What data is available for using sildenafil or other PDE5i's in WHO Group 2 PH? Is there anything specific for use in patients with an LVAD for this indication?

Comment by InpharmD Researcher

Available data for phosphodiesterase-5 inhibitors (PDE5i), primarily sildenafil, in World Health Organization (WHO) Group 2 pulmonary hypertension (PH) shows variable results across heterogeneous patient populations. Multiple randomized trials in patients with heart failure with reduced or preserved ejection fraction and PH have reported improvements in exercise capacity, quality of life, and pulmonary hemodynamics; however, one study showed no significant benefit (see Table 1). Notably, no data were identified evaluating PDE5i use specifically in patients with an LVAD for WHO Group 2 PH.

Background

A 2019 Cochrane meta-analysis investigated the use of phosphodiesterase-5 inhibitors (PDE5i) for the various WHO Group classifications of pulmonary hypertension. In patients with Group 2 pulmonary hypertension (PH) due to left-heart disease, phosphodiesterase-5 inhibitors (PDE5i) demonstrated mixed outcomes compared to placebo. Five randomized controlled studies were included, all utilizing sildenafil. Moderate-certainty evidence from three randomized controlled trials (RCTs) showed that PDE5i significantly improved World Health Organization (WHO) functional class (OR 0.53, 95% CI 0.32–0.87) and increased six-minute walk distance by 34 meters (95% CI 23–46). However, PDE5i had no clear effect on mortality (OR 1.27, 95% CI 0.28–5.80). Quality of life, assessed via the Kansas City Cardiomyopathy Questionnaire, showed improvement but with low certainty due to limited data. Hemodynamically, PDE5i reduced mean pulmonary arterial pressure by 10.17 mmHg (95% CI 8.35–11.99 lower) but had no significant impact on cardiac index. The evidence was downgraded for heterogeneity, imprecision, or small sample sizes in some outcomes. Overall, PDE5i may improve functional capacity and hemodynamics in Group 2 PH, but their effect on survival remains uncertain. [1]

Additionally, a 2020 systematic review reported the efficacy and safety of PDE5i in treating PH secondary to left heart disease (LHD) with elevated pulmonary vascular resistance (PVR). This review included five randomized clinical trials comparing PDE5i to placebo in patients diagnosed with PH due to left heart disease confirmed through right heart catheterization. The review identified that sildenafil was well tolerated and provided improvements in pulmonary hemodynamics, exercise capacity, and quality of life in patients with elevated PVR, specifically highlighting significant reductions in pulmonary vascular resistance, mean pulmonary artery pressure, and pulmonary capillary wedge pressure. The review found that sildenafil effectively improved exercise capacity as measured by peak VO2 and 6-minute walk test distances in several studies, with a noted improvement in chronic heart failure symptomatology and quality of life indices. The trials included in the review addressed various underlying conditions, including heart failure with both reduced and preserved ejection fractions, and showed that sildenafil could potentially alleviate symptoms associated with PH-LHD. However, the systematic review also noted the need for further research through larger, multi-center prospective randomized controlled trials to confirm these benefits, given the small sample sizes and single-center nature of the included studies. [2]

References:

[1] Barnes H, Brown Z, Burns A, Williams T. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database Syst Rev. 2019;1(1):CD012621. Published 2019 Jan 31. doi:10.1002/14651858.CD012621.pub2
[2] Sanchez Palacios GM, Schmidt C, Wichman T. Targeted therapy with phosphodiesterase 5 inhibitors in patients with pulmonary hypertension due to heart failure and elevated pulmonary vascular resistance: a systematic review. Pulm Circ. 2020;10(3):2045894020948780. Published 2020 Oct 7. doi:10.1177/2045894020948780
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What data is available for using sildenafil or other PDE5i's in WHO Group 2 PH? Is there anything specific for use in patients with an LVAD for this indication?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-5 for your response.

Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (the SilHF study): a randomized placebo-controlled multicentre trial
Design

Randomized, double-blind, placebo-controlled, multinational trial

N= 69
Objective To determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT
Study Groups

Sildenafil (n= 45)

Placebo (n= 24)
Inclusion Criteria

Symptomatic outpatients aged >18 years with HFrEF (NYHA class II–III and LVEF ≤40%), elevated BNP (>100 pg/ml) or NT-proBNP (>400 pg/ml), and PHT at screening (PASP ≥40 mmHg on echocardiography)
Exclusion Criteria

Acute coronary syndrome, angiography or hospitalization within last 3 months, angina, severe valvular heart disease, symptomatic lung disease, 6MWT distance >475 m, eGFR <40 ml/min/1.73 m2, systemic systolic or diastolic arterial pressures >160 mmHg and >90 mmHg, respectively
Methods

Patients were randomly assigned to receive sildenafil or placebo in a 2:1 ratio. Sildenafil was up-titrated to a target maintenance dose of 40 mg three times a day over 2 weeks. Visits were conducted at screening, inclusion, up-titration, 8 weeks, 16 weeks, 24 weeks, and a final follow-up at 36 weeks. The 6MWT and quality of life assessments were conducted at baseline, 8 weeks, and 24 weeks.
Duration 36 weeks
Outcome Measures Primary: Patient global assessment by VAS, 6MWT at 24 weeks Secondary: Safety, tolerability, changes in symptoms (NYHA class), quality of life (KCCQ and EuroQol-5D), changes in renal function and PASP
Baseline Characteristics   All (n= 69) Placebo (n= 24) Sildenafil (n= 45)  
Age (years) 68 (62–74) 69 (63–74) 67 (62–74)  
Women 11 (15.9%) 2 (8.3%) 9 (20.0%)  
CAD 47 (68.1%) 17 (70.8%) 30 (66.7%)  
Stroke 4 (5.8%) 0 (0.0%) 4 (8.9%)  
PCI/CABG 35 (51.5%) 14 (58.3%) 21 (47.7%)  
Smoking 7 (10.1%) 2 (8.3%) 5 (11.1%)  
Hypertension 38 (55.1%) 14 (58.3%) 24 (53.3%)  
Dyslipidaemia 49 (71.0%) 20 (83.3%) 29 (64.4%)  
Diabetes 24 (34.8%) 10 (41.7%) 14 (31.1%)  
Atrial fibrillation 32 (46.4%) 9 (37.5%) 23 (51.1%)  
Weight (kg) 81.0 (70.1–89.5) 80.0 (73.8–86.7) 81.0 (70.0–89.6)  
BMI (kg/m2) 27.1 (24.0–29.6) 27.0 (25.8–28.4) 27.2 (23.8–29.9)  
SBP (mmHg) 115 (105–128) 121 (107–131) 113 (101–127)  
DBP (mmHg) 70 (61–76) 70 (64–79) 66 (61–75)  
Heart rate (bpm) 71 (65–76) 70 (67–76) 73 (64–76)  
NYHA class II 32 (46%) 12 (50%) 18 (44%)  
NYHA class III 37 (54%) 12 (50%) 25 (56%)  
LVEF (%) 29 (24–35) 29 (25–35) 29 (23–35)  
PASP (mmHg) 45 (42–55) 44 (40–62) 45 (42–54)  
6MWT distance (m) 374 (312–427) 406 (351–450) 353 (311–400)  
EQ-5D health utility score 0.796 (0.672–0.883) 0.805 (0.700–0.883) 0.779 (0.620–0.850)  
EQ-5D VAS 62.5 (45.8–71.2) 62.5 (50.0–73.8) 62.5 (45.0–70.0)  
KCCQ clinical summary score 71.9 (58.3–83.3) 74.5 (64.7–85.4) 71.3 (52.6–82.3)  
KCCQ overall summary score 60.8 (48.2–73.1) 66.2 (56.5–74.2) 58.3 (45.3–72.4)  

Values are mean (interquartile range), or n (%).

6MWT, six minute walk test; ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EQ‐5D, EuroQol‐5 dimensions; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; VAS, visual analogue scale.
Results   Placebo (n= 24) Sildenafil (n= 45) Difference Estimate (95% CI), p-value p-Value
6MWT distance at 24 weeks (m) 420.0 (94.4) 365.4 (154.3) −2.8 (−38.5, 32.9) 0.8765
EQ-5D VAS change at 24 weeks 4.3 (17.0) 2.9 (16.4) −1.57 (−10.64, 7.50) 0.7295
EQ-5D health utility score change at 24 weeks −0.015 (0.341) 0.035 (0.179) 0.058 (−0.089, 0.205) 0.4312
KCCQ clinical summary score change at 24 weeks 2.5 (15.1) 0.5 (15.4) −2.2 (−10.4, 5.9) 0.5879
Adverse Events

