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Background: The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial., Objectives: The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs)., Methods: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used., Results: Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I 2  = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I 2  = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I 2  = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I 2  = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups., Conclusions: Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding., Competing Interests: Funding Support and Author Disclosures Dr Piazza has received research support from Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation; and has received consulting fees from Bristol Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, Namsa, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. Dr Jiménez has received research support from Daiichi-Sankyo and Sanofi; and has received consulting fees from Bristol Myers Squibb/Pfizer Alliance, Daiichi-Sankyo, Leo Pharma, Rovi, and Sanofi. Dr Monreal has received research support from Sanofi, Leo, and Rovi; and has received consulting fees from Sanofi. Dr Pengo has received lecture fees from Werfen Group. Dr Cortes-Hernandez has received institutional research funding from Bayer Hispania to conduct the APS RCT. Dr Connors has received research funding to her institution from CSL Behring; has received consulting fees from Abbott; has received honoraria for lectures from Bristol Myers Squibb, Roche, and Sanofi; and has participated on the advisory board of Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the submitted work. Dr Kanthi is an inventor on a pending patent application by the University of Michigan on the use of biogases in vascular disease (US202201670756A1); and is supported by the National Heart, Lung, and Blood Institute Intramural Research Program and the Lasker Foundation. Dr Krumholz has received (within the last 3 years) expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, the Arnold and Porter Law Firm, and the Martin/Baughman Law Firm; is a cofounder of Refactor Health, an enterprise health care artificial intelligence–augmented data management company, and HugoHealth, a personal health information platform; and is associated with contracts through Yale University from Johnson and Johnson. Dr Middeldorp has received grants and personal fees from Daiichi-Sankyo; has received grants and personal fees from Bayer, Pfizer, and Boehringer Ingelheim; and has received personal fees from Portola/Alexion, Abbvie, Bristol Myers Squibb Pfizer, Norgine, and Viatris, all paid to her institution. Dr Falanga has received honoraria/consulting fees from Stago, Sanofi, Daiichi-Sankyo, Leo Pharma, and Pfizer. Dr Goldhaber has received research support from Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen, National Heart, Lung, and Blood Institute, and Pfizer; and has received consulting fees from Agile, Bayer, and Pfizer. Dr Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of IVC filters; and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital and a Career Development Award from the American Heart Association and VIVA Physicians (#938814). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background: Anticoagulation requires urgent reversal in cases of life-threatening bleeding or invasive procedures., Study Design and Methods: Network meta-analysis for comparing the safety and efficacy of warfarin reversal strategies including plasma and prothrombin complex concentrates (PCCs)., Results: Seven studies including 594 subjects using reversal agents plasma, 3-factor-PCC (Uman Complex and Konyne), and 4-factor-PCC (Beriplex/KCentra, Octaplex, and Cofact) met inclusion criteria. Compared with plasma, patients receiving Cofact probably have a higher rate of international normalized ratio (INR) correction (risk difference [RD] 499 more per 1000 patients, 95% confidence interval [CI], 176-761, low certainty[LC]); higher reversal of bleeding (323 more per 1000 patients, 11-344 more, LC); and fewer transfusion requirements (0.96 fewer units, 1.65-0.27 fewer, LC). Patients receiving Beriplex/KCentra probably have a higher rate of INR correction (476 more per 1000 patients, 332-609 more, LC); higher reversal of bleeding (127 more per 1000 patients, 43 fewer to 236 more); and similar transfusion requirements (0.01 fewer units, 0.31 fewer to 0.28 more, high/moderate certainty). Patients receiving Octaplex probably have a higher rate of INR correction (RD 579 more per 1000 patients, 189-825 more, LC)., Conclusions: PCCs probably provide an advantage in INR reversal compared to plasma. There was no added risk of adverse events with PCCs., (© 2022 AABB.)

History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p = 0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p = 0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery., (© 2021 Wiley Periodicals LLC.)

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT., (© 2021 by The American Society of Hematology.)

Venous thromboembolism (VTE; deep vein thrombosis and/or pulmonary embolism) is a well-established cause of morbidity and mortality in the medical and surgical patient populations. Clinical research in the prevention and treatment of VTE has been a dynamic field of study, with investigations into various treatment modalities ranging from mechanical prophylaxis to the direct oral anticoagulants. Aspirin has long been an inexpensive cornerstone of arterial vascular disease therapy, but its role in the primary or secondary prophylaxis of VTE has been debated. Risk-benefit tradeoffs between aspirin and anticoagulants have changed, in part due to advances in surgical technique and postoperative care, and in part due to the development of safe, easy-to-use oral anticoagulants. We review the proposed mechanisms in which aspirin may act on venous thrombosis, the evidence for aspirin use in the primary and secondary prophylaxis of VTE, and the risk of bleeding with aspirin as compared with anticoagulation., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests., (© 2020 by The American Society of Hematology.)

