Direct Oral Anticoagulants Users Research Articles

Effectiveness and Safety of the Coadministration of Rifampin and Warfarin versus Direct Oral Anticoagulants: A Cohort Study.

Pharmacokinetic studies have shown that rifampin reduces the levels of oral anticoagulants during the initiation of coadministration, raising concerns about an increased thrombotic risk, but there are limited comparative clinical outcomes between rifampin and warfarin compared with direct oral anticoagulants (DOACs). This study aimed to evaluate the effectiveness and safety of concurrent use of rifampin and warfarin versus DOACs, with assessments of outcome-associated factors and oral anticoagulant (OAC) management quality. A total of 142 patients given rifampin plus warfarin (n = 56) or DOACs (n = 86) for over 7 days were included, and their clinical data and outcomes were compared. The median Charlson Comorbidity Index and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score of the two groups were 2 and 3, respectively. The incidence rate of composite ischemic or thromboembolic events was 2.16 and 1.44 per 10,000 patient-days in the warfarin and DOAC groups, respectively, with an adjusted hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.02-7.34). The incidence rate of composite major bleeding or clinically relevant nonmajor bleeding events was 1.58 and 1.52 per 10,000 patient-days in the warfarin and DOAC groups, respectively, with an adjusted HR of 1.12 (95% CI 0.32-4.45). The risk of composite bleeding events increased with a higher HAS-BLED score (HR: 1.62, 95% CI: 1.02-2.63). Moreover, 34.3% of warfarin users maintained a percent time in therapeutic range of above 50%. Furthermore, 77.9% of DOAC users received appropriate dosing. No significant differences were observed in terms of the incidence of thrombotic or bleeding events between the two groups during coadministration. In addition, a higher HAS-BLED score was associated with a greater risk of bleeding events regardless of the class of OACs used. Finally, close monitoring of bleeding events should be considered.

Direct oral anticoagulants and the risk of adverse clinical outcomes among patients with different body weight categories: a large hospital-based study

ObjectiveThrough predictable pharmacokinetics—including a convenient fixed-dose regimen, direct oral anticoagulants (DOACs) are preferred over previous treatments in anticoagulation for various indications. However, the association between higher body weight and the risk of adverse consequences is not well studied among DOAC users. We aim to explore the association of body weight and adverse clinical outcomes in DOAC users.MethodsA total of 97,413 anonymised DOAC users in a tertiary care setting were identified following structured queries on the electronic health records (EHRs) to extract the feature-rich anonymised dataset. The prepared dataset was analysed, and the features identified with machine learning (ML) informed the adjustments of covariates in the multivariate regression analysis to examine the association. Kaplan–Meier analysis was performed to evaluate the mortality benefits of DOACs.ResultsAmong DOAC users, the odds of adverse clinical outcomes, such as clinically relevant non-major bleeding (CRNMB), ischaemic stroke, all-cause mortality, and prolonged hospital stay, were lower in patients with overweight, obesity, or morbid obesity than in patients with normal body weight. The odds of ischaemic stroke (OR 0.42, 95% CI: 0.36–0.88, p = 0.001) and all-cause mortality (OR 0.87, 95% CI: 0.81–0.95, p = 0.001) were lower in patients with morbid obesity than in patients with normal body weight. In the Kaplan–Meier analysis, apixaban was associated with a significantly lower rate of mortality overall and in obesity and overweight subgroups than other DOACs (p < 0.001). However, rivaroxaban performed better than apixaban in the morbid obesity subgroup (p < 0.001).ConclusionThis study shows the positive effects of DOAC therapy on clinical outcomes, particularly in patients with high body weight. However, this still needs validation by further studies particularly among patients with morbid obesity.

