Development and Validation of a Predictive Model for Intracranial Haemorrhage in Patients on Direct Oral Anticoagulants.

BACKGROUND: Intracranial haemorrhage (ICH) poses a significant threat to patients on Direct Oral Anticoagulants (DOACs), with existing risk scores inadequately predicting ICH risk in these patients. We aim to develop and validate a predictive model for ICH risk in DOAC-treated patients. METHODS: 24,794 patients treated with a DOAC were identified in a province-wide electronic medical and health data platform in Tianjin, China. The cohort was randomly split into a 4:1 ratio for model development and validation. We utilized forward stepwise selection, Least Absolute Shrinkage and Selection Operator (LASSO), and eXtreme Gradient Boosting (XGBoost) to select predictors. Model performance was compared using the area under the curve (AUC) and net reclassification index (NRI). The optimal model was stratified and compared with the DOAC model. RESULTS: The median age is 68.0 years, and 50.4% of participants are male. The XGBoost model, incorporating six independent factors (history of hemorrhagic stroke, peripheral artery disease, venous thromboembolism, hypertension, age, low-density lipoprotein cholesterol levels), demonstrated superior performance in the development dateset. It showed moderate discrimination (AUC: 0.68, 95% CI: 0.64-0.73), outperforming existing DOAC scores (ΔAUC = 0.063, P = 0.003; NRI = 0.374, P < 0.001). Risk categories significantly stratified ICH risk (low risk: 0.26%, moderate risk: 0.74%, high risk: 5.51%). Finally, the model demonstrated consistent predictive performance in the internal validation. CONCLUSION: In a real-world Chinese population using DOAC therapy, this study presents a reliable predictive model for ICH risk. The XGBoost model, integrating six key risk factors, offers a valuable tool for individualized risk assessment in the context of oral anticoagulation therapy.

A Case of Rivaroxaban-induced Hematomyelia of Thoracic Spinal Cord in Patient with Acute Renal Failure.

Hematomyelia associated with direct oral anticoagulants (DOACs) is rare. In this report, a case of a 78-year-old male with paraplegia due to hematomyelia after medication of rivaroxaban, which is the first case in which acute renal failure is closely associated with the onset and underwent surgical evacuation is presented. The patient was initially misdiagnosed as a spinal cord infarction, and appropriate therapeutic intervention was not provided. One year later, the patient's symptoms did not improve, he is dependent on a wheelchair for daily activities, and cystostomy was performed. During administration of DOACs, hemorrhagic lesion should be strongly suspected in a patient with acute renal failure.

Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Comprehensive Review.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia associated with an increased risk of stroke due to disrupted heart function and potential clot formation. This review examines current management strategies for stroke prevention in AF, focusing on the efficacy, safety, and long-term outcomes of anticoagulation therapies. Anticoagulants, including novel oral anticoagulants (NOACs) and vitamin K antagonists, play a crucial role in reducing stroke risk by preventing clot formation in the heart. Recent studies highlight NOACs as superior alternatives to traditional therapies, offering improved safety profiles and enhanced patient adherence. Despite the risk of bleeding complications, judicious use of anticoagulants significantly improves clinical outcomes in AF patients. The review synthesizes evidence from clinical trials and meta-analyses to underscore the pivotal role of NOACs in transforming stroke prevention strategies in AF. Moreover, it discusses emerging interventions such as left atrial appendage occlusion and emphasizes the importance of personalized, patient-centered care in optimizing treatment decisions for AF patients at risk of stroke.

Group-based trajectory modeling to identify adherence patterns for direct oral anticoagulants in Medicare beneficiaries with atrial fibrillation: a real-world study on medication adherence.