Background: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type., Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526., Findings: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high., Interpretation: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival., Funding: Canadian Institutes of Health Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is a viral infection that can, in severe cases, result in cytokine storm, systemic inflammatory response and coagulopathy that is prognostic of poor outcomes. While some, but not all, laboratory findings appear similar to sepsis-associated disseminated intravascular coagulopathy (DIC), COVID-19- induced coagulopathy (CIC) appears to be more prothrombotic than hemorrhagic. It has been postulated that CIC may be an uncontrolled immunothrombotic response to COVID-19, and there is growing evidence of venous and arterial thromboembolic events in these critically ill patients. Clinicians around the globe are challenged with rapidly identifying reasonable diagnostic, monitoring and anticoagulant strategies to safely and effectively manage these patients. Thoughtful use of proven, evidence-based approaches must be carefully balanced with integration of rapidly emerging evidence and growing experience. The goal of this document is to provide guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of anticoagulant therapies in patients with COVID-19. We discuss in-hospital and post-discharge venous thromboembolism (VTE) prevention, treatment of suspected but unconfirmed VTE, laboratory monitoring of COVID-19, associated anticoagulant therapies, and essential elements for optimized transitions of care specific to patients with COVID-19.

Background: Randomized controlled trials (RCTs) have demonstrated that low-dose direct oral anticoagulants (DOACs), including rivaroxaban and apixaban, may help reduce the incidence of cancer-associated venous thromboembolism (VTE)., Methods: A cost-utility analysis was performed from the health sector perspective using a Markov state-transition model in patients with cancer who are at intermediate-to-high risk for VTE. Transition probability, relative risk, cost, and utility inputs were obtained from a meta-analysis of the RCTs and relevant epidemiology studies. Differences in cost, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) per patient were calculated over a lifetime horizon. One-way, probabilistic, and scenario sensitivity analyses were conducted., Results: In patients with cancer at intermediate-to-high risk for VTE, treatment with low-dose DOAC thromboprophylaxis for 6 months, compared with placebo, was associated with 32 per 1000 fewer VTE and 11 per 1000 more major bleeding episodes over a lifetime. The incremental cost and QALY increases were $1445 and 0.12, respectively, with an ICER of $11,947 per QALY gained. Key drivers of ICER variations included the relative risks of VTE and bleeding as well as drug cost. This strategy was 94% cost effective at the threshold of $50,000 per QALY. The selection of patients with Khorana scores ≥3 yielded the greatest value, with an ICER of $5794 per QALY gained., Conclusions: Low-dose DOAC thromboprophylaxis for 6 months appears to be cost-effective in patients with cancer who are at intermediate-to-high risk for VTE. The implementation of this strategy in patients with Khorana scores ≥3 may lead to the highest cost-benefit ratio., (© 2020 American Cancer Society.)

Oncology patients are at a high risk of experiencing venous thromboembolism. Historically, venous thromboembolisms in cancer patients have been managed with low-molecular-weight heparin on the basis of the CLOT trial published in 2003. However, recent prospective data provide evidence for safe and effective direct oral anticoagulant use in this population. The purpose of this review article is to evaluate the current body of literature surrounding direct oral anticoagulant use in the oncology population and to highlight key practical considerations when prescribing these agents for patients with cancer.

