COPD is a condition characterized by airway obstruction and is currently the 4th leading
cause of death in Canada. Patients with COPD experience significant exertional dyspnea,
which has been shown to reduce quality of life and physical activity, and increase risk
of mortality. Much work has examined the mechanisms for dyspnea in moderate and severe
COPD, but the mechanisms for dyspnea in patients with mild COPD, in whom symptoms are
often disproportionate to the degree of airway obstruction, are not well understood. Mild
COPD patients show an exaggerated ventilatory response to exercise, determined by the
ventilatory response to carbon dioxide production (V̇E/V̇CO2), which is a key contributor
to dyspnea and is predictive of mortality. Recent work suggests that the increased
V̇E/V̇CO2 during exercise in mild COPD is secondary to increased deadspace (i.e.
ventilation with no perfusion) and/or ventilation/perfusion (V̇ A/Q) inequality (i.e.
poor matching of ventilation to perfusion). Researchers have proposed that the increased
deadspace or V̇A/Q inequality is secondary to pulmonary vascular dysfunction and
hypoperfusion of the pulmonary capillaries. Recently we have shown that iNO reduces
dyspnea, and V̇E/V̇CO2, and improves exercise capacity in mild COPD, suggesting that
pulmonary vascular dysfunction is an important contributor to exercise intolerance in
mild COPD. Importantly, this work demonstrated that pulmonary NO mediated vasodilation
pathways are intact, and are a viable target for improving exercise tolerance in mild
COPD. Therefore, we hypothesize that sildenafil, which potentiates intrinsic NO mediated
vasodilation mechanisms, will improve exercise tolerance in mild COPD.
Compared to disease free controls, mild COPD patients have a blunted diffusion capacity
and pulmonary capillary blood volume response to exercise. In the supine position, which
minimizes flow heterogeneity through removal of the coronal gravity-induced pressure
gradient, diffusion capacity and pulmonary capillary blood volume responses to exercise
were not corrected. The implication of this finding is that even mild COPD, there is a
degree of permanent vascular destruction, in addition to reversible pulmonary vascular
dysfunction. It is presently unknown when or if in the COPD severity continuum there is a
transition from treatable pulmonary vascular dysfunction to irreversible pulmonary
vascular destruction.
Sildenafil was previously tested in moderate to severe COPD with mixed success. Blanco et
al. tested the effect of sildenafil (20 or 40 mg dose) on hemodynamics and gas exchange
in a sample of patients with moderate to severe COPD. Eighty-five percent of the sample
had pulmonary hypertension defined as mean pulmonary artery pressure >20 mmHg. Sildenafil
significantly reduced pulmonary artery pressure at rest and during exercise (-6 and -11
mmHg respectively), and improved VA/Q inequality. Rietema et al. found no benefit of
sildenafil (3x50mg daily for 3 months) on stroke volume (supine, rest/exercise) or
exercise capacity in moderate to severe COPD. In a randomized, placebo controlled trial,
sildenafil (3x20 mg daily, 3 months) did not improve pulmonary rehabilitation outcomes
including cycle endurance time, 6 minute walk distance, or quality of life. It is not
known why the promising reduction in pulmonary artery pressure and improved V̇A/Q
matching did not translate to increased stroke volume or exercise capacity with chronic
sildenafil dosing. Results may partially be explained by supine body positioning during
measurement of stroke volume, and the generally late disease state of COPD patients.
Pulmonary vascular dysfunction observed early in disease progression may transition to
irrevocable vascular/pulmonary structural changes, for which iNO or sildenafil have
limited utility. Accordingly, a secondary objective of the present study is to gain
understanding of pathological vascular progression in COPD to identify the therapeutic
window for pulmonary vascular intervention. We hypothesize that sildenafil will have
greater cardiopulmonary benefit (increased diffusion capacity at rest and during
exercise, greater decrease in pulmonary artery pressure) in early, mild COPD as compared
to moderate-severe COPD, indicative of vascular dysfunction in mild COPD transitioning to
vascular destruction in later disease states.
Trial Objectives
To examine the effect of acute oral sildenafil on maximal oxygen consumption (peak
V̇O2) during exercise in the continuum of COPD
To examine whether acute oral sildenafil improves exertional dyspnea in COPD.