BACKGROUND: Suboptimal adherence to direct oral anticoagulants (DOACs) among atrial fibrillation (AF) patients remains currently a major concern due to the increased risk of cardiac and thromboembolic events. AIM: To identify longitudinal distinct trajectories of DOAC adherence and sociodemographic and clinical factors associated with each trajectory. METHOD: Patients with AF who were prescribed with DOAC from July 2016-December 2017 were identified among patients enrolled in the Medicare Advantage Plan. Patients were followed up for a year after the index date to calculate the monthly proportion of days covered (PDC). The monthly PDC was incorporated into the logistic group-based trajectory model to evaluate distinct patterns of adherence. A multinomial regression model was carried out to assess various predictors associated with each trajectory. Sub-group analysis was conducted among incident DOAC users. RESULTS: Total of 1969 patients with AF, four distinct trajectories of adherence were selected: adherent 36.8%, gaps in adherence 9.3%, gradual decline in adherence 29.7%, and rapid decline in adherence 24.2%. Significant predictors associated with suboptimal adherence trajectories were age (75 years or older), gender (male vs female), low-income subsidy health plan, prevalent users, and presence of comorbidities. Among 933 incident users, three adherence trajectories were identified: adherent trajectory (31.8%), rapid decline in adherence (32.5%), and gradual decline in adherence (35.6%). The significant predictors among incident users were gender (male vs female), low-income subsidy health plan, HAS-BLED score ≥ 2, and presence of coronary artery disease. CONCLUSION: Adherence to DOACs was suboptimal among the total population and incident users.

Successful direct oral anticoagulant management of asymptomatic superior mesenteric vein thrombosis after adjuvant chemotherapy for colorectal cancer patient: A case report.

Owing to advances in cancer treatment and the diversification of treatment methods, cancer-associated thrombosis is increasing. Cancer can cause blood clots by activating the blood clotting system, increasing clotting factors through inflammation, reducing blood flow due to immobilization and damaging blood vessels through treatments such as chemotherapy. In clinical practice, superior mesenteric vein (SMV) thrombosis is occasionally observed in patients with cancer; however, certain cases of asymptomatic thrombosis can be serious. In the present case, a 71-year-old woman underwent laparoscopic high anterior resection for colorectal cancer. The patient received capecitabine as postoperative adjuvant chemotherapy for 6 months. Contrast-enhanced CT after the completion of chemotherapy revealed a sizable thrombus in the SMV. The thrombus occupied the SMV lumen without evident intestinal ischemia. D-dimer levels were elevated. Since the patient remained asymptomatic, edoxaban (30 mg/day) was administered in an outpatient setting. Six months later, contrast-enhanced CT confirmed thrombus resolution. No hemorrhagic events were observed during edoxaban treatment. In conclusion, cancer and chemotherapy are risk factors for thrombosis, indicating that regular D-dimer measurements may be necessary during cancer treatment. In addition, edoxaban may be an effective therapeutic tool for SMV thrombosis during chemotherapy for cancer.

Can edoxaban be used at extremes of bodyweight and in patients with a creatinine clearance ≥95 ml/min? - A population pharmacokinetic analysis.

BACKGROUND: Clinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin. OBJECTIVE: To derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics. METHOD: Edoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function. RESULTS: Data from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min. CONCLUSIONS: Our population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.

Prognosis of Patients With Ischemic Stroke With Prior Anticoagulant Therapy: Direct Oral Anticoagulants Versus Warfarin.

