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Many patients with impaired renal function have concurrent indications for anticoagulant therapy, including atrial fibrillation and venous thromboembolism. For mild chronic kidney disease, data from clinical trials and existing guidelines can be applied to clinical management. The benefits and harms of anticoagulation therapy in patients with more advanced renal impairment are nuanced, as both thrombotic and bleeding risk are increased. Until recently, data regarding anticoagulants in severe renal impairment were primarily observational, but emerging evidence includes a few small clinical trials and the emergence of novel agents hypothesized to have improved efficacy and safety in this population. In this review, we summarize existing data on anticoagulation in patients with chronic kidney disease. We suggest a framework for anticoagulation decision-making in the burgeoning worldwide population of patients with chronic kidney disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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: This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously., Methods: We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update., Conclusion: New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations., (Copyright © 2021. Published by Elsevier Inc.)

Both time in therapeutic range (TTR) for anticoagulation and depression are associated with dementia risk. The purposes of this study were to examine the impact of depression on TTR and to describe the partitioned contribution of depression and TTR on long-term dementia risk. We studied 14,953 patients anticoagulated with warfarin (target INR 2-3) for atrial fibrillation (AF), venous thromboembolism (VTE), or a mechanical heart valve from 2003 to 2015. We excluded patients with a diagnosis of dementia before or within 6 months of warfarin initiation. We examined the association of depression with TTR using finite mixture modeling and logistic regression and utilized multivariable Cox hazard regression to determine the association of TTR and depression with incident dementia at 3 and 13 years. Forty % (n = 6055) of patients were diagnosed with depression before or while on warfarin. Patients with depression had significantly lower TTR and were 1.37 times more likely to have TTR <50% than non-depressed patients (p <0.0001). During follow-up, 4.2% of patients received the diagnosis of dementia within 3 years as compared to 12% during all-time follow up. The 3-year risk of dementia was highest for patients with a ≤50% TTR regardless of depression status. The 3-year dementia risk was associated with TTR (p <0.0001) but not depression. However, for all-time dementia both TTR (p <0.0001) and depression (p <0.0001) as well as their interaction (p = 0.049) were associated with dementia. Depression increased the risk of long-term dementia by 1.69 fold (95% CI: 1.33, 2.15) for patients with the lowest TTR. Depression is prevalent in patients managed with warfarin and is associated with significant decreases in TTR. In conclusion, decreased TTR appears to increase 3-year dementia risk and both low TTR and depression interact to increase risk for all-time dementia in patients taking warfarin., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown., Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery., Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016., Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application., Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more., Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%)., Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Observational trials suggest that the implementation and quality of long-term anticoagulation impact dementia risk. Emerging evidence suggests that direct oral anticoagulants may improve long-term risk of dementia in AF patients. This manuscript describes the rational and trial design of the the Cognitive Decline and Dementia in Atrial Fibrillation Patients (CAF) Trial. CAF investigates if AF patients randomized to dabigatran etexilate will have long-term higher cognition scores and lower rates of dementia compared in the long term to dose-adjusted warfarin (International Normalized Ratio [INR]: 2.0-3.0). As of 27 February 2019, a total of 120 subjects will be enrolled at one investigational site in the United States and will be followed for 2 years after study enrollment. To date, 97 have been enrolled. The average age is 74.2 years, 53% are male, and 9% had a prior stroke. In this Vanguard study, patients will be followed for 2 years after study enrollment. These prospective, randomized data will inform the understanding of two anticoagulants in AF patients as it relates to risk of cognitive decline and dementia. Cranial imaging and biomarkers collected will assist in understanding mechanisms of brain injury., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: The efficacy and safety of managing patients with low-risk pulmonary embolism (PE) without hospitalization requires objective data from