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* From the Departments of Cardiology (Drs. Lang and Skoro-Sajer) and Pulmonology (Dr. Kneussl), Vienna General Hospital and Medical University of Vienna, Austria; Cardiology Department (Drs. Gomez-Sanchez and Escribano), Hospital Doce de Octubre, Madrid, Spain; and Department of Cardiology (Drs. Naeije and Vachiery), Hôpital Erasme, Bruxelles, Belgium.
Correspondence to: Jean-Luc Vachiery, MD, Department of Cardiology, Hôpital Erasme, Route de Lennik 808, B-1070 Bruxelles, Belgium; e-mail: jean-luc.vachiery{at}ulb.ac.be
Abstract
Study objectives: The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter.
Design: Multicenter retrospective study.
Setting: Three European university hospitals.
Methods: Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 ± 17.2 months (± SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival.
Results: At 3 years, significant improvements from baseline were observed in mean SMWD (305 ± 11 to 445 ± 12 m, p = 0.0001), Borg dyspnea score (5.7 ± 0.2 to 4.5 ± 1, p = 0.0006), and NYHA class (3.20 ± 0.04 to 2.1 ± 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 ± 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively.
Conclusions: Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.
Key Words: chronic thromboembolic pulmonary hypertension • exercise capacity • pulmonary arterial hypertension • survival • treprostinil
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are severely disabling disorders characterized by sustained elevations of pulmonary vascular resistance, ultimately leading to right-heart failure and death.1 PAH has recently been defined as a group of diseases including idiopathic PAH (iPAH) and pulmonary hypertension (PH) associated with other conditions such as congenital left-to-right shunts (congenital heart disease [CHD]), connective tissue diseases (CTDs), portal hypertension, HIV infection, or anorectic drug intake. CTEPH shares pathophysiologic, hemodynamic, and clinical characteristics with PAH2 and carries a poor long-term survival in the absence of appropriate therapy.23
Long-term IV epoprostenol has been widely used in patients with advanced forms of iPAH, leading to substantial short-term and long-term clinical benefits with a significant improvement in survival.456 Similar observations were made in other forms of PAH,789 although the beneficial effect on survival was not uniformly confirmed.9 Despite favorable outcomes, continuous epoprostenol therapy is not an ideal treatment. Due to instability and a very short half-life (1 to 2 min), epoprostenol must be administered as a continuous infusion through a permanently implanted IV catheter. This may expose patients to potentially life-threatening complications, such as catheter-related thrombosis or infections, sepsis, and delivery system malfunctions, resulting in poorly tolerated rapid underdosing. Thus, other modes of prostacyclin delivery have been proposed using stable prostacyclin analogues administered orally, by inhalation, or subcutaneously.1011
Treprostinil sodium, a stable prostacyclin analog, shares pharmacologic actions similar to epoprostenol with comparable acute hemodynamic effects.11 However, in contrast to epoprostenol, treprostinil is chemically stable at room temperature and neutral pH and has a longer half-life (3 to 4 h) permitting continuous subcutaneous administration, avoiding the risks inherent to the delivery mode of epoprostenol. Although the distribution half-life of the drug is calculated to be approximately 40 min, it has been our experience that it takes at least 3 to 4 h after stopping the drug before symptoms occur. These are usually mild and have not resulted in serious hemodynamic compromise. In the largest multicenter, double-blind, placebo-controlled study12 in PAH, subcutaneous treprostinil improved exercise capacity measured by the 6-min walking distance (SMWD) and the Borg dyspnea scale. These changes were associated with improvements in New York Heart Association (NYHA) class and an index of clinical signs and symptoms. Interestingly, this study was the first to include other major causes of PAH such as CTD and CHD.12 Moreover, safe transitioning from long-term subcutaneous epoprostenol to subcutaneously infused treprostinil can be achieved over a short period of time, with persistent clinical benefit, albeit in well-selected patients.13
Whether the favorable outcomes observed with subcutaneous treprostinil can be maintained over time remains uncertain. Moreover, pain at the subcutaneous infusion site has been an important concern, potentially leading to treatment discontinuation. Therefore, the major objectives of this open-label, multicenter retrospective study were to analyze the long-term benefit of subcutaneously infused treprostinil on exercise capacity, functional status, and survival in a large population with PH of various etiologies.
Materials and Methods
Patients
From December 1998 to October 2003, 122 patients with PH were treated with subcutaneous treprostinil in three expert European centers, including patients participating in existing treprostinil trials and patients meeting clinical indications to receive drug therapy. All patients accepted to participate in the trial; informed consent was obtained before study initiation following a recommendation of the local ethics committees.