BACKGROUND: Direct oral anticoagulants (DOACs) have been the drug of choice for preventing ischemic stroke in patients with atrial fibrillation since 2014. In previous studies, the stroke risk while taking warfarin was 2 per 100 patient-years and 1.5% per year while taking DOACs. We hypothesized that even if ischemic stroke occurred during anticoagulation therapy with DOACs, the prognosis was likely to be better than that with warfarin. METHODS AND RESULTS: Data from 2002 to 2019, sourced from a nationwide claims database, were used to identify atrial fibrillation patients using International Classification of Diseases codes. Patients who experienced an ischemic stroke during anticoagulation were categorized by the drugs used (warfarin, dabigatran, apixaban, rivaroxaban, and edoxaban). The primary outcome was mortality within 3 months and 1 year after the ischemic stroke. Among the 9578 patients with ischemic stroke during anticoagulation, 3343 received warfarin, and 6235 received DOACs (965 dabigatran, 2320 apixaban, 1702 rivaroxaban, 1248 edoxaban). The DOACs group demonstrated lower risks of 3-month (adjusted hazard ratio [HR], 0.550, [95% CI, 0.473-0.639]; P<0.0001) and 1-year mortality (adjusted HR, 0.596 [95% CI, 0.536-0.663]; P<0.0001) than the warfarin group. Apixaban and edoxaban within the DOAC group exhibited particularly reduced 1-year mortality risk compared with other DOACs (P<0.0001). CONCLUSIONS: Our study confirmed that DOACs have a better prognosis than warfarin after ischemic stroke. The apixaban and edoxaban groups had a lower risk of death after ischemic stroke than the other DOAC groups.

Paravertebral Block for Multiple Rib Fractures in an Anticoagulated Trauma Patient.

This case report presents the complex analgesia management of a 52-year-old male with a significant medical history including atrial fibrillation treated with apixaban, essential trigeminal neuralgia, non-ischemic cardiomyopathy, and chronic systolic heart failure. The patient experienced a loss of control while riding a motorized bicycle, resulting in a fall and head injury with no loss of consciousness. Upon admission, he tested positive for ethanol, cannabinoids, and oxycodone. The physical exam was significant for right cephalohematoma and right elbow hematoma. Imaging revealed multiple injuries, including right rib fractures (T3-12) with hemothorax. Right paravertebral catheters were placed in the intensive care unit (ICU).

Direct Oral Anticoagulant Treatment for Atherosclerosis-Induced Aortic Mural Thrombus in an Elderly Male With Aspirin Resistance.

Aortic mural thrombus is associated with atherosclerosis in a vast majority of cases and could result in multiple organ damage, leading to higher morbidity and mortality rates. Although aspirin could be effective for primary prevention in atherosclerosis-induced aortic mural thrombus, aspirin resistance, which refers to the inadequate response to aspirin therapy, allows the progression of thrombus. Classically, warfarin could be an effective treatment for thromboembolic diseases, while in recent years, direct oral anticoagulants (DOACs) have shown superior safety and efficacy, particularly in elderly patients. This report presents the case of an elderly male with chronic aortic mural thrombi due to atherosclerosis and aspirin resistance who achieved favorable outcomes following treatment with DOACs. DOACs could be a possible option for managing aortic mural thrombus with aspirin resistance.

Effectiveness of Direct Oral Anticoagulants and Vitamin K Antagonists in Preventing Stroke in Patients With Atrial Fibrillation and Liver Cirrhosis: A Systematic Review and Meta-Analysis.

Patients with atrial fibrillation and concurrent liver cirrhosis have been excluded from major clinical trials evaluating direct oral anticoagulants (DOACs) due to safety concerns. This has led to uncertainty regarding the optimal anticoagulant therapy in this population at high risk of thromboembolic events. We conducted a systematic review and meta-analysis to compare the effectiveness and safety of DOACs versus vitamin K antagonists (VKAs) in patients with atrial fibrillation and liver cirrhosis. Databases including Embase, MEDLINE/PubMed, and Web of Science were searched for relevant studies. The primary effectiveness outcome was stroke or systemic embolism, and the safety outcome was major bleeding events. A total of 10 studies were included in the meta-analysis. Compared to VKAs, the use of DOACs was associated with a significantly lower risk of stroke or systemic embolism (RR: 0.78, 95% CI: 0.65-0.92, p=0.005). The risk of all-cause mortality was comparable between the two groups (RR: 0.89, 95% CI: 0.74-1.07, p=0.23). Notably, DOACs demonstrated a significantly lower risk of major bleeding events (RR: 0.67, 95% CI: 0.61-0.73, p<0.01) compared to VKAs. This meta-analysis suggests that DOACs may be a favorable alternative to VKAs for the prevention of thromboembolic events in patients with atrial fibrillation and liver cirrhosis, with a lower risk of stroke or systemic embolism and major bleeding. However, further research is needed to establish optimal dosing strategies and assess the safety and efficacy of DOACs in patients with advanced liver disease.

