Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death in the US [ 1 ] and is common among Veterans [ 2 ]. Despite recent advances in management of COPD, dyspnea remains a debilitating symptom [ 3 ] that is associated with high health care utilization [ 4 ] and is a better predictor of survival than severity of airflow limitation [ 5 ]. Dyspnea limits physical function, leading to a vicious downward spiral of fear/panic/inactivity that may cause depression and anxiety [ 3 , 6 ]. The resulting functional impairment can lead to social isolation, maladaptive lifestyle changes, and downstream negative health consequences. The causes of dyspnea in COPD are multi‐factorial, including airflow limitation, reduced inspiratory capacity, dynamic hyperinflation, left ventricular dysfunction, hypoxemia, and pulmonary hypertension (PH) [ 7 , 8 , 9 ]. PH commonly complicates COPD. The pathophysiology of PH in COPD includes regional hypoxic vasoconstriction, polycythemia, endothelial injury leading to decreased vasodilator tone, vascular remodeling, loss of pulmonary microvessels due to emphysematous destruction of alveolar‐capillary septa, and hyperinflation causing compression of microvessels [ 10 ]. Up to 90% of patients with severe COPD have mean pulmonary artery pressure (mPAP) > 20 mmHg [ 11 ]. Patients with PH and chronic lung disease report shortness of breath as their most bothersome symptom with significant impact on health‐related quality of life (HRQL) and function [ 3 ]. Thus, alleviating dyspnea in patients with COPD and PH (COPD‐PH) is an important goal of therapy.
In a previous Department of Veterans Affairs‐funded study (ClinicalTrials. gov identifier: NCT01862536 ), we assessed the effects of a daily oral phosphodiesterase type 5 inhibitor (PDE5i), tadalafil, on exercise tolerance, as assessed by the primary outcome 6‐min Walk Distance (6MWD), as well as on secondary outcomes that included dyspnea among 42 Veterans with COPD‐PH randomized to tadalafil or placebo [ 12 ]. We did not find any effect of tadalafil on 6MWD or on pulmonary hemodynamics at 6 or 12 months. However, Veterans reported significantly improved dyspnea, as assessed by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ); after 6 months in the tadalafil group, scores improved (decreased) by a median of 4.0 points, whereas they worsened (increased) by a median of 12 points in the placebo group ( p = 0.02). Therefore, the between‐group difference in the changes in dyspnea score was 16 points. The minimal clinically important difference (MCID) for the UCSD SOBQ score is 5 units [ 12 ]. Clinically and statistically – the potential effect of tadalafil on dyspnea we observed in that trial was very large. In addition, Veterans randomized to tadalafil reported a significantly lower number of COPD exacerbations than Veterans randomized to placebo. While there were numerically more deaths in the tadalafil group than the placebo group in the prior study, there were twice as many patients ( n = 28) assigned to tadalafil as placebo ( n = 14); the observed difference in mortality ( n = 5 vs. n = 1) was not statistically significant. Furthermore, 3/5 deaths in the tadalafil group occurred before receiving any study medication, making a mechanistic link between tadalafil use and mortality less likely. The two groups did not differ significantly in the number of other adverse events reported.
The previous study was limited by challenges in participant recruitment, with a major limitation being eligibility for enrollment required a previous clinical right heart catheterization (RHC) demonstrating PH. A study RHC was also performed after 6 months of treatment. However, given the large potential positive effects of tadalafil therapy noted in the prior study on an important patient‐centered outcome, dyspnea, not currently amenable to specific pharmacologic therapy in COPD‐PH, we designed this follow‐up study to examine the effect of 6 months of treatment with tadalafil versus placebo on dyspnea as measured by UCSD SOBQ (primary outcome) among Veterans with COPD‐PH. To facilitate recruitment and potential clinical translation, this new trial primarily uses noninvasive markers of PH – i.e., estimated pulmonary artery systolic pressure (ePASP) by transthoracic echocardiography and the pulmonary artery to aorta ratio (PA/A ratio) as measured on chest computed tomography.
Secondary outcomes include: physical activity measured as daily step count using actigraphy, exercise capacity as measured by 6MWD, and clinically important deterioration, a validated composite outcome defined as an increase of at least 4 units in the St. George's Respiratory Questionnaire (SGRQ) total score; or at least 1 moderate‐severe exacerbation of COPD; or a decrease in FEV 1 of ≥ 100 mL on spirometry [ 13 , 14 ]. In addition, we assess the effects of tadalafil versus placebo on spirometry and whether noninvasive measures of PH (ePASP, PA/A ratio) change over the course of the study and whether any such changes are associated with changes in dyspnea score. Finally, this study was designed to be able to assess multiple patient‐centered outcomes remotely if necessary: the primary outcome (UCSD SOBQ) and several secondary outcomes (COPD exacerbations, SGRQ total score, and actigraphy).
This study has been approved by the VA Central IRB (IRB number: 1740337) and has been registered in Clinicaltrials. gov ( NCT05937854 ). Recruitment of participants has begun.
Methods
Clinical Trial Design
This is a prospective, randomized, double‐blind, placebo‐controlled clinical trial to test the hypothesis that PDE‐5 inhibition improves dyspnea in patients with COPD‐PH. One hundred twenty‐six Veterans will be randomized in a 1:1 ratio to treatment with once‐daily tadalafil or oral placebo stratified across 5 VA sites (VA Boston Health Care, VA Providence Health Care, VA Atlanta Health Care, VA Nebraska‐Western Iowa Health Care in Omaha, and Rocky Mountain Regional VAMC in Denver).
Recruitment
Eligible participants are identified through (1) in‐clinic referrals; (2) medical record review of echocardiography, lung cancer screening and right heart catheterization databases (3) utilization of the Corporate Data Warehouse (CDW) through VA Informatics and Computing Infrastructure (VINCI) to identify Veterans with the diagnosis of COPD using International Classification of Diseases (ICD) and Current Procedural Terminology (CPT) codes; and (4) advertisements placed in clinics and waiting rooms in the participating VA Medical Centers. Manual chart review by study staff will confirm potentially eligible participants identified by these methods.
Details of study recruitment methods are provided in the Supplemental Material.
All potentially eligible Veterans are contacted via recruitment letters sent through postal mail, followed by follow‐up phone call(s). Veterans may also contact study staff from study advertisement posted in Primary Care, Pulmonary, and Cardiology clinics at participating sites. Interested Veterans are scheduled for a Screening visit with study staff.
Screening Visit
The screening visit begins with confirming eligibility and written informed consent. After informed consent, participants undergo a history and physical exam including collection of vital signs. Clinical evidence of inadequately treated COPD or volume overload prompts a 4‐week run‐in period to facilitate optimization of medical therapy with assistance from the Veteran's routine care team, with scheduled visit to rescreen for eligibility thereafter. Figure 1 lists the remaining screening visit procedures. Echocardiography or chest CT are ordered or performed as needed. After review of eligibility criteria (see Tables 1 and 2 ), including results of echocardiography and chest CT, eligible participants proceed to randomization. This visit is scheduled within 14 days of completion of screening procedures.
