Dose Of Dabigatran Research Articles

Protein S contributes to the paradoxical increase in thrombin generation by low-dose dabigatran in the presence of thrombomodulin.

Low dose of dabigatran paradoxically increased thrombin generation through inhibition of protein C activation. Protein S is a co-factor in the activation of protein C. However, the role of protein S in the enhancement of thrombin generation has not been addressed. Firstly, we measured thrombin generation by calibrated automated thrombinography (CAT) and prothrombin fragments 1+2 (F1+2) assays. Secondly, we assessed activated protein C (APC) formation in normal or protein S-deficient plasma spiking with dabigatran. Then, protein C activation was measured. Finally, heavy chain of factor Va (FVa) and its degradation products were detected by western blot. CAT assay showed that 70-141 ng/ml dabigatran paradoxically increased thrombin generation in normal plasma. However, higher concentrations of dabigatran (283 ng/ml) suppressed the level of ETP. F1+2 assay showed the similar results. In protein S-deficient or protein C-deficient plasma, the paradoxical increase in thrombin generation was absent. Level of generated APC was to a similar extent inhibited by dabigatran in normal and protein S-deficient plasma. Low-dose dabigatran inhibited the protein S-dependent inactivation of factor Va. Protein S participated in the paradoxical enhancement of thrombin generation in normal plasma spiking with low concentrations of dabigatran. Increased thrombin generation at low dabigatran can be explained by reduced thrombin-thrombomodulin mediated APC formation and subsequent reduced FVa inactivation that is protein S-dependent.

Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial Fibrillation.

Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.

His bundle pacing in a patient with atrioventricular conduction abnormalities, persistent atrial flutter at high thromboembolic and bleeding risk after hybrid coronary revascularization and left atrial appendage closure - case report

We present a case of a 78-year-old patient with persistent atrial fl utter, history of atrial fi brillation and atrioventricular conduction disturbances, including fi rst-degree atrioventricular block (AVB) and paroxysmal complete AVB. Echocardiography revealed mildly reduced left ventricular ejection fraction (LVEF, 44%). The patient had high thromboembolic risk, had previous ischemic stroke, suffered from chronic coronary artery disease treated with hybrid coronary revascularization (minimally invasive direct coronary artery bypass grafting and subsequent percutaneous coronary intervention) as well as left atrial appendage closure. Because of high bleeding risk, double antiplatelet therapy (acetylsalicylic acid and clopidogrel) combined with low dose of low-molecular-weight heparin after cardiac surgery were introduced. Due to persistent atrial fl utter, complete AVB, lack of intraventricular conduction abnormalities, mildly reduced LVEF and expected high right ventricle pacing burden, the patient was referred for dual-chamber pacemaker implantation using conduction system pacing (CSP), preferentially His bundle pacing (HBP). The procedure was performed with good outcome and CSP was utilized via HBP. After reassessment of thromboembolic and bleeding risk, the patient was discharged home on reduced dose of dabigatran. Short-term follow-up showed stable HBP parameters along with no additional symptoms. Despite good short-term outcomes and no complications in studied patient, large randomized controlled trials are needed to verify long-term safety and effi cacy of HBP to optimize clinical care of patients with atrioventricular conduction abnormalities using a personalized approach. 

Dabigatran pharmacokinetic-pharmacodynamic in sheep: Informing dose for anticoagulation during cardiopulmonary bypass.

The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. Five sheep were given intravenous dabigatran 4mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480min, and 24h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15mg/kg administered 120min after dabigatran 4mg/kg and its effect on R-time was observed. A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453L/min/70kg), intercompartment clearance (Q 0.268L/min/70kg), central volume of distribution (V1 2.94L/70kg), peripheral volume of distribution (V2 9.51L/70kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2mg/L) eliciting half of the maximal effect (EMAX 180min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04min. Idarucizumab 15mg/kg reduced R-time by approximately 5min. Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25mg/kg followed by a maintenance infusion of dabigatran 0.0175mg/kg/min for 30min and a subsequent infusion dabigatran 0.0075mg/kg/min achieves a steady state target concentration of 5mg/L in a sheep model.

