Renin-Angiotensin-Aldosterone System Inhibitor Use and Mortality in Pulmonary Hypertension

Insights From the Veterans Affairs Clinical Assessment Reporting and Tracking Database
Published:October 04, 2020DOI:


      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.


      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.


      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.

      Key Words


      AA (aldosterone antagonist), ACEI (angiotensin converting enzyme inhibitor), ARB (angiotensin receptor blocker), BNP (B-type natriuretic peptide), CART (Clinical Assessment Reporting and Tracking), HR (hazard ratio), PAH (pulmonary arterial hypertension), PAWP (pulmonary artery wedge pressure), PH (pulmonary hypertension), PVR (pulmonary vascular resistance), RAAS (renin-angiotensin-aldosterone system), RHC (right heart catheterization), RV (right ventricle), VA (Department of Veterans Affairs)
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        • Simonneau G.
        • Montani D.
        • Celermajer D.S.
        • et al.
        Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
        Eur Respir J. 2019; 53: 1801913
        • Vonk Noordegraaf A.
        • Chin K.M.
        • Haddad F.
        • et al.
        Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update.
        Eur Respir J. 2019; 53: 1801900
        • Vachiery J.L.
        • Tedford R.J.
        • Rosenkranz S.
        • et al.
        Pulmonary hypertension due to left heart disease.
        Eur Respir J. 2019; 53: 1801897
        • Nathan S.D.
        • Barbera J.A.
        • Gaine S.P.
        • et al.
        Pulmonary hypertension in chronic lung disease and hypoxia.
        Eur Respir J. 2019; 53: 1801914
        • Humbert M.
        • Sitbon O.
        • Chaouat A.
        • et al.
        Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.
        Circulation. 2010; 122: 156-163
        • Gall H.
        • Felix J.F.
        • Schneck F.K.
        • et al.
        The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups.
        J Heart Lung Transplant. 2017; 36: 957-967
        • Newman J.H.
        • Rich S.
        • Abman S.H.
        • et al.
        Enhancing insights into pulmonary vascular disease through a precision medicine approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop report.
        Am J Resp Crit Care Med. 2017; 195: 1661-1670
        • Elinoff J.M.
        • Agarwal R.
        • Barnett C.F.
        • et al.
        Challenges in pulmonary hypertension: controversies in treating the tip of the iceberg.
        Am J Resp Crit Care Med. 2018; 198: 166-174
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        Circulation. 2013; 128: 1810-1852
        • Whelton P.K.
        • Carey R.M.
        • Aronow W.S.
        • et al.
        2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        Hypertension. 2018; 71: e13-e115
        • de Man F.S.
        • Handoko M.L.
        • Guignabert C.
        • Bogaard H.J.
        • Vonk-Noordegraaf A.
        Neurohormonal axis in patients with pulmonary arterial hypertension: friend or foe?.
        Am J Resp Crit Care Med. 2013; 187: 14-19
        • Maron B.A.
        • Leopold J.A.
        The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series).
        Pulm Circ. 2014; 4: 200-210
        • Maron B.A.
        • Leopold J.A.
        Emerging concepts in the molecular basis of pulmonary arterial hypertension: part ii: neurohormonal signaling contributes to the pulmonary vascular and right ventricular pathophenotype of pulmonary arterial hypertension.
