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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 has 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 1229 evaluable patients, 74% were female, mean age of 47 ± 15 years, baseline six-minute walk distance (6MWD) 345 ± 74 m and 75% were World health Organization (WHO) functional class (FC) III/IV. Of the patients receiving spironolactone, 43% were on subcutaneous treprostinil, compared to 29.9% of those 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). Additionally, spironolactone-treated patients tended to have higher hazard of clinical worsening (p < 0.01). A propensity analysis was performed and when controlled for disease severity, revealed 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 reported outcomes of 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.

SUBMITTER: Safdar Z

PROVIDER: S-EPMC8591657 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function.Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24?weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include the effect of spironolactone on the change in placebo-corrected maximal oxygen consumption; plasma markers of vascular inflammation and peripheral blood mononuclear cell gene expression profiles; sympathetic nervous system activation, renin-angiotensin-aldosterone system activation and sex hormone metabolism; and right ventricular structure and function using echocardiography and novel high-resolution magnetic resonance imaging-based techniques. Safety and tolerability of spironolactone will be assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects.ClinicalTrials.gov: NCT01712620.

Project description:Large administrative healthcare (including insurance claims) databases are used for various retrospective real-world evidence studies. However, in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, identifying patients retrospectively based on administrative codes remains challenging, as it relies on code combinations (algorithms) and the accuracy for patient identification of most of them is unknown. This study aimed to assess the performance of various algorithms in correctly identifying patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension in administrative databases. A systematic literature review was performed to find publications detailing code-based algorithms used to identify pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients. PheValuator, a diagnostic predictive modelling tool, was applied to three US claims databases, yielding models that estimated the probability of a patient having the disease. These models were used to evaluate the performance characteristics of selected pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension algorithms. With increasing algorithm complexity, average positive predictive value increased (pulmonary arterial hypertension: 13.4-66.0%; chronic thromboembolic pulmonary hypertension: 10.3-75.1%) and average sensitivity decreased (pulmonary arterial hypertension: 61.5-2.7%; chronic thromboembolic pulmonary hypertension: 20.7-0.2%). Specificities and negative predictive values were high (≥97.5%) for all algorithms. Several of the algorithms performed well overall when considering all of these four performance parameters, and all algorithms performed with similar accuracy across the three claims databases studied, even though most were designed for patient identification in a specific database. Therefore, it is the objective of a study that will determine which algorithm may be most suitable; one- or two-component algorithms are most inclusive and three- or four-component algorithms identify most precise pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension populations, respectively.

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

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