American Journal of Respiratory and Critical Care Medicine

Rationale: Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension. The prostacyclin analog treprostinil is also efficacious by subcutaneous infusion, is easier to administer, and has a longer half-life. With the demonstration of bioequivalence between subcutaneous and intravenous treprostinil, intravenous treprostinil may have an overall better risk–benefit profile than intravenous epoprostenol.

Objective: To evaluate the safety and efficacy of transitioning patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil.

Methods: Patients enrolled in a 12-wk prospective open label study were switched from intravenous epoprostenol to intravenous treprostinil over 24 to 48 h. The intravenous treprostinil dose was adjusted to minimize symptoms/side effects.

Results: Thirty-one patients (mean age, 43 yr; 22 women) were enrolled. Twenty-seven patients completed the protocol; 4 patients transitioned back to epoprostenol. Six-minute walk distance (n = 27; baseline, 438 ± 16 m; Week 12, 439 ± 16 m), Naughton-Balke treadmill test time (n = 26; baseline, 582 ± 50 s; Week 12, 622 ± 48 s), functional class, and Borg score were maintained with intravenous treprostinil at Week 12 versus intravenous epoprostenol before transition. At Week 12, mean pulmonary artery pressure increased 4 ± 1 mm Hg (n = 27, p < 0.01), cardiac index decreased 0.4 ± 0.1 L/min/m2 (n = 27, p = 0.01), and pulmonary vascular resistance increased 3 ± 1 Wood units · m2 (n = 26, p < 0.01). No serious adverse events were attributed to treprostinil.

Conclusions: These data suggest that transition from intravenous epoprostenol to intravenous treprostinil is safe and effective; whether the hemodynamic differences associated with intravenous treprostinil are clinically important requires longer follow-up.

Intravenous epoprostenol, the first drug approved for the treatment of pulmonary arterial hypertension (PAH), improves exercise capacity, hemodynamics, and quality of life in patients with idiopathic PAH (IPAH) (1, 2), PAH associated with connective tissue disease (3, 4), and PAH associated with congenital heart disease (5, 6), as well as improving survival in IPAH (2). However, because of its short half-life (2–3 min) (7), lack of stability at room temperature, and neutral pH, sudden cardiopulmonary collapse can occur with infusion interruption (8).

Treprostinil is a tricyclic benzidene prostacyclin analog with pharmacologic actions similar to those of epoprostenol (9, 10). Treprostinil has theoretical advantages over epoprostenol because of its stability at room temperature, an elimination half-life of 4.6 h (subcutaneous), and its ability to be administered by continuous subcutaneous infusion. Although subcutaneous treprostinil is safe and efficacious (11, 12), its use is limited by infusion site pain, which can lead to discontinuation by patients (12).

Early trials demonstrated similar acute hemodynamic effects between intravenous and subcutaneous treprostinil, and intravenous epoprostenol (13). To determine bioequivalence, 51 healthy subjects received treprostinil in a randomized, cross-over study at a dose of 10/ng/kg/min for 72 h by each route with a 4-d washout period between routes (11). Bioequivalence was demonstrated with no significant difference in steady state ratios, areas under curves, peak plasma concentration, and pharmacokinetics. The elimination half-life of intravenous therapy was 4.4 h. Given the potential advantages of intravenous treprostinil over intravenous epoprostenol, we evaluated whether patients with stable PAH, receiving intravenous epoprostenol infusion, could be safely transitioned to intravenous treprostinil with maintenance of efficacy and with a similar safety profile.

This was a multicenter open-label investigator-initiated trial designed to evaluate the safety and efficacy of transition from intravenous epoprostenol to intravenous treprostinil. The primary end point was performance on the 6-min walk test. Secondary end points included exercise performance by a Naughton-Balke treadmill test, the Borg dyspnea score, World Health Organization (Geneva, Switzerland) functional class, and hemodynamic parameters. All patients were receiving optimal doses of conventional therapies for their PAH, including oral vasodilators, diuretics, digoxin, and oxygen if indicated, as well as a stable dose of intravenous epoprostenol for at least 1 mo before transitioning from intravenous epoprostenol to intravenous treprostinil.

