[Risk of recurrence and duration of anticoagulant treatment after deep venous thromboembolism and pulmonary embolism].

If anticoagulant therapy is stopped, the risk of recurrence after unprovoked venous thromboembolism is high. After anticoagulant treatment for at least three months, the indication for prolonging therapy should be decided after thorough evaluation of individual risk factors for recurrence and bleeding. Clinical parameters, imaging modalities and D-dimer levels can guide this decision. The lower risk of bleeding on non-vitamin K-antagonist oral anticoagulants compared to warfarin is expected to increase the number of patients on extended treatment, but costs and patients' preferences should be considered.

Adherence to dabigatran etexilate in atrial fibrillation patients intended to undergo electrical cardioversion.

AIMS: Effective anticoagulation in patients undergoing electrical cardioversion (ECV) for symptomatic atrial fibrillation is important to prevent adverse events. High medication adherence is a requirement. In patients with newly diagnosed atrial fibrillation (n = 169) who were intended to undergo ECV, the aim of this study was to measure self-reported short- and long-term adherence, evaluate whether dabigatran plasma concentrations reflect adherence, measure treatment satisfaction and assess whether adherence and treatment satisfaction are correlated. METHODS AND RESULTS: Plasma concentrations (liquid-chromatography tandem mass spectrometry), the 8-point Morisky Medication Adherence Scale (MMAS-8) and the Anti-Clot Treatment Scale (ACTS) were measured after 3 weeks and 7 weeks of treatment. Combined mean peak (1-3 h after intake) and trough (10-16 h after intake) plasma concentrations were 175 (SD 109) ng/mL and 75 (SD 45) ng/mL, respectively. There was no relationship between short-term adherence (last 3 days) or long-term adherence (last 3-4 weeks) and plasma concentrations, unless the last intake was more than 48 h ago. After 7 weeks high, moderate, and low adherence, according to the MMAS-8, was seen in 74%, 21%, and 5% of patients, respectively. Treatment satisfaction was high (median ACTS score 68.5, range 46-75 points). Treatment satisfaction and adherence were not correlated. CONCLUSION: The percentage of patients in the high adherence group (74%) was lower than expected, which is a matter of concern. Dabigatran plasma concentrations could not detect short- or long-term non-adherence, unless the drug was last taken more than 48 h ago. Treatment satisfaction did not correlate with adherence.

Comprehensive characteristics of the anticoagulant activity of dabigatran in relation to its plasma concentration.

BACKGROUND: Issues with laboratory measurement of dabigatran include: 1. Do coagulation assays reflect dabigatran plasma concentrations? 2. Do samples from patients treated with dabigatran have the same coagulability as dabigatran-spiked samples from healthy volunteers? 3. What is the long-term stability of dabigatran after storage at -80 °C? This study aims to evaluate these questions. MATERIALS AND METHODS: Ecarin chromogenic assay (ECA), a laboratory-developed diluted thrombin time (LD-dTT), prothrombin time (PT) and activated partial thromboplastin time (APTT) and ROTEM® were used to measure dabigatran anticoagulant activity and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure dabigatran plasma concentrations. ROTEM® (EXTEM, INTEM, FIBTEM) was performed in whole blood and the other assays in platelet poor plasma (PPP), both in samples spiked with dabigatran (0, 25, 50, 100, 250, 500 and 1000 ng/mL) from healthy donors and in ex vivo samples from patients treated with dabigatran etexilate. Citrated PPP samples were frozen and stored at -80 °C, 1, 3, 6 and 12 months until analysis. RESULTS: EXTEM and FIBTEM clotting time (CT), ECA and LD-dTT correlate well with dabigatran plasma concentrations. With the exception of few ROTEM® parameters, there were no differences between spiked and patient samples. Samples were stable for at least 12 months at -80 °C. CONCLUSIONS: EXTEM and FIBTEM CT, ECA and LD-dTT are suitable for measuring the effect of dabigatran in treated patients. In general, results from spiked plasma samples are similar to those of patient samples. Storage of dabigatran plasma samples for up to 12 months does not influence measured levels.

