Tadalafil for Treatment of Pulmonary Hypertension: Mechanisms, Evidence, and Emerging Perspectives

Pulmonary arterial hypertension (PAH), a subset of pulmonary hypertension (PH), remains a progressive and debilitating disease marked by vascular remodeling and elevated pulmonary vascular resistance. Tadalafil, a phosphodiesterase type 5 inhibitor (PDE-5i), plays a central role in the nitric oxide-cyclic guanosine monophosphate pathway, enhancing vasodilation and reducing right ventricular afterload. Compared with sildenafil, tadalafil offers the advantages of once-daily dosing, a longer half-life, and favorable tolerability. A randomized controlled trial and its long-term extension demonstrated significant improvements in 6-minute walk distance, functional class, and hemodynamic parameters in patients with PAH, with sustained efficacy and an acceptable safety profile over time. Current international guidelines recommend tadalafil both as monotherapy and in combination regimens, particularly with endothelin receptor antagonists like ambrisentan, for World Health Organization functional class (WHO-FC) II or III PAH patients. Beyond PAH, tadalafil's therapeutic potential in WHO Group 2 PH, especially in heart failure with preserved ejection fraction, has been investigated with mixed results. While preclinical models suggest benefits in left ventricular function and remodeling, the PASSION (Tadalafil for treatment of combined postcapillary and precapillary pulmonary hypertension in patients with heart failure and preserved ejection fraction) trial in heart failure with preserved ejection fraction with combined post- and precapillary PH failed to demonstrate clinical benefit. These findings underscore the need for additional studies to define tadalafil's role outside Group 1 PH and to better stratify patients who may benefit through biomarker- or phenotype-guided approaches.