Topic

Pulmonary hypertension

Vasodilator therapy, combination strategies, and activin signalling.

Start two drugs, not one. Initial combination ambrisentan and tadalafil halved clinical failure compared with either as monotherapy in treatment-naive pulmonary arterial hypertension (AMBITION), ending sequential add-on therapy as the default.

The vasodilator classes were each established on walk distance. Sildenafil improved six-minute walk distance by about 45 m with no added benefit above 20 mg three times daily (SUPER-1), and riociguat by 36 m, including on top of existing therapy (PATENT-1). The field then moved to event-driven outcomes: macitentan cut morbidity and mortality events by 45% (SERAPHIN) and oral selexipag cut disease progression and hospitalisation by 40%, without a mortality difference (GRIPHON).

Sotatercept works on remodelling rather than tone, and in high-risk patients already on maximum tolerated background therapy it reduced death, transplantation or hospitalisation by 76% — an effect size rare in this field, and large enough that the trial was stopped early (ZENITH).

Group 3 disease finally has a positive trial. Systemic vasodilators had repeatedly failed or harmed patients with pulmonary hypertension due to lung disease by worsening ventilation- perfusion matching. Inhaled treprostinil, delivered to ventilated lung, improved six-minute walk distance by 31 m (INCREASE) — and prompted the trial of the same drug in IPF without requiring pulmonary hypertension at all (TETON-2).

Activin signalling inhibition

Trial	Year	Therapy	Effect	Finding
HYPERION	2025	Sotatercept		Sotatercept reduced clinical worsening when given within a year of diagnosis
ZENITH	2025	Sotatercept		Sotatercept cut death, transplant or hospitalisation by three quarters in high-risk PAH

Estimating pulmonary pressures non-invasively

Trial	Year	Therapy	Effect	Finding
Fisher 2009 diagnostic accuracy	2009	Doppler echocardiography		Doppler estimates of pulmonary pressure were out by more than 10 mmHg in half of cases
Arcasoy 2003 diagnostic accuracy	2003	Doppler echocardiography		Echocardiography misclassified half of patients with advanced lung disease as having pulmonary hypertension

Endothelin receptor antagonists

Trial	Year	Therapy	Effect	Finding
SERAPHIN	2013	Macitentan		Macitentan cut morbidity and mortality events by 45% in pulmonary arterial hypertension

Initial combination therapy

Trial	Year	Therapy	Effect	Finding
AMBITION	2015	Ambrisentan plus tadalafil		Starting two vasodilators at once halved clinical failure compared with either alone

Phosphodiesterase-5 inhibitors

Trial	Year	Therapy	Effect	Finding
SUPER-1	2005	Sildenafil		Sildenafil improved walk distance and haemodynamics, with no dose-response above 20 mg

Prostacyclin pathway agents

Trial	Year	Therapy	Effect	Finding
GRIPHON	2015	Selexipag		Selexipag cut disease progression and hospitalisation by 40%, without a mortality difference