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

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

Anticoagulation in pediatric cancer–associated venous thromboembolism:a subgroup analysis of EINSTEIN-Jr

Anticoagulant treatment of pediatric cancer–associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. This trial was registered at www.clinicaltrials.gov as #NCT02234843

Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis Infections in Men With Nongonococcal Urethritis: Predictors and Persistence After Therapy

Background. Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), and Trichomonas vaginalis (TV) are sexually transmitted infections (STIs) associated with nongonococcal urethritis (NGU). We assessed their predictors and persistence after treatment

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Rivaroxaban or Aspirin for extended treatment of venous thromboembolism

Background: although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. Methods: in this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. Results: a total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. Conclusions: among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439)

Scaling Dynamic Response and Destructive Metabolism in an Immunosurveillant Anti-Tumor System Modulated by Different External Periodic Interventions

On the basis of two universal power-law scaling laws, i.e. the scaling dynamic hysteresis in physics and the allometric scaling metabolism in biosystem, we studied the dynamic response and the evolution of an immunosurveillant anti-tumor system subjected to a periodic external intervention, which is equivalent to the scheme of a radiotherapy or chemotherapy, within the framework of the growth dynamics of tumor. Under the modulation of either an abrupt or a gradual change external intervention, the population density of tumors exhibits a dynamic hysteresis to the intervention. The area of dynamic hysteresis loop characterizes a sort of dissipative-therapeutic relationship of the dynamic responding of treated tumors with the dose consumption of accumulated external intervention per cycle of therapy. Scaling the area of dynamic hysteresis loops against the intensity of an external intervention, we deduced a characteristic quantity which was defined as the theoretical therapeutic effectiveness of treated tumor and related with the destructive metabolism of tumor under treatment. The calculated dose-effectiveness profiles, namely the dose cumulant per cycle of intervention versus the therapeutic effectiveness, could be well scaled into a universal quadratic formula regardless of either an abrupt or a gradual change intervention involved. We present a new concept, i.e., the therapy-effect matrix and the dose cumulant matrix, to expound the new finding observed in the growth and regression dynamics of a modulated anti-tumor system