To examine the cardio-pulmonary effects and mechanisms of oral sildenafil.
Trial Design
Primary Study Endpoints/Secondary Endpoints Primary study endpoints for the proposed
study are:
Exercise capacity as determined by maximal oxygen consumption (peak V̇O2).
Secondary study endpoints for the proposed study are:
Dyspnea during exercise (modified Borg scale, 1-10)
Pulmonary function during exercise (V̇ E/V̇CO2, pulmonary capillary blood volume,
diffusion capacity)
Cardiac output as determined by impedance cardiography.
Pulmonary artery pressure (estimated from rest/stress echocardiography).
Study Design
Randomized, double-blinded, placebo controlled cross-over design
Treatment: Sildenafil (oral), 25 mg; Placebo: Medical grade placebo pill
Seven sessions will be completed within an 8-week period in the following order:
Visit 1) Participant enrollment and familiarization, medical history, COPD assessment
test (CAT), modified Medical Research Council (mMRC) dyspnea scale, standard pulmonary
function test (PFT, including bronchodilator control) and a staged to maximal
cardiopulmonary exercise test (CPET) with electrocardiography (ECG), pulse oximetry, and
intermittent blood pressure and rating of perceived exertion (RPE, leg fatigue and
dyspnea, modified Borg scale). A small blood sample will be collected via finger prick to
measure hemoglobin (to correct DLCO). An additional venous blood sample will be collected
for analysis of blood biomarkers to characterize participants including serum analysis of
interleukin 6, c-reactive protein and tumor necrosis factor alpha.
Visits 2 and 3) Participants will be administered oral placebo/sildenafil (randomly
ordered), wait for 30 minutes and then begin testing. Participants will undergo a staged
to maximal CPET (gas exchange analysis, heart rate, cardiac output measured by impedance
cardiography, blood pressure, RPE, arterial oxygen saturation).
Visits 4 and 5) Participants will be administered oral placebo/sildenafil (randomly
ordered), wait for 30 minutes and then begin testing. Testing will start with measurement
of resting diffusion capacity, pulmonary capillary blood volume (Vc), and membrane
diffusion capacity (Dm) using the multiple fractional inspired oxygen (FIO2)-DLCO
technique. Participants will then cycle at 40 W and 50% of peak work rate as determined
from Visit 1, measurements will be repeated during steady-state exercise. Heart rate,
oxygen saturation, and carboxyhemoglobin will be monitored throughout. A small blood
sample will be collected via finger prick following each stage (rest, 40W, 50% of peak
work rate) to measure hemoglobin to correct DLCO values.
Visit 6) Participants will undergo non-randomized control and then sildenafil rest and
handgrip stress echocardiography. Echocardiography will be used to estimate cardiac
volumes, function and pulmonary artery systolic pressure at rest and during handgrip
stress. Isometric handgrip stress echocardiography was previously used in healthy and
clinical populations to evoke marked cardiac stress without hyperpnoea- a major factor
compromising image quality, particularly in COPD due to dynamic hyperinflation.
Visit 7) Participants will undergo chest computed tomography to characterize lung
structure and emphysema.
Visit 1 is anticipated to take ~2 hours. Visits 2 and 3 are anticipated to take ~1.5
hours. Visits 4 and 5 are anticipated to take 2 hours. Visit 6 is anticipated to take 2
hours. Visit 7 is anticipated to take 1 hour. The anticipated total study duration is ~12
hours.
Data Analysis
A mixed-effects model will be used to evaluate the change in V̇O2peak with sildenafil. A
two-way repeated measures ANOVA will be used to test for a difference in VO2peak response
in mild COPD compared to COPD free controls. Two-way repeated measures ANOVA will be used
to evaluate changes in dyspnea, cardiac output, ventilation, ventilatory efficiency
(V̇E/V̇CO2), diffusion capacity and capillary blood volume during exercise. Variance in
V̇O2peak changes will be explored using Pearson's regression and moderation analysis of
echo-derived cardiac factors and pulmonary function/gas exchange. A three-way repeated
measures ANOVA will be used to test for differences in pulmonary capillary blood volume
response to sildenafil between mild and moderate COPD.