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Upfront Combination Therapy With Ambrisentan and TadalafilIin Treatment Naive Patients With Pulmonary Arterial Hypertension (PAH): Subgroup Analyses by Functional Class (FC), Etiology, and Region From the AMBITION Study
October 2014, Vol 146, No. 4_MeetingAbstracts
Critical Care | October 2014
Upfront Combination Therapy With Ambrisentan and TadalafilIin Treatment Naive Patients With Pulmonary Arterial Hypertension (PAH): Subgroup Analyses by Functional Class (FC), Etiology, and Region From the AMBITION Study Lewis Rubin, MD; Joan Barbera, MD; Adaani Frost, MD; Hossein-Ardeschir Ghofrani, MD; Marius Hoeper, MD; Vallerie McLaughlin, MD; Andrew Peacock, MD; Gerald Simonneau, MD; Jean-Luc Vachiery, MD; Hunter Gillies, MD; Christiana Blair, MS; Julia Harris, MS; Jonathan Langley, MS; Nazzareno Galie, MD Gilead Sciences, Foster City, CA
Chest. 2014;146(4_MeetingAbstracts):339A. doi:10.1378/chest.2056519
Abstract SESSION TITLE: Late-Breaking Abstracts SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 28, 2014 at 08:45 AM - 10:00 AM PURPOSE: In AMBITION, combination therapy with ambrisentan and tadalafil significantly improved the primary endpoint of time to clinical failure (TcF) compared to monotherapy, with a reduction in risk of 50% (HR 0.502, 95% CI: 0.348, 0.724; P=0.0002). Since the responses to therapy by clinical characteristics may be useful in identifying populations most likely to benefit from upfront combination therapy, we performed a pre-specified subgroup analysis of TcF by FC, disease etiology, geographic region, age, gender and baseline walk distance.
METHODS: 500 PAH patients were randomized to upfront combination therapy (n=253) or monotherapy with ambrisentan 10mg (n=126) or tadalafil 40 mg (n=121) once daily. Hazard ratios (HR; 95% confidence intervals) were calculated using Cox proportional hazards regression modeling to determine the effect of combination therapy versus pooled monotherapy in patients within the subgroups described. RESULTS: Of the 500 patients 56% were I/HPAH and 44% were APAH, 31% were FC II and 69% were FC III, and 46% were from North America (NA) and 54% were from rest of world (ROW); 78% were female; 32% were ≥65 years in age; and median baseline walk distance was 364 m. For the comparison of combination to pooled monotherapy, the TcF HR for NA was 0.505 (95% CI: 0.295, 0.866) and 0.506 (95% CI: 0.307, 0.834) for ROW; for age <65 years HR was 0.524 (95% CI: 0.322, 0.852) and 0.454 (95% CI: 0.260, 0.792) for age ≥65 years; for females HR was 0.473 (95% CI: 0.308, 0.726) and 0.581 (95% CI: 0.283, 1.194) for males; for baseline walk <364 m HR was 0.537 (95% CI: 0.349, 0.827) and 0.380 (95% CI: 0.187, 0.769) for baseline walk ≥364 m. The HR for FC and etiology will also be presented as well as safety and tolerability. The benefit risk profile will be presented.
CONCLUSIONS: Upfront combination of ambrisentan and tadalafil consistently outperformed pooled monotherapy on the endpoint of TcF across a variety of subgroups.
CLINICAL IMPLICATIONS: This consistent outperformance of upfront combination therapy of ambrisentan and tadalafil suggests that this approach may be beneficial across a variety of PAH patients as described. DISCLOSURE: Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: http://www.vice.com/read/curtis-snow-is-trying-to-go-legit, Consultant fee, speaker bureau, advisory committee, etc.: Giliead, United Therapeutics, Actelion, GeNO Marius Hoeper: Consultant fee, speaker bureau, advisory committee, etc.: "Consultation fees from Actelion Consultation fees from Bayer Consultation fees from GSK Consultation fees from Pfizer", Consultant fee, speaker bureau, advisory committee, etc.: "Speaker fees from Actelion Speaker fees from Bayer Speaker fees from GSK Speaker fees from Pfizer" Vallerie McLaughlin: University grant monies: "Research grants to University of Michigan for participation in multicenter clinical trials-Actelion, Research grants to University of Michigan for participation in multicenter clinical trials-Bayer Research grants to University of Michigan for participation in multicenter clinical trials-Ikaria Research grants to University of Michigan for participation in multicenter clinical trials-Novartis", Consultant fee, speaker bureau, advisory committee, etc.: "Consulting fees and travel related expenses-Actelion Consulting fees and travel related expenses-Bayer Consulting fees and travel related expenses-Gilead Consulting fees and travel related expenses-United Therapeutics" Hunter Gillies: Employee: I am an employee of Gilead Sciences Inc. Christiana Blair: Employee: I am currently employeed by Gilead Sciences and I own Gilead Sciences stock. Jonathan Langley: Employee: I am an employee of Gilead Sciences Inc. The following authors have nothing to disclose: Joan Barbera, Adaani Frost, Hossein-Ardeschir Ghofrani, Andrew Peacock, Gerald Simonneau, Jean-Luc Vachiery, Julia Harris, Nazzareno Galie No Product/Research Disclosure Information
