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BACKGROUND: Many patients with heart failure (HF) are treated with warfarin or non-vitamin K oral anticoagulants (NOACs). Randomized outcome-driven comparisons of different anticoagulant strategies in HF are lacking. Data from international, government-mandated registries may be useful in understanding the real-life use of various anticoagulants and how they are linked to outcomes.STUDY QUESTION: To assess 2015 annual all-cause mortality, myocardial infarction, and stroke rates co-reported for warfarin and NOACs in subjects with and without HF in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.STUDY DESIGN: We extracted and examined outcome cases in subjects with HF and on warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban and stratified these according to anticoagulants.MEASURES AND OUTCOMES: Annual all-cause mortality, myocardial infarction, and stroke in FAERS.ANALYSIS METHOD: Odds ratio (OR) and χ(Equation is included in full-text article.)for oral anticoagulants from FAERS with and without HF among complete primary reports issued in 2015.RESULTS: FAERS reported 137,026 HF cases, with death co-reported in 42,942 (31.3%). In total, 11,278 (8.2%) HF patients were treated with anticoagulants, with more prescribed warfarin (n = 8260) than all NOACs combined (n = 3018). Very few reports for edoxaban were available. Warfarin consistently displayed a signal for excess adverse events compared to NOACs: OR (95% confidence interval) for the composite of mortality, myocardial infarction, and stroke were 1.91 (1.76-2.07) versus apixaban, 1.92 (1.81-2.03) versus dabigatran, 4.09 (3.38-4.37) versus rivaroxaban, and 2.64 (2.53-2.76) versus all NOACs combined (all P < 0.001). Warfarin, compared to all NOACs combined, demonstrated higher rates of all-cause mortality [OR = 2.69 (95% confidence interval, 2.49-2.90)], myocardial infarction [5.30 (4.17-6.74)], stroke [OR = 8.85 (6.61-11.84)], and ischemic stroke [OR = 12.73 (8.87-18.27); all P < 0.001].CONCLUSIONS: Annual 2015 FAERS profiles in HF patients reveal that warfarin was numerically dominant. Warfarin was associated with higher risk of death, myocardial infarction, and stroke compared to NOACs. These observational data provide real-world insight into a potential safety benefit of NOACs over warfarin in the setting of HF.

Objective: Inactivation of matrix Gla protein (MGP), using vitamin K antagonists or vitamin K deficiency results in increased vascular calcification, which has been associated with increased risk of symptomatic or ruptured abdominal aortic aneurysm (AAA). Insufficient activation of MGP leads to increased levels of undercarboxylated forms of MGP, measured as a dephosphorylated, undercarboxylated MGP (dp-ucMGP) in plasma. This study aimed to investigate whether the level of inactivated MGP influenced the risk of having an AAA, the risk of AAA progression, and overall mortality. Methods: This combined case control and cohort study was based on data from the randomised, clinically controlled Viborg Vascular (VIVA) screening trial. Cases (n = 487) with an AAA and controls (n = 189) with neither peripheral artery disease nor AAA, had their plasma quantified for dp-ucMGP. Plasma levels were compared with the presence of an AAA, AAA growth rate, need for repair, and overall mortality. dp-ucMGP was divided into tertiles in regression analyses. Results: The plasma levels of dp-ucMGP were higher for AAA cases compared with controls (median of 517 pmol/L vs. 495 pmol/L, p = .036). Adjusted analyses regarding dp-ucMGP being predictive of AAA, AAA growth rate, and need for repair all failed to show correlation. Overall mortality for AAA cases exhibited a significant association for the third tertile of dp-ucMGP with a hazard ratio of 2.55 (95% CI 1.29 – 5.05) compared with the first tertile. Overall mortality for controls was not correlated with dp-ucMGP plasma levels. Conclusion: dp-ucMGP did not correlate with the risk of having an AAA, AAA growth rate, or risk of surgery. For people with an AAA, dp-ucMGP was correlated with an increased mortality risk for the highest tertile of dp-ucMGP. This could suggest a role for prophylactic measures with vitamin K2 supplements to people at risk of AAA.

