Derivation of the non-inferiority margin for the evaluation of direct oral anticoagulants in the treatment of venous thromboembolism

BACKGROUND: Direct oral anticoagulants that target a single coagulation factor have been developed as an alternative to standard therapies with heparin and/or vitamin K antagonists. The purpose of this study was to derive non-inferiority margins suitable for randomised clinical studies designed to evaluate these agents for the treatment of venous thromboembolism (VTE). METHODS: We performed a systematic review to derive non-inferiority margins suitable for use in studies evaluating direct oral anticoagulants for the treatment of VTE. A PubMed search identified publications that evaluated current standard treatment versus placebo, ‘no treatment’ or ‘less intensive treatment’ in patients with symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Publications were eligible if they had a randomised study design, included patients with symptomatic DVT and/or PE, used objective diagnostic methods to document the index event and reported objectively confirmed symptomatic recurrent VTE. RESULTS: Fourteen publications were included in the analysis. Recurrent VTE occurred in 25 (1.5%) out of 1715 patients who received current standard of care and in 157 (9.2%) out of 1711 patients who received placebo, ‘no treatment’ or ‘less intensive treatment’, for an odds ratio of 0.18 (95% confidence interval, 0.14−0.25; test for heterogeneity, p=0.87). In order to preserve 50% or 75% of the established treatment effect using a linear scale, the corresponding thresholds for non-inferiority equalled 2.50 and 1.75, respectively. CONCLUSIONS: This systematic review and statistical approach determined non-inferiority margins suitable for use in studies of direct oral anticoagulants for the treatment of DVT and/or PE

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism : a pooled analysis of the EINSTEIN-DVT and PE randomized studies

Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. Results: 8282 patients were enrolled. 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 rivaroxaban-treated patients (2.1%) compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority<0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p=0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban was similar compared with standard-therapy. Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups

Predicting Recurrent Venous Thromboembolism in Patients With Deep-Vein Thrombosis: Development and Internal Validation of a Potential New Prediction Model (Continu-8).

Background: Previous prediction models for recurrent thromboembolism (VTE) are often complicated to apply and have not been implemented widely. Aim: To develop and internally validate a potential new prediction model for recurrent VTE that can be used without stopping anticoagulant treatment for D-dimer measurements in patients with provoked and unprovoked DVT. Methods: Cohort data of 479 patients treated in a clinical care pathway at Maastricht University Medical Center were used. Predictors for the Cox proportional hazards model (unprovoked DVT, male gender, factor VIII levels) were derived from literature and using forward selection procedure. The scoring rule was internally validated using bootstrapping techniques and the predictive ability was compared to existing prediction models. Results: Patients were followed for a median of 3.12 years after stopping anticoagulation treatment (IQR 0.78, 3.90). Sixty-four of 479 patients developed recurrent VTE (13%). The scoring rule consisted of unprovoked DVT (yes: 2 points), male sex (yes: 1 point), and factor VIII > 213 % (yes: 2 points) and was categorized into three groups [i.e., low risk (score 0), medium risk (scores 1, 2, or 3) and high risk (scores 4 and 5)]. The concordance statistic was 0.68 (95% CI: 0.61, 0.75). Conclusion: The discriminative ability of the new Continu-8 score was adequate. Future studies shall verify this score in an independent setting without stopping anticoagulation treatment

Carotid stiffness in young adults: a life-course analysis of its early determinants The Amsterdam Growth and Health Longitudinal Study

Cardiovascular risk factors affecting arterial stiffness in adulthood may develop at different critical periods earlier in life. We examined whether the trajectories, from adolescence to young adulthood, of blood pressure, body fatness and fat distribution, blood lipids, cardiorespiratory fitness, and heart rate determined levels of arterial stiffness in young adults. We investigated 373 apparently healthy adults in whom cardiovascular risk factors were repeatedly examined between the ages of 13 and 36 years and carotid stiffness estimates were obtained at the age of 36 years. Differences in the mean levels and the trajectories of risk factors throughout the 24-year longitudinal period between subjects with different levels of carotid stiffness at age 36 years were analyzed with generalized estimating equations. Compared with individuals with less stiff carotid arteries, those with stiffer carotid arteries at the age of 36 years were characterized from ages 13 to 36 years by greater levels of and steeper increases in blood pressure and central fatness, independently of each other and other risk factors. These increases were already present in adolescence, preceded the development of poorer levels of blood lipids, cardiorespiratory fitness, and heart rate, which were evident during adulthood only, and explained to a great extent the deleterious association between these risk factors and carotid stiffness at the age of 36 years. Multiple and intertwined mechanisms involved in the pathogenesis of arterial stiffness have their origins in early life. Blood pressure and central fatness have a pivotal role herein and should be specifically targeted to prevent arterial stiffening and its cardiovascular sequelae

