Effectiveness of Spironolactone Plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension (from the [ARIES] Study 1 and 2 Trials)

doi:10.1016/j.amjcard.2013.04.051

The American Journal of Cardiology

Volume 112, Issue 5, 1 September 2013, Pages 720-725

https://doi.org/10.1016/j.amjcard.2013.04.051 Get rights and content

In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor–mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.

Section snippets

Methods

Patients with World Health Organization (WHO) group I PAH who had received treatment in the randomized, placebo-controlled phase III trials ARIES-1 (n = 201) and ARIES-2 (n = 192) were eligible for analysis. The full methods and results for both studies have been reported previously.7, 8 Patients received for 12 weeks either placebo or the selective endothelin type-A receptor antagonist ambrisentan at 5 or 10 mg/day orally in ARIES-1 or 2.5 or 5 mg/day orally in ARIES-2. The primary end point

Results

Of patients randomized to placebo (n = 132) or ambrisentan 10 mg/day (n = 67), concurrent spironolactone use was identified for 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with ambrisentan alone (n = 57), patients in the ambrisentan + spironolactone group (n = 10) were more likely to have WHO functional class III/IV and tended to have worse baseline 6-MWD, pulmonary vascular resistance, and plasma BNP concentration, although no clinically meaningful differences between treatment

Discussion

Despite increasing evidence implicating the involvement of vasoactive hormones such as aldosterone in the pathophysiology of PAH,2, 6, 10, 11, 12 reports on the clinical application of aldosterone antagonists in this disease are limited to only individual patients.3, 13 This study represents the first report describing data collected systematically in patients with PAH for whom spironolactone was identified as part of the therapeutic profile.

Akin to ARIES-1 and ARIES-2, we observed that

Acknowledgment

The authors wish to graciously acknowledge the efforts of the ARIES trial investigators.

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Ambrisentan, selective ETA receptor antagonist was evaluated in ARIES-1 and ARIES-2 trial and exhibited improvements in 6MWD and NYHA FC. Ambrisentan was shown to be more effective and reduced liver side effects in comparison with bosentan (Maron et al., 2013). Sitaxentan, a selective ETA receptor antagonist, was voluntarily withdrawn by the licence holder from market in 2010 due to its liver toxicity cases in trials.
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Gene expression analyses and in vitro studies point at an interaction between endothelial cells and other cell types in the process, involving the endothelin-1 signaling pathway and paracrine crosstalk via exosomes.50,108,109,111 A post hoc analysis from the Ambrisentan for the Treatment of Pulmonary Arterial Hypertension (ARIES) 1 and 2 trials suggested a beneficial effect of spironolactone when added to the endothelin-1 receptor antagonist ambrisentan in patients with PH.112 A prospective randomized phase 2 clinical trial on MRA use in PH is currently ongoing (NCT01712620). Knowledge of MR effects in cardiovascular disease continues to expand, pointing to new potential indications for MRAs.
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Pulmonary hypertension (PH) is a devastating condition characterized by pulmonary vascular remodelling, leading to progressive increase in pulmonary artery pressure and subsequent right ventricular failure. Aldosterone and the mineralocorticoid receptor (MR), a nuclear transcription factor, are key drivers of cardiovascular disease and MR antagonists are well-established in heart failure. Now, a growing body of evidence points at a detrimental role of MR in PH. Pharmacological MR blockade attenuated PH and prevented RV failure in experimental models. Mouse models with cell selective MR deletion suggest that this effect is mediated by MR in endothelial cells. While the evidence from experimental studies appears convincing, the available clinical data on MR antagonist use in patients with PH is more controversial. Integrated analysis of clinical data together with MR-dependent molecular alterations may provide insights why some patients respond to MRA treatment while others do not. Potential ways to identify MRA ‘responders’ include the analysis of underlying PH causes, stage of disease, or sex, as well as new biomarkers.
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Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and frequently is associated with pulmonary hypertension (PH). HFpEF associated with PH may be difficult to distinguish from precapillary forms of PH, although this distinction is crucial because therapeutic pathways are divergent for the two conditions. A comprehensive and systematic approach using history, clinical examination, and noninvasive and invasive evaluation with and without provocative testing may be necessary for accurate diagnosis and phenotyping. After diagnosis, HFpEF associated with PH can be subdivided into isolated postcapillary pulmonary hypertension (IpcPH) and combined postcapillary and precapillary pulmonary hypertension (CpcPH) based on the presence or absence of elevated pulmonary vascular resistance. CpcPH portends a worse prognosis than IpcPH. Despite its association with reduced functional capacity and quality of life, heart failure hospitalizations, and higher mortality, therapeutic options focused on PH for HFpEF associated with PH remain limited. In this review, we aim to provide an updated overview on clinical definitions and hemodynamically characterized phenotypes of PH, pathophysiologic features, therapeutic strategies, and ongoing challenges in this patient population.
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Two previous studies suggest that AA therapy indeed is prescribed preferentially in patients with greater pulmonary vascular disease burden. First, in the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study (ARIES) trial of ambrisentan for PAH, enrolled patients were treated with spironolactone based on the discretion of their personal physician.19 Analysis of these patients demonstrated that 61% of patients were prescribed spironolactone to treat “RV failure,” “refractory edema,” or “electrolyte imbalances.”
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.
Is RAAS inhibitor use associated with lower mortality in a large cohort of patients with hemodynamically confirmed PH?
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.

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: This work was supported by grants HL105301 to Dr. Leopold; HL61795, HL48743, HL107192, HL070819, and HL108630 to Dr. Loscalzo; 1K08HL111207-01A1 to Dr. Maron from the US National Institutes of Health (Bethesda, Maryland) and the Lerner Foundation (Boston, Massachusetts) at Brigham and Women's Hospital (Dr. Maron) and grant 11POST6720000 to Dr. Maron from the American Heart Association (Dallas, Texas).

: See page 725 for disclosure information.

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MiscellaneousEffectiveness of Spironolactone Plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension (from the [ARIES] Study 1 and 2 Trials)

Section snippets

Methods

Results

Discussion

Acknowledgment

Contemp Clin Trials

Am J Cardiol

J Am Coll Cardiol

J Heart Lung Transplant

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

Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension

Am J Respir Crit Care Med

[Activity of renin-angiotensin-aldosterone system (RAAS) and vasopressin level in patients with primary pulmonary hypertension]

Ter Arkh

A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial

Trials

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

Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Study 1 and 2

Circulation

Miscellaneous
Effectiveness of Spironolactone Plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension (from the [ARIES] Study 1 and 2 Trials)