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Journal Club

Journal Club. Roselle Almeida. ARIES -3. Ambrisentan. Type A selective endothelin receptor antagonist Orally active, once daily. Aims. To study the efficacy and safety of Ambrisentan in a Diverse population of patients with PH 24 weeks of therapy. Endpoints. Primary - 6MWD

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Journal Club

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  1. Journal Club Roselle Almeida

  2. ARIES -3

  3. Ambrisentan • Type A selective endothelin receptor antagonist • Orally active, once daily

  4. Aims • To study the efficacy and safety of Ambrisentan in a Diverse population of patients with PH 24 weeks of therapy

  5. Endpoints • Primary - 6MWD • Secondary – • BNP • Borg dyspnea index • WHO functional class • Time to clinical worsening of PH and survival

  6. Patients • 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, sleep-disordered breathing, alveolar hypoventilation disorders; • Group 4 patients with PH due to proximal or distal chronic thromboembolic obstruction • Group 5 patients -sarcoidosis.

  7. Inclusion criteria • 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%. • 6MWD 150 - 450 m at baseline. • Previously discontinued bosentan or sitaxsentan due to AST >3 ULN Or <3 × upper limit of normal at screening. • On PAH therapies: chronic prostacyclinanalog therapy (IV epoprostenol,., IV or SC treprostinil, Remodulin or inhaled iloprost, Ventavis or sildenafil (Revatio

  8. Study Design • Long-term • open-label • single-arm • 42 centers in the United States, Australia, and Canada

  9. Pros • More diverse PH population • Increase in 6MWD observed in the subpopulation of PAH patients receiving ambrisentanmonotherapy 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

  10. Cons • 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

  11. LFTS • 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

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