Digital dashboards for direct oral anticoagulant surveillance, intervention and operational efficiency: uptake, obstacles, and opportunities

Direct oral anticoagulants (DOAC) are the most widely prescribed oral anticoagulants in the United States. Despite advantages over warfarin, system-level improvements are needed to optimize outcomes. While Veterans Health Administration and others have described successful DOAC management dashboard implementation, the extent of use nationally is unknown. A survey of Anticoagulation Forum’s members was conducted to assess access to digital tools available within a dashboard and to describe implementation models. An Expert Forum was subsequently convened to identify barriers to dashboard development and adoption. Responses were received from 340 targeted recipients (8.5% of invitees). Only a minority of inpatient (25/52, 48.1%) and outpatient (47/133, 35.3%) respondents outside of Veterans Health Administration were able to generate rosters of DOAC users on-demand, and fewer had the ability to digitally display key clinical data elements, identify drug-related problems, document interventions, or generate reports. The lack of regulatory requirements regarding Anticoagulation Stewardship was identified by the Expert Forum as the major barrier to widespread development of digital tools for improved anticoagulation management. While some health systems have demonstrated the feasibility of DOAC dashboards and described their impact on quality and efficiency, these tools do not appear to be widely available in the United States apart from Veterans Health Administration. The lack of regulatory requirements for Anticoagulation Stewardship may be the primary barrier to the development of digital resources to better manage anticoagulants. Efforts to secure regulatory requirements for Anticoagulation Stewardship are needed, and evidence of improvements in clinical and financial outcomes through DOAC dashboard use will likely bolster such efforts.

Impact of cerebral small vessel disease burden and drug level at admission on direct oral anticoagulant associated intracerebral hemorrhage.

Direct oral anticoagulant (DOAC)-associated intracerebral hemorrhage (ICH) is a catastrophic complication. The aim of this study was to investigate the association between computed tomography (CT)-based cerebrovascular small vessel disease (SVD) burden and DOAC-ICH as well as the DOAC concentration upon hospital admission and ICH outcome. The study included two cohorts: (1) DOAC-ICH: patients who suffered from DOAC-ICH and underwent drug level measurements upon admission; (2) DOAC-non-ICH: stable DOAC users who underwent head CT without ICH during treatment. We categorized the DOAC levels of the DOAC-ICH patients as low (<50 ng/mL), medium (50-300 ng/mL), and high (>300 ng/mL). The CT-based SVD burden (including white matter lesions [WML], lacunes, and cerebral atrophy) was evaluated, and SVD scores (range, 0-3) were used to evaluate SVD severity. A total of 43 DOAC-ICH patients and 177 DOAC-non-ICH patients were enrolled. DOAC-ICH patients were more likely to have WML, lacunes, or cerebral atrophy compared to DOAC-non-ICH patients. After adjustment, the SVD burden was associated with DOAC-ICH, with a higher risk of more severe SVD (SVD score of 2; odds ratio [OR], 10.3 [3.17, 33.3]; score of 3; OR, 16.8 [4.50, 62.6]). The proportions of patients with high, medium, and low drug levels in the DOAC-ICH group were 16.3%, 55.8%, and 27.9%, respectively. Additionally, the high-level group displayed a larger hematoma size and had worse functional outcomes at 3 months than the other two groups. The severity of SVD burden was associated with DOAC-ICH. Furthermore, high DOAC levels in ICH were associated with unfavorable clinical outcomes. To address the potential selection bias from these two cohorts, a prospective study to investigate the co-contribution of drug levels and SVD to DOAC-ICH is essential.

Oral anticoagulant treatment and risk of kidney disease-a nationwide, population-based cohort study.

Direct oral anticoagulants (DOACs) are recommended as first-line treatment of atrial fibrillation. Whether DOAC use is associated with lower risks of kidney complications compared with vitamin K antagonists (VKAs) remains unclear. We examined this association in a nationwide, population-based cohort study. We conducted a cohort study including patients initiating oral anticoagulant treatment within 3months after an atrial fibrillation diagnosis in Denmark during 2012-18. Using routinely collected creatinine measurements from laboratory databases, we followed patients in an intention-to-treat approach for acute kidney injury (AKI) and chronic kidney disease (CKD) progression. We used propensity-score weighting to balance baseline confounders, computed weighted risks and weighted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing DOACs with VKAs. We performed several subgroup analyses and a per-protocol analysis. We included 32 781 persons with atrial fibrillation initiating oral anticoagulation (77% initiating DOACs). The median age was 75years, 25% had a baseline estimated glomerular filtration rate <60mL/min/1.73 m2, and median follow-up was 2.3 (interquartile range 1.1-3.9) years. The weighted 1-year risks of AKI were 13.6% in DOAC users and 15.0% in VKA users (HR 0.86, 95% CI 0.82; 0.91). The weighted 5-year risks of CKD progression were 13.9% in DOAC users and 15.4% in VKA users (HR 0.85, 95% CI 0.79; 0.92). Results were similar across subgroups and in the per-protocol analysis. Initiation of DOACs was associated with a decreased risk of AKI and CKD progression compared with VKAs. Despite the potential limitations of observational studies, our findings support the need for increased clinical awareness to prevent kidney complications among patients who initiate oral anticoagulants.