Objectives: A history of gastrointestinal bleeding (GIB) in patients with atrial fibrillation (AF) may impact decisions about anticoagulation treatment. We sought to determine whether prior GIB in patients with AF taking anticoagulants was associated with an increased risk of stroke or major hemorrhage., Methods: We analyzed key efficacy and safety outcomes in patients with prior GIB in ARISTOTLE. Centrally adjudicated outcomes according to GIB history were analyzed using Cox proportional hazards models adjusted for randomized treatment and established risk factors., Results: A total of 784 (4.3%) patients had prior GIB events (321 [41%] lower, 463 [59%] upper); 215 (27%) occurred <1 year before study enrollment. Patients with prior GIB were older, had more comorbidities, and higher CHADS 2 and HAS-BLED scores than those with no GIB. Major GIB occurred more frequently in those with prior GIB (lower: aHR 1.72, 95% CI 0.86-3.42; upper: aHR 3.13, 95% CI 1.97-4.96). This association with major GIB was more pronounced in patients with GIB <1 year before randomization versus no recent GIB (recent lower: aHR 2.58, 95% CI 0.95-7.01; recent upper: aHR 5.16, 95% CI 2.66-10.0). There was no association between prior GIB and risk of stroke/systemic embolism or all-cause death. In those with prior GIB, the apixaban versus warfarin relative risks for stroke/systemic embolism, hemorrhagic stroke, death, or major bleeding were consistent with the results of the overall trial., Conclusions: In patients with AF on oral anticoagulants, prior GIB was associated with an increased risk of subsequent major GIB but not stroke, intracranial bleeding, or all-cause mortality. For the key outcomes of stroke, hemorrhagic stroke, death, and major bleeding, we found no evidence that the treatment effect (apixaban vs. warfarin) was modified by a history of GIB., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin., Methods: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models., Results: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11-2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16-2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome., Conclusions: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Background: The purpose of the study was to examine the association between the type of preceding oral anticoagulant use (warfarin or direct oral anticoagulants [DOACs]) and in-hospital mortality among patients admitted with gastrointestinal bleeding., Methods: In this observational cohort study, all patients admitted with a first-time gastrointestinal bleeding from January 2011 to March 2017 while receiving any oral anticoagulant therapy prior to admission were identified using data from Danish nationwide registries. The risk of in-hospital mortality according to type of oral anticoagulation therapy was examined by multivariable logistic regression models., Results: Among 5,774 patients admitted with gastrointestinal bleeding (median age, 78 years [25th-75th percentile, 71-85 years]; 56.8% men), 2,038 (35.3%) were receiving DOACs and 3,736 (64.7%) were receiving warfarin prior to admission. The unadjusted in-hospital mortality rates were 7.5% for DOAC (7.2% for dabigatran, 6.4% for rivaroxaban, and 10.1% for apixaban) and 6.5% for warfarin. After adjustment for baseline demographic and clinical characteristics, there was no statistically significant difference in in-hospital mortality between prior use of any DOAC and warfarin (unadjusted odds ratio [OR] 1.18 [95% CI 0.95-1.45], adjusted OR 0.97 [95% CI 0.77-1.24]). Similar results were found for each individual DOAC as compared with warfarin (dabigatran: unadjusted OR 1.12 [95% CI 0.84-1.49], adjusted OR 0.96 [95% CI 0.71-1.30]); rivaroxaban: unadjusted OR 0.98 [95% CI 0.71-1.37], adjusted OR 0.84 [95% CI 0.59-1.21]; and apixaban: unadjusted OR 1.62 [95% CI 0.84-1.49], adjusted OR 1.22 [95% CI 0.83-1.79])., Conclusions: Among patients admitted with gastrointestinal bleeding, there was no statistically significant difference in in-hospital mortality between prior use of DOAC and warfarin., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: While trials have demonstrated non-inferiority of direct oral anticoagulant drugs (DOAC) to low-molecular-weight heparins (LMWH) for the treatment of cancer associated thrombosis (CAT), it is unclear if the newer intervention is cost-effective., Methods: We performed a cost-utility analysis using a Markov state-transition model over a time horizon of 60 months in a hypothetical cohort of 65-year-old patients with active malignancy and first acute symptomatic CAT who were eligible to receive either rivaroxaban/edoxaban or dalteparin. We obtained transition probability, relative risk, cost, and utility inputs from the literature. We estimated the differential impact on costs and quality-adjusted life years (QALYs) per patient and performed one-way and probabilistic sensitivity analyses to test the robustness of results., Results: Using the base-case analysis over 60 months, DOAC versus dalteparin was associated with an incremental cost reduction of $24,129 with an incremental QALY reduction of 0.04. In the one-way sensitivity analysis, the cost of dalteparin contributed the most to the incremental cost difference; relative risk of death related to underlying cancer contributed the most of the incremental QALY difference. The probabilistic sensitivity analysis confirmed the base-case analysis, with a large reduction in cost but small reduction in QALYs., Conclusion: Rivaroxaban or edoxaban as compared to dalteparin is cost saving from a payer's perspective for the treatment of CAT. Professional organizations and healthcare systems may want to consider this analysis in future practice recommendations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE., Methods: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development., Results: The final RAM, named the "SAVED" score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets., Conclusions: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.

