Outcomes of direct oral anticoagulants with aspirin vs warfarin with aspirin: a registry-based cohort study.

Background: For patients anticoagulated with direct oral anticoagulants (DOACs) or warfarin and on aspirin (ASA) for nonvalvular atrial fibrillation and/or venous thromboembolism, it is unclear if bleeding outcomes differ. Objectives: To assess bleeding rates for ASA with DOACs vs warfarin and one another. Methods: Registry-based cohort study of patients followed by a 6-center quality improvement collaborative in Michigan using data from 2009 to 2022. The study included adults on ASA with warfarin or DOACs for atrial fibrillation and/or venous thromboembolism without a recent myocardial infarction or heart valve replacement. Results: After propensity matching by anticoagulant class, we compared 2 groups of 1467 patients followed for a median of 18.0 months. Any bleeding and nonmajor bleeding was increased with DOACs + ASA compared with warfarin + ASA (32.2 vs 27.8 and 27.1 vs 22.9 events/100 patient-years; relative risks [RRs], 1.1 and 1.2; 95% CIs, 1.1-1.2 and 1.1-1.3, respectively). After matching by drug, patients on apixaban + ASA vs warfarin + ASA had more bleeding (31.2 vs 27.8 events/100 patient-years; RR, 1.1; 95% CI, 1.0-1.2) and nonmajor bleeding but less major bleeding (3.8 vs 4.7 events/100 patient-years; RR, 0.8; 95% CI, 0.6-1.0) and emergency room visits for bleeding. Patients on rivaroxaban + ASA vs warfarin + ASA had more bleeding (39.3 vs 26.3 events/100 patient-years, RR, 1.5; 95% CI, 1.3-1.6), nonmajor bleeding, and thrombosis. Patients on apixaban + ASA vs rivaroxaban + ASA had significantly less bleeding (22.5 vs 39.3/100 patient-years; RR, 0.6; 95% CI, 0.5-0.7), nonmajor bleeding, major bleeding (2.1 vs 5.5 events/100 patient-years; RR, 0.4; 95% CI, 0.2-0.6), emergency room visits for bleeding, and thrombotic events. Conclusion: Patients on DOAC + ASA without a recent myocardial infarction or heart valve replacement had more nonmajor bleeding but otherwise similar outcomes compared with warfarin + ASA. Patients treated with rivaroxaban + ASA experienced more adverse clinical events compared with warfarin + ASA or apixaban + ASA.

Timing of Off-Label Dosing of Direct Oral Anticoagulants in Three Large Health Systems.

BACKGROUND: While direct oral anticoagulants (DOACs) may be viewed as simpler to manage then warfarin, they present their own unique management challenges resulting in frequent off-label dosing. It is unknown to what extent off-label dosing occurs when a patient is started on a DOAC versus later in their treatment. OBJECTIVES: We aimed to characterize when off-label DOAC dosing is occurring and to evaluate the effectiveness of prescribing oversight using a registry-based intervention. METHODS: We evaluated data from the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry, a retrospective quality improvement process using data abstractors, from 2018 - 2022 on the number of "alerts" that are generated in response to dosing deviating from evidence-based guidelines. RESULTS: Among a sample of 1,261 to 1,563 annual DOAC-treated patients in the MAQI2 registry, off-label dosing was relatively common. Over the 5-year period from 2018 through 2022, there were 735 total dosing alerts. Alerts occurred more frequently during a follow-up than at the time of initial prescribing, 69.0% (507) versus 31.0% (228) respectively. After initial review by quality improvement abstractors, 18.2% of alerts (134) resulted in contact to the prescriber. When the prescriber was contacted, it led to an intervention 74.6% of the time. The most common intervention was a change in DOAC dosing. CONCLUSIONS: This study demonstrates the benefit of DOAC prescribing oversight using a registry-based intervention to monitor for off-label dosing for the entirety of the time period a patient is prescribed DOAC as deviations in evidence-based prescribing occur frequently during the follow-up period.

Comparative effectiveness of warfarin management strategies: a systematic review and network meta-analysis.

