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In this randomized trial involving 13,885 patients with symptomatic peripheral artery disease (PAD), ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates with ticagrelor and clopidogrel. Peripheral artery disease is considered to be a clinical manifestation of systemic atherosclerosis affecting the vascular territories supplying the lower limbs. Most patients presenting with peripheral artery disease do not have a clinical history of cardiac or cerebral ischemic events, yet these patients are at high risk for myocardial infarction, ischemic stroke, and cardiovascular death. 1 Concomitant clinical evidence of coronary or cerebrovascular disease only magnifies this risk. 2 Therapies to reduce the ischemic risk associated with atherosclerosis have focused on patients with acute coronary syndromes and stable coronary artery disease. Antithrombotic drugs, mainly antiplatelet therapies and statins, are the cornerstone of . . .

Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction–defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

Aims Despite receiving guideline‐directed medical heart failure (HF) therapy, patients with pulmonary hypertension associated with left heart disease (PH‐LHD) experience higher mortality and hospitalization rates than the general HF population. AZD3427 is a functionally selective, long‐acting mimetic of relaxin, a hormone that has the potential to induce vasodilation and prevent fibrosis. In a phase 1b study conducted in patients with HF, AZD3427 demonstrated a favourable safety and pharmacokinetic profile. To address the unmet medical need in patients with PH‐LHD in the context of HF, AZD3427 is currently under development as a potential treatment option. Methods and results The Re‐PHIRE study is a phase 2b, randomized, double‐blind, placebo‐controlled, multicentre, dose‐ranging study to evaluate the effect of AZD3427 on a broad range of PH‐LHD phenotypes. In total, 220 patients will be randomized to four treatment groups to receive a subcutaneous injection of AZD3427 or placebo every 2 weeks for 24 weeks. The primary endpoint of the study is the change in pulmonary vascular resistance in patients treated with AZD3427 versus placebo after 24 weeks of treatment. Key secondary endpoints include changes in mean pulmonary arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance, 6‐min walking distance, N‐terminal pro B‐type natriuretic peptide levels, echocardiographic parameters, and health‐related quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire). Conclusions Re‐PHIRE is the first study of a relaxin mimetic in patients with PH‐LHD. The insights gained from the Re‐PHIRE study are expected to inform the further development of AZD3427 in the PH‐LHD population, including identifying the most suitable pulmonary hypertension and HF phenotypes for treatment.