Mechanical Aortic Valve Thrombosis During Anticoagulation Using Oral Rivaroxaban: A Case Report.

Direct oral anticoagulants (DOACs) are widely used in cardiovascular medicine. Although rivaroxaban has potential benefits for anticoagulation in certain contexts, DOACs remain contraindicated in patients with mechanical heart valves. This case report highlights the life-threatening risks of rivaroxaban use in patients with mechanical aortic valves, underscoring the lack of proven efficacy and the necessity of adhering to established anticoagulation protocols with warfarin for this patient population. Here, we report a case of a 65-year-old man who had previously undergone aortic valve replacement and developed a thrombus in the mechanical aortic valve six months after switching from warfarin to rivaroxaban. The patient experienced a sudden loss of consciousness and chest discomfort. Echocardiography revealed a thrombus in the valve requiring urgent reoperation and replacement with a bioprosthetic valve. The postoperative recovery was uneventful.

Risk Factors for Treatment Transition in Patients with Low-Risk Atrial Fibrillation Patients Undergoing Anticoagulation Monotherapy: A Large Claims Database Study in Japan.

The global prevalence of atrial fibrillation (AF) is rising, paralleling increased life expectancy. Early rhythm control benefits AF management. However, in low-risk, often asymptomatic, AF patients, anticoagulant monotherapy is the selected treatment, aligning with current guidelines. However, early AF progression in these low-risk individuals is not well-understood. Thus, this study aims to: 1) determine the proportion of low-risk AF patients who worsen within a year of initial AF diagnosis and 2) identify risk factors such treatment transitions. We analyzed data from 18623 AF patients, spanning January 2005 to June 2017. Low-risk patients were those on anticoagulant monotherapy ± rate control, following the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias. We defined 2 patterns of treatment transition for 1) initiating ablation or antiarrhythmic drug therapy and 2) solely using antiarrhythmic drugs. This retrospective cohort study was employed a 12-month study, following a 6-month screening period. We included 1874 patients for all rhythm control (analysis 1) and 1503 for only medication-based control (analysis 2). The primary endpoint, treatment transition of AF under monotherapy, occurred in 28.4% of patients in analysis 1 and 10.8% in analysis 2. Risk factors common to both scenarios were male gender, baseline rate control drug use, and rivaroxaban selection, as identified by multiple logistic regression. These findings suggest a higher AF treatment transition trend in patients starting rivaroxaban, calling for further research. The study highlights the importance of informed early rhythm control initiation decisions in clinical settings.

Temporal Changes in Long-Term Outcomes of Venous Thromboembolism From the Warfarin Era to the Direct Oral Anticoagulant Era.

BACKGROUND: There have been limited data on the changes in clinical outcomes after the introduction of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) in real clinical practice. We evaluated the changes in management strategies and long-term outcomes from the warfarin era to the DOAC era. METHODS AND RESULTS: We compared the 2 series of multicenter COMMAND VTE (Contemporary Management and Outcomes in Patients With Venous Thromboembolism) registries in Japan enrolling consecutive patients with acute symptomatic VTE: Registry 1: 3027 patients in the warfarin era (2010-2014) and Registry 2: 5197 patients in the DOAC era (2015-2020). The prevalence of DOAC use increased more in Registry 2 than in the Registry 1 (Registry 1: 2.6% versus Registry 2: 79%, P<0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in Registry 2 than in Registry 1 (10.5% versus 9.5%, P=0.02), and the risk reduction of recurrent VTE in Registry 2 remained significant even after adjusting the confounders (hazard ratio [HR], 0.78 [95% CI, 0.65-0.93]; P=0.005). The cumulative 5-year incidence of major bleeding was not significantly different between the 2 registries (12.1% versus 13.7%, P=0.26), and the risk of major bleeding between the 2 registries was not significantly different even after adjusting the confounders (HR, 1.04 [95% CI, 0.89-1.21]; P=0.63). CONCLUSIONS: Along with the shift from warfarin to DOACs, there was a lower risk of recurrent VTE in the DOAC era than in the warfarin era, whereas there was no apparent change in the risk of major bleeding, which might still be an unmet need even in the DOAC era.

Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I2 = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I2 = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I2 = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I2 = 0%). DOACs increased the risk of clinically relevant non-major bleeding (CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I2 = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I2 = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I2 = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I2 = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I2 = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.

Time-in-therapeutic-range defined warfarin and direct oral anticoagulants in atrial fibrillation: a Nationwide Cohort Study.

BACKGROUND: Little is known how individual time-in-therapeutic-range (TTR) impacts the effectiveness and safety of warfarin therapy compared to direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF). OBJECTIVE: To compare the effectiveness and safety of standard dose DOACs to warfarin in patients with AF, while categorizing warfarin treated patients into quartiles based on their individual TTR. MATERIALS AND METHODS: We conducted a nationwide study including all patients with new-onset AF between 2011 and 2018 in Finland. Hazard ratios (HR) were calculated using Cox regression analysis with the inverse probability of treatment weighted method to assess the risks of ischaemic stroke (IS), intracranial haemorrhage (ICH) and mortality for users of apixaban (n = 12,426), dabigatran (n = 4545), rivaroxaban (n = 12,950) and warfarin (n = 43,548). RESULTS: The median TTR for warfarin users was 72%. Compared to the second best TTR quartile (reference), the risk of IS was higher in the two poorest TTR quartiles, and lower in the best TTR quartile and on rivaroxaban [2.35 (95% confidence interval, 1.85-2.85), 1.44 (1.18-1.75), 0.60 (0.47-0.77) and 0.72 (0.56-0.92)]. These differences were non-significant for apixaban and dabigatran. HR of ICH was 6.38 (4.88-8.35) and 1.87 (1.41-2.49) in the two poorest TTR groups, 1.44 (1.02-1.93) on rivaroxaban, and 0.58 (0.40-0.85) in the best TTR group compared to the reference group. Mortality was higher in the two poorest TTR groups and lowest in the best TTR group. CONCLUSIONS: The outcome was unsatisfactory in the two lowest TTR quartiles - in half of the patients treated with warfarin. The differences between the high TTR groups and standard dose DOACs were absent or modest.

Feasibility of atezolizumab and bevacizumab combination regimens in patients with hepatocellular carcinoma and lung cancer taking direct oral anticoagulants.

AIM: Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs. METHODS: This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed. RESULTS: The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039). CONCLUSIONS: DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs.

Direct oral anticoagulant therapy in adolescent venous thromboembolism: A systematic review.