Patients with either PAH or distal CTEPH were considered for analysis. Diagnosis was established according to standard criteria, including a mean pulmonary artery pressure (PAPm) 
25 mm Hg at rest, a pulmonary capillary wedge pressure < 15 mm Hg, and a pulmonary vascular resistance > 3 Wood units. Patients with significant respiratory or left-heart disorder were excluded, as defined by radiographically significant parenchymal lung disease, total lung capacity < 60% predicted, or FEV1/FVC ratio < 50%, evidence of valvular heart disease, pericardial constriction, left ventricular dysfunction, renal dysfunction (serum creatinine 2.5 mg/dL), and uncontrolled sleep apnoea. No patient was a responder to high-dose oral calcium antagonist therapy.
Functional Assessment and Outcome
A baseline evaluation included a complete medical history and a physical examination, a SMWD according to international guidelines, and right-heart catheterization with an acute reversibility testing. Clinical status, NYHA class, and SMWD were assessed at 6-month intervals in all patients during the study period. Repeated right-heart catheterization was not mandatory and was available in a small subset of patients. Therapy-related effects such as subcutaneous infusion site pain were measured using a subjective, 11-point visual analog scale (from 0, no pain; to 10, severe pain). Self-management of the drug delivery system was also assessed.
Treatment and Dosing
On treatment initiation, all patients received a continuous subcutaneous infusion of treprostinil administered through a commercially available infusion pump (Minimed models 506 and 407C; Medronic; Minneapolis, MN). Treprostinil sodium was initiated in the hospital at a starting dose of 1.25 to 4 ng/kg/min and up-titrated in an outpatient setting at least once a week by dose increment of 1.25 ng/kg/min with a target dose of at least 20 ng/kg/min at 3 months. Further increments were essentially governed by symptom progression and/or side effects. All changes in conventional therapy were monitored and recorded.
Statistical Analysis
All analyses were performed on an intention-to-treat basis, and efficacy variables were assessed until < 25% of patients remained in the study. The changes over time were analyzed using a repeated-measures analysis of variance (PROC MIXED procedure; SAS Institute; Cary, NC) that takes into account missing values. For continuous parameters, changes from baseline were calculated for each patient at each time point. Data are presented as mean ± SE. The statistical significance of each change was tested using either a paired t test or a Wilcoxon signed-rank test as appropriate. Patients terminating therapy for any reason were considered treatment failures.
The date of subcutaneous treprostinil initiation was used as the index date for determining survival, which was calculated using Kaplan-Meier estimates. Treatment failure was used to determine event-free survival and was defined as one of the following: death, transplantation, hospitalization for clinical worsening, transition to IV epoprostenol, need for combination therapy, or atrial septostomy.
Results
Baseline Characteristics
Baseline demographic and hemodynamic characteristics are shown in Table 1
. Other etiologies included patients with Osler disease (n = 4), toxic oil syndrome (n = 5), and hepatitis C in the absence of cirrhosis (n = 1). PH included PAH (n = 99), iPAH and CHD being the leading causes, and CTEPH (n = 23). Despite lower PAPm at baseline in CTEPH patients, the two groups were comparable. Five CTEPH patients had undergone previous pulmonary thromboendarterectomy, with favorable hemodynamic outcome in three patients and persistent PH in the remaining patients. Eighteen patients were classified as inoperable based on the following: (1) a mismatch between the degree of hemodynamic compromise and the distality of most proximal thrombi, (2) type IV disease, and (3) severe comorbidities. Acute reversibility challenge was performed in all patients as part of the diagnostic evaluation; and responders, defined as patients with a drop of PAPm by > 10 mm Hg or < 40 mm Hg,14 accounted for 5.7% of the population. However, none of those turned out to be candidates for high-dose calcium-channel blocker therapy. Baseline therapy included anticoagulants (n = 116), diuretics (n = 108), digoxin (n = 45), low-dose calcium antagonists (n = 33), angiotensin-converting enzyme inhibitors (n = 7), theophylline (n = 4), angiotensin receptor blockers (n = 2), and dipyridamole (n = 1). No patients received other specific treatment for PAH, including sildenafil and bosentan, and six patients were awaiting transplantation.