Aims: To determine the preventability of serious adverse drug reactions (ADRs) related to the use of direct oral anticoagulants (DOACs), and to explore contributing factors to preventable ADRs. Results were compared with vitamin K antagonists (VKAs). Methods: We conducted a prospective observational study in the emergency departments of two teaching hospitals from July 2015 to January 2016. Patients admitted with a thrombotic or bleeding event while under DOAC or VKA were included. Four independent reviewers assessed causality, seriousness and preventability of ADRs using pilot-tested scales. For cases of serious and potentially preventable ADRs, we performed semi-structured interviews with general practitioners to identify contributing factors to ADRs. The primary outcome was the proportion of serious ADRs that were potentially preventable. Results: The analysis included 46 DOAC and 43 VKA patients (median age 79 years). Gastrointestinal (n = 34) and intracranial (n = 16) bleedings were the most frequent ADRs. Results were that 53% of DOAC- and 61% of VKA-related serious ADRs were deemed potentially preventable. Prescribing issues and inadequate monitoring were frequent for DOAC and VKA respectively. We identified many causes of preventable ADRs that applied to all oral anticoagulants, such as pharmacodynamic drug interactions and lack of communication. Conclusions: More than half of serious ADRs were potentially preventable for both DOACs and VKAs. Interventions focusing on prescribing, patient education and continuity of care should help improve the use of DOACs in practice.

Background: Despite the efficacy of vitamin K antagonists against stroke in patients with atrial fibrillation (AF), the underuse of this therapy is well documented. Objectives: To evaluate trends and predictors of oral anticoagulants utilization in patients with AF. Methods: Observational, retrospective, serial cross-sectional study between 2011-2016. Comparisons between groups were performed using the Student t, Mann-Whitney and Chi-square tests. Logistic regression was used to identify independent predictors of anticoagulation. A p value < 0.05 was considered significant. Results: A total of 377 patients were analyzed. The mean age was 70 ± 15 years; 52% were male and 75% were anticoagulated (20% with VKA and 55% with DOAC). Over 5 years, the overall frequency of anticoagulation increased by 22.4%. The use of DOACs increased from 29% to 70%, whereas the use of VKA decreased from 36% to 17%. The use of antiplatelet agents alone also fell from 21% to 6%. The predictors of anticoagulation were previous episodes of AF (OR 3.1, p < 0.001), hypertension (OR 3.0, p < 0.001) and HASBLED score (OR 0.5, p < 0.001). The predictors of DOAC use were serum creatinine (OR 0.2, p = 0.002), left atrial size (OR 0.9, p = 0.003) and biological valve prosthesis (OR 0.1, p = 0.007). Of the 208 patients using DOACs, 63 (30%) received inadequate prescriptions: 5 with severe drug interactions and 58 with incorrect dosing. Conclusions: Between 2011 and 2016, DOACs were rapidly incorporated into clinical practice, replacing AVKs and antiplatelets, and contributing to greater use of anticoagulation in patients with AF.

International audience; Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.

Introduction: The availability of non-vitamin K antagonist oral anti-coagulants alongside vitamin K antagonists has offered a variety of options for anti-coagulation, but has also necessitated a good understanding of the pharmacological properties of each of these drugs prior to their use, to maximise the therapeutic benefit and minimise patient harm Areas covered: This review article outlines the pharmacokinetic and pharmacodynamic profiles of the currently licensed VKAs and NOACs that are most commonly used in clinical practice, with the aim of demonstrating how variations in these characteristics influence their use in clinical practice. A literature search was conducted on PubMed using keywords and relevant articles published by the 31 st of December 2018 were included. Expert opinion: The effect of a drug is determined by a combination of elements which include patient characteristics and external factors, in addition to its pharmacokinetic and pharmacodynamic properties. A good understanding of these is essential. Despite the wealth of information available, particularly on VKAs, our knowledge on the pharmacology responsible for certain drug effects and inter-individual variations is still limited. Increasing efforts are being made to understand these and include focus on pharmacogenomics and drug transporter proteins.