Table 1
Inclusion criteria.
| Inclusion criteria |
| 1. Outpatients with Chronic Obstructive Pulmonary Disease (COPD), defined as airflow limitation with post‐bronchodilator obstruction on baseline visit spirometry, identified by FEV1/FVC < 70% or < the lower limit of normal (5th percentile of a normal population based on Global Lung Function Initiative reference equations), OR any emphysema on chest CT noted in a clinical radiology report confirmed by study investigator review. |
| 2. Eligible subjects must have Pulmonary Hypertension (PH) documented as follows: a. Main Pulmonary Artery/Ascending Aorta (PA/A) diameter > 1.0 on clinically available CT scans within 12 months OR b. Outpatient echocardiography done within 6 months of enrollment demonstrating PA sys ≥ 34 mmHg OR c. Mean PA Pressure > 20 on Right Heart Catheterization done within 6 months of enrollment and when Veteran is clinically stable. |
| 3. Eligible subjects must be dyspneic, as quantitated by a score of at least 20 on the baseline University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ), assessed at the time of the baseline visit. |
| 4. Treatment with at least one long‐acting bronchodilator for at least 4 weeks, assessed at the time of the baseline visit by chart review and patient interview. |
| 5. Age 35–89 years |
| 6. Women of childbearing potential must meet one of the following criteria for the previous three months AND must have a negative pregnancy test on the day of testing. If more than 36 h since the participant's last pregnancy test, they will be tested again at the study visit. a. have been using a contraceptive measure (an intrauterine device (IUD), a contraceptive implant, oral contraceptives, barrier methods, or abstinence) b. have a male partner with a vasectomy c. have a tubal ligation procedure or a medical diagnosis (such as infertility) or therapies/procedures that precludes pregnancy (such as cancer treatments or endometrial ablation) d. are in a same‐sex relationship e. have a male partner not capable of fathering children because of congenital anomalies, other surgery, or medical treatment |
| 7. Women who are not considered to be of childbearing potential who have been surgically sterilized (e.g.,: removal of ovaries or fallopian tubes, or hysterectomy) or are post‐menopausal (no menstrual period for more than 6 months). |
Table 2
Exclusion criteria.
| Exclusion criteria |
| 1. Diagnosis of Pulmonary Hypertension (PH) in the following subgroups of the updated World Health Organization Clinical Classification: a. Group 1 (Idiopathic, heritable, drug‐ or toxin‐induced, Pulmonary Arterial Hypertension associated with connective tissue disease, congenital heart disease) b. Group 2 (left atrial hypertension) c. Group 3 PH not attributable to Chronic Obstructive Pulmonary Disease (COPD) d. Group 4 (chronic thromboembolic PH) or other forms of PH not associated with primary lung disease. |
| 2. Systemic hypotension in the ambulatory setting (at least 3 reproducible measurements of systolic blood pressure (BP) < 89 mmHg, recorded by a health care provider over 1 week). |
| 3. Moderate or severe hepatic impairment (Child‐Pugh B and C). |
| 4. Severe renal insufficiency (estimated glomerular filtration rate 5. (eGFR) < 30 mL/min/1.73 m 2 ) |
| 6. Echocardiography within 6 months showing greater than moderate aortic stenosis (aortic valve area < 1.0 cm 2 ), greater than moderate mitral regurgitation, or diastolic dysfunction (Any two of the following: Average E/e' > 14, Septal e' velocity < 7 or lateral e' velocity <10, Left Atrial volume index > 34 ml/m 2 ). Left ventricular ejection fraction (LVEF) < 50%. Any aortic or mitral valve replacement. |
| 7. Any acute or chronic impairment (other than dyspnea) that limits ability to comply with the study requirements. |
| 8. Current unstable angina, myocardial infarction or stroke within 6 months. |
| 9. Requirement for nitrate therapy for any clinical indication. |
| 10. Active prescription for a phosphodiesterase 5 (PDE‐5) inhibitor or other pulmonary vasodilator other than oxygen as a PH treatment. |
| 11. History of the following retinal disorders: retinitis pigmentosa, non‐arteritic anterior ischemic optic neuropathy, or crowded optic disc noted on ophthalmology examinations recorded in CPRS. |
| 12. Contraindications: PDE‐5i allergy, penile anatomical deformations, sickle cell anemia, multiple myeloma, leukemia, bleeding disorders, active peptic ulcer disease, retinitis pigmentosa or other retinal disorders listed above. |
| 13. Use of any of the following: rifampin, systemic anti‐fungal azole agents, protease inhibitors, phenobarbital, dilantin. |
| 14. Pregnant, possibly pregnant by report, or if breastfeeding. If found to be pregnant at the study visit, the study visit will not be conducted. |
| 15. Pulmonary veno‐occlusive disease |
| 16. Hypoxia (reproducible ambulatory arterial oxygen saturation (SaO2) < 90% on supplemental oxygen at rest recorded by a health care provider over 1 week). |
| 17. Diagnosis of Obstructive Sleep Apnea without a prescription for treatment. |
| 18. Newly prescribed (less than 4 weeks duration) bronchodilator or diuretic therapy or new enrollment in pulmonary rehabilitation at the time of Baseline. |
| 19. Students, VA employees, persons with impaired decision making, illiterate and non‐English speakers, and terminally ill patients. |
| 20. COPD or congestive heart failure (CHF) exacerbation within the past 4 weeks. |
| 21. On‐going therapy with doxazosin. |
Randomization Visit
Randomization visit procedures are summarized in Figure 1 . Randomized treatment assignments are prepared by the study statistician using a computer‐generated random number assignment in which participants are allocated in a 1:1 ratio to treatment with once daily encapsulated tadalafil or identical encapsulated oral placebo stratified by site. To ensure that enrollment remains balanced, randomization at each site is in blocks of randomly chosen sizes of four and six, with equal numbers of participants assigned to each treatment in each block. The assignments are given to the central research pharmacy which then prepares the study medication provided to participants at each of the 5 sites. Study medication is mailed to the local site pharmacy. Study medication is shipped in identical containers containing 3 months of medication. Participants, local pharmacists, and investigators are blinded regarding the study drug.
At the time of screening visit or related imaging (echocardiography, CT) visits, participants are provided a Stepwatch Activity Monitor (SAM) and instructed to wear it during all waking hours for 7 consecutive days while going about their usual activities. The physical activity step‐count data are downloaded from the Stepwatch at the randomization visit.
The participant is then given one capsule (20 mg) of the assigned study medication and monitored for 1 h. If blood pressure (BP) and SaO 2 are stable, participants are instructed to take one capsule per day for 3 days and to contact the study team if any adverse events or side effects such as headache, lightheadedness, or dizziness occur. They are also given a pulse oximeter if they do not have one and asked to notify study staff if SaO 2 < 90% on room air or their usually prescribed supplemental oxygen. If this occurs, they are asked to return to the VAMC for evaluation and determination of continuation in the study.
Safety Visits
Three days after randomization, a telephone assessment is conducted by study staff to monitor for changes in clinical status including dizziness, chest pain, syncope, or light headedness. Any recorded symptoms are reviewed by the local site investigator. Veterans who report new or worsened symptoms of dizziness/lightheadedness, chest pain, syncope, or shortness of breath that are of significant concern (in the opinion of the site investigator) after 3 days on one capsule of study drug (tadalafil 20 mg or placebo) per day are withdrawn from the study. If no new symptoms are reported on the 3‐day follow up telephone call, the study drug is up‐titrated to 2 capsules (40 mg tadalafil or placebo) orally daily and participants are instructed to notify the investigators of any new symptoms. If Veterans report dizziness or syncope, they are advised to withhold the study drug and return for in‐person assessment.
