In 1980, shortly after the first human administration of intravenous prostacyclin (epoprostenol sodium) in a newborn with persistent PH (Lock et al. 1979), Watkins et al. reported on a 8-year-old girl with IPAH in whom the acute infusion of the substance resulted in a dramatic decrease in pulmonary vascular resistance by more than 50% (Watkins et al. 1980). As nicely reviewed by Long and Rubin (Long et al. 1987), during the following years epoprostenol was acutely tested in about 100 patients, and 70 % of them showed a decrease in PVR by greater than 20 %. Moreover, the vasodilatory effect of epoprostenol predicted the acute vascular response to nifedipine, hydralazine, and dilitazem, the only available vasodilators at that time.
The first long-term continuous intravenous administration of epoprostenol was reported by Higenbottam et al. in 1984 (Higenbottam et al. 1984), who also presented the first series of 10 patients three years later (Jones et al. 1987). All except one of these cases demonstrated a subjective and objective improvement in exercise tolerance.
The first randomized and controlled study of continuous intravenous epoprostenol was published in 1990 (Rubin et al. 1990), followed by the landmark study of Barst (Barst et al. 1996). These two trials including patients with IPAH were followed by a third larger study in PAH related to scleroderma (see table). In all trials the 6-minute walking distance imporved with epoprostenol but decreased with conventional therapy, resulting in a significant difference.
Epoprostenol is delivered continuously through a permanently implanted central venous catheter using a portable infusion pump. Continuous infusion is usually initiated at doses of 1-2 ng/kg/min and increased by 1-2 ng/kg/min every 1-2 days as tolerated, based on symptoms, blood pressure, and physical examination. Once an initial level of 6-10 ng/kg/min is achieved (usually within 1-2 weeks), most patients require dose increases of 1-2 ng/kg/min every 2-4 weeks in order to sustain clinical improvement, although dose requirements are variable. Serial exercise testing may be useful in guiding therapy during this phase of treatment (Wax et al. 1999).
Minor complications were mostly related to the side effects of epoprostenol and included jaw pain, diarrhea, flushing, headaches, anorexia, nausea and vomiting. Serious complications were most often due to the delivery system and included catheter-related sepsis, thrombosis and malfunctions of the drug-delivery system such as occlusions, hemorrhage, dislodgements of the catheter, pneumothorax, and pump malfunctions resulting in temporary interruption of the infusion.
In the following years the results of various open-label studies (Barst et al. 1994; Shapiro et al. 1997; Higenbottam et al. 1998; McLaughlin et al. 2002; Sitbon et al. 2002; Kuhn et al. 2003) indicated a continued improvement in exercise tolerance, NHYA functional class and prognosis compared with the expected survival according to the NIH historical cohort (D''Alonzo et al. 1991) (see figure). In one of the largest series of 162 patients from Rush-Presbyterian-St Luke''s Medical Centre, Chicago, the two- and three year survival was 76 % and 63 % compared to 46 % and 35 % calculated by the NIH formula (McLaughlin et al. 2002). Interestingly, in contrast to previous observations, baseline hemodynamic measurements more or less ceased to be important prognostic factors, whereas exercise capacity, NYHA class and response to epoprostenol treatment emerged as most important predictors of survival (McLaughlin et al. 2002; Sitbon et al. 2002; Kuhn et al. 2003).
Intravenous epoprostenol was admitted by the FDA for the treatment of primary pulmonary hypertension in 1995, extended later on to patients with collagen vascular disease and pulmonary hypertension. Unfortunately, serious complications remained to be a problem and resulted in 2 deaths out of 18 patients in one series (Barst et al. 1994), and at least 8 out of 178 cases in another (Sitbon et al. 2002). In addition, it soon became evident that there was rapid tachyphylaxis necessitating regular increases in dosage, for instance from a mean infusion rate in ng/kg/min of 7 at baseline to 18 at one year, 37 at two years and 53 at three years (Barst et al. 1994). The latter dosage would result in costs of about 725 000.- Swiss francs.
