Nick van Es

Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials

In the last 4 years, 6 phase 3 trials including a total of 27,023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding.

Deep vein thrombosis and pulmonary embolism

Deep vein thrombosis and pulmonary embolism, collectively referred to as venous thromboembolism, constitute a major global burden of disease. The diagnostic work-up of suspected deep vein thrombosis or pulmonary embolism includes the sequential application of a clinical decision rule and D-dimer testing. Imaging and anticoagulation can be safely withheld in patients who are unlikely to have venous thromboembolism and have a normal D-dimer. All other patients should undergo ultrasonography in case of suspected deep vein thrombosis and CT in case of suspected pulmonary embolism. Direct oral anticoagulants are first-line treatment options for venous thromboembolism because they are associated with a lower risk of bleeding than vitamin K antagonists and are easier to use. Use of thrombolysis should be limited to pulmonary embolism associated with haemodynamic instability. Anticoagulant treatment should be continued for at least 3 months to prevent early recurrences. When venous thromboembolism is unprovoked or secondary to persistent risk factors, extended treatment beyond this period should be considered when the risk of recurrence outweighs the risk of major bleeding.

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Background Low‐molecular‐weight heparin is the standard treatment for cancer‐associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. Methods In this open‐label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low‐molecular‐weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. Results Of the 1050 patients who underwent randomization, 1046 were included in the modified intention‐to‐treat analysis. A primary‐outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, ‐3.4 percentage points; 95% CI, ‐7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). Conclusions Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682.)

Edoxaban for treatment of venous thromboembolism in patients with cancer: Rationale and design of the hokusai VTE-cancer study

Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial

BACKGROUND Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial. METHODS We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight <60 kg, or who were receiving concomitant treatment with the P-glycoprotein inhibitors quinidine or verapamil) or warfarin (dose adjusted to maintain the international normalised ratio between 2·0 and 3·0) or placebos for either group for at least 3 months up to 12 months. All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days. Edoxoban (or placebo) was started after discontinuation of initial heparin; warfarin (or placebo) started concurrently with the study regimen of heparin. In our analysis we examined data for a subgroup of these patients who had a history of cancer or who had been categorised as having active cancer by the study physician at the time of enrolment. Additionally, all patients with a history of cancer were reviewed post hoc and categorised according to the presence or absence of active cancer. The primary efficacy outcome was the proportion of these patients with symptomatic recurrent venous thromboembolism during the 12-month study period, analysed in the modified intention-to-treat population, with an upper limit of the CI for the hazard ratio (HR) of 1·5. The principal safety outcome was the proportion of patients who had clinically relevant bleeding in the population of patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT00986154. FINDINGS Of 771 patients with cancer enrolled in the trial, 378 were assigned to edoxaban and 393 to warfarin. Recurrent venous thromboembolism occurred in 14 (4%) of 378 patients given edoxaban and in 28 (7%) of 393 patients given warfarin (hazard ratio [HR] 0·53, 95% CI 0·28-1·00; p=0·0007). The upper limit of this 95% CI did not exceed the non-inferiority margin of 1·5 that was prespecified for the trial. Clinically relevant bleeding (major or non-major) occurred in 47 (12%) of 378 patients who received edoxaban and in 74 (19%) of 393 patients who received warfarin; HR for clinically relevant bleeding 0·64, 95% CI 0·45-0·92; p=0·017. Major bleeding occurred in ten (3%) of 378 patients with a history of cancer who received edoxaban and in 13 (3%) of 393 who received warfarin (HR 0·80, 95% CI 0·35-1·83). INTERPRETATION Edoxaban might be as effective as warfarin for the treatment of patients with cancer with venous thromboembolism, and with less clinically relevant bleeding. Additional clinical trials of edoxaban versus low-molecular-weight heparin for the treatment of venous thromboembolism in patients with cancer are warranted. FUNDING Daiichi Sankyo.

