Treatment Of Symptomatic Venous Thromboembolism Research Articles

FDA approval summary: Dalteparin for the treatment of symptomatic venous thromboembolism in pediatric patients.

On May 16, 2019, the U.S. Food and Drug Administration (FDA) approved dalteparin sodium for the treatment of symptomatic venous thromboembolism (VTE) to reduce the risk of recurrence in pediatric patients 1month of age and older. Approval was primarily based on FDA review of a single-arm trial evaluating dalteparin administered subcutaneous twice daily in 38 pediatric patients with symptomatic VTE. Efficacy was based on the achievement of therapeutic plasma anti-Xa levels. The FDA concluded that dalteparin has efficacy and acceptable safety for pediatric patients.

Comparative study of safety and effectiveness of rivaroxaban and warfarin in patients with acute deep venous thrombosis

Objectives To evaluate the safety and effectiveness of the oral anti-factor Xa (rivaroxaban) in comparison with that of traditional oral (warfarin) anticoagulants in patients in acute stage of deep-vein thrombosis. 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. Patients and methods A prospective study was conducted to compare 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. Results Our study included 200 patients in the acute stage of deep venous thrombosis. Half of them were treated by oral anti-factor Xa (rivaroxaban), which showed no significant difference in safety and effectiveness with warfarin. Partial and complete recanalization occurred in 64 and 16%, respectively, for rivaroxaban and in 48 and 24%, respectively, for warfarin, whereas pulmonary embolism and bleeding occurred in 8 and 16%, respectively, for rivaroxaban and 16 and 12%, respectively, for warfarin. Rivaroxaban was noninferior to warfarin with respect to primary efficacy and adverse effect outcome. Conclusion Our study results show nonsignificant difference between oral anti-factor Xa and the Low Molecular Weight Heparin (LMWH) and vitamin K antagonist technique in the treatment of acute stage of deep-vein thrombosis, but the oral anti-factor Xa (rivaroxaban) has an upper hand in being orally taken and needs less monitoring of coagulation profile.

Vitamin K antagonists versus low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism.

People with venous thromboembolism (VTE) generally are treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH), followed by three months of vitamin K antagonists (VKAs). Treatment with VKAs requires regular laboratory measurements and carries risk of bleeding; some patients have contraindications to such treatment. Treatment with LMWH has been proposed to minimise the risk of bleeding complications. This is the second update of a review first published in 2001. The purpose of this review was to evaluate the efficacy and safety of long term treatment (three months) with LMWH versus long term treatment (three months) with VKAs for symptomatic VTE. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), The Cochrane Vascular Information Specialistalso searched clinical trials registries for ongoing studies. Randomised controlled trials comparing LMWH versus VKA for long treatment (three months) of symptomatic VTE. Two review authors independently evaluated trials for inclusion and methodological quality. Review authors independently extracted data and assessed risk of bias. We resolved disagreements by discussion and performed meta-analysis using fixed-effect models with Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs). Outcomes of interest were recurrent VTE, major bleeding, and mortality. We used GRADE to assess the overall quality of evidence supporting these outcomes. Sixteen trials, with a combined total of 3299 participants fulfilled our inclusion criteria. According to GRADE, the quality of evidence was moderate for recurrent VTE, low for major bleeding, and moderate for mortality. We downgraded the quality of the evidence for imprecision (recurrent VTE, mortality) and for risk of bias and inconsistency (major bleeding).We found no clear differences in recurrent VTE between LMWH and VKA (Peto OR 0.83, 95% confidence interval (CI) 0.60 to 1.15; P = 0.27; 3299 participants; 16 studies; moderate-quality evidence). We found less bleeding with LMWH than with VKA (Peto OR 0.51, 95% CI 0.32 to 0.80; P = 0.004; 3299 participants; 16 studies; low-quality evidence). However, when comparing only high-quality studies for bleeding, we observed no clear differences between LMWH and VKA (Peto OR 0.62, 95% CI 0.36 to 1.07; P = 0.08; 1872 participants; seven studies). We found no clear differences between LMWH and VKA in terms of mortality (Peto OR 1.08, 95% CI 0.75 to 1.56; P = 0.68; 3299 participants; 16 studies; moderate-quality evidence). Moderate-quality evidence shows no clear differences between LMWH and VKA in preventing symptomatic VTE and death after an episode of symptomatic DVT. Low-quality evidence suggests fewer cases of major bleeding with LMWH than with VKA. However, comparison of only high-quality studies for bleeding shows no clear differences between LMWH and VKA. LMWH may represent an alternative for some patients, for example, those residing in geographically inaccessible areas, those who are unable or reluctant to visit the thrombosis service regularly, and those with contraindications to VKA.

Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism in 400 Patients With Active Cancer: A Single-Center Experience.

To study the safety and efficacy of rivaroxaban-a direct oral anticoagulant-use in patients with active cancer and venous thromboembolism (VTE). Retrospective cohort study of 400 patients with active cancer and associated VTE, defined as deep venous thrombosis and/or pulmonary embolism. This single-center study was carried out from January 2012 to June 2015. The aim of this study was to determine the efficacy and safety, using the incidence of recurrent symptomatic VTE and major bleeding, respectively, throughout the treatment with rivaroxaban. Of the 400 patients enrolled, 223 (55.8%) were female. A total of 362 (90.5%) patients had solid tumors and 244 (61%) had metastatic disease. A total of 302 (75.5%) received initial parenteral therapy with enoxaparin (median: 3, mean: 5.6, standard deviation [SD]: 6.4 days) followed by rivaroxaban. Ninety-eight patients (24.5%) were treated with on label rivaroxaban treatment. Recurrence rates were 3.25% with major bleeding occurring in 5.5% during the anticoagulant therapy (median: 118, mean: 163.9, SD: 159.9 days). Rivaroxaban can be an attractive alternative for the treatment of cancer-associated thrombosis.

Edoxaban: A Novel Factor Xa Inhibitor for the Management of Non-valvular Atrial Fibrillation and Venous Thromboembolism.

Warfarin has been a highly prevalent agent for over 70 years; however, its use has been limited by drug-drug interactions, adverse events, and the need for frequent monitoring. To minimize these complications, several non-vitamin K oral anticoagulants have been approved, including the latest agent, edoxaban. Edoxaban is a factor Xa inhibitor approved for the prevention of stroke/systemic embolism in patients with non-valvular atrial fibrillation and for the treatment of venous thromboembolism. Edoxaban was largely studied in the Edoxaban versus Warfarin in Patients with Atrial Fibrillation (ENGAGE AF-TIMI 48) and Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism (Hokusai-VTE) trials, both showing noninferiority when compared with warfarin. Similar to other oral anticoagulants, the most serious adverse effects of edoxaban are related to bleeding. However, there are currently no approved reversal agents. Andexanet alfa and ciraparantag are the latest agents being studied for reversal. This article provides an overview of the safety and efficacy along with the advantages and disadvantages of edoxaban.

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.

Oral Rivaroxaban Versus Standard Therapy for the Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