Background: The management of warfarin therapy presents clinical challenges due to its narrow therapeutic index. We aimed to evaluate the comparative effectiveness of different management strategies in patients using warfarin. Methods: PubMed, Embase, Cochrane CENTRAL, CINAHL, and EBSCO Open Dissertation were searched from inception to 8 May 2024. Randomized controlled trials that compared the following interventions: patient self-management (PSM), patient self-testing (PST), anticoagulation management services (AMS), and usual care in patients prescribed warfarin for any indication were included. Risk ratios (RR) with 95% confidence interval (CI) were estimated using a random-effects model. Surface under the cumulative ranking curves (SUCRA) were used to rank different interventions. The certainty of evidence was assessed using the Confidence in Network Meta-Analysis (CINeMA) online platform. This study is registered with PROSPERO (CRD42023491978). Findings: Twenty-eight trials involving 8100 participants were included, with follow-up periods of 1-24 months. Mean warfarin dosages were 4.9-7.2 mg/day. Only PSM showed a significant reduction of major TE risk compared with usual care (RR = 0.41; 95% CI: 0.24, 0.71; I2 = 0.0%) with moderate certainty of evidence. The 97.6% SUCRA also supported the beneficial effects of PSM over other interventions. The combined direct and indirect evidence showed significantly higher TTR in PSM compared with usual care (MD = 7.39; 95% CI: 2.39, 12.39), with very low certainty. However, direct evidence showed non-significant TTR improvement (MD = 6.49; 95% CI: -3.09, 16.07, I2 = 96.1%). No differences across various strategies were observed in all-cause mortality, major bleeding, stroke, transient ischemic attack, and hospitalization. Interpretation: PSM reduces the risk of major TE events compared with usual care, tends to improve anticoagulation control, and should be considered where appropriate. Funding: Agency for Healthcare Research and Quality (grant ID 5R18HS027960).

In device-detected AF, DOACs vs. aspirin or placebo reduce ischemic stroke and increase major bleeding.

SOURCE CITATION: McIntyre WF, Benz AP, Becher N, et al. Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: a study-level meta-analysis of the NOAH-AFNET 6 and ARTESiA trials. Circulation. 2024;149:981-988. 37952187.

Illustrated State-of-the-Art Capsules of the ISTH 2024 Congress.

Here, we present a series of illustrated capsules from the State of the Art (SOA) speakers at the 2024 International Society on Thrombosis and Haemostasis Congress in Bangkok, Thailand. This year's Congress marks the first time that the International Society on Thrombosis and Haemostasis has held its flagship scientific meeting in Southeast Asia and is the first to be organized by an international Planning Committee. The Bangkok program will feature innovative science and clinical updates from around the world, reflecting the diversity and multidisciplinary growth of our field. In these illustrated SOA capsules, you will find an exploration of novel models of thrombosis and bleeding and biomaterial discoveries that can trigger or block coagulation. Thromboinflammation is now understood to drive many disease states, and the SOA speakers cover cellular and coagulation responses to COVID-19 and other infections. The theme of crosstalk between coagulation and inflammation expands with capsules on protein S signaling, complement, and fibrinolytic inhibitors. Novel agents for hemophilia and thrombosis prevention are introduced. Challenging clinical conditions are also covered, such as inherited platelet disorders and antiphospholipid antibody syndrome. The scientific program in Bangkok will also showcase the work of clinicians and scientists from all parts of the world and chronicle real-world challenges. For example, 2 SOA capsules address the diagnosis and management of von Willebrand disease in low-income settings. Take some time to browse through these short illustrated reviews; we're sure that you'll be entertained, educated, and inspired to further explore the world of thrombosis and hemostasis.

Trends in Initial Anticoagulation Among US Patients Hospitalized With Acute Pulmonary Embolism 2011-2020.

STUDY OBJECTIVE: Guidelines recommend low-molecular-weight heparin (LMWH) and direct oral anticoagulants (DOACs) rather than unfractionated heparin (UFH) for treatment of acute pulmonary embolism (PE) given their efficacy and reduced risk of bleeding. Using data from a large consortium of US hospitals, we examined trends in initial anticoagulation among hospitalized patients diagnosed with acute PE. METHODS: We conducted a retrospective study of inpatient and observation cases between January 1, 2011, and December 31, 2020, among individuals aged more than or equal to 18 years treated at acute care hospitals contributing data to the Premier Healthcare Database. Included cases received a diagnosis of acute PE, underwent imaging for PE, and received anticoagulation at the time of admission. The primary outcome was the initial anticoagulant selected for treatment. RESULTS: Among 299,016 cases at 1,045 hospitals, similar proportions received initial treatment with UFH (47.4%) and LMWH (47.9%). Between 2011 and 2020, the proportion of patients initially treated with UFH increased from 41.9% to 56.3%. Over this period, use of LMWH as the initial anticoagulant was reduced from 58.1% in 2011 to 37.3% in 2020. The proportion of cases admitted to the ICU, treated with mechanical ventilation or vasopressors, and inpatient mortality were stable. Factors most strongly associated with receipt of UFH were admission to the ICU (odds ratio [OR] 6.90; 95% confidence interval [CI] 6.31 to 7.54) or step-down unit (OR 2.30; 95% CI 2.16 to 2.45), receipt of thrombolysis (OR 4.25; 95% CI 3.09 to 5.84) or vasopressors (OR 1.83; 95% CI 1.32 to 2.54), and chronic renal disease (OR 1.67; 95% CI 1.54 to 1.81). CONCLUSIONS: Despite recommendations that LMWH and DOACs be considered first-line for most patients with acute PE, use of UFH is common and increasing. Further research is needed to elucidate factors associated with persistent use of UFH and opportunities for deimplementation of low-value care.

