Sildenafil Improves Health-Related Quality of Life in Patients With Pulmonary Arterial Hypertension*

doi:10.1378/chest.07-0592

Chest

Volume 133, Issue 1, January 2008, Pages 183-189

https://doi.org/10.1378/chest.07-0592 Get rights and content

Background

Sildenafil inhibits phosphodiesterase-5, enhancing cyclic guanosine monophosphate- mediated relaxation of pulmonary vasculature and is effective in treating patients with pulmonary arterial hypertension (PAH).

Methods

Patients with PAH (n = 278) received oral sildenafil (20, 40, or 80 mg three times daily) in a 12-week, double-blind, placebo-controlled study and an open-label extension. Health-related quality of life (HRQoL) was recorded by patients using the Medical Outcomes Study 36-item short form (SF-36) and EuroQol 5D (EQ-5D) questionnaires at baseline and after 12 and 24 weeks of therapy. Data are presented for patients who received sildenafil for up to 24 weeks.

Results

Sildenafil-treated patients, compared with placebo-treated patients, exhibited significant improvement in exercise capacity at week 12 (p < 0.001). Increases from baseline to week 12 were observed in all SF-36 domains for sildenafil-treated patients, with statistically significant improvements, compared with placebo-treated control subjects, in physical functioning (p < 0.001), general health (p < 0.001), and vitality (p < 0.05). Statistically significant improvements were also observed for the EQ-5D current health status (p < 0.01) and utility index (p < 0.01). These benefits were maintained for 24 weeks. Treatment groups were pooled for analyses as the results for the 6-min walk distance, SF-36, and EQ-5D were not dose dependent.

Conclusions

Sildenafil improves HRQoL of PAH patients. These improvements appear to be maintained for at least 24 weeks. The effects are strongest in domains addressing the physical impact of health on daily activities and patients' overall perception of health.

Section snippets

Study Design

The complete details of the double-blind SUPER study design have been published elsewhere.²⁰ Briefly, 278 patients with symptomatic PAH were randomized to receive placebo or sildenafil, 20, 40, or 80 mg orally tid for 12 weeks. Those patients completing this double-blind phase of the study were eligible to participate in an open-label extension at the highest tolerated dose, not exceeding 80 mg tid. Study medication was added to the patient's background therapy. Patients receiving medication

Baseline Characteristics

The baseline characteristics of the patients in the placebo group and the combined sildenafil treatment group were comparable (Table 1), as were those in the individual sildenafil treatment groups.²⁰ The mean 6MWD at baseline in the study population was 344 m, which is a diminished exercise capacity compared to a healthy population.²⁰²¹ The baseline SF-36 values (Fig 1, top, A) also show impairment compared to the norm,²² with the greatest decreases in scores in the physical functioning and

Discussion

These data demonstrate that, in addition to significant improvements in exercise capacity,²⁰ treatment with sildenafil also results in significant benefits in HRQoL in patients with PAH. As there was no dose effect in 6MWD or HRQoL assessments, the data for all sildenafil-treated patients were combined and analyzed as a single group.

The baseline data confirm the considerable impairment experienced by patients with PAH, both in terms of exercise capacity (6MWD test, 344 m vs 400 to 700 m,