Direct Oral Anticoagulants Affect Activated Clotting Time During and Bleeding Events After Percutaneous Coronary Intervention

Inappropriately high activated clotting time (ACT) during percutaneous coronary intervention (PCI) is associated with an increased risk of bleeding events. However, whether the prescription of direct oral anticoagulants (DOACs) affects ACT kinetics during heparin use and adverse clinical events in patients who underwent PCI remains unclear. We aimed to evaluate the relations between ACT changes during and adverse clinical events after PCI in patients who were prescribed DOAC. This observational study included 246 patients who underwent PCI at the 2 cardiovascular centers who were not receiving warfarin and whose ACT was recorded immediately before and 30minutes after injection of unfractionated heparin. Patients were divided into 2 groups according to DOAC prescription at the time of the index PCI: DOAC users (n=31) and nonusers (n=215). Any bleeding and systemic thromboembolic events were investigated until 30days after PCI. The average age of this population was 70.5years, and 66.3% were male. Average ACT was significantly higher in DOAC users than nonusers both before and 30minutes after unfractionated heparin induction (157.2±30.1 vs 131.8±25.1seconds, p<0.001; 371.1±122.2 vs 308.3±82.2seconds, p<0.001; respectively). The incidence of systemic thromboembolism after PCI was low and comparable between the 2 groups (0% vs 3.7%, p=0.60). However, the rate of any bleeding event was significantly higher in DOAC users than in nonusers (16.1% vs 4.7%, p=0.028). Patients receiving DOAC have higher ACT during PCI and higher incidence of bleeding events than those not receiving DOAC.

Risk Profiles of New Users of Oral Anticoagulants Between 2011 and 2019 in Germany.

Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany. Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation. Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%. This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.

Management of anticoagulation in atrial fibrillation patients in Italy: insight from the &lt;i&gt;Atrial Fibrillation-Survey on Anticoagulated Patients Register&lt;/i&gt; (AF-START)

The survey on anticoagulated patients register (START-Register) is an independent, prospective, inception-cohort observational study aimed at providing information on patients on vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in Italy. In this study, we describe the cohort of atrial fibrillation (AF) patients in the START-Register and report outcomes and changes in anticoagulant prescription from 2011 to 2021. The study included 11,078 AF patients, enrolled in 47 Italian centers distributed all over the Country; the median age was 77 years (range 18-99 years); 6029 (54.3%) were men; 5135 (46.4%) were on VKAs, and 5943 (53.6%) were on DOACs. Warfarin was the most prescribed VKA (98.4%), and apixaban was the most prescribed DOAC (31.6%). Among DOAC users, 4022 (67.7%) patients were naive to anticoagulation, and 2562 (43.1%) patients were treated with a reduced dose. DOAC patients were significantly older than VKA patients (median age 79 years vs 76 years respectively, P&lt;0.001), but no gender difference was detected. The mean CHA2DS2VASc score was higher in DOAC users than in VKA users (3.7 vs 3.6; P=0.03). The mean HAS-BLED score was not different between the two groups. During follow-up, 542 bleeding events were recorded [2.44 per 100 patient-years (pt-yrs)]; 240 were major (1.08 per 100 pt-yrs), and 301 were clinically relevant non-major bleedings (1.34 per 100 pt-yrs). 146 thrombotic events were recorded during follow-up (0.66 per 100 pt-yrs). The total mortality rate was 3.5 per 100 pt-yrs; the mortality rate was 4.54 per 100 pt-yrs among patients on VKAs and 2.31 per 100 pt-yrs among patients on DOACs. During the last 10 years, in Italy, AF patient management has changed with the large spread of DOACs all over the Country. DOAC patients are frequently treated with reduced doses and show a lower mortality rate in comparison to patients on VKAs.

