Conditions: Heart Failure With Reactive Pulmonary Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether Sildenafil 20mg taken three times a day is effective in the treatment of Heart Failure with Reactive Pulmonary Hypertension. This is a double-blind, placebo controlled trial.

Detailed description:
Patients will be screened at the time of a diagnositic Right Heart Catheterization. Patients will be selected based on pressures measured during this procedure, current medications, and current symptoms. At baseline a 6 minute walk test and quality of life questionnaire will be administered. Medical records will be reviewed and results of recent testing will be recorded. Qualifying participants will be randomized to receive 90 days of either placebo or sildenafil 20 mg three times a day. Randomized patients will be followed for safety and efficacy by phone and as otherwise clinically indicated.

At the end of the 90 day treatment period, patients will be evaluated via 6 minute walk, quality of life questionnaire, and other diagnostic tests as clinically indicated. Primary outcome will be change in the 6 minute walk distance. Secondary outcomes will be based on clinically available results such as change in heart pressures measured by right heart catheterization and echocardiogram.

At the end of the treatment period, providers and patients will be unblinded in order to optimize further treatment.

To achieve statistical significance, 64 patients will be enrolled and randomized.

Arms:
arm 1: Placebo three times per day, orally arm 2: Sildenafil 20 mg three times per day, orally

Interventions: intervention 1: Sildenafil intervention 2: Placebo
Intervention descriptions: intervention 1: 20 mg three times daily by mouth for 90 days intervention 2: One capsule three times daily by mouth for 90 days

Protocol document:
Prot_SAP_000.pdf: 
Version Date 4/4/16 
  
1
 
 
Sildenafil in Heart Failure with Reactive Pulmonary Hypertension (Sildenafil HF) 
 
PI: 
 
 
Maya Guglin, MD, PhD 
CoInvestigators: 
Navin Rajagopalan, MD; David Booth, MD; Paul Anaya, MD, PhD 
Statistician:  
Richard Charnigo, PhD 
Pharmacist:  
Tracy Macaulay, PharmD 
Sponsor: 
 
Gill Heart Institute 
 
Scientific Rationale 
 
In 2007, Lewis et al1 from Massachusetts General Hospital published a paper on sildenafil, a type 5 
phosphodiesterase inhibitor, in heart failure (HF). A single oral dose of 50 mg reduced resting and exercise 
pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased 
resting and exercise cardiac index (P<0.05 for all) without altering mean arterial pressure, heart rate, or 
pulmonary capillary wedge pressure. Peak VO2 increased (15+/-9%) and ventilatory response to CO2 output 
(VE/VCO2 slope) decreased (16+/-5%) just one hour after sildenafil treatment. Improvements were confined to 
patients with secondary pulmonary hypertension (PH). The study group was 13 patients, which was enough to 
demonstrate statistical significance of the findings. 
Pulmonary hypertension (PH) in heart failure (HF) is associated with poor outcomes. In a Mayo Clinic study, 
there was a strong positive graded association between pulmonary artery systolic pressure (PASP) and 
mortality. Increasing PASP was associated with an increased risk of death (hazard ratio [HR]: 1.45, 95% 
confidence interval [CI]: HR: 2.07, 95% CI: 1.62 to 2.64 for the highest PASP tertile versus lowest PASP 
tertile. This association was independent of age, sex, comorbidities, ejection fraction, and diastolic function 2.    
Elevated right sided pressures in HF usually result from elevated left ventricular filling pressures. In HF, there 
are two major components of PH: hydrostatic and vasoreactive3.  Hydrostatic, or the passive component, 
reflects the backward transmission of elevated left ventricular end diastolic pressure. Therefore, pulmonary 
artery diastolic pressure correlates tightly with the pulmonary capillary wedge pressure (PCWP).  Normally, the 
pulmonary vasculature is characterized by low pressure, low resistance and high distensibility. It can 
accommodate a significant increase in blood flow with a minimal elevation of pulmonary arterial pressure. 
When this compensatory capacity is exceeded, there is an elevation in pulmonary arterial pressure. The 
effective treatment for such PH is diuretic therapy or other means of fluid removal.  
The vasoreactive component of PH develops with long-standing PH. It is characterized by vasospasm, 
vasoconstriction, and eventually morphologic changes of the pulmonary vasculature. The degree of PH is 
considered “out of proportion” to the PCWP.  In other words, PH persists independently of the PCWP. 
Pulmonary vascular resistance and the transpulmonary gradient are elevated. Diuretics are, therefore, 
ineffective for treatment of reactive PH, and other medical treatment options are limited.  In HF, reactive PH is 
associated with worst outcomes.  In one study involving HF patients, the presence of reactive PH carried a 
higher risk of death (HR: 1.55; 95% CL: 1.11, 2.20; p < 0.001) 4.   
Finally, no treatment option currently exists for reactive PH in the setting of HF. Multiple studies indicate that 
phosphodiesterase-5 inhibitors may be an effective therapy in this setting5 6-8. In particularly, when patients 
with biventricular HF, poor right ventricular function, and increased transpulmonary gradient received 
sildenafil 20 mg three times a day, in addition to other HF medications, it resulted in a significant decrease of 
pulmonary pressures, improvement in right ventricular function, decrease in  NTproBNP serum levels,  as well 
a substantial improvement of the 6-minute walk distance by 91±54 m.9 Importantly, there was a very modest 
reduction in pulmonary capillary wedge pressure, indicating that the reactive, and not the passive component of 
PH is the principal therapeutic target for sildenafil. 


