PDE5i-ERA Combo Improves Exercise Capacity, Reduces Risk of Death in PAH, Review Says

A combination therapy of endothelin receptor antagonists (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) — two different agents that induce blood vessels’ widening and relaxation —improves exercise capacity, and reduces the risk of death and disease worsening in people with pulmonary arterial hypertension (PAH), a review study finds.

The study, “Effect of Combination Therapy of Endothelin Receptor Antagonist and Phosphodiesterase-5 Inhibitor on Clinical Outcome and Pulmonary Haemodynamics in Patients with Pulmonary Arterial Hypertension: A Meta-Analysis,” was published in Clinical Drug Investigation.

PAH is a rare, life-threatening disorder caused by a narrowing of the arteries in the lungs, which results in high blood pressure. Over the last decade, PAH therapies have substantially improved, researchers say. Individuals now have the possibility of combining PAH-specific agents, which have different mechanisms of action, to achieve the best possible outcome.

PDE5i and ERA are vasodilator compounds that lower blood pressure by inducing blood vessels’ widening and relaxation. Some PDE5i are Revatio (sildenafil) and Adcirca (tadalafil). ERAs include Letairis (ambrisentan), Tracleer (bosentan), Opsumit (macitentan) and Thelin (sitaxentan).

These classes of compounds work by targeting different molecules, so scientists thought their vasodilator effects might be boosted if used in combination. Now, the pairing of PDE5i and ERA has become “one of the widely used combinations for PAH treatment in clinical practice.”

However, there has been some “inconclusive” evidence as to its effectiveness.

“Though this combination therapy progressively has become the standard of care in PAH, several studies have yielded varying results,” the researchers said.

To learn more, investigators performed a systematic literature review to have a better understanding of the impact of the PDE5i-ERA combo therapy in people with PAH.

After screening three large online databases — Medline, Cochrane Library, and the International Clinical Trial Registry Platform (ICTRP), by the World Health Organization — they selected six randomized, controlled trials and one retrospective study for further analysis. The seven had been published between 2009 and 2017.

All of the studies evaluated the effects of the PDE5i-ERA combination on patients’ exercise capacity — assessed using the six-minute walking test — compared with PDE5i or ERA therapy alone. The six-minute walking test measures the distance an individual is able to cover in six minutes while walking on a flat and rigid surface.

The mean distance that PAH patients who were treated with the combo therapy were able walk increased by 15.64 meters (approximately 51.3 feet) by the end of study period, compared with those treated with single agents. This finding indicates that ERA and PDE5i, when used together, significantly improve the exercise capacity of people with PAH.

Five of the seven studies included in the analysis also evaluated disease-worsening patterns. Results showed that people treated with the combo therapy were less likely to experience disease worsening events.

The therapy’s impact on pulmonary vascular resistance (PVR) — a measure of heart strain induced by high blood pressure in the lungs — was assessed in four of the seven studies. However, no significant differences in PVR were found between patients receiving the combination therapy versus the monotherapy treatment regimen.

Results from five studies that evaluated the levels of N‐terminal pro‐brain natriuretic peptide (NT-proBNP), a prognostic marker of PAH, showed that the PDE5i-ERA therapy was more effective at reducing the NT-proBNP than monotherapy.

“This meta-analysis proved that ERA and PDE5i combination therapy substantially improved the exercise capacity, significantly reduced the risk of PAH-related mortality and morbidity by reducing clinical worsening events and improved right ventricular systolic [heart] function by reducing NT-proBNP over monotherapy,” the researchers said.

Future studies “should undertake large population-based and long-term randomised controlled trials, mainly with upfront combinations and with more standardized endpoints to make conclusive evidence and contribute to the clinical practice guidelines for better patient management” they concluded.