Veterans return to the clinic for an in‐person safety visit 6 days after randomization for assessment of symptoms and measurement of BP and SaO 2 . If BP or SaO 2 are outside study parameters (systolic BP < 89 mmHg and SaO 2 < 90% on supplemental oxygen at rest) on 3 successive measurements or if there is > 30 mmHg drop in systolic blood pressure from baseline accompanied by symptoms (dizziness/lightheadedness) or intolerable dyspepsia/flushing/headache, then the study drug will be down‐titrated to one capsule per day (20 mg QD). If symptoms persist, then the participant will be instructed to stop the study drug, but we will continue to follow them.
Follow‐Up Study Procedures and Visits
Participants will be contacted monthly either by telephone or in clinic to ascertain any problems or adverse drug effects. A Symptom Assessment Form is used as a standardized approach for asking about change of symptoms.
Participants are seen or contacted a total of ten times over 6 months. Six visits are in‐clinic, with four visits conducted over the phone. At each follow up visit, medication compliance is assessed by pill counting, adverse events and medication changes recorded, and exacerbation history (COPD, heart failure) is queried and recorded. Study procedures are repeated at months 1, 3, and 6 study visits. Participants who cannot attend an in‐person clinic visit at 1, 3, and 6 months are interviewed by phone to complete study questionnaires. At months 2, 4, and 5, study staff conduct telephone calls to monitor participant safety and medication compliance. Data collected at the different study visits are outlined in Figure 1 . All data are collected by research personnel who are blinded to participant group (as are the investigators).
Outcomes
Primary Outcome Measure
The UCSD SOBQ was chosen as the instrument to measure the primary outcome, dyspnea [ 15 ].
Dyspnea is measured at baseline, 1, 3, and 6 months. The UCSD SOBQ is a validated self‐administered questionnaire with 24 items. Twenty‐one of the items ask about the degree of shortness of breath with various activities while 3 items ask about activity limitations due to shortness of breath, fear of harm from overexertion, and fear of shortness of breath. Items are scored from 0 (not at all) to 5 (maximally). The total score therefore ranges from 0 to 120, with 120 representing the greatest shortness of breath impact. The minimal clinically important difference (MCID) of the UCSD SOBQ is ± 5 units/points [ 16 ] and cut‐offs for small (5 point‐difference), moderate (11 point‐difference), and large differences (16 point‐difference) have been defined [ 17 ]. In a validation study, the reported mean ( ± SD) of UCSD SOBQ scores was 62 ( ± 19) points in all COPD patients and 42 ( ± 23) points in GOLD Stage II COPD [ 18 ]. A minimal score of ≥ 20 points in UCSD SOBQ for inclusion into the study appropriately excludes participants with minimal dyspnea who may fail to show improvement while minimizing substantial regression to the mean effects.
While a large number of instruments are available for measurement of dyspnea [ 19 ], the UCSD SOBQ had several advantages for our study. First, it provided continuity with our prior study, allowing evaluation of consistency in findings. Second, the UCSD SOBQ measures dyspnea in the three domains classified by the American Thoracic Society – sensory/perceptual experience, affective distress, and symptoms/disease impact or burden (on functional performance/activity), specifically within the past week [ 19 ], and thus is relatively comprehensive while specifying the period of time being evaluated, an advantage when the instrument is administered repeatedly over time. Third, the UCSD SOBQ has demonstrated longitudinal changes in COPD even in the absence of lung function changes [ 20 ] and has been shown to be responsive to interventions such as pulmonary rehabilitation [ 21 ]. Therefore, we feel the UCSD SOBQ is an appropriate choice for measurement of our primary outcome.
Protocols for secondary outcome measures are described in the Supplemental Materials.
Primary and secondary study outcomes are listed in Table 3 . Safety outcomes are outlined in Table 4 .
Table 3
Primary and secondary Outcomes.
| Construct | Measure(s) | Categorization | Timing |
| Primary outcomes | |||
| University of California San Diego Shortness of Breath Questionnaire | Dyspnea Score Questionnaire | Continuous | 0, 1, 3, 6 M |
| Secondary outcomes | |||
| UCSD SOBQ Minimal Clinically Important Difference (MCID) | Score Questionnaire (MCID 5 points) | Categorical (Worse, No Change, Better) | 0, 1, 3, 6 M |
| St. George's Respiratory Questionnaire (SGRQ) | Health Related Quality of Life (HRQL) Score Questionnaire | Continuous | 0, 1, 3, 6 M |
| SGRQ MCID | Score Questionnaire (MCID 4 units) | Categorical (Worse, No Change, Better) | 0, 1, 3, 6 M |
| Estimated Pulmonary Artery Systolic Pressure (ePASP or eRVSP) | Pressure calculated from echocardiogram | Continuous | 0 and 6 M |
| Tricuspid Annular Plane Systolic Excursion | Calculated from echocardiogram | Continuous | 0 and 6 M |
| Daily step count | Average of 7 days from actigraphy | Continuous | 0, 3, 6 M |
| Acute Exacerbation (AE) of COPD | Report by participant, medical record | Count | Throughout study |
| MCID AECOPD | Report by participant, medical record (MCID 1 mod‐severe exacerbation) | Binary (Yes/no) | 0 and 6 M |
| 6 Min walk distance | In clinic testing | Continuous | 0, 3, and 6 M |
| Pulmonary Artery/Aorta (PA/A) ratio | Measured from low dose CT scan | Continuous (Abnormal > 1.0) | 0 and 6 M |
| Forced expiratory volume (FEV 1 ) (% predicted) | In clinic spirometry testing | Continuous | 0, and 6 M |
| MCID FEV 1 | In clinic spirometry testing (MCID ‐100+ ml) | Binary (Yes/no) | 0 and 6 M |
| Forced vital capacity (FVC) (% predicted) | In clinic spirometry testing | Continuous | 0, and 6 M |
| FEV 1 /FVC ratio | In clinic spirometry testing | Continuous | 0, and 6 M |
| Removal from study | Report from PI | Binary (Yes/no) | 0, 1, 3, 6 M |
| Clinically important difference of COPD | Presence or absence of ≥ 1 MCID SGRQ, MCID AECOPD, and MCID FEV 1 | Binary (Yes/no) | 6 M |
Table 4
Safety Outcomes.
| SAFETY | |||
| Construct | Measure(s) | Categorization | Timing |
| Decompensated Left Ventricular Failure Hospitalization | Report by participant, Medical record | Binary (yes/no) Date | Throughout study |
| Other significant adverse event (e.g. fatality, acute myocardial infarction, hospitalization for pneumonia, hemoptysis, ER visit, hospitalized overnight for any reason) | Report by participant, Medical record | Binary (yes/no) Date | Throughout study |
| SaO 2 (%) ( < 90% on supplemental oxygen at rest) | In clinic testing | Binary | Day 6 0, 1, 3, 6 M |
| Systolic blood pressure (systolic BP < 89,mmHg) | In clinic testing | Binary | Day 6 0, 1, 3, 6 M |
Sample Size
In our previous study we observed a median decrease (improvement) in the UCSD SOBQ dyspnea score of 4 units in the tadalafil treatment group and median increase (worsening) in dyspnea of 12 units ( p = 0.02) in the placebo group over 6 months with a between‐group difference of 16 points. Therefore, we expect an increase in dyspnea over 6 months in the placebo arm. In the prior study, 26% of participants withdrew or dropped out before 6 months. Therefore, we conservatively assumed that 26% of participants randomized will discontinue taking medication during the current 6‐month clinical trial and that those 26% will have outcomes as if they were in the placebo group. Therefore, the average effect in the randomized tadalafil group will be 2.14 points (74% with a 5‐point decrease and 26% with a 6‐point increase). Combined with a 6‐point increase on average on placebo, the expected difference would be 8.14 points assuming that all patients randomized are analyzed in an intent‐to‐treat analysis. A sample size of 126 (63 per group) then gives 90% power to detect a significant between‐group difference greater than zero with a two‐sided test of significance at a 5% level of significance assuming a standard deviation of 14 points. We would still have 80% power if the between‐group difference were as small as 7.2 points.
