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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Introduction For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring. Patients and methods To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values. Results The mean peak PT values at months 3 and 6 or 12 were 21.9 ± 5 and 21.7 ± 6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ± 5.1 and 15.3 ± 2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding. Conclusions PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as # NCT00440193 (EINSTEIN-DVT) and # NCT00439777 (EINSTEIN-PE).

Background Although epidemiological studies report a lower risk of venous thromboembolism (VTE) than in the Western world, VTE rates in Asia may be underestimated. Furthermore, it is uncertain whether VTE outcomes differ in Asia and the rest of the world (ROW). Methods GARFIELD-VTE is a global, prospective, non-interventional study of real-world treatment practices. In this study, we compared baseline characteristics, treatment patterns, and 12-month outcomes in Asia and ROW. Results Of the 10,684 enrolled patients, 1822 (17.1%) were Asian (China n = 420, Hong Kong n = 98, Japan n = 148, Malaysia n = 244, South Korea n = 343, Taiwan n = 232, Thailand n = 337). Compared with ROW patients, those from Asia were more often female (57.4% vs. 48.0%), non-smokers (74.0% vs. 58.9%) and had a lower BMI (24.8 kg/m2 vs. 29.1 kg/m2). Asian patients were more likely to be managed in the hospital (86.9% vs. 70.4%) and to have active cancer (19.8% vs. 8.1%) or a history of cancer (19.1% vs. 12.0%). Asian patients received no anticoagulation more frequently than ROW patients (6.5% vs. 2.1%). Over 12-months follow-up, the rate of all-cause mortality (per 100 person-years [95% confidence interval]) was higher in Asians (15.2 [13.4–17.3] vs. 5.9 [5.4–6.5]). Adjusted hazard ratios indicated a higher risk of all-cause mortality in Asian patients than the ROW (1.32 [1.08–1.62]). The frequencies of major bleeding and recurrent VTE were similar. Conclusion Asian patients have different risk profiles, treatment patterns and a higher risk of mortality compared with the ROW.

Introduction Clinical characteristics and outcomes of venous thromboembolism (VTE) patients with concomitant anemia are unclear. This study compares baseline characteristics, treatment patterns, and 24-month outcomes in patients with and without anemia within GARFIELD-VTE. Materials and methods GARFIELD-VTE ( ClinicalTrials.gov : NCT02155491 ) is a global, prospective, non-interventional registry of real-world treatment practices. Of the 10,679 patients enrolled in GARFIELD-VTE, 7698 were eligible for analysis. Primary outcomes were all-cause mortality, recurrent VTE, and major bleeding in VTE patients with or without concomitant anemia over 24-months after diagnosis. Event rates and 95% confidence intervals were estimated using Poisson regression. Adjusted hazard ratios were calculated using Cox proportional hazard models. Results Distribution of VTE events in 2771 patients with anemia and 4927 without anemia was similar (deep-vein thrombosis alone: 61·1% vs. 55·9%, pulmonary embolism ± deep vein thrombosis: 38·9% vs. 44·0%, respectively). Patients with anemia were older (62.6 year vs. 58.9 years) than those without. At baseline, VTE risk factors that were more common in patients with anemia included hospitalization (22·0% vs. 6·8%), surgery (19·2% vs. 8·2%), cancer (20·1% vs. 5·6%) and acute medical illness (8·3% vs. 4·2%). Patients with anemia were more likely to receive parenteral anticoagulation therapy alone than those without anemia (26·6% vs. 11·7%) and less likely to receive a direct oral anticoagulant (38·5% vs. 53·5%). During 24-months of follow-up, patients with anemia had a higher risk (adjusted hazard ratio [95% confidence interval]) of all-cause mortality (1·84 [1·56–2·18]), major bleeding (2·83 [2·14–3·75]). Among anemia patients, the risk of all-cause mortality and major bleeding remained higher in patients with severe anemia than in those with mild/moderate anemia, all-cause mortality: HR 1·43 [95% CI: 1·21–1·77]; major bleeding: HR 2·08 [95% CI: 1·52–2·86]). Conclusions VTE patients with concomitant anemia have a higher risk of adverse clinical outcomes compared with those without anemia. Further optimization of anticoagulation therapy for VTE patients with anemia is warranted.