Wells Rule and D-Dimer Testing to Rule Out Pulmonary Embolism A Systematic Review and Individual-Patient Data Meta-analysis

The diagnosis of pulmonary embolism (PE) cannot be based on clinical features alone because the signs and symptoms of PE are not specific (1). Objective imaging tests, including computed tomography pulmonary angiography (CTPA), are therefore warranted to confirm or refute the presence of PE (2). Only 15% to 25% of presenting patients have PE (3), so CTPA is not an appropriate first-line test because of radiation exposure, costs, and risk for contrast-induced nephropathy. To guide decisions about who should be referred for imaging, various diagnostic algorithms have been developed over the past 2 decades. They aim to identify patients at low risk for PE in whom imaging and anticoagulant treatment can be safely withheld. One frequently used algorithm consists of the sequential application of the dichotomized Wells rule (4), which estimates the clinical probability of PE, and d-dimer testing. Pulmonary embolism can be considered ruled out in patients with a Wells score of 4 or less and a negative d-dimer test result (conventionally 500 g/L) (5). This combination is present in approximately 30% to 40% of those with suspected PE (3). The latter proportion is commonly called the efficiency of the algorithm. The proportion of these patients with symptomatic venous thromboembolism (VTE) during 3-month follow-up (the failure rate) is less than 1% (3). It has recently been shown that the efficiency can be safely increased by applying an age-adjusted d-dimer positivity threshold, which is defined as the age of patients multiplied by 10 g/L in those older than 50 years (6). Although many studies have validated the clinical utility and safety of the dichotomized Wells rule combined with d-dimer testing in excluding PE, an individual-patient data (IPD) meta-analysis can address important questions with greater precision and power. First, what is the overall efficiency and safety of the Wells rule and fixed d-dimer testing? Second, what is the performance of this strategy in clinically important subgroups? Third and most important, how do the efficiency and safety of age-adjusted d-dimer testing compare with fixed d-dimer testing? To answer these questions, we did a systematic review and IPD meta-analysis combining patient-level data from 6 large, prospective outcome studies in which diagnostic management of clinically suspected PE had been guided by the Wells rule and d-dimer testing. Using the fixed and age-adjusted d-dimer thresholds, we estimated the efficiency and failure rate of this diagnostic algorithm overall; in inpatients; and in persons with cancer, chronic obstructive pulmonary disease (COPD), age 75 years or older, previous VTE, and delayed presentation. Methods We developed a protocol (Supplement) and followed the guidance of the PRISMA-IPD (Preferred Reporting Items for Systematic reviews and Meta-Analyses of individual participant data) Statement (7). Supplement. Supplementary Material Supplement. Statistical Code Data Sources and Searches We searched MEDLINE and EMBASE from 1 January 1998 (the year in which the Wells score was introduced) (8) to 13 February 2016. The search was based on a previously published search strategy (3), which included terms for pulmonary embolism and d-dimer, and an adapted search filter for diagnostic and prognostic studies (9). We restricted the search to original studies in adults. No language restrictions were applied. The full search strategy is provided in Appendix Table 1. Two authors (N.E. and T.H.) independently screened the titles and abstracts of the identified articles and independently assessed the full-text articles for eligibility. Conflicts were resolved by discussion. Appendix Table 1. Full Electronic Search Strategy Study Selection Eligible studies included those that had prospectively enrolled, consecutive, hemodynamically stable adults presenting in a secondary care setting (emergency department or inpatient ward) with signs and symptoms suggestive of acute PE. At the individual level, the clinical probability of PE had to be assessed by the Wells rule and followed by quantitative d-dimer testing in patients with a Wells score of 4 or less (indicating PE unlikely). According to the study protocol, patients with a PE-unlikely Wells score and a negative d-dimer test result were to be managed without imaging and anticoagulant therapy but prospectively followed for 3 months to document the occurrence of VTE (Appendix Figure). By applying these criteria, we aimed to identify all studies that prospectively evaluated the current diagnostic management of patients with suspected PE in a secondary care setting. Appendix Figure. Diagnostic management of pulmonary embolism in the present IPD meta-analysis. IPD= individual-patient data; PE= pulmonary embolism. * The Wells score is a sum score of the following 7 variables: alternative diagnosis less likely than PE (3 points), clinical signs and symptoms