Introduction: It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population., Materials and Methods: We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality., Results: We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42-1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05-2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85-6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85-1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis., Conclusions: DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2-3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) are surpassing warfarin as the anticoagulant of choice for stroke prevention in nonvalvular atrial fibrillation. DOAC outcomes in elective periprocedural settings have not been well elucidated and remain a source of concern for clinicians. The aim of this meta-analysis was to evaluate the periprocedural safety and efficacy of DOACs versus warfarin in patients with nonvalvular atrial fibrillation., Methods: We reviewed the literature for data from phase III randomized controlled trials comparing DOACs with warfarin in the periprocedural period among patients with nonvalvular atrial fibrillation. Substudies from 4 trials (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation], and ENGAGE-AF [Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation]) were included in the meta-analysis. DOACs as a group and warfarin were compared in terms of the 30-day pooled risk for stroke/systemic embolism, major bleeding, and death, according to whether the study drug was interrupted or not periprocedurally. The overall relative risk (RR) was estimated with a random-effects model. The I 2 test was used to assess heterogeneity in RR among the studies., Results: In the uninterrupted anticoagulant strategy, there were no differences in the rates of stroke/systemic embolism (pooled risk, 0.6% [29 events/4519 procedures] versus 1.1% [31/2971]; RR, 0.70; 95% confidence interval [CI], 0.41-1.18) and death (1.4% versus 1.8%; RR, 0.77; 95% CI, 0.53-1.12) between DOACs and warfarin and significantly fewer major bleeding events (2.0% versus 3.3%; RR, 0.62; 95% CI, 0.47-0.82) with DOACs compared to warfarin. Under an interrupted strategy, there was no significant difference between DOACs versus warfarin for stroke/systemic embolism (0.4% [41/9260] versus 0.5% [31/7168]; RR, 0.95; 95% CI, 0.59-1.55), major bleeding (2.1% versus 2.0%; RR, 1.05; 95% CI, 0.85-1.30), and death (0.7% versus 0.6%; RR, 1.24; 95% CI, 0.76-2.04). The studies were homogeneous ( I 2 =0.0%) for all calculated pooled associations except for the RR of death in the interrupted strategy ( I 2 =26.3%)., Conclusions: The short-term safety and efficacy of DOACs and warfarin are not different in patients with nonvalvular atrial fibrillation periprocedurally. Under an uninterrupted anticoagulation strategy, DOACs are associated with a 38% lower risk of major bleeding compared with warfarin.

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting., Competing Interests: N. Kraaijpoel has nothing to disclose. M. Di Nisio reports personal fees from Daiichi Sankyo. F.I. Mulder has nothing to disclose. N. van Es reports personal fees from Daiichi Sankyo and Pfizer. J. Beyer-Westendorf reports grants and personal fees from Bayer AG, Boehringer-Ingelheim, Daiichi Sankyo, Pfizer and Portola. M. Carrier reports grants from BMS and Leo Pharma, and personal fees from Pfizer, Bayer, Sanofi and Leo Pharma. D. Garcia reports grants and personal fees from Daiichi Sankyo, Janssen and Incyte, and personal fees from BMS and Boehringer-Ingelheim. M. Grosso, M.F. Mercuri, G. Zhang and L. Schwocho are employees of Daiichi Sankyo Inc. A.K. Kakkar reports grants and personal fees from Bayer AG, and personal fees from Boehringer-Ingelheim, Janssen Pharma, Sanofi SA and Verseon. S. Middeldorp reports grants and personal fees from GSK, BMS/Pfizer, Aspen and Daiichi Sankyo, and personal fees from Bayer, Boehringer-Ingelheim, and grants from Sanquin. C. Rojas Hernandez reports personal fees from Daiichi Sankyo. A. Santamaria reports personal fees from Bayer AG, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, LeoPharma, Sanofi-Aventis, Rovia and SOBI. A. Segers reports grants from Daiichi Sankyo, IONIS Pharmaceuticals and Janssen Pharmaceuticals. P. Verhamme reports grants and personal fees from Bayer Healthcare, LeoPharma, Daiichi Sankyo and Boehringer-Ingelheim, and personal fees from BMS, Portola, Medscape, Medtronic and Pfizer. T.F. Wang has nothing to disclose. J.I. Weitz reports personal fees from Daiichi-Sankyo, Bayer Healthcare, BMS, Boehringer-Ingelheim, Ionis Pharmaceuticals, Janssen, Johnson and Johnson, Pfizer, Portola, Medscape and Novartis. J.I. Zwicker reports grants from Quercegen and Incyte, and personal fees from Daichii Sankyo and Parexel. H.R. Büller reports personal fees from Daiichi Sankyo, Bayer Healthcare, BMS/Pfizer, Boehringer-Ingelheim, Portola, Medscape, Eli Lilly, Sanofi Aventis and Ionis. G.E. Raskob reports personal fees from Daiichi Sankyo, Itreas, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Isis Pharmaceuticals, Janssen, Pfizer and Portola., (Georg Thieme Verlag KG Stuttgart · New York.)

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Tenth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on September 22 and 23, 2017. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Venous thromboembolism (VTE) represents a major global burden of disease and requires collaborative efforts to conduct large, high-quality investigator-initiated and academically sponsored studies addressing the most relevant clinical questions. Owing to increasing regulatory requirements, the highly competitive nature of peer-reviewed funding and costs associated with conducting large, multinational clinical trials, completing practice-changing research constitutes a growing challenge for clinical investigators. As clinical trialists interested in VTE, we founded INVENT (International Network of Venous Thromboembolism Clinical Research Networks) in an effort to promote and accelerate patient-oriented, investigator-initiated, international collaborative research, to identify, prioritize and answer key clinical research questions for patients with VTE. We report on our activities to formalize the INVENT network and our accomplishments in our first year., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 .).