Time-in-therapeutic-range defined warfarin and standard dose direct oral anticoagulants in atrial fibrillation: Ischemic stroke, intracranial hemorrhage and death in a nationwide registry study

Abstract Background and aims Direct oral anticoagulants (DOACs) have almost replaced warfarin in stroke prevention of patients with atrial fibrillation (AF). However, little is known whether DOACs are more efficacious or safer than warfarin having information on time-in-therapeutic-range (TTR) in the warfarin-treated patients. Methods The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients combining data from several Finnish health care registers. We analyzed all new-onset AF patients from 2011 to 2018 with available laboratory data. The rates of ischemic stroke (IS), intracranial hemorrhage (ICH) and mortality during oral anticoagulation (OAC) use were analyzed until maximum follow-up of 730 days. Confounding factors by baseline characteristics as well as medications were taken into account by an inverse probability of treatment weighted analysis. For warfarin users, TTR was calculated and patient quartiles by TTR were assigned. The rates of IS, ICH and mortality in TTR quartiles for warfarin users were compared to standard dose dabigatran (150 mg bd.), apixaban (5mg bd.) and rivaroxaban (20mg od.). Results Altogether, 73 469 new-onset AF patients with OAC therapy (50.4 % male, mean age 73.0 years, 43 548 on warfarin, with mean TTR 66% and median TTR 72%) were followed for 76 546 patient years (py). The rate of IS among patients with standard dose DOACs was 0.73/100 py for dabigatran (n=4 545)[HJK1] , 1.05/100 py for apixaban (n=12 426) and 0.83/100 py for rivaroxaban (n=12 950). In the TTR quartiles of patients on warfarin, rates of IS were 3.5, 1.8, 1.2 and 0.74/100 py from the lowest (mean TTR 32%) to the highest quartile (mean TTR 90%), respectively. The weighted rates of IS were 1.3, 1.1 and 0.87/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.2, 1.7, 1.2 and 0.7/100 py. The respective rates of ICH were 0.47, 0.62 and 0.67/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.6, 0.99, 0.51 and 0.32/100 py. The weighted rates of ICH were 0.70, 0.65 and 0.73/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.4, 0.96, 0.51 and 0.30/100 py. For mortality, the raw incidence rates were 1.2, 2.8 and 2.1/100 py for for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 16.5, 5.3, 2.3, and 1.5/100 py. The weighted rates were 1.6, 2.9, and 2.6, for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 14.6, 4.8, 2.0, and 1.3/100 py. The Figures provide cumulative incidence of IS and total mortality (crude rates) of the analyzed OAC groups. Conclusions The rates of IS, ICH and mortality were highest among patients on warfarin in the two lowest TTR quartiles, whereas the differences between high TTR groups and standard dose DOACs were only modest.Cumulative incidence of ischemic strokeCumulative mortality rate

Effect of direct oral anticoagulant dabigatran on early bone healing: An experimental study in rats.

Dabigatran belongs to the new generation of direct oral anticoagulants (DOACs). Its advantages are oral administration and no need for international normalized ratio (INR) monitoring. Although its use has increased, its potential side effects on bone healing and remodeling have not been fully investigated. The present study aimed to evaluate the possible effects of dabigatran on early bone healing. Sixteen male Wistar rats were divided into two groups; in group A, 20-mg/kg dabigatran dose was administered orally daily for 15 days, while group B served as a control. Two circular bone defects (d=6 mm) were created on either side of the parietal bones. Two weeks after surgery and euthanasia of the animals, tissue samples (parietal bones that contained the defects) were harvested for histological and histomorphometric analysis. Statistical analysis was performed with a significance level of α=0.5. No statistically significant differences were found between the two groups regarding the regenerated bone (21.9% vs. 16.3%, P=0.172) or the percentage of bone bridging (63.3% vs. 53.5%, P=0.401). Dabigatran did not affect bone regeneration, suggesting that it might be a safer drug compared to older anticoagulants known to lead to bone healing delay.