The proportions of patients with SAE were similar in each group, 5 (21%) with placebo and 15 (33%) with sildenafil. AE were also similar in each group (22% with sildenafil vs. 17% with placebo). There were no deaths in the placebo group, but four (8.9%) in those assigned to sildenafil. Temporary withdrawals from treatment were significantly higher in the sildenafil group (10 vs. 0, p= 0.01).
Study Author Conclusions Chronic treatment with sildenafil did not improve symptoms, quality of life or exercise capacity for patients with HFrEF and moderate PHT assessed by echocardiography. Routine administration of sildenafil to this population is not recommended.
Critique The study was underpowered due to a smaller sample size than planned, which limits the ability to detect significant effects. The use of echocardiography instead of right heart catheterization may have affected the assessment of PHT. Despite these limitations, the study provides valuable insights into the lack of efficacy of sildenafil in this patient population, highlighting the need for further research with larger sample sizes and more precise diagnostic methods.

 

References:

Cooper TJ, Cleland JGF, Guazzi M, et al. Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (the SilHF study): a randomized placebo-controlled multicentre trial. Eur J Heart Fail. 2022;24(7):1239-1248. doi:10.1002/ejhf.2527

 

Phosphodiesterase 5 Inhibitor Sildenafil in Patients with Heart Failure with Preserved Ejection Fraction and Combined Pre- and Postcapillary Pulmonary Hypertension: A Randomized Open-Label Pilot Study

Design

Randomized, controlled, open-label, single-center study

N= 50

Objective

To investigate the effect of chronic phosphodiesterase 5 inhibitor (PDE5) inhibition with sildenafil on exercise capacity, right ventricular (RV) function, and pulmonary haemodynamic parameters in patients with heart failure with preserved ejection fraction (HFpEF) and combined postcapillary pulmonary hypertension (Cpc-PH) determined by echocardiography

Study Groups

Sildenafil group (n= 30)

Control group (n= 20)

Inclusion Criteria

Patients with stable heart failure of New York Heart Association (NYHA) functional class II-III with preserved left ventricular (LV) ejection fraction (> 50%) and Cpc-PH determined by echocardiography as high LV-filling pressures and pulmonary artery systolic pressure (PASP) > 40 mmHg

Exclusion Criteria

Receipt of nitrates, advanced pulmonary disease, revascularization within 3 months, evidence of myocardial ischemia during stress echocardiography, chronic atrial flutter/fibrillation, significant left-sided structural valve disease, hypertrophic cardiomyopathy, infiltrative or inflammatory myocardial diseases, pericardial disease, severe or very severe COPD (GOLD stage III-IV), or noncardiac conditions precluding participation

Methods

Patients received 25 mg of sildenafil thrice daily for the first 3 months with an increase to 50 mg thrice daily for another 3 months. Echocardiography, 6-min walk test, exercise echocardiography, and NT-proBNP blood level analysis were performed at baseline and 6 months after randomization.

Duration

6 months

Outcome Measures

Primary: Change in 6-min walking distance

Secondary: Change in NYHA functional class, exercise duration and maximal achieved workload during cycle ergometry, mitral E/e′ ratio and PASP both at rest and during diastolic stress

Baseline Characteristics

  

Sildenafil (n= 30)

Control (n= 20)

  

Age, years

 71 ± 7 71 ± 8  

Female

13 (43%) 13 (65%)  

NYHA II/III

 20/10 (67%/33%) 13/7 (65%/35%)  

Systolic blood pressure, mm Hg

 130 ± 14 127 ± 12  

Diastolic blood pressure, mm Hg

 80 ± 11 76 ± 10  
BMI, kg/m2 30 ± 6 29 ± 4  
Hypertension (BP ≥ 140/90 mmHg) 30 (100%) 20 (100%)  

Ischemic heart disease

 

 15 (50%) 7 (35%)  
Diabetes mellitus 10 (33%) 4 (20%)  
CKD 26 (87%) 14 (70%)  

Drug therapy

ACEI/ARB

β-Blockers

Diuretics

Calcium channel blockers

Statins

 

30 (100%)

21 (70%)

28 (93%)

15 (50%)

26 (87%)

 

20 (100%)

18 (90%)

19 (95%)

7 (35%)

18 (90%)

  