Adolescent venous thromboembolism (VTE) has unique challenges in management, complications, and compliance to anticoagulants. Direct oral anticoagulants (DOACs) have been approved for pediatric VTE management, with an increasing use especially in adolescents. Primary objective is to evaluate the safety and efficacy of DOAC therapy in adolescent VTE. Secondary objectives include adverse events, bleeding events, and overall mortality. A SR protocol was registered in PROSPERO 2022 (CRD42022363928). Databases were searched from inception to September 22, 2022. Studies with children aged 10-18 years, VTE diagnosis, DOAC therapy, randomized control trials (RCTs), cohort, and relevant study types were included. Studies including prophylaxis, non-DOAC therapy, arterial thrombosis, age outliers, non-relevant study types were excluded. Findings are reported in accordance to PRISMA 2020. Nine reports from five studies, published between 2016 and 2022, were included. Rivaroxaban was the most common DOAC. VTE recurrence was 0.02% in the rivaroxaban phase III trial and one patient in the dabigatran phase IIb/III trial. Complete/partial thrombus resolution (CR/PR) was 76.6% in the rivaroxaban phase III trial, and 83.9% in the dabigatran phase IIb/III trial. CR/PR was found to be 68.4% in Dhaliwal et al. study and 83.3% in Hassan et al. study. Major bleeding occurred in one patient. Headache and gastrointestinal symptoms were commonly seen. All-cause mortality occurred in a patient due to cancer progression. DOAC therapy in adolescent VTE had CR/PR in two-thirds of the patients, with low incidence of VTE recurrence and major bleeding. As there are only two randomized controlled trial (RCTs), future adolescents' studies are required to validate our results.

Potential interactions between medications for rate control and direct oral anticoagulants: Population-based cohort and case-crossover study.

BACKGROUND: Direct oral anticoagulants (DOACs) are commonly co-prescribed with amiodarone/diltiazem/verapamil, but whether there is a drug interaction between these drugs is unclear. OBJECTIVE: The purpose of this study was to investigate the risk of clinical outcomes associated with concomitant use of DOACs and amiodarone/diltiazem/verapamil. METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from January 1, 2011, to December 31, 2019. We used a cohort design to estimate hazard ratios for ischemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality, comparing DOACs + amiodarone/diltiazem/verapamil users and DOACs + beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window vs referent window within an individual also was conducted. RESULTS: Of 397,459 DOAC users, we included 9075 co-prescribed amiodarone, 9612 co-prescribed diltiazem, and 2907 co-prescribed verapamil. There was no difference in risk of any outcomes between DOACs + amiodarone/diltiazem/verapamil users vs DOACs + beta-blocker users in the cohort design. However, in the case-crossover design, we observed an odds ratio (OR) of 2.09 (99% confidence interval [CI] 1.37-3.18) for all-cause mortality associated with initiation of a DOAC while taking amiodarone, which was greater than that observed for DOAC monotherapy (OR 1.30; 99% CI 1.25-1.35). Similar findings were observed for cardiovascular mortality and all-cause mortality respectively with diltiazem. CONCLUSION: Our study showed no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem, or verapamil. Elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.

A Pilot Study Describing DOAC Level Results and Association With Clinical Outcomes.

Purpose: Describe direct oral anticoagulant (DOAC) level ordering and interpretation practices in association with clinical outcomes at a vascular medicine clinic. Methods: This study was a retrospective, observational study including patients who had a DOAC level ordered and assessed while on DOAC therapy. The primary outcome was the proportion of DOAC levels within previously reported ranges. Secondary outcomes included thrombotic events, major and clinically relevant non-major bleeding events, and the proportion of DOAC level results which prompted a change in the therapeutic plan. Results: A total of 43 patients who had a DOAC level ordered while on DOAC therapy were included in the study. More patients were on apixaban than other DOACs, and the most common indication for anticoagulation was deep vein thrombosis (DVT) or pulmonary embolism (PE). The most common reasons for ordering DOAC levels included history of gastric bypass (n = 20) and drug-drug interactions (n = 8). Most patients on apixaban had in-range levels (n = 24) compared to out of-range levels (5 patients). More patients on rivaroxaban had a level out-of-range (n = 10) than in-range (n = 4). One patient had a DVT, resulting in hospitalization and change in DOAC therapy. Two patients had bleeding events, with 1 hospitalization and change in DOAC therapy. DOAC level results also prompted changes in therapeutic plans for 9 of the patients. Conclusion: DOAC level results did not always correlate with expected outcomes, and further research is warranted to clarify which clinical situations may benefit from ordering DOAC levels.