Background: Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial., Methods: The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer., Results: There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.53-2.26) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, 0.64-0.93) (P interaction = .37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, 0.11-0.83) versus without cancer (HR, 0.86; 95% CI, 0.78-0.95), but not in remote cancer (HR, 1.46; 95% CI, 1.01-2.10) (interaction P = .0028)., Conclusions: Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Ninth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on October 15, 2016. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Misdiagnosis of heparin-induced thrombocytopenia (HIT) is common and exposes patients to high-risk therapies and potentially serious adverse events. The primary objective of this study was to evaluate the impact of collaboration between an inpatient pharmacy-driven anticoagulation management service (AMS) and hospital reference laboratory to reduce inappropriate HIT antibody testing via pharmacist intervention and use of the 4T pre-test probability score. Secondary objectives included clinical outcomes and cost-savings realized through reduced laboratory testing and decreased unnecessary treatment of HIT. This was a single center, pre-post, observational study. The hospital reference laboratory contacted the AMS when they received a blood sample for an enzyme-linked immunosorbent HIT antibody (HIT Ab). Trained pharmacists prospectively scored each HIT Ab ordered by using the 4T score with subsequent communication to physicians recommending for or against processing and reporting of lab results. Utilizing retrospective chart review and a database for all patients with a HIT Ab ordered during the study period, we compared the incidence of HIT Ab testing before and after implementation of the pharmacy-driven 4T score intervention. Our intervention significantly reduced the number of inappropriate HIT Ab tests processed (176 vs. 63, p < 0.0001), with no increase in thrombotic or hemorrhagic events. Overall incidence of suspected and confirmed HIT was <3 and <0.005 %, respectively. Overall cost savings were $75,754 (US) or 62 % per patient exposed to heparin between the pre and post intervention groups. Collaboration between inpatient pharmacy AMS and hospital reference laboratories can result in reduction of misdiagnosis of HIT and significant cost savings with similar safety.

Direct oral anticoagulants (DOACs) have been approved for the treatment of venous thromboembolism and atrial fibrillation based on randomized controlled trials (RCTs) of direct comparisons with vitamin K antagonists. Despite having more than 100,000 patients enrolled, safety and efficacy are debated in selected populations. Although DOACs are reviewed as a class of anticoagulant, pharmacokinetic differences exist such that different medications may be beneficial in distinct clinical settings. Synthesizing available evidence based on phase III RCTs, post hoc subgroup analyses, and pooled metaanalyses, this review provides an overview of DOACs and scrutinizes individual differences in their applications for the special populations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Tecarfarin is a novel vitamin K antagonist that is metabolised by carboxyl estererase, thereby eliminating the variability associated with cytochrome-mediated metabolism. EmbraceAC was designed to compare the quality of anticoagulation with tecarfarin and warfarin as determined by time in therapeutic range (TTR). In this phase 2/3 randomised and blinded trial, 607 patients with indications for chronic anticoagulation were assigned to warfarin (n=304) or tecarfarin (n=303). Dosing of study drugs was managed by a centralised dose control centre, which had access to genotyping. The primary analysis tested superiority of tecarfarin over warfarin for TTR. Patients were recruited between May 12, 2008 and May 12, 2009. TTR with tecarfarin and warfarin were similar (72.3 % and 71.5 %, respectively; p=0.51). In those taking CYP2C9 interacting drugs, the TTR on tecarfarin (n=92) was similar to that on warfarin (n=87, 72.2 % and 69.9 %, respectively; p=0.15). In patients with mechanical heart valves, the TTR of tecarfarin (n=42) was similar to that of warfarin (n=42, 68.4 % and 66.3 %, respectively; p=0.51). The same was true for the TTR in patients with any CYP2C9 variant allele and on CYP2C9-interacting drugs (tecarfarin, n=24, 76.5 % vs warfarin, n=31, 69.5 %; p=0.09). There was no difference in thromboembolic or bleeding events. In conclusion, superiority of tecarfarin over warfarin for TTR was not demonstrated. The TTR with tecarfarin was similar to that with well-controlled warfarin and tecarfarin appeared to be safe and well tolerated with few major bleeding and no thrombotic events. Favourable trends in certain subpopulations make tecarfarin a promising oral anticoagulant that deserves further study.

The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits., Methods and Analysis: First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials., Ethics and Dissemination: Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings., Trial Registration Number: PROSPERO CRD42013003526., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings.

Venous thromboembolism (VTE) is a highly prevalent complication of malignancy with emerging changes in incidence, diagnosis and treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. We address a) the appropriate workup to search for occult malignancy in patients with idiopathic VTE, b) identification of high-risk cancer patients for primary thromboprophylaxis, c) the appropriate immediate and long-term treatment for people with cancer diagnosed with acute thromboembolism, d) the appropriate duration of anticoagulation and e) the appropriate treatment strategy in patients with recurrent VTE on anticoagulation. Areas of controversy and future directions in this field are highlighted.