On the other hand, it was also shown that epoprostenol has a sustained hemodynamic long-term effect which surpassed the level reached at acute vasodilator testing at baseline (McLaughlin et al. 1998; McLaughlin et al. 2002; Sitbon et al. 2002). In one study over a period of 17 months all except one of 27 patients had improvement in symptoms and hemodynamic measures with an overall mean reduction in pulmonary vascular resistance of 53% (McLaughlin et al. 1998). In all but one patient the long-term decrease in PVR exceeded the acute response to adenosine challenge at base line.
No maximal dose has been established, and some patients who have been receiving therapy for many years are on doses of 150-200 ng/kg/min with sustained clinical and hemodynamic benefit. Excessive dosing may produce high output cardiac states; reduction of the dose in this setting is appropriate provided rebound pulmonary hypertension does not occur (Rich et al. 1999).
Recently, there have been reports on successful withdrawal of epoprostenol after commencing various oral vasodilator treatments in four adult patients (Kim et al. 2003) and three children (Ivy et al. 2004). In addition, transition to subcutaneous treprostinil has bee successful in eight patients (Vachiery et al. 1561).
Randomized controlled trial of continuous intravenous epoprostenol¹
|Trial||Rubin et al. 1990||Barst et al. 1996||Badesch et al. 2002|
|NYHA II / II / IV (%)||9 / 65 / 26||0 / 75 / 25||5 / 78 / 17|
|Improvement in 6-MW (m) compared to controls||+45||+60||+94|
|Improvement in other endpoints||Hemodyn||
Hemodyn, NYHA, QOL, Survival
|Side effects||Pulmonary edema (1)
¹Modified according to Galié et al., 2004; 6-MW = 6-minute walking distance; Hemodyn = hemodynamics; QOL = Quality of life
Epoprostenol for other indications
As shown in the randomized controlled trial mentioned above, continuous intravenous epoprostenol improves exercise capacity, hemodynamics and functional class in patients with PAH associated with scleroderma spectrum of disease (Badesch et al. 2000). However, survival is significantly worse in these cases compared to IPAH (Kuhn et al. 2003), and seems not to be improved with epoprostenol (Badesch et al. 2000). It is important to notice that epoprostenol may lead to fatal pulmonary edema in single scleroderma patients (Humbert et al. 1999). This might be due to the fact that significant venous involvement is not infrequent in these patients (Naeye 1963; Yousem 1990; Morassut et al. 1992) and that in analogy to PVOD (Palmer et al. 1998) and PCH (Humbert et al. 1998; Almagro et al. 2002) this can lead to increased pulmonary perfusion in the presence of downstream vascular obstruction (Davis et al. 1754). Heart disease associated with scleroderma may be another precipitating factor (Strange et al. 2000). If pulmonary edema occurs at acute testing, epoprostenol might later be cautiously reinstituted (Farber et al. 1999).There are small reports on patients with systemic lupus erythematosus (Robbins et al. 2000).
An uncontrolled study in 20 patients with PAH associated with congenital heart defects demonstrated an improvement in exercise capacity and NYHA functional class (Rosenzweig et al. 1999). Although there was no response during acute testing, repeat right heart catheterization after one year in 16 cases showed a mean decrease in PVR by 21 %.
In patients with severe portopulmonary hypertension epoprostenol often has a profound effect on pulmonary hemodynamics and serves as a brigde to liver transplantation, which can be safely untertaken when mPAP is decrreased below 35 mmHg (Kuo et al. 1997; Krowka et al. 1999).
Uncontrolled trials have shown that epoprostenol improves exercise capacity, functional class and possibly survival in patients with PAH related to HIV infection (Petitpretz et al. 1994; Aguilar et al. 2000; Nunes et al. 2003).
Successful use of epoprostenol was reported in eight cases with persistent pulmonary hypertension of the newborn (Eronen et al. 1997). All patients survived without extracorporeal membrane oxygenation.
Some patients with CTEPH may benefit from epoprostenol, either as a bridge to pulmonary endarterectomy or definite treatment in inoperable situations (Nagaya et al. 2003; Bresser et al. 2004). Short-term preoperative adminsitration reduced PVR by a mean of 28 % in 33 patients (Nagaya et al. 2003). Treatment during a period of 11 months, however, improved or stabilized only 6 out of 9 patients (Bresser et al. 2004). Thus, as for other vasodilators, treatment might be considered in patients with CTEPH but should not defer PEA.