Despite strong recommendations against the use of pulmonary arterial hypertension (PAH) therapies for non-PAH forms of pulmonary hypertension (PH), there is a pattern of indiscriminate off-label use in these populations that is not supported by clinical evidence, according to an article published in Circulation.

In this analysis of prescribing trends for off-label PAH therapies, researchers considered the treatment gap for PH from left-sided heart disease (World Health Organization [WHO] group 2) or chronic hypoxic lung disease (WHO group 3) PH, given that there are currently no approved therapies. Because of the increased prevalence of WHO group 2 and group 3 PH over that of PAH, there is significant evidence placed on the potential for PAH therapies to modulate clinical risk in other forms of PH.

Several observational studies and some prospective clinical trials have assessed the efficacy of endothelin receptor antagonists and phosphodiesterase type V inhibitors, prompting class III recommendations for the use of PAH therapy in patients with WHO group 2 or group 3 PH.

The researchers suggested that worse outcomes in patients with WHO group 2 or group 3 PH compared with patients with PAH may be attributable, in part, to the frequent use of contraindicated PAH therapies, which affect systemic vascular beds and may result in adverse hemodynamic consequences.

Widespread use of PAH treatments in these populations may be due to well-intentioned practitioners seeking to mitigate PH-associated clinical risk, as well as the influence of anecdotal experiences on practice patterns. Incomplete testing and incorrect diagnoses are likely the most common reasons for inappropriate prescribing. Disagreement regarding the cause of PH, which is often multifactorial and not confined to a single group, is exacerbated by incomplete testing. Finally, practice-driven practice patterns may contribute to drug prescription selection.

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The researchers suggested that prescribing PAH therapy without a bona fide clinical indication warrants attention and that there is a reason for reform of the current prescribing pattern of PAH drugs. More research is needed to discover treatment-responsive subgroups in identifying WHO group 2 and group 3 patients who may be suitable for PAH treatments. Identification of appropriate and novel drug targets will likely come with expanding existing knowledge on the genetic and molecular basis of PH.


Maron BA, Ryan JJ. A concerning trend for patients with pulmonary hypertension in the era of evidence-based medicine. Circulation. 2019;139(16):1861-1864.