Measurement of dabigatran: previously demonstrated Hemoclot® Thrombin Inhibitor assay reagent instability on Sysmex CS-2100i is no longer an issue.

The Hemoclot® Thrombin Inhibitor (HTI) assay has been recommended for measurement of dabigatran concentrations in specific clinical situations. Traditionally, reagents for biochemical assays are prepared from instructions found in the package insert. For the HTI reagents the manufacturer recommends incubating the reagents much longer than indicated in the package insert. These recommendations are added to the application sheets designed for different analyzers. Many clinicians and laboratory personnel may be unaware of the discrepancy between the two instructions, resulting in incorrect handling of the reagents. The aim of this study was to investigate the effect of the two different preparation methods on reagent stability and test results. For the standard concentration range, reagent stability on Sysmex CS-2100i was only two hours instead of the eight hours indicated by the producer when following package insert instructions (incubation time: 15 min). Stability was increased to five hours when following the application sheet (incubation time: 60 min). Two years later, the study was repeated using samples of patients treated with dabigatran etexilate. This time, reagent stability was at least six hours. Since the reagent composition was unchanged, the increased stability could be due to changed logistics by the supplier, with stock and transfer closer by. Previously demonstrated HTI reagent instability is no longer an issue at our laboratory. The reliability of results of clinical studies in which the assay has been used is potentially compromised.

Cholestatic liver injury as a side-effect of dabigatran and the use of coagulation tests in dabigatran intoxication and after reversal by idarucizumab in bleeding and sepsis.

Idarucizumab, an antidote specific for dabigatran, became available recently. Dabigatran is not associated with increased risk of hepatotoxicity in comparison with warfarin, but it is seen as a rare side-effect. Cases of cholestatic liver injury due to dabigatran have not been reported previously. We present a case of severe gastro-intestinal bleeding with underlying dabigatran intoxication in a patient with renal failure and the effect of reversal of dabigatran using idaruzicumab on coagulation assays. International normalized ratio (INR) and activated partial thromboplastin time (APTT) results were elevated in a setting of sepsis, possibly due to liver failure. INR and APTT can be elevated if sepsis is complicated by disseminated intravascular coagulation (DIC) or liver failure, making it challenging to determine dabigatrans contribution to their prolongation. A rebound effect after administration of idarucizumab and slow elimination of dabigatran due to reduced kidney function could be detected using the Hemoclot® diluted thrombin time (dTT) in this situation, in contrast to with non-dilutional assays. Before admission, cholestatic liver injury started shortly after initiation of dabigatran etexilate therapy. As no other cause was found, this liver injury was likely to be drug-induced. Bleeding cessated promptly after administration of idarucizumab in dabigatran intoxication. In conclusion, the anticoagulant effect of dabigatran can be measured by Hemoclot® dTT in sepsis and cholestatic liver injury was seen as a possible rare side-effect of dabigatran treatment.

Translation, Cultural Adaptation, and Psychometric Properties of the Danish Version of the Anti-Clot Treatment Scale.

Background The Anti-Clot Treatment Scale (ACTS) is a 17-item, 2-factor (Burdens and Benefits), patient-reported outcome instrument to evaluate patient satisfaction with oral anticoagulant treatment. Objectives This study aimed to translate and culturally adapt the English version of the ACTS into Danish and to subsequently validate the Danish version in a population of patients treated with dabigatran etexilate for atrial fibrillation. Methods The ACTS was translated into Danish and culturally adapted. This prospective phase 4 study included 232 respondents who completed the Danish ACTS after 1 month of treatment with dabigatran etexilate for atrial fibrillation. Psychometric properties were evaluated. For test-retest reliability, the ACTS was measured twice, 2 weeks apart, in a subgroup of 50 stable patients. Results Generally, a high level of treatment satisfaction was found. Confirmatory factor analysis showed a suboptimal fit for the two-factor model of the original version. Using modification indices of confirmatory factor analysis, a four-factor model had the best fit. Cronbach's α for internal consistency was acceptable at 0.78. There was good test-retest reliability with intraclass correlation at 0.80. Smallest detectable changes (SDCs) for individual patients were 5.89 points for the total ACTS, 5.57 for the reverse Burdens, and 3.34 for Benefits scores. Group SDCs were 0.39, 0.37, and 0.22 respectively. Substantial ceiling effects limit the ability to detect improvement at the high end of the scale. Conclusion The Danish version of the ACTS has inadequate structural validity. Reliability was acceptable. Ceiling effects challenge detection of improvement of treatment satisfaction in clinical practice in this patient population.

