Beyond a single pathway: combination therapy in pulmonary arterial hypertension

Abstract

There is a strong rationale for combining therapies to simultaneously target three of the key pathways implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Evidence to support this strategy is growing, and a number of studies have demonstrated that combination therapy, administered as either a sequential or an initial regimen, can improve long-term outcomes in PAH. Dual combination therapy with a phosphodiesterase-5 inhibitor and an endothelin receptor antagonist is the most widely utilised combination regimen. However, some patients fail to achieve their treatment goals on dual therapy and may benefit from the addition of a third drug. The use of triple therapy in clinical practice was previously reserved for patients with severe disease due to the need for parenteral administration of prostanoids. Although triple therapy with parenteral prostanoids plays a key role in the management of severe PAH, the approval of oral therapies that target the prostacyclin pathway means that all three pathways can now be targeted with oral drugs at an earlier disease stage. Furthermore, there is evidence demonstrating that this approach can delay disease progression. Based on the evidence available, it is becoming increasingly clear that all PAH patients should be offered the benefits of combination therapy.

FIGURE 1

Macitentan as part of combination therapy significantly reduced the risk of morbidity/mortality events (composite primary end-point) versus placebo in incident and prevalent pulmonary arterial hypertension (PAH) patients. Kaplan–Meier curves for PAH patients receiving background PAH-specific therapy at baseline. HR: hazard ratio. ^#: log rank. Reproduced and modified from [8] with permission from the publisher.

FIGURE 2

Selexipag significantly reduced the risk of morbidity/mortality (composite primary end-point) versus placebo in incident and prevalent pulmonary arterial hypertension (PAH) patients. Kaplan–Meier curves for a) patients not on background PAH therapy at baseline; b) patients on phosphodiesterase type-5 inhibitor (PDE-5i) monotherapy at baseline; c) patients on endothelin receptor antagonist (ERA) monotherapy at baseline; and d) patients on dual combination therapy (ERA + PDE-5i). HR: hazard ratio. Reproduced with permission [37].

FIGURE 3

Initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure (composite primary end-point) versus pooled monotherapy in incident pulmonary arterial hypertension patients. Kaplan–Meier curves for treatment-naïve pulmonary arterial hypertension patients. HR: hazard ratio. Reproduced from [9] with permission from the publisher.

FIGURE 4

Future perspectives on the use of combination therapy to treat pulmonary arterial hypertension. The choice of combination therapy regimen will be influenced by the risk status at diagnosis and the response to initial medical therapy. Inadequate clinical response is defined as a patient who does not achieve or maintain a low-risk profile [11, 12]. WHO FC: World Health Organization functional class; NO: nitric oxide; ET: endothelin; PGI₂: prostacyclin; inh.: inhaled. ^#: for eligible patients.