PURPOSE: Current treatment approaches for pulmonary arterial hypertension (PAH) often entail observing deterioration in a patient on a single agent before instituting a second one. This strategy could be problematic, as patients may not recover function lost due to progressive PAH, and some have suggested that altering this paradigm to resemble that used in cancer chemotherapy may be more beneficial. This open-label pilot study is the first to investigate the potential safety and efficacy of a first-line combination strategy in PAH in contrast to an "add-on" strategy.
METHODS: Consecutive WHO class III patients with idiopathic and connective tissue disease (CTD) associated PAH were enrolled. Patients were included if hemodynamics were consistent with standard criteria for PAH with 6 minute walk test (6 MWT) distance between 150 and 450 m, and excluded for major comorbidities or prior exposure to PAH therapies. Bosentan 62.5 mg bid and sildenafil 20 mg tid were started simultaneously, with bosentan uptitrated at 4 weeks to 125 mg bid as per standard practice. Baseline and 4 month outcome measures included 6 MWT, resting hemodynamics, CAMPHOR quality of life questionnaires, and echocardiographic parameters.
RESULTS: Preliminary analysis of available data in the first 8 patients showed a mean age of 60 ± 18 years, with 3 IPAH and 5 CTD-PAH. Two patients experienced elevated liver enzymes within the first 9 weeks, with one having to withdraw from the protocol. 6 MWT improved by 53 m from 307 ± 105 m to 360 ± 129 m (p=0.04, n=6). The three domains of the CAMPHOR all showed a trend toward improvement, with symptom scores reaching significance at 8 months (13.4 ± 4.4 vs 3.5 ± 2.6, p=0.03). Pulmonary vascular resistance fell from 12 ± 4 to 7 ± 4 Wood units (p<0.01, n=5) and tricuspid annular plane systolic excursion (TAPSE) improved from 1.6 ± 0.5 to 1.9 ± 0.4 cm (p=0.01, n=6).
CONCLUSIONS: First-line oral combination therapy with bosentan and sildenafil was associated with improvements in 6 MWT, symptoms, and hemodynamic and echocardiographic parameters. This strategy appears to be relatively safe and well tolerated.
CLINICAL IMPLICATIONS: The magnitude and durability of clinical improvements and the risks of early hepatotoxicity remain unclear pending further patient enrolment and follow up. (ClinicalTrials.gov id#NCT01247116)
DISCLOSURE: Naushad Hirani: Grant monies (from industry related sources): Actelion, Gilead, United Therapeutics, Glaxo-Smith-Kline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Glaxo-Smith-Kline, Lilly
Doug Helmersen: Grant monies (from industry related sources): Actelion, Bayer, Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Glaxo-Smith-Kline, Pfizer
The following authors have nothing to disclose: Aiden Brazil, Tiffany Poon, Sid Viner, Mitesh Thakrar
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