Symptomatic Recurrent Venous Thromboembolism Research Articles

Multicenter dose‐finding and efficacy and safety outcomes in neonates and children treated with dalteparin for acute venous thromboembolism

Low molecular weight heparins (LMWHs) constitute the mainstay of anticoagulant therapy for pediatric venous thromboembolism (VTE). The safety and effectiveness of dalteparin, an LMWH, has not been established in children, and pediatric data on dalteparin for VTE are limited to one single-center experience. To establish dose-finding (primary endpoint) and efficacy/safety outcomes (secondary endpoints) in children treated with dalteparin in a substudy of the Kids-DOTT trial. A prospective multicenter trial using dalteparin subcutaneously twice daily for acute VTE in children aged ≤ 21 years was conducted under an investigator-held Investigational New Drug application registered with the US Food and Drug Administration. Initial weight-based dosing per protocol was as follows: infants (< 12 months), 150 IU kg(-1) ; children (1-12 years), 125 IU kg(-1) ; and adolescents (13-18 years), 100 IU kg(-1) . Bleeding events were categorized according to ISTH criteria. Descriptive non-parametric statistics were employed for all analyses. Eighteen patients (67% male) were enrolled from January 2010 to October 2013 across four centers. No supratherapeutic levels were observed. Median (range) therapeutic doses by age group were as follows: infants (n = 3), 180 IU kg(-1) (146-181 IU kg(-1) ); children (n = 7), 125 IU kg(-1) (101-175 IU kg(-1) ); and adolescents (n = 8), 100 IU kg(-1) (91-163 IU kg(-1) ). The median duration of dalteparin use was 48 days (range: 2-169 days), and the median follow-up was 10.5 months (range: 2-35 months). There were no related serious adverse events, no clinically relevant bleeding events, and no symptomatic recurrent VTEs. Dalteparin successfully achieved targeted anti-factor Xa levels in 18 children and young adults with acute VTE with a standardized age-based dosing regimen, with a favorable safety and efficacy profile.

Efficacy and Safety of the New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban, and Edoxaban in the Treatment and Secondary Prevention of Venous Thromboembolism: A Systematic Review and Meta-analysis of Phase III Trials

The aim was to perform a review of the efficacy and safety of new oral anticoagulants (NOAs) in the management of venous thromboembolism (VTE). This was a systematic review and meta-analysis. On March 26, 2014, Medline, Embase, and the Cochrane trial register were searched for randomized controlled trials (RCTs) comparing the NOAs dabigatran, rivaroxaban, apixaban, and edoxaban with vitamin K antagonists (VKAs) in VTE treatment and secondary prevention. Two investigators assessed the methodological quality of the RCTs. The main study outcomes (efficacy, safety and net clinical benefit) were expressed as risk ratios (RR) with 95% confidence interval (CI). Ten RCTs, mostly with low risk of bias, with nearly 38,000 patients, were identified. In six trials of treatment, NOAs were equally effective as VKAs in preventing recurrent symptomatic VTE (RR 0.89, 95% CI 0.75–1.05), but major bleeding occurred less often (1.08% vs. 1.73% for VKAs, RR 0.63, 95% CI 0.51–0.77), leading net clinical benefit to favor NOAs (RR 0.79, 95% CI 0.70–0.90). Fatal bleeding occurred less often with NOAs (0.09% vs. 0.18% for VKAs), a difference that approached statistical significance (RR 0.51, 95% CI 0.26–1.01). In three secondary prevention trials, NOAs reduced VTE recurrence rates to 1.32% (vs. 7.24% with placebo, RR 0.17, 95% CI 0.12–0.24) and fatal pulmonary embolism (PE) (including unexplained deaths) to 0.1% (vs. 0.29% for placebo, RR 0.37, 95% CI 0.10–1.38) at the expense of clinically relevant non-major bleeding (4.3% vs. 1.8% for placebo, RR 2.32, 95% CI 1.65–3.35), but not major bleeding. All-cause mortality rate was reduced to 0.41% with NOAs (vs. 0.86% with placebo, RR 0.38, 95% CI 0.18–0.79). Net clinical benefit favored NOAs (RR 0.21, 95% CI 0.15–0.29), and NNT was 18. Compared to VKAs, NOAs are not only effective in treating VTE but also safer in terms of bleeding, thereby conferring clinical benefit. Their safety and efficacy was confirmed further in secondary prevention trials.

Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials

Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials. We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1:1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0-3·0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777. In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0·67, 95% CI 0·35 to 1·30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0·80, 95% CI 0·54 to 1·20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0·42, 95% CI 0·18 to 0·99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0·98, 95% CI 0·28-3·43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0·93, 95% CI 0·66-1·30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0·62, 95% CI 0·21-1·79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0·80, 95% CI 0·34-1·88). The overall frequency of major bleeding in patients with only a history of cancer (one [<1%] patient in the rivaroxaban group vs four [2%] patients in the standard therapy group; HR 0·23, 95% CI 0·03-2·06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0·58, 95% CI 0·37-0·91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0·47, 95% CI 0·15-1·45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0·33, 95% CI 0·08-1·31). In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted. Bayer HealthCare Pharmaceuticals and Janssen Research & Development.

Dabigatran etexilate: a review of its use in the treatment of acute venous thromboembolism and prevention of venous thromboembolism recurrence.

Dabigatran etexilate (Pradaxa(®), Prazaxa(®)) has recently been approved for the treatment of acute venous thromboembolism (VTE) and prevention of VTE recurrence. Dabigatran etexilate is an oral prodrug of dabigatran, a selective, reversible, competitive, direct thrombin inhibitor. Dabigatran etexilate has a wide therapeutic range that allows for fixed-dose administration without the need for routine monitoring, a requirement of standard vitamin K antagonist (VKA) therapy. In randomized phase III trials in patients with acute VTE (RE-COVER and RE-COVER II), long-term treatment with oral dabigatran etexilate 150mg twice daily for 6months after initial parenteral anticoagulation was noninferior to dose-adjusted warfarin with regard to the incidence of recurrent symptomatic VTE or related death. In randomized trials of patients with previously treated VTE, extended dabigatran etexilate treatment was noninferior to warfarin (RE-MEDY) and significantly more effective than placebo (RE-SONATE) with regard to the incidence of recurrent VTE or related death. Dabigatran etexilate was generally well tolerated, with a similar incidence of major bleeding to that with warfarin in individual studies (although pooled data showed a significantly lower incidence in patients with acute VTE), and significantly lower incidences of the combined endpoint of major or clinically relevant nonmajor bleeding and of any bleeding than with warfarin. However, in the RE-SONATE trial, dabigatran etexilate was associated with a higher risk of bleeding than placebo. In conclusion, dabigatran etexilate is a valuable treatment option for acute VTE and prevention of VTE recurrence, providing an effective and convenient alternative to standard VKA therapy with the potential for a lower overall rate of bleeding.

The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study

The optimal duration of anticoagulation for women who had venous thromboembolism (VTE) associated with estrogen use is unknown. To test the hypothesis that women who had a first VTE while using estrogens have a low risk of recurrence. A Prospective cohort study of 630 women (333 estrogen users, 297 non-users) with a first VTE, who were followed for an average of 69 months after anticoagulation withdrawal. Women with a previous or secondary VTE, coagulation inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, requirement of long-term antithrombotic therapy or homozygosity or double heterozygosity for factor V Leiden and/or the G20210A prothrombin mutation were excluded. The endpoint was objectively documented symptomatic recurrent VTE. VTE recurred in 22 (7%) estrogen users and in 49 (17%) non-users. After 1, 2 and 5 years, the cumulative probability of recurrence was 1% (95% confidence interval [CI], 0-2), 1% (95% CI, 0-2) and 6% (95% CI, 3-9) among estrogen users and 5% (95% CI, 2-7), 9% (95% CI, 6-13) and 17% (95% CI, 12-22) among non-users. Compared with non-users, estrogen users had an adjusted relative risk (RR) of recurrent VTE of 0.4 (95% CI, 0.2-0.8). Compared with non-users in the respective age groups, the RR of recurrence was 0.4 (95% CI, 0.2-0.8) among estrogen-containing-contraceptive users and 0.7 (95% CI, 0.3-1.5) among women using estrogen-containing menopausal hormone therapy. Women who had their first VTE while using estrogens have a low risk of recurrent VTE. These women might not benefit from extended anticoagulant therapy.

