Factor XI inhibitors for the prevention of cardiovascular disease: A new therapeutic approach on the horizon?

Anticoagulant drugs that are currently used to prevent and/or treat thrombosis have some limitations that hinder their ability to meet specific clinical requirements. While these drugs effectively reduce the rates of thrombotic events, they simultaneously increase the risk of bleeding. Moreover, their risk-to-benefit balance is problematic in some patients, such as those with severe chronic kidney disease or those at high bleeding risk. A novel anticoagulation method, FXI inhibition has emerged as a promising alternative. It demonstrates a strong rationale for the prevention and treatment of venous thromboembolism and the potential fulfillment of unmet clinical needs in the cardiovascular field. A number of FXI inhibitors are currently undergoing clinical investigation. The objective of this review is to provide an overview of early results of research on FXI inhibitors in the cardiovascular setting, offering valuable insights into their potential role in shaping the future of anticoagulation.

Current and emerging drug strategies for the prevention of venous thromboembolism in acutely ill medical inpatients.

INTRODUCTION: Venous thromboembolism (VTE) is a common complication in patients hospitalized for acute medical illnesses. Therefore, medical inpatients require a careful VTE and bleeding risk assessment to drive optimal strategies for VTE prevention. Low molecular weight heparin and fondaparinux have long been used for inhospital prophylaxis for patients at increased risk of VTE. The selection of patients who require post-discharge prophylaxis, and the role of direct oral anticoagulants remain debated. New molecules currently under development may contribute to improve the risk benefit of VTE prevention in this setting. AREAS COVERED: This text summarizes the evidence on approved treatments and on other drugs for the prevention of VTE in acutely ill medical patients. The main focus is on their pharmacological properties, clinical efficacy and safety, and the current license approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency). The trials presented consider both inhospital and extended prophylaxis. EXPERT OPINION: Thanks to the potentially favorable safety profile, factor XI inhibitors may play a role in the prevention of VTE in this setting. The expert opinion section discusses pharmacological properties, prophylaxis trials, and potential clinical applications of this novel class of drugs.

Intracranial bleeding risk after minor traumatic brain injury in patients on antithrombotic drugs.

BACKGROUND: Intracranial haemorrhage (ICH) risk after minor traumatic brain injury (mTBI) in patients on antithrombotic treatment is unclear. We compared ICH rates in mTBI patients on single, double and no antithrombotic therapy. Antithrombotic drugs encompassed vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) and antiplatelets. Secondary aim was to identify potential predictors of ICH. METHODS: We retrospectively analysed consecutive adults referred to our emergency department for mTBI. All clinical information was retrieved by patients' charts review. Patients were divided in 5 groups: 1) no antithrombotic users, 2) antiplatelet users, 3) vitamin K antagonist users, 4) direct oral anticoagulants users, and 5) double antithrombotic users. RESULTS: A total of 1846 patients were enrolled, mean age 71 years (IQR 46-83); 1222 (66.2%) were in group 1, 407 (22.0%) in group 2, 120 (6.5%) in group 3, 51 (2.7%) in group 4 and 46 (2.5%) in group 5. At entry, 1387 (75.1%) patients underwent brain CT, 787 (64.4%) in group 1, 387 (95.1%) in group 2, 119 (99.2%) in group 3 and 51 (100%) in group 4 and 43 (93.5%) in group 5. ICH was documented in 36 patients (4.6%; CI 95%: 3.2-6.3) in group 1, 22 (5.9%; CI 95%: 3.6-8.5) in group 2, 5 (4.2%; CI 95%: 1.4-9.5) in group 3, 2 (3.9%; CI 95%: 0.5-13.5) in group 4 and 3 (7.0%; CI 95%: 1.5-19.1) in group 5 (p-value for across groups comparison = 0.86). At multivariable analysis GCS < 15 (OR 7.95 CI 95%: 3.12-20.28), post-traumatic amnesia (OR 6.49; CI 95%:3.57-11.82), vomiting (OR 4.45 CI 95%:1.47-13.50), clinical signs of cranial fractures (OR 8.41 CI 95%: 2.12-33.33), scalp lesions (OR 2.31 CI 95%: 1.09-4.89), but none of antithrombotic drugs were independently associated with ICH. CONCLUSION: mTBI-related ICH rate was similar in patients with and without antithrombotic use. Potential predictors of ICH can be drawn from patients' clinical examination.

Ultrasound elastography is useful to distinguish acute and chronic deep vein thrombosis.