Budget and health impact of switching eligible patients with atrial fibrillation to lower- dose dabigatran

ABSTRACT Objectives: To assess the comparative budget and health impact of lower-dose dabigatran versus reduced doses of apixaban and rivaroxaban in atrial fibrillation (AF) patients eligible for a lower-/reduced-dose due to individual patient characteristics in the Netherlands. Methods: A budget impact model was developed in accordance with ISPOR guidelines. A 3-year-time horizon was considered, and analyses were conducted from a Dutch healthcare payer’s perspective. The model applies published data to local AF-epidemiology, allowing calculations to estimate clinical events (strokes and haemorrhages) and costs. The analyses were based on real-world outcomes from patients with AF receiving a first direct oral anticoagulant (DOAC) prescription for low-dose dabigatran (110 mg) and a reduced dose of apixaban (2.5 mg) or rivaroxaban (15 mg). Two situations of switching treatments from one to another DOAC were modelled: switching from apixaban to dabigatran and from rivaroxaban to dabigatran. Base case results were given as savings per 100 patient-year, per total Dutch population, and events avoided. A univariate sensitivity analysis was conducted to explore the uncertainty around epidemiological and event costs input data. Scenario analyses were performed to estimate the effect of different market shares and potential price reductions due to future patent expiry for the total real-world population from the Netherlands. Results: The 3-years outcomes of switching patients eligible for a lower-/reduced-dose due to individual patient characteristics from apixaban or rivaroxaban to dabigatran resulted in cost savings estimated at €157 or €72 thousand per 100 patient-years, respectively, or €146 million per total Dutch population. Looking into the clinical events, dabigatran reflected the lowest number of mortalities, ischemic strokes, major bleeding, non-major bleeding, and haemorrhagic stroke compared to apixaban and rivaroxaban. The sensitivity analysis consistently reflected cost savings, with the ischeamic stroke events having the biggest impact. Accounting for the Dutch situation, both scenarios showed total savings ranging from €45 to €229 million over 3 years. Conclusions: Switching eligible AF-patients from reduced-dose apixaban or rivaroxaban to lower-dose dabigatran has the potential to reduce healthcare payer’s budget expenditures and provide health gains. Cost savings can potentially be further enhanced by market share adjustments and further price reductions.

Effectiveness and safety of Dabigatran 110 mg versus 150 mg for Stroke Prevention in Patients with Atrial Fibrillation at High Bleeding Risk

PurposeThe effectiveness and tolerability of a reduced dose (110 mg) of dabigatran versus the standard dose (150 mg) were evaluated in subgroups of patients with atrial fibrillation (AF) at high bleeding risk. MethodsEligible patients were adults with AF and a creatinine clearance rate ≥30 mL/min who were initiated on treatment with dabigatran (index) between 2016 and 2018. High–bleeding-risk subgroups were identified: (1) age ≥80 years; (2) moderate renal impairment (creatinine clearance rate 30–<50 mL/min); and (3) recent bleeding or a HAS-BLED score of ≥3. Fine-Gray subdistribution hazard regression models with inverse probability of treatment weights were used to investigate associations between dabigatran dose and three outcomes: stroke or systemic embolism, major bleeding requiring hospitalization, and all-cause mortality. FindingsAmong 7858 patients with AF and a high bleeding risk (age ≥80 years, 3472; moderate renal impairment, 1574; recent bleeding or HAS-BLED score ≥3, 2812), 32.3% received reduced-dose dabigatran. Compared with the standard dose, use of the reduced dose of dabigatran was not associated with an increased risk for stroke or systemic embolism but was associated with a lower risk for major bleeding (HR = 0.65; 95% CI, 0.44–0.95) and all-cause mortality (HR = 0.78; 95% CI, 0.65–0.92) in patients aged ≥80 years. The use of reduced-dose dabigatran was associated with a lower risk for major bleeding (HR = 0.54; 95% CI, 0.30–0.95) and all-cause mortality among patients with moderate renal impairment (HR = 0.53; 95% CI, 0.40–0.71). ImplicationsLower risks for bleed and mortality associated with reduced- versus standard-dose dabigatran in patients with AF and a high bleeding risk suggest a better dosing strategy.

How good is time-in-therapeutic-range defined warfarin treatment compared to standard dose direct oral anticoagulants? Incidence of stroke in atrial fibrillation in a nationwide registry study

