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Beraprost Therapy for Pulmonary Arterial Hypertension - Beraprost Therapy for Pulmonary Arterial Hypertension
Description:
The goal of the trial was to evaluate the effect of beraprost on disease progression, exercise capacity, hemodynamics, and quality of life over one year of therapy among patients with World Health Organization (WHO) functional class II or III pulmonary arterial hypertension (PAH).
Hypothesis:
Treatment with beraprost will reduce disease progression and increase exercise capacity, hemodynamics, and quality of life among patients with PAH.
Study Design
Study Design:
Patients Enrolled: 116
Mean Follow Up: 12 months
Mean Patient Age: mean age 42 years
Female: 85%
Patient Populations:
Baseline peak VO2 during exercise between 8 and 28 ml/kg/min determined during upright cycle ergometry, a resting mean pulmonary artery pressure ≥25 mm Hg, mean pulmonary capillary wedge pressure ≤15 mm Hg, and pulmonary vascular resistance >3 U
Exclusions:
Started or stopped any PAH therapy within one month before screening
Primary Endpoints:
Composite endpoint of disease progression, defined as death, transplantation, epoprostenol rescue, or >25% decrease in peak VO2
Secondary Endpoints:
Exercise capacity assessed by six-minute walk test and peak VO2, Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life
Drug/Procedures Used:
Patients were randomized to the maximal tolerated dose of beraprost sodium (median dose 120 μg four times per day; n=60) or placebo (n=56) for 12 months.
Principal Findings:
The study was stopped early by the sponsor after all patients had nine months of follow-up in order to accelerate assessment of the study results. Data were available for 93% of patients through 12 months. The primary endpoint of disease progression was lower in the beraprost arm compared with placebo at six months (1.7% vs. 19.6%, p=0.002), but did not differ at three months (0% vs. 5.4%, p=0.109), nine months (13.3% vs. 26.8%, p=0.102), or 12 months (17.9% vs. 28.8%, p=0.254). There was no difference in the median change from baseline in peak oxygen consumption (VO2) during exercise between the beraprost arm and placebo arm at three months (median difference 35.4, p=0.125), six months (39.6, p=0.204), nine months (57.0, p=0.160), and 12 months (66.0, p=0.084).
Distance walked during six minutes was significantly further in the beraprost group than the placebo group at month three (median difference 22 m, p=0.010) and month six (31 m, p=0.016), but did not differ at either month nine (p=0.098) or 12 (p=0.180). Borg dyspnea score did not differ significantly at any timepoint, nor did hemodynamic parameters or quality of life. Among adverse events, headache, jaw pain, vasodilation (flushing), diarrhea, and palpitations occurred significantly more frequently in the beraprost arm.
Interpretation:
Among patients with WHO functional class II or III PAH, beraprost was associated with a reduction in the primary endpoint of disease progression at six months, but not at three, nine, or 12 months. The secondary endpoint of six-minute walk distance was also improved at six months but not the later timepoints, indicating beraprost therapy may have early benefit during treatment, but the benefit diminishes over time.
A similar early benefit occurred with beraprost therapy in patients with PAH in the ALPHABET study, which showed an improvement in three-month exercise capacity. Despite the early benefits, patients in the present study who were treated with beraprost had increases in several adverse events.
References:
Barst RJ, McGoon M, McLaughlin V, et al., for the Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2119-25.
Keywords: Epoprostenol, Vasodilation, Follow-Up Studies, Pulmonary Wedge Pressure, Ergometry, Diarrhea, Dyspnea, Headache, Oxygen Consumption, Quality of Life, Hypertension, Pulmonary, Vascular Resistance, Maximum Tolerated Dose, Disease Progression
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