Background: Whether and when to resume oral anticoagulant therapy for patients who survive warfarin-related intracranial hemorrhage (ICH) remains a dilemma lacking consensus recommendations and high-quality evidence to guide clinical decision making., Objective: To determine the incidences of recurrent ICH, thrombosis, and death in relation to resumption or non-resumption of warfarin therapy during the 365 days after incident ICH., Methods: We conducted a retrospective cohort study of adult patients in an integrated healthcare delivery system who were receiving warfarin therapy at the time of incident (index) ICH between 1/1/2000 and 12/31/2007 and survived to hospital discharge. The primary outcomes were recurrent ICH, thrombosis (stroke, systemic embolism, and venous thromboembolism), and all-cause mortality during the 365 days following index ICH. Patients were assigned to one of two groups defined by warfarin therapy resumption after the index ICH., Results: There were 160 patients discharged from the hospital following warfarin-related index ICH; of these 54 (33.8%) resumed warfarin therapy and 106 (66.2%) did not. Recurrent ICH occurred in a numerically greater, but statistically non-significant, proportion of patients who did not resume warfarin therapy (7.6% vs. 3.7%, p=0.497). Similarly, patients who did not resume warfarin had a three-fold higher (12.3% vs. 3.7%, p=0.092) and approximately two-fold higher (31.1% vs. 18.5%, p=0.089) rates of thrombosis and all-cause mortality, respectively, during follow up., Conclusion: Resumption of warfarin therapy following warfarin-associated ICH appeared not to be associated with increased risk of recurrent ICH but trended toward reduced thrombosis and all-cause mortality., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding., Methods: We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding., Results: In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority)., Conclusions: In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

Integration of accepted practice standards into electronic health record systems can facilitate standardization of anticoagulation care delivery and result in improved anticoagulation safety. However, the majority of commonly used electronic health record systems are lacking the specialized features necessary for optimal anticoagulation management. The Task Force on Electronic Health Records of the New York State Anticoagulation Coalition provides such a Consensus Statement in this issue of the journal. The Anticoagulation Forum endorses these recommendations and advises the electronic health record industry and health information technology programmers at the institutional level to adopt these recommendations in a comprehensive and timely manner., (© The Author(s) 2014.)

More than 4 years have passed since the first approval of a target-specific oral anticoagulant (TSOAC) in the United States, and the number of clinicians who have prescribed (or considered prescribing) one or more of these medications is increasing. Although these agents may, in properly selected patients, offer advantages over more traditional therapies, their lack of familiarity can be intimidating. Clinicians who are prescribing the TSOACs face a number of management questions not definitively answered by the registration trials. This chapter reviews some of these situations, including updated information on the periprocedural management of TSOACs and the latest evidence about how to best measure TSOAC effect. The lack of an antidote and other considerations that may be relevant when deciding between newer and more traditional anticoagulant medications are also discussed., (© 2014 by The American Society of Hematology. All rights reserved.)

Background: Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin., Objectives: This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial., Methods: Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization., Results: In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant., Conclusions: Amiodarone use was associated with significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when used with warfarin. Apixaban consistently reduced the rate of stroke and systemic embolism, death, and major bleeding compared with warfarin in amiodarone-treated patients and patients who were not on amiodarone., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Non-vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations., Objectives: This study's objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban., Methods: We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2)., Results: We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R(2) = 0.92 to 0.99) and ecarin-based assays (R(2) = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R(2) = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification., Conclusions: Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age., Methods and Results: A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (P < 0.001 for all). Apixaban was more effective than warfarin in preventing stroke and reducing mortality across all age groups, and associated with less major bleeding, less total bleeding, and less intracranial haemorrhage regardless of age (P interaction >0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes., Conclusion: The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: The aim of this study was to determine the risk of major clinical and thromboembolic events after cardioversion for atrial fibrillation in subjects treated with apixaban, an oral factor Xa inhibitor, compared with warfarin., Background: In patients with atrial fibrillation, thromboembolic events may occur after cardioversion. This risk is lowered with vitamin K antagonists and dabigatran., Methods: Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, we conducted a post-hoc analysis of patients undergoing cardioversion., Results: A total of 743 cardioversions were performed in 540 patients: 265 first cardioversions in patients assigned to apixaban and 275 in those assigned to warfarin. The mean time to the first cardioversion for patients assigned to warfarin and apixaban was 243 ± 231 days and 251 ± 248 days, respectively; 75% of the cardioversions occurred by 1 year. Baseline characteristics were similar between groups. In patients undergoing cardioversion, no stroke or systemic emboli occurred in the 30-day follow-up period. Myocardial infarction occurred in 1 patient (0.2%) receiving warfarin and 1 patient receiving apixaban (0.3%). Major bleeding occurred in 1 patient (0.2%) receiving warfarin and 1 patient receiving apixaban (0.3%). Death occurred in 2 patients (0.5%) receiving warfarin and 2 patients receiving apixaban (0.6%)., Conclusions: Major cardiovascular events after cardioversion of atrial fibrillation are rare and comparable between warfarin and apixaban. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: The effect of antibiotic coadministration on the international normalized ratio (INR) in a relatively stable, real-world warfarin population has not been adequately described. Case reports and studies of healthy volunteers do not account for the potential contribution of acute illness to INR variability., Objective: To compare the risk of excessive anticoagulation among patients with stable warfarin therapy purchasing an antibiotic (antibiotic group) with the risk in patients purchasing a warfarin refill (stable controls) and patients with upper respiratory tract infection but not receiving an antibiotic (sick controls)., Design, Setting, and Participants: A retrospective, longitudinal cohort study evaluated patients receiving warfarin between January 1, 2005, and March 31, 2011, at Kaiser Permanente Colorado, an integrated health care delivery system. Continuous data were expressed as mean (SD) or median (interquartile range). Multivariable logistic regression analysis was used to identify factors independently associated with a follow-up INR of 5.0 or more. A total of 5857 (48.8%), 5579 (46.5%), and 570 (4.7%) patients were included in the antibiotic, stable control, and sick control groups, respectively. Mean age was 68.3 years, and atrial fibrillation was the most common (44.4%) indication for anticoagulation., Exposures: Warfarin therapy with a medical visit for upper respiratory tract infection or coadministration of antibiotics., Main Outcomes and Measures: Primary outcomes were the proportion of patients experiencing a follow-up INR of 5.0 or more and change between the last INR measured before the index date and the follow-up INR., Results: The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more., Conclusions and Relevance: Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.