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): The Finnish Foundation for Cardiovascular Research, and Helsinki and Uusimaa Hospital District research fund. Background and aims Direct oral anticoagulants (DOACs) have largely replaced warfarin in patients with atrial fibrillation (AF) to reduce risk of stroke. However, it is not known whether DOACs are more efficacious in preventing stroke or safer than good-quality warfarin treatment with high time in therapeutic range (TTR). Methods The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients that combines data from several Finnish health care registers. We analyzed all new-onset AF patients in Finland from January 2011 to December 2018 with laboratory data available. Comorbidities, concomitant medications and CHA2DS2-VASc -scores were recorded until date of AF diagnosis. OAC purchases from diagnosis of AF to the end of study were analyzed. ICD-10 diagnoses for stroke (ischemic or hemorrhagic) or transient ischemic attack during OAC use were analyzed until maximum follow-up of 730 days. Confounding factors by baseline characteristics as well as medications were taken in account by use of an inverse probability of treatment weighted analysis. For warfarin users, time in therapeutic range (TTR) was calculated and patient quartiles by TTR were assigned. Rate of stroke in different TTR quartiles for warfarin users were compared to standard dose dabigatran (150 mg bd.), apixaban (5mg bd.) and rivaroxaban (20mg od.). Results Altogether, 74 008 new-onset AF patients with OAC therapy (50.4 % male, mean age 73.0 years, 43 549 on warfarin, with mean TTR 66% and median TTR 72%) were followed for 109 143 patient years (py). Rate of stroke among patients with standard dose direct oral anticoagulants was 6.0/100 py for dabigatran (n=4545), 6.2/100 py for apixaban (n=12 426) and 4.0/100 py for rivaroxaban (n=12 950). In the TTR quartiles of patients on warfarin, rates of stroke were 9.3, 7.2, 5.5 and 4.3/100 py from the lowest (mean TTR 32%) to the highest quartile (mean TTR 90%), respectively. The weighted rates of stroke were 6.3, 6.1 and 4.5/100 py for dabigatran, apixaban and rivaroxaban, respectively, and for warfarin from the lowest to the highest quartile: 8.8, 7.0, 5.5 and 4.2/100 py, respectively. The Figure provides survival probabilities (crude rates) of stroke with confidence intervals of the analysed OAC groups. Conclusion Rates of stroke were evidently the highest among patients on warfarin in the two lowest TTR quartiles, while the differences between high TTR groups and standard dose DOACs were only modest.

Acute ischemic stroke in a patient taking Dabigatran that was neutralized by idarucizumab before fibrinolysis: The first clinically successful case in Vietnam

Non-vitamin K antagonist oral anticoagulants are used more and more popularly because they are more effective than vitamin K antagonists. Dabigatran is the only non–vitamin K antagonist oral anticoagulant with an antidote, idarucizumab, in Vietnam. The rate of ischemic stroke while using Dabigatran annually is very rare, only 1.75%. We present the first clinical case in Vietnam using Dabigatran with acute ischemic stroke; patient is a 58 years old female, with history of atrial fibrillation, pacemaker, hypertension, old ischemic stroke, using Dabigatran 150mg, 2 tablets/day. The patient was admitted to the Bach Mai Hospital because of weakness on the right side of the body at the 3rd hour, NIHSS of 10 points, CT scans confirmed acute ischemic stroke due to occlusion of the left M3 segment, the last dose of dabigatran was taken 6 hours prior. The patient was given 2 jars of idarucizumab 2.5g, then rt-PA at a dose of 0.6 mg/kg. The patient improved, the NIHSS score was 3 points, and there was no bleeding in the control CT scan. The patient was discharged after 4 days of treatment, with an mRS score of 1.

P464 ELEVATED SPONTANEOUS INR: THE COMPLEXITY OF REAL LIFE BETWEEN CARDIOLOGY AND HEMATOLOGY

Abstract Direct acting oral anticoagulants (DOACs) have guaranteed safety and convenience of use in anticoagulated patients. DOACs only require monitoring of hepato–renal function. But how to handle a patient with persistently elevated INR (International Normalized Ratio) in the absence of anticoagulant therapy? We present the case of a 77 years old woman with hypertension and hypothyroidism. The patient was admitted to our division for high frequency atrial fibrillation with initial heart failure. The patient gradually improved with rate control therapy (metoprolol and digoxin) and a few diuretic therapy. The echocardiogram didn’t showed anything significant. Laboratory tests showed a persistently elevated INR, even after she achieved clinical stability. Liver funcion tests and abdomen echography were normal. Patient’s CHA2DS2–VASc risk score was 3 with indication to anticoagulant therapy. We opted for rate control therapy because, in the absence of a diagnosis, there was uncertainty as to start or not anticoagulation therapy, with the doubt whether the persistently high INR corresponded to real anticoagulation. We didn‘t want to expose the patient to bleeding risks by initiating a DOAC. Blood tests showed mild to moderate factor X deficiency with prolonged dRVVT (diluited Russel Viper Venom time) but normal aPTT (activated partial thromboplastin time). Factor X (FX) deficiency is a rare hereditary bleeding disorder characterized by decreased antigen and/or activity of FX leading to mild to severe bleeding symptoms. Severe congenital form manifests itself early while heterozygous patients are often asymptomatic. Indeed, no previous literature data are reported about use of DOACs in this kind of patient. In mild to moderate FX deficiency there are no known contraindications for the use of anticoagulant therapy. According to the hematologist we started low–dose dabigatran, the only DOAC that acts by directly inhibiting thrombin. Regular 6 months follow–up. In conclusion this case was particularly challenging because of the lack of indications about how to manage these patients. The complexity of patients in real–life goes beyond the guidelines, which must therefore be adapted to the individual case

