Epoprostenol Sodium
Epoprostenol sodium (GlaxoSmithKline’s Flolan) has been available in the United States for the treatment of pulmonary arterial hypertension (idiopathic pulmonary arterial hypertension [pulmonary arterial hypertension], familial pulmonary arterial hypertension [familial pulmonary arterial hypertension], and associated pulmonary arterial hypertension [associated pulmonary arterial hypertension]) since 1995; the agent is also available in most of Europe and in Japan. Epoprostenol has an extremely short half-life of two to seven minutes; hence, it is administered as a continuous IV infusion through a central-line catheter. Medication must be kept cold for reasons of stability, a requirement that makes administration somewhat problematic.
Epoprostenol’s mechanism of action follows that outlined for the prostacyclin analogues in general. Treatment causes direct vasodilation of pulmonary and systemic vascular beds via activation of prostanoid receptors. It also inhibits platelet activation.
Several clinical trials have assessed the benefits of epoprostenol therapy in pulmonary arterial hypertension. A 12-week, multicenter, open-label trial compared the effects of epoprostenol plus standard symptom-relieving therapy (oral vasodilators, anti-coagulation, and diuretics) with standard symptom-relieving therapy alone in 81 patients with pulmonary arterial hypertension (pulmonary arterial hypertension/familial pulmonary arterial hypertension) who were New York Heart Association (NYHA) classes III and IV. Results demonstrated a statistically significant (p < 0.002) improvement in exercise capacity as measured by the six-minute walk test — the distance an individual can walk in six minutes (6MWD) — in 41 patients treated with continuous-infusion epoprostenol (362 meters at 12 weeks compared with 315 meters at baseline); the 6MWD actually declined in the group treated with conventional therapy. Improvements were also observed in quality of life (p < 0.01) and hemodynamics (pulmonary artery pressure and pulmonary vascular resistance).
Several studies have assessed the long-term effect of continuous-infusion epoprostenol. One large study investigated 162 patients diagnosed with pulmonary arterial hypertension (pulmonary arterial hypertension/familial pulmonary arterial hypertension) treated with continuous-infusion epoprostenol for a mean of 36.1 months. The one-, two-, and three-year survival rates for the epoprostenol group were 87.8%, 76.3%, and 62.8%, respectively, compared with survival rates of 58.9%, 46.3%, and 35.4% based on historical data. The authors reported that baseline predictors of survival included tolerance to exercise, NYHA functional class, right atrial pressure, and acute vasodilator response to adenosine.
Researchers have evaluated continuous infusion of IV epoprostenol in patients with associated pulmonary arterial hypertension related to connective tissue disease. A randomized, open-label, controlled study included 111 patients with moderate-to-severe pulmonary arterial hypertension with scleroderma-associated disease. Patients received continuous-infusion epoprostenol or conventional therapy for pulmonary arterial hypertension; the follow-up period was 12 weeks. Results showed an improvement in exercise capacity, as measured by the 6MWD, in the epoprostenol-treated group compared with the conventional treatment group. The difference between treatment groups in median walk distance at week 12 was 108 m (95% confidence interval = 52.5-180 m; p < 0.001). Hemodynamics also improved in those treated with epoprostenol. Twenty-one patients in the epoprostenol-treated group and no patients in the conventional therapy group showed improvements in terms of NYHA functional class. Borg dyspnea index scores (a common method of measuring breathlessness) and dyspnea-fatigue ratings dropped in the epoprostenol group, and there was a trend toward an improvement in the severity of Raynaud’s syndrome — fewer new digital ulcers formed. The researchers did not observe a survival difference in this population during the study period, but the study’s design meant it was not significantly powered to detect such a difference.
One study revealed that continuous-infusion epoprostenol improved exercise capacity, hemodynamics, and quality of life in patients with pulmonary arterial hypertension associated with a congenital heart defect who had failed conventional therapy (digitalis, diuretics, oxygen, warfarin, calcium-channel blockade, and surgery if operable).
Side effects commonly associated with epoprostenol therapy include flushing, headache, jaw pain, diarrhea, nausea, blotchy erythematous rash, and muscu-loskeletal pain in the feet and legs. These side effects are generally dose-related and usually respond to a reduction in dose. Because the agent is administered via continuous IV infusion, complications, including line-related infections (exit-site reactions, tunnel infections and cellulitis, bacteremia, sepsis), catheter-associated venous thrombosis, thrombocytopenia, and ascites (fluid in the peritoneal cavity, a common symptom of hepatic disease) may occur.
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