Both atrial fibrillation (AF) and chronic kidney disease (CKD) are highly prevalent, especially with increasing age and associated comorbidities, such as hypertension, diabetes, heart failure, and vascular disease. The relationship between both AF and CKD seems to be bidirectional: CKD predisposes to AF while onset of AF seems to lead to progression of CKD. Stroke prevention is the cornerstone of AF management, and AF patients with CKD are at higher risk of stroke, mortality, cardiac events, and bleeding. Stroke prevention requires use of oral anticoagulants, which are either vitamin K antagonists (eg, warfarin), or the nonvitamin K antagonist oral anticoagulants (NOACs). While NOACs have been shown to be effective in mild-to-moderate renal dysfunction, there are a paucity of data regarding NOACs in severe and end-stage renal dysfunction. This review first discusses the evidence for NOACs in CKD. Second, we summarize the current knowledge regarding the efficacy and safety of NOACs to prevent AF-related stroke and systemic embolism in severe and end-stage renal disease.

Aims: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used as thromboembolic prophylaxis in cardioversion. We examined the waiting time to cardioversion and the outcomes in patients with non-valvular atrial fibrillation (AF) of > 48 h of duration who were treated with either NOACs or warfarin.Methods and results: Anticoagulation was handled in a structured, multidisciplinary AF-clinic. The objectives were the waiting time to cardioversion, and thromboembolism and major bleeding events within 60 days. In total, 2150 electrical cardioversions were performed; 684 (31.8%) of patients were on NOACs and 1466 (68.2%) were on warfarin. The waiting time to non-TOE-guided cardioversion was significantly shorter in the NOAC group compared with the warfarin group for all cardioversions (P Conclusion: In a real-world clinical setting with anticoagulation handled in a structured multidisciplinary AF clinic, the waiting time to cardioversion was shorter with NOACs compared to warfarin. The rates of thromboembolism and major bleeding events were low, with NOACs shown to be as effective and safe as warfarin.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been proposed as an alternative to vitamin K antagonists (VKA) for atrial fibrillation (AF) patients. Some studies have proposed that well-managed warfarin therapy is still a valid alternative as efficacious as NOACs but the potential impact and absolute effect of NOACs in "real world" optimally management of VKA AF patients is unknown.PURPOSE: To estimate the potential absolute benefit in clinical outcome rates if the optimally anticoagulated "real-world" AF patients with acenocoumarol had been treated with NOACs.METHODS: We included 1361 patients stable on acenocoumarol with a time in therapeutic range of 100% for the previous 6months and 6.5years of follow-up. The estimation of clinical events avoided was calculated applying absolute risk reductions, relative risk reductions and hazard ratios from the pivotal clinical trials, relative to acenocoumarol.RESULTS: Compared to acenocoumarol, the highest estimated event reduction for stroke was seen with dabigatran 150mg, with an estimated reduction of 0.53%/year. For major bleeding, the highest estimated reduction was seen with apixaban (0.88%/year). For mortality, the largest estimated reduction was with dabigatran 150mg (0.75%/year). In net clinical outcome, apixaban had the estimated highest reduction (1.23%/year). All NOACs showed significantly lower rates for intracranial haemorrhage.CONCLUSION: In optimally acenocoumarol anticoagulated AF patients, estimated reductions in stroke, bleeding and net clinical outcomes with various NOACs are evident. NOACs would potentially show an improvement even among optimally VKA AF patients.