Dabigatran Dosing Proposal for Adults With Atrial Fibrillation: Stress-Testing Renal Function Range in Real World Patients.

Dabigatran is the first of four direct-acting oral anticoagulants approved to prevent stroke in adult patients with atrial fibrillation using a fixed two-dose scheme compared with warfarin dosing adjusted to a prothrombin time range associated with optimal risk reduction in stroke and serious bleeding. The pivotal phase III trial found dabigatran, depending on dose, is superior to warfarin in stroke reduction and similar in bleeding risk while also showing dabigatran efficacy and safety correlate with steady-state plasma concentrations. Because the relationship between dabigatran dose and plasma concentration is highly variable, a previously developed population pharmacokinetic model of over 9,000 clinical trial patients was used as a basis for simulations comparing the performance of dosing via the drug label to other proposed doses and regimens. Assessment of dosing regimen performance was based on simulations of trough plasma levels within the therapeutic concentration range of 75-150 ng/mL over a renal function range of 15-250 mL/min creatinine clearance, representing extremes for real-world patients. An improved regimen that best achieves this therapeutic range was identified, requiring five different dosing schedules, corresponding to specified renal function ranges, compared with the two approved in the label. The discussion focuses on how this information could better inform patient outcomes and future dabigatran development.

Integrated Machine Learning Decision Tree Model for Risk Evaluation in Patients with Non-Valvular Atrial Fibrillation When Taking Different Doses of Dabigatran.

The new generation of nonvitamin K antagonists are broadly applied for stroke prevention due to their notable efficacy and safety. Our study aimed to develop a suggestive utilization of dabigatran through an integrated machine learning (ML) decision-tree model. Participants taking different doses of dabigatran in the Randomized Evaluation of Long-Term Anticoagulant Therapy trial were included in our analysis and defined as the 110 mg and 150 mg groups. The proposed scheme integrated ML methods, namely naive Bayes, random forest (RF), classification and regression tree (CART), and extreme gradient boosting (XGBoost), which were used to identify the essential variables for predicting vascular events in the 110 mg group and bleeding in the 150 mg group. RF (0.764 for 110 mg; 0.747 for 150 mg) and XGBoost (0.708 for 110 mg; 0.761 for 150 mg) had better area under the receiver operating characteristic curve (AUC) values than logistic regression (benchmark model; 0.683 for 110 mg; 0.739 for 150 mg). We then selected the top ten important variables as internal nodes of the CART decision tree. The two best CART models with ten important variables output tree-shaped rules for predicting vascular events in the 110 mg group and bleeding in the 150 mg group. Our model can be used to provide more visualized and interpretable suggestive rules to clinicians managing NVAF patients who are taking dabigatran.

Reduced dose direct oral anticoagulants compared with warfarin with high time in therapeutic range in nonvalvular atrial fibrillation

Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78–0.93), intracranial bleeding HR 0.64 (0.51–0.80), hemorrhagic stroke HR 0.68 (0.50–0.92), gastrointestinal bleeding HR 0.81 (0.69–0.96) and all-cause stroke HR 0.87 (0.76–0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63–0.78) and HR 0.80 (0.69–0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59–0.96), with higher major bleeding risk, HR 1.31 (1.15–1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03–1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.

Impact of dabigatran dose on drug levels in asian patients with atrial fibrillation or venous thromboembolism: evidence from pharmacological to clinical outcomes.