Patients with cancer have long been an important and enigmatic part of basic science and clinical research in thromboembolic disease. The reciprocal deleterious effects on outcomes of a cancer diagnosis on patients with thrombosis and a thrombotic event on patients with cancer have been observed and documented for more than a century. Patients with cancer continue to be one of the more difficult populations to manage using the available unfractionated and low-molecular-weight heparins and the oral vitamin K antagonists. High rates of failure and bleeding complications have made researchers and practitioners alike seek newer more effective anticoagulation agents. The novel oral direct thrombin and activated factor Xa inhibitors have been shown in large clinical trials to be safe and efficacious in many prophylaxis and treatment settings. However, practitioners who treat patients with cancer should be cautious using these agents until more studies are specifically performed in this thrombophilic patient population.

Background: Patients with atrial fibrillation who are vitamin K antagonist (VKA)-naive may have a higher risk of thrombosis and/or bleeding than VKA-experienced patients., Methods and Results: Using data from ARISTOTLE, we assessed baseline characteristics and the treatment effect of apixaban versus warfarin in the VKA-naive and VKA-experienced cohorts. We compared rates of study drug discontinuation and time-in-therapeutic range. Overall, 7,800 (43%) were VKA naive, and 10,401 were VKA experienced. At baseline, both groups were similar with respect to age and congestive heart failure, hypertension, age, diabetes, stroke score (CHADS2). Fewer VKA-naive patients had a history of prior stroke (18% vs 21%) or prior bleeding (10% vs 22%) and were more often female (39% vs 33%). The effect of apixaban on the primary efficacy and safety outcomes was similar in VKA-naive (stroke/systemic embolism: hazard ratio [HR] 0.86, 95% CI 0.67-1.11 and major bleeding: HR 0.73, 95% CI 0.59-0.91) and VKA-experienced populations (stroke/systemic embolism: HR 0.73, 95% CI 0.57-0.95, P value for interaction = 0.39 and major bleeding: HR 0.66, 95% CI 0.55-0.80, P value for interaction = 0.50). Permanent study drug discontinuation was numerically less likely in patients receiving apixaban whether they were VKA naive (HR for discontinuation: 0.87, 95% CI 0.79-0.95) or VKA experienced (HR for discontinuation: 0.93, 95% CI 0.85-1.02). Among patients receiving warfarin, the mean/median times in therapeutic range were lower in the VKA-naive group (VKA-naive: 57.5/61.4, VKA-experienced: 66.0/69.1, P < .001)., Conclusion: The treatment effects of apixaban (vs warfarin) were not modified by VKA naivety. The rates of stroke/systemic embolism and major bleeding were numerically lower among the patients assigned to apixaban, irrespective of prior VKA use., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Introduction: This study tests the hypothesis that nonadherence with INR monitoring is associated with an increased risk for warfarin-related bleeding and thrombosis and describes patient characteristics associated with INR monitoring nonadherence., Materials and Methods: This was a retrospective, longitudinal, matched cohort study wherein patients were categorized into adherent and nonadherent cohorts; adherent patients were matched 2:1 to nonadherent patients. The primary study endpoint was the first occurrence of bleeding or thromboembolism. Multivariate logistic regression modeling identified patient characteristics associated with INR monitoring adherence or nonadherence., Results: A total of 4995 and 2544 patients contributed 10729 and 5385 patient-years of warfarin therapy in the adherent and nonadherent groups, respectively. The rate of thromboembolic events during follow up was higher in the nonadherent group than in the adherent group (0.95% vs. 0.62% per patient-year, respectively; p=0.019) and nonadherence to INR monitoring was associated with a moderately higher risk of thromboembolism (adjusted Hazard Ratio=1.51; 95% confidence interval=1.04 - 2.20). The difference in bleeding between the two groups was not statistically significant., Conclusions: Repeatedly missing INR tests is an easily identified clinical parameter that is associated with moderately increased risk for thromboembolism in patients taking chronic warfarin therapy. Clinicians should carefully consider the underlying thromboembolic risk and extent of nonadherence when weighing the benefits of continued warfarin therapy for a given patient., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aims: It is uncertain whether the benefit from apixaban varies by type and duration of atrial fibrillation (AF)., Methods and Results: A total of 18 201 patients with AF [2786 (15.3%) with paroxysmal and 15 412 (84.7%) with persistent or permanent] were randomized to apixaban or warfarin. In this pre-specified secondary analysis, we compared outcomes and treatment effect of apixaban vs. warfarin by AF type and duration. The primary efficacy endpoint was a composite of ischaemic or haemorrhagic stroke or systemic embolism. The secondary efficacy endpoint was all-cause mortality. There was a consistent reduction in stroke or systemic embolism (P for interaction = 0.71), all-cause mortality (P for interaction = 0.75), and major bleeding (P for interaction = 0.50) with apixaban compared with warfarin for both AF types. Apixaban was superior to warfarin in all studied endpoints, regardless of AF duration at study entry (P for all interactions >0.13). The rate of stroke or systemic embolism was significantly higher in patients with persistent or permanent AF than patients with paroxysmal AF (1.52 vs. 0.98%; P = 0.003, adjusted P = 0.015). There was also a trend towards higher mortality in patients with persistent or permanent AF (3.90 vs. 2.81%; P = 0.0002, adjusted P = 0.066)., Conclusion: The risks of stroke, mortality, and major bleeding were lower with apixaban than warfarin regardless of AF type and duration. Although the risk of stroke or systemic embolism was lower in paroxysmal than persistent or permanent AF, apixaban is an attractive alternative to warfarin in patients with AF and at least one other risk factor for stroke, regardless of the type or duration of AF.