of deep venous thrombosis (3 points), previous deep venous thrombosis or PE (1.5 points), tachycardia (1.5 points), immobilization or surgery within the past 4 wk (1.5 points), active cancer (treatment in the past 6 mo, current treatment, or palliative care; 1 point), and hemoptysis (1 point). Fixed d-dimer testing (500 g/L) or age-adjusted d-dimer testing (age10 g/L in patients aged >50 years), according to study protocol. Data Extraction and Quality Assessment Authors of studies fulfilling the inclusion criteria were invited to provide IPD, and all agreed. We sought study-level information on d-dimer assays used; imaging tests done to confirm PE; and definitions of the outcomes, regardless of whether outcome measures were adjudicated by an independent committee. Patient-level data collected at baseline included information on demographics, risk factors for VTE, Wells score items, d-dimer levels (converted to g/L), and results of imaging tests. We also collected follow-up data about anticoagulant treatment for reasons other than VTE, symptomatic VTE, mortality, or loss to follow-up. We followed the subgroup definitions used in each study without any adjustments and ascertained these definitions by the case report forms of the studies and variable labels in the study databases. Two authors who were not involved in the original studies independently assessed each study for potential sources of bias and applicability concerns using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool (10). Data Synthesis and Analysis Our analysis focused on the efficiency and failure rate of the diagnostic strategy. Efficiency was defined as the number of patients with a Wells score of 4 or less and a negative d-dimer test result relative to the total number of patients. We evaluated the efficiency of 2 d-dimer positivity thresholds: the conventional, fixed threshold of 500 g/L and an age-adjusted threshold, which was defined as the age of patients multiplied by 10 g/L in patients older than 50 years. For example, the age-adjusted strategy in a patient aged 75 years would lead to a d-dimer positivity threshold of 750 g/L. To evaluate age-adjusted d-dimer testing in our study, we reclassified patients enrolled in studies that evaluated fixed d-dimer testing according to the age-adjusted d-dimer threshold post hoc. The failure rate was defined as the proportion of patients with symptomatic deep venous thrombosis, nonfatal PE, or fatal PE during 3-month follow-up or objectively confirmed PE at baseline that was previously ruled out on the basis of a Wells score of 4 or less and a negative d-dimer test result. Death was considered to be caused by PE if it was confirmed by autopsy, if an imaging test for PE yielded positive results just before death, or in the case of sudden death due to unknown reasons. The efficiency and failure rates were calculated overall and in clinically important high-risk subgroups, including inpatients and patients with cancer, COPD, age 51 to 74 years, age 75 years or older, previous VTE, and symptoms lasting more than 7 days. Statistical Analysis To avoid bias associated with excluding missing data (11), we used multiple imputation separately within each study (10 times). The proportion of missing values is reported in Appendix Table 2. Results across the multiply imputed data sets were combined by using the Rubin rule (12) (Appendix). Appendix Table 2. Proportion of Missing Values in Each Study* A single-stage meta-analytic approach was used (13, 14) to analyze the efficiency and failure rates. The overall efficiency (the proportion of patients in whom imaging could be withheld) was estimated using a multilevel logistic regression model (also called a generalized linear mixed-effects model), with the combination of a Wells score of 4 or less and a negative d-dimer test result as the outcome variable. To account for the clustering of observations within studies, we specified a random effect for the intercept. For the analysis in subgroups, we used a full random-effects model (13) by adding the subgroup indicator as a covariate and allowing a study-specific random effect. From these models, we calculated the marginal probabilities (with 95% CIs) of having a PE-unlikely Wells score and a negative d-dimer test result, both overall and in the different subgroups (Appendix). Differences in efficiency between subgroups were tested by using the Wald test statistic with the significance level set at 0.05. The absolute difference in the efficiency of the fixed and age-adjusted d-dimer testing strategies was calculated by subtracting the point estimates of the marginal probabilities from the 2 models. The 95% CIs around these estimates were obtained by repeating the analyses in 500 bootstrap samples (Appendix). Using similar methods, we estimated the failure ratethe proportion of patients with symptomatic VTE during 3-month follow-up in whom the Wells score and d-dimer test result had ruled out PE at baseline. The outcome variable in this multilevel logistic re