        Circulation. 2015; 131: 2079-2091
        • Vaillancourt M.
        • Chia P.
        • Sarji S.
        • et al.
        Autonomic nervous system involvement in pulmonary arterial hypertension.
        Resp Res. 2017; 18: 201
        • de Man F.S.
        • Tu L.
        • Handoko M.L.
        • et al.
        Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension.
        Am J Resp Crit Care Med. 2012; 186: 780-789
        • da Silva Goncalves Bos D.
        • Happe C.
        • Schalij I.
        • et al.
        Renal denervation reduces pulmonary vascular remodeling and right ventricular diastolic stiffness in experimental pulmonary hypertension.
        JACC Basic Transl Sci. 2017; 2: 22-35
        • Maron B.A.
        • Zhang Y.Y.
        • White K.
        • et al.
        Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.
        Circulation. 2012; 126: 963-974
        • Maron B.A.
        • Opotowsky A.R.
        • Landzberg M.J.
        • Loscalzo J.
        • Waxman A.B.
        • Leopold J.A.
        Plasma aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence of left ventricular heart failure: a pilot study.
        Eur J Heart Fail. 2013; 15: 277-283
        • Maron B.A.
        • Waxman A.B.
        • Opotowsky A.R.
        • et al.
        Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials).
        Am J Cardiol. 2013; 112: 720-725
        • Maron B.A.
        • Oldham W.M.
        • Chan S.Y.
        • et al.
        Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis.
        Circulation. 2014; 130: 168-179
        • Aghamohammadzadeh R.
        • Zhang Y.Y.
        • Stephens T.E.
        • et al.
        Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.
        FASEB J. 2016; 30: 2511-2527
        • Boehm M.
        • Arnold N.
        • Braithwaite A.
        • et al.
        Eplerenone attenuates pathological pulmonary vascular rather than right ventricular remodeling in pulmonary arterial hypertension.
        BMC Pulm Med. 2018; 18: 41
        • Samokhin A.O.
        • Stephens T.
        • Wertheim B.M.
        • et al.
        NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension.
        Science Transl Med. 2018; 10: eaap7294
        • Vonk Noordegraaf A.
        • Westerhof B.E.
        • Westerhof N.
        The relationship between the right ventricle and its load in pulmonary hypertension.
        J Am Coll Cardiol. 2017; 69: 236-243
        • Vonk-Noordegraaf A.
        • Haddad F.
        • Chin K.M.
        • et al.
        Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.
        J Am Coll Cardiol. 2013; 62: D22-D33
        • van de Veerdonk M.C.
        • Kind T.
        • Marcus J.T.
        • et al.
        Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.
        J Am Coll Cardiol. 2011; 58: 2511-2519
        • Vachiery J.L.
        • Delcroix M.
        • Al-Hiti H.
        • et al.
        Macitentan in pulmonary hypertension due to left ventricular dysfunction.
        Eur Respir J. 2018; 51: 1701886
        • Packer M.
        • McMurray J.J.V.
        • Krum H.
        • et al.
        Long-Term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure: primary results of the ENABLE Trials.
        JACC Heart Fail. 2017; 5: 317-326
      1. Blanco I, Gimeno E, Munoz PA, et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Resp Crit Care Med.181(3):270-278.