BACKGROUND: Optimal time in therapeutic range (TTR) of vitamin K antagonists (VKAs) is crucial for cardiovascular events (CVEs) prevention in non-valvular atrial fibrillation (NVAF). The relationship between temporal changes of TTR and the incidence of CVEs has been poorly investigated. We investigated 1) temporal trends of TTR in a long-term follow-up of NVAF patients; 2) the incidence of CVEs according to changes of TTR.METHODS: Prospective observational study including 1341 NVAF outpatients (mean age 73.5 years, 42.5% male) starting VKAs. Patients were divided into 4 groups: Group 0: Optimal TTR, consistently ≥70% (n = 241); Group 1: Temporally worsening TTR, from above to below 70% (n = 263); Group 2: Temporally improving TTR, from below to above 70% (n = 270); Group 3: Suboptimal TTR, consistently RESULTS: In a mean follow-up of 37.7 months (4214.2 patient-years), 108 CVEs occurred (2.6%/year). Survival analysis showed a graded increased risk of CVEs in relation to temporal changes in TTR, with the worst outcomes in Groups 1 and 3 (log-rank test p = 0.013). Multivariable Cox proportional hazards regression analysis showed that Group 1 vs. 0 (HR: 2.096; 95%CI 1.061-4.139, p = 0.033), Group 3 vs. 0 (HR: 2.292; 95%CI 1.205-4.361, p = 0.011), CHA2DS2VASc score (HR:1.316; 95%CI 1.153-1.501, p CONCLUSION: A decrease of TTR

Background Cardiovascular disease is the leading cause of death in end-stage renal disease and is strongly associated with vascular calcification. Both kidney transplantation and phosphate binders may lower the risk of vascular calcification. Vascular calcification is actively inhibited by vitamin-K-dependent matrix γ-carboxyglutamic acid protein (MGP). Whether kidney transplantation or phosphate binders affect vitamin K status is unknown. Therefore, we studied the influence of kidney transplantation and phosphate binder use on vitamin K status. Methods We measured plasma desphospho-uncarboxylated MGP (dp-ucMGP), a marker reflecting low vitamin K status, in a cross-sectional study of patients on hemodialysis (n = 82), peritoneal dialysis (n = 31) or who recently received a kidney transplantation (n = 36). By medication inventory, we assessed phosphate binder use. With linear regression, we assessed the influence of kidney transplantation and phosphate binder use on natural-log-transformed dp-ucMGP, adjusting for potential confounders. Results Mean age of patients was 52±13 years; 102 (68%) were male. Dp-ucMGP levels were significantly lower in kidney transplant recipients (median 689 pmol/L) compared to patients on dialysis (median 1537 pmol/L, p

Background— We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake Methods and Results— This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICH any ), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICH ECASS-II ) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICH NINDS ); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8–22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1–1.6). ICH any was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICH ECASS-II and sICH NINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. Conclusions— IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

PURPOSE: The efficacy and tolerability of vitamin K antagonists (VKAs) depends on the quality of anticoagulant control, reflected by the mean time in therapeutic range (TTR) of international normalized ratio 2.0 to 3.0. In the present study, we aimed to investigate the association between TTR and change in TTR (ΔTTR) with the risk of mortality and clinically significant events in a consecutive cohort of atrial fibrillation (AF) patients.METHODS: We included 1361 AF patients stable on VKAs (international normalized ratio 2.0-3.0) during at least the previous 6 months. After 6 months of follow-up we recalculated TTR, calculated ΔTTR (ie, the difference between baseline and 6-month TTRs) and investigated the association of both with the risk of mortality and "clinically significant events" (defined as the composite of stroke or systemic embolism, major bleeding, acute coronary syndrome, acute heart failure, and all-cause deaths).FINDINGS: The median ΔTTR at 6 months of entry was 20% (interquartile range 0-34%), 796 (58.5%) patients had a TTR reduction of at least 20%, while 330 (24.2%) had a TTR IMPLICATIONS: Our findings suggest that in AF patients anticoagulated with VKAs, a change in TTR over 6 months (ie, ΔTTR) is an independent risk factor for mortality and clinically significant events. Even in a cohort with good anticoagulation control, the risk for mortality and clinically significant events increases with every point deterioration of TTR.