Rivaroxaban: A Review of Its Use in the Treatment of Deep Vein Thrombosis or Pulmonary Embolism and the Prevention of Recurrent Venous Thromboembolism

Rivaroxaban (Xarelto(®)), an oral direct factor Xa inhibitor, is approved for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE. It is administered at a fixed oral dose and does not require routine coagulation monitoring. In the EINSTEIN-DVT and EINSTEIN-PE trials, in over 8,000 patients with DVT and/or PE, a single-drug approach with rivaroxaban was shown to be noninferior to standard therapy consisting of subcutaneous enoxaparin sodium overlapping with and followed by an oral dose-adjusted vitamin K antagonist (enoxaparin-VKA) with regard to the incidence of symptomatic recurrent venous thromboembolism (VTE) after 3, 6 or 12 months of treatment. Rivaroxaban was generally well tolerated in patients with DVT or PE, with no significant between-group differences in clinically relevant bleeding between the rivaroxaban and enoxaparin-VKA groups. Notably, rivaroxaban was associated with a significantly lower rate of major bleeding compared with enoxaparin-VKA when EINSTEIN-DVT and EINSTEIN-PE data were pooled. Pharmacoeconomic analyses indicated that rivaroxaban may be a cost-effective alternative to enoxaparin-VKA for the treatment of DVT or PE and prevention of recurrent VTE. Extended prophylaxis with rivaroxaban reduced the incidence of symptomatic recurrent VTE to a greater extent than placebo in the EINSTEIN-Extension trial, but was associated with a non-significant increase in the risk of clinically relevant bleeding compared with placebo. In conclusion, rivaroxaban is a reasonable alternative to standard therapy for the treatment of DVT and PE, and as extended thromboprophylaxis.

Direct Oral Anticoagulants for Acute Venous Thromboembolism

In the past decades, the two-stage treatment of initial parenteral heparin followed by vitamin K antagonists (VKA) has been the standard therapy for patients with acute venous thromboembolism (VTE). With the advent of direct oral anticoagulants (DOACs), previously known as n ew or n on-VKA oral anticoagulants (NOACs), this era has come to an end. In this issue of Circulation , Schulman et al. report on the results of the RE-COVER II study that investigated the efficacy and safety of dabigatran for the treatment of acute VTE1. The study included patients with acute deep vein thrombosis (DVT) and pulmonary embolism (PE) who were treated for 6 months with dabigatran 150 mg twice daily or warfarin targeted to an international normalized ratio (INR) between 2 and 3, after initial parenteral heparin, mostly low-molecular-weight heparin (LMWH). The study shows that parenteral heparin followed by dabigatran was as effective as heparin overlapped with and followed by warfarin. The primary endpoint of recurrent symptomatic VTE occurred in 2.3% of patients randomized to dabigatran and in 2.2% of patients randomized to warfarin. Moreover, bleeding was less frequent in the dabigatran group. Thus, the RE-COVER II study confirms the results of the RE-COVER study with an identical design.2

Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies

BackgroundThe worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients.MethodsA total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted-dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding.ResultsThe primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36–3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31–1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight ≤50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy.ConclusionsIn Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world.Trial registration numberEINSTEIN PE, ClinicalTrials.gov NCT00439777; EINSTEIN DVT, ClinicalTrials.gov NCT00440193

Comparative Efficacy and Safety Of Dabigatran Etexilate and Rivaroxaban For The Treatment Of Deep Vein Thrombosis and Pulmonary Embolism