ABSTRACT Objective: To compare the efficacy and safety of oral rivaroxaban with that of enoxaparin/vitamin K antagonist (VKA) in patients with cancer among 8282 patients with acute venous thromboembolism (VTE) enrolled in the EINSTEIN programme. Rationale: Patients with cancer and VTE constitute a medical challenge for physicians because anticoagulant treatment is indicated to prevent recurrent VTE but is associated with a high risk of major bleeding. Methods: EINSTEIN DVT and EINSTEIN PE were randomized, event-driven, non-inferiority, open-label phase III studies. Patients were treated for 3, 6 or 12 months with rivaroxaban (15 mg twice daily for 21 days followed by 20 mg once daily) or enoxaparin/VKA (international normalized ratio 2.0–3.0) and followed for suspected recurrent VTE, bleeding and mortality. Cancer patients were classified as: active cancer at baseline (diagnosis or treatment within 6 months before enrolment or recurrent/metastatic cancer) or diagnosed during the study (n = 655); or a history of cancer (n = 469). Results: Recurrent VTE occurred with a similar incidence in the rivaroxaban and enoxaparin/VKA groups in patients with active cancer (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.35–1.30) and patients with a history of cancer (HR 0.98; 95% CI 0.28–3.43). In patients with active cancer, the risk of major bleeding was significantly reduced in the rivaroxaban group (HR 0.42; 95% CI 0.18–0.99), whereas it was similar between treatments in patients with a history of cancer (HR 0.23; 95% CI 0.03–2.06). Mortality occurred with a similar incidence between treatments in patients with active cancer (HR 0.93; 95% CI 0.64–1.35) and patients with a history of cancer (HR 1.12; 95% CI 0.30–4.22). Rivaroxaban Enoxaparin/VKA HR (95% CI) Recurrent VTE, n (%) Active cancer 16/354 (4.5) 20/301 (6.6) 0.67 (0.35–1.30) History of cancer 5/233 (2.1) 5/236 (2.1) 0.98 (0.28–3.43) Major bleeding, n (%) Active cancer 8/353 (2.3) 15/298 (5.0) 0.42 (0.18–0.99) History of cancer 1/231 (0.4) 4/236 (1.7) 0.23 (0.03–2.06) Mortality, n (%) Active cancer 58/354 (16.4) 53/301 (17.6) 0.93 (0.64–1.35) History of cancer 5/233 (2.1) 4/236 (1.7) 1.12 (0.30–4.22) Conclusions: Rivaroxaban had similar efficacy to enoxaparin/VKA in patients with VTE and active cancer or a history of cancer, but was associated with a significant reduction in major bleeding in patients with active cancer. Disclosure: M.H. Prins: is a consultant advisor for Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Pfizer, Sanofi, Boehringer Ingelheim, GlaxoSmithKline (GSK), LEO, and ThromboGenics; T. Lensing, F. Misselwitz, A.F. Pap, M. Trajanovic and S.D. Berkowitz: is an employee of Bayer HealthCare Pharmaceuticals; P. Prandoni: has received consultant fees from Bayer Pharma, Daiichi Sankyo, Pfizer, Boehringer-Ingelheim and Sanofi-Aventis; A.T. Cohen: has received consultancy and clinical trial funding from Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi, GSK, Johnson & Johnson, Mitsubishi Pharma, Pfizer, Portola, Sanofi-aventis, Schering-Plough & Takeda; B.L. Davidson: has received travel support from Bayer Healthcare, and is a steering committee member for Bayer HealthCare and Daiichi Sankyo;P. Wells: has received research support from Bristol-Myers Squibb, Pfizer; has participated on scientific advisory boards for Bayer Schering Pharma, Pfizer & Boehringer Ingelheim; and has received honoraria from Bayer Schering Pharma, Pfizer & Biomerieux.

Edoxaban was noninferior to warfarin for preventing recurrent venous thromboembolism, with less bleeding

Source Citation Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-15. 23991658

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

BackgroundStandard 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.MethodsA 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.ResultsA total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients 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 were similar compared with standard-therapy.ConclusionThe 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.Trial registrationEINSTEIN-PE: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.

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.

Long-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: A meta-analysis of 5 randomized trials in non-cancer and cancer patients

PurposeDue to its specific pharmacokinetic profile, tinzaparin, a low-molecular-weight heparin (LMWH), appears not to be associated with anti-factor Xa accumulation. Our meta-analysis aimed at determining whether long-term curative doses of tinzaparin is a valuable alternative to vitamin K antagonists (VKA) for the treatment of symptomatic venous thromboembolism (VTE), especially in patients with cancer who are at higher risk of recurrence and bleeding. Materials and MethodsA systematic literature search identified randomized studies on long-term tinzaparin compared to VKA in patients with VTE. Outcome measures were VTE recurrence, major bleeding, deaths and net clinical benefit combining the three endpoints during the treatment period and at one year. Pooled relative risk was estimated using the logarithm of the relative risk (RR) method based on a fixed-effect model in the overall population and cancer population. ResultsFive randomized controlled studies were eligible. No difference between groups in VTE recurrence was found in the overall population (RR=0.85 [0.55; 1.31]). In cancer patients, a non-significant 38% VTE risk reduction in favor of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]). The difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). The incidence of major bleeding in the tinzaparin group was not significantly different from the VKA group in the overall population and cancer patients. ConclusionsTinzaparin appears as a valuable option for long-term treatment of patients in whom VKA are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE.

