PURPOSE: Clinical deterioration occurs in some patients with pulmonary arterial hypertension (PAH) despite treatment with a single drug. Targeting complimentary drug signalling pathways may increase overall treatment efficacy.
METHODS: We retrospectively analyzed the clinical outcomes of 40 patients at three of 82 participating sites enrolled in STRIDE-3(a long-term open-label trial evaluating the safety/efficacy of sitaxsentan 100mg qd in WHO Group 1 PAH) in whom sildenafil was combined with the selective endothelin-A receptor antagonist sitaxsentan.
RESULTS: Forty patients (idiopathic PAH, n=18; PAH associated with connective tissue disease, n=12; PAH associated with congenital heart disease, n=8; PAH associated with anorexigen use, n=1; chronic thromboembolic pulmonary hypertension, n=1)were treated with the combination of sitaxsentan and sildenafil (≥20mg tid). The reasons for combination therapy were: failure to meet treatment goals (in the opinion of the clinical investigator; 68%), worsening hemodynamics (8%) or decrease in six minute walk distance (6MWD) and/or WHO functional class (FC;24%). Mean duration of sitaxsentan treatment prior to the addition of sildenafil was 14.2 months. Six patients received sildenafil pre-sitaxsentan. At combination therapy initiation, 6MWD was 365±113m, pulmonary arterial pressure (mPAP), 50±18mmHg, right arterial pressure (mRAP), 8±5mmHg, cardiac index, 2.5±0.7L/min/m2, pulmonary vascular resistance (PVR), 1119±580dynes/s/cm5, with the majority of patients WHO FC III (56%) (FC II, 33%). Three months after combination therapy, 6MWD increased by 18±50m (p<0.05, n=37 with follow-up); in 18 patients with 12 month follow-up data, 6MWD remained increased versus pre-combination, i.e. 39±6m increase (p<0.05). Significant reductions in PVR (–82±150dynes/s/cm5) were seen in 16 patients re-catheterised at 4 months. WHO FC improved in 32% (n=6); was unchanged in 58% (n=11) and deteriorated in 11% (n=2) of patients after 12 months of combination treatment. One patient had hepatic transaminase >3xULN which resolved after 1 month without therapy interruption.
CONCLUSION: The combination of sildenafil with sitaxsentan therapy appears efficacious and well tolerated in patients with PAH.
CLINICAL IMPLICATIONS: The combination of sildenafil and sitaxsentan may improve patient outcomes versus either drug alone.
DISCLOSURE: Raymond Benza, Grant monies (from industry related sources) Research grants and honoraria from Gilead, United Therapeutics, Actelion and Encysive.; No Product/Research Disclosure Information