Risk of venous thromboembolism or hemorrhage among individuals with chronic kidney disease on prophylactic anticoagulant after hip or knee arthroplasty.

Chronic kidney disease (CKD) confers a high risk of thrombosis and bleeding. However, little evidence exists regarding the optimal choice of postoperative thromboprophylaxis in these patients. We conducted a population-based, retrospective cohort study among adults ≥66 years old with CKD undergoing hip or knee arthroplasty who had filled an outpatient prophylactic anticoagulant prescription between 2010 and 2020 in Ontario, Canada. The primary outcomes of venous thrombosis (VTE) and hemorrhage were identified by validated algorithms using relevant diagnoses and billing codes. Overlap-weighted cause-specific Cox proportional hazard models were used to examine the association of direct oral anticoagulants (DOAC) on the 90-day risk of VTE and hemorrhage compared with low-molecular-weight heparin (LMWH). A total of 27 645 patients were prescribed DOAC (N = 22 943) or LMWH (N = 4702) after arthroplasty. Rivaroxaban was the predominant DOAC (94.5%), while LMWH mainly included enoxaparin (67%) and dalteparin (31.5%). DOAC users had higher eGFRs, fewer co-morbidities, and surgery in more recent years compared to LMWH users. After weighing, DOAC (compared with LMWH) was associated with a lower risk of VTE (DOAC: 1.5% vs. LMWH: 2.1%, weighted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.94) and a higher risk of hemorrhage (DOAC: 1.3% vs. LMWH: 1.0%, weighted HR 1.44, 95% CI 1.04-1.99). Additional analyses including a more stringent VTE defining algorithm, different eGFR cut-offs, and limiting to rivaroxaban and enoxaparin showed consistent findings. Among elderly adults with CKD, DOAC was associated with a lower VTE risk and a higher hemorrhage risk compared to LMWH following hip or knee arthroplasty.

Reimbursement and use of oral anticoagulants during 2014–2022 - A register-based study

BackgroundVitamin K antagonists, warfarin in particular, have been the mainstay of anticoagulation therapy, but their use has declined in many countries since direct oral anticoagulants (DOACs) have entered the market. ObjectiveTo examine utilization trends of oral anticoagulants (OACs) in Finland considering the reimbursement of DOACs and changes to national treatment guidelines for the treatment of atrial fibrillation (AF). MethodsBoth public, aggregated data on reimbursed OAC dispensations and individual-level data on electronic dispensations during 2014–2022 were applied. Data on electronic dispensations during 2015–2016 were used to study OAC initiations. Data on entitlements to reimbursement for DOACs came from public data. ResultsIn 2014, there were almost 20,000 DOAC users, rising to 214,000 in 2022. The number of warfarin users declined since 2015 from over 181,000 to around 59,000 users in 2022, DOACs exceeding warfarin in the number of users in 2019. The total DOAC costs were higher than warfarin costs each year. Rivaroxaban was the most widely used DOAC during 2014–2018, and apixaban during 2019–2022. In 2015, there were more warfarin (56.7%) than DOAC (43.3%) initiators, but the result was opposite for 2016 (warfarin 39.4%, DOACs 60.6%). The number of individuals entitled to reimbursement for DOACs has increased steadily, and in 2022, there were over 196,000 individuals entitled to this reimbursement due to AF. ConclusionsThe uptake of DOACs in Finland appears to have been gradual and slower than in many other countries. During the 2010s, the treatment guidelines for AF were more cautious in recommending DOACs than the European guidelines. The use of DOACs increased as their reimbursement became less restrictive.

Risk of hospitalization for upper gastrointestinal bleeding in Helicobacter pylori eradicated patients newly started on warfarin or direct oral anticoagulants: A population-based cohort study.

