Pulmonary arterial hypertension: Rationale for using multiple vs. single drug therapy

Figures

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  Figure 1.. Mortality rates in patients with pulmonary arterial hypertension (PAH), left-sided heart failure with reduced ejection fraction (HFrEF), and left-sided heart failure with preserved ejection fraction (HFpEF). An extrapolated Kaplan–Meier analyses converging different data sets to compare mortality rates from HFpEF (purple dotted line), HFrEF (green solid line), and PAH (observed, blue dotted line; predicted, red line). Adapted with permission from Ref. [9].

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  Figure 2.. Selected recommendations for efficacy of (A) sequential add-on and (B) initial drug combination therapy for pulmonary arterial hypertension according to World Health Organization Functional Class. Specific references in support of sub-recommendations are provided as insets. ERA, endothelin receptor antagonist; PDE-5i, phosphodiesterase type-5 inhibitor; WHO-FC, World Health Organization Functional Class. Adapted with permission from Ref. [16].

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  Figure 3.. Biological hypothesis for repurposing spironolactone therapy and proof-of-concept supportive clinical data. (A) Schematic representation of the biological hypothesis supporting combination spironolactone (SPIRO) plus endothelin type-A receptor (ETA) antagonism for the treatment of PAH. Stimulation of pulmonary artery smooth muscle cells (PASMC) ETA and endothelin type-B receptor (ETB) are the major and minor signaling pathways, respectively, that modulate endothelin-1 (ET-1)-dependent pulmonary vasoconstriction in PAH. In contrast, pulmonary artery endothelial cell (PAEC) ETB stimulation by ET-1 promotes pulmonary vasodilation. In PAH, hyperaldosteronism is associated with a pulmonary vasculopathy that is due, in part, to increased oxidant stress levels that inhibits ETB function. Therefore, two potential treatment targets within the aldosterone-endothelin receptor axis are exposed: ETA to inhibit the major pulmonary vasoconstrictor pathway and the mineralocorticoid receptor (MR) to preserve ETB-dependent vasodilation. (B) A retrospective analysis of ARIES-1 and -2 trials30 were performed. Change from baseline in the 6-MWD. Mean ± SE change from baseline in the 6-MWD at week 4,…