Original clinical science
Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension

https://doi.org/10.1016/j.healun.2012.02.025Get rights and content

Background

Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension.

Methods

Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m2). Treprostinil dose adjustments were driven by clinical symptoms and side effects.

Results

The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years.

Conclusion

First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

Section snippets

Patients and methods

The database used in this study has been under the auspices of the Ethics Committee of the Medical University of Vienna (#972/2009). Patients provided written informed consent. Patient disposition is shown in Figure 1.

Patient characteristics

Between June 1, 1999, and November 30, 2010, SC treprostinil was started in 111 patients with severe pre-capillary PH (Table 1). There was an 11.7% discontinuation rate due to side effects throughout the median observation time of 56 months (IQR, 31–91 months). At baseline by the WHO FC, 62 patients (56%) were classified as III and 49 (44%) as IV. PAH was present in 69 patients (62%), categorized by a diagnosis of IPAH in 33 (29.7%), PAH associated with congenital heart disease in 21 (18.9%),

Discussion

The ability to conduct large, prospective randomized controlled trials over years with morbidity and death as primary end points for PH is limited by patient numbers, economic constraints, and ethical constraints to using a placebo. Therefore, all information and evidence leading to novel drug approval have been based on 12- to 24-week studies and their open-label phases. This is a particular shortfall for SC treprostinil, demonstrating a between-treatment group difference in median 6MWD of

Disclosure statement

R.S.-K. has served as a paid consultant for AOPOrphan Pharmaceuticals AG and has received compensation for scientific symposia from Actelion, GlaxoSmithKline, and AOPOrphan Pharmaceuticals AG. N.S.-S. has served as a paid consultant for Actelion, Nycomed, Pfizer, GlaxoSmithKline, United Therapeutics Corporation, and AOPOrphan Pharmaceuticals AG and has received educational grants and compensations for scientific symposia from Actelion, Nycomed, Pfizer, GSK, United Therapeutics Corporation, and

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