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Safety and Tolerability
During the period of analysis, treatment was discontinued in 13 patients (10.6%) for reasons including clinical worsening with transition to IV epoprostenol (n = 4), cutaneous contact allergy to subcutaneously infused treprostinil (n = 1), depression (n = 1), and withdrawal of consent (n = 1); interestingly, only six patients (4.9%) discontinued treatment due to infusion site pain. Patients who transitioned to IV epoprostenol remained in NYHA functional class IV, and subsequently died (n = 2), or underwent lung transplantation.
As expected, infusion site pain was the most significant drug-related event, reported by 82% of patients (Table 2 ). However, symptoms were usually mild (mean score of 4.7 on the visual analog scale) and transient with 71.3% patients reporting a pain duration < 4 days. More importantly, 20% of patients were free of pain. Site pain was unpredictable, appeared less severe in patients within a stable social network, and did not appear to be dose related. Because pain starts on an average 2 to 3 days after the site change, it usually subsides 3 to 5 days after site change and disappears thereafter, patients classified overall pain with 5 ± 3.1 on the visual analog scale. Systemic pain medication was discouraged and not used long term by those patients remaining on therapy. Site changes were performed every 5 to 28 days, and patients changing less frequent than once per week appeared to have less pain.
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Survival Analysis
During study evaluation, 48 patients presented with at least one of the predetermined criteria for treatment failure. These included death (n = 31), transplantation (n = 5), and clinical worsening (n = 20) requiring an atrial septostomy (n = 7) and/or a combined therapy with either bosentan or sildenafil (n = 22). Two patients awaiting transplantation were taken off the list because of persistent clinical improvement. Death and clinical worsening occurred on average 13.4 ± 2.4 months and 15.7 ± 2.2 months after treatment initiation, respectively.
Survival rates by Kaplan Meier analysis reached 88.6%, 70.6%, and 65.6% after 1 year, 3 years, and 4 years, respectively (Fig 2 , top, A). The probability of event-free survival as defined above was similar to overall survival rate (Fig 2, center, B). Interestingly, survival rates were comparable in all groups when separated by etiology, suggesting that subcutaneously infused treprostinil therapy may provide a survival benefit irrespective of the cause of PH (Fig 2, bottom, C).
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This is the first study reporting the long-term effects of subcutaneous administration of treprostinil, a stable prostacyclin analog, in a large population of patients with severe PH. The results show that subcutaneously infused treprostinil improves functional state and exercise capacity, and may provide survival benefit across the whole spectrum of PAH and CTEPH. These effects were consistently maintained in the long term. Additionally, tolerance of subcutaneous treprostinil appeared better than previously reported.
Efficacy
The clinical benefit of a 12-week therapy with subcutaneously infused treprostinil has been demonstrated in a large randomized-controlled trial. Although the improvement in SMWD was moderate (+ 17 m vs baseline in the treated group), it was associated with significant changes in patients’ condition, assessed by a clinical score derived from major signs and symptoms of PAH.12 In addition, pain at the subcutaneous site hindered up-titration, resulting in underdosage of subcutaneously infused treprostinil and a dose-dependent effect. These long-term data clearly show that marked improvements are gained over the long term, and are sustained for the treatment duration with no loss of efficacy when the drug is up-titrated. Accordingly, our 12-month improvements of SMWDs by 73 m and Borg scores by 1.3 positively measure up to studies of similar duration with epoprostenol5615 or iloprost.16
CTEPH
The results are consistent across the whole spectrum of PH, including inoperable CTEPH and persisting PH after pulmonary endarterectomy (PEA). In these patients, no therapeutic recommendations have been established. The rationale to consider treating CTEPH and PAH with similar drug regimens is based on similar pathophysiologic and clinical features. CTEPH is believed to result from single or recurrent episodes of pulmonary embolism, leading to progressive obstruction of the pulmonary vascular bed.17 Even in patients with predominant proximal obstruction, vascular lesions of pulmonary arteriopathy exist in unobstructed zones and in more distal segments of the pulmonary vascular bed.18 Thus, significant PH can persist despite surgical correction, supporting the hypothesis of a downstream increase in resistance similar to PAH.19 Finally, the clinical courses of CTEPH and PAH are comparable in terms of clinical presentation, functional impairment, and prognosis.217
Although medical therapy for CTEPH has been limited, several reports have indicated that CTEPH patients can significantly benefit from vasodilator therapy. Patients have been bridged to PEA with IV epoprostenol,20 or treated on a compassionate-use basis.8 In a randomized controlled study21 with inhaled iloprost, 50 of 220 patients had distal CTEPH and apparently did not benefit from treatment. Furthermore, sildenafil has been shown to benefit patients with CTEPH.22 Our data are in keeping with these reports, supporting the hypothesis that medical therapy for PAH may be effective in CTEPH.