Dabigatran is commonly used in atrial fibrillation (AF) or venous thromboembolism (VTE). However, there was limited data on dabigatran levels in Asian patients.This study aimed to investigate plasma levels of dabigatran 110mg (D110) or 150mg (D150) twice daily and their impact on clinical outcomes in Thai patients. This was a prospective cohort study including patients who were diagnosed with AF or VTE and were prescribed either D110 or D150. Plasma dabigatran levels were measured using the diluted thrombin time method. All patients were observed for bleeding and thrombotic complications for 12 months after enrollment.Ninety patients were included in the study (45 in the D110 groupand 45 in the D150 group). For the D110 group, there was no significant difference in trough and peak levels in patients with creatinine clearance (CrCl) < 50 ml/min compared to those with CrCl ≥ 50 ml/min. For the D150 group, patients with CrCl < 50 ml/min had significantly higher trough and peak levels compared to those with CrCl ≥ 50 ml/min (P = 0.016 for trough, P = 0.005 for peak). Multivariate regression analysis showed females and low CrCl were independent risk factors for high dabigatran levels. Most patients (83.33%) who experienced bleeding complications had peak levels within the expected range.D150 was associated with higher plasma dabigatran levels, especially in those with impaired renal function.

Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation.

We aimed to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model from healthy Chinese subjects and real-world non-valvular atrial fibrillation (NVAF) patients. We also investigated meaningful intrinsic and extrinsic factors and related biomarkers for bleeding events. We characterized the integrated PK/PD models based on rich PK/PD data [dabigatran concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and anti-factor IIa (anti-FIIa) activity] from 118 healthy volunteers and sparse PD data [APTT, PT, and anti-FIIa] from 167 patients with NVAF after verifying the model extrapolation performance. We also documented the correlations between PD biomarkers and clinically relevant bleeding events over one year. Next, we used the final integrated PK/PD model (a two-compartment, linear model with first-order absorption) to evaluate the influence of dosage and individual covariates on PD parameters. The age, high-density liptein cholesterol (HDL-C), and creatinine clearance (CrCL) improved the PK model fit. The linear direct-effects PD model described the correlation between APTT, PT, and anti-FIIa and plasma concentration. CrCL improved the PD model fit. Anti-FIIa was more sensitive to the increase in dabigatran exposure than APTT and PT in the PD model. Therefore, fixed dabigatran doses could be prescribed for patients with NVAF without adjusting for age and HDL-C. We observed an elevated bleeding tendency with higher peak and trough values of APTT, PT, and anti-FIIa. Randomized studies should be performed to evaluate the efficacy and safety of low-dose dabigatran in Chinese patients with NVAF.

Application of Activators Ecarin and Factor Xa in Thrombelastography for Measurement of Anticoagulant Effect of Direct Oral Anticoagulants Using TEG 5000.

There are situations where monitoring direct oral anticoagulants (DOACs) would be useful, including bleedings and trauma. The thromboelastographic technique has proven useful in bleeding situations in trauma and heart surgery. The aim of this study was to examine the effect of DOACs on all currently commercially available conventional TEG®5000 assays as well as novel modified assay using Ecarin and human factor Xa (HFXa). Healthy male volunteers were given single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg. Kaolin, RapidTEG, functional fibrinogen, PlateletMapping assay, and novel modified assays using Ecarin and HFXa were prepared. All TEG parameters were recorded. DOAC concentrations were correlated to the parameters with highest response to the DOAC effect. Sensitivity and negative predictive value of the parameter with highest response to DOAC concentration of 50 ng/mL was calculated. None of the conventional TEG assays demonstrated significant response to the effect on apixaban. Using Ecarin, reaction time R was strongly correlated with dabigatran concentrations. Using HFXa assay, R was strongly correlated with rivaroxaban and apixaban concentrations: r = 0.96, 0.84, and 0.86, respectively; p < 0.0001 for all. The R times obtained with the modified assays demonstrated strong sensitivity and negative predictive values for DOAC levels of ≥50 ng/mL. We have demonstrated that TEG®5000 can monitor the DOAC effect on hemostasis when the appropriate activator is used with significant correlation with DOAC concentrations. Larger clinical studies are warranted for correlation of TEG profile and clinical outcomes.

Hemoclot Thrombin Inhibitor Assay and Expected Peak-Trough Levels of Dabigatran: A Multicenter Study.