Essentials Ultrasound elastography uses tissue deformation to assess the relative quantification of its elasticity. Compression and duplex ultrasonography may be unable to correctly determine the thrombus age. Ultrasound elastography may be useful to distinguish between acute and chronic deep vein thrombosis. The exact determination of the thrombus age could have both therapeutic and prognostic implications. BACKGROUND: Background Ultrasound elastography (UE) imaging is a novel sonographic technique that is commonly employed for relative quantification of tissue elasticity. Its applicability to venous thromboembolic events has not yet been fully established; in particular, it is unclear whether this technique may be useful in determining the age of deep vein thrombosis (DVT). Thus, the aim of this study was to assess the role of UE in distinguishing acute from chronic DVT. Methods Consecutive patients with a first unprovoked acute and chronic (3 months old) DVT of the lower limbs were analyzed. Patients with recurrent DVT or with a suspected recurrence were excluded. The mean elasticity index (EI) values of acute and chronic popliteal and femoral vein thrombosis were compared. The accuracy of the EI in distinguishing acute from chronic DVT was also assessed by measuring the sensitivity, specificity, positive and negative predictive values, and likelihood ratios. Results One-hundred and forty-nine patients (mean age 63.9 years, standard deviation 13.6; 73 males) with acute and chronic DVT were included. The mean EI of acute femoral DVT was higher than that of chronic femoral DVT (5.09 versus 2.46), and the mean EI of acute popliteal DVT was higher than that of chronic popliteal DVT (4.96 versus 2.48). An EI value of > 4 resulted in a sensitivity of 98.9% (95% confidence interval [CI] 93.3-99.9), a specificity of 99.1% (95% CI 94.8-99.9), a positive predictive value of 91.1% (95% CI 77.9-97.1), a negative predictive value of 98.6% (95% CI 91.3-99.9), a positive likelihood ratio of 13.23 (95% CI 93-653) and a negative likelihood ratio of 0.001 (95% CI 0.008-0.05) for acute DVT. Conclusions UE appears to be a promising technique for distinguishing between acute and chronic DVT. Larger prospective studies are warranted to confirm our preliminary findings.

Residual vein obstruction in patients diagnosed with acute isolated distal deep vein thrombosis associated with active cancer.

After acute proximal deep vein thrombosis (DVT) the thrombotic mass decreases, especially during the first months of anticoagulation. The persistence of residual vein obstruction (RVO) may predict future recurrence in patients with cancer-associated DVT. We aimed to evaluate the proportion of patients with RVO after an episode of cancer associated isolated distal DVT (IDDVT), to identify variables associated with RVO, and to provide initial evidence of its association with recurrent VTE. We performed a post-hoc analysis of a multicenter cohort study of patients with isolated cancer-associated acute IDDVT. We included patients who underwent a control ultrasonography at the end of the anticoagulant treatment between day 30 and day 365 after index IDDVT, given that no recurrent VTE had already occurred on anticoagulant treatment. A total of 153 patients had ultrasonographic follow-up after a median of 92 days from index IDDVT: 45.8% had RVO and 54.2% exhibited complete recanalization. Female sex, Body Mass Index > 30 Kg/m2 and involvement of axial calf veins showed the strongest association with RVO. The risk of recurrence was twofold higher in patients with (versus without) RVO. RVO persisted in approximately half of patients with an episode of cancer-associated IDDVT at anticoagulant discontinuation. Patients with RVO appeared to be at a higher risk for recurrent events.

The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism.

Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding. SUMMARY: Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.

Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study.

OBJECTIVE: To investigate the characteristics and outcome of abnormal vaginal bleeding in women receiving edoxaban or warfarin for treatment of venous thromboembolism (VTE). DESIGN AND SETTING: Post hoc analysis of the Hokusai-VTE study, a multicentre, randomised, double-blind trial comparing edoxaban with warfarin for acute symptomatic VTE. POPULATION: Women below 50 years receiving edoxaban or warfarin for treatment of VTE. METHODS: We collected data on diagnostic measures, treatment, and clinical outcome of abnormal vaginal bleeding events. MAIN OUTCOME MEASURES: Occurrence of major and clinically relevant nonmajor (CRNM) abnormal vaginal bleeding events. RESULTS: In all, 628 women aged under 50 years were treated with edoxaban and 665 with warfarin. The rate of abnormal vaginal bleeding was 15/100 person-years (py) (95% CI 11-19) in women receiving edoxaban and 9/100 py (95% CI 6-12) in the warfarin group (hazard ratio: 1.7, 95% CI 1.1-2.5). Major abnormal vaginal bleeding occurred in eight (1.3%) women on edoxaban and in three (0.9%) women receiving warfarin [odds ratio (OR) 2.8; 95% CI 0.8-10.8], and CRNM abnormal vaginal bleeding occurred in 53 (8.4%) women treated with edoxaban and in 37 (5.6%) on warfarin therapy (OR 1.6, 95% CI 1.0-2.4). Over 85% of all vaginal bleeds were characterised by heavy menstrual bleeding. Major bleeds frequently required treatment, and in more than 75% of patients anticoagulant therapy was adjusted. The severity of clinical presentation and course of major and CRNM bleeds was mild in most patients. CONCLUSIONS: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin. Reassuringly, most events could be managed conservatively and had a mild outcome. TWEETABLE ABSTRACT: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin.