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Clinical studies of sildenafil in HF are summarized in Table 1. The best results were obtained when the patients 
were selected based on the presence of reactive pulmonary hypertension, namely increased pulmonary vascular 
resistance and transpulmonary gradient. 
 
No randomized controlled clinical trials, testing sildenafil in HF, selected patients based on these criteria. None 
of the trials, therefore, utilized the full potential of phosphodiesterase -5 inhibitors in HF. Specifically, the 
recent multicenter, double-blind, placebo-controlled, parallel-group, randomized RELAX trial included patients 
with unknown pulmonary pressures – they were not among inclusion criteria. Understandably, the trial failed to 
demonstrate favorable effects of sildenafil10.  
 
Many physicians, treating patients with advanced HF, use sildenafil empirically, based on the literature. 
Phosphodiestherase-5 inhibitors for PH in HF is currently not approved by the FDA and is used as an off label 
indication in patients with HF. A randomized controlled trial including patients with appropriate criteria can 
demonstrate benefits of sildenafil in this common and growing condition. 
 
Table 1. Clinical studies of sildenafil in heart failure, grouped by outcomes 
 
Study/Date 
Patients 
N 
PH 
Intervention 
Duration 
Outcome 
Positive 
Zakliczynski et al     
2007 11 
Case Series 
Transplant 
candidates 
6 
TPG  > 12 
and/or  
PVR > 2.5  
 
No 
reversibility  
with sodium 
nitroprusside 
50 mg BID 
1 month 
3 - normal TPG and PVR 
2 - acceptable responsiveness  
of pulmonary HTN to  
nitroprusside 
1 – no difference 
 
Guazzi et al, 200712 
 
NYHA II/III 
EF<45% 
46 
None 
50 mg TID 
6 months 
Improved peak VO2,  
endothelial function, 
symptoms 
Dumitrescu et al, 
20119 
Case series 
 
Biventricular 
failure 
NYHA  
III/IV 
EF<40 
TAPSE<17 
9 
PAP mean ≥ 
25                     
PCWP ≥15       
TPG >12   
 
20 mg TID 
5 months 
Increased 6 minute walk  
distance, improved Echo, 
hemodynamics, BNP 
Guazzi et al,  
201113 
double-blind, 
randomized, placebo-
controlled 
HFpEF 
44 
PASP>40 by 
echo 
50 mg TID 
12 
months 
Improvement in QOL, 
symptoms, hemodynamics, 
echo 
Pons et al, 2012 14 
retrospective 
Transplant 
candidates 
15 
MPAP>25  
PVR >2.5 
and/or 
TPG >12 
20-60 TID 
5-6 
months 
MPAP, PVR, and TPG 
decreased. All successfully 
transplanted 
Reichenbach et al, 
2012 15 
non-randomized, 
retrospective case–
control study 
Transplant 
candidates 
32 
TPG>15 
20-60 TID 
~1 year 
Improved hemodynamics, 
clinical status,  60%  
transplanted 
De Santo et al, 2012 16 
prospective, non-
randomized, 
open label 
uncontrolled pilot trial 
Transplant 
candidates 
31 
PVR >6 WU, 
unresponsive 
to 
vasodilators 
25 mg 
TID 
uptitrated 
every 2 
weeks to 75 
mg TID 
3 months 
All successfully transplanted 


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Guazzi et al, 201117 
Prospective, 
Randomized, Placebo-
Controlled Study 
NYHA II/III 
EF<40% 
E/e’>10 
45 
None 
50 TID 
12 
months 
Improved LV diastolic function 
and cardiac geometry, 
functional capacity and clinical 
status    
Guazzi et al,  
201218 randomized, 
placebo-controlled 
 
