Construction of warfarin population pharmacokinetics and pharmacodynamics model in Han population based on Bayesian method.

The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.

Direct oral anticoagulants for oral anticoagulants-naïve Asian patients with atrial fibrillation and end-stage renal disease undergoing dialysis.

In Asian patients with atrial fibrillation (AF) and end-stage renal disease (ESRD) undergoing dialysis, the use of direct oral anticoagulants (DOACs) remains debatable. From the national health insurance claims data in South Korea, we included 425 new users of OAC among patients with non-valvular AF and ESRD undergoing dialysis between 2013 and 2020. Patients were categorized into DOAC (n = 106) and warfarin group (n = 319). Clinical outcomes, including ischemic stroke, myocardial infarction (MI), intracranial hemorrhage (ICH), and gastrointestinal (GI) bleeding, were compared between the two groups using inverse probability of treatment weighting (IPTW) analysis. During the median follow-up of 3.2 years, the incidence of ischemic stroke was significantly reduced in the DOAC compared to the warfarin group [Hazard ratio (HR) 0.07; P = 0.001]. However, the incidence of MI (HR 1.32; P = 0.41) and GI bleeding (HR 1.78; P = 0.06) were not significantly different between the two groups. No ICH events occurred in the DOAC group, although the incidence rate did not differ significantly between the two groups (P = 0.17). In Asian patients with AF and ESRD undergoing dialysis, DOACs may be associated with a reduced risk of ischemic stroke compared with warfarin. The MI, ICH, and GI bleeding rates may be comparable between DOACs and warfarin.

Apixaban Versus Vitamin K Antagonists in Patients With Antiphospholipid Syndrome: A Cohort Study.

ABSTRACT: Current guidelines recommend that direct anticoagulants should not be used in prevention of recurrent thrombosis in patients with antiphospholipid syndrome (APS). However, except for triple-positive APS and rivaroxaban use, little evidence supports such recommendation. In a real-life cohort study, we evaluated the risk of thromboembolism and bleeding in patients with APS on apixaban versus vitamin K antagonists (VKA). We enrolled 152 patients with APS (aged 44 years [interquartile range 36-56], 83% women), including 66 patients treated with apixaban 5 mg bid and 86 with warfarin (target international normalized ratio [INR] 2-3). During a median follow-up of 53 months, we recorded venous thromboembolism, ischemic stroke, or myocardial infarction, along with major bleeding. We observed 4 thrombotic events (6.1%, 3 venous thromboembolism and 1 ischemic stroke) in patients on apixaban and 12 events (14%, 9 venous thromboembolism, 2 ischemic strokes and 1 myocardial infarction) in VKA patients. Patients with APS on apixaban had similar risk of recurrent thromboembolism compared with those on warfarin (hazard ratio [HR] = 0.327, 95% confidence interval [CI]: 0.104-1.035). Thromboembolic events occurred less commonly in statin users (8% vs. 50%, P = 0.01) and more frequently in triple-positive APS (50% vs. 22.1%, P = 0.028) and in patients with higher D-dimer at baseline ( P = 0.023); the latter difference was present in the apixaban group ( P = 0.02). Patients on apixaban had similar risk of major bleeding compared with warfarin (HR = 0.54, 95% CI: 0.201-1.448). In real-life patients with APS, apixaban appears to be similar to VKA for the prevention of thromboembolism and risk of bleeding, which might suggest that some patients with APS could be treated with apixaban.

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.

Long-term discontinuation of warfarin in a patient with HeartMate 3 left ventricular assist device without thromboembolic events.

The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left ventricular assist device HeartMate 3 (Abbott Laboratories, Abbott Park, IL, USA) serves as bridging therapy to transplantation and/or destination therapy. Current guidelines recommend anticoagulation with a vitamin K antagonist in combination with low-dose aspirin. We herein report a challenging anticoagulation regimen in a patient with a HeartMate 3 in whom systemic anticoagulation with warfarin was not feasible for 4 years because of low compatibility and a rare X-factor deficiency. This is a rare hematological disorder, estimated to affect approximately 1 in every 500,000 to 1,000,000 people in the general population. The patient finally received a modified anticoagulation regimen involving the combination of rivaroxaban and clopidogrel without warfarin. Under this regimen, the patient remained free of thromboembolic complications for 4 years with in situ placement of the left ventricular assist device. This case illustrates that under specific circumstances, long-term absence of warfarin therapy is feasible in patients with a HeartMate 3.

