Tadalafil for Pulmonary Hypertension Due to Chronic Lung Disease
Condition: Pulmonary Hypertension; Chronic Obstructive Pulmonary Disease (COPD)
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Hypertension, Pulmonary; Hypertension
Study type: Interventional
Phase: Phase 2

Summary: 
      The functional, social, and economic burden of chronic obstructive lung disease (COPD) on the
      healthcare system is extraordinary. COPD is the fourth leading cause of death in the United
      States, and some estimates attribute up to $33.2 billion in health care costs to
      COPD-associated morbidity and mortality annually. The burden of COPD to the VA Healthcare
      system parallels these findings. According to the VA HSR&D Health Economics Resource Center,
      COPD ranks 5th among the 40 most common chronic clinical conditions in the U.S. Veteran
      patient population, is responsible for >14,000 VA hospital admission annually, and increases
      by $1,051/patient the total annual health care cost burden on the VA Healthcare system.
      Importantly, COPD is associated with frequent emergency room visitation and/or
      hospitalization patients. Pulmonary hypertension is a common co-morbid condition that worsen
      morbidity and mortality in patients with COPD. This study will examine the potential for
      tadalafil, a phosphodiesterase type-5 (PDE-5) inhibitor to improve functional status by
      decreasing pulmonary hypertension. Results from this study are expected to define the
      potential use of PDE-5 inhibitors in COPD-induced pulmonary hypertension. If successful, this
      treatment option may improve quality of life and outcomes for the large number of Veterans
      afflicted with PH due to COPD.
    

Detailed description: 
      Project Summary/Abstract This VA CSR&D Merit Review Award for a Clinical Trial proposal
      describes a 5-year program to support a prospective, placebo-controlled, randomized clinical
      trial (RCT) evaluating the effect of phosphodiesterase type-5 (PDE-5) inhibition with
      tadalafil at 40 mg daily over 12 months on exercise capacity in patients with at least
      moderate pulmonary hypertension (PH) PH (mean pulmonary artery pressure (mPAP) > 25 mm Hg,
      pulmonary vascular resistance (PVR)>3.0 Woods units, pulmonary capillary wedge pressure
      (PCWP) <18 mm Hg) due to chronic obstructive pulmonary disease (COPD) GOLD stage II or
      higher, FEV1FVC <70). PDE-5 inhibitors are recommended for World Health Organization (WHO)
      Category 1 PH but there is no evidence based recommendation supporting the use of these
      inhibitors in COPD-induced PH (WHO Category 3). In order to ensure maximum patient enrollment
      and to increase the clinical and demographic diversity of patients included in this study,
      the proposed research will be conducted at four VA sites: Boston VA Healthcare System,
      Providence VA Medical Center, the Greater Los Angeles VA Healthcare System , Atlanta VA and
      Denver VA. The research team includes senior investigators with extensive experience in the
      clinical management of patients with COPD and PH. The principal investigators (PI) for this
      study is Dr. Ronald H. Goldstein (Chief, Pulmonary Medicine at the Boston Healthcare System)
      and Dr Sharon Rounds (Chief, Medical Service, Providence VA). Dr Shelley Shapiro will serve
      as site PI at the Greater Los Angeles VA Healthcare System.

      Within the Veteran population, COPD ranks among the most common chronic diseases and inflicts
      a substantial clinical and economic burden on the VA Healthcare System. Importantly, the vast
      majority of COPD-associated mortality and morbidity, including hospital admissions, is
      derived from a relatively select subpopulation of patients. There is emerging evidence to
      suggest that clinically evident PH is a key determinate of risk in COPD for exacerbations and
      progression of disease. The investigators found that moderate or severe PH is associated with
      significantly increased rates of COPD-related hospital readmission as compared to similar
      Veterans with COPD and only mild PH. Moreover, this trend was not influenced by differences
      in conventional measures of COPD disease severity (i.e., forced expiratory volume in 1 second
      [FEV1]) and was irrespective of supplemental oxygen status. These observations are in support
      of previously established clinical observations from others demonstrating that traditional
      COPD therapies, including supplemental oxygen, are ineffective at modulating sustained
      improvements to cardiopulmonary hemodynamics in patients with COPD and PH. It is established
      in specific forms of PH in which hypoxia is not the central mediator of disease progression
      that restoration of NO--dependent signaling in pulmonary vascular tissue is effective at
      attenuating pulmonary vascular remodeling to improve cardiopulmonary hemodynamics, exercise
      tolerance, and quality of life. The extent to which therapies that preserve NO--dependent
      signaling in pulmonary vascular tissue are effective in PH due to chronic lung disease,
      however, is not known.

      Under physiological conditions, the enzyme phosphodiesterase type-5 (PDE-5) functions to
      maintain pulmonary vascular tone by degrading cGMP a key signaling intermediary involved in
      NO--dependent signaling. However, in PH due to lung disease, pulmonary vascular levels of NO-
      are diminished while PDE-5 levels are increased. This raises the possibility that PDE-5
      inhibition is a potential strategy by which to increase NO- bioavailability and attenuate PH
      in patients with COPD, and sets the framework for the central hypothesis of the current
      proposal is that pharmacological inhibition of PDE-5 will improve functional capacity as
      assessed by 6 minute walk test in patients with COPD-induced moderate to severe PH. The
      secondary outcome measures will assess whether this change in functional status is
      accompanied by an improvement in maximal oxygen uptake during cardiopulmonary testing (VO2)
      and changes in vascular remodeling as assessed by cardiopulmonary hemodynamics. To test this
      hypothesis, a RCT will be conducted using tadalafil (40 mg orally daily) or placebo. The
      primary outcome measurements will be the six minute walk test. The secondary outcome measures
      will be functional assessment using peak volume of oxygen consumption (VO2) and the
      hemodynamic measures of PVR and mPAP. Additional information will be obtained related to the
      non-invasive assessment of pulmonary artery systolic pressure and right ventricular (RV)
      function including tricuspid annular plane systolic excursion, pulmonary artery acceleration
      time, and changes to the pulmonary outflow tract Doppler envelope, dyspnea, health related
      quality of life assessed by validated standardized questionnaires and the frequency of COPD
      exacerbations after 12 months. Results from this study are expected to define the potential
      use of PDE-5 inhibitors in COPD-induced PH. If successful, this treatment option may improve
      quality of life and outcomes for the large number of Veterans afflicted with PH due to COPD.
    

Intervention name(s): Tadalafil; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Daily use of study drug to treat pulmonary hypertension.; Daily use in double blind study.
Other intervention name(s): Cialis
Intervention MeSH terms: Tadalafil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Randomized trial; COPD; tadalafil; Phosphodiesterase inhibitor; Pulmonary hypertension