PA systolic pressure

 58.6 ± 14.9 55.5 ± 13.5  

PVR, Wood units

 3.33 ± 0.64 3.19 ± 0.47  

Abbreviations: BMI, body mass index; CKD, chronic kidney disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotension receptor blocker; PA, pulmonary artery, PVR, pulmonary vascular resistance

Results

Endpoint

Sildenafil (n= 30)

Control (n= 20)

p-value

6-min walk distance increase, m

 50 (95% CI 36 to 64) 0 <0.001

NYHA functional class improvement

 Yes No <0.001

Exercise duration increase, s

 75 (95% CI 23 to 130) 0 <0.001
PASP decrease, mm Hg 17.0 (95% CI 20.4 to 13.5) 0.9 (95% CI −2.7 to 4.5) <0.001
PVR decrease, Wood units 0.65 (95% CI −0.76 to −0.53) 0.03 (95% CI −0.13 to 0.08) <0.001
Abbreviations: CI, confidence interval

Adverse Events

 No symptomatic hypotension, facial flushing, or vision changes were reported. Systemic blood pressure and heart rate did not vary significantly from baseline values in either group.

Study Author Conclusions

In a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH.

InpharmD Researcher Critique

The study's strengths include its focus on a specific subset of HFpEF patients with Cpc-PH and the use of echocardiography to assess outcomes. However, the absence of a placebo control, the single-center design, non-blinded approach, and relatively small sample size limit the generalizability of the findings. Additionally, the lack of invasive assessment of pulmonary haemodynamics is a significant limitation, as echocardiography, while useful, is not the gold standard for PH diagnosis.



References:

Belyavskiy E, Ovchinnikov A, Potekhina A, Ageev F, Edelmann F. Phosphodiesterase 5 inhibitor sildenafil in patients with heart failure with preserved ejection fraction and combined pre- and postcapillary pulmonary hypertension: a randomized open-label pilot study. BMC Cardiovasc Disord. 2020;20(1):408. Published 2020 Sep 10. doi:10.1186/s12872-020-01671-2

Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension
Design

Placebo-controlled, double-blind, parallel-group, single-center study

N= 34
Objective

To test the hypothesis that sildenafil would lower pulmonary vascular resistance and improve exercise capacity in patients with heart failure complicated by pulmonary hypertension
Study Groups

Sildenafil (n= 17)

Placebo (n= 17)
Inclusion Criteria

Patients ≥18 years of age with left ventricular systolic dysfunction (LV ejection fraction ≤0.4), New York Heart Association class II to IV chronic heart failure, and secondary pulmonary hypertension (mean pulmonary arterial pressure ≥25 mm Hg)
Exclusion Criteria

Noncardiac limitation to exercise, provocable ischemia, hemodynamic instability, ongoing nitrate therapy, concentric LV hypertrophy, critical aortic stenosis, long-term use of medications that inhibit cytochrome P450 3A4
Methods

Patients were randomized to 12 weeks of treatment with sildenafil (25 to 75 mg orally 3 times daily) or placebo. Cardiopulmonary exercise testing was conducted before and after treatment. Hemodynamic measurements were taken at rest and during exercise. Quality of life was assessed using the Minnesota Living With Heart Failure questionnaire.
Duration 12 weeks
Outcome Measures

Primary: Change in peak VO2 from baseline

Secondary: 6-minute walk distance, Minnesota Living With Heart Failure score, pulmonary vascular resistance, cardiac output
Baseline Characteristics   Sildenafil (n= 17) Placebo (n= 17)
Age, years 54 ± 4 62 ± 3
Male sex 82% 88%
Primary cause of HF - Ischemic heart disease 47% 53%
NYHA class II 53% 53%
Diabetes mellitus, 18% 29%
Weight, kg 80 ± 4 78 ± 4
RV ejection fraction 0.33 ± 0.03 0.35 ± 0.02
LV ejection fraction 0.19 ± 0.02 0.20 ± 0.02
Distance walked in 6 min, m 379 ± 25 352 ± 21
Peak VO2, mL/kg/min 12.2 ± 0.7 10.2 ± 0.8
Results   Sildenafil (n= 17) Placebo (n= 17) p-Value
Change in peak VO2, mL/kg/min 1.8 ± 0.7 -0.27 0.02
6-minute walk distance, m 62 29 0.047
Minnesota Living With Heart Failure score -14 0 0.01
Pulmonary vascular resistance, % change -20 ± 6 0 0.02
Cardiac output, % change 38 ± 10 0 0.004
Adverse Events