Data Analysis
Analysis of the effect of treatment group on the primary outcome, dyspnea, will compare change in the UCSD SOBQ score between baseline and 6 months among all Veterans randomized to the tadalafil and placebo groups in a linear regression model adjusting for VA site by which randomization is stratified. Any measurements taken within a 4‐week window before and after 6 months will be accepted as a 6‐month measurement. We will also look at changes at 1 and 3 months and will accept any measurements within a 2‐week window of those times. These windows will reduce the number of missing observations.
We will also fit longitudinal data models to assess changes in UCSD SOBQ scores over time using the 0‐, 1‐, 3‐, and 6‐month measurements. The longitudinal model will include time and treatment group as categorical fixed factors with an unstructured covariance matrix. The interaction of time and treatment group will test the difference between groups over time. The model will return a comparison of the treatment groups at each time point as well as an assessment of the change over time. The longitudinal model can also account for observations missing at random over the course of the study [ 22 ].
Secondary outcomes (see Table 3 ) will be analyzed in a similar manner. Continuous outcomes will be analyzed with linear regression, binary outcomes with logistic regression, and count outcomes by Poisson (or negative binomial) regression. For each outcome, we will analyze change at each time point at which data are collected as well as longitudinal change.
Adequacy of randomization will be assessed by comparing baseline characteristics between the treatment groups. Sensitivity analyses will be performed to assess the effect of any substantial imbalances found among baseline characteristics by including imbalanced covariates as predictors in the outcome regression analyses. All models will be checked for standard regression assumptions such as normality, linearity, homoscedastic variances and appropriate modifications such as variable transformation (e.g., to a logarithmic scale) will be investigated if assumptions are not met. All analyses will report treatment effects along with 95% confidence intervals and p ‐values.
Missing Data: We will attempt to minimize missing 6‐month outcomes by contacting participants who left the study or stopped taking medication before 6 months and requesting that they complete the 6‐month UCSD SOBQ primary outcome measure, the SGRQ, and adverse event monitoring. To assess the assumption that the outcomes are missing at random conditional on their previous values, we will examine the association of missing outcome values with available predictors. If the missing data are imbalanced with respect to these factors, we will use multiple imputation using all available baseline and follow‐up data and adjust results accordingly to draw proper inferences.
Dose Effects: All participants are initially given one capsule (20 mg) of study drug which will be titrated up to two capsules (40 mg) after 3 days if tolerated. During the study, some participants' doses may be reduced to 20 mg or stopped entirely. Thus, we anticipate that individuals may have periods of three dosing regimens (0, 20, and 40 mg). We will analyze the potential effect of dose with different definitions including total prescribed dose, last prescribed dose, dose prescribed longest, any (vs. no dose), and duration of any dose. Control participants can be included in these analyses either as assigned a zero dose or as assigned the placebo dose with an interaction between dose and an indicator for treatment group.
Compliance Analyses: In addition to prescribed changes in dosing, participant dosing may vary because of lack of compliance to the prescribed dosing schedule. Compliance will be assessed by pill counts at study visits and questions asked in person and by phone. As sensitivity analyses for both the binary treatment and the treatment dosing analyses above, we will also analyze individuals according to the treatment/dose actually taken as measured, for example, by pill counts. Alternatively, participants unable to tolerate a 20 mg dose and who discontinue treatment at 3 days can be analyzed as control participants. In addition, to assess potential effects of measured confounders on compliance and treatment effects, we will assess the relationship between compliance and baseline characteristics and account for any associations by regression adjustment. To account for potential unmeasured confounders, we can use randomized treatment as an instrumental variable, model the probability of compliance using principal stratification and then estimate the effect of the treatment taken adjusted for compliance. In addition, to assess the potential impact if participants guess which treatment they are taking, we will ask at 6 months whether or not they thought they were on treatment and then use this information as a covariate to adjust for the effect of correctly or incorrectly guessing treatment [ 23 ].
Effect Modifiers: In addition to testing for differences in treatment by site which will be a prespecified interaction, we will perform exploratory analyses of interactions with treatment for other potential effect modifiers as listed in Supporting Table 1 of the Supporting Material.
Discussion
PH associated with COPD carries an ominous prognosis, with increased association with acute exacerbations, hospitalizations, and mortality [ 11 , 24 , 25 ]. In addition, left ventricular dysfunction causing systolic or diastolic heart failure occurs in up to 30% of patients with COPD [ 10 , 26 , 27 ]. The World Symposium on Pulmonary Hypertension (WSPH) classifies PH into five groups. PH in COPD (Group 3, due to lung diseases and/or hypoxia) is the second most common group. Some patients with COPD also have Group 2 PH due to left heart disease, the most common classification, and can be classified as Group 2/3 overlap. A small group of patients with PH “out of proportion” to PFT abnormalities may have Group 1 Pulmonary Arterial Hypertension with incidental COPD [ 11 ]. In 2019, the WSPH proposed a classification system for PH associated with chronic lung disease that was based on categorization of mean pulmonary pressures and pulmonary vascular resistance into severity categories [ 28 ]. However, the clinical utility of this classification has been questioned [ 29 ], considering the continuum of risk for increased morbidity and mortality demonstrated in part by data from the VA [ 30 ].
PH within the Veteran population has been shown to be underdiagnosed and undertreated [ 31 ]. Using the VA right heart catheterization database, co‐investigators on this clinical trial demonstrated that even mild degrees of PH are associated with greater hospitalization risk and mortality [ 30 ]. Accordingly, the WSPH lowered the threshold to establish the diagnosis of PH to mPAP > 20 mmHg [ 32 ]. Furthermore, co‐investigators on this study have reported that estimated PA systolic pressure (ePASP) > 30 mmHg on echocardiography is abnormal, is associated with 5‐year mortality of over 25%, and is frequently associated with cardiopulmonary and metabolic comorbidities [ 33 ]. In the ASPIRE registry, PH due to lung disease had a worse prognosis than other PH groups [ 34 ]. In addition, Stewart et al have demonstrated that PA systolic pressures > 30 on echocardiography are associated with worse mortality in a large Australian observational cohort [ 35 ]. Using data from the Department of Veterans Affairs and Vanderbilt University, Garry et al showed that PASP > 35 mmHg on transthoracic echocardiography was associated with greater mortality [ 36 ]. Thus, there is a need to develop risk reduction approaches for management of even mildly elevated PA pressures associated with COPD.
Decreased bioavailable levels of the vasodilator, anti‐mitogenic, and anti‐fibrotic molecule nitric oxide (NO) are implicated in the pathogenesis of COPD‐PH [ 37 ]. The phosphodiesterase type‐5 inhibitor (PDE‐5i) drug class restores NO signaling and is a therapy to improve cardiopulmonary hemodynamics and outcomes in Group 1 Pulmonary Arterial Hypertension [ 38 ]. Preclinical studies in cigarette smoke‐induced models of lung injury have reported prevention of pulmonary hypertension by PDE‐5i [ 39 , 40 ]. This provides a biological rationale for treatment with PDE‐5i as a strategy to mitigate morbidity in COPD‐PH.