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fifth International Symposium of Thrombosis and Anticoagulation was held in Belo Horizonte, Minas Gerais, Brazil, on October 18-19, 2012. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Objective: To provide recommendations for optimized anticoagulant therapy in the inpatient setting and outline broad elements that need to be in place for effective management of anticoagulant therapy in hospitalized patients; the guidelines are designed to promote optimization of patient clinical outcomes while minimizing the risks for potential anticoagulation-related errors and adverse events., Data Sources: The medical literature was reviewed using MEDLINE (1946-January 2013), EMBASE (1980-January 2013), and PubMed (1947-January 2013) for topics and key words including, but not limited to, standards of practice, national guidelines, patient safety initiatives, and regulatory requirements pertaining to anticoagulant use in the inpatient setting. Non-English-language publications were excluded. Specific MeSH terms used include algorithms, anticoagulants/administration and dosage/adverse effects/therapeutic use, clinical protocols/standards, decision support systems, drug monitoring/methods, humans, inpatients, efficiency/ organizational, outcome and process assessment (health care), patient care team/organization and administration, program development/standards, quality improvement/organization and administration, thrombosis/ drug therapy, thrombosis/prevention and control, risk assessment/standards, patient safety/standards, and risk management/methods., Study Selection and Data Extraction: Because of this document's scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors and are endorsed by the Board of Directors of the Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The board is composed of physicians, pharmacists, and nurses with demonstrated expertise and experience in the management of patients receiving anticoagulation therapy., Data Synthesis: Recommendations for delivering optimized inpatient anticoagulation therapy were developed collaboratively by the authors and are summarized in 8 key areas: (1) process, (2) accountability, (3) integration, (4) standards of practice, (5) provider education and competency, (6) patient education, (7) care transitions, and (8) outcomes. Recommendations are intended to inform the development of coordinated care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized inpatient anticoagulation therapy are intended to apply to all clinicians involved in the care of hospitalized patients receiving anticoagulation therapy., Conclusions: Anticoagulants are high-risk medications associated with a significant rate of medication errors among hospitalized patients. Several national organizations have introduced initiatives to reduce the likelihood of patient harm associated with the use of anticoagulants. Health care organizations are under increasing pressure to develop systems to ensure the safe and effective use of anticoagulants in the inpatient setting. This document provides consensus guidelines for anticoagulant therapy in the inpatient setting and serves as a companion document to prior guidelines relevant for outpatients.