Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial.

Background: Gastrointestinal (GI) bleeding is a common complication of oral anticoagulation.

Objectives: This study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial.

Methods: The primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days.

Atherosclerosis stabilization with PCSK-9 inhibition: An evolving concept for cardiovascular prevention.

Monoclonal antibodies (mAbs) to proprotein convertase subtilisin/kexin type 9 (PCSK-9) can further lower LDL-C by ≥60% in statin-treated patients. Preliminary data suggest they may reduce cardiovascular (CVD) events. Ongoing PCSK-9 mAb cardiovascular outcomes trials could provide the opportunity to determine whether a "legacy effect" similar to that observed for statins will occur over the post-trial observation period.

A cluster randomized trial of objective risk assessment versus standard care for acute coronary syndromes: Rationale and design of the Australian GRACE Risk score Intervention Study (AGRIS).

Background: Assessing risk and weighing the potential benefits from evidence-based therapies are essential in the clinical decision making process of optimizing care and outcomes for patients presenting with acute coronary syndromes (ACS). Such practices are advocated in international clinical guidelines of ACS care. While the GRACE risk score (GRS) is a guideline advocated, well-validated risk stratification tool, its utility in improving care and outcomes remains unproven, and its application has been limited in routine clinical practice.

The effect of sequence context on the activity of cytosine DNA glycosylases.

We have prepared single (N204D) and double (N204D:L272A) mutants of human uracil DNA glycosylase (hUDG), generating two cytosine DNA glycosylases (hCDG and hCYDG). Both these enzymes are able to excise cytosine (but not 5-methylcytosine), when this base is part of a mismatched base pair. hCDG is more active than the equivalent E.

Long-term outcomes for women versus men with unstable angina/non-ST-segment elevation myocardial infarction managed medically without revascularization: insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial.

Background: Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin.

Methods: Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 [39%]) and men (n = 5,676 [61%]) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d.

Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial.

Unlabelled: Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization.

Methods: This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months.

Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial).

Background: The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial.

Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C-Terminal Substitution on Biological Activity.

The duocarmycins are potent antitumor agents with potential for use in the development of antibody-drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents.

Systemic Atherosclerotic Inflammation Following Acute Myocardial Infarction: Myocardial Infarction Begets Myocardial Infarction.

Background: Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.

Methods And Results: Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan.

Impact of chronic kidney disease on long-term ischemic and bleeding outcomes in medically managed patients with acute coronary syndromes: Insights from the TRILOGY ACS Trial.

Aims: We aimed to study the relationship of chronic kidney disease stages with long-term ischemic and bleeding outcomes in medically managed acute coronary syndrome patients and the influence of more potent antiplatelet therapies on platelet reactivity by chronic kidney disease stage.

Methods And Results: We estimated creatinine clearance for 8953 medically managed acute coronary syndrome patients enrolled in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial. Patients were classified by chronic kidney disease stage: normal renal function/mild (creatinine clearance >60 mL/min); moderate (creatinine clearance 30-60 mL/min); severe (creatinine clearance <30 mL/min).

10-Year Mortality Outcome of a Routine Invasive Strategy Versus a Selective Invasive Strategy in Non-ST-Segment Elevation Acute Coronary Syndrome: The British Heart Foundation RITA-3 Randomized Trial.

Background: The RITA-3 (Third Randomised Intervention Treatment of Angina) trial compared outcomes of a routine early invasive strategy (coronary arteriography and myocardial revascularization, as clinically indicated) to those of a selective invasive strategy (coronary arteriography for recurrent ischemia only) in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). At a median of 5 years' follow-up, the routine invasive strategy was associated with a 24% reduction in the odds of all-cause mortality.

Objectives: This study reports 10-year follow-up outcomes of the randomized cohort to determine the impact of a routine invasive strategy on longer-term mortality.

Cardiovascular Risk Factors and In-hospital Mortality in Acute Coronary Syndromes: Insights From the Canadian Global Registry of Acute Coronary Events.

Background: There are conflicting data regarding the relationship between the number of modifiable traditional risk factors and prognosis in acute coronary syndromes (ACS). This controversy might in part be explained by the differential use of prehospital medications.

Methods: Using data from the Canadian, multicentre Global Registry of Acute Coronary Events (GRACE) (1999-2008), we stratified 13,686 ACS patients into 3 groups (0, 1-2, vs 3-4 risk factors) and compared their baseline characteristics, in-hospital treatments, and outcomes.

Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial.

Background: p38 mitogen-activated protein kinase (MAPK) mediates cytokine production and amplification of the inflammatory cascade. Through inhibition of p38 MAPK, losmapimod appears to attenuate the inflammatory response in the vascular wall and thus may help stabilize plaques.

Study Design: The LATITUDE-TIMI 60 trial is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study planned to be conducted in a 3-stage design.

Synthesis, anti-mycobacterial activity and DNA sequence-selectivity of a library of biaryl-motifs containing polyamides.

The alarming rise of extensively drug-resistant tuberculosis (XDR-TB) strains, compel the development of new molecules with novel modes of action to control this world health emergency. Distamycin analogues containing N-terminal biaryl-motifs 2(1-5)(1-7) were synthesised using a solution-phase approach and evaluated for their anti-mycobacterial activity and DNA-sequence selectivity. Thiophene dimer motif-containing polyamide 2(2,6) exhibited 10-fold higher inhibitory activity against Mycobacterium tuberculosis compared to distamycin and library member 2(5,7) showed high binding affinity for the 5'-ACATAT-3' sequence.

Frailty is associated with worse outcomes in non-ST-segment elevation acute coronary syndromes: Insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial.

Aims: Little is known regarding consequences of frailty in patients with acute coronary syndrome (ACS). We assessed the associations of frailty and outcomes in ACS patients who were participating in a clinical trial.

Methods And Results: The TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial randomized 9326 patients planned for medical management to prasugrel or clopidogrel.

An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI).

Background: Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes.

Efficacy and safety of vorapaxar as approved for clinical use in the United States.

Background: Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA).

Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

Background: Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

Methods: For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study.

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

Background: In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.

High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study.

Objective: To evaluate the diagnosis of myocardial infarction using a high sensitivity troponin I assay and sex specific diagnostic thresholds in men and women with suspected acute coronary syndrome.

Design: Prospective cohort study.

Setting: Regional cardiac centre, United Kingdom.

Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-up.

Purpose: Short-term outcomes have been well characterized in acute coronary syndromes; however, longer-term follow-up for the entire spectrum of these patients, including ST-segment-elevation myocardial infarction, non-ST-segment-elevation myocardial infarction, and unstable angina, is more limited. Therefore, we describe the longer-term outcomes, procedures, and medication use in Global Registry of Acute Coronary Events (GRACE) hospital survivors undergoing 6-month and 2-year follow-up, and the performance of the discharge GRACE risk score in predicting 2-year mortality.

Methods: Between 1999 and 2007, 70,395 patients with a suspected acute coronary syndrome were enrolled.

Impact of Human Development Index on the profile and outcomes of patients with acute coronary syndrome.

Objective: To study the impact of national economic and human development status on patient profiles and outcomes in the setting of acute coronary syndrome (ACS).

Methods: We conducted a retrospective analysis of the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial (TRILOGY ACS) population (51 countries; 9301 patients). Outcome measures compared baseline characteristics and clinical outcomes through 30 months by 2010 country-level United Nations Human Development Indices (HDIs) and per-capita gross national income.