A report from the Pulmonary Vascular Research Institute meta‐registry indicated that treatment of COPD complicated by PH (diagnosed by right heart catheterization) with a PDE5 inhibitor actually improved mortality [ 41 ]. Gredic et al. summarized randomized controlled trials of PH‐directed oral therapies in humans with PH associated with COPD [ 11 ]. Rao [ 42 ] reported that the PDE5i sildenafil improved 6 min walk distance (6MWD) in a 12‐week trial of COPD‐PH, but this was not observed by Blanco [ 43 ] in a similar trial. Vitulo reported that sildenafil improved PVR, BODE index, and quality of life in a 16‐week trial in patients with severe PH and COPD [ 44 ]. Of note, Vitulo also noted decreased dyspnea, as assessed by MMRC score, after 4 months of sildenafil, thereby supporting the approach of the current clinical trial [ 44 ]. In contrast, Lederer reported that a higher dose of sildenafil worsened oxygenation and quality of life with no effect on 6MWD in patients with COPD in a 4‐week trial [ 45 ]. Goudie et al reported that 10 mg per day of tadalafil decreased PA pressure, as assessed by echocardiography, but did not improve quality of life or 6MWD over 12 weeks [ 46 ]. These studies reported conflicting effects of PDE‐5i on dyspnea and quality of life, with 1 study showing improvement with sildenafil in severe PH complicating COPD [ 42 ]. Different drugs were used at differing doses, for differing treatment and follow‐up times. None of these studies had dyspnea as a primary outcome variable, nor did any use a valid dyspnea measure that comprehensively assesses the multi‐dimensional aspects of dyspnea (i.e., sensory‐perceptual, affective, and impact domains) as recommended by the American Thoracic Society [ 47 ], with demonstrated validity, reliability, and high sensitivity to detect clinically meaningful changes [ 16 ]. Based on the results of our previous trial of tadalafil in patients with COPD‐PH showing improvement in UCSD SOBQ at 6 months [ 12 ], we propose to study the effects of tadalafil on dyspnea in Veterans with COPD and PH with a treatment time of 6 months.
Tadalafil is an oral PDE5i that was approved by the Food and Drug Administration (FDA) in 2009 for use in treating pulmonary arterial hypertension (WHO Group 1). In WHO group 1 patients, tadalafil was effective in improving 6MWD and time to clinical worsening, as well as mean pulmonary artery pressure and PVR [ 38 ]. We selected tadalafil for investigation because of its pharmacokinetic profile (t1/2 of 17.5 h; mean oral clearance of 2.48 L/h) [ 48 ], favoring once‐daily dosing and drug adherence. Generic tadalafil is available, but is not currently approved for the treatment of WHO group 3 PH. It will be administered as a standard dose of 40 mg (two 20 mg pills, encapsulated). Tadalafil is FDA‐approved at 40 mg daily, its highest effective dose.
Data on tadalafil dosing for dyspnea in COPD‐PH is limited. The study by Goudie et al of tadalafil 10 mg daily in COPD‐PH did not examine dyspnea per se but did not show any improvement in quality‐of‐life measures, including symptom scores, at that dosage [ 49 ]. Based on our prior study, which utilized a dose of 40 mg tadalafil daily, the dosage approved for treatment of pulmonary arterial hypertension, we have chosen a target dose of 40 mg daily in the treatment arm, after initiating the study drug at a dose of 20 mg daily. Using the higher dose may increase our ability to identify clinically meaningful outcomes, but we will allow down‐titration, if needed. As noted above, we anticipate that we will have an opportunity to analyze the effects of different doses based on participant tolerability. An IND waiver from the FDA has been obtained.
Our previous study of tadalafil in COPD‐PH was limited by inability to meet recruitment goals, at least in part due to a requirement for right heart catheterization before study enrollment and at 6 months [ 12 ]. There is increasing evidence that noninvasive imaging measures of PH have reasonable diagnostic accuracy and prognostic significance in various conditions associated with PH, including COPD. These measures include ePASP or RVSP on echocardiography and the ratio of the pulmonary artery to aorta on chest CT. For example, a systematic review and meta‐analysis found a PA/A ratio ≥ 1.0 had a sensitivity of 69%, specificity of 89%, and area under the receiver operating curve of 0.90 for detection of PH in COPD [ 50 ]. A PA/A ratio > 1.0 also relates to frequency of acute exacerbations of COPD [ 51 ], RV dysfunction and reduced pulmonary vascular volume [ 51 ], mortality in moderate‐severe COPD [ 52 , 53 , 54 ], acute exacerbations and mortality in the syndrome of preserved ratio impaired spirometry [ 55 ], and survival among patients diagnosed with lung cancer [ 53 ].
Regarding echocardiography, decreases in FEV 1 and FEV 1 /FVC are related to increased echocardiography‐derived ePASP in the general population, with a 1 mmHg increase in ePASP for every 10% decrement in FEV 1 /FVC [ 56 ]; in this population‐based study, ePASP was significantly associated with increased mortality (HR of 3.7% per 1 mmHg) in study participants with COPD [ 56 ]. Co‐investigators on this study reported in a review of published literature that an ePASP > 30 mmHg on echocardiography is abnormal in most healthy individuals and is associated with a 5‐year mortality of 29% in patients referred for clinical echocardiography [ 33 ]. Therefore, ePASP is a prognostic marker, including in COPD patients with PH. In patients with COPD referred for lung transplantation, an ePASP > 45 mmHg had a sensitivity of 76%, specificity of 65% and negative predictive value was 93% for presence of PH by right heart catheterization (defined similarly by PASP), although positive predictive value was only 32% and ePASP both under‐ and overestimated right heart catheterization PASP [ 57 ]. However, this study was of a subgroup with advanced lung disease meriting lung transplantation referral and did not use the current diagnostic standard of mPAP > 20 mmHg by right heart catheterization as the reference definition of PH.
In an attempt to balance the poor prognosis signified by noninvasive imaging markers of PH in COPD, the diagnostic accuracy of these markers for PH in COPD, and the feasibility and safety of performing invasive testing for PH in this patient population, we chose an estimated PA systolic pressure ≥ 34 mmHg on transthoracic echocardiography and PA/A ratio > 1.0 on chest CT to identify Veterans with COPD‐PH in the current study. We have included enrollment into the study based on mPAP > 20 mmHg on clinically indicated RHC within the previous 6 months if the RHC was done when the patient was clinically stable.
We acknowledge that these screening and inclusion criteria are imperfect and may potentially under‐ or over‐estimate presence or degree of PH. However, in “real world” practice, pulmonary vasodilators are frequently prescribed without right heart catheterization, and are associated with risk of harm, with the recommendation to study appropriate patient selection criteria for use [ 58 ]. This study is an attempt to do this in a controlled clinical trial setting. In our study, we also use transthoracic echocardiography to exclude those individuals with evidence of systolic or diastolic left ventricular dysfunction or severe valvular disease who may have concomitant group 2 PH and would be unlikely to benefit from PDE5 inhibition.
Our inclusion and exclusion may not fully exclude COPD patients with other forms of PH. With deep multimodal phenotyping of PH patients at expert centers, mixed pulmonary hypertension groups have been found to be common – in the PVDOMICS study, about 45% of those with group 3 PH also were felt to have a secondary PH grouping, and, conversely, group 3 risk factors including COPD were also prevalent throughout the PH cohort enrolled [ 59 ]. In the current study, we are attempting, in a real‐world setting, to utilize chart records, noninvasive tools and assessments to attempt to exclude other important diseases that may lead to PH. However, even with more exhaustive investigations of PH in this patient population, accurate exclusion of causes of PH other than COPD may not be possible. Attempts to exclude all other potential causes of PH in adult patients with COPD through more restrictive inclusion criteria would also result in less generalizable results in a highly curated group of study participants. However, the enrolled population will be one with a diagnosis of COPD who are symptomatic from dyspnea despite current treatment with bronchodilators, and who have features of pulmonary hypertension on commonly employed noninvasive testing. This is a population for whom effective treatment of dyspnea is currently lacking.