Subjects in the sildenafil group experienced fewer hospitalizations for heart failure and a higher incidence of headache than those in the placebo group without incurring excess serious adverse events
Study Author Conclusions

Phosphodiesterase 5 inhibition with sildenafil improves exercise capacity and quality of life in patients with systolic heart failure with secondary pulmonary hypertension.
Critique

The study demonstrated significant improvements in exercise capacity and quality of life with sildenafil treatment. However, the small sample size and single-center design may limit the generalizability of the findings. Further large-scale studies are needed to confirm these results and assess long-term safety and efficacy.

 

References:

Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116(14):1555-1562. doi:10.1161/CIRCULATIONAHA.107.716373

Therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension
Design

Uncontrolled study

N= 9
Objective To evaluate the therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension, focusing on clinical symptoms, exercise capacity, and prognostically relevant parameters
Study Groups All patients (n= 9)
Inclusion Criteria Patients with biventricular heart failure (LVEF <40%), impaired RV function (TAPSE <17 mm), NYHA class III/IV, reactive PH (PAPmean ≥25 mmHg), elevated left ventricular filling pressures (PCWP/LVEDP ≥15 mmHg), and increased TPG (>12 mmHg)
Exclusion Criteria Not specified
Methods

Patients received sildenafil (20 mg tid) in addition to stable, guideline-oriented CHF treatment. Right heart catheterization was performed before and after sildenafil initiation. Echocardiographic parameters, serum markers (NTproBNP), and exercise capacity (6MWD) were recorded.
Duration Mean follow-up: 19.7±6.9 weeks
Outcome Measures

Primary: Decrease in mean pulmonary artery pressure (PAPmean), transpulmonary gradient (TPG), pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PCWP)

Secondary: Improvement in RV function, reduction in NTproBNP levels, increase in 6-minute walking distance (6MWD)
Baseline Characteristics   All patients (n= 9)
Age, years 67.4±2.2
NYHA class III 7 patients
NYHA class IV 2 patients
Results   Initial Sildenafil Mean change p-Value
PAPsyst (mmHg) 83.0±3.8 57.7±8.0 −25.4±5.0 0.001
PAPmean (mmHg) 53.0±1.8 35.8±3.9 −17.2±3.4 <0.001
PAPdiast (mmHg) 31.2±1.5 20.3±1.8 −10.9±1.8 <0.001
PCWP (mmHg) 27.9±2.3 20.6±7.6 −7.3±3.0 0.04
TPG (mmHg) 26.4±2.5 13.6±1.9 −13.8±2.2 <0.001
PVR (Wood units) 9.5±1.8 4.4±0.7 −5.0±1.9 0.03
NTproBNP (ng/l) 6350 ± 1435 3056 ± 382 -3293 ± 1591 0.008
6MWD (m) 235±55 326±45 +91±54 0.02
Adverse Events No significant adverse events reported
Study Author Conclusions Sildenafil significantly improved clinical symptoms, exercise capacity, and prognostically relevant parameters in highly selected patients with CHF, PH, and impaired RV function. However, findings should be interpreted with caution due to the small sample size and preliminary nature of the study
Critique The study's strengths include the focus on a specific patient group and the use of predefined hemodynamic criteria. Limitations include the small sample size, uncontrolled design, and short follow-up period. The study's findings are preliminary and require further investigation through controlled studies to confirm the therapeutic potential and safety of sildenafil in this patient population

 

References:

Dumitrescu D, Seck C, Möhle L, Erdmann E, Rosenkranz S. Therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension. Int J Cardiol. 2012;154(2):205-206. doi:10.1016/j.ijcard.2011.10.064

 

Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction: A Target of Phosphodiesterase-5 Inhibition in a 1-Year Study

Design

Double-blind, randomized, placebo-controlled, 1-year study

N= 44

Objective

To probe whether pulmonary hemodynamics and right ventricular (RV) performance in heart failure with preserved ejection fraction (HFpEF) with pulmonary hypertension (PH) may be targets of PDE5 inhibition with sildenafil

Study Groups

Placebo (n= 22)

Sildenafil (n= 22)

Inclusion Criteria

LVEF ≥50%, sinus rhythm, no hospitalization in the 6 months preceding recruitment, pulmonary artery (PA) systolic pressure ≥40 mm Hg