Oral Rivaroxaban for the Acute and Continued Treatment of Symptomatic Venous Thromboembolism. the Einstein-DVT and Einstein-Extension Study

AbstractAbstract 187 BackgroundNew oral anticoagulants hold the promise of simple fixed-dose regimens without the need for monitoring and could make extended use more attractive. Current guidelines advise indefinite therapy in a substantial proportion of DVT patients. The Einstein-DVT study was designed to compare rivaroxaban, a direct oral factor Xa inhibitor, to enoxaparin followed by oral vitamin K antagonist (VKA) treatment in patients with acute DVT for either 3, 6, or 12 months. In Einstein-Extension, patients who had completed 6 to 12 months of anticoagulant treatment for either DVT or PE were randomized to receive rivaroxaban or placebo for an additional 6 or 12 months. Study DesignEinstein-DVT was an open label, event-driven (target 88 confirmed recurrent VTEs) non-inferiority study. Subjects with a confirmed acute symptomatic DVT without symptomatic PE were randomized to receive either oral rivaroxaban 15 mg twice-daily for 3 weeks followed by 20 mg once-daily or initial treatment with enoxaparin (1 mg/kg twice daily) followed by oral VKA treatment (warfarin or acenocoumarol, target INR 2.5, range 2.0 to 3.0). Einstein-Extension was a randomized, double-blind, event-driven (target 30 confirmed recurrent VTEs), placebo-controlled, superiority study that evaluated rivaroxaban 20 mg once-daily for an additional 6 or 12 months. The primary efficacy outcome for both studies was recurrent non-fatal or fatal symptomatic venous thromboembolism (VTE). The principal safety outcome was clinically relevant bleeding (major or clinically relevant non-major bleeding) in Einstein-DVT and major bleeding only in Einstein-Extension. All study outcomes were adjudicated by a central and blinded committee. ResultsEinstein-DVT: the ITT-population consisted of 1,731 rivaroxaban and 1,718 enoxaparin/VKA recipients and rivaroxaban demonstrated non-inferior efficacy to enoxaparin/VKA for the primary outcome (rivaroxaban 36 events (2.1%), enoxaparin/VKA 51 events (3.0%), hazard ratio (HR), 0.68; 95% CI 0.44 –1.04, p <0.0001 for non-inferiority, 0.076 for superiority). Major and non-major clinically relevant bleeding occurred in 8.1% of subjects in both treatment groups (HR 0.97; 95% CI 0.76 –1.22, p =0.77) and major bleedings occurred in 14 (0.8%, 1 fatal) and 20 (1.2%, 5 fatal) of the rivaroxaban and enoxaparin/VKA recipients, respectively (HR 0.65; 95% CI 0.33 –1.28, p =0.21). The net clinical benefit defined as the primary efficacy outcome plus major bleeding showed a HR of 0.67 (95% CI 0.47 – 0.95; p=0.027). In the rivaroxaban group, 38 (2.2%) subjects died versus 49 (2.9%) in the enoxaparin/VKA group (HR 0.67; 95% CI 0.44 – 1.02). The time spent in the therapeutic INR range during VKA treatment was 58%. Einstein-Extension: the ITT population consisted of 602 rivaroxaban and 594 placebo subjects and rivaroxaban demonstrated superiority to placebo for the primary outcome (rivaroxaban 8 events (1.3%), placebo 42 events (7.1%), HR 0.18; 95% CI, 0.09 – 0.39; p<0.0001; number needed to treat: 15) over a mean study treatment period of approximately 6.5 months. Major bleeding did not occur in placebo subjects and was observed in 4 (0.7%, none were fatal) rivaroxaban subjects (p=0.11). Clinically relevant non-major bleeding was noted in 7 (1.2%) and 32 (5.4%) of the placebo and rivaroxaban recipients, respectively (p<0.0001). Two (0.3%) patients in the placebo group died versus 1 (0.2%) in the rivaroxaban group. Efficacy and safety results were consistent across all pre-specified subgroups in both studies. ConclusionsAgainst a background of prolonging anticoagulant treatment for many months to years, this study indicates that oral rivaroxaban, 15 mg twice-daily for 3 weeks followed by 20 mg once-daily, could provide clinicians and patients with a simple, single-drug approach for the acute and continued treatment of DVT that potentially improves the benefit–risk profile of anticoagulation. Disclosures:Buller:Bayer Schering Pharma: Consultancy, Research Funding.