PurposeDabigatran concentrations monitoring are gaining importance of special situations, but limited data are available for the expected peak and trough levels. The hemoclot thrombin inhibitor (HTI) is dabigatran-calibrated quantitative determination of dabigatran concentration. This study aims to validate HTI assay as the quantification choice of dabigatran, and providing the expected peak and trough levels.Materials and MethodsThis is a multi-center methodology validate study, including seven hospitals from Beijing, Shanghai, Henan, Hunan, Chongqing, and Fujian. We retrospectively analyzed plasma samples taken from 118 healthy subjects and 183 patients receiving dabigatran. Dabigatran concentrations were measured with HTI assay and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Linear regression, Spearman correlation and Bland-Altman analysis were used in this study.ResultsThe mean concentration ratio of HPLC-MS/MS and HTI assays was 1.03 and 0.98 at 2 and 12 h, and the acceptance ranges for both the ratio limit as well as the limit of agreement were met, suggesting good agreement between the HTI-derived plasma concentrations and HPLC-MS/MS. The reference detection range of single dose dabigatran 150 mg in healthy subjects was 33–159 ng/ml. About 500 blood samples were taken from 183 patients suggested that the expected peak and trough levels range of dabigatran 110 mg was about 95–196 and 36–92 ng/ml.ConclusionHemoclot thrombin inhibitor assay can be a good quantitative detection method of dabigatran. Expected peak and trough levels provide a basis for the rational use of dabigatran, and provide important Asian population data for the update of the international clinical guidelines for hematological testing.Clinical Trial Registration[https://clinicaltrials.gov], identifier [NCT03161496].

Off-label underdosing of four individual NOACs in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of observational studies.

Although several meta-analyses have examined the effects of off-label underdosing of nonvitamin K antagonist oral anticoagulants (NOACs) compared with their recommended doses in patients with atrial fibrillation (AF), they combined different kinds of NOACs in their primary analyses. Herein, we first conducted a meta-analysis to separately assess the effects of off-label underdosing versus on-label dosing of four individual NOACs on adverse outcomes in the AF population. The PubMed and Embase database were systemically searched until November 2021 to identify the relevant studies. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by utilizing a random-effects model. A total of nine studies with 144,797 patients taking NOACs were included in the meta-analysis. In the pooled analysis, off-label underdosing of rivaroxaban was related to an increased risk of stroke or systemic embolism (HR=1.31, 95% CI 1.05-1.63; p=.02), whereas off-label underdosing of apixaban was associated with a higher risk of all-cause death (HR=1.21, 95% CI 1.05-1.40; p=.01). When comparing off-label underdosing versus on-label dosing of dabigatran or edoxaban, no differences were found in the primary and secondary clinical outcomes. Off-label underdosing of rivaroxaban may increase the risk of stroke or systematic embolism, whereas off-label underdosing of apixaban may heighten the incidence of all-cause death.

Cost-Utility Analysis of Dabigatran and Warfarin for Stroke Prevention Among Patients With Nonvalvular Atrial Fibrillation in India

ObjectivesDabigatran has a better safety profile and requires less monitoring, but is costlier than warfarin. This study evaluated the cost-utility of dabigatran relative to warfarin for preventing stroke in nonvalvular atrial fibrillation (NVAF) in India. MethodsA Markov decision analysis model was developed to compare dabigatran (110 or 150 mg twice a day) to warfarin titrated to target prothrombin time in patients with NVAF at high risk of stroke. Model utilities and transition probabilities were based on literature and costs on market prices. Data on out-of-pocket expenses and income lost were taken from a nationally representative survey. We adopted a societal perspective and discounted both costs and outcomes at 3%. Ischemic stroke, intracranial bleed, other major bleeds, and death were outcomes of NVAF. The model projected the costs, life-years, and quality-adjusted life-years (QALYs) for each intervention over a lifetime. We used gross domestic product per capita of India (US dollars [US$]1889) as the cost-effectiveness threshold. Sensitivity analyses were conducted. ResultsTreatment with either dose of dabigatran was associated with gain in life-years and QALYs compared with warfarin. The discounted incremental cost-effectiveness ratios/QALYs for both doses of dabigatran (110 mg US$7519; 150 mg US$6634) were above the cost-effectiveness threshold, and the probability of being cost-effective at this threshold was low. Cost of dabigatran was an important factor in determining incremental cost-effectiveness ratio. Price reduction of 150 mg dose by 49% will make it cost-effective. ConclusionsDabigatran is not cost-effective in the Indian societal context. Reducing the price of dabigatran 150 mg by half will make it cost-effective.