Dyspnea is the primary focus of the current study as it is a clinically relevant, patient‐centered outcome. Four recent workshops sponsored by the ATS and/or NHLBI highlighted the need for patient‐centered outcome research, including the symptoms and experiences of patients with chronic lung disease and following critical illness [ 60 , 61 , 62 , 63 ]. The US FDA recognizes the importance of patient‐reported outcomes and provides guidance on the development of medical products to assess outcomes defined as “any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else [ 64 ].” The importance of patient‐centered outcome research was highlighted by the implementation of the Affordable Care Act, which authorized the development of the Patient‐Centered Outcomes Research Institute (PCORI) with an aim to improve the quality and relevance of evidence to help patients, families, clinicians, insurers, and policy makers make informed health care decisions [ 65 ]. Some advocate that a patient‐reported outcome is always important [ 66 ]. As noted above, in patients with COPD, there is poor correlation of physiologic measures (e.g., FEV 1 ) with dyspnea, and dyspnea is highly prognostic of survival. Therefore, the primary outcome measure – dyspnea as assessed by the UCSD SOBQ – is clinically significant.
Systemic hypotension and hypoxemia may complicate use of PDE5i in patients with COPD, in addition to side effects of headache, dizziness, dyspepsia, and flushing. A systematic review published by Isa et al indicated that tadalafil reduced PA pressure in COPD, with headache being the most common adverse event [ 67 ]. In this study we assess for side effects in safety visits on Day 6 after randomization, including symptoms, BP, and SpO 2 . If BP or SpO 2 are outside study parameters on 3 successive measurements or if there is > 30 mmHg drop in systolic blood pressure from baseline accompanied by symptoms (dizziness/lightheadedness) or intolerable dyspepsia/flushing/headache, then the study drug will be down‐titrated to one capsule per day (20 mg QD). If symptoms persist, then the patient will be instructed to stop the study drug, but we will continue to follow them. Participants are assessed for compliance with the study drug and side effects during subsequent study visits as well.
In summary, because of the importance of dyspnea among persons with COPD complicated by PH, in BETTER COPD‐PH we will assess the effect of maximally tolerated dose of tadalafil on dyspnea in a prospective, randomized, multi‐center, placebo‐controlled clinical trial. The trial design takes into account aspects of “real world” practice and includes noninvasive screening testing and patient‐centered outcome measures. We believe that successful completion of this clinical trial will provide important data on the utility and safety of PDE5 inhibitors in the management of COPD‐PH.
Author Contributions
S. Rounds, E. DeSanti, and M. Jankowich developed the draft of this manuscript. All authors contributed to the design of the study protocol and editing of the manuscript.
Ethical Statement
This study has been reviewed and approved by the Department of Veterans Affairs Central IRB.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
BETTER COPD. PH Supplemental Figure 1.
Protocol Manuscript Supplement FINAL 7.31.25.
Acknowledgments
The views expressed are those of the authors and do not reflect the views of the Department of Veterans Affairs or the U.S. Government.
BETTER‐COPD‐PH Study Group
Jayashri Aragam, MD, MBBS 2 , Brack Hattler, MD 6 , Tim Lahm, MD 6 , Kristin L. Bailey, MD 4 , Debra Romberger, MD 4 , Gautam Kumar, MD 3 , Joshua Detelich, MD 3 , Jussi Saukkonen, MD 2 , Emily Wan, MD 2 , Shelsey Johnson, MD 2 , Malisa Barber, MS 1 , Christopher Halladay, SCM 1 , Kathleen LaCerda 2 , Renee LeClaire, MPH 2 , Alexis Thavenet 4 , Makkawi Makkawi 6 , Mehret Tekle LPN 6 , Susan Burbach, RN 4 , Jenna Eggert, RN 4 , Julia Gillotti 1 , Sridhar Tanukonda 3 , Tiffany Elliott 3 , Radhika Mungara 3 , Matthew Lejy, RN 3
Elena DeSanti and Matthew Jankowich are Co‐First Authors
Contributor Information
Ronald H. Goldstein, Email: ronald.goldstein@va.gov.
Sharon Rounds, Email: Sharon_Rounds@brown.edu.
the BETTER COPD‐PH Study Group:
Jayashri Aragam , Brack Hattler , Tim Lahm , Kristin L. Bailey , Debra Romberger , Gautam Kumar , Joshua Detelich , Jussi Saukkonen , Emily Wan , Shelsey Johnson , Malisa Barber , Christopher Halladay , Kathleen LaCerda , Renee LeClaire , Alexis Thavenet , Makkawi Makkawi , Mehret Tekle , Susan Burbach , Jenna Eggert , Julia Gillotti , Sridhar Tanukonda , Tiffany Elliott , Radhika Mungara , and Matthew Lejy
References
1. Xu J., Murphy S. L., Kockanek K. D., and Arias E., “Mortality in the United States, 2018,” NCHS Data Brief 355 (2020): 1–8.
2. Sharafkhaneh A., Petersen N. J., Yu H. J., Dalal A. A., Johnson M. L., and Hanania N. A., “Burden of COPD in a Government Health Care System: A Retrospective Observational Study Using Data From the US Veterans Affairs Population,” International Journal of Chronic Obstructive Pulmonary Disease 5 (2010): 125–132.
3. DuBrock H. M., Nathan S. D., Reeve B. B., et al., “Pulmonary Hypertension Due to Interstitial Lung Disease or Chronic Obstructive Pulmonary Disease: A Patient Experience Study of Symptoms and Their Impact on Quality of Life,” Pulmonary Circulation Apr‐Jun 11, no. 2 (2021): 20458940211005641.
4. Byng D., Lutter J. I., and Wacker M. E., “Determinants of Healthcare Utilization and Costs in COPD patients: First Longitudinal Results From The German COPD cohort COSYCONET,” International Journal of Chronic Obstructive Pulmonary Disease 14 (2019): 1423–1439.
5. Nishimura K., Izumi T., Tsukino M., and Oga T., “Dyspnea Is a Better Predictor of 5‐year Survival Than Airway Obstruction in Patients With COPD,” Chest 121, no. 5 (2002): 1434–1440.
6. Ries A. L., “Minimally Clinically Important Difference for the UCSD Shortness of Breath Questionnaire, Borg Scale, and Visual Analog Scale,” COPD: Journal of Chronic Obstructive Pulmonary Disease 2, no. 1 (2005. Jan): 105–110.
7. Anzueto A. and Miravitlles M., “Pathophysiology of Dyspnea in COPD,” Postgraduate Medicine 129, no. 3 (2017. Apr 3): 366–374.
8. O'Donnell D. E. and Laveneziana P., “Dyspnea and Activity Limitation in COPD: Mechanical Factors,” COPD: Journal of Chronic Obstructive Pulmonary Disease 4, no. 3 (2007. Jan): 225–236.
9. Blanco I., Tura‐Ceide O., Peinado V., and Barberà J. A., “Updated Perspectives on Pulmonary Hypertension in COPD,” International Journal of Chronic Obstructive Pulmonary Disease 15 (2020): 1315–1324.