Antidotes for the direct oral anticoagulants: What news?

The direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulants for both stroke prevention in patients with non-valvular atrial fibrillation and the treatment and secondary prevention of venous thromboembolism. DOACs cause bleeding, albeit less than warfarin. Most bleeding complications can be controlled by general reversal strategies and supportive care. However, in case of life-threatening bleeding, or when urgent invasive procedures are needed, a more rapid and thorough reversal may be required. Idarucizumab, andexanet alfa and ciraparantag have been developed as reversal agents for the DOACs. To date idarucizumab is the only approved antidote and is specific for dabigatran. Andexanet alfa, a reversal agent for the factor Xa inhibitors, is still under investigation, but its approval by regulatory agencies is expected soon. Ciraparantag, a universal antidote, is in an earlier stage of development. Based on the results of clinical trials to date, these compounds appear to be breakthrough for urgent and emergency reversal. When administered at fixed doses, they ensured a rapid, efficient and safe restoration of haemostasis. From a practical perspective, all hospitals should develop local protocols to ensure safe and efficient clinical implementation of reversal strategies. Post-marketing studies will be essential to assess the evolution of management strategies and to confirm the safety and effectiveness of these agents.

The effect of recanalization on long-term neurological outcome after cerebral venous thrombosis.

Essentials The role of cerebral venous thrombosis (CVT) recanalization on neurologic outcome is still debated. We studied a large cohort of 508 CVT patients with 419 patient years of radiological follow-up. Recanalization rate is high during the first months after CVT and neurologic outcome is favorable. High recanalization grade of CVT independently predicts good neurological outcome. SUMMARY: Background Studies with limited sample size and with discordant results described the recanalization time-course of cerebral venous thrombosis (CVT). The neurological outcome after a first episode of CVT is good, but the role of recanalization on neurological dependence is still debated. Objectives The aim of the study is to assess the recanalization rate after cerebral venous thrombosis (CVT) and its prognostic role in long-term neurological outcome. Patients/Methods In a retrospective observational multicenter cohort study, patients with an acute first episode of CVT with at least one available imaging test during follow-up were enrolled. Patency status of the vessels was categorized as complete, partial or not recanalized. Neurological outcome was defined using the modified Rankin scale (mRS) as good (mRS = 0-1) or poor (mRS = 2-6). Results Five-hundred and eight patients (median [IQR] age, 39 [28.5-49] years; 26% male) were included. Complete or partial recanalization was not differently represented in patients undergoing scans at different periods of time (from 28-day to 3 month-period up to a 1-3 year-period). mRS at the time of follow-up imaging was available in 483 patients; 92.8% of them had a mRS of 0-1. CVT recanalization (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.59-4.13) was positively associated, whereas cancer (OR, 0.29; 95% CI, 0.09-0.88), and personal history of venous thromboembolism (VTE) (OR, 0.36; 95% CI, 0.14-0.92) were negatively associated as independent predictors of favorable (mRS = 0-1) outcome at follow-up. Conclusions Most patients with a first CVT had complete or partial recanalization at follow-up. Recanalization was independently associated with a favorable neurological outcome.

Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm.

Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D-dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. SUMMARY: Background Age-adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age-adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3-month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut-off (defined as age times 10 µg L-1 , or age times 5 µg L-1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0-6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04-1.37) in group 1; 1.12% (95% CI, 0.44-2.85) in group 2; and 1.89% (95% CI, 0.64-5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.

Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians.

Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants SUMMARY: One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti-Xa or anti-IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter-laboratory variability and allow inter-study comparisons. The impact of the DOACs on hemostasis testing may cause false-positive or false-negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors.

Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study.

Essentials Late sequelae of isolated superficial vein thrombosis (iSVT) have rarely been investigated. We studied 411 consecutive outpatients with acute iSVT with a median follow-up of three years. Male sex and cancer are risk factors for future deep vein thrombosis or pulmonary embolism. Patients without cancer appear to be at a negligible risk for death. SUMMARY: Background Studies of long-term thromboembolic complications and death following acute isolated superficial vein thrombosis (iSVT) of the lower extremities are scarce. Objectives To investigate the course of iSVT in the setting of an observational multicenter study. Methods We collected longitudinal data of 411 consecutive outpatients with acute, symptomatic, objectively diagnosed iSVT who were previously included in the cross-sectional ICARO study. Four patients followed for < 30 days and 79 with concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE) were excluded from the present analysis. The primary outcome was symptomatic DVT or PE. The safety outcomes were major bleeding and all-cause death. Results The median follow-up time was 1026 days (interquartile range 610-1796). Symptomatic DVT/PE occurred in 52 (12.9%) patients, giving annualized rates of 1.3% (95% confidence interval [CI] 0.3-3.9%) on anticoagulant treatment and 4.4% (95% CI 3.2-5.8%) off anticoagulant treatment. Male sex (adjusted hazard ratio [HR] 2.03 [95% CI 1.16-3.54]) and active solid cancer (adjusted HR 3.14 [95% CI 1.11-8.93]) were associated with future DVT/PE, whereas prior DVT/PE failed to show significance, most likely because of bias resulting from prolonged anticoagulant treatment. Three major bleeding events occurred on treatment, giving an annualized rate of 1.4% (95 CI 0.3-4.0%). Death was recorded in 16 patients (annualized rate: 1.1% [95% CI 0.6-1.7%]), and was attributable to cancer (n = 8), PE (n = 1), cardiovascular events (n = 3), or other causes (n = 4). Conclusions The long-term risk of DVT/PE after anticoagulant discontinuation for acute iSVT is clinically relevant, especially in males and in the presence of active cancer. The risk of death appears to be negligible in patients without cancer.

External validation of the DASH prediction rule: a retrospective cohort study.

Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects. SUMMARY: Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a 'low-risk' (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51-1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.

Clinical course of isolated distal deep vein thrombosis in patients with active cancer: a multicenter cohort study.

Essentials Isolated distal deep vein thrombosis (IDDVT) is frequently associated with cancer. No study has specifically evaluated the long-term clinical course of cancer-associated IDDVT. Patients with cancer-associated IDDVT are at very high risk of symptomatic recurrence and death. We observed low rates of major bleeding during anticoagulation. SUMMARY: Background Although isolated distal deep vein thrombosis (IDDVT) is frequently associated with cancer, no study has specifically evaluated the long-term clinical course of IDDVT in this setting. Aim To provide data on the rate of recurrent venous thromboembolism (VTE), major bleeding events and death in IDDVT patients with active cancer. Patients and Methods Consecutive patients with active cancer and an objective IDDVT diagnosis (January 2011 to September 2014) were included from our files. We collected information on baseline characteristics, IDDVT location and extension, VTE risk factors, and type and duration of anticoagulant treatment. Results A total of 308 patients (mean age 66.2 [standard deviation (SD), 13.2 years]; 57.1% female) with symptomatic IDDVT and a solid (n = 261) or hematologic (n = 47) cancer were included at 13 centers. Cancer was metastatic in 148 (48.1%) patients. All but three (99.0%) patients received anticoagulant therapy, which consisted of low-molecular-weight heparin in 288 (93.5%) patients. Vitamin K antagonists were used for the long-term treatment in 46 (14.9%) patients, whereas all others continued the initial parenteral agent for a mean treatment duration of 4.2 months (SD, 4.6 months). During a total follow-up of 355.8 patient-years (mean, 13.9 months), there were 47 recurrent objectively diagnosed VTEs for an incidence rate of 13.2 events per 100 patient-years. During anticoagulant treatment, the annual incidence of major bleeding was 2.0 per 100 patient-years. Conclusions Cancer patients with IDDVT have a high risk of VTE recurrence. Additional studies are warranted to investigate the optimal intensity and duration of anticoagulant treatment for these patients.

A comparative study using thrombin generation and three different INR methods in patients on Vitamin K antagonist treatment.