Feasibility and acceptability of patient- and clinician-level antithrombotic stewardship interventions to reduce gastrointestinal bleeding risk in patients using warfarin (Anticoagulation with Enhanced Gastrointestinal Safety): a factorial randomized controlled pilot trial.

Background: Overuse of antiplatelet therapy and underuse of gastroprotection contribute to preventable bleeding in patients taking anticoagulants. Objectives: (1) Determine the feasibility of a factorial trial testing patient activation and clinician outreach to reduce gastrointestinal (GI) bleeding risk in patients prescribed warfarin-antiplatelet therapy without proton pump inhibitor gastroprotection and (2) assess intervention acceptability. Methods: Pragmatic 2 × 2 factorial cluster-randomized controlled pilot comparing (1) a patient activation booklet vs usual care and (2) clinician notification vs clinician notification plus nurse facilitation was performed. The primary feasibility outcome was percentage of patients completing a structured telephone assessment after 5 weeks. Exploratory outcomes, including effectiveness, were evaluated using chart review, surveys, and semistructured interviews. Results: Among 47 eligible patients, 35/47 (74.5%; 95% CI, 58.6%-85.7%) met the feasibility outcome. In the subset confirmed to be high risk for upper GI bleeding, 11/29 (37.9%; 95% CI, 16.9%-64.7%) made a medication change, without differences between intervention arms. In interviews, few patients reported reviewing the activation booklet; barriers included underestimating GI bleeding risk, misunderstanding the booklet's purpose, and receiving excessive health communication materials. Clinicians responded to notification messages for 24/47 patients (51.1%; 95% CI, 26.4%-75.4%), which was lower for surgeons than nonsurgeons (22.7% vs 76.0%). Medical specialists but not surgeons viewed clinician notification as acceptable. Conclusion: The proposed trial design and outcome ascertainment strategy were feasible, but the patient activation intervention is unlikely to be effective as designed. While clinician notification appears promising, it may not be acceptable to surgeons, findings which support further refinement and testing of a clinician notification intervention.

Optimizing Use of High-Sensitivity Troponin for Risk-Stratification of Acute Pulmonary Embolism.

BACKGROUND: High-sensitivity troponin T (HS-TnT) may improve risk-stratification in hemodynamically stable acute pulmonary embolism (PE), but an optimal strategy for combining this biomarker with clinical risk-stratification tools has not been determined. STUDY HYPOTHESIS: We hypothesized that different HS-TnT cutoff values may be optimal for identifying (1) low-risk patients who may be eligible for outpatient management and (2) patients at increased risk of clinical deterioration who might benefit from advanced PE therapies. METHODS: Retrospective analysis of hemodynamically stable patients in the University of Michigan acute ED-PE registry with available HS-TnT values. Primary and secondary outcomes were 30-day mortality and need for intensive care unit-level care. Receiver operating characteristic curves were used to determine optimal HS-TnT cutoffs in the entire cohort, and for those at higher risk based on the simplified Pulmonary Embolism Severity Index (PESI) or imaging findings. RESULTS: The optimal HS-TnT cutoff in the full cohort, 12 pg/mL, was significantly associated with 30-day mortality (odds ratio [OR]: 3.94, 95% confidence interval [CI]: 1.48-10.50) and remained a significant predictor after adjusting for the simplified PESI (sPESI) score and serum creatinine (adjusted OR: 3.05, 95% CI: 1.11-8.38). A HS-TnT cutoff of 87 pg/mL was associated with 30-day mortality (OR: 5.01, 95% CI: 2.08-12.06) in patients with sPESI ≥1 or right ventricular dysfunction. CONCLUSION: In this retrospective, single-center study of acute PE patients, we identified distinct optimal HS-TnT values for different clinical uses-a lower cutoff, which identified low-risk patients even in the absence of other risk-stratification methods, and a higher cutoff, which was strongly associated with adverse outcomes in patients at increased risk.

