Pulmonary arterial hypertension (PAH) is a rare and severe disease that continues to progress over time. Although there is no cure, recent advances in treatment strategies with increased therapeutic options have offered an improvement in prognosis and survival.
PAH-specific therapies have been developed to target one of three major pathways known to be involved in the development of PAH. Combination therapy (using two or more classes of drugs together) is an option in the management of PAH to simultaneously target multiple pathways involved in the disease pathogenesis. Evidence to support combination therapy is growing.. The recommend initial combination therapy for PAH or double or triple sequential combination therapy in cases of inadequate clinical results or in cases of deterioration.
Adapted from Humbert et al. 2014
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET, endothelin; GMP, guanosine monophosphate; GTP, guanosine triphosphate: IP, prostacyclin; NO, nitric oxide; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5; PGl2, prostacyclin; sGC, soluble guanylate cyclase
The endothelin-1 expression level is upregulated in patients with PAH, causing potent vasoconstriction and smooth muscle cell proliferation. Endothelin receptor antagonists (ERAs) act by blocking the binding of endothelin to its receptors to prevent this process.
Phosphodiesterase type-5 (PDE-5) inhibitors and guanylate cyclase stimulators act on the nitric oxide pathway to promote vasodilation and have antiproliferative effects on vascular smooth muscle cells.
Prostacyclin induces potent vasodilation and inhibition of platelet aggregation and has both cytoprotective and antiproliferative effects. Prostacyclin receptor agonists and prostacyclin analogues act by helping to correct the deficiency in endogenous prostacyclin seen in patients with PAH.
Upon diagnosis, patients are assessed for risk of disease progression. Guidelines recommend regular multiparameter risk assessment, both at diagnosis and follow-up (every 3–6 months) to allow the treatment strategy to be tailored to the individual patient at the earliest opportunity. The risk status of patients can be categorised as either low, intermediate or high. This corresponds to an estimated 1-year mortality of <5%, 5–20% or >20% respectively and is based on a number of determinants including WHO functional class, exercise capacity and haemodynamic parameters. There is no single variable that can provide sufficient prognostic information on its own; a multidimensional approach is required.
Adapted from Humbert 2022
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