Extracellular vesicles, tissue factor, cancer and thrombosis – discussion themes of the ISEV 2014 Educational Day

Although the association between cancer and venous thromboembolism (VTE) has long been known, the mechanisms are poorly understood. Circulating tissue factor–bearing extracellular vesicles have been proposed as a possible explanation for the increased risk of VTE observed in some types of cancer. The International Society for Extracellular Vesicles (ISEV) and International Society on Thrombosis and Haemostasis (ISTH) held a joint Educational Day in April 2014 to discuss the latest developments in this field. This review discusses the themes of that event and the ISEV 2014 meeting that followed.

Cancer-associated unsuspected pulmonary embolism

Clinically unsuspected pulmonary embolism (UPE) is frequently diagnosed in cancer patients undergoing routine computed tomography scans for staging purposes or treatment response evaluation. The reported incidence of UPE ranges from 1% to 5% which probably represents an underestimation. A significant proportion of cancer patients with UPE actually do have pulmonary embolism (PE) related symptoms. However, these can erroneously be attributed to the cancer itself or to cancer therapy leading to a delayed or missed diagnosis. The incidence of UPE is likely to increase further with the improvements of imaging techniques. Radiologic features of UPE appear similar to symptomatic PE with nearly half of the UPE located in central pulmonary arteries and one third involving both lungs. UPE in cancer patients is not a benign condition with rates of recurrent venous thromboembolic events, bleeding and a mortality rate comparable to cancer patients with symptomatic PE. Current guidelines suggest that UPE should receive similar initial and long-term anticoagulant treatment as for symptomatic PE. However, direct evidence regarding the treatment of UPE is scarce and treatment indications are largely derived from studies performed in cancer patients with symptomatic venous thromboembolism. Selected subgroups of cancer patients with UPE such as those with sub-segmental UPE may be treated conservatively by withholding anticoagulation and avoiding the associated bleeding risk, although this requires further evaluation.

Clinical Significance of Tissue Factor-Exposing Microparticles in Arterial and Venous Thrombosis.

Microparticles (MP) are small extracellular vesicles (30-1,000 nm) that are released from activated cells or platelets. Exposure of negatively charged phospholipids and tissue factor (TF) renders MP procoagulant. Normal plasma levels of intravascular TF-exposing MP (TFMP) are low, but their number may rise in pathological conditions, including cancer and infectious disease. Emerging evidence indicates an important role for these circulating TFMP in the pathogenesis of thrombotic complications such as venous thromboembolism and disseminated intravascular coagulation, whereas their contribution to arterial thrombosis is less studied. Despite serious limitations of the currently available assays for measuring TFMP levels or the procoagulant activity associated with TFMP with respect to sensitivity and specificity, the scientific interest in TFMP is rapidly growing because their application as prognostic biomarkers for thrombotic complications is promising. Future advances in detection methods will likely provide more insight into TFMP and eventually improve their clinical utility.

Effects of cancer on platelets.

The main function of circulating platelets is to stop bleeding upon vascular injury by the formation of a hemostatic plug. The presence of cancer results in numerical and functional abnormalities of platelets. Thrombocytosis is commonly observed in cancer patients and is associated with decreased survival. Conversely, thrombocytopenia has been shown to have antimetastatic effects in experimental models. Tumor cells also can induce changes in the platelet activation status, both in direct and indirect manners. Direct tumor cell-induced platelet aggregation enables the formation of a cloak of aggregated platelets around circulating tumor cells (CTCs) that shields them from attacks by the immune system and facilitates metastasis to distant sites. Cancer also can induce platelet activation in various indirect ways. Tumor cells shed small extracellular vesicles that expose the transmembrane protein tissue factor (TF)--the initiator of the extrinsic coagulation cascade. The abundant presence of TF in the circulation of cancer patients can result in local generation of thrombin, the most potent platelet activator. Another pathway of indirect platelet activation is by increased formation of neutrophil extracellular traps in the presence of tumor-secreted granulocyte colony-stimulating factor (G-CSF). Last, tumor cells may regulate the selective secretion of angiogenic proteins from platelet granules, which enables the tumor to stimulate and stabilize the immature neovasculature in the tumor environment. Since there is little doubt that the cancer-induced platelet alterations are beneficial to tumor growth and dissemination, it could be worthwhile to intervene in the underlying mechanisms for anticancer purposes. Antiplatelet and anticoagulant agents that inhibit platelet activation and thrombin generation can potentially slow cancer progression, although the clinical evidence thus far is not unequivocal.