Clinical outcomes after discontinuing anticoagulant therapy in patients with first unprovoked venous thromboembolism.

BACKGROUND: The duration of anticoagulation for a first episode of unprovoked venous thromboembolism (VTE) should balance the likelihood of VTE recurrence against the risk of major bleeding. OBJECTIVES: Analyze rates and case-fatality rates (CFRs) of recurrent VTE and major bleeding after discontinuing anticoagulation in patients with a first unprovoked VTE after at least 3 months of anticoagulation. METHODS: We compared the rates and CFRs in patients of the Registro Informatizado Enfermedad Trombo Embólica (RIETE) and Contemporary management and outcomes in patients with venous thromboembolism registries. We used logistic regression models to identify predictors for recurrent pulmonary embolism (PE) and major bleeding. RESULTS: Of 8261 patients with unprovoked VTE in RIETE registry, 4012 (48.6%) had isolated deep vein thrombosis (DVT) and 4250 had PE. Follow-up (median, 318 days) showed 543 recurrent DVTs, 540 recurrent PEs, 71 major bleeding episodes, and 447 deaths. The Contemporary management and outcomes in patients with venous thromboembolism registry yielded similar results. Corresponding CFRs of recurrent DVT, PE, and major bleeding were 0.4%, 4.6%, and 24%, respectively. On multivariable analyses, initial PE presentation (hazard ratio [HR], 3.03; 95% CI, 2.49-3.69), dementia (HR, 1.47; 95% CI, 1.01-2.13), and anemia (HR, 0.72; 95% CI, 0.57-0.91) predicted recurrent PE, whereas older age (HR, 2.11; 95% CI, 1.15-3.87), inflammatory bowel disease (HR, 4.39; 95% CI, 1.00-19.3), and anemia (HR, 2.24; 95% CI, 1.35-3.73) predicted major bleeding. Prognostic scores were formulated, with C statistics of 0.63 for recurrent PE and 0.69 for major bleeding. CONCLUSION: Recurrent DVT and PE were frequent but had low CFRs (0.4% and 4.6%, respectively) after discontinuing anticoagulation. On the contrary, major bleeding was rare but had high CFR (24%). A few clinical factors may predict these outcomes.

Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease.

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases.

Anticoagulation Stewardship to Bridge the Implementation Gap in Perioperative Anticoagulation Management.

Lack of alignment of care protocols among providers in health care is a driver of increased costs and suboptimal patient outcomes. Perioperative anticoagulation management is a good example of a complex area where protocol creation is a clinical challenge that demands input from multiple experts. Questions regarding the need for anticoagulation interruptions are frequent. Yet, due to layers of complexity involving analysis of anticoagulation indication, surgical risk, and anesthesia-associated bleeding risk as well as institutional practices, there is heterogeneity in how these interruptions are approached. The recent perioperative anticoagulation guidelines from the American College of Chest Physicians summarize extensive evidence for the management of anticoagulant and antiplatelet medications in patients who undergo elective interventions. However, implementation of these guidelines by individual clinicians is highly varied and often does not follow the best available clinical evidence. Against this background, anticoagulation stewardship units, which exist to improve safety and quality monitoring for the anticoagulated patient, are of growing interest. These units provide a bridge for the implementation of value-based, high-quality guidelines for patients who need perioperative anticoagulation interruption. We use a case to pragmatically illustrate the problem and tactics for change management and implementation science that may facilitate the adoption of perioperative anticoagulation guidelines.

Assessment of Population-Based Approach to Direct Oral Anticoagulant Management.