US medical centers. We sought to determine the 90-day composite rate of recurrent symptomatic VTE, major bleeding events, and all-cause mortality among consecutive patients diagnosed with acute low-risk PE managed without inpatient hospitalization; and to measure patient satisfaction., Methods: We performed a prospective cohort single-arm management study conducted from January 2013 to October 2016 in five EDs. We enrolled 200 consecutive adults diagnosed with objectively confirmed acute PE and assessed to have a low risk for mortality using the Pulmonary Embolism Severity Index (PESI) score (< 86), echocardiography, and whole-leg compression ultrasound (CUS). The primary intervention was observation in the ED or hospital (observation status) for > 12 to < 24 h, followed by outpatient management with Food and Drug Administration-approved therapeutic anticoagulation. Patients were excluded for a PESI ≥ 86, echocardiographic signs of right heart strain, DVT proximal to the popliteal vein, hypoxia, hypotension, hepatic or renal failure, contraindication to therapeutic anticoagulation, or another condition requiring hospital admission. The primary outcome was 90-day composite rate of all-cause mortality, recurrent symptomatic VTE, and major bleeding., Results: The composite outcome occurred in one of 200 patients (90-day composite rate = 0.5%; 95% CI, 0.02%-2.36%). No patient suffered recurrent VTE or died during the 90-day follow-up period. A major bleed occurred in one patient. Patients indicated a high level of satisfaction with their care., Conclusions: Treatment of carefully selected patients with acute PE and low risk by PESI < 86, echocardiography, and CUS without inpatient hospitalization is safe and acceptable to patients. Results must be viewed with caution because of the small sample size relative to the end point and the generalizability surrounding availability of emergent echocardiography., Trial Registry: ClinicalTrials.gov; No.: NCT02355548; URL: www.clinicaltrials.gov., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines suggest anticoagulation of patients with high pretest probability of pulmonary embolism (PE) while awaiting diagnostic test results (preemptive anticoagulation). Data relevant to the practice of preemptive anticoagulation are not available., Methods: We reviewed 3,500 consecutive patients who underwent CT pulmonary angiography (CTPA) at two EDs. We classified the pretest probability for PE using the revised Geneva Score (RGS) as low (RGS 0-3), intermediate (RGS 4-10), or high (RGS 11-18). We classified patients with a high pretest probability of PE as receiving preemptive anticoagulation if therapeutic anticoagulation was given before CTPA completion. Patients with a high bleeding risk and those receiving treatment for DVT before CTPA were excluded from the preemptive anticoagulation analysis. We compared the time elapsed between ED registration and CTPA completion for patients with a low, intermediate, and high pretest probability for PE., Results: We excluded three of 3,500 patients because CTPA preceded ED registration. Of the remaining 3,497 patients, 167 (4.8%) had a high pretest probability for PE. After excluding 29 patients for high bleeding risk and 21 patients who were treated for DVT prior to CTPA, only two of 117 patients (1.7%) with a high pretest probability for PE received preemptive anticoagulation. Furthermore, 37 of the remaining 115 patients (32%) with a high pretest probability for PE had a preexisting indication for anticoagulation but did not receive preemptive anticoagulation. The time from ED registration to CTPA completion did not differ based on the pretest probability of PE., Conclusions: Physicians rarely use preemptive anticoagulation in patients with a high pretest probability for PE. Clinicians do not expedite CTPA examinations for patients with a high pretest probability for PE., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown., Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation., Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016., Interventions: Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment., Main Outcomes and Measures: The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty., Results: Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths., Conclusions and Relevance: Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing., Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

