Effect of spironolactone use in pulmonary arterial hypertension – analysis from pivotal trial databases

Abstract

Spironolactone, a common diuretic used in the treatment of pulmonary arterial hypertension (PAH), improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function within pulmonary endothelial cells. Spironolactone has demonstrated vascular remodeling properties and reduced all-cause mortality in patients with severe heart failure. Despite widespread use, however, its effect on morbidity and mortality in PAH have not been fully explored. A large cohort of PAH patients from a harmonized dataset from four pivotal trials were analyzed to characterize the patient population and outcomes associated with spironolactone treatment. Of 1,229 evaluable patients, 74% female, mean age 47±15yrs, baseline six-minute walk distance (6MWD) 345±74m and 75% World health Organization (WHO) functional class (FC) III/IV. Of the patients receiving spironolactone, 43% were on subcutaneous treprostinil, compared to 29.9% of patients who were not receiving spironolactone. Long-term spironolactone-treated PAH patients were older (P=0.01), had lower baseline 6MWD (P=0.01) and cardiac index (P<0.01), higher baseline Borg dyspnea score (P=0.01), WHO functional class, and right arterial pressure (P<0.01). Spironolactone patients tended to have higher hazard of clinical worsening (P<0.01). However, propensity analysis, when controlled for disease severity, showed that spironolactone treated patients did not demonstrate improved outcomes, in terms of survival and clinical worsening. Across studies, the current analysis has demonstrated that the actions of spironolactone within the context of the PAH disease process may differ from its action in CHF patients. Despite the results reported with spironolactone use in patients with left heart disease, these findings may not translate to right heart failure and pulmonary vascular pathology as similar outcomes have not necessarily been recognized in the PAH patient population. Future studies are needed to explore these findings further.

New Drugs and Therapies in Pulmonary Arterial Hypertension

“…Elevated levels of aldosterone are seen in PAH due to dysfunction in the RAAS, which leads to elevated levels of Ag II that in turn directly stimulates aldosterone production in the adrenal gland and pulmonary vasculature [ 190 ]. Elevated levels of aldosterone activate the mineralocorticoid receptors in cardiac cells and pulmonary vasculature to promote vascular remodeling and consequent RV dysfunction in PAH [ 190 , 192 ]. In the pulmonary vasculature, aldosterone facilitates activation and vascular infiltration of monocytes, macrophages, and lymphocytes, which promote inflammation.…”

Cardio-Oncology: Mechanisms, Drug Combinations, and Reverse Cardio-Oncology

“…Spironolactone is an aldosterone antagonist that blocks the final step of the reninangiotensin-aldosterone system. Aldosterone antagonists have a positive effect on cardiac fibrosis and are often used in severe HF and myocardial infarction [227,228]. Animal studies have shown that spironolactone exhibits cardioprotective effects by attenuating DOXinduced myocardial fibrosis, apoptosis, and myocardial collagen volume fraction [229].…”

Strategizing Drug Therapies in Pulmonary Hypertension for Improved Outcomes

“…The question of whether there are structural benefits to mineralocorticoid receptor antagonists (MRAs) in PAH aside from the fluid balance effect is currently being explored. An open-label RCT is currently underway investigating spironolactone in PAH patients, with 6MWD and TTCW as endpoints [ 56 ].…”