A Concerning Trend for Patients With Pulmonary Hypertension in the Era of Evidence-Based Medicine
Authors: Bradley A. Maron, John J. Ryan
Journal: Circulation (2019)

ulmonary hypertension (PH) is an abnormal elevation in pulmonary arterial blood pressure.Regardless of the underlying cause, PH is an independent risk factor for adverse outcome.Pulmonary arterial hypertension (PAH) is a rare form of PH, which is characterized by plexogenic vascular remodeling.Although therapeutic advances have been made in PAH, currently there are no approved therapies for PH from left-sided heart disease (World Health Organization [WHO] group 2) or chronic hypoxic lung disease (WHO group 3) PH.The importance of this treatment gap is amplified when considering that the prevalence of WHO group 2 or 3 is >2500-fold greater than PAH.Furthermore, the elevated pulmonary artery pressure in patients with WHO group 2 and 3 PH corresponds to an adjusted mortality risk increase of ≥50%. 1 Perhaps it is for these reasons that significant emphasis has been placed on the potential for PAH therapies to modulate clinical risk in other forms of PH.Specifically, the efficacy of endothelin receptor antagonists and phosphodiesterase type V inhibitors has been assessed in numerous observational studies and some prospective clinical trials involving patients with WHO group 2 or 3 PH (Table ).Although data from some small studies may appear encouraging, overall, these data have prompted a class III recommendation (treatment is not useful or effective, and may be harmful) from international expert consensus panels for the use of PAH therapy in patients with WHO group 2 or 3 PH. 2 Despite these strong recommendations against using PAH therapies in non-PAH forms of PH, a troubling pattern suggesting the indiscriminant off-label use of PAH therapies has emerged in these populations.In the Giessen PH registry, published in 2017, from one of the world's leading PH centers, 40% of patients referred to the center with a diagnosis of WHO group 2 PH were on PAH therapies.In patients referred for WHO group 3 PH, 78% were on PAH therapies. 3In addition, a recently published population-based cohort study in Ontario, Canada showed that phosphodiesterase type V inhibitor was cumulatively prescribed for more patients with WHO group 2 PH than patients with PAH, and the use of phosphodiesterase type V inhibitors and endothelin receptor antagonists continues to rise in this cohort. 4It is particularly sobering that, in both of these studies, the prognosis was poorer in patients with WHO group 2 and WHO group 3 PH than in patients with PAH.Although speculative, it is worth considering whether this is attributable, at least in part, to the frequent use of contraindicated PAH medicines.These medicines affect systemic vascular beds as well, which may result in adverse hemodynamic consequences.A number of potential reasons may account for widespread use of PAH treatments in patients with WHO group 2 or 3 PH.First, alternative pharmacotherapies with proven benefit specific to the lung circulation do not exist.Thus, it may be perceived as tempting by (well-intended) practitioners to prescribe PAH therapies in an effort to mitigate PH-associated clinical risk.Second, anecdotal experience