Among patients with atrial fibrillation (AF), the risk of stroke risk is a significant concern. CHADS 2 and CHA 2 DS 2 -VASc ≤2 scoring have been used to stratify patients into categories of risk. Without randomized, prospective data, the need and type of long-term antithrombotic medications for thromboembolism prevention in lower risk AF patients remains controversial. We sought to define the long-term impact of anticoagulant and antiplatelet therapy use in AF patients at low risk of stroke. A total of 56,764 patients diagnosed with AF and a CHADS 2 score of 0 or 1, or CHA 2 DS 2 -VASc score of 0, 1, or 2 were studied. Antithrombotic therapy was defined as aspirin, clopidogrel (antiplatelet therapy), or warfarin monotherapy (anticoagulation) initiated within 6 months of AF diagnosis. End points included all-cause mortality, cerebrovascular accident, transient ischemic attack (TIA), and major bleed. The average age of the population was 67.0 ± 14.1 years and 56.6% were male. In total, 9,682 received aspirin, 1,802 received clopidogrel, 1,164 received warfarin, and 46,042 did not receive any antithrombotic therapy. Event rates differed between patients with a CHADS 2 score of 0 and 1; 18.5% and 37.8% had died, 1.7% and 3.4% had a stroke, 2.2% and 3.2% had a TIA, and 14% and 12.5% had a major bleed, respectively (p <0.0001 for all). The rates of stroke, TIA, and major bleeding increased as antithrombotic therapy intensity increased from no therapy, to aspirin, to clopidogrel, and to warfarin (all p <0.0001). Similar outcomes were observed in low-risk CHA 2 DS 2 -VASc scores (0 to 2). In low-risk AF patients with a CHADS 2 score of 0 to 1 or CHA 2 DS 2 -VASc score of 0 to 2, the use of aspirin, clopidogrel, and warfarin was not associated with lower stroke rates at 5 years compared with no therapy. However, the use of antithrombotic agents was associated with a significant risk of bleed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism chemoprophylaxis remains underutilized in hospitalized medical patients at high risk for venous thromboembolism. We assessed the effect of a health care quality-improvement initiative comprised of a targeted electronic alert, comparative practitioner metrics, and practitioner-specific continuing medical education on the rate of appropriate venous thromboembolism chemoprophylaxis provided to medical inpatients at high risk for venous thromboembolism., Methods: We performed a multicenter prospective observational cohort study in an urban Utah hospital system. All medical patients admitted to 1 of 2 participating hospitals from April 1, 2010 to December 31, 2012 were eligible. Patients were members of the "control" (April 1, 2010 to December 31, 2010), "intervention" (January 1, 2011 to December 31, 2011), or "subsequent year" (January 1, 2012 to December 31, 2012) group. The primary outcome was the rate of appropriate chemoprophylaxis among patients at high risk for venous thromboembolism. Secondary outcomes included rates of symptomatic venous thromboembolism, major bleeding, all-cause mortality, heparin-induced thrombocytopenia, physician satisfaction, and alert fatigue., Results: The rate of appropriate chemoprophylaxis among patients at high risk for venous thromboembolism increased (66.1% control period vs 81.0% intervention period vs 88.1% subsequent year; P <.001 for each comparison). A significant reduction of 90-day symptomatic venous thromboembolism accompanied the quality initiative (9.3% control period, 9.7% intervention period, 6.7% subsequent year; P = .009); 30-day venous thromboembolism rates also significantly decreased., Conclusions: A multifaceted intervention was associated with increased appropriate venous thromboembolism chemoprophylaxis among medical inpatients at high risk for venous thromboembolism and reduced symptomatic venous thromboembolism. The effect of the intervention was sustained., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Randomized acute coronary syndrome (ACS) trials testing various antithrombotic (AT) regimens have largely excluded patients with coexisting conditions and indications for anticoagulation (AC). The purpose of this study is to examine the 2-year clinical outcomes of patients with ACS with indication for AC due to venous thromboembolism (VTE) during hospitalization for the ACS event or a prior or new diagnosis of atrial fibrillation (AF) with a CHADS2 (Congestive heart failure; Hypertension; Age; Diabetes; previous ischemic Stroke) score ⩾2., Methods: ACS patients with AC indication from 2004 to 2009 were identified (n = 619). A Cox proportional hazards model was used to examine the primary efficacy outcome of major adverse cardiovascular events (MACE) including all-cause death, myocardial infarction (MI) or stroke. The primary explanatory variable was at-discharge antithrombotic strategy [single antiplatelet ± AC, dual antiplatelet (DAP) ± AC or AC only; referent DAP + AC]., Results: A total of 261 (42.2%) patients had a MACE event. AT strategy was not a significant factor for MACE (all p > 0.09). The factors associated with MACE were high mortality risk score [hazard ratio (HR)=1.87, 95% confidence interval (CI): 1.39- 2.52; p < 0.001), prior MI (HR = 1.44, 95% CI: 1.03-2.01; p= 0.033) and presentation of ST elevation MI (HR = 2.70, 95% CI: 1.61-4.51; p < 0.001) or non-ST elevation MI (HR = 1.70, 95% CI: 1.15-2.49; p < 0.001) compared with angina., Conclusions: In this real world observational study, the at-discharge AT strategy was not significantly associated with the 2-year risk of MACE. These findings do not negate the need for randomized trials to generate evidence-based approaches to management of this important population., (© The Author(s), 2016.)