Anti-vitamin K (AVK) were the only oral anticoagulants available for the treatment of venous thromboembolism for about half a century until the recent approval of novel oral agents dabigatran, rivoraxaban, apixaban and edoxaban. Randomized phase 3 trials have demonstrated that patients receive similarly effective anticoagulation with the DOACs when compared with warfarin, with similar or reduced risk of bleeding. Extended therapy trials have consistently demonstrated superior effectiveness for DOACs treatment when compared with placebo in preventing VTE recurrence. These new classes of medications are less cumbersome to use and they do not require frequent laboratory monitoring or have numerous drug interactions. Although DOACs allow for simplification of treatment in the majority of patients with acute VTE, they have not been tested in all subgroups of patients. This review summarizes the major trials that led to the approval of these agents, clinical settings or subgroups of patients in whom s...

Background - The benefit of preoperative bridging in surgical patients with continuous anticoagulant therapy is debatable, and drawing of meaningful conclusions may have been limited by mixed procedures with different thromboembolic and bleeding risks in most published studies. Patients and methods - This was an observational cohort treatment study in consecutive primary unilateral total hip and knee arthroplasty patients between January 2010 and November 2013 in 8 Danish fast-track departments. Data were collected prospectively on preoperative comorbidity and anticoagulants in patients with preoperative vitamin K antagonist (VKA) treatment. We performed 30-day follow-up on in-hospital complications and re-admissions through the Danish National Patient Registry and patient records. Results - Of 13,375 procedures, 649 (4.7%) were in VKA patients with a mean age of 73 (SD 9) years and a median length of stay of 3 days (IQR: 2-4). Preoperative bridging was used in 430 (67%), while 215 (33%) were paused. Of 4 arterial thromboembolic events (ATEs) (0.6%), 2 were in paused patients and 2 were in bridged patients (p = 0.6). Of 3 venous thromboembolic events (VTEs) (0.5%), 2 were in paused patients and 1 was in a bridged patient (p = 0.3). Of 8 major bleedings (MBs) (1.2%), 1 was in a paused patient and 7 were in bridged patients (p = 0.3), 5 of whom received therapeutic bridging. Similar results were found in a propensity-matched cohort. Interpretation - In contrast to recent studies in mixed surgical procedures, no statistically significant differences in ATE, VTE, or MB were found between preoperative bridging and pausation of VKA patients. However, the higher number of thromboembolic events in paused patients and the higher number of major bleedings in bridged patients warrant more extensive investigation.

Some evidence suggests that long-term use of vitamin K antagonists (VKAs) has a cancer chemopreventive effect. Such aneffect would have considerable implications in terms of understanding tumor biology. To evaluate if long-term VKA treatmentinfluences the risk of developing cancer, we performed a matched case–control analysis. We used data from four Danishnationwide registers. Cases were all Danish individuals with a first-time cancer diagnosis (except nonmelanoma skin cancer)between 2000 and 2009. For each case, eight controls, matched by birth year and gender, were selected from the sourcepopulation by risk-set sampling. Long-term VKA use was defined as exposure to VKA for a period of 3 or more years.Conditional logistic regression was used to compute odds ratios (ORs) for cancer associated with long-term VKA exposure,adjusting for potential confounders. Prespecified subanalyses were performed for selected cancer sites, subgroups andmeasures of exposure. A total of 238,196 cases and 1,713,176 controls were included. The adjusted OR for cancer associatedwith long-term VKA exposure was 0.99 (95% CI: 0.95–1.02). Long-term VKA use was associated with increased ORs foralcohol- or obesity-related cancer sites, whereas we observed a decreased risk of prostate cancer (OR: 0.86; 95% CI:0.78–0.95). Our study does not support a general chemopreventive effect of VKA drugs. However, in accordance with findingsfrom previous studies, we found an inverse association between use of VKA and prostate cancer.