Objective Two novel oral anticoagulants recently have been investigated for the treatment of deep vein thrombosis and/or pulmonary embolism: dabigatran etexilate (dabigatran) and rivaroxaban. The aim of this analysis was to compare their efficacy and safety. Methods Randomized, controlled trials investigating dabigatran or rivaroxaban were identified by a systematic review. Direct meta-analyses and anchored (adjusted) indirect comparisons (AICs) were performed using aggregated results for the following endpoints for the overall treatment duration: first recurrent symptomatic venous thromboembolism (VTE) or VTE-related death, major bleeding events (MBEs), MBEs or clinically relevant bleeding events (CRBEs), and all-cause mortality. Results Four trials were identified; two compared dabigatran with warfarin and two compared rivaroxaban with vitamin K antagonists. The results of the trials, and the direct meta-analyses of the two dabigatran trials and the two rivaroxaban trials, are presented in Table 1. Overall, there was little evidence of heterogeneity in treatment effects among the RE-COVER trials (VTE or VTE-related death, MBEs, MBEs or CRBEs, all-cause mortality: P= 0.82, 0.67, 0.97, 0.97, respectively; I2= 0%). There was some evidence of heterogeneity among the EINSTEIN trials for VTE or VTE-related death (P=0.11; I2=61.9%) and all-cause mortality (P=0.16; I2=50%), but none for MBEs and MBEs/CRBEs with I2= 0% (P= 0.43, 0.47). In the AICs, sensitivity analyses were performed to explore potential trial heterogeneity arising from differences in the type of index VTE and time with an international normalized ratio between 2.0 and 3.0. AIC results suggested that dabigatran was associated with a lower risk of MBEs/CRBEs than rivaroxaban (upper 95% confidence limits for relative risks were less than 1.00). There was no evidence to suggest a difference between dabigatran and rivaroxaban with respect to prevention of recurrent symptomatic VTE or VTE-related death, MBEs, or all-cause mortality. Conclusions Dabigatran may be associated with a lower risk of major or clinically relevant bleeding; there was no evidence to suggest a difference among drugs in prevention of recurrent VTE, MBEs, or overall mortality. Disclosures: Clemens: Boehringer Ingelheim Pharma GmbH &amp; Co. KG: Employment. Off Label Use: Dabigatran etexilate, direct oral thrombin inhibitor, anticoagulant effect; indications for stroke prevention in atrial fibrillation patients in about 90 countries including US; indication for primary VTE prevention in total hip or knee replacement patients in about 100 countries excluding US. Abeysinghe:Boehringer Ingelheim International GmbH: Consultancy. Gonschior:Boehringer Ingelheim GmbH: Employment. Hösel:Boehringer Ingelheim GmbH: Consultancy. Lock:Boehringer Ingelheim International GmbH: Consultancy. Wolowacz:Boehringer Ingelheim International GmbH: Consultancy. Woods:Boehringer Ingelheim International GmbH: Consultancy. Zimovetz:Boehringer Ingelheim International GmbH: Consultancy.

Edoxaban For Long-Term Treatment Of Venous Thromboembolism In Cancer Patients

Edoxaban For Long-Term Treatment Of Venous Thromboembolism In Cancer Patients

Use Of Novel Oral Anticoagulants For Treatment Of Venous Thromboembolism (VTE) In Patients With Malignancy: Meta-Analysis Of Randomized Controlled Trials