Direct oral anticoagulants (DOACs) have been used in clinical practice in the United States for the last 4 to 6 years. Although DOACs may be an attractive alternative to warfarin in many patients, long-term outcomes of use of these medications are unknown. We performed a propensity-matched analysis to report patient important outcomes of death, stroke/transient ischemic attack (TIA), bleeding, major bleeding, and dementia in patients taking a DOAC or warfarin. Patients receiving long-term anticoagulation from June 2010 to December 2014 for thromboembolism prevention with either warfarin or a DOAC were matched 1:1 by index date and propensity score. Multivariable Cox hazard regression was performed to determine the risk of death, stroke/TIA, major bleed, and dementia by the anticoagulant therapy received. A total of 5,254 patients were studied (2,627 per group). Average age was 72.4 ± 10.9 years, and 59.0% were men. Most patients were receiving long-term anticoagulation for AF management (warfarin: 96.5% vs DOAC: 92.7%, p <0.0001). Rivaroxaban (55.3%) was the most commonly used DOAC, followed by apixaban (22.5%) and dabigatran (22.2%). The use of DOACs compared with warfarin was associated with a reduced risk of long-term adverse outcomes: death (p = 0.09), stroke/TIA (p <0.0001), major bleed (p <0.0001), and bleed (p = 0.14). No significant outcome variance was noted in DOAC-type comparison. In the AF multivariable model patients taking DOAC were 43% less likely to develop stroke/TIA/dementia (hazard ratio 0.57 [CI 0.17, 1.97], p = 0.38) than those taking warfarin. Our community-based results suggest better long-term efficacy and safety of DOACs compared with warfarin. DOAC use was associated with a lower risk of cerebral ischemic events and new-onset dementia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. We previously found a significantly increased risk of dementia in AF patients taking warfarin with a low percentage of time in therapeutic range. The purpose of this study was to determine the extent to which AF itself increases dementia risk, in addition to long-term anticoagulation exposure., Methods and Results: A total of 10 537 patients anticoagulated with warfarin (target INR 2-3), managed by the Clinical Pharmacist Anticoagulation Service with no history of dementia were included. Warfarin indication was for AF (n=4460), thromboembolism (n=5868), and mechanical heart valve(s) (n=209). Patients in the latter 2 categories were included only if they had no prior history of AF. The primary outcome was dementia. Patients with AF were older and had higher rates of hypertension, diabetes, heart failure, and stroke. AF patients experienced higher rates of total dementia (5.8% versus 1.6%, P<0.0001), Alzheimer disease (2.8% versus 0.9%, P<0.0001), and vascular dementia (1.0% versus 0.2%, P<0.0001). A propensity analysis of 6030 patients was performed to account for baseline demographics differences. Long-term risk of dementia remained significant in AF patients compared with matched non-AF patients (total dementia: hazard ratio [HR]=2.42 [1.85-3.18], P<0.0001; Alzheimer: HR=2.04 [1.40-2.98], P<0.0001; senile: HR=2.46 [1.58-3.86], P<0.0001). Low percent therapeutic range compared with a higher percent therapeutic range was associated with dementia risk in both AF (26-50% versus >75%: HR=2.51, P=0.005) and non-AF groups (≤25% versus >75%: HR=3.92, P<0.0001)., Conclusions: The presence of AF significantly increases risk of dementia, including Alzheimer's disease, compared with matched patients receiving warfarin anticoagulation for other reasons. Quality of anticoagulation management remains an important risk factor for dementia in all patients., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: An explicit approach to warfarin dose adjustment using computerized clinical decision support (CDS) improves warfarin management. We report metrics of quality for warfarin management before and after implementation of CDS in a large health care system., Methods: A total of 2591 chronically anticoagulated patients were eligible for inclusion. We compared interpatient time in therapeutic range (TTR) and international normalized ratio (INR) variability before and after implementation of CDS. We report outcomes of major bleeding, thrombosis, and health care utilization., Results: Implementation of CDS significantly improved TTR (from 63.99% to 65.13%; P = .04) and reduced out-of-range INRs (from 42.39% to 39.97%; P < .001). Venous thromboembolism (relative risk [RR] 0.41; P < .001) emergency department utilization (RR 0.62; P < .001), and hospitalization (RR 0.62; P < .001) were reduced after CDS implementation. Major hemorrhage was more frequent after CDS implementation (RR 1.42; P = .01)., Conclusion: The CDS warfarin management was associated with improved TTR and decreased INR variability in a large cohort of chronically anticoagulated patients. Clinically relevant outcomes were broadly improved, although more bleeding events were observed., (© The Author(s) 2014.)