Eligible patients were between 12 and 65 yr of age with either World Health Organization class II or III IPAH, PAH associated with connective tissue disease, or congenital heart disease, with a Naughton-Balke treadmill test time of between 2 and 16 min before transition. All patients had received 3 mo or more of epoprostenol therapy before enrollment.

Patients were hospitalized for transition from intravenous epoprostenol to intravenous treprostinil. The infusion of treprostinil was increased through an intravenous line while simultaneously reducing the dose of intravenous epoprostenol. Downtitration of epoprostenol with simultaneous uptitration of treprostinil with vital sign monitoring occurred over a 24- to 48-h period. Patients were discharged on achieving a dose of intravenous treprostinil that was no lower than the dose of intravenous epoprostenol. The intravenous treprostinil dose was higher than the intravenous epoprostenol dose if the patient had symptoms that were characteristic of prostacyclin withdrawal—for example, increased shortness of breath.

Outpatient dose titration was based on symptoms of dyspnea on exercise and prostacyclin side effects. The dose of intravenous treprostinil was adjusted to achieve pretransition exercise capacity. Patients were evaluated with a 6-min walk test, Borg dyspnea score, treadmill test, and functional class assessment at baseline (before transition) and at Weeks 6 and 12; right heart catheterization was performed at baseline and at Week 12. At the end of the 12 wk, patients were given the option to continue intravenous treprostinil.

Statistical Analysis

Study population and dosing data are presented as means ± SD; outcome data (including baseline data presented in the context of study outcomes) are presented as means ± SE. Changes in baseline to Week 12 for primary and secondary end points were tested by Wilcoxon signed-rank test. p values are based on two-sided tests and values less than 0.05 were considered significant. No imputation was used for missing values. When presented in the context of study outcomes, baselines for each assessment were matched to their respective nonmissing follow-up values. To evaluate whether there were any relationships between the exercise tests and hemodynamics (mean pulmonary artery pressure cardiac index and pulmonary vascular resistance index), we performed both parametric and nonparametric correlation testing with Pearson and Spearman rank statistics.

Thirty-one patients were enrolled between February 2003 and September 2004; their mean age was 43 yr (range, 12–68 yr). Twenty-two of the subjects were female. Twenty-one had IPAH, six had PAH associated with connective tissue diseases, and four had PAH associated with congenital heart disease. All patients were class III or class IV before epoprostenol initiation. The mean duration of intravenous epoprostenol therapy was 4.2 ± 0.6 yr (range, 0.4–11.4 yr). For the 31 patients, the baseline 6-min walk distance was 441 ± 81 m, baseline treadmill test time was 580 ± 271 s, and the intravenous epoprostenol dose was 40 ± 4 ng/kg/min (range, 10–97 ng/kg/min; Table 1). At the time of hospital discharge (after transition to intravenous treprostinil), the intravenous treprostinil dose was 47 ± 24 ng/kg/min (range, 15–115 ng/kg/min). All patients had further increases in their intravenous treprostinil dose over the 12-wk period. At Week 6, the dose was 60 ± 23 ng/kg/min (15–96 ng/kg/min), and at Week 12 the dose was 83 ± 38 ng/kg/min (24–180 ng/kg/min).

TABLE 1. BASELINE DEMOGRAPHICS


Parameter

Value
Mean age, yr43 (12–68)
Sex, female:male22 (71%):9 (29%)
Etiology of PAH, n
 IPAH21 (68%)
 CTD6 (19%)
 CHD4 (13%)
 Functional class, n
 I0
 II24
 III7
 IV0
Baseline 6-min walk distance, mean ± SD441 ± 81 m
Baseline treadmill time, mean ± SD580 ± 271 s
Epoprostenol dose, ng/kg/min40 ± 4 (10–97)
Time on epoprostenol, yr
4.2 ± 0.6 (0.4–11.4)

Definition of abbreviations: CHD = congenital heart disease; CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension.