Comparison of Four Bleeding Risk Scores to Identify Rivaroxaban-treated Patients With Venous Thromboembolism at Low Risk for Major Bleeding

Objectives Outpatient treatment of acute venous thromboembolism (VTE) requires the selection of patients with a low risk of bleeding during the first few weeks of anticoagulation. The accuracy of four systems, originally derived for predicting bleeding in VTE treated with vitamin K antagonists (VKAs), was assessed in VTE patients treated with rivaroxaban. Methods All patients treated with rivaroxaban in the multinational EINSTEIN deep vein thrombosis (DVT) and pulmonary embolism (PE) trials were included. Major bleeding was defined as ≥2 g/dL drop in hemoglobin or ≥2-unit blood transfusion, bleeding in critical area, or bleeding contributing to death. The authors examined the incidence of major bleeding in patients with low-risk assignment by the systems of Ruiz-Gimenez et al. (score = 0 to 1), Beyth et al. (score = 0), Kuijer et al. (score = 0), and Landefeld and Goldman. (score = 0). For clinical relevance, the definition of low risk for all scores except Kuijer includes all patients < 65 years with no prior bleeding history and no comorbid conditions (current cancer, renal insufficiency, diabetes mellitus, anemia, prior stroke, or myocardial infarction). Results A total of 4,130 patients (1,731 with DVT only, 2,399 with PE with or without DVT) were treated with rivaroxaban for a mean (±SD) duration of 207.6 (±95.9) days. Major bleeding occurred in 1.0% (40 of 4,130; 95% confidence interval [CI] = 0.7% to 1.3%) overall. Rates of major bleeding for low-risk patients during the entire treatment period were similar: Ruiz-Gimenez et al., 12 of 2,622 (0.5%; 95% CI = 0.2% to 0.8%); Beyth et al., nine of 2,249 (0.4%; 95% CI = 0.2% to 0.8%); Kuijer et al., four of 1,186 (0.3%; 95% CI = 0.1% to 0.9%); and Landefeld and Goldman, 11 of 2,407 (0.5%; 95% CI = 0.2% to 0.8%). At 30 days, major bleed rates for low-risk patients were as follows: Ruiz-Gimenez et al., five of 2,622 (0.2%; 95% CI = 0.1% to 0.4%); Beyth et al., five of 2,249 (0.2%; 95% CI = 0.1% to 0.5%); Kuijer et al., three of 1,186 (0.3%; 95% CI = 0.1% to 0.7%); and Landefeld and Goldman, seven of 2,407 (0.3%; 95% CI = 0.1% to 0.6%). No low-risk patient had a fatal bleed. Conclusions Four scoring systems that use criteria obtained in routine clinical practice, derived to predict low bleeding risk with VKA treatment for VTE, identified patients with less than a 1% risk of major bleeding during full-course treatment with rivaroxaban

Addendum to “on the measurability of a function which occurs in a paper by A. C. Zaanen”

Current guidelines discourage combined oral contraceptive (COC) use in women with hereditary thrombophilic defects. However, qualifying all hereditary thrombophilic defects as similarly strong risk factors might be questioned. Recent studies indicate the risk of venous thromboembolism (VTE) of a factor V Leiden mutation as considerably lower than a deficiency of protein C, protein S, or antithrombin. In a retrospective family cohort, the VTE risk during COC use and pregnancy (including postpartum) was assessed in 798 female relatives with or without a heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin G20210A mutation. Overall, absolute VTE risk in women with no, single, or combined defects was 0.13 (95% confidence interval 0.08-0.21), 0.35 (0.22-0.53), and 0.94 (0.47-1.67) per 100 person-years, while these were 0.19 (0.07-0.41), 0.49 (0.18-1.07), and 0.86 (0.10-3.11) during COC use, and 0.73 (0.30-1.51), 1.97 (0.94-3.63), and 7.65 (3.08-15.76) during pregnancy. COC use and pregnancy were independent risk factors for VTE, with highest risk during pregnancy postpartum, as demonstrated by adjusted hazard ratios of 16.0 (8.0-32.2) versus 2.2 (1.1-4.0) during COC use. Rather than strictly contraindicating COC use, we advocate that detailed counseling on all contraceptive options, including COCs, addressing the associated risks of both VTE and unintended pregnancy, enabling these women to make an informed choice. (Blood. 2011;118(8):2055-2061

Higher Plasma Soluble Receptor for Advanced Glycation End Products (sRAGE) Levels Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes: A 12-Year Follow-Up Study

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and allcause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS - We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6 -12.5). RESULTS - The incidence of fatal and nonfatal CVD and allcause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13-3.21) and 2.12 (1.26 -3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91-2.77) for fatal and nonfatal CVD events and to 1.90 (1.09 -3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036). CONCLUSIONS - Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association