AbstractUse of Novel oral anticoagulants for treatment of venous thromboembolism (VTE) in patients with malignancy: meta-analysis of randomized controlled trials BackgroundVenous thromboembolism (VTE) is a frequent complication of cancers. Patients with cancer have at least a 6 fold increased risk for VTE compared to those without cancer, and the diagnosis of VTE in cancer patient is associated with a 2-4 fold decreased survival during the first year. The mainstays of anticoagulant treatment in cancer patients remain unfractionated heparin, LMWH, and the Vitamin K antagonists (VKAs), with current guideline favoring the use of LMWH. Novel oral anticoagulants (NOAs) that directly inhibit factor Xa and thrombin, including dabigatran, rivaroxaban, and apixaban, represents a milestone in the prevention and treatment of VTE. However, there have been no clinical trials to test the efficacy of NOAs in cancer patients, therefore, use of these agents in cancer population is an extrapolation of published results with general population. ObjectivesDetermine the efficacy of novel oral anticoagulants (thrombin inhibitor; dabigatran, and direct factor Xa inhibitors; rivaroxaban and apixaban) in VTE treatment in patients with cancer. Data sourceA systematic review was conducted using MEDLINE and EMBASE up to July 2013. Key words used included venous thromboembolism, pulmonary embolism, deep venous thrombosis, cancer, dabigatran, rivaroxaban, and apixaban. Due to the fact that no randomized controlled trials (RCTs) in cancer population, we combined data that were extracted from major RCTs that include cancer patients and performed a sub-group analysis. ResultsThree randomized controlled trials (RCTs) were reviewed, and a total of 550 patients with cancers were analyzed. NOAs are not inferior to the current standard anticoagulant therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist, to prevent symptomatic recurrent venous thromboembolism. Odd ratio (OR) is 0.988 (95% CI, 0.51-1.94). There is no significant heterogeneity. The major bleeding events were not analyzed due to lack of sub-group data in the trials. ConclusionCancer patients have different hemodynamics and unique features that make the treatment of VTE challenging. These includes: tumor-associated pro-coagulant, venous stasis and endothelial damage from chemotherapy and catheters, an increased risk of anticoagulant-related bleeding, and the complexity of anticoagulant control because of the occurrence of urgent procedures. The development of NOAs provided new modalities to treat VTEs in cancer patients, as it showed that NOAs is non-inferior to the current standard anticoagulant therapy. However, large scale randomized controlled trials specifically targeted cancer patients are needed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Statin Use Was Associated With a Non-Significant Reduction In The Observed Incidence Of Recurrent VTE In Einstein-DVT and Einstein-PE

BackgroundSeveral observational studies in patients at high risk of arterial vascular disease have shown that statin use is associated with a decreased risk of venous thromboembolism (VTE). A recent meta-analysis showed that the odds ratio for a first venous thromboembolic event for statin users was 0.89 (95% confidence interval [CI], 0.78–1.01) compared with non-users (Rahmini K, et al. PLoS Med 2012;9: e1001310 doi:10.1371/journal.pmed.1001310). ObjectiveTo evaluate the risk of recurrent VTE in patients with VTE treated with an anticoagulant (rivaroxaban or enoxaparin/vitamin K antagonist [VKA]) in relation to the concomitant use of statin therapy in the EINSTEIN-DVT and EINSTEIN-PE studies. MeasurementsIncidence densities of symptomatic recurrent VTE and major bleeding were expressed per 100 patient-years of exposure (or not) to statins. A Cox proportional hazards model was employed, with statin use as a time-dependent variable, for each treatment group (rivaroxaban vs enoxaparin/VKA) and adjusted for aspirin use, age, body mass index, cardiac disorders, gender, and creatinine clearance at baseline. ResultsA total of 1509 (18%) of the 8240 patients included in EINSTEIN-DVT and EINSTEIN-PE used statins during the course of the studies. Statin users were more likely to have cardiovascular disorders (31% vs 10%) and also used aspirin more often (26% vs 5%). During statin/rivaroxaban treatment, recurrent VTE occurred with an incidence of 2.0 per 100 patient-years versus 3.6 during non-statin-use (adjusted hazard ratio [HR], 0.62; 95% CI, 0.29–1.32). During statin/enoxaparin/VKA use, recurrent VTE occurred at an incidence of 3.2 per 100 patient-years versus 4.0 during non-statin-use (adjusted HR, 0.89; 95% CI, 0.47–1.69). Major bleeding during statin/rivaroxaban treatment occurred at an incidence of 2.2 per 100 patient-years versus 1.6 during non-statin-use (adjusted HR, 0.92; 95% CI, 0.43–1.98). During statin/enoxaparin/VKA treatment, the rate of major bleeding was 3.7 per 100 patient-years compared with 3.0 during non-statin-use (adjusted HR, 0.69; 95% CI, 0.36–1.32). Due to the adjustments in the Cox regression model the direction of these hazard ratios are in contrast to the crude comparison of rates by patient-years. This is largely because, in general, statin users are older and most of the major bleeding events in statin users occur in the ≥60 years age group. LimitationsThe study comprised a post-hoc analysis of data collected in two randomized clinical trials. Because the analyses were not a comparison of randomized groups, residual confounding is possible. ConclusionsA modest, but not statistically significant, reduction in recurrent VTE was observed with statin use in patients treated for VTE. This reduction was similar in patients receiving enoxaparin/VKA or rivaroxaban therapy. Disclosures:Gebel:Bayer HealthCare AG: Employment, Equity Ownership. Prins:Bayer HealthCare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; sanofi-aventis: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; LeoPharma: Consultancy, Honoraria, Research Funding; ThromboGenics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Lensing:Bayer HealthCare: Employment.

Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism

BackgroundWhether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear.MethodsIn a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.ResultsA total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro–brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98).ConclusionsEdoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.)

Oral Apixaban for the Treatment of Acute Venous Thromboembolism

BackgroundApixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.MethodsIn this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.ResultsThe primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.ConclusionsA fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

Edoxaban for the long‐term treatment of venous thromboembolism: rationale and design of the Hokusai‐venous thromboembolism study – methodological implications for clinical trials

New oral anticoagulants may simplify long-term therapy by eliminating the need for laboratory monitoring. Edoxaban is an oral, direct inhibitor of factorXa that is given in a fixed dose once daily. The Hokusai-VTE study is a randomized, double-blind trial to evaluate whether initial low molecular weight heparin (LMWH) followed by edoxaban (60mg once daily) is non-inferior to LMWH followed by warfarin (International Normalized Ratio of 2.0-3.0) for the prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism (VTE). The primary efficacy outcome is symptomatic recurrent VTE during the 12-month study period. The principal safety outcome is clinically relevant bleeding (major or non-major) occurring during or within 3days of stopping study treatment. A clinical events committee adjudicates all suspected outcome events. A unique study design feature is the flexible treatment duration of between 3 and 12months to simulate usual clinical practice, and enabled by: (i) double-blinding to minimize bias that could occur if knowledge of the patient's treatment influenced the duration of therapy; and (ii) follow-up for 12months of all patients and inclusion in the primary efficacy analysis, regardless of the duration of therapy received. A second innovative design feature is the strategy for achieving an appropriate time in therapeutic range in the warfarin group, with central tracking for each participating center and feedback to the investigators. The standard methods combined with innovative design features should achieve study results that are both scientifically valid and relevant to clinical practice.

New Anticoagulants Show Promise in Treatment of Clotting

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism (VTE) in three industry-sponsored randomized clinical trials. However, the researchers said that more data are needed in patients over 75 years old. Both medications also reduced the risk of bleeding complications, the investigators said. The results were published online in the New England Journal of Medicine. In the first trial, two doses of apixaban were compared with placebo in 2,486 patients with VTE who had finished standard anticoagulation therapy, Dr. Giancarlo Agnelli of the University of Perugia (Italy) and his colleagues reported. The study subjects were enrolled at 328 medical centers in 28 countries. They were randomly assigned to receive a 2.5-mg dose (840 subjects), a 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for 1 year. The primary efficacy outcome was a composite of symptomatic recurrent VTE or death from any cause. This occurred in 3.8% of the maintenance-dose group and 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Clinically relevant but nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo. “It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment,” the researchers said. In a separate report on two trials, Dr. Sam Schulman and his associates examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. In one trial, 2,866 VTE patients who had completed at least 3 months of anticoagulation therapy and were considered to be at increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute, Hamilton, Ont., and his colleagues. The other trial involved 1,343 VTE patients who had completed at least 3 months of anticoagulation therapy but were not considered to be at increased risk of recurrence. These subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries. In the first trial, recurrent symptomatic VTE or VTE-related death occurred in 1.8% of the dabigatran group and 1.3% of the warfarin group, thus meeting the criteria for noninferiority to warfarin in preventing recurrent or fatal VTE. In the second trial, this outcome occurred in 0.4% of the dabigatran group, compared with 5.6% of the placebo group, so the drug was significantly more effective than placebo at preventing recurrent or fatal VTE. Dr. Jean M. Conners of the hematology division at Brigham and Women's Hospital, Boston, in a comment accompanying the reports, said, “The crux of using the new oral anticoagulants in clinical practice … lies in the selection of appropriate patients. Patients in these studies were younger (average age, 56 years), with fewer coexisting diseases and a lower bleeding risk than patients typically seen in practice.” Better risk-stratification strategies are needed to identify patients who stand to benefit most from extended anticoagulation, she said. Dr. Agnelli's study was funded by Bristol-Myers Squibb (BMS) and Pfizer. Dr. Schulman's trials were funded by Boehringer Ingelheim.

