Interaction of acenocoumarol and sitaxentan in pulmonary arterial hypertension T. Pulido, J. Sandoval, I. Roquet, R. Gutie ´ rrez, T. Rueda, H. Pen ˜ a, E. Santos, M. T. Miranda and E. Lupi National Heart Institute, Mexico City, Mexico ABSTRACT Background Sitaxentan inhibits the metabolism of warfarin, resulting in a need for adjustment of warfarin dose when both drugs are coadministered. We report the long-term effects on bleeding of acenocoumarol co-admin- istered as part of conventional therapy for pulmonary hypertension with sitaxentan in a subset of patients enrolled in the Sitaxentan To Relieve ImpaireD Exercise-3 (STRIDE-3) study. Materials and methods STRIDE-3 is an ongoing, long-term, open-label trial, evaluating the safety and efficacy of sitaxentan, 100 mg once daily, in patients with pulmonary arterial hypertension. Information on bleeding events was collected prospectively, including the type of event, severity, anticoagulant use and investigator attri- bution of causality. Coagulation tests were performed on a monthly basis. A clinically significant interaction was defined as an international normalized ratio (INR) ‡ 5Æ0, or any minor bleeding event plus an INR > 2Æ0 and < 5Æ0. Results Of 55 patients enrolled in STRIDE-3, 50 received acenocoumarol. Average follow-up was 158Æ6 ± 57Æ6 weeks. The average dose of anticoagulant therapy was 3Æ9±1Æ3 mg week )1 (range, 1Æ5–7Æ0 mg week )1 ). Following treatment, an INR ‡ 5 in at least one INR determination was observed in 13 patients, although none of these patients had a clinically significant bleeding event. Dose reductions in acenocoumarol were performed to adjust target INR to 1Æ5–2Æ0. Two patients died of massive haemoptysis, but these episodes were not attributed to a drug interaction. Four patients with an INR > 2Æ0 and < 5Æ0 experienced a minor bleeding event (nosebleeds ⁄ gingivitis). Conclusions No clinically significant bleeding events were recorded with coadministration of sitaxentan and acenocoumarol in this patient subgroup. These results suggest that coadministration of sitaxentan and acenocoumarol is clinically manageable and well tolerated. Keywords Acenocoumarol, pulmonary arterial hypertension, sitaxentan. Eur J Clin Invest 2009; 39 (S2): 14–18 Introduction Pulmonary arterial hypertension (PAH) is a group of chronic diseases that affect small pulmonary vessels, characterized by progressive increases in pulmonary vascular resistance and pulmonary arterial pressure (PAP) and resulting in right ventricular failure and pre-mature death [1]. Current evidence suggests that abnormalities of blood coagulation factors, antithrombotic factors and the fibrinolytic system contribute to a prothrombotic state in patients with PAH [2]. The rationale for the use of oral anticoagulant treatment in patients with PAH is based on the presence of traditional risk factors for venous thromboembolism (i.e. heart failure and sedentary lifestyle), as well as the demonstration of thrombophilic pre-disposition, thrombotic changes in the pulmonary microcirculation and in the elastic pulmonary arteries [1,3,4]. In a retrospective analysis, Fuster et al. showed a better prognosis in patients with primary pulmonary hypertension who were receiving anticoagulation therapy in addition to conventional This paper forms part of the supplement entitled ‘Update on endothe- lin-related diseases’. It is related to discussions at the workshop ‘Endothelin-related diseases’ at 42nd Annual Scientific Meeting of the European Society for Clinical Investigation (ESCI) in Geneva, Switzer- land, 26–29 March 2008. The workshop and the production costs of the present supplement were supported with an unrestricted Educational Grant from Encysive Pharmaceuticals Inc. In June 2008, Encysive was acquired by Pfizer Inc who funded the publication and formatting costs of this supplement. The study was funded by Encysive. Thomas Stringer and Tracy Johnson formatted the manuscript according to the journal’s style requirements. 14 European Journal of Clinical Investigation Vol 39 DOI: 10.1111/j.1365-2362.2009.02116.x ORIGINAL ARTICLE