BackgroundLow-molecular-weight heparin (LMWH) is usually recommended for the treatment of cancer-associated thrombosis (CAT) but this treatment requires burdensome daily injections. We did a systematic review to compare the efficacy and safety of direct oral anticoagulants (DOAC), vitamin K antagonists (VKA) and LMWH in patients with CAT.MethodsWe searched Pubmed, Embase and CENTRAL for randomised controlled trials comparing DOAC, VKA and LMWH in patients with CAT. Pairwise and network meta-analyses were computed for venous thromboembolism (VTE) recurrence and bleeding complications.ResultsWe identified 14 studies, including 4,661 patients. In pairwise comparison, DOAC were superior to LMWH to prevent VTE recurrence (HR 0.63; 95% CI 0.42-0.96) and LMWH was superior to VKA (HR 0.53; 95% CI 0.40-0.70). The rate of major bleeding was higher with DOAC compared to LMWH (HR 1.78; 95% CI 1.11-2.87). In the network meta-analysis, DOAC had a lower, but non-significant, rate of VTE recurrence compared to LMWH (HR 0.74; 95% CI 0.54-1.01). Both DOAC (HR 0.42; 95% CI 0.29-0.61) and LMWH (HR 0.57; 95% CI 0.44-0.75) were associated with lower rates of recurrence compared to VKA. No significant difference in major bleeding rate was observed in the network meta-analysis. Inconsistency was observed between pairwise and network meta-analysis comparisons for major bleeding.ConclusionsDOAC are effective to prevent VTE recurrence in patients with CAT but are associated with an increased risk of bleeding compared to LMWH. The choice of anticoagulant should be personalised, taking into account the patient's bleeding risk, including cancer site, and patient's values and preferences.

See also Mismetti P, Laporte S. New oral antithrombotics: a need for laboratory monitoring. For. This issue, pp 621–6.

This update describes contemporary studies of clinical relevance in angiology and hemostasis. We discuss newer developments for the treatment of haemophilia, with a focus on drugs with longer-half lives. Direct anticoagulants (DOAC: rivaroxaban, apixaban, edoxaban and dabigatran) and their approved prescription in Switzerland are summarized, with a description of antidotes that will be available in the near future. We will present new data on the utility of cancer screening at the diagnosis of idiopathic venous thromboembolism (VTE) and on the evaluation of DOAC in patients with cancer-related VTE. Finally, new studies evaluating the clinical risk-benefit of anticoagulation bridging for patients with vitamin K antagonists undergoing procedures do not support the use of such bridging in the majority of patients.

Essentials It is not known if initiation of glucose-lowering drugs alters the efficacy of vitamin K antagonists (VKA). We examined if glucose-lowering drugs affected international normalized ratio (INR) in VKA-treated patients. Upon initiating glucose-lowering drugs, 51% of patients had INR values below the therapeutic window. Monitoring of INR levels should be intensified upon initiation of glucose-lowering drugs. SummaryBackground It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon. Objectives The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon. Patients/methods We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment. Results Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of −0.3 [95% CI: −0.1; −0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA. Conclusion Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.

PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of 4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome definitions, and other drugs. ResultsWe identified 513 VKA users with at least 1 INR measurement 4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared to warfarin (IRR, 3.37; 95%CI, 2.50-4.53 and IRR, 1.46; 95%CI, 1.20-1.76, respectively). We observed larger IRRs with stricter outcome definitions. Concomitant tramadol and VKA exposure was also associated with an increased rate of low INR measurements (i.e., Purpose: We present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. Methods: We used a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of ≥4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome definitions, and other drugs. Results: We identified 513 VKA users with at least 1 INR measurement ≥4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared to warfarin (IRR, 3.37; 95%CI, 2.50-4.53 and IRR, 1.46; 95%CI, 1.20-1.76, respectively). We observed larger IRRs with stricter outcome definitions. Concomitant tramadol and VKA exposure was also associated with an increased rate of low INR measurements (i.e.

