JOURNAL CLUB
Roselle Almeida
AMBRISENTAN
Type A selective endothelin receptor antagonist
 Orally active, once daily

AIMS
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To study the efficacy and safety of Ambrisentan
in a
Diverse population of patients with PH
24 weeks of therapy
ENDPOINTS
Primary - 6MWD
 Secondary –
 BNP
 Borg dyspnea index
 WHO functional class
 Time to clinical worsening of PH and survival

PATIENTS
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Group I PAH -Idiopathic, familial PAH assoc
with CTD , CHF HIV ,, drugs and toxins, thyroid
disorders, glycogen storage disease, Gaucher’s
disease, hemoglobinopathies, or splenectomy;
Group 3 patients with PH associated with
chronic hypoxemia including COPD,ILD, sleepdisordered breathing, alveolar hypoventilation
disorders;
Group 4 patients with PH due to proximal or
distal chronic thromboembolic obstruction
Group 5 patients -sarcoidosis.
INCLUSION CRITERIA
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Mean PAP ≥25 mmHg, PVR >3 mmHg/L/min (240 dynes
seconds/cm5), and PCWP or LVEDP of <15 mmHg.
TLC ≥70% of predicted , fev1 ≥65%,
ILD/COPD - higher mean PAP>35 mmHg and a higher
PVR >3.5 mmHg/L/min; 280 dynes seconds/cm5
ILD =TLC ≥60% and COPD patients Fev1 ≥50%.
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6MWD 150 - 450 m at baseline.
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Previously discontinued bosentan or sitaxsentan due to
AST >3 ULN Or <3 × upper limit of normal at screening.
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On PAH therapies: chronic prostacyclin analog therapy (IV
epoprostenol,., IV or SC treprostinil, Remodulin or inhaled
iloprost, Ventavis or sildenafil (Revatio
STUDY DESIGN
Long-term
 open-label
 single-arm
 42 centers in the United States, Australia, and
Canada

Etiology
%
Idiopathic PAH/Familial PAH
31
CTD
18
Chronic thromboembolic obs
13
COPD
11
ILD
9
Drugs/toxins
6
Congenital heart disease
4
Sarcoidosis
3
HIV
2
Sleep disordered breathing
2
Others
1
PROS
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More diverse PH population
Increase in 6MWD observed in the subpopulation of PAH patients
receiving ambrisentan monotherapy was consistent with that
observed for similar PAH populations in the ARIES-1 and ARIES-2
6MWD results were observed in this study for PAH patients receiving
background sildenafil and/or chronic prostanoid therapy.
Increase in mean 6MWD for the proximal or distal chronic
thromboembolic obstruction subpopulation was suggestive of a
clinically relevant treatment effect.
Exercise capacity for the chronic obstructive pulmonary disease and
interstitial lung disease subgroups may have been limited by
progression
of the underlying lung disease
CONS
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Lack of a placebo or active comparator
Subgroup analyses were limited by the small
sample size
Large number of subjects who either
discontinued or had missing data
WHO functional class and the Borg dyspnea
index were suggestive of clinical benefit –
subjective
Last observation carried forward imputation- No
penalty for patients who died
LFTS
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Sitaxentan (ThelinTM), another endothelin
receptor antagonist indicated for the treatment of
PAH, was recently withdrawn from the market
due to the association with potentially life
threatening liver toxicity.
Increases in these tests have also been reported
with ambrisentan; however, in controlled studies
these events have occurred at rates less than
placebo events