Study Design and Rationale for Investigating Phosphodiesterase type 5 Inhibition for the Treatment of Pulmonary Hypertension Due to Chronic Obstructive Lung Disease: The TADA‐PHiLD (TADAlafil for Pulmonary Hypertension Associated with Chronic Obstructive Lung Disease) Trial

Abstract

In patients with chronic obstructive pulmonary disease (COPD), moderate or severe pulmonary hypertension (COPD-PH) is associated with increased rates of morbidity and mortality. Despite this, approaches to treatment and the efficacy of phosphodiesterase type 5 inhibition (PDE-5i) in COPD-PH are unresolved. We present the clinical rationale and study design to assess the effect of oral tadalafil on exercise capacity, cardiopulmonary hemodynamics, and clinical outcome measures in COPD-PH patients. Male and female patients 40-85 years old with GOLD stage 2 COPD or higher and pulmonary hypertension diagnosed on the basis of invasive cardiac hemodynamic assessment (mean pulmonary artery pressure [mPAP] >30 mmHg, pulmonary vascular resistance [PVR] >2.5 Wood units, and pulmonary capillary wedge pressure ≤18 mmHg at rest) will be randomized at a 1∶1 ratio to receive placebo or oral PDE-5i with tadalafil (40 mg daily for 12 months). The primary end point is change from baseline in 6-minute walk distance at 12 months. The secondary end points are change from baseline in PVR and mPAP at 6 months and change from baseline in peak volume of oxygen consumption ([Formula: see text]) during exercise at 12 months. Changes in systemic blood pressure and/or oxyhemoglobin saturation (Sao2) at rest and during exercise will function as safety outcome measures. TADA-PHiLD (TADAlafil for Pulmonary Hypertension assocIated with chronic obstructive Lung Disease) is the first sufficiently powered randomized clinical trial testing the effect of PDE-5i on key clinical and drug safety outcome measures in patients with at least moderate PH due to COPD.

The Heterogeneity of Clinical Practice Patterns among an International Cohort of Pulmonary Arterial Hypertension Experts

“…37 No consensus was observed among experts for the use of PDE-Vi therapy in WHO group 3 pulmonary hypertension, which is in concert with varying opinions reported on this issue in the literature. 32,38 There are several limitations to this study beyond factors intrinsic to survey research that merit discussion when interpreting our findings. First, our approach was to solicit survey responses from self-identified PAH experts belonging to medical organizations with an established commitment to pulmonary vascular disease.…”

“…11,15,32 Failure to adhere to consensus recommen- dations in pulmonary vascular disease, in turn, is associated with suboptimal rates of diagnosis and treatment. In one study by Deaño and colleagues, 11 pulmonary hypertension misdiagnosis rates were as high as 52%, which was associated with similar rates of inappropriate therapy.…”

“…Several recent publications have demonstrated that a mismatch between expert consensus recommendations and applied clinical care patterns exists for patients with pulmonary vascular disease and have shown that this trend is consistent across various patient populations, including community-based, referred, and military veteran cohorts. 11,15,32 Failure to adhere to consensus recommen- . Regional differences and the use of a multidisciplinary approach to the management of pulmonary arterial hypertension (PAH) patients.…”

“…Several recent publications have demonstrated that a mismatch between expert consensus recommendations and applied clinical care patterns exists for patients with pulmonary vascular disease and have shown that this trend is consistent across various patient populations, including community-based, referred, and military veteran cohorts. 11,15,32 Failure to adhere to consensus recommen- dations in pulmonary vascular disease, in turn, is associated with suboptimal rates of diagnosis and treatment. In one study by Dean ˜o and colleagues, 11 pulmonary hypertension misdiagnosis rates were as high as 52%, which was associated with similar rates of inappropriate therapy.…”

The role of phosphodiesterase inhibitors in the management of pulmonary vascular diseases

“… 288 , 291 There is now an ongoing study (TADA-PHiLD trial) which is a multicenter, prospective, randomized, placebo-controlled, double-blind clinical trial that aims to characterize the efficacy and safety profile of PDE5 inhibitors (specifically tadalafil) in patients with chronic obstructive lung disease and moderate to severe pulmonary hypertension. 292 Moreover, circulatory exercise impairment remains unstudied, and the low prevalence of this condition might explain why these studies have not yet been performed to date. 293 …”