10. Chaouat A., Naeije R., and Weitzenblum E., “Pulmonary Hypertension in COPD,” European Respiratory Journal 32, no. 5 (2008): 1371–1385.
11. Gredic M., Blanco I., Kovacs G., et al., “Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease,” British Journal of Pharmacology Jan. 178, no. 1 (2021): 132–151.
12. Maron B. A., Brittain E. L., Hess E., et al., “Tadalafil for Veterans With Chronic Obstructive Pulmonary Disease—Pulmonary Hypertension: A Multicenter, Placebo‐Controlled Randomized Trial,” Pulmonary Circulation 12 (2022): e12043.
13. Anzueto A. R., Kostikas K., Mezzi K., et al., “Indacaterol/Glycopyrronium Versus Salmeterol/Fluticasone in the Prevention of Clinically Important Deterioration in COPD: Results From the FLAME Study,” Respiratory Research Jun. 19, no. 1 (2018): 121.
14. Rabe K. F., Halpin D. M. G., Han M. K., et al., “Composite Endpoints in COPD: Clinically Important Deterioration in the UPLIFT Trial,” Respiratory Research Jul. 21, no. 1 (2020): 177.
15. Jones P., Miravitlles M., van der Molen T., and Kulich K., “Beyond FEV1 in COPD: A Review of Patient‐Reported Outcomes and Their Measurement,” International Journal of Chronic Obstructive Pulmonary Disease 7 (2012): 697–709.
16. Jones P. W., Beeh K. M., Chapman K. R., Decramer M., Mahler D. A., and Wedzicha J. A., “Minimal Clinically Important Differences in Pharmacological Trials,” American Journal of Respiratory and Critical Care Medicine 189, no. 3 (2014): 250–255.
17. Horita N., Miyazawa N., Morita S., et al., “Small, Moderate, and Large Changes, and the Minimum Clinically Important Difference in the University of California, San Diego Shortness of Breath Questionnaire,” COPD J Chronic Obstr Pulm Dis 11, no. 1 (2014. Feb): 26–32.
18. Eakin E. G., Validation of a new dyspnea measure: the UCSD Shortness of Breath Questionnaire (Chest: University of California, 1998). 113, 619–624.
19. Parshall M. B., Schwartzstein R. M., Adams L., et al., “An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea,” American Journal of Respiratory and Critical Care Medicine 185, no. 4 (2012. Feb 15): 435–452.
20. Mahler D. A., Ward J., Waterman L. A., and Baird J. C., “Longitudinal Changes in Patient‐Reported Dyspnea in Patients With COPD,” COPD: Journal of Chronic Obstructive Pulmonary Disease 9, no. 5 (2012. Sep 27): 522–527.
21. Ries A. L., Make B. J., Lee S. M., et al., “The Effects of Pulmonary Rehabilitation In The National Emphysema Treatment Trial,” Chest 128, no. 6 (2005. Dec): 3799–3809.
22. Fitzmaurice G. M., Laird N. M., and Ware J. H., Applied Longitudinal Analysis (John Wiley and Sons, 2011). 2nd ed..
23. Lee J. Y., Moore P., Kusek J., and Barry M., “Treatment Assignment Guesses by Study Participants in a Double‐Blind Dose Escalation Clinical Trial of Saw Palmetto,” Journal of Alternative and Complementary Medicine 20, no. 1 (2014): 48–52.
24. Cook D. P., Xu M., Martucci V. L., et al., “Clinical Insights into Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease,” Pulmonary Circulation 12, no. 1 (2022): 12006.
25. Wijeratne D. T., Lajkosz K., Brogly S. B., et al., “Increasing Incidence and Prevalence of World Health Organization Groups 1 to 4 Pulmonary Hypertension: A Population‐Based Cohort Study in Ontario, Canada,” Circulation: Cardiovascular Quality and Outcomes 11, no. 2 (2018): 003973.
26. Rennard S. I., Locantore N., Delafont B., et al., “Identification of Five Chronic Obstructive Pulmonary Disease Subgroups With Different Prognoses in the Eclipse Cohort Using Cluster Analysis,” Annals of the American Thoracic Society 12, no. 3 (2015): 303–312.
27. Rutten F. H., Cramer M. J. M., Grobbee D. E., et al., “Unrecognized Heart Failure in Elderly Patients With Stable Chronic Obstructive Pulmonary Disease,” European Heart Journal 26, no. 18 (2005): 1887–1894.
28. Blanco I., “Updated Perspectives on Pulmonary Hypertension in COPD,” International journal of chronic obstructive pulmonary disease 15 (2020): 1315–1324.
29. Oldham W. M., Hemnes A. R., Aldred M. A., et al., “NHLBI‐CMREF Workshop Report on Pulmonary Vascular Disease Classification,” Journal of the American College of Cardiology 77, no. 16 (2021): 2040–2052.
30. Maron B. A., Brittain E. L., Hess E., et al., “Pulmonary Vascular Resistance and Clinical Outcomes in Patients With Pulmonary Hypertension: A Retrospective Cohort Study,” Lancet Respiratory Medicine 8, no. 9 (2020): 873–884.
31. Maron B. A., Choudhary G., Khan U. A., et al., “Clinical Profile and Underdiagnosis of Pulmonary Hypertension in US Veteran Patients,” Circulation: Heart Failure 6, no. 5 (2013): 906–912.
32. Simonneau G., Montani D., Celermajer D. S., et al., “Haemodynamic Definitions and Updated Clinical Classification of Pulmonary Hypertension,” European Respiratory Journal 53, no. 1 (2019): 1801913.
33. Jankowich M., Maron B. A., and Choudhary G., “Mildly Elevated Pulmonary Artery Systolic Pressure on Echocardiography: Bridging the Gap in Current Guidelines,” Lancet Respiratory Medicine 9 (2021): P1185–P1191.
34. Hurdman J., Condliffe R., Elliot C. A., et al., “ASPIRE Registry: Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre,” European Respiratory Journal Apr. 39, no. 4 (2012): 945–955.
35. Stewart S., Chan Y. K., Playford D., Harris S., and Strange G. A., “Incident Pulmonary Hypertension in 13 488 Cases Investigated With Repeat Echocardiography: A Clinical Cohort Study,” ERJ Open Research 9, no. 5 (2023. Sep): 00082‐2023.
36. Garry J. D., Kundu S., Annis J., et al., “Incidence of Pulmonary Hypertension in the Echocardiography Referral Population [Internet],” Annals of the American Thoracic Society 22 (2025): 679–688, 10.1513/AnnalsATS.202407-716OC.
37. Dinh‐Xuan A. T., Higenbottam T. W., Clelland C. A., et al., “Impairment of Endothelium‐Dependent Pulmonary‐Artery Relaxation in Chronic Obstructive Lung Disease,” New England Journal of Medicine 324, no. 22 (1991): 1539–1547.
38. Maron B. A. and Galiè N., “Diagnosis, Treatment, and Clinical Management of Pulmonary Arterial Hypertension in the Contemporary Era: A Review,” JAMA Cardiology 1, no. 9 (2016): 1056–1065.
39. Domínguez‐Fandos D., Valdés C., Ferrer E., et al., “Sildenafil in a Cigarette Smoke‐Induced Model of COPD in the Guinea‐Pig,” European Respiratory Journal 46, no. 2 (2015): 346–354.
40. Seimetz M., Parajuli N., Pichl A., et al., “Cigarette Smoke‐Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice,” PLoS One 10, no. 6 (2015): e0129327.