Critical Care | October 2014
Upfront Combination Therapy With Ambrisentan and TadalafilIin Treatment Naive Patients With Pulmonary Arterial Hypertension (PAH): Subgroup Analyses by Functional Class (FC), Etiology, and Region From the AMBITION Study Lewis Rubin, MD; Joan Barbera, MD; Adaani Frost, MD; Hossein-Ardeschir Ghofrani, MD; Marius Hoeper, MD; Vallerie McLaughlin, MD; Andrew Peacock, MD; Gerald Simonneau, MD; Jean-Luc Vachiery, MD; Hunter Gillies, MD; Christiana Blair, MS; Julia Harris, MS; Jonathan Langley, MS; Nazzareno Galie, MD Gilead Sciences, Foster City, CA
Chest. 2014;146(4_MeetingAbstracts):339A. doi:10.1378/chest.2056519
Abstract SESSION TITLE: Late-Breaking Abstracts SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 28, 2014 at 08:45 AM - 10:00 AM PURPOSE: In AMBITION, combination therapy with ambrisentan and tadalafil significantly improved the primary endpoint of time to clinical failure (TcF) compared to monotherapy, with a reduction in risk of 50% (HR 0.502, 95% CI: 0.348, 0.724; P=0.0002). Since the responses to therapy by clinical characteristics may be useful in identifying populations most likely to benefit from upfront combination therapy, we performed a pre-specified subgroup analysis of TcF by FC, disease etiology, geographic region, age, gender and baseline walk distance.
METHODS: 500 PAH patients were randomized to upfront combination therapy (n=253) or monotherapy with ambrisentan 10mg (n=126) or tadalafil 40 mg (n=121) once daily. Hazard ratios (HR; 95% confidence intervals) were calculated using Cox proportional hazards regression modeling to determine the effect of combination therapy versus pooled monotherapy in patients within the subgroups described. RESULTS: Of the 500 patients 56% were I/HPAH and 44% were APAH, 31% were FC II and 69% were FC III, and 46% were from North America (NA) and 54% were from rest of world (ROW); 78% were female; 32% were ≥65 years in age; and median baseline walk distance was 364 m. For the comparison of combination to pooled monotherapy, the TcF HR for NA was 0.505 (95% CI: 0.295, 0.866) and 0.506 (95% CI: 0.307, 0.834) for ROW; for age <65 years HR was 0.524 (95% CI: 0.322, 0.852) and 0.454 (95% CI: 0.260, 0.792) for age ≥65 years; for females HR was 0.473 (95% CI: 0.308, 0.726) and 0.581 (95% CI: 0.283, 1.194) for males; for baseline walk <364 m HR was 0.537 (95% CI: 0.349, 0.827) and 0.380 (95% CI: 0.187, 0.769) for baseline walk ≥364 m. The HR for FC and etiology will also be presented as well as safety and tolerability. The benefit risk profile will be presented.
CONCLUSIONS: Upfront combination of ambrisentan and tadalafil consistently outperformed pooled monotherapy on the endpoint of TcF across a variety of subgroups.
CLINICAL IMPLICATIONS: This consistent outperformance of upfront combination therapy of ambrisentan and tadalafil suggests that this approach may be beneficial across a variety of PAH patients as described. DISCLOSURE: Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: http://www.vice.com/read/curtis-snow-is-trying-to-go-legit, Consultant fee, speaker bureau, advisory committee, etc.: Giliead, United Therapeutics, Actelion, GeNO Marius Hoeper: Consultant fee, speaker bureau, advisory committee, etc.: "Consultation fees from Actelion Consultation fees from Bayer Consultation fees from GSK Consultation fees from Pfizer", Consultant fee, speaker bureau, advisory committee, etc.: "Speaker fees from Actelion Speaker fees from Bayer Speaker fees from GSK Speaker fees from Pfizer" Vallerie McLaughlin: University grant monies: "Research grants to University of Michigan for participation in multicenter clinical trials-Actelion, Research grants to University of Michigan for participation in multicenter clinical trials-Bayer Research grants to University of Michigan for participation in multicenter clinical trials-Ikaria Research grants to University of Michigan for participation in multicenter clinical trials-Novartis", Consultant fee, speaker bureau, advisory committee, etc.: "Consulting fees and travel related expenses-Actelion Consulting fees and travel related expenses-Bayer Consulting fees and travel related expenses-Gilead Consulting fees and travel related expenses-United Therapeutics" Hunter Gillies: Employee: I am an employee of Gilead Sciences Inc. Christiana Blair: Employee: I am currently employeed by Gilead Sciences and I own Gilead Sciences stock. Jonathan Langley: Employee: I am an employee of Gilead Sciences Inc. The following authors have nothing to disclose: Joan Barbera, Adaani Frost, Hossein-Ardeschir Ghofrani, Andrew Peacock, Gerald Simonneau, Jean-Luc Vachiery, Julia Harris, Nazzareno Galie No Product/Research Disclosure Information