Prompt, accurate diagnosis of deep vein thrombosis (DVT) is essential. A single, whole-leg ultrasound (whole-leg US) has been used to exclude DVT, but limited data exist for patients with high pretest probability (PTP) for DVT. This diagnostic management study tested the rate of venous thromboembolism (VTE) in patients with a PTP of "DVT likely" per the simplified Wells score when anticoagulation is withheld based on a single, negative whole-leg US. Consecutive patients presenting during coordinator shifts with a PTP of DVT likely were enrolled. Anticoagulation was withheld after a single, negative whole-leg US. The outcome was objectively confirmed VTE in 3 months. All 167 patients completed the follow-up. A single patient death was adjudicated as possibly caused by VTE, resulting in a VTE rate of 0.60% (95% confidence interval: 0.02%-3.29%). Whole-leg US should be further studied in diagnostic algorithms that utilize PTP scoring and D-dimer testing.

Background: Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager., Methods and Results: A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ≤1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance., Conclusions: These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

Unlabelled: Calciphylaxis is a rare, usually fatal vasculopathic disorder characterized by cutaneous ischemia and necrosis due to calcification of arterioles. Although calciphylaxis is most frequently associated with end-stage renal disease (ESRD) and secondary hyperparathyroidism, it has been reported infrequently among patients on warfarin. No standard treatment has been established for atypical calciphylaxis; however, a potentially beneficial treatment is hyperbaric oxygen therapy (HBOT). A high degree of clinical suspicion, early diagnosis, and understanding the pathophysiology of this disease promotes the optimal management of this extremely morbid and often fatal condition., Case Report: We present a 63-year-old Polynesian woman with biopsy-proven calciphylaxis in the absence of ESRD or elevated serum calcium levels while taking warfarin. Therapeutic dose enoxaparin was substituted for warfarin and she received 40 sessions of HBOT during which lower extremity ulcers resolved., Discussion: Warfarin has been implicated when calciphylaxis presents in an atypical fashion. No guidelines exist for treatment of atypical calciphylaxis in the setting of concomitant warfarin therapy. Up to 80% of calciphylaxis patients die within 1 year of diagnosis. Our patient was changed to low-molecular-weight heparin and received HBOT., Conclusion: We present what we believe is the first case of atypical calciphylaxis thought to be attributable to warfarin treated with a therapeutic substitution of anticoagulant and HBOT leading to resolution of cutaneous lesions.

Context: In patients with suspected lower extremity deep vein thrombosis (DVT), compression ultrasound (CUS) is typically the initial test to confirm or exclude DVT. Patients with an initial negative CUS result often require repeat CUS after 5 to 7 days. Whole-leg CUS may exclude proximal and distal DVT in a single evaluation., Objective: To determine the risk of venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT following a single negative whole-leg CUS result., Data Sources: MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases were searched for articles published from January 1970 through November 2009. Supplemental searches were performed of Internet resources, reference lists, and by contacting content experts., Study Selection: Included studies were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who did not receive anticoagulant therapy, and were followed up at least 90 days for venous thromboembolism events., Data Extraction: Two authors independently reviewed and extracted data regarding a single positive or negative whole-leg CUS result, occurrence of venous thromboembolism during follow-up, and study quality., Results: Seven studies were included totaling 4731 patients with negative whole-leg CUS examinations who did not receive anticoagulation. Of these, up to 647 patients (13.7%) had active cancer and up to 725 patients (15.3%) recently underwent a major surgery. Most participants were identified from an ambulatory setting. Venous thromboembolism or suspected venous thromboembolism-related death occurred in 34 patients (0.7%), including 11 patients with distal DVT (32.4%); 7 patients with proximal DVT (20.6%); 7 patients with nonfatal pulmonary emboli (20.6%); and 9 patients (26.5%) who died, possibly related to venous thromboembolism. Using a random-effects model with inverse variance weighting, the combined venous thromboembolism event rate at 3 months was 0.57% (95% confidence interval, 0.25%-0.89%)., Conclusion: Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up.