Safety
In this long-term trial, infusion site pain, the adverse event most commonly associated with subcutaneously infused treprostinil, did not cause significant medical problems. Only a small proportion of patients (4.9%) discontinued treatment due to this complication. Most cases were mild and transient, and appeared to be independent of subcutaneous treprostinil dose. Importantly, in our experience, diminishing the rate of site changes in the individual patient parallels a decrease in pain. In our study, the incidence of site-related infections or complications were minor and did not result in hospitalization or death. Cellulitis, abscesses, and bleeding were reported in 8.2%, 13.1%, and 7.4%, respectively, throughout the study, representing an infectious complication rate of 0.23 per patient and per year. Only 4% of abscesses required surgical drainage, whereas the majority was of minor clinical significance. For comparison, the infection and septicemia rates reported with central line catheters have been reported as 0.09 to 0.68 per patient per year, while septicemia rates can reach 0.39 per patient per year.2021222324
Survival
The natural history of iPAH is rapidly progressive, with a reported median survival rate < 3 years in the absence of appropriate therapy.2 Compared to conventional therapy, IV epoprostenol significantly improves the 3-month survival rate.4 Single-center observations confirm this positive effect both in iPAH56 and in PAH as a group of diseases.23 There is a significant benefit already achieved at 3 months compared to conventional treatment.4 The 4.5-year survival rates of 65.54% and 3.5-year event-free survival rates of 68.95% calculated in our trial compare favorably to long-term results with epoprostenol. Five-year iPAH survival rates with epoprostenol have been reported as 38 to 54%.5623 For comparison, these data56 have been plotted in comparison with subcutaneous treprostinil survival curves in Figure 3
. The observed survival rate in 32 iPAH patients treated with subcutaneous treprostinil was better than expected survival3 and close to previously reported data on iPAH receiving IV epoprostenol.5 Despite disparities in these two studies, the baseline hemodynamics of those latter 162 patients followed up with IV epoprostenol5 were similar to the iPAH patients in the present study, allowing for a comparison across studies (Fig 3). Recently, Gomberg-Maitland et al25 reported a two-times dose increase of IV treprostinil compared with IV epoprostenol for maintaining clinical symptom-oriented health status. Based on these data, one would have to assume underdosing of subcutaneously infused treprostinil in the patients of the present study. By contrast, we have found significant functional improvement (NYHA class and 6-min walking test). Moreover, our outcome results overlap with those observed with IV epoprostenol (Fig 3). One explanation may be a cumulative dosing effect that occurs due to the prolonged half-life of subcutaneously infused treprostinil.
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Conclusions
In summary, our data suggest that long-term subcutaneous treprostinil appears to be a safe and efficacious therapeutic option for a large majority of patients with PH of varying etiologies. Subcutaneously infused treprostinil may be a safe alternative to epoprostenol.
Acknowledgements
The authors thank Jackie Turner, Steve Dawber, Carl Sterritt, Georg Fischer, and Marie-Thérèse Gautier for their help in the preparation of this article.
Footnotes
Abbreviations: CHD = congenital heart disease; CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension; iPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PAPm = mean pulmonary artery pressure; PEA = pulmonary endarterectomy; PH = pulmonary hypertension; SMWD = 6-min walking distance
This study was funded in part via a grant from United Therapeutics Corporation, Research Triangle Park, NC, as patients from the original P1:06 trial were included.
Received for publication September 22, 2005. Accepted for publication December 12, 2005.
References
This article has been cited by other articles:
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  R. L. Benza, B. K. Rayburn, J. A. Tallaj, S. V. Pamboukian, and R. C. Bourge Treprostinil-Based Therapy in the Treatment of Moderate-to-Severe Pulmonary Arterial Hypertension: Long-term Efficacy and Combination With Bosentan Chest, July 1, 2008; 134(1): 139 - 145. [Abstract] [Full Text] [PDF]
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M. Rubenfire, V. V. McLaughlin, R. P. Allen, G. Elliott, M. H. Park, M. Wade, and R. Schilz Transition From IV Epoprostenol to Subcutaneous Treprostinil in Pulmonary Arterial Hypertension: A Controlled Trial Chest, September 1, 2007; 132(3): 757 - 763. [Abstract] [Full Text] [PDF]
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