41. Tello K., Yogeswaran A., Majeed R. W., et al., “Association of Phosphodiesterase‐5 Inhibitor Treatment With Improved Survival in Pulmonary Hypertension Associated With COPD in the Pulmonary Vascular Research Institute GoDeep Meta‐Registry,” Chest 167, no. 1 (January 2025): 224–240.
42. Rao R. S., Singh S., Sharma B. B., Agarwal V. V., and Singh V., “Sildenafil Improves Six‐Minute Walk Distance in Chronic Obstructive Pulmonary Disease: A Randomised, Double‐Blind, Placebo‐Controlled Trial,” Indian Journal of Chest Diseases & Allied Sciences 53, no. 2 (2011): 81–85.
43. Blanco I., Santos S., Gea J., et al., “Sildenafil to Improve Respiratory Rehabilitation Outcomes in COPD: A Controlled Trial,” European Respiratory Journal 42, no. 4 (2013): 982–992.
44. Vitulo P., Stanziola A., Confalonieri M., et al., “Sildenafil in Severe Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease: A Randomized Controlled Multicenter Clinical Trial,” Journal of Heart and Lung Transplantation 36, no. 2 (2017): 166–174.
45. Lederer D. J., Bartels M. N., Schluger N. W., et al., “Sildenafil for Chronic Obstructive Pulmonary Disease: A Randomized Crossover Trial,” COPD: Journal of Chronic Obstructive Pulmonary Disease 9, no. 3 (2012): 268–275.
46. Goudie A. R., Lipworth B. J., Hopkinson P. J., Wei L., and Struthers A. D., “Tadalafil in Patients With Chronic Obstructive Pulmonary Disease: A Randomised, Double‐Blind, Parallel‐Group, Placebo‐Controlled Trial,” Lancet Respiratory Medicine 2, no. 4 (2014): 293–300.
47. Parshall M. B., Schwartzstein R. M., Adams L., et al., “An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea,” American Journal of Respiratory and Critical Care Medicine 185, no. 4 (2012): 435–452.
48. Forgue S. T., Patterson B. E., Bedding A. W., et al., “Tadalafil Pharmacokinetics in Healthy Subjects,” British Journal of Clinical Pharmacology 61, no. 3 (2006): 280–288.
49. Goudie A. R., Lipworth B. J., Hopkinson P. J., Wei L., and Struthers A. D., “Tadalafil in Patients With Chronic Obstructive Pulmonary Disease: A Randomised, Double‐Blind, Parallel‐Group, Placebo‐Controlled Trial,” Lancet Respiratory Medicine 2, no. 4 (April 2014): 293–300.
50. Wu X., Shi Y., Wang X., Yu X., and Yang M., “Diagnostic Value of Computed Tomography‐Based Pulmonary Artery to Aorta Ratio Measurement in Chronic Obstructive Pulmonary Disease With Pulmonary Hypertension: A Systematic Review and Meta‐Analysis,” Clinical Respiratory Journal 16, no. 4 (April 2022): 276–283.
51. Wells J. M., Washko G. R., Han M. K., et al., “Pulmonary Arterial Enlargement and Acute Exacerbations of COPD,” New England Journal of Medicine 367, no. 10 (September 2012): 913–921.
52. LaFon D. C., Bhatt S. P., Labaki W. W., et al., “Pulmonary Artery Enlargement and Mortality Risk in Moderate to Severe COPD: Results From Copdgene,” European Respiratory Journal 55, no. 2 (2020. 2020): 1901812.
53. Eul B., Cekay M., Pullamsetti S. S., et al., “Noninvasive Surrogate Markers of Pulmonary Hypertension Are Associated With Poor Survival in Patients With Lung Cancer,” American Journal of Respiratory and Critical Care Medicine 203, no. 10 (2021): 1316–1319.
54. Terzikhan N., Bos D., Lahousse L., et al., “Pulmonary Artery to Aorta Ratio and Risk of All‐Cause Mortality in the General Population: The Rotterdam Study,” European Respiratory Journal 49, no. 6 (June 2017): 1602168.
55. Wade R. C., Simmons J. P., and Boueiz A., “Pulmonary Artery Enlargement Is Associated With Exacerbations and Mortality in Ever‐Smokers With Preserved Ratio Impaired Spirometry,” American Journal of Respiratory and Critical Care Medicine 204 (2021): 481–485.
56. Loth D. W., Lahousse L., Leening M. J. G., et al., “Pulmonary Function and Diffusion Capacity Are Associated With Pulmonary Arterial Systolic Pressure in the General Population: The Rotterdam Study,” Respiratory Medicine Nov. 132 (2017): 50–55.
57. Arcasoy S. M., Christie J. D., Ferrari V. A., et al., “Echocardiographic Assessment of Pulmonary Hypertension in Patients With Advanced Lung Disease,” American Journal of Respiratory and Critical Care Medicine Mar. 167, no. 5 (2003): 735–740.
58. Gillmeyer K. R., Miller D. R., Glickman M. E., et al., “Outcomes of Pulmonary Vasodilator Use in Veterans With Pulmonary Hypertension Associated With Left Heart Disease and Lung Disease,” Pulmonary Circulation 11, no. 2 (2021): 1–12.
59. Hemnes A. R., Leopold J. A., Radeva M. K., et al., “Clinical Characteristics and Transplant‐Free Survival Across the Spectrum of Pulmonary Vascular Disease,” Journal of the American College of Cardiology 80, no. 7 (August 2022): 697–718.
60. Aronson K. I., Danoff S. K., Russell A. M., et al., “Patient‐Centered Outcomes Research in Interstitial Lung Disease: An Official American Thoracic Society Research Statement,” American Journal of Respiratory and Critical Care Medicine 204, no. 2 (2021): e3–e23.
61. Semler M. W., Bernard G. R., Aaron S. D., et al., “Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report,” American Journal of Respiratory and Critical Care Medicine Aug. 202, no. 4 (2020): 511–523.
62. Feemster L. C., Saft H. L., Bartlett S. J., et al., “Patient‐Centered Outcomes Research in Pulmonary, Critical Care, and Sleep Medicine. An Official American Thoracic Society Workshop Report,” Annals of the American Thoracic Society 15, no. 9 (2018): 1005–1015.
63. Mackay A. J., Kostikas K., Murray L., et al., “Patient‐Reported Outcomes for the Detection, Quantification, and Evaluation of Chronic Obstructive Pulmonary Disease Exacerbations,” American Journal of Respiratory and Critical Care Medicine Sep. 198, no. 6 (2018): 730–738.
64. FaD A. Principles for selecting, developing, modifying, and adapting patient‐reported outcome instruments for us in medical device evaluation [Internet]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/principles-selecting-developing-modifying-and-adapting-patient-reported-outcome-instruments-use .
65. Washington A. E. and Lipstein S. H., “The Patient‐Centered Outcomes Research Institute–Promoting Better Information, Decisions, and Health,” New England Journal of Medicine 365, no. 15 (October 2011): e31.
66. Basch E., “Patient‐Reported Outcomes ‐ Harnessing Patients' Voices to Improve Clinical Care,” New England Journal of Medicine 376, no. 2 (2017): 105–108.
67. Isa N., Mudhafar D., Ju C., et al., “Effects of Phosphodiesterase‐5 Inhibitors in Patients With Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta‐Analysis,” COPD: Journal of Chronic Obstructive Pulmonary Disease 19, no. 1 (2022. Dec 31): 300–308.
Associated Data
Supplementary Materials
BETTER COPD. PH Supplemental Figure 1.
Protocol Manuscript Supplement FINAL 7.31.25.