        • Stolz D.
        • Rasch H.
        • Linka A.
        • et al.
        A randomised, controlled trial of bosentan in severe COPD.
        Eur Respir J. 2008; 32: 619-628
        • Raghu G.
        • Behr J.
        • Brown K.K.
        • et al.
        Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial.
        Ann Intern Med. 2013; 158: 641-649
        • Kim D.
        • Lee K.M.
        • Freiman M.R.
        • et al.
        Phosphodiesterase-5-inhibitor therapy for pulmonary hypertension in the US: actual vs recommended use.
        Ann Am Thorac Soc. 2018; 15: 693-701
        • Maron B.A.
        • Stephens T.E.
        • Farrell L.A.
        • et al.
        Elevated pulmonary arterial and systemic plasma aldosterone levels associate with impaired cardiac reserve capacity during exercise in left ventricular systolic heart failure patients: a pilot study.
        J Heart Lung Transplant. 2016; 35: 342-351
        • Farber M.O.
        • Weinberger M.H.
        • Robertson G.L.
        • Fineberg N.S.
        The effects of angiotensin-converting enzyme inhibition on sodium handling in patients with advanced chronic obstructive pulmonary disease.
        Am Rev Resp Dis. 1987; 136: 862-866
        • MacNee W.
        Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part two.
        Am J Resp Crit Care Med. 1994; 150: 1158-1168
        • Konigshoff M.
        • Wilhelm A.
        • Jahn A.
        • et al.
        The angiotensin II receptor 2 is expressed and mediates angiotensin II signaling in lung fibrosis.
        Am J Resp Cell Mol Biol. 2007; 37: 640-650
        • Maron B.A.
        • Hess E.
        • Maddox T.M.
        • et al.
        Association of borderline pulmonary hypertension with mortality and hospitalization in a large patient cohort: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking program.
        Circulation. 2016; 133: 1240-1248
        • Maddox T.M.
        • Plomondon M.E.
        • Petrich M.
        • et al.
        A national clinical quality program for Veterans Affairs catheterization laboratories (from the Veterans Affairs Clinical Assessment, Reporting, and Tracking program).
        Am J Cardiol. 2014; 114: 1750-1757
        • Sohn M.W.
        • Arnold N.
        • Maynard C.
        • Hynes D.M.
        Accuracy and completeness of mortality data in the Department of Veterans Affairs.
        Popul Health Metr. 2006; 4: 2
        • Leary P.J.
        • Hess E.
        • Baron A.E.
        • et al.
        H2-receptor antagonist use and mortality in pulmonary hypertension: insight from the VA-CART program.
        Am J Resp Crit Care Med. 2018; 197: 1638-1641
        • Juurlink D.N.
        • Mamdani M.M.
        • Lee D.S.
        • et al.
        Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
        N Engl J Med. 2004; 351: 543-551
        • Morrison D.A.
        • Adcock K.
        • Collins C.M.
        • Goldman S.
        • Caldwell J.H.
        • Schwarz M.I.
        Right ventricular dysfunction and the exercise limitation of chronic obstructive pulmonary disease.
        J Am Coll Cardiol. 1987; 9: 1219-1229
        • Chaouat A.
        • Weitzenblum E.
        • Krieger J.
        • Oswald M.
        • Kessler R.
        Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients.
        Chest. 1996; 109: 380-386
        • Mohammed S.F.
        • Hussain I.
        • AbouEzzeddine O.F.
        • et al.
        Right ventricular function in heart failure with preserved ejection fraction: a community-based study.
        Circulation. 2014; 130: 2310-2320
        • Redfield M.M.
        • Jacobsen S.J.
        • Burnett Jr., J.C.
        • Mahoney D.W.
        • Bailey K.R.
        • Rodeheffer R.J.
        Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
        JAMA. 2003; 289: 194-202
        • Lloyd-Jones D.
        • Adams R.J.
        • Brown T.M.
        • et al.
        Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association.
        Circulation. 2010; 121: 948-954
        • Hyduk A.
        • Croft J.B.
        • Ayala C.
        • Zheng K.
        • Zheng Z.J.
        • Mensah G.A.
        Pulmonary hypertension surveillance—United States, 1980-2002.
        MMWR Surveill Summ. 2005; 54: 1-28
        • Maron B.A.
        • Choudhary G.
        • Khan U.A.
        • et al.
        Clinical profile and underdiagnosis of pulmonary hypertension in US veteran patients.
        Circ Heart Fail. 2013; 6: 906-912
        • Anhang Price R.
        • Sloss E.M.
        • Cefalu M.
        • Farmer C.M.
        • Hussey P.S.
        Comparing quality of care in Veterans Affairs and non-Veterans Affairs settings.
        J Gen Intern Med. 2018; 33: 1631-1638
        • Wayant C.
        • Scott J.
        • Vassar M.
        Evaluation of lowering the P value threshold for statistical significance from .05 to .005 in previously published randomized clinical trials in major medical journals.
        JAMA. 2018; 320: 1813-1815
        • Ventetuolo C.E.
        • Hess E.
        • Austin E.D.
        • et al.
        Sex-based differences in veterans with pulmonary hypertension: results from the veterans affairs-clinical assessment reporting and tracking database.
        PLoS One. 2017; 12e0187734
        • Corkish ME D.L.
        • Clarke M.M.
        • Murray B.P.
        • Rose-Jones L.J.
        Rates of hospitalization associated with the use of aldosterone receptor antagonists in patients with pulmonary arterial hypertension.
        Pulm Circ. 2019; 9 (2045894019868422)
        • Walker A.M.
        Confounding by indication.
        Epidemiology. 1996; 7: 335-336
        • Weiss N.S.
        All-cause mortality as an outcome in epidemiologic studies: proceed with caution.
        Eur J Epidemiol. 2014; 29: 147-149
        • Merrill M.
        • Sweitzer N.K.
        • Lindenfeld J.
        • Kao D.P.
        Sex differences in outcomes and responses to spironolactone in heart failure with preserved ejection fraction: a secondary analysis of TOPCAT Trial.
        JACC Heart Fail. 2019; 7: 228-238