Background Chronic anticoagulation with vitamin K antagonists (VKAs) prevents ischaemic stroke and systemic embolism in people with non-valvular atrial fibrillation (AF) but dose adjustment, coagulation monitoring and bleeding limits its use. Direct thrombin inhibitors (DTIs) are under investigation as potential alternatives. Objectives To assess (1) the comparative efficacy of long-term anticoagulation using DTIs versus VKAs on vascular deaths and ischaemic events in people with non-valvular AF, and (2) the comparative safety of chronic anticoagulation using DTIs versus VKAs on (a) fatal and non-fatal major bleeding events including haemorrhagic strokes, (b) adverse events other than bleeding and ischaemic events that lead to treatment discontinuation and (c) all-cause mortality in people with non-valvular AF. Search methods We searched the Cochrane Stroke Group Trials Register (July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, May 2013), MEDLINE (1950 to July 2013), EMBASE (1980 to October 2013), LILACS (1982 to October 2013) and trials registers (September 2013). We also searched the websites of clinical trials and pharmaceutical companies and handsearched the reference lists of articles and conference proceedings. Selection criteria Randomised controlled trials (RCTs) comparing DTIs versus VKAs for prevention of stroke and systemic embolism in people with non-valvular AF. Data collection and analysis All three review authors independently performed data extraction and assessment of risk of bias. Primary analyses compared all DTIs combined versus warfarin. We performed post hoc analyses excluding ximelagatran because this drug was withdrawn from the market owing to safety concerns. Main results We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601 of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran 36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of bias and statistical heterogeneity of the studies included were low. The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01). Authors' conclusions DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected no difference in death from all causes.

BackgroundDetailed data on real-life utilization of vitamin K antagonists (VKAs) and new oral anticoagulants (NOACs) in atrial fibrillation are sparse. ObjectivesTo describe the dynamics of VKA and NOAC use: that is, (i) how patients moved in and out of, as well as between, use of VKAs and NOACs; (ii) how patients adhered to treatment; and (iii) which type of prescriber initiated, maintained, and changed treatment with VKAs and NOACs. MethodsWe conducted a drug utilization study in the region of southern Denmark (population 1.2 million) using prescription data. We included all subjects using VKAs or NOACs during the period of August 22, 2011, through June 30, 2013, restricted to subjects with a diagnosis of atrial fibrillation. ResultsWe identified 20911 subjects, of whom 20769 and 1639 used VKAs and NOACs, respectively. The number of VKA users was stable at similar to 14000 subjects during the study period, whereas the number of NOAC users increased to 903. The majority of NOAC users had previously used VKAs (n=974), whereas 389 anticoagulant-naive users initiated NOAC therapy. Among the latter, 51.2% had changed to VKAs within 6months. 57.3% of VKA users were initiated by a hospital physician, whereas maintenance treatment was predominantly handled by the patient's general practitioner (97.6%). Switches from NOAC to VKA were initiated by a general practitioner in 69.2% of the cases. For users of NOACs, these numbers were 73.5%, 94.0%, and 63.3%. ConclusionsA large proportion of NOAC users switch to a VKA within a short time frame. The reasons for this are not clear. Background: Detailed data on real-life utilization of vitamin K antagonists (VKAs) and new oral anticoagulants (NOACs) in atrial fibrillation are sparse. Objectives: To describe the dynamics of VKA and NOAC use: that is, (i) how patients moved in and out of, as well as between, use of VKAs and NOACs; (ii) how patients adhered to treatment; and (iii) which type of prescriber initiated, maintained, and changed treatment with VKAs and NOACs. Methods: We conducted a drug utilization study in the region of southern Denmark (population 1.2 million) using prescription data. We included all subjects using VKAs or NOACs during the period of August 22, 2011, through June 30, 2013, restricted to subjects with a diagnosis of atrial fibrillation. Results: We identified 20 911 subjects, of whom 20 769 and 1639 used VKAs and NOACs, respectively. The number of VKA users was stable at ~ 14 000 subjects during the study period, whereas the number of NOAC users increased to 903. The majority of NOAC users had previously used VKAs (n = 974), whereas 389 anticoagulant-na€ive users initiated NOAC therapy. Among the latter, 51.2% had changed to VKAs within 6 months. 57.3% of VKA users were initiated by a hospital physician, whereas maintenance treatment was predominantly handled by the patient's general practitioner (97.6%). Switches from NOAC to VKA were initiated by a general practitioner in 69.2% of the cases. For users of NOACs, these numbers were 73.5%, 94.0%, and 63.3%. Conclusions: A large proportion of NOAC users switch to a VKA within a short time frame. The reasons for this are not clear.