Background Many patients with venous thromboembolism (VTE) are elderly, have multiple comorbidities and take several concomitant medications. Physicians may prefer warfarin over direct oral anticoagulants (DOACs) in such patients because comparative data are lacking. This analysis was designed to determine the effects of advanced age, comorbidities, and polypharmacy on the efficacy and safety of edoxaban and warfarin in patients with VTE. Methods Using data from the Hokusai-VTE study, we report rates of recurrent VTE and of clinically relevant bleeding by age category ( 2) and concomitant medications ( 5). Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for edoxaban versus warfarin were determined and Kaplan-Meier methodology was used to construct time-to-event curves. At 3 months, pre- and postdose levels of edoxaban were measured using mass spectrometry. For warfarin-treated patients, the time in therapeutic range was calculated. The study was approved by institutional review boards; informed consent was obtained. Results Recurrent VTE increased with advanced age, multiple comorbidities, and polypharmacy in warfarin-treated patients but not with edoxaban. Edoxaban was more effective than warfarin in patients ≥ 75 years of age and in those with multiple comorbidities. In the 517 patients over 80 years of age, recurrent VTE occurred in 2.8% given edoxaban and in 5.7% given warfarin (HR 0.51, 95% CI 0.21–1.24). Bleeding increased with age, comorbidity, and polypharmacy regardless of treatment, but the relative safety of edoxaban versus well-managed warfarin was maintained. Age, comorbidity, and polypharmacy did not impact edoxaban concentrations. Conclusions These data suggest that a once-daily fixed dose of edoxaban is more effective and at least as safe as warfarin in high-risk VTE patients identified by older age, more comorbidities, and polypharmacy. Clinical trial registration: NCT00986154

Background: The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6 months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively).Methods: To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6 months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2).Results: Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2.Conclusions: This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons. (C) 2016 Elsevier Ltd. All rights reserved.

This review provides the rationale for dual pathway inhibition with the combination of low-dose rivaroxaban (2.5 mg twice daily) to attenuate thrombin generation and aspirin (100 mg once daily) to reduce platelet activation. Such therapy has been licensed for secondary prevention in patients with coronary or peripheral artery disease.

Although the non-vitamin antagonist oral anticoagulants produce less intracranial bleeding than warfarin, serious bleeding still occurs. Therefore, the search for safer anticoagulants continues. Factor XII and factor XI have emerged as promising targets whose inhibition has the potential to prevent thrombosis with little or no disruption of hemostasis. Thus, thrombosis is attenuated in mice deficient in factor XII or factor XI and patients with congenital factor XII deficiency do not bleed and those with factor XI deficiency rarely have spontaneous bleeding. Strategies targeting factor XII and XI include antisense oligonucleotides to decrease their synthesis, inhibitory antibodies or aptamers, and small molecule inhibitors. These strategies attenuate thrombosis in various animal models and factor XI knockdown with an antisense oligonucleotide in patients undergoing knee replacement surgery reduced postoperative venous thromboembolism to a greater extent than enoxaparin without increasing bleeding. Therefore, current efforts are focused on evaluating the efficacy and safety of factor XII and factor XI directed anticoagulant strategies.

Background In adults with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of dabigatran etexilate is 150 mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. Methods Single-arm, open-label phase 4 study ( NCT01184989 ) in Caucasian patients receiving dabigatran etexilate 75 mg 1–4 h after surgery and 150 mg qd on days 2–10 (TKR) or days 2–35 (THR). Plasma total dabigatran concentrations (day 6 ± 1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). Results Of 112 patients (mean CrCl 42.5 mL/min, age 79.1 years, 69.6% female), 100 completed the study. Geometric mean trough and peak dabigatran concentrations were 47.5 ng/mL (10th–90th percentile 19.7–120) and 166 ng/mL (49.1–364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50–500 ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ± 15%. Conclusions These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150 mg qd dose of dabigatran etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of dabigatran levels would be helpful.