To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori-eradicated patients newly started on warfarin or direct oral anti-coagulants (DOACs). We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population-based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACsusers in H. pylori-eradicated patients. Secondary analysis included the UGIB risk between H. pylori-eradicated and H. pylori-negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time-varying covariables. Among H. pylori-eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09-0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non-users of acid-suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori-eradicated and H. pylori-negative patients newly started on warfarin (HR: 0.63,95% CI 0.33-1.19) or DOACs (HR: 1.37, 95% CI 0.45-4.22). In H. pylori-eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori-eradicated and H. pylori-negative patients.

Reduction of major gastrointestinal bleeding risk with proton pump inhibitor therapy in patients with atrial fibrillation receiving direct oral anticoagulant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This research was supported by a grant from the Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health &amp; Welfare, Republic of Korea (grant number: HC21C0028). Background In patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), gastrointestinal bleeding (GIB) is itself a serious event for the patient, and it causes an increase in the thromboembolic risk caused by discontinuation of anticoagulation therapy. There are limited data on the benefit of preventive PPI use to reduce the risk of GIB in DOAC users. Methods We included patients with AF receiving DOAC from 2013 to 2020 based on the Korean Health Insurance Review and Assessment database. For comparison between patients with and without PPI, propensity score (PS) weighting method was used. Primary outcome was major GIB and secondary outcomes were major upper GIB and upper GIB requiring transfusion. Results A total of 171,494 patients were included (mean 72±10 years, mean CHA2DS2-VASc 4.3±1.8; 50,577 of rivaroxaban, 23,010 of dabigatran, 54,461 of apixaban, and 43,446 of edoxaban). Among the total population, 40% of patients were prescribed PPI and 55% of PPI users were prescribed low dose PPI. After PS weighting, patients with PPI were associated with lower risks of major GIB, major upper GIB, and upper GIB requiring transfusion than those without PPI (hazard ratio [95% confidence interval]; 0.816 [0.758-0.878], 0.834 [0.770-0.901], and 0.814 [0.734-0.902], respectively, Figure A). Patients with low dose PPI showed significant risk reduction for major GIB, major upper GIB, and upper GIB requiring transfusion than those without PPI (0.570 [0.515-0.632], 0.563 [0.505-0.628], and 0.505 [0.435-0.587], respectively). The protective effect of PPI was slightly different among DOAC types (Figure B). In the subgroup analyses, major GIB risk reduction of PPI co-therapy was more accentuated in patients older than 75 years and those with underlying GI disease or symptoms. Conclusion In this largest Asian cohort of patients with AF receiving DOAC, PPI co-therapy might be beneficial to reduce the risk of major GIB and upper GIB. This was consistently observed with low-dose PPI. The protective effect of PPI was more pronounced in the high bleeding risk patients.

Venous thromboembolism recurrence among one-and-done direct oral anticoagulant users: a retrospective longitudinal study.

Direct oral anticoagulants (DOACs) are the American Society of Hematology guideline-recommended treatment for venous thromboembolism (VTE) in the United States (US). To compare risk of VTE recurrence between patients who, following the first fill, discontinued ("one-and-done") versus those who continued ("continuers") DOACs. Open source US insurance claims data (04/1/2017 to 10/31/2020) were used to select adult patients with VTE initiated on DOACs (index date). Patients with only one DOAC claim during the 45-day landmark period (starting on the index date) were classified as one-and-done and the remaining as continuers. Inverse probability of treatment weighting was used to reweight baseline characteristics between cohorts. VTE recurrence based on the first post-index deep vein thrombosis or pulmonary embolism event was compared using weighted Kaplan-Meier and Cox proportional hazard models from landmark period end to clinical activity or data end. 27% of patients initiating DOACs were classified as one-and-done. After weighting, 117,186 and 116,587 patients were included in the one-and-done and continuer cohorts, respectively (mean age 60years; 53% female; mean follow-up 15months). After 12months of follow-up, the probability of VTE recurrence was 3.99% and 3.36% in the one-and-done and continuer cohorts; the risk of recurrence was 19% higher in the one-and-done cohort (hazard ratio [95% confidence interval] = 1.19 [1.13, 1.25]). Substantial proportion of patients discontinued DOAC therapy after the first fill, which was associated with significantly higher risk of VTE recurrence. Early access to DOACs should be encouraged to reduce the risk of VTE recurrence.