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Citation Excerpt :
It is the most important test method to evaluate the exercise tolerance of PAH patients, and it is also the key method to validate whether the treatment is effective. A 12-week, double-blind and placebo-controlled study suggested that Sildenafil can improve health-related quality of life (6MWD, SF-36, and EQ-5D) in patients with PAH and no dose-dependent [24]. In addition, many studies used 6MWD as the measure of exercise capacity to evaluate the outcomes of PH-COPD [25,26].
Pulmonary hypertension (PH) is a severe and prevalent complication of chronic obstructive pulmonary disease (COPD), with low quality of life and poor prognosis. This study was designed to evaluate the efficacy and safety of Sildenafil in the treatment of PH caused by COPD (COPD-PH) and provide reference for clinical treatment.
We systematically searched PubMed, EMBASE, Cochrane Library, Clinical Trials.gov databases, Wanfang Data and CNKI for comprehensive literature reporting Sildenafil for randomized controlled trials (RCT) of COPD-PH. Quality assessment, data analysis used the modified Jadad scale and RevMan5.3 software.
A total of 9 RCTs involving 579 patients were included in our study. The primary outcome measure was Six minutes walking distance (6MWD). Secondary observations were Pulmonary artery systolic pressure (PASP), Borg dyspnea index, and Survey scale (SF-36). Our data demonstrate that Sildenafil can improve 6WMD [29.64, 95% CI (13.78, 45.50), P < 0.00001] and PASP [−7.86, 95% CI (−11.26, −4.46) P < 0.00001] of COPD-PH, compared with the control group. However, SF-36 [2.64, 95% CI (−6.85, 12.14) P = 0.59] and Borg dyspnea index [−0.28, 95% CI (−1.08, 0.52) P = 0.49] have no significant difference between those two groups. Adverse reactions in the Sildenafil treatment group were tolerated headaches and digestive symptoms, which were relatively safe.
Available clinical evidence indicates that Sildenafil seems to be safe and effective for COPD-PH and can improve the patients' 6WMD. However, large-sample, high-quality multicenter RCTs are still needed to provide stronger evidence-based medical evidence.
Pulmonary Arterial Hypertension: A Palliative Medicine Review of the Disease, Its Therapies, and Drug Interactions
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Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.
Right Ventricular Function is Associated With Quality of Life in Patients With Systemic Lupus Erythematosus Associated Pulmonary Arterial Hypertension
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Sixty (60) consecutive patients with SLE-APAH (all female, mean age 33.6 ± 8.2 years) were recruited from May 2013 to November 2014. Echocardiograph, right heart catheterisation, SLE disease activity index (SLEDAI), and functional status and SF-36 generic questionnaire were assessed.
Echocardiograph-derived RV systolic function was significantly correlated with haemodynamics (p < 0.05), with tricuspid annular plane systolic excursion (TAPSE) showing the strongest correlation with pulmonary vascular resistance (R² = 0.278, p < 0.001) and cardiac index (R² = 0.215, p < 0.001). Patients with a TAPSE<17 mm had a shorter 6-minute-walk-distance (6MWD), lower mixed venous oxygen saturation, and higher plasma N-terminal pro-brain natriuretic peptide (p < 0.05). Patients with TAPSE <17 mm had lower physical component summary (PCS) and mental component summary (MCS) scores than those with TAPSE ≥17 mm (35.5 ± 13.2 vs. 55.0 ± 15.5; 46.3 ± 15.3 vs. 64.8 ± 18.8, respectively, all p < 0.05). On multiple regression analysis, a TAPSE <17 mm was independently related to lower PCS (β −15.797, 95% confidence interval [CI] −24.746 to −6.848, p = 0.001) and lower MCS (β −12.887, 95% CI −24.018 to −1.755, p = 0.024).
TAPSE is a useful index for RV function assessment, and is associated with HRQOL in patients with SLE-APAH.
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Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-β signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.
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This work was sponsored by Pfizer Ltd.

Dr. Pepke-Zaba was a paid consultant for Pfizer, Ltd; Ms. Gilbert and Ms. Collings are current employees of Pfizer, Ltd; and Mr. Brown is a former employee of Pfizer, Ltd.

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Chest

Original ResearchCARDIOVASCULAR DISEASESildenafil Improves Health-Related Quality of Life in Patients With Pulmonary Arterial Hypertension*

Background

Methods

Results

Conclusions

Section snippets

Study Design

Baseline Characteristics

Discussion

Heart Lung

Chest

J Clin Epidemiol

J Am Coll Cardiol

Ann Allergy Asthma Immunol

Treatment of pulmonary arterial hypertension

N Engl J Med

Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology

Eur Heart J

Pulmonary arterial hypertension

N Engl J Med

Measurement of quality of life in pulmonary hypertension and its significance

Eur Respir J

A comparative review of generic quality-of-life instruments

Pharmacoeconomics

Measuring quality of life: using quality of life measures in the clinical setting

BMJ

Original Research
CARDIOVASCULAR DISEASE
Sildenafil Improves Health-Related Quality of Life in Patients With Pulmonary Arterial Hypertension*