The antithrombotic activity of tecarfarin, a novel orally active vitamin K epoxide reductase inhibitor, was assessed in canine and rabbit thrombosis models. In dogs, once-daily oral doses of 0.5mg/kg tecarfarin selectively reduced the levels of the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and prolonged the prothrombin time (PT). A 4 to 7day course of oral tecarfarin (0.05 - 0.5mg/kg) prolonged the PT by 3 to 5-fold and reduced thrombus formation in arterial and venous segments subjected to a combination of electrical injury and flow-limiting constriction. To compare the effects of tecarfarin with those of warfarin, rabbits were given once-daily oral doses of 1mg/kg tecarfarin, 1.5mg/kg warfarin, or saline for 2days. After verifying increases in the PT with tecarfarin and warfarin, blood loss from standardized ear incisions was measured to assess hemorrhagic potential. Then, after intravenous injection of (125)I-labeled rabbit fibrinogen, thrombosis was induced in an isolated jugular vein segment by a combination of balloon catheter-induced endothelial denudation and venous occlusion. Compared with the saline control, both tecarfarin and warfarin prolonged the PT, increased blood loss from the ear incisions, and attenuated thrombus formation. Thus, like warfarin, tecarfarin attenuates venous and arterial thrombus formation in animal models by reducing the levels of the vitamin K-dependent coagulation factors.

We have made great strides in the diagnosis, treatment and prevention of venous thromboembolism (VTE). Despite these advances, however, questions remain. Perhaps the most important unmet need is the development and implementation of strategies to increase the uptake of guidelines for thromboprophylaxis. VTE is largely preventable with appropriate prophylaxis. New oral anticoagulants have the potential to further streamline VTE prevention and treatment. Although heparin, low molecular weight heparins or fondaparinux are frequently used for thromboprophylaxis in hospitalized medical or surgical patients, these agents are not ideal for out-of-hospital use. There is now good evidence that patients undergoing major orthopaedic surgery require extended thromboprophylaxis. Medical patients may also benefit from extended prophylaxis. The new oral anticoagulants will be more convenient than existing agents for this purpose and will help physicians and patients to adhere to optimal preventive strategies. VTE treatment also may be simplified with the new oral anticoagulants. With a rapid onset of action, these drugs may obviate the need for a parenteral anticoagulant for initial therapy. In addition, the new agents have the potential to streamline extended VTE therapy because, unlike vitamin K antagonists, they can be given in fixed doses without the need for coagulation monitoring.

The inability of the heparin–antithrombin complex to inhibit fibrin-bound thrombin limits the utility of heparin for treatment of arterial thrombosis. In contrast with heparin, melagatran, a direct thrombin inhibitor (DTI), is equally effective at inhibiting fluid-phase thrombin and thrombin bound to fibrin. This reflects the ability of melagatran, a reversible, active site-directed DTI, to access the active site of thrombin even when it is fibrin-bound. Because bivalent DTIs, such as hirudin, compete with fibrin for access to the fibrin-binding site on thrombin, bivalent DTIs produce less inhibition of fibrin-bound thrombin than free thrombin when given in low doses. Consequently, higher doses of hirudin are needed for complete inhibition of fibrin-bound thrombin resulting in a steep dose–response curve. This phenomenon, combined with the fact that hirudin irreversibly inhibits thrombin, may account for hirudin's narrow therapeutic window. In a rabbit arterial thrombosis prevention and ear bleeding model, melagatran produced less bleeding than hirudin when the two agents were given at doses that produced nearly complete inhibition of thrombosis. The more favourable benefit-to-risk profile of melagatran in this model likely reflects better access to fibrin-bound thrombin and the reversible nature of the melagatran/thrombin complex. The theoretical advantages of melagatran may endow it with mechanistic advantages over heparin, and safety advantages over hirudin. Large-scale clinical trials are under way to evaluate the utility of an orally active prodrug form of melagatran for prevention and treatment of venous and arterial thrombosis.

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Cancer-associated thrombosis is a major cause of morbidity and mortality. Although anticoagulation remains the mainstay for prevention and treatment of thrombosis, current anticoagulants are problematic in cancer patients. Parenteral anticoagulants, such as heparin or low-molecular heparin, require daily subcutaneous injection, whereas warfarin requires coagulation monitoring and frequent dose adjustments. Idrabiotaparinux, a reversible long-acting pentasaccharide, and new oral anticoagulants, such as dabigatran etexilate, rivaroxaban and apixaban, have been designed to replace warfarin for extended prevention or treatment of VTE. Clinical trials with these agents have yielded promising results, and dabigatran etexilate and rivaroxaban are already licensed in many countries for thromboprophylaxis after elective hip or knee replacement surgery. In the coming years, these drugs are likely to replace warfarin for most indications. This paper addresses their potential role for prevention and treatment of cancer-related thrombosis.