Compliance to perioperative anticoagulation protocols in elderly patients undergoing elective orthopedic procedures: a retrospective observational cohort study on 548 patients

BackgroundCompliance with perioperative anticoagulation guidelines is essential to minimize bleeding and thromboembolic risks in patients undergoing surgery. Compared to vitamin-K antagonists (VKAs), perioperative management of direct oral anticoagulants (DOACs) contains fewer steps. Therefore, we hypothesized that noncompliance with guidelines in VKA users is higher than in DOAC users. The primary aim of our study was to investigate the difference in noncompliance to perioperative anticoagulant management guidelines between elderly patients using VKAs versus those using DOACs. The secondary aim was to determine the difference in occurrence of conflicting information communicated to the patients and the difference in incidence of coagulation-related adverse events.MethodsThis retrospective non-controlled observational cohort study examined elderly patients undergoing elective orthopedic surgery in a teaching hospital in the Netherlands. All patients undergoing elective orthopedic surgery between 1 May 2016 and 1 January 2020, aged 70 years and over, using VKAs or DOACs were selected. Nonelective surgeries were excluded. The primary outcome was the noncompliance to perioperative anticoagulant management guidelines. Secondary outcomes were missing or conflicting information on anticoagulation management communicated to the patient and coagulation-related adverse events. For continuous data, the unpaired T-test was used and for categorical data, the chi-square test.ResultsIn patients using VKAs, noncompliance to one of the steps of perioperative anticoagulation management was 81%, compared to 55% in patients using DOACs (p < 0.001). In most cases, VKAs or DOACs were interrupted for longer than recommended. In 13% of patients using a VKA with perioperative bridging, bridging was not conducted as recommended in the guidelines. In 13% of patients using a DOAC, a low-molecular-weight heparin (LMWH) was prescribed while a DOAC had already been restarted postoperatively. VKA users received conflicting information about perioperative anticoagulation management more often than DOAC users (33% versus 20%; p < 0.001). No difference was seen in postoperative coagulation-related complications.ConclusionGuidelines compliance in DOAC users is higher than in VKA users. Clinical decision support to help in selecting the right interruption interval in DOAC users, simplified standardized perioperative management, good coordination of instructions given to patients, and familiarity with updated guidelines are important in reducing noncompliance.

Early hip fracture surgery is safe for patients on direct oral anticoagulants.

To determine how preoperative direct oral anticoagulant (DOAC) use affects rates of blood transfusion, clinically important blood loss, and 30-day mortality in patients with hip fracture undergoing surgery within 48 hours of presentation to the emergency department. Retrospective cohort study. Academic trauma center. A total of 535 patients with hip fracture who underwent open cephalomedullary nail fixation or arthroplasty either taking a direct oral anticoagulant or no form of chemical anticoagulant/antiplatelet agent before presentation (control). Demographics, time to surgery, type of surgery, blood transfusion requirement, clinically important blood loss, and 30-day mortality. Forty-one patients (7.7%) were taking DOACs. DOAC patients were older (81.7 vs. 77 years, P = 0.02) and had higher BMI (26.9 vs. 24.2 kg/m2, P = 0.01). Time from admission to surgery was similar between DOAC users (20.1 hours) and the control (18.7 hours, P > 0.4). There was no difference in receipt of blood transfusion (P = 0.4), major bleeding diagnosis (P = 0.2), acute blood loss anemia diagnosis (P = 0.5), and 30-day mortality (P = 1) between the DOAC and control group. This was true when stratifying by type of surgery as well. Our results suggest that early surgery may be safe in patients with hip fracture taking DOACs despite theoretical risk of increased bleeding. Because early surgery has previously been associated with decreased morbidity and mortality, we suggest that hip fracture surgery should not be delayed because a patient is taking direct oral anticoagulants. Prognostic Level III.

Comparative validation of HAS-BLED, GARFIELD-AF and ORBIT bleeding risk scores in Asian people with atrial fibrillation treated with oral anticoagulant: A report from the COOL-AF registry.