Background: As preferences for oral anticoagulation shift from warfarin to direct oral anticoagulants (DOACs), a new care management model is needed. A population approach leveraging a DOAC Dashboard was implemented to track all patients on a DOAC followed by a physician at an academic medical center. The DOAC Dashboard is a real-time report within the electronic health record (EHR) that identifies patients who require evaluation for DOAC dose/therapy adjustment due to changing renal function, age, weight, indication, and/or significant drug-drug interaction (DDI). Objective: This study aims to describe the initial phase of DOAC Dashboard implementation, to evaluate the effectiveness of interventions, and to assess a multidisciplinary approach to management. Method: Retrospective descriptive study of the DOAC Dashboard from August 22, 2019, to January 20, 2022. Primary outcomes include total number of alerts addressed and interventions needed. Secondary outcome is the proportion of interventions implemented by the prescribing clinician. Result: A total of 10 912 patients were identified by the DOAC Dashboard at baseline. A total of 5038 alerts were identified, with 668 critical alerts, 3337 possible critical alerts, and 1033 other alerts. Pharmacists addressed 1796 alerts during the study period (762 critical alerts and 1034 possible critical). Critical alerts included 62 significant DDI, 379 inappropriate dosing, and 321 others. Of the critical alerts, intervention was needed in 291 cases (38%), with 255 (88%) of proposed interventions implemented. Critical alerts and possible critical alerts not requiring intervention were resolved by data entry. Conclusion: The DOAC Dashboard provides an efficient method of identifying patients on DOACs that require dose adjustments or therapeutic modifications.

Longitudinal associations between exclusive, dual and polytobacco use and respiratory illness among youth.

Background: The health consequences of polytobacco use are still well not understand. We evaluated prospective associations between exclusive, dual, and polytobacco use and diagnosed bronchitis, pneumonia, or chronic cough among US youth. Methods: Data came from Waves 1-5 of the Population Assessment of Tobacco and Health Study. We categorized time-varying past 30-day tobacco use into seven categories: (1) non-current use; exclusive use of 2) cigarettes, 3) electronic nicotine delivery systems (ENDS), or 4) other combustible products (OC; pipes, hookah, and cigars); dual use of 5) ENDS + cigarettes or ENDS + OC 6) cigarettes + OC; or 7) polyuse of all three products. The outcome was incident diagnosis of bronchitis, pneumonia, or chronic cough. We conducted weighted multilevel Poisson models (person n = 17,517, 43,290 observations) to examine the longitudinal exposure-outcome relationship, adjusting for covariates: sex, age, race and ethnicity, parental education, body mass index, secondhand smoke exposure, and household use of combustible products. Results: Compared to nonuse, exclusive cigarette use (Incidence Rate Ratio (IRR) = 1.83, 95% CI 1.25-2.68), exclusive ENDS use (IRR = 1.53, 95% CI 1.08-2.15), combustible product + ENDS dual use (IRR = 1.90, 95% CI 1.18-3.04), cigarettes + OC dual use (IRR = 1.96, 95% CI 1.11-3.48), and polytobacco use (IRR = 3.06 95% CI 1.67-5.63) were associated with a higher incidence of bronchitis, pneumonia, or chronic cough. Conclusion: We found that exclusive, dual, and poly tobacco use was associated with higher incidence of bronchitis, pneumonia, or chronic cough; Moreover, the incidence rate ratio for polytobacco use was higher than the incidence rate ratio for exclusive use compared to non-current use.

Current Gaps in the Provision of Safe and Effective Anticoagulation in Atrial Fibrillation and the Potential for Factor XI-Directed Therapeutics.

The global prevalence of atrial fibrillation is rapidly increasing, in large part due to the aging of the population. Atrial fibrillation is known to increase the risk of thromboembolic stroke by 5 times, but it has been evident for decades that well-managed anticoagulation therapy can greatly attenuate this risk. Despite advances in pharmacology (such as the shift from vitamin K antagonists to direct oral anticoagulants) that have increased the safety and convenience of chronic oral anticoagulation in atrial fibrillation, a preponderance of recent observational data indicates that protection from stroke is poorly achieved on a population basis. This outcomes deficit is multifactorial in origin, stemming from a combination of underprescribing of anticoagulants (often as a result of bleeding concerns by prescribers), limitations of the drugs themselves (drug-drug interactions, bioaccumulation in renal insufficiency, short half-lives that result in lapses in therapeutic effect, etc), and suboptimal patient adherence that results from lack of understanding/education, polypharmacy, fear of bleeding, forgetfulness, and socioeconomic barriers, among other obstacles. Often this adherence is not reported to treating clinicians, further subverting efforts to optimize care. A multidisciplinary, interprofessional panel of clinicians met during the 2023 International Society of Thrombosis and Haemostasis Congress to discuss these gaps in therapy, how they can be more readily recognized, and the potential for factor XI-directed anticoagulants to improve the safety and efficacy of stroke prevention. A full appreciation of this potential requires a reevaluation of traditional teaching about the "coagulation cascade" and decoupling the processes that result in (physiologic) hemostasis and (pathologic) thrombosis. The panel discussion is summarized and presented here.