Note: The editorial process for this paper was fully handled by Prof Christian Weber, Editor in Chief.

Physicians are confronted with many new antithrombotic drugs, either antiplatelet agents or new oral anticoagulants (NOAC). Targets of NOAC are specific (either anti-IIa or antiXa) and clinical studies have shown that NOAC are as efficacious and as safe as "old" anticoagulants (heparin, low molecular weight heparin, vitamin K antagonists); moreover they present some advantages. Indeed, NOAC have a wide therapeutic window and do not require laboratory monitoring. Therefore, it is very tempting to prescribe them on a large scale basis in patients at risk or having thromboembolic diseases. However, things are not so simple in the day-to-day practice and this review aims at answering in a brief and simplified manner to some questions.

International audience; BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

During the past five decades, anticoagulant therapy has consisted of rapidly acting parenteral drugs (unfractionated heparin [UFH] low-molecular-weight heparins [LMWH]) for prevention of venous thromboembolism and initial treatment of arterial and venous thromboembolism, whereas vitamin K antagonists (VKA) are used for longer term oral treatment. These drugs act by indirectly inhibiting several activated plasma clotting factors (UFH, LMWH) or by blocking the synthesis of some of them (VKA). In recent years, compounds that specifically block activated coagulation factor X (FXa) or thrombin have been developed. Thus, fondaparinux, and its long-acting derivative idraparinux, are administered subcutaneously. These substances inhibit F Xa indirectly via antithrombin. Small molecules have also been developed that directly block FXa (rivaroxaban, apixaban) or thrombin (dabigatran etexilate) following oral administration. In the present review we discuss the currently available evidence supporting the use of these new anticoagulants, in particular rivaroxaban and dabigatran etexilate, in the setting of thromboprophylaxis following major orthopaedic surgery, and the broader perspectives that these new drugs may open up in the next few years.

To discuss new features that were published during the past few years on diagnosis and treatment of venous thromboembolism (VTE). Progress has been made in assessing clinical probability of pulmonary embolism (PE), in addressing the particular aspects of PE diagnosis in the elderly, in evaluating the diagnostic performance of single- and multi-detector row helical computed tomography (hCT), and in looking at the role of D-dimer measurement and lower limb venous compression ultrasonography in the diagnostic work-up of PE. New therapeutic options have also been proposed. Diagnosing VTE depends upon several, mainly non-invasive diagnostic tools that must be used sequentially, depending on the clinical situation and the local expertise. In the vast majority of patients, a noninvasive work-up is feasible and the diagnostic algorithms are becoming simpler. We focused on new developments of clinical probability assessment, PE in the elderly, potential new uses of D-dimer measurement, advent of multidetector row helical computed tomography and utility of ultrasonography to detect deep vein thrombosis in PE suspected patients. Treatment of acute venous thromboembolism consists of parenteral administration of heparin (usually low-molecular-weight heparin or, more recently, fondaparinux) overlapped and followed by oral vitamin K antagonists that will be administered for a certain period of time (usually 3 to 12 months), depending upon the estimated risks of recurrence and bleeding in each individual patient. Contemporary features include the controversial possibility of reducing the intensity of oral anticoagulant treatment (INR 1.5–2) after an initial full-intensity treatment (INR 2–3) period of 3 to 12 months, and the emergence of new anticoagulant drugs such as direct oral synthetic inhibitors of thrombin or factor Xa.