added 2 research items
Pulmonary vascular diseases
PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease with a median survival of 2.8 years from diagnosis. Recently, the development of target-specific drugs including endothelin receptor antagonists, have improved time to clinical worsening and survival in patients with PAH. Sitaxsentan is a highly-selective endothelin-A receptor antagonist with proven efficacy in exercise capacity and quality of life in patients with PAH; however, limited data are available on the long-term survival of patients with PAH treated with this drug. Within our center in Mexico City, we sought to evaluate the effects on survival of long-term treatment with sitaxsentan, in a subset of patients from the STRIDE-3 trial. METHODS: STRIDE-3, is an ongoing, open-label trial evaluating the long-term safety of sitaxsentan 100mg qd in PAH. Survival was assessed in patients treated with sitaxsentan for up to 4 years and rates compared with predicted survival according to the NIH equation at 1, 2 and 3 years. RESULTS: Thirtysix patients with PAH from our department, who were included in STRIDE-3, were analysed. Of these, 33 were diagnosed with idiopathic PAH and 3 with PAH associated with connective tissue disease (mPAP 66±22mmHg, RAP 9.7±6mmHg, CI 2.6±0.9L/min/m2). All 36 patients (30 females, age range 30±11years) were treated with sitaxsentan 100mg qd long-term plus conventional therapy (mean time 148±54weeks; range 26−220weeks). At baseline, patients were in WHO functional class II, n=31; or III, n=5, and 6 minute walk distance was 320±98m. After treatment with sitaxsentan, cumulative survival in patients was 96%, 79% and 75% at 1, 2 and 3 years, respectively, versus predicted survival of 71%, 60% and 50%, based on the NIH equation (p<0.05). Four patients withdrew voluntarily from the study (withdrawal was not drug related). Five patients required combination therapy (sildenafil) because of clinical deterioration and 18 patients remain on sitaxsentan monotherapy at 3 years. CONCLUSION: Sitaxsentan improves long-term survival in patients with PAH in WHO functional class II and III. CLINICAL IMPLICATIONS: Sitaxsentan monotherapy is another option for target-specific treatment of pulmonary arterial hypertension. DISCLOSURE: Tomas Pulido, Grant monies (from industry related sources) The author has been a principal investigator for some of the STRIDE studies and his institution has received research grants from Encysive.; No Product/Research Disclosure Information
Until recent years, pulmonary arterial hypertension was considered as an untreatable disease. However, with the better knowledge in its pathobiology, new drugs have been developed. These new drugs can be divided in three main groups: 1. Prostacyclin analogs (Epoprostenol, iloprost, treprostinil); 2. Endothelin antagonists (Bosentan, sitaxsentan); and 3. Phosphodiesterase-5 inhibitors (Sildenafil). Numerous studies have evaluated the safety and efficacy of these drugs, showing significant improvement in exercise capacity, quality of life and time to worsening. Some of them have even showed a better survival when compared with conventional treatment. Despite these advances, pulmonary arterial hypertension remains an incurable disease, so the focus of new studies is the combination of two or more drugs with a different mechanism of action.
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-administered 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. 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 attribution of causality. Coagulation tests were performed on a monthly basis. A clinically significant interaction was defined as an international normalized ratio (INR) >/= 5.0, or any minor bleeding event plus an INR > 2.0 and < 5.0. Of 55 patients enrolled in STRIDE-3, 50 received acenocoumarol. Average follow-up was 158.6 +/- 57.6 weeks. The average dose of anticoagulant therapy was 3.9 +/- 1.3 mg week(-1) (range, 1.5-7.0 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 1.5-2.0. Two patients died of massive haemoptysis, but these episodes were not attributed to a drug interaction. Four patients with an INR > 2.0 and < 5.0 experienced a minor bleeding event (nosebleeds/gingivitis). 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.
Idiopathic pulmonary hypertension (IPH), formerly known as primary pulmonary hypertension (PPH), is one of the most severe forms of pulmonary hypertension and is included as part of a group of disorders known as pulmonary arterial hypertension (PAH). The term IPAH refers to elevation of pulmonary pressure with no apparent cause; it is a chronic and progressive disease with a median survival, before the advent of specific targeted therapy, of 2.8 years, its incidence is about 1–2 cases per million people per year with a prevalence of 13.5 cases per million people per year in the United States and 6.5 cases per million per year in France. It is most commonly seen in women (male:female ratio of 1:2–2.9) of childbearing age but can occur in either gender and at any age.1-3