Patients undergoing rehabilitation after thromboembolic stroke have a relatively high incidence of venous thromboembolism (VTE). Warfarin, with a target international normalized ratio (INR) of 2.0-3.0 is effective for the prevention of VTE. However, because stroke is a major risk factor for bleeding with warfarin, a less intense regimen (target INR2.0), might safely prevent VTE in stroke rehabilitation patients.This study was a randomized, double-blind, placebo-controlled trial of 2 mg of warfarin in patients undergoing rehabilitation following completed stroke. The major efficacy endpoint was symptomatic, objectively proven VTE or asymptomatic VTE detected by monthly duplex ultrasonography (DU) of the proximal leg veins or mandatory bilateral contrast venography performed at the end of the study. The major safety endpoint was bleeding.There were 475 patients screened for enrollment, 355 had one or more exclusion criterion, and 17 had previously undetected proximal DVT on admission. Of the 103 eligible and consenting patients, 56 received warfarin and 47 received placebo. Of the randomized patients, 88 had successful venography (47 warfarin and 41 placebo). In the warfarin group, three (8%) patients had DVT and one (2%) had proximal DVT whereas in the placebo group, seven (20%) had DVT and five (13%) had proximal DVT. The risk ratio for any DVT in warfarin-treated patients relative to placebo-treated patients was 0.39 (95% confidence interval (CI), 0.13-1.37). For proximal DVT, the risk ratio was 0.17 (95% CI, 0.01-1.4). No patients suffered major bleeding.A fixed dose of 2 mg of warfarin per day in patients undergoing stroke rehabilitation is safe and associated with a relative risk reduction of about 80% in the incidence of proximal DVT and 60% in overall DVT.

Low-molecular weight heparin (LMWH) is increasingly used in place of unfractionated heparin (UFH) in patients with unstable angina, and phase II clinical trials using fondaparinux for this indication are underway. Because unstable angina patients often require urgent percutaneous coronary interventions (PCI) or aortocoronary bypass surgery, a point-of-care test is needed to monitor the anticoagulant effect of these agents. The activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are the tests most often used to monitor heparin. The purpose of this in vitro study was to determine whether the ACT or the aPTT can be used to monitor the anticoagulant effect of low-molecular weight heparin and fondaparinux. The ACT and aPTT were measured after heparin, enoxaparin or fondaparinux was added to the blood of healthy volunteers, in doses with equivalent inhibitory activity against activated factor X (factor Xa). To mimic the clinical scenario where an unstable angina patient, who has already received enoxaparin, is urgently taken for PCI or bypass surgery, the ACT was determined after heparin was added to blood containing clinically relevant doses of enoxaparin. We determined that enoxaparin produced significantly less prolongation of both the ACT and the aPTT than heparin, whereas fondaparinux had no effect on either of these tests. Addition of enoxaparin to heparin-containing plasma did not prolong the ACT beyond that produced by heparin alone. The ACT and aPTT therefore cannot be used to monitor low-molecular weight heparin or fondaparinux, highlighting the need for a point-of-care anti-factor Xa assay.

Thrombin plays a central role in thrombosis. Consequently, most current antithrombotic treatment strategies are aimed at blocking the activity of thrombin, or preventing its generation. Although heparin has been a cornerstone of treatment, it has limitations. Thus, the anticoagulant response to heparin is unpredictable, the heparin/antithrombin complex is unable to inhibit fibrin-bound thrombin, an important trigger of thrombus growth, and heparin is neutralized by platelet factor 4. Direct thrombin inhibitors were developed to overcome these limitations. Unlike heparin, direct thrombin inhibitors produce a predictable anticoagulant response that is unaffected by platelet factor 4, and they inhibit fibrin-bound thrombin. Three parenteral direct thrombin inhibitors--hirudin, bivalirudin and argatroban--are currently licensed for use in North America, and orally available direct thrombin inhibitors are under investigation. This review summarizes the clinical trial data with direct thrombin inhibitors and provides perspective on the role of direct thrombin inhibitors in the face of other new anticoagulants currently under development.