Exercise Capacity

There was no statistically significant difference between the 6-min walk test distance at baseline on intravenous epoprostenol, and the 6-min walk test performed at Week 12 on intravenous treprostinil in the 27 patients who completed the study (n = 27; 438 ± 16 m at baseline; 439 ± 16 m at Week 12; Figure 1). Four of the 27 patients had an increase in walk distance of 10% or more; two had a decrease of 10% or more. At Week 6 there was a decrease of 12 ± 12 m in the 6-min walk distance, and at Week 12 there was an increase of 1 ± 6 m (p = nonsignificant). Patients with IPAH or PAH associated with either connective tissue disease or congenital heart disease responded similarly. The Naughton-Balke treadmill test also demonstrated no significant difference in exercise tolerance from baseline to Week 12 (n = 26; 582 ± 50 s at baseline; 622 ± 48 s at Week 12). Twelve of the 26 patients had an increase in treadmill time of 10% or more and six patients had a decrease of 10% or more. At Week 6 there was a decrease of 25 ± 31 s; at Week 12 there was an increase of 40 ± 24 s. The Borg dyspnea score was 2.3 ± 0.3 at baseline and 2.1 ± 0.3 at Week 12 (p = nonsignificant).

Hemodynamic Parameters

At Week 12, mean pulmonary artery pressure had increased 4 ± 1 mm Hg (n = 27, p < 0.01), cardiac index had decreased 0.4 ± 0.1 L/min/m2 (n = 27, p = 0.01), and pulmonary vascular resistance had increased by 3 ± 1 Wood units · m2 (n = 26, p < 0.01) versus before transition (see Table 2). There were no significant changes in right atrial pressure, systemic blood pressure, or heart rate. We found no relationship between the changes observed in either 6-min walk distance or treadmill time and the changes in hemodynamics.

TABLE 2. CARDIOPULMONARY HEMODYNAMICS


Hemodynamic Parameter

Baseline (n)

Change at Week 12 (n)
Mean right atrial pressure, mm Hg6 ± 1 (27)0 ± 1 (27)
Mean pulmonary artery pressure, mm Hg46 ± 3 (27)4 ± 1 (27)*
CI, L/min/m23.0 ± 0.1 (27)–0.4 ± 0.1 (27)
PVRI, Wood units · m213 ± 1 (26)3 ± 1 (26)*
Mean systemic arterial pressure, mm Hg80 ± 2 (21)1 ± 2 (21)
HR, bpm
83 ± 2 (24)
–1 ± 2 (24)

Definition of abbreviations: bpm = beats per minute; CI = cardiac index; HR = heart rate; PVRI = pulmonary vascular resistance index.

Data are expressed as means ± SE. Twenty-seven of the 31 patients completed the study.

*p < 0.01.

p = 0.01.

Functional Class

At the time of transition, of the 31 subjects enrolled, 24 (77%) patients were functional class II and 7 (23%) were class III on long-term intravenous epoprostenol for a mean of 4.2 ± 0.6 yr. Of the 27 patients completing 12 wk, 22 (81%) were class II and 5 (19%) were class III at baseline. At Week 12, 2 of the 22 patients who were class II at baseline were class I, and 1 of the 22 patients who was class II at baseline was class III; totals in each class at Week 12: 2 (7%) class I, 19 (71%) class II, and 6 (22%) class III (Figure 2). The functional class changes did not correlate with the hemodynamic changes.

Laboratory Results

There were no significant laboratory value changes except that the platelet count was higher at Week 12, that is, 242,000 ± 15,000 versus 195,000 ± 11,000 than at baseline on long-term intravenous epoprostenol (p = 0.0001).

Adverse Events

There were no deaths during the 12-wk study period. Four subjects were transitioned back to intravenous epoprostenol: three due to leg pain and one with worsening PAH symptoms in the setting of pneumonia. One patient had syncope. Four patients reported worsening dyspnea while the treprostinil dose was being uptitrated. Other adverse events that were reported were typical of prostacyclin-related side effects and included leg pain, arm pain, headache, jaw pain, and diarrhea (Tables 3 and 4).

TABLE 3. SERIOUS ADVERSE EVENTS




Number of Events (%)*
Catheter-related complication1 (3%)
Catheter-related infection1 (3%)
Dizziness1 (3%)
Syncope1 (3%)
Worsening dyspnea1 (3%)
Noncardiac chest pain
1 (3%)

*% = percentage of patients with one or more events.