INTRODUCTION: Vitamin K antagonist (VKA) treatment requires routine monitoring using the international normalized ratio (INR). However, different INR assays may vary in their results. The aim of this study was to assess the agreement of three different INR methods, compared with thrombin generation, in patients on VKA treatment. METHODS: Sixty patients attending the Anticoagulation Clinic at Mater Dei Hospital (Msida, Malta) for VKA monitoring between August and September 2015 were enrolled. The INR was tested using a point-of-care (POC) device (CoaguChek XS Plus, Roche Diagnostics) for both capillary and venous blood samples, a photo-optical (Sysmex CS-2100i/CA-1500, Siemens) and a mechanical clot detection system (Thrombolyzer XRC, Behnk Elektronik). All assays used human recombinant thromboplastin as reagent. Thrombin generation was performed using the calibrated automated thrombogram. RESULTS: There was a negative curvilinear correlation between the endogenous thrombin potential and different INR assays (r≤-.75) and a strong positive linear correlation between the CoaguChek XS Plus on capillary samples and the other INR methodologies (r≥.96). CONCLUSION: All different INR assays showed good correlation with the thrombin generation potential. The POC INR showed one of the highest correlation coefficients with thrombin generation, confirming the POC devices as an accurate, valid alternative to laboratory INR in VKA patients.

Oral contraception and menstrual bleeding during treatment of venous thromboembolism: Expert opinion versus current practice: Combined results of a systematic review, expert panel opinion and an international survey.

INTRODUCTION: The optimal management of oral contraception and menstrual bleeding during treatment of venous thromboembolism (VTE) is largely unknown. We aimed to elicit expert opinion and compare that to current practice as assessed by a world-wide international web-based survey among physicians. METHODS: 10 international thrombosis experts and 10 abnormal uterine bleeding experts independently completed a questionnaire containing three hypothetical patient cases each with four different scenarios, and additional queries covering different severities of VTE, patient circumstances, hormonal contraceptives and both thrombotic and bleeding complications. The consensus percentage was set a priori at ≥70%. The same questionnaire with randomized case scenarios was presented to international physicians via newsletters of the ISTH and national scientific communities. Differences between the expert groups and daily clinical care were assessed. RESULTS: Expert recommendations were divergent and differed in several important points from clinical practice. In contrast to common practice in which contraceptives are discontinued at the moment of a VTE diagnosis, the thrombosis experts agreed to continue oral contraception (OC) during the anticoagulation treatment period. Also, experts reached consensus on treating patients with anticoagulation-associated abnormal uterine bleeding with tranexamic acid, although this is not supported by strong evidence from the literature. No consensus was reached on the optimal anticoagulant drug class. CONCLUSIONS: International experts' opinions on handling of contraceptives and management of anticoagulant-associated abnormal uterine bleeding in female VTE patients are divergent and management in clinical practice is heterogeneous. There is a great need of further studies on these topics.

Long-term treatment of cancer-associated thrombosis: the choice of the optimal anticoagulant.

Patients with cancer-associated thrombosis (CAT) carry a higher risk of recurrence, bleeding and mortality as compared with non-cancer patients. The specific profiles of cancer patients, combining frequent co-morbidities, the use of anti-tumoral therapies and the cancer progression itself, represent a major therapeutic challenge for choosing a long-term anticoagulant treatment. This review discusses the practical basis of making a choice between the available drugs for a long-term antithrombotic strategy, linked to their pharmacology, mechanism of action, evidence of clinical benefits, and advantages and limitations in such a complex clinical context. In patients with cancer, low-molecular-weight heparins (LMWHs) are the preferred option for the secondary prevention of venous thromboembolism according to current guidelines, because their efficacy is significantly superior to vitamin K antagonists (VKAs). Even though LMWHs are effective and safe in cancer patients, they require daily subcutaneous injections, which may be problematic for a long-term therapy that may exceed 6 months' duration. Compared with VKAs, non-vitamin-K antagonist oral anticoagulants or direct oral anticoagulants (DOACs) are more target specific and do not require laboratory monitoring, whereas the oral route of administration makes them potentially attractive alternatives to LMWH. In randomized controlled trials in the general population DOACs have been shown to be non-inferior to VKAs in terms of efficacy with a lower rate of clinically relevant or major bleeding. However, given the limited number of cancer patients enrolled in these studies (with poorly defined active cancer), available trials are inconclusive regarding the usefulness of DOACs in the cancer setting. Ongoing head-to-head comparisons vs. LMWH in patients with CAT may allow an informed choice to be made regarding the DOAC option.