Long-term Treatment With Oral Sildenafil in Addition to Continuous IV Epoprostenol in Patients With Pulmonary Arterial Hypertension

doi:10.1378/chest.123.4.1293

Chest

Volume 123, Issue 4, April 2003, Pages 1293-1295

https://doi.org/10.1378/chest.123.4.1293 Get rights and content

Objectives:

To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol.

Design:

Open, uncontrolled trial.

Setting:

University hospital.

Patients:

Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively.

Interventions:

Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil.

Results:

One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen.

Conclusion:

Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.

Section snippets

Materials and Methods

For measurements of hemodynamic and gas exchange parameters, a thermodilution pulmonary artery catheter was inserted before and after 5 months treatment with sildenafil. A 6-min walking test (6MWT) was performed before and after the sildenafil trial. The dose of epoprostenol and iloprost was not changed in the 3 months before and during the sildenafil trial. The 6MWT distance and the hemodynamic measurements were made before the administration of sildenafil and iloprost. The study was approved

Discussion

Addition of sildenafil to the long-term therapy with IV epoprostenol improved pulmonary arterial pressures and the 6MWT distance in all three patients without significant adverse effects at the reported doses. IV epoprostenol is now established as a treatment to be considered for all patients with PPH, and hundreds of patients worldwide experienced the beneficial effect of this treatment. Introduced initially as a bridge to transplantation, it is now considered superior to lung transplantation

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There are more references available in the full text version of this article.

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In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous epoprostenol improved 6-minute walk distance (6MWD) and hemodynamics and delayed time to clinical worsening in a 16-week randomized, placebo-controlled trial (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil [PACES-1]).
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Although reliable assessments of safety and efficacy require a long-term randomized trial, the addition of sildenafil to background intravenous epoprostenol therapy appeared generally to be well tolerated in PAH patients.
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In fact, decrease level of endothelium-dependent NO production has been observed in the pulmonary vascular tissue of patients with PAH [7]. To achieve similar or additive responses, pulmonary vascular cGMP levels can also be elevated by inhibition of the cGMP-dependent PDE-5 responsible for cGMP hydrolysis in the lung [20,21,25,26]. Our results indicate that P1 enhances endothelium-derived NO production.
Pulmonary vascular endothelial nitric oxide (NO) synthase (eNOS)-derived NO is the major stimulant of cyclic guanosine 5′-monophosphate (cGMP) production and NO/cGMP-dependent vasorelaxation in the pulmonary circulation. We recently synthesized multiple peptides and reported that an eleven amino acid (SSWRRKRKESS) peptide (P1) but not scrambled P1 stimulated the catalytic activity but not expression of eNOS and causes NO/cGMP-dependent sustained vasorelaxation in isolated pulmonary artery (PA) segments and in lung perfusion models. Since cGMP levels can also be elevated by inhibition of phosphodiesterase type 5 (PDE-5), this study was designed to test the hypothesis that P1-mediated vesorelaxation is due to its unique dual action as NO-releasing PDE-5 inhibitor in the pulmonary circulation. Treatment of porcine PA endothelial cells (PAEC) with P1 caused time-dependent increase in intracellular NO release and inhibition of the catalytic activity of cGMP-specific PDE-5 but not PDE-5 protein expression leading to increased levels of cGMP. Acute hypoxia-induced PA vasoconstriction ex vivo and continuous telemetry monitoring of hypoxia (10% oxygen)-induced elevated PA pressure in freely moving rats were significantly restored by administration of P1. Chronic hypoxia (10% oxygen for 4 weeks)-induced alterations in PA perfusion pressure, right ventricular hypertrophy, and vascular remodeling were attenuated by P1 treatment. These results demonstrate the potential therapeutic effects of P1 to prevent and/or arrest the progression of hypoxia-induced PAH via NO/cGMP-dependent modulation of hemodynamic and vascular remodeling in the pulmonary circulation.
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Six studies reported a beneficial effect20,28,31–33,55 and 1 study demonstrated a trend towards improved functional class.30 Six studies reported haemodynamics (PAP and/or PVR) as outcomes, all of which demonstrated a beneficial effect with dual therapy.20,28,29,31,33,36 None of the studies reported quality of life as an outcome.
Use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in idiopathic pulmonary arterial hypertension (IPAH) and systemic sclerosis-associated PAH (SSc-PAH) patients. However, patients often deteriorate on monotherapy. The objective of this study is to evaluate the effect of dual therapy on outcomes in IPAH and SSc-PAH.
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Twenty-six observational studies and 6 randomized trials were identified. Using combination PDE-5 inhibitor and prostaglandin analogues, 6/7 studies reported improvement in 6MWD, 6/8 studies reported improvement in FC, 6/6 studies reported improvement in haemodynamics and 1 trial demonstrated improvement in QoL and time-to-clinical-worsening. Using combination ERA and prostaglandin analogues, 4/6 studies and 1 trial reported improvement in 6MWD, 3/3 studies and 1 trial reported improvement in FC, 4/5 studies and 1 trial reported improvement in PAP. Using combination ERA and PDE-5 inhibitor, 4/7 studies reported an improvement in 6MWD, and 2/6 report improvement in FC.
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Chest

Selected ReportsLong-term Treatment With Oral Sildenafil in Addition to Continuous IV Epoprostenol in Patients With Pulmonary Arterial Hypertension

Objectives:

Design:

Setting:

Patients:

Interventions:

Results:

Conclusion:

Section snippets

Materials and Methods

Discussion

Treatment of primary pulmonary hypertension with intravenous epoprostenol (prostacyclin)

Br Heart J

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension

N Engl J Med

Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects

Circulation

Critical care

Critical Care

Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension

Novel peptide for attenuation of hypoxia-induced pulmonary hypertension via modulation of nitric oxide release and phosphodiesterase -5 activity

Dual therapy in IPAH and SSc-PAH. A qualitative systematic review

Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction

Selected Reports
Long-term Treatment With Oral Sildenafil in Addition to Continuous IV Epoprostenol in Patients With Pulmonary Arterial Hypertension