Renin-Angiotensin-Aldosterone System Inhibitor Use and Mortality in Pulmonary Hypertension: Insights From the Veterans Affairs Clinical Assessment Reporting and Tracking Database

Abstract

Background: The renin-angiotensin-aldosterone system (RAAS) contributes to pulmonary hypertension (PH) pathogenesis. Although animal data suggest that RAAS inhibition attenuates PH, it is unknown if RAAS inhibition is beneficial in PH patients.

Research question: Is RAAS inhibitor use associated with lower mortality in a large cohort of patients with hemodynamically confirmed PH?

Study design and methods: We used the Department of Veterans Affairs Clinical Assessment Reporting and Tracking Database to study retrospectively relationships between RAAS inhibitors (angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and aldosterone antagonists [AAs]) and mortality in 24,221 patients with hemodynamically confirmed PH. We evaluated relationships in the full and in propensity-matched cohorts. Analyses were adjusted for demographics, socioeconomic status, comorbidities, disease severity, and comedication use in staged models.

Results: ACEI and ARB use was associated with improved survival in unadjusted Kaplan-Meier survival analyses in the full cohort and the propensity-matched cohort. This relationship was insensitive to adjustment, independent of pulmonary artery wedge pressure, and also was observed in a cohort restricted to individuals with precapillary PH. AA use was associated with worse survival in unadjusted Kaplan-Meier survival analyses in the full cohort; however, AA use was associated less robustly with mortality in the propensity-matched cohort and was not associated with worse survival after adjustment for disease severity, indicating that AAs in real-world practice are used preferentially in sicker patients and that the unadjusted association with increased mortality may be an artifice of confounding by indication of severity.

Interpretation: ACEI and ARB use is associated with lower mortality in veterans with PH. AA use is a marker of disease severity in PH. ACEIs and ARBs may represent a novel treatment strategy for diverse PH phenotypes.

Keywords: aldosterone; angiotensin converting enzyme; epidemiology; pharmacology; pulmonary hypertension.

Copyright © 2020. Published by Elsevier Inc.

Figures

Figure 1

Flow chart showing study sample. Cohorts studied included the full study cohort as well as limited cohorts used for propensity-matched analyses. AA = aldosterone antagonist; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker.

Figure 2

A-B, Kaplan-Meier curves showing that ACEI or ARB use is associated with decreased mortality in veterans with pulmonary hypertension. A, Outcome of mortality for ACEI or ARB users and nonusers for the full cohort (14,912 users and 9,309 nonusers). Five-year mortality in ACEI or ARB users was 35.0% (5,212 events) compared with 41.2% in nonusers (3,837 events). χ2 = 154.8. B, Outcome of mortality for the propensity-matched cohort (7,480/group). ACEI or ARB use was defined as use of either medication class within 90 days of right heart catheterization. χ2 = 65.8. Group comparisons were performed by log rank test. ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker.

Figure 3

A-B, Kaplan-Meier curves showing that AA use is associated with increased mortality in veterans with pulmonary hypertension, with a less robust association in the propensity-matched cohort. A, Outcome of mortality for AA users and nonusers for the full cohort (4,092 users and 20,129 nonusers). Five-year mortality in AA users was 39.2% (1,606 events) compared with 37.0% in nonusers (7,443 events). χ2 = 14.1. B, Outcome of mortality for the propensity-matched cohort (3,936/group). AA use was defined as use within 90 days of right heart catheterization. χ2 = 4.5. Group comparisons were performed by log rank test. Note the lower χ2 value and less robust statistical significance in the propensity-matched cohort. AA = aldosterone antagonist.