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

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.^5- 7

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.

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.