Bilateral adrenal gland hemorrhage in a patient treated with rivaroxaban.

This is the report of a case of a 63-year-old woman, with a history of recurrent deep vein thrombosis, who was admitted with abdominal pain and diagnosed with bilateral adrenal hemorrhage, resulting in acute adrenal insufficiency. Several risk factors for adrenal hemorrhage were present: stress because of infection, treatment with the factor Xa-inhibitor rivaroxaban and the presence of antiphospholipid antibodies. Venous thrombosis of the adrenal glands with subsequent hemorrhagic infarction is a possible mechanism. It is currently unclear if patients with antiphospholipid syndrome can be treated effectively and safely with a nonvitamin K-antagonist oral anticoagulant.

Reversal Strategies for NOACs: State of Development, Possible Clinical Applications and Future Perspectives.

The non-vitamin K antagonist oral anticoagulants (NOACs) are used for thromboembolic prophylaxis of patients with atrial fibrillation and in the treatment as well as secondary prophylaxis of patients with venous thromboembolism. Even though NOACs have a better safety profile than vitamin K antagonists (VKAs), there will still be bleeding complications on NOAC treatment. In some cases, stopping the NOAC and non-drug-related management such as manual compression and interventional endoscopy will be sufficient to stop the bleeding. In more serious bleeding events and before acute surgery, coagulation factor concentrates or NOAC-specific antidotes could be used. Coagulation factor concentrates can be used in patients with haemophilia and to reverse the effect of VKAs but, in NOAC-treated patients, results are inconsistent and these agents could potentially have pro-thrombotic effects. Specific antidotes for NOACs are expected to be on the market soon. Phase III clinical trials with a humanized antibody fragment directed against dabigatran (idarucizumab) and recombinant, modified factor Xa (andexanet alfa) are ongoing. A molecule (aripazine) with broad activity against various anticoagulants including NOACs is currently undergoing phase II trials. For use of these specific antidotes, it is desirable that measurements for coagulation activity with a short response delay are widely available for the different NOACs and further research in this field is needed. Furthermore, guidelines for antidote use, including general measures for the treatment of NOAC-related bleeding, should be available.

Traditional SCORE-based health check fails to identify individuals who develop acute myocardial infarction.

INTRODUCTION: Atherosclerotic cardiovascular disease (CVD), including acute myocardial infarction (AMI), is caused by well-known risk factors. They constitute important therapeutic targets, but their predictive value is disputed. We evaluated the effectiveness of the risk scoring system (SCORE) and thresholds for pharmacotherapy re-commended in the European guidelines on CVD prevention. MATERIAL AND METHODS: The medical records of 605 consecutive patients hospitalized for a first AMI were reviewed. Patients with pre-existing CVD, diabetes, or incomplete information on risk factors were excluded. Those not treated with statin before AMI were risk stratified based on risk factors. A SCORE ≥ 5% or ≥ 10% was considered to qualify for preventive medication in young adults (age ≤ 60 years) or elderly (age > 60 years), respectively. RESULTS: Before AMI, 40 (9%) used statin. Among non-statin users, only five of the 109 young adults had a SCORE ≥ 5%, and 23 of the 284 elderly had a SCORE ≥ 10%. Among women, only three elderly qualified for treatment. More than four times more patients would have qualified for treatment with the high-risk country chart used in 2011. The incremental value of the novel high-density lipoprotein adjusted SCORE charts was limited. CONCLUSION: Few patients admitted with a first AMI used statin. Among non-statin users, SCORE and the recommended thresholds for pharmacotherapy identified no women and less than one out of ten men who untreated were destined for an AMI before 61 years of age. The preventive potential of a traditional risk factor-based health check is limited. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.