Effect of PDE5 inhibitor on respiratory symptoms in COPD complicated by pulmonaryhypertension

Providence Va Medical Center, Providence RI

Investigators

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the US and is common among Veterans. Dyspnea, a debilitating symptom of COPD, dramatically worsens health related quality of life, is associated with a reduction in daily physical activity and greater health care utilization and is more closely associated with survival than severity of airflow limitation. Thus, it is important to have effective treatments that reduce dyspnea for Veterans with COPD. Pulmonary hypertension (PH) is a common complication of COPD that is associated with severe dyspnea, more frequent acute exacerbations of COPD, and increased mortality. There are multiple causes of PH associated with COPD (COPD-PH), including decreased bioavailable levels of the vasodilator nitric oxide (NO). Phosphodiesterase type-5 inhibitor (PDE-5i) therapy restores NO signaling and improves cardiopulmonary hemodynamics and dyspnea among patients with Pulmonary Arterial Hypertension. However, studies of PDE-5i medications in COPD-PH have shown conflicting results due to differing doses or durations of therapy and differing definitions of PH. In a prior study (ClinicalTrials.gov.identifier: NCT01862536), we investigated the effects of up to 12 months of oral PDE-5i therapy with tadalafil on 6 minute walk distance (6MWD), a measure of exercise capacity in Veterans with COPD-PH, in a multi- center randomized placebo-controlled trial funded by the Department of Veterans Affairs. While tadalafil did not change 6MWD at 6 and 12 months (the primary outcome), the treatment group experienced changes in important secondary outcomes, with clinically meaningful improvement in patient-reported dyspnea and COPD-related health related quality of life after 6 months of therapy. Additionally, over 6 months, dyspnea worsened in the placebo group, and patients receiving PDE-5i therapy suffered fewer exacerbations. A limitation of this study was its small sample size. Given the importance of mitigating dyspnea among patients with COPD, we will assess the effect of maximally tolerated therapy with tadalafil specifically on dyspnea powered as a primary outcome. In 126 participants with COPD-PH (63 treatment and 63 placebo) receiving usual clinical care for COPD, we propose to evaluate effects of tadalafil on dyspnea among patients with COPD-PH in a prospective, double-blind, placebo-controlled clinical trial. Aim 1: As primary outcome, we will determine whether 6 months of daily oral tadalafil is more effective than placebo in reducing severity of patient-reported dyspnea, assessed by the University of California- San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), in Veterans with COPD-PH. We hypothesize that patients receiving tadalafil will report less dyspnea than those receiving placebo. Aim 2: As a secondary outcome, we will determine the effectiveness of tadalafil therapy on physical activity, assessed by objective daily step count, and functional capacity, assessed by 6MWD. We hypothesize that patients on tadalafil therapy will have improved physical activity and functional capacity. Aim 3: As a secondary outcome, we will also assess the effects of tadalafil therapy on time to clinically important deterioration, a validated composite outcome defined as increase > 4U in the total health-related quality of life (St. George’s Respiratory Questionnaire, SGRQ), decreased FEV1 of > 100ml, or moderate- severe acute exacerbations of COPD. We hypothesize that Veterans with COPD-PH receiving tadalafil will be less likely to have clinically important deterioration. Aim 4: In exploratory analyses, we will assess whether changes in noninvasive measures of PH (CT scan, cardiac echo) are associated with changes in dyspnea. We hypothesize that patients receiving tadalafil will have decreased PA/A ratio on CT scan, and decreased ePASP on echocardiography. This study may provide evidence for a new therapy for dyspnea in COPD complicated by PH.