Treatment of Cancer-Associated Venous Thrombosis

Venous thromboembolism (VTE) is an important complication in cancer patients, which is associated with bad outcome. Increased recurrence rates and bleeding complications as compared to non-cancer patients during the treatment of VTE, require special attention. This review aims to summarize the available evidence on both the anticoagulant and non-anticoagulant treatment of symptomatic VTE in patients with active malignancy.

Does low-molecular-weight heparin influence cancer-related mortality?

Does low-molecular-weight heparin influence cancer-related mortality?

Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Long-Term Treatment of Symptomatic Venous Thromboembolism: Is There Any Difference in Cancer-Related Mortality?

Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Long-Term Treatment of Symptomatic Venous Thromboembolism: Is There Any Difference in Cancer-Related Mortality?

Meta-analysis of the randomized comparisons between low-molecular weight heparin (LMWH) with oral anticoagulants (OA) for the long-term treatment of symptomatic venous thromboembolism (VTE): no difference in cancer-related mortality

8145 Background: Long-term low-molecular-weight heparin (LMWH) has the advantage that this regimen is administered once-daily and does not require any anticoagulant monitoring. By contrast, because...

Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants

The management of venous thromboembolism (VTE) requires an initial treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), followed by oral anticoagulants (OA) for at least 3 months. OA treatment however, requires laboratory monitoring of anticoagulation, carries a definite risk of bleeding, and may be contraindicated in some patients. As an alternative to vitamin K antagonists, subcutaneous LMWH has been proposed and evaluated in randomized clinical trials, but they are all small studies that lack the power to establish if these two treatment modalities are equivalent in efficacy or safety. The objective of this review was to evaluate the efficacy (VTE recurrence) and safety (bleeds and deaths) of long-term treatment of VTE with LMWH compared with OA. A secondary endpoint was to evaluate the effect of LMWH on cancer mortality. Computerized searches of MedLine and EmBase were performed. In addition, randomized clinical trials were located through personal communication with colleagues, and through the manual scanning of meeting proceedings and reference lists of relevant studies. When necessary, the authors of the selected papers were called to obtain additional information. Two reviewers (AI and FG) reviewed and extracted data independently using a standard form. The primary analysis was performed for efficacy and safety endpoints on an intention-to-treat basis for the study period of randomized treatment. A meta-regression analysis was used to investigate the relationship between daily dose and clinical outcome. Seven studies that fulfillled our predefined criteria were identified, for a total of 1379 patients. When all studies were combined, a statistically non-significant reduction in the risk of VTE (OR 0.66; 95% confidence interval [CI] 0.41, 1.07) and in the risk of major bleeding (OR 0.45; 95% CI 0.18, 1.11) in favor of LMWH treatment was found. No difference in total mortality (OR 1.19; 95% CI 0.78, 1.83) or in cancer-related mortality was observed between the LMWH and the OA treatment. The results of this meta-analysis indicate that a 3-month course of LMWH is as effective and safe as a corresponding period of OA treatment, and may thus be considered as a valuable alternative option for patients in whom OA treatment appears contraindicated or problematic.

Treatment of symptomatic venous thromboembolism: improving outcomes.