HF patients 
with exercise 
oscillatory 
breathing 
32 
None 
50 TID 
12 
months 
Improved peak VO2,  
hemodynamics 
Behling et al,  
200819 double-blind, 
randomized, placebo-
controlled 
Outpatients 
with HF, 
EF<40% 
19 
None 
50 TID 
4 weeks 
Improved peak VO2, decreased  
PASP 
Negative 
Redfield et al, 201310 
double-blind, 
randomized, placebo-
controlled 
HFpEF 
216 (113 
sildenafil) 
None 
20 mg TIDx 
12 weeks, 
followed by 
60 mg TID 
for 12 
weeks. 
6 months 
No improvement in exercise  
capacity or clinical status 
Amin et al, 2013 20 
double-blind, 
randomized, placebo-
controlled 
NYHA II/III 
EF<35% 
106 
None 
25-50 mg 
TID 
12 weeks 
No improvement in exercise  
capacity or clinical status 
1. Specific hypotheses 
Phosphodiesterase- 5 inhibitors in heart failure with secondary reactive pulmonary hypertension improve 
exercise capacity, hemodynamic, echocardiographic parameters, and quality of life 
2. Trial design 
Patients over 18 years of age with HF who have PH by right heart catheterization (mean pulmonary artery 
pressure ≥ 25 mm Hg, pulmonary capillary wedge pressure  ≥ 15 mm Hg, and pulmonary vascular resistance 
>3WU) will be eligible for randomization to sildenafil 20 mg, or placebo three times a day for 3 months. At 
baseline, a 6 minute walk test and quality of life questionnaire will be performed (Kansas City Cardiomyopathy 
Questionnaire) from 7 days prior to 3 days after qualifying right heart catheterization. If the echo was done for 
clinical indications within one month of enrollment, the data will be used. Laboratory tests are routinely 
obtained before right heart catheterization (comprehensive metabolic panel and NT-proBNP) and will be 
recorded for the study. 
Participants will return for follow-up visits as needed for clinical indications. Our study coordinator will 
document changes of symptoms, changes in therapies, and capture clinical events like unscheduled hospital 
visits. For study purpose, the only follow-up visit will take place in 3 months. At that time, an echocardiogram, 
right heart catheterization, six minute walk, laboratory tests, and quality of life questionnaire will be repeated if 
clinically indicated. In addition, we will evaluate for signs and symptoms of HF (dyspnea, increased cough, 
paroxysmal nocturnal dyspnea, peripheral edema, S3 gallop, increased heart rate) at baseline and at the follow-
up visit. These assessments are part of routine care for HF patients.  The 3 month assessments should take place 
from 80-97 days following randomization whenever possible. 
Measurements and calculations by 2D echo will include left ventricular end systolic and end-diastolic 
dimensions, left ventricular ejection fraction by Simpson’s method, left atrial volume, severity of mitral and 
tricuspid regurgitation, velocity of tricuspid regurgitation, diameter of inferior vena cava and its variability with 
respirations, and right ventricular function by tricuspid annular plane systolic excursion. 
Measurements by right heart catheterization will include right atrial pressure, right ventricular systolic and end 
diastolic pressure, pulmonary arterial systolic, diastolic, and mean pressure, and pulmonary capillary wedge 
pressure. Cardiac output and cardiac index will be calculated both by Fick and thermodilution methods. 


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The majority of study information will be collected from routine care for standard clinical indications. 
Primary outcome  
 
6 minute walk distance 
 
Secondary outcomes 
Percent of change of pulmonary arterial pressures (systolic, diastolic, and mean) and pulmonary vascular 
resistance from the baseline 
Percent of change of cardiac index from the baseline 
Percent of change in tricuspid annular plane systolic excursion 
3. Objectives 
Primary Objective: 
The primary objective of this study is to determine whether sildenafil for treatment of HF with reactive PH can 
improve exercise tolerance measured by 6 minute walk distance 
Secondary Objectives: 
The secondary objectives of this study are to determine whether sildenafil for treatment of HF with reactive PH 
can improve hemodynamics, right ventricular function, or quality of life 
4. Eligibility (include rationales for selecting or excluding particular cohorts) 
Inclusion criteria: 
 ≥ 18 years of age 
 Known chronic heart failure appropriately treated with angiotensin converting enzyme antagonists, 
angiotensin receptor blockers, and beta blockers, unless contraindicated, not indicated, or poorly 
tolerated 
 Indications for right heart catheterization, other than for biopsy 
 Pulmonary artery mean pressure >25 mm Hg, pulmonary capillary wedge pressure >15 mmHg, and 
pulmonary vascular resistance >3 WU  as measured by right heart catheterization within 3 days of 
planned randomization 
 
