Savion Gropper

Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation

Background Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding. Methods In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple‐therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110‐mg and 150‐mg dual‐therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110‐mg dual‐therapy group or the triple‐therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow‐up (mean follow‐up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. Results The incidence of the primary end point was 15.4% in the 110‐mg dual‐therapy group as compared with 26.9% in the triple‐therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150‐mg dual‐therapy group as compared with 25.7% in the corresponding triple‐therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual‐therapy groups combined as compared with 13.4% in the triple‐therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups. Conclusions Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE‐DUAL PCI ClinicalTrials.gov number, NCT02164864.)

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patients burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate Oral Liquid Formulation in Infants with Venous Thromboembolism.

Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship, safety and tolerability of DE oral liquid formulation (OLF) in infants with VTE (aged < 12 months) who had completed standard anticoagulant treatment in an open-label, phase IIa study. Patients received a single-dose of DE OLF (based on an age- and weight-adjusted nomogram) yielding an exposure comparable to 150 mg in adults. The PK end point was plasma concentration of total dabigatran; PD end points included activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and diluted thrombin time (dTT). Safety end points included incidence of all bleeding and other adverse events (AEs). Ten patients were screened; eight entered the study (age range, 41-169 days). The geometric mean (gMean) total dabigatran plasma concentrations 2 hours post-dose (around peak concentrations) were 120 ng/mL with a geometric coefficient of variation (gCV) of 62.1%. The gMean at 12 hours post-dosing was 60.4 ng/mL (gCV 30%). PK/PD relationship was linear for ECT and dTT (R2 = 0.858 and 0.920, respectively), while total dabigatran concentration and aPTT showed a non-linear correlation. There were no deaths, treatment discontinuations or treatment-related AEs. In conclusion, DE was well tolerated without any treatment-related AEs in infants. The observed PK/PD relationships were comparable with the established profile in older patients with VTE.

Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open‐label, single‐arm study. The pharmacokinetic–pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism.

Comparison of Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation: A Multicriteria Decision Analysis

BACKGROUND Decision on the most appropriate oral anticoagulation therapy for stroke prevention in patients with nonvalvular atrial fibrillation is difficult because multiple treatment options are available, and these vary in their clinical effects and relevant nonclinical characteristics. OBJECTIVES To use a multicriteria decision analysis (MCDA) to compare the oral anticoagulants apixaban, dabigatran, edoxaban, rivaroxaban, and vitamin K antagonist (VKAs; specifically warfarin) in patients with nonvalvular atrial fibrillation. METHODS We identified the evaluation criteria through a targeted literature review and clinical judgment. The final evaluation model included nine clinical events and four other criteria. We ranked possibly fatal clinical event criteria on the basis of the differences in risks of fatal events and the corresponding window of therapeutic opportunity, as observed in clinical trials. Clinical judgment was used to rank other criteria. Full criteria ranking was used to calculate centroid weights, which were combined with individual treatment performances to estimate the overall value score for each treatment. RESULTS Using such an MCDA, dabigatran yielded the highest overall value, approximately 6% higher than that of the second-best treatment, apixaban. Dabigatran also had the highest first-rank probability (0.72) in the probabilistic sensitivity analysis. Rivaroxaban performed worse than the other non-VKA oral anticoagulants, but better than VKAs (with both having 0.00 first-rank probability). The results were insensitive to changes in model structure. CONCLUSIONS When all key oral anticoagulant value criteria and their relative importance are investigated in an MCDA, dabigatran appears to rank the highest and warfarin the lowest.

Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials

Background  Physiological age-related changes in the haemostatic and coagulation systems result in differing anticoagulant assay responses to standard anticoagulants. Therefore, we investigated the response of anticoagulant assays to dabigatran etexilate (DE) in children compared with adults. Objective  This article assesses the relationship between plasma dabigatran concentration and coagulation assay results across age groups in children and adults. Patients and Methods  Data from three clinical trials in which children received DE following standard of care for venous thromboembolism were compared with data from adult clinical trials. The effects of dabigatran concentration on diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) were analysed graphically and with modelling. Results  The concentration–dTT relationships were consistent in children across all ages and adults in the graphical analysis. For ECT and aPTT, relationships based on ratios over baseline were similar across all ages; absolute clotting times showed that the same exposure resulted in longer clotting times in some of the children aged < 1 year versus adults. Modelling showed concentration–clotting time relationships for all three assays were largely comparable between adults and children, except in those aged < 2 months, in whom there was a slight upward shift in ECT and aPTT relative to adults. Conclusion  Results suggest that developmental haemostatic changes will have little impact on response to DE. However, further paediatric clinical trials assessing the relationship between coagulation assay responses and clinical outcomes will be needed to confirm this finding.

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

Essentials There is no data on the use of idarucizumab in children with venous thromboembolism (VTE). We present the design of a trial that will assess the safety of idarucizumab in children with VTE. Patients will be recruited from two ongoing trials in children treated with dabigatran for VTE. Idarucizumab provides additional re‐assurance when rapid reversal of dabigatran effects is needed.

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism

Essentials Current standard of care (SOC) for pediatric venous thromboembolism (VTE) has limitations. Dabigatran etexilate (DE) versus SOC will be studied in children with VTE in a phase IIb/III trial. A dosing algorithm for DE in children will be assessed guiding dosing. Valuable data on the safety and efficacy of DE for VTE in children will be obtained.

Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.