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The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme. MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST-elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70–100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50–70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all-cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01433627. Between Oct 11, 2011, and Nov 7, 2014, we randomly assigned 8404 patients to receive radial (4197 patients) or femoral (4207 patients) access. Of these 8404 patients, 7213 were included in the MATRIX antithrombin type study and were randomly assigned to bivalirudin (3610 patients) or heparin (3603 patients). Patients assigned to bivalirudin were included in the MATRIX treatment duration study, and were randomly assigned to post-procedure infusion (1799 patients) or no post-procedure infusion (1811 patients). At 1 year, major adverse cardiovascular events did not differ between patients assigned to radial access compared with those assigned to femoral access (14·2% vs 15·7%; rate ratio 0·89, 95% CI 0·80–1·00; p=0·0526), but net adverse clinical events were fewer with radial than with femoral access (15·2% vs 17·2%; 0·87, 0·78–0·97; p=0·0128). Compared with heparin, bivalirudin was not associated with fewer major adverse cardiovascular (15·8% vs 16·8%; 0·94, 0·83–1·05; p=0·28) or net adverse clinical events (17·0% vs 18·4%; 0·91, 0·81–1·02; p=0·10). The composite of urgent target vessel revascularisation, stent thrombosis, or net adverse clinical events did not differ with or without post-procedure bivalirudin infusion (17·4% vs 17·4%; 0·99, 0·84–1·16; p=0·90). In patients with acute coronary syndrome, radial access was associated with lower rates of net adverse clinical events compared with femoral access, but not major adverse cardiovascular events at 1 year. Bivalirudin with or without post-procedure infusion was not associated with lower rates of major adverse cardiovascular events or net adverse clinical events. Radial access should become the default approach in acute coronary syndrome patients undergoing invasive management. Italian Society of Invasive Cardiology, The Medicines Company, Terumo, amd Canada Research Chairs Programme.

Patients with acute heart failure who received ularitide had greater reductions in systolic blood pressure and in levels of N-terminal pro–brain natriuretic peptide than those receiving placebo but had no improvement in cardiovascular mortality. Acute presentation with new-onset heart failure and rapid worsening of preexisting heart failure are two of the most common causes of hospitalization worldwide. 1 The disorder in each case is characterized by intravascular volume expansion and ventricular distention, which may cause myocardial injury in the absence of coronary artery disease or occlusion. 2 – 4 Episodes are associated with an accelerated rate of disease progression; each hospitalization for heart failure increases the risk of subsequent admissions as well as the risk of death from cardiovascular causes. 5 The first few hours after the initial presentation with acute heart failure may represent a period of . . .

In 7213 patients with an acute coronary syndrome, the rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin. Post-PCI bivalirudin infusion did not reduce the risk of stent thrombosis. The most effective antithrombotic regimen for preventing ischemic complications while limiting bleeding risk in patients with an acute coronary syndrome who are undergoing invasive treatment remains unknown. 1 – 3 Two of the most commonly used antithrombotic regimens worldwide 4 , 5 are unfractionated heparin, an indirect thrombin inhibitor, with or without the concomitant use of a glycoprotein IIb/IIIa inhibitor, and bivalirudin, a direct thrombin inhibitor, with a glycoprotein IIb/IIIa inhibitor added only for periprocedural ischemic complications. Previous studies that have compared these two options among patients who were undergoing invasive treatment for an acute coronary syndrome have provided conflicting results with respect to . . .

Patients undergoing PCI for acute myocardial infarction were randomly assigned to heparin or bivalirudin anticoagulation. There was no significant difference between the two strategies in the rate of the composite of death, myocardial infarction, or major bleeding.

This trial compared the combination of abciximab and unfractionated heparin with bivalirudin in patients with non–ST-segment elevation MI who were undergoing coronary stenting. The two regimens had similar efficacy, but there was more bleeding with abciximab and heparin. An invasive strategy of coronary angiography, with revascularization when appropriate, is recommended for high-risk patients who have an acute coronary syndrome. 1 , 2 Owing to the key role that the rupture of an atherosclerotic plaque, which is highly prothrombotic, plays in the pathogenesis of these syndromes, 3 identifying the most appropriate adjunctive antithrombotic therapy before, during, and after percutaneous coronary intervention (PCI) has been the target of extensive research for the past three decades. Abciximab is a glycoprotein IIb/IIIa inhibitor with potent platelet-antiaggregative effects. 4 Although the administration of abciximab during PCI was not associated with a clinical benefit in patients in stable . . .

In a randomized trial, 2218 patients with STEMI were assigned to prehospital treatment with either bivalirudin or heparin with optional glycoprotein IIb/IIIa inhibitors. At 30 days, the bivalirudin group had significantly less major bleeding than the heparin group. Primary percutaneous coronary intervention (PCI), which is the standard of care for the treatment of patients with ST-segment elevation myocardial infarction (STEMI), 1 , 2 requires adjunctive antithrombotic treatment with anticoagulants and antiplatelet agents. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 3 bivalirudin (Angiomax, Angiox, the Medicines Company), as compared with unfractionated heparin and routine use of glycoprotein IIb/IIIa inhibitors, reduced rates of major bleeding and death at 30 days, with a survival benefit that extended to 3 years, 4 albeit with an increased rate of acute stent thrombosis. A number of changes have occurred in clinical . . .

We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m2, 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m2 orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] vs 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ22df=4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Cancer Research UK and KAEL-GemVax.

