11):1377-1384
PubMed   |  Link to Article
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs.  Am J Epidemiol. 2003;158(9):915-920
PubMed   |  Link to Article
Charlson MEPP, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.  J Chronic Dis. 1987;40(5):373-383
PubMed   |  Link to Article
Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J, Glynn RJ. Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data.  Am J Epidemiol. 2001;154(9):854-864
PubMed   |  Link to Article
Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.  J Clin Epidemiol. 2004;57(12):1288-1294
PubMed   |  Link to Article
Nallamothu BK, Hayward RA, Bates ER. Beyond the randomized clinical trial: the role of effectiveness studies in evaluating cardiovascular therapies.  Circulation. 2008;118(12):1294-1303
PubMed   |  Link to Article
Hutchinson-Jaffe AB, Goodman SG, Yan RT,  et al; Canadian Acute Coronary Syndromes (ACS) Registry I and II Investigators and Canadian Global Registry of Acute Coronary Events (GRACE/GRACE 2) Investigators.  Comparison of baseline characteristics, management and outcome of patients with non-ST-segment elevation acute coronary syndrome in versus not in clinical trials.  Am J Cardiol. 2010;106(10):1389-1396
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Study Patients in the Different Study Groupsa

References

Kushner FG, Hand M, Smith SC Jr,  et al.  2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2009;54(23):2205-2241
PubMed   |  Link to Article
Hunt SA, Abraham WT, Chin MH,  et al; American College of Cardiology Foundation; American Heart Association.  2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation.  J Am Coll Cardiol. 2009;53(15):e1-e90
PubMed   |  Link to Article
Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.  JAMA. 2006;296(11):1377-1384
PubMed   |  Link to Article
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs.  Am J Epidemiol. 2003;158(9):915-920
PubMed   |  Link to Article
Charlson MEPP, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.  J Chronic Dis. 1987;40(5):373-383
PubMed   |  Link to Article
Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J, Glynn RJ. Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data.  Am J Epidemiol. 2001;154(9):854-864
PubMed   |  Link to Article
Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.  J Clin Epidemiol. 2004;57(12):1288-1294
PubMed   |  Link to Article
Nallamothu BK, Hayward RA, Bates ER. Beyond the randomized clinical trial: the role of effectiveness studies in evaluating cardiovascular therapies.  Circulation. 2008;118(12):1294-1303
PubMed   |  Link to Article
Hutchinson-Jaffe AB, Goodman SG, Yan RT,  et al; Canadian Acute Coronary Syndromes (ACS) Registry I and II Investigators and Canadian Global Registry of Acute Coronary Events (GRACE/GRACE 2) Investigators.  Comparison of baseline characteristics, management and outcome of patients with non-ST-segment elevation acute coronary syndrome in versus not in clinical trials.  Am J Cardiol. 2010;106(10):1389-1396
PubMed   |  Link to Article

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