TABLE 4. MOST FREQUENT ADVERSE EVENTS




Number of Events (%)
Extremity pain*22 (71%)
Headache14 (45%)
Diarrhea8 (26%)
Jaw pain7 (23%)
Nausea6 (19%)
Dyspnea5 (16%)
Fatigue4 (13%)
Flushing4 (13%)
Palpitations4 (13%)
Peripheral edema
3 (10%)

*Includes foot, arm, leg, and toe pain.

% = percentage of patients with one or more events.

This is the first clinical trial to evaluate the safety and efficacy of intravenous treprostinil in patients previously treated with intravenous epoprostenol. Patients were safely transitioned to intravenous treprostinil in the hospital with further uptitration of the intravenous treprostinil dose on an outpatient basis. Twelve weeks after transitioning from intravenous epoprostenol to intravenous treprostinil, exercise capacity (assessed by the 6-min walk test and the Naughton-Balke treadmill test), functional class, and Borg dyspnea score remained unchanged.

The potency of intravenous treprostinil relative to intravenous epoprostenol in these patients was unclear at the start of the study. Treprostinil was dosed on the basis of dyspnea with effort as a clinical end point, similar to current intravenous epoprostenol dosing recommendations. The 12-wk dose of intravenous treprostinil was greater than twice the dose of intravenous epoprostenol (before transition). It was interesting to note that some of the hemodynamic parameters changed even though measures of exercise remained stable. Whether the hemodynamic differences between treatment with intravenous treprostinil versus intravenous epoprostenol could have been minimized by further uptitration of the intravenous treprostinil is unknown. It is unclear whether the hemodynamic changes after 12 wk of intravenous treprostinil versus long-term intravenous epoprostenol are clinically important. Longer follow-up is needed to adequately evaluate these changes.

Patients in the study with extremity pain characterized their leg pain differently from that reported with intravenous epoprostenol. Despite these differences, the severity of pain overall appeared to be similar to pain experienced while receiving intravenous epoprostenol. However, three patients transitioned back to intravenous epoprostenol from intravenous treprostinil because of severe leg pain. All these patients had preexisting leg pain of varying intensity while receiving intravenous epoprostenol at study entry. We expect, as with epoprostenol, that there will be patient variability, with more or less pain associated with the different therapies. As no standard questionnaire reporting side effects was administered before transition, and quality of life was assessed by individual physician questioning, we are unable to judge overall quality of life with intravenous treprostinil versus intravenous epoprostenol.

One patient had syncope with exertion 4 wk after transition. With increasing intravenous treprostinil dose, the patient had no further events; this patient also had decreased exercise capacity at Week 4, consistent with a subtherapeutic dose. However, at 12 wk, exercise capacity was back to baseline. An unexpected finding was the increase in platelet count; because of the small sample size it is unclear whether the degree of thrombocytopenia will be less with long-term intravenous treprostinil versus long-term intravenous epoprostenol.

Analogs of effective therapies are developed to improve safety, convenience, and/or clinical benefit. On the basis of this initial clinical experience, it appears safe to transition patients with stable PAH from intravenous epoprostenol to intravenous treprostinil with maintenance of exercise capacity and functional class at Week 12. Whether the hemodynamic differences seen after 12 wk of intravenous treprostinil versus long-term intravenous epoprostenol will be clinically meaningful or persist with long-term intravenous treprostinil will require further follow-up. The elimination half-life of treprostinil is considerably longer than that of epoprostenol: 4.4 h versus 6 min, respectively. Although this portends a lower risk of rebound pulmonary hypertension on sudden withdrawal or dose reduction, it should be noted that plasma levels may fall below a patient's therapeutic threshold in a shorter period of time.

Although this study demonstrates the ability to transition patients from intravenous epoprostenol to intravenous treprostinil, long-term data on exercise capacity, functional class, hemodynamic assessment, and survival are needed to ultimately determine whether intravenous treprostinil is as efficacious as intravenous epoprostenol.

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Correspondence and requests for reprints should be addressed to Mardi Gomberg-Maitland, M.D., M.Sc., Pulmonary Hypertension Center, University of Chicago Hospitals, 5841 South Maryland Avenue, MC 2016, Chicago, IL 60637. E-mail:

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