Antithrombotic therapy with unfractionated heparin (UFH) and warfarin for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) became widely accepted in the early 1960s. Subsequent clinical trials have focused on the importance of early intravenous UFH in the treatment of venous thromboembolic events, the method of heparin administration, the importance of rapid anticoagulation to prevent recurrent venous thromboembolism (VTE), and the optimal duration of UFH administration. Low-molecular-weight heparin (LMWH) represents a significant advance over UFH therapy for VTE. Developed in the late 1980s, LMWH has become an excellent alternative to UFH because it offers superior efficacy and safety, improved pharmacokinetics, longer half-life, and once- or twice-daily subcutaneous administration without the need for laboratory monitoring. Fondaparinux is the first of a new class of antithrombotic agents that targets factor Xa. Based on studies of the heparin binding site of antithrombin, this novel pentasaccharide has superior pharmacokinetics and bioavailability when compared with LMWH and can be administered once daily. Studies in patients undergoing major orthopedic surgery and in those with proximal DVT indicate that the efficacy and safety of fondaparinux may represent an improvement over those of LMWH.

Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism.

Patients who have had an episode of symptomatic venous thromboembolism are usually treated for at least five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin. Thereafter, they received a three month course of a vitamin K antagonist, with a dose adjusted to achieve an International Normalized Ratio between 2.0 and 3.0. Some patients have contraindications to vitamin K antagonists. In addition, treatment with vitamin K antagonists has the disadvantage of regular laboratory measurements. The objective of this review was to evaluate the efficacy and safety of long-term treatment of symptomatic venous thromboembolism with low-molecular-weight heparins compared with vitamin K antagonists. Computerized searches of MEDLINE, EMBASE and Current Contents were made and relevant journals were hand-searched using the search strategy described by the Cochrane Peripheral Vascular Disease Group. In addition, randomized clinical trials were located through personal communication with colleagues. Where necessary, the reviewers contacted pharmaceutical companies for further information. Two reviewers evaluated studies independently for methodological quality. Two reviewers reviewed and extracted data independently using a standard form. Primary analysis concerned all patients in the studies during the period of randomized treatment. Additional separate analyses were performed for category I and category II studies; studies that used similar initial treatments in both study arms and those that used different treatment regimes during the initial treatment; and the total period of follow-up in the different studies. Five studies were identified that fulfilled our predefined criteria (three category I and two category II studies). When all five studies were combined, a statistically non-significant reduction of the risk of recurrent symptomatic venous thromboembolism in favor of low-molecular-weight heparin treatment (OR 0.72; 95% CI [0.42, 1.23]) was found. In category I studies, analysis of the pooled data showed a statistically non-significant reduction of the risk of recurrent symptomatic venous thromboembolism in favor of low-molecular-weight heparin treatment (OR 0.75; 95% CI [0.40, 1.39]). This OR was mainly due to one possibly confounded study, and after omitting this study from the analysis a statistically non-significant reduction of the risk of recurrent symptomatic venous thromboembolism in favor of vitamin K antagonist treatment remained (OR 1.95; 95% CI [0.74, 5.19]). No differences in the risk of bleeding (OR 0.63; 95% CI [0.21, 1.88]) and mortality (OR 1.13; 95% CI [0.47, 2.69] were observed. Low-molecular-weight heparins are possibly as effective and safe as vitamin K antagonists in the prevention of recurrent symptomatic venous thromboembolism after an episode of symptomatic deep venous thrombosis, but have the disadvantage of much higher medicinal costs. Treatment with low-molecular-weight heparin is possibly a safe alternative in some patients; for example patients who live in geographically inaccessible places; patients who are reluctant to go to the thrombosis service on a regular basis; and patients with contraindications to vitamin K antagonists (e.g. pregnant women). Therefore, in the absence of definitive evidence on the safety and efficacy of low-molecular-weight heparins compared with vitamin K antagonists, we believe that treatment with vitamin K antagonists is still the treatment of choice in the prevention of recurrent symptomatic venous thromboembolism after an episode of deep venous thrombosis, in the majority of patients.