Apixaban for Extended Treatment of Venous Thromboembolism

BackgroundApixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.MethodsIn this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months.ResultsA total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.ConclusionsExtended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.)

Catheter-directed Thrombolysis with Argatroban and tPA for Massive Iliac and Femoropopliteal Vein Thrombosis

Catheter-directed thrombolysis (CDT) is a highly effective approach in the treatment of deep venous thrombosis (DVT). There are no data on the primary use of CDT with argatroban and tissue plasminogen activator (tPA) in patients without heparin-induced thrombocytopenia (HIT). The aim of this study was to evaluate the efficacy and safety of the combined administration of argatroban and tPA during CDT for massive DVT in patients without HIT. Thirty-three patients with massive symptomatic iliac and femoropopliteal DVT underwent CDT with tPA and argatroban within 28 ± 6 h of presentation. The dose of tPA was 0.75-1 mg/h through the infusion port and that of argatroban at 0.3-1 μg/kg/min through the side port of the sheath. The patients were evaluated for the efficacy and safety of CDT and recurrent symptomatic venous thromboembolism (VTE) at a mean follow-up of 22 months. There was no bleeding or iatrogenic pulmonary embolism with the CDT regimen we used. Grade III lysis (complete resolution of thrombus on venography) was achieved in 30 patients (91 %). In 3 patients with additional inferior vena cava filter thrombosis, further thrombectomy of the filter was required. No patient developed recurrent VTE. Concomitant administration of argatroban and tPA is a highly safe and effective regimen for CDT for massive DVT.

Prediction of Recurrent Venous Thromboembolism by Clot Lysis Time: A Prospective Cohort Study

Venous thromboembolism (VTE) is a chronic disease, which tends to recur. Whether an abnormal fibrinolytic system is associated with an increased risk of VTE is unclear. We assessed the relationship between fibrinolytic capacity (reflected by clot lysis time [CLT]) and risk of recurrent VTE. We followed 704 patients (378 women; mean age 48 yrs) with a first unprovoked VTE for an average of 46 months after anticoagulation withdrawal. Patients with natural coagulation inhibitor deficiency, lupus anticoagulant, cancer, homozygosity for factor V Leiden or prothrombin mutation, or requirement for indefinite anticoagulation were excluded. Study endpoint was symptomatic recurrent VTE. For measurement of CLT, a tissue factor-induced clot was lysed by adding tissue-type plasminogen activator. Time between clot formation and lysis was determined by measuring the turbidity.135 (19%) patients had recurrent VTE. For each increase in CLT of 10 minutes, the crude relative risk (RR) of recurrence was 1.13 (95% CI 1.02–1.25; p = 0.02) and was 1.08 (95% CI 0.98–1.20; p = 0.13) after adjustment for age and sex. For women only, the adjusted RR was 1.14 (95% CI, 0.91–1.42, p = 0.22) for each increase in CLT of 10 minutes. CLT values in the 4th quartile of the female patient population, as compared to values in the 1st quartile, conferred a risk of recurrence of 3.28 (95% CI, 1.07–10.05; p = 0.04). No association between CLT and recurrence risk was found in men. Hypofibrinolysis as assessed by CLT confers a moderate increase in the risk of recurrent VTE. A weak association between CLT and risk of recurrence was found in women only.

Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies

AbstractAbstract 20Harry R. Büller, MD, PhD on behalf of the EINSTEIN Investigators. BackgroundThe EINSTEIN DVT and EINSTEIN PE studies showed that a fixed-dose regimen of rivaroxaban was non-inferior to standard therapy of subcutaneous enoxaparin followed by vitamin K antagonist (VKA) for the treatment of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), with similar occurrence of clinically relevant bleeding (The EINSTEIN Investigators. N Engl J Med 2010;363:2499–510; The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97). This prespecified pooled analysis compared rivaroxaban with the standard therapy for the primary efficacy and safety outcomes, including subgroup analyses for body weight, age, and renal function. MethodsThis data pool included all patients and events from EINSTEIN DVT (patients with acute symptomatic DVT without PE) and EINSTEIN PE (patients with acute symptomatic PE with or without DVT). Both studies shared an open-label, randomized, non-inferiority design and compared oral, fixed-dose rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous body weight-adjusted enoxaparin followed by warfarin or acenocoumarol (international normalized ratio 2–3) for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism (the composite of recurrent DVT or nonfatal or fatal PE); safety outcomes included the composite of major and clinically relevant non-major bleeding, and major bleeding alone. Adjudication was done by a single committee. Subgroup analyses for efficacy and safety were performed. ResultsThe intention-to-treat population included 4150 rivaroxaban patients and 4131 enoxaparin/VKA patients. Rivaroxaban demonstrated non-inferior efficacy to enoxaparin/VKA for the primary efficacy outcome (rivaroxaban: 86 events [2.1%], enoxaparin/VKA: 95 events [2.3%]; hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.66–1.19; p<0.0001 for non-inferiority). Major and clinically relevant non-major bleeding occurred in 388 patients (9.4%) in the rivaroxaban group and 412 patients (10.0%) in the enoxaparin/VKA group (HR=0.93; 95% CI 0.81–1.06; p=0.272), and major bleeding occurred in 40 (1.0%, 3 fatal) and 72 (1.7%, 8 fatal) of the rivaroxaban and enoxaparin/VKA recipients, respectively (HR=0.54; 95% CI 0.37–0.79; p=0.002). Efficacy was consistent for rivaroxaban compared with enoxaparin/VKA among the various subgroups, whereas increasing age and declining renal function were associated with a strong reduction in major bleeding in favor of rivaroxaban (Table). Major bleeding was consistently lower in the rivaroxaban recipients for all body weight categories. ConclusionThis analysis demonstrates that the simple, single-drug approach with oral rivaroxaban has an improved benefit–risk profile compared with standard therapy for the treatment of symptomatic venous thromboembolism. The reduction in major bleeding in favor of rivaroxaban was most pronounced in elderly patients and those with moderate renal impairment (creatinine clearance <50 mL/min), and was consistent among various body weight categories, thereby obviating the need for a rivaroxaban dose adjustment in these subgroups.TableSubgroup analyses of the primary efficacy outcome and major bleedingPrimary efficacy outcomeMajor bleedingRivaroxaban n/N (%)Enoxaparin/VKA n/N (%)HR (95% CI)Rivaroxaban n/N (%)Enoxaparin/VKA n/N (%)HR (95% CI)Age, years<6555/2606 (2.1)53/2590 (2.0)1.01 (0.69–1.47)19/2592 (0.7)24/2579 (0.9)0.76 (0.41–1.38)65–7516/888 (1.8)19/914 (2.1)0.87 (0.45–1.69)13/883 (1.5)20/913 (2.2)0.68 (0.34–1.37)>7515/656 (2.3)23/627 (3.7)0.61 (0.32–1.17)8/655 (1.2)28/624 (4.5)0.26 (0.12–0.56)Weight, kg≤7029/1147 (2.5)31/1145 (2.7)0.92 (0.55–1.52)17/1141 (1.5)25/1140 (2.2)0.65 (0.35–1.20)>70–9033/1821 (1.8)43/1826 (2.4)0.75 (0.47–1.18)15/1811 (0.8)32/1824 (1.8)0.47 (0.26–0.87)>9024/1174 (2.0)21/1158 (1.8)1.14 (0.63–2.05)8/1171 (0.7)15/1151 (1.3)0.49 (0.21–1.16)Creatinine clearance, mL/min≥8049/2748 (1.8)52/2787 (1.9)0.94 (0.64–1.39)23/2739 (0.8)29/2776 (1.0)0.79 (0.46–1.37)50–<8024/1030 (2.3)30/992 (3.0)0.76 (0.44–1.30)14/1024 (1.4)30/993 (3.0)0.44 (0.24–0.84)<5011/332 (3.3)11/322 (3.4)0.95 (0.41–2.20)3/329 (0.9)13/320 (4.1)0.21 (0.06–0.73) Disclosures:No relevant conflicts of interest to declare.