Exclusion Criteria

Patients receiving nitrates, history of pulmonary disease, alternative causes of PH, angina pectoris, acute coronary syndrome, atrial flutter/fibrillation, anemia, pericardial disease, renal failure, cardiac amyloidosis, genetically determined cardiomyopathy, systemic diseases precluding participation

Methods

Patients were randomly assigned to receive placebo or sildenafil (50 mg thrice daily). Evaluations at baseline, 6, and 12 months included medical review, laboratory work, chest x-ray, hemodynamic and ultrasound measurements, pulmonary function tests, and quality-of-life assessment. Hemodynamic measurements were performed using a thermodilution balloon-tipped catheter

Duration

1 year

Outcome Measures

Primary: Pulmonary hemodynamics and RV performance

Secondary: Quality of life, systemic and left heart hemodynamics, pulmonary function

Baseline Characteristics

  

Placebo (n= 22)

Sildenafil (n= 22)

Age, years

 73 (53 to 79) 72 (62 to 81)

Female

4 (18%) 5 (23%)

BSA, m2

 1.93 ± 0.28 1.95 ± 0.26

BMI, kg/m2

 30.2 ± 8.9 31.8 ± 11.3

Hypertension

 22 22

Hypertension + diabetes mellitus

 3 4

LV ejection fraction

 60 ± 6 60 ± 4

Heart rate, bpm

 69 ± 10 71 ± 8

Systolic blood pressure, mm Hg

 147 ± 17 153 ± 15

Diastolic blood pressure, mm Hg

 84 ± 11 87 ± 13

Cardiac index, L/min/m2

 2.33 ± 0.64 2.39 ± 0.59

Stroke volume index, mL/m2

 33 ± 3 35 ± 4
Systemic vascular resistance index, dyne/s/cm−5/m2 2694 ± 688 2717 ± 724

Drug therapy

Diuretics

ACEI/ARB

Digoxin

β-Blockers 

Ca2+ channel blockers

 

18 (82%)

21 (95%)

2 (9%)

17 (77%)

4 (18%)

 

16 (72%)

21 (95%)

3 (13%)

19 (86%)

6 (27%)

Abbreviations: BSA, body surface area; BMI, body mass index; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

Results

Endpoint

Placebo (n= 22)

Sildenafil (n= 22)

Mean right atrial pressure, mm Hg

 23.1 ± 5.5 10.6 ± 3.6*

Pulmonary artery systolic pressure, mm Hg

 52.1 ± 5.1 30.4 ± 3.6*
Pulmonary artery diastolic pressure, mm Hg 29.7 ± 6.2 18.6 ± 4.5*
Mean pulmonary artery pressure, mm Hg 36.8 ± 5.1 22.3 ± 3.7*
Mean wedge pulmonary pressure, mm Hg 21.9 ± 2.0 18.7 ± 2.3*
Transpulmonary gradient, mm Hg 14.5 ± 2.3 3.8 ± 2.1*
Pulmonary arteriolar resistance, Wood units 3.27 ± 0.9 1.18 ± 0.50*
Pulmonary arterial elastance, mm Hg/mL 0.69 ± 0.08 0.39 ± 0.05*
RV end-diastolic pressure, mm Hg 20.1 ± 5.4 12.8 ± 3.4*
RV mean systolic ejection rate, mL/s 242 ± 20.6 276 ± 25.1*

Quality of life

Breathlessness

Fatigue

Emotional function

 

16.6 ± 6.0

20.3 ± 4.3

25.4 ± 5.4

 

22.2 ± 6.5*

27.5 ± 5.6*

29.2 ± 4.7*

*At 6 months vs baseline; p< 0.01

Adverse Events

Not specified in the provided text.

Study Author Conclusions

The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility, and lung interstitial water metabolism. These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy.

InpharmD Researcher Critique

The study provides valuable insights into the potential of PDE5 inhibitors in treating pulmonary hypertension in HFpEF, showing significant improvements in hemodynamics and quality of life. However, the small sample size limits the precision of effect estimation, and the study's findings may not be generalizable to all HFpEF patients due to the specific inclusion criteria and the focus on a high blood pressure etiology. Further research is needed to confirm these results and explore the long-term impact on clinical outcomes.



References:

Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124(2):164-174. doi:10.1161/CIRCULATIONAHA.110.983866