Pulmonary Arterial Hypertension: Combination Therapy in Practice

Marsha Burks; Simone Stickel; Nazzareno Galiè

Disclosures

Am J Cardiovasc Drugs. 2018;18(4):249-257. 

In This Article

Combination Therapy in the Treatment of PAH

Therapies are available that each target one of the three pathogenic pathways underlying PAH: the endothelin (ET) pathway, targeted by endothelin receptor antagonists (ERAs); the nitric oxide (NO) pathway, targeted by phosphodiesterase type 5 inhibitors (PDE-5is) and soluble guanylate cyclase (sGC) stimulators; and the prostacyclin (PGI2) pathway, targeted by synthetic PGI2, PGI2 analogs and IP prostacyclin receptor agonists. The decision on when and which therapies to combine should be primarily based on the patient's 1-year mortality risk, as determined by comprehensive, multiparameter risk assessments.[2,3] For patients considered to be at low or intermediate risk, the ESC/ERS guidelines recommend either initial or sequential double oral combination therapy.[2,3] For treatment-naïve, high-risk patients, the guidelines provide a clear recommendation for initial combination therapy including an intravenous (IV) PGI2 analog.[2,3]

These recommendations are based on a growing body of evidence that supports the use of double oral combination therapy as an effective treatment strategy in PAH,[1] including long-term outcome data from large RCTs.[10–12] More recently, the long-term GRIPHON study has, for the first time, provided RCT evidence in support of triple combination therapy, in addition to double combination therapy, including the oral selective IP prostacyclin receptor agonist, selexipag.[12]

In our clinical practice, drugs targeting the ET and NO pathways are most commonly used as first-line combination therapy. The majority of patients are treated with an ERA combined with a PDE-5i; however, some receive double oral combination therapy with an ERA and an sGC stimulator. Therapies targeting the PGI2 pathway are also frequently administered in double or triple combination regimens, especially in patients with severe PAH.

As for any disease, the potential for a greater number of side effects when using multiple therapies versus a single therapy should be considered. While ERAs, PDE-5is, sGC stimulators and therapies targeting the PGI2 pathway have distinct modes of action and exert a different range of effects on the pulmonary vasculature,[13] all of these agents induce vasodilation. As a result, there is a clear overlap in their safety profiles. For example, all of these drugs are associated with adverse events (AEs) such as headache, hypotension and edema.[14–19] With this in mind, treating patients with more than one of these drugs may result in additive side effects and a greater number of AEs compared with monotherapy. This was observed in the AMBITION study, which reported that edema and headache occurred more frequently in patients taking a combination of ambrisentan and tadalafil compared with patients treated with either drug as monotherapy (Table 1).[11] Despite some differences in the frequency of AEs, the tolerability of initial combination therapy with an ERA and a PDE-5i is supported by the similar rates of discontinuations due to AEs observed with combination therapy and with monotherapy (Table 1).[11] Similarly, in the long-term GRIPHON study, the frequency with which AEs were reported increased with the number of therapies (Table 2).[20] However, patients receiving selexipag as part of a sequential double or triple combination therapy regimen had broadly comparable rates of discontinuations due to AEs, albeit in both groups this was higher than in patients receiving monotherapy (Table 2).[20]

Additive side effects are thought to be less likely with sequential than initial combination therapy as patients adapt to the systemic vasodilatory effects of the first drug before another is added. The tolerability of sequential combination therapy is supported by data from the SERAPHIN trial, in which macitentan was generally well-tolerated, despite the majority (64%) of patients receiving a PAH therapy at baseline.[10] Similar results were obtained with riociguat in the PATENT trial, in which 50% of patients were receiving PAH therapies at baseline.[21] Low discontinuation rates due to AEs have also been demonstrated in RCTs where therapies targeting the PGI2 pathway are used in sequential double combination therapy.[12,22,23,24]

PAH therapies are also associated with side effects that are not related to vasodilation. For example, ERAs, PDE-5is and sGC stimulators have been associated with anemia, PDE-5is and sGC stimulators can cause muscle pain, and bosentan has been associated with liver enzyme elevations. However, drug or drug-class–specific side effects are not expected to be additive during combination therapy.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....