Comparative data between the HAS-BLED, GARFIELD-AF and ORBIT score are limited in anticoagulated Asian patients with atrial fibrillation (AF). We compared the performance of the 3 scores in a nationwide registry. AF patients treated with oral anticoagulants in the COOL-AF registry were studied. We fitted the variables of the HAS-BLED, GARFIELD-AF and ORBIT score to major bleeding in Cox model. We explored a modified HAS-BLED by addition of sex and body weight. Discrimination, calibration, net reclassification index (NRI) and decision curve analysis were used to compare the performance of the 3 models. Of 3402 patients in the registry, 2568 patients who received oral anticoagulant at baseline were studied. Majority of patients (91.1%) received warfarin. The rate of major bleeding was 2.11 per 100 person-years. The C-statistics of the GARFIELD-AF, HAS-BLED, modified HAS-BLED and ORBIT score were 0.65 (95% confidence interval [CI] 0.63-0.67), 0.66 (95%CI 0.64-0.68), 0.69 (95%CI 0.67-0.71) and 0.64 (95%CI 0.62-0.66) respectively. There was good agreement between predicted and observed bleeding in the deciles of HAS-BLED and GARFIELD-AF scores, while the modified HAS-BLED score and ORBIT score overestimated the risk in the last decile. The modified HAS-BLED score had superior NRI than the HAS-BLED score (26.9%, 95%CI 9.7%-42.2%) and the ORBIT score (31.9%, 95%CI 9.0-53.6%). The NRI between the modified HAS-BLED and GARFIELD-AF score was similar. The net benefit curve of the 4 models were overlapping among different thresholds. The clinical utility for bleeding prediction of GARFIELD-AF, HAS-BLED, modified HAS-BLED and ORBIT scores were similar in anticoagulated Asian patients with AF participating in the COOL-AF registry. We found no advantage of the ORBIT over HAS-BLED score for bleeding risk prediction, even in direct oral anticoagulant users.

The association between direct oral anticoagulant concentration upon acute stroke and stroke outcome

BackgroundThis study aimed to investigate the association between direct oral anticoagulant (DOAC) concentration upon acute ischemic stroke (IS) or intracranial hemorrhage (ICH) and stroke outcomes. MethodsPatients aged ≥20 years treated with DOACs, including dabigatran, rivaroxaban, apixaban, or edoxaban, and developed acute IS or ICH were enrolled to measure DOAC concentration at the time of hospital presentation by using ultrahigh-performance liquid chromatography with tandem mass spectrometry. Ischemic stroke patients was categorized into low (<50 ng/mL) and effective (≥50 ng/mL) groups. The primary outcome was poor functional outcomes at 3 months (modified Rankin Scale scores of 4–6). ResultsA total of 138 patients were enrolled, including 105 IS (76.1%) and 33 ICH patients. In the IS cohort, the average DOAC concentration was 85.7 ± 88.6 ng/mL (low DOAC concentration: 42.9%). Low level group had numerically higher NIHSS (14 versus 9, p = 0.37), significantly poorer functional outcomes at 3 months (odds ratio [OR], 5.08 [1.32, 19.63]), and higher chance of stroke-in-evolution (OR, 6.83 [1.64, 28.41]). In the ICH cohort, the average DOAC concentration was 128.9 ± 111.9 ng/mL. Reversal therapy was administered in 60.6% of patients. Hematoma growth occurred in 35.7% patients. The DOAC concentration was similar across patients with or without reversal therapy, and with or without hematoma growth. ConclusionAmong DOAC users who developed IS, low drug concentrations at hospital presentation predicted poor outcomes.

Ischemic Stroke and Systemic Embolism Among One-and-Done Direct Oral Anticoagulant Users with Non-valvular Atrial Fibrillation.

