PURPOSE: Ambrisentan is an ETA-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH). We examined the changes in several clinical parameters following 24 weeks of ambrisentan given to PAH patients with a suboptimal response to phosphodiesterase-5 inhibitor (PDE5i) therapy.
METHODS: This was an open-label efficacy and safety study. Entry criteria included WHO functional class III and pulmonary vascular resistance (PVR) ≥ 400 dyne.sec/cm5. Patients received 5mg ambrisentan once-daily for 4 weeks with a dose increased to 10mg once-daily for an additional 20 weeks. The primary endpoint was change from baseline in PVR at Week 24. Additional endpoints included 6-minute walk distance (6MWD), Borg Dyspnea Index (BDI), and NT-pro B-type natriuretic peptide (NT-proBNP).
RESULTS: Thirty-three subjects were recruited. At baseline, PVR was 761±307 dyne.sec/cm5, mean pulmonary arterial pressure (mPAP) was 50±10 mmHg, cardiac index was 2.5±0.7 L/min/m2, and mean right atrial pressure (mRAP) was 8.5±4.8 mmHg. Improvements were observed for PVR (-249 dyne.sec/cm5, 95% CI: -338 to -160; p<0.0001), mPAP (-5.4, 95% CI: -8.3 to -2.5; p=0.0007), and cardiac index (+0.58 L/min/m2, 95% CI: 0.25 to 0.90; p=0.0011). mRAP was unchanged (-0.06 mmHg, 95% CI: -1.7 to 1.6; p= 0.936). At baseline, 6MWD was 362±99 m, BDI scores were 3.7±2.1, and NT-proBNP was 717±618 ng/L. Improvements were observed for 6MWD (+18 m, 95% CI: 0.5 to 36; p=0.0437), BDI (-0.9, 95% CI: -1.5 to -0.2; p= 0.0097), and NT-pro BNP (-31%, 95% CI: -49% to -17%; p=0.0216). No patients died and one patient experienced clinical worsening. The most frequent adverse events were nasal congestion (30%), headache (21%) and peripheral edema (18%).
CONCLUSIONS: Addition of ambrisentan therapy to PAH patients with a sub-optimal response to PDE5i therapy was well tolerated and provided clinically relevant improvements in hemodynamic parameters (mPAP, cardiac index and PVR) and 6MWD over 24 weeks.
CLINICAL IMPLICATIONS: In PAH patients with an inadequate response to PDE5i therapy alone, adding ambrisentan may improve hemodynamics and exercise ability.
DISCLOSURE: Ronald Oudiz: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Bayer, Biomarin, Eli Lilly, Gilead, Pfizer, LungRx, United Therapeutics, Grant monies (from industry related sources): Actelion, Bayer, Biomarin, Eli Lilly, Gilead, Pfizer, LungRx, United Therapeutics
S. Shapiro: Grant monies (from industry related sources): Gilead, United Therapeutics, Actelion, Bayer, Medtronics, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, United Therapeutics, Novartis, Actelion, GeNO
F. Torres: Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Actelion, Pfizer, Novartis, GeNo, Bayer, United Therapeutics
J. Feldman: Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Gilead
A. Frost: Grant monies (from industry related sources): Gilead, Actelion, Bayer, Novartis, Lilly, United Therapeutics, Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Bayer, Novartis, Pfizer, United Therapeutics
M. Allard: Employee: Gilead Sciences. Inc.
C. Blair: Employee: Gilead Sciences Inc.
H. Gillies: Employee: Gilead Sciences Inc.
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