Exclusion criteria: 
 Hypersensitivity, allergy, or intolerable side effects of sildenafil 
 Contraindication to sildenafil including need for nitric oxide donors such as organic nitrates or organic 
nitrates in any other form regularly and/or intermittently or current nitrate therapy 
 History of primary PH, connective tissue disorders, severe COPD, pulmonary embolism, or left to right 
shunts 
o Primary (idiopathic) Pulmonary Hypertension in patients without history of heart failure 
o Pulmonary hypertension in patients with systemic scleroderma 
o Pulmonary hypertension due to congenital heart disease 
o Pulmonary hypertension due to severe COPD 
o Pulmonary hypertension in patients with systemic scleroderma 
o Pulmonary hypertension due to congenital heart disease 
o Pulmonary hypertension due to severe COPD or interstitial lung disease 
 History of heart transplant, VAD, or any other solid organ transplant 
 Likely to have solid organ transplant or any other major surgery during study enrollment/treatment 
period 
 Liver cirrhosis as primary diagnosis 


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 History of massive pulmonary embolism 
 Acute pulmonary embolism 
 Female subject who is pregnant, breastfeeding, or one who is unwilling to practice an acceptable 
method of birth control unless postmenopausal or sterile. 
 Unreliability as a study participant based on the investigator’s (or designee’s) knowledge of the subject 
(eg, alcohol or other substance abuse, inability, unwillingness to adhere to the protocol, documented 
non-compliance or vulnerable population 
 Currently enrolled in another investigational drug or device clinical study, or less than 30 days since 
completing study 
 Current diagnosis of HIV or AIDS 
 End stage renal disease undergoing dialysis 
 End stage liver disease 
 Co-morbidities, if it limits exercise tolerance 
       - morbid obesity (BMI>40) 
       - COPD with oxygen dependence 
       - severe peripheral vascular disease with intermittent claudication 
‘      - status post amputation of lower extremity(s) at any level 
             - severe degenerative joint disease preventing normal walking 
             - CVA with long term sequella affecting ability to walk 
5. Arms/regimens  
  
 
 
 
Echo 
6-minute walk 
NT-proBNP 
Quality of Life Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Diagnosis of HF 
Clinically indicated Right Heart Catheterization
  mPAP>25 mmHg 
 Pulmonary Capillary Wedge Pressure 
>15 mmHg 
Pulmonary vascular resistance >3 WU 
Randomize  
Placebo 
Outcome Measures of Assessment: 
Right Heart Catheterization 
Echo   
6 minute walk 
QOL 
Sildenafil 
20 mg TID PO 


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6. Statistical design in detail (include one primary and any secondary endpoint(s), any stratification to 
be used in the randomization, sample size with power justification, analysis plan including plans for 
formal interim analysis, projected monthly accrual rate) 
Sample size was calculated at 32 patients per arm, 64 patients total  
Primary and secondary endpoints are as noted above. Patients will be randomized to treatment versus placebo 
in a 1:1 ratio using permuted blocks of variable size, to which the principal investigator (and the patients 
themselves) will be blinded. Planned sample size is 64, as described below. Data will be analyzed on an intent-
to-treat basis, as described below. An interim analysis will also take place after data have been acquired for 
(approximately) 32 subjects, using a temporary alpha of 0.01 to mitigate inflation of Type I error probability 
due to multiple testing. Results of interim data analysis will be shared with Data Safety Monitoring Board, 
which will advise the principal investigator on whether to continue with the study.  
Planned sample size of 64 will provide nearly 80% power, using the final alpha of 0.05, to detect a difference 
between groups on a numerical outcome variable for which the effect size is approximately 0.7, in the sense 
that a typical person in the treatment group would be approximately seven-tenths of one standard deviation 
better than a typical person in the control group. This is slightly greater than the effect size of approximately 0.6 
observed by Mathai and colleagues for the exercise endpoint, but we anticipate being able to reduce variability 
by considering change scores from baseline to 3 months rather than just the final results at 3 months. 
Each numerical outcome variable will be examined for approximate normality, and appropriate corrective 
action (e.g., log transformation prior to further data analysis) will be considered if approximate normality is 
untenable. A linear mixed model will be fit relating each outcome variable to group (between-subjects factor: 
treatment vs. placebo) and time (within-subjects factor: baseline vs. 3 months), with random effects for subjects 
and embedded linear contrasts to compare groups on change from baseline to 3 months. Although 
randomization is anticipated to balance groups on demographic and clinical characteristics, in the unlikely 
event that groups are imbalanced we can modify the linear mixed modeling to adjust for any covariates on 
which groups are imbalanced. Loss to follow-up is anticipated to be small, but in the unlikely event of more 
than 10% attrition from either group we can employ multiple imputation or another method for handling 
missing data. Groups will be compared on adverse events (e.g., re-hospitalization) using Fisher’s exact test.  
7. Source of agents: investigational pharmacy at UK (Chandler Hospital) 
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