Direct oral anticoagulants (DOACs) are essential in ischemic stroke/systemic embolism (SE) prevention among patients with nonvalvular atrial fibrillation (NVAF). This study compared the risk of ischemic stroke/SE among patients with NVAF who discontinued DOACs following the first fill ("one-and-done") relative to patients who continued DOACs beyond the first fill ("continuers"). De-identified data from Symphony Health, an ICON plc Company, PatientSource®, April1, 2017 to October31, 2020, were used to identify adults with NVAF initiated on DOACs (index date). Patients with only one DOAC claim during the 90-day landmark period starting on the index date were classified as one-and-done and the remaining as continuers. Inverse probability of treatment weighting was used to balance baseline characteristics in the cohorts. Time from the landmark period end to the first ischemic stroke/SE event or, among those without the event, to clinical activity or data end was compared between balanced cohorts using survival analysis. Of patients initiating DOACs, 23.6% were classified as one-and-done users. After weighting was performed, 241,159 and 238,889 patients comprised the one-and-done and continuer cohorts, respectively. At 12months of follow-up, the probability of ischemic stroke/SE was 1.44% in the one-and-done cohort and 1.00% in the continuer cohort [hazard ratio (95% confidence interval) 1.44 (1.34-1.54); p < 0.0001]. Results at earlier and later time points and in a sensitivity analysis with a 75-day landmark period were similar. A substantial proportion of patients were one-and-done DOAC users, which was associated with significantly higher risk of ischemic stroke/SE events. There is an unmet need to improve access and encourage continuous use of DOACs among patients with NVAF so that severe and fatal complications may be mitigated.

Impact of amiodarone on plasma concentration of direct oral anticoagulant in patients with atrial fibrillation

Amiodarone increases exposure of direct oral anticoagulants (DOACs). We aimed to analyze the effects of concurrent amiodarone use on DOAC concentrations and clinical outcomes. Patients who were ≥20 years of age, had atrial fibrillation, and took DOAC were enrolled to provide trough and peak samples for DOAC concentration measurements using ultra-high-performance liquid chromatography-tandem mass spectrometry. The results were compared with concentrations reported in clinical trials to define above, within, or under the expected range. The outcomes of interest were major bleeding and any gastrointestinal bleeding. Multivariate logistic regression and Cox proportional hazards model were used to determine the impact of amiodarone on above-range concentration and clinical outcomes, respectively. A total of 722 participants (420 men, 58.2%) were enrolled to provide 691 trough samples and 689 peak samples. Among them, 21.3% concurrently used amiodarone. The proportion of patients with above-range trough and peak concentrations was 16.4% and 30.2%, respectively, for amiodarone users, in contrast to 9.4% and 19.8% for amiodarone non-users. The use of amiodarone was associated with above-range trough and peak concentrations (odds ratio [OR]=2.00 [1.16, 3.47] and 1.82 [1.19, 2.79], respectively). However, amiodarone was not a significant predictor of major bleeding or any gastrointestinal bleeding. Concurrent amiodarone use led to increased DOAC concentration but was not associated with a higher risk of major bleeding or any gastrointestinal bleeding. Therapeutic monitoring of DOAC users concurrently taking amiodarone may be recommended for patients with an additional risk of increased DOAC exposure.

Insights into the Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Older Adults with Atrial Fibrillation: A Structured Narrative Review.

Older adults, the fastest growing population, represent almost 50% of all users of direct oral anticoagulants (DOACs). Unfortunately, we have very little relevant pharmacological and clinical data on DOACs, especially in older adults with geriatric profiles. This is highly relevant as pharmacokinetics and pharmacodynamics (PK/PD) often differ substantially in this population. Hence, we need to obtain a better understanding of the PK/PD of DOACs in older adults, to ensure appropriate treatment. This review summarises the current insights into PK/PD of DOACs in older adults. A search was undertaken up to October 2022 to identify PK/PD studies of apixaban, dabigatran, edoxaban, and rivaroxaban, that included older adults aged ≥75 years. This review identified 44 articles. Older age alone did not influence exposure of edoxaban, rivaroxaban and dabigatran, while apixaban peak concentrations were 40% higher in older adults than in young volunteers. Nevertheless, high interindividual variability in DOAC exposure in older adults was noted, which can be explained by distinctive older patient characteristics, such as kidney function, changes in body composition (especially reduced muscle mass), and co-medication with P-gp inhibitors, which is in line with the current dosing reduction criteria of apixaban, edoxaban, and rivaroxaban. Dabigatran had the largest interindividual variability among all DOACs since its dose adjustment criterion is only age, and thus it is not a preferable option. Additionally, DOAC exposure, which fell outside of on-therapy ranges, was significantly related to stroke and bleeding events. No definite thresholds linked to these outcomes in older adults have been established.