Bivalirudin is a direct thrombin inhibitor. As compared with a combination of heparin and a glycoprotein IIb/IIIa inhibitor, bivalirudin use resulted in less bleeding and lower 30-day mortality among patients undergoing PCI for acute myocardial infarction. However, bivalirudin was associated with a higher rate of acute stent thrombosis within 24 hours. As compared with a combination of heparin and a glycoprotein IIb/IIIa inhibitor, bivalirudin use resulted in less bleeding and lower 30-day mortality among patients undergoing PCI for acute myocardial infarction. However, bivalirudin was associated with a higher rate of acute stent thrombosis within 24 hours. Primary percutaneous coronary intervention (PCI) in patients with evolving ST-segment elevation myocardial infarction decreases infarct size and the rates of recurrent ischemia, reinfarction, and stroke and improves survival, as compared with pharmacologic reperfusion therapy. 1 , 2 Nonetheless, the prognosis after primary PCI has remained essentially unchanged over the past decade, with neither stents nor other novel devices or drugs improving survival beyond that achievable with balloon angioplasty alone. 3 – 8 Treatment with glycoprotein IIb/IIIa inhibitors may decrease the short- and long-term risk of death, 9 , 10 and these agents are used in more than 90% of patients who undergo primary PCI in the . . .

In the HORIZONS-AMI trial, patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) who were treated with the thrombin inhibitor bivalirudin had substantially lower 30-day rates of major haemorrhagic complications and net adverse clinical events than did patients assigned to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). Here, we assess whether these initial benefits were maintained at 1 year of follow-up. Patients aged 18 years or older were eligible for enrolment in this multicentre, open-label, randomised controlled trial if they had STEMI, presented within 12 h after the onset of symptoms, and were undergoing primary PCI. 3602 eligible patients were randomly assigned by interactive voice response system in a 1:1 ratio to receive bivalirudin (0·75 mg/kg intravenous bolus followed by 1·75 mg/kg per h infusion; n=1800) or heparin plus a GPI (control; 60 IU/kg intravenous bolus followed by boluses with target activated clotting time 200–250 s; n=1802). The two primary trial endpoints were major bleeding and net adverse clinical events (NACE; consisting of major bleeding or composite major adverse cardiovascular events [MACE; death, reinfarction, target vessel revascularisation for ischaemia, or stroke]). This prespecified analysis reports data for the 1-year follow-up. Analysis was by intention to treat. Patients with missing data were censored at the time of withdrawal from the study or at last follow-up. This trial is registered with ClinicalTrials.gov, number NCT00433966. 1-year data were available for 1696 patients in the bivalirudin group and 1702 patients in the control group. Reasons for participant dropout were loss to follow-up and withdrawal of consent. The rate of NACE was lower in the bivalirudin group than in the control group (15·6% vs 18·3%, hazard ratio [HR] 0·83, 95% CI 0·71–0·97, p=0·022), as a result of a lower rate of major bleeding in the bivalirudin group (5·8% vs 9·2%, HR 0·61, 0·48–0·78, p<0·0001). The rate of MACE was similar between groups (11·9% vs 11·9%, HR 1·00, 0·82–1·21, p=0·98). The 1-year rates of cardiac mortality (2·1% vs 3·8%, HR 0·57, 0·38–0·84, p=0·005) and all-cause mortality (3·5% vs 4·8%, HR 0·71, 0·51–0·98, p=0·037) were lower in the bivalirudin group than in the control group. In patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus a GPI. This finding has important clinical implications for the selection of optimum treatment strategies for patients with STEMI. Cardiovascular Research Foundation, with unrestricted grant support from Boston Scientific Corporation and The Medicines Company.

Primary results of the HORIZONS-AMI trial have been previously reported. In this final report, we aimed to assess 3-year outcomes. HORIZONS-AMI was a prospective, open-label, randomised trial undertaken at 123 institutions in 11 countries. Patients aged 18 years or older were eligible for enrolment if they had ST-segment elevation myocardial infarction (STEMI), presented within 12 h after onset of symptoms, and were undergoing primary percutaneous coronary intervention. By use of a computerised interactive voice response system, we randomly allocated patients 1:1 to receive bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI; pharmacological randomisation; stratified by previous and expected drug use and study site) and, if eligible, randomly allocated 3:1 to receive a paclitaxel-eluting stent or a bare metal stent (stent randomisation; stratified by pharmacological group assignment, diabetes mellitus status, lesion length, and study site). We produced Kaplan-Meier estimates of major adverse cardiovascular events at 3 years by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00433966. Compared with 1802 patients allocated to receive heparin plus a GPI, 1800 patients allocated to bivalirudin monotherapy had lower rates of all-cause mortality (5·9% vs 7·7%, difference −1·9% [−3·5 to −0·2], HR 0·75 [0·58–0·97]; p=0·03), cardiac mortality (2·9% vs 5·1%, −2·2% [−3·5 to −0·9], 0·56 [0·40–0·80]; p=0·001), reinfarction (6·2% vs 8·2%, −1·9% [−3·7 to −0·2], 0·76 [0·59–0·99]; p=0·04), and major bleeding not related to bypass graft surgery (6·9% vs 10·5%, −3·6% [−5·5 to −1·7], 0·64 [0·51–0·80]; p=0·0001) at 3 years, with no significant differences in ischaemia-driven target vessel revascularisation, stent thrombosis, or composite adverse events. Compared with 749 patients who received a bare-metal stent, 2257 patients who received a paclitaxel-eluting stent had lower rates of ischaemia-driven target lesion revascularisation (9·4% vs 15·1%, −5·7% [−8·6 to −2·7], 0·60 [0·48–0·76]; p<0·0001) after 3 years, with no significant differences in the rates of death, reinfarction, stroke or stent thrombosis. Stent thrombosis was high (≥4·5%) in both groups. The effectiveness and safety of bivalirudin monotherapy and paclitaxel-eluting stenting are sustained at 3 years for patients with STEMI undergoing primary percutaneous coronary intervention. Boston Scientific and The Medicines Company.