Clinical versus fixed warfarin dosing and the impact on quality of anticoagulation (The ClinFix trial).

Different dosing strategies exist to initiate warfarin, most commonly fixed warfarin dosing (FWD), clinical warfarin dosing (CWD), and genetic-guided warfarin dosing (GWD). Landmark trials have shown GWD to be superior when compared to FWD in the EU-PACT trial or CWD in the GIFT trial. COAG trial did not show differences between GWD and CWD. We aim to compare the anticoagulation quality outcomes of CWD and FWD. This is a prospective cohort study with a retrospective comparator. Recruited subjects in the CWD (prospective) arm were initiated on warfarin according to the clinical dosing component of the algorithm published in www.warfarindosing.org. The primary efficacy outcome was the percentage time in the therapeutic range (PTTR) from day 3 to 6 till day 28 to 35. The study enrolled 122 and 123 patients in the CWD and FWD, respectively. The PTTR did not differ statistically between CWD and FWD (62.2 ± 26.2% vs. 58 ± 25.4%, p = 0.2). There was also no difference between both arms in the percentage of visits with extreme subtherapeutic international normalized ratio (INR) (<1.5; 15 ± 18.3% vs. 16.8 ± 19.1%, p = 0.44) or extreme supratherapeutic INR (>4; 7.7 ± 14.7% vs. 7.5 ± 12.4%, p = 0.92). We conclude that CWD did not improve the anticoagulation quality parameters compared to the FWD method.

Safety and Efficacy of Direct Oral Anticoagulants vs Warfarin in Patients With Obesity and Venous Thromboembolism: A Retrospective Analysis.

BACKGROUND: Current venous thromboembolism guidelines recommend using direct oral anticoagulants (DOACs) over warfarin regardless of obesity status; however, evidence remains limited for the safety and efficacy of DOAC use in patients with obesity. This retrospective analysis sought to demonstrate the safety and efficacy of DOACs compared with warfarin in a diverse population of patients with obesity in light of current prescribing practices. METHODS: A retrospective cohort study was conducted at a large academic health system between July 2014 and September 2019. Adults with an admission diagnosis of deep vein thrombosis (DVT) or pulmonary embolism, with weight greater than 120 kg or a body mass index greater than 40, and who were discharged on an oral anticoagulant were included. Outcomes included occurrence of a thromboembolic event (DVT, pulmonary embolism, or ischemic stroke), bleeding event requiring hospitalization, and all-cause mortality within 12 months following index admission. RESULTS: Out of 787 patients included, 520 were in the DOAC group and 267 were in the warfarin group. Within 12 months of index hospitalization, thromboembolic events occurred in 4.23% of patients in the DOAC group vs 7.12% of patients in the warfarin group (hazard ratio, 0.6 [95% CI, 0.32-1.1]; P = .082). Bleeding events requiring hospitalization occurred in 8.85% of DOAC patients vs 10.1% of warfarin patients (hazard ratio, 0.93 [95% CI, 0.57-1.5]; P = .82). A DVT occurred in 1.7% and 4.9% of patients in the DOAC and warfarin groups, respectively (hazard ratio, 0.35 [95% CI, 0.15-0.84]; P = .046). CONCLUSION: No significant differences could be determined between DOACs and warfarin for cumulative thromboembolic or bleeding events, pulmonary embolism, ischemic stroke, or all-cause mortality. The risk of DVT was lower with apixaban and rivaroxaban. Regardless of patient weight or body mass index, physicians prescribed DOACs more commonly than warfarin.

Utility of TTR-INR guided warfarin adjustment protocol to improve time in therapeutic range in patients with atrial fibrillation receiving warfarin.

Warfarin remains the most prescribed oral anticoagulant of choice in atrial fibrillation (AF) patient in resource-limited settings. Despite evidence linking Time in Therapeutic Range (TTR) to patient outcomes, its use in clinical practice is not widespread. This prospective study explores the impact of a TTR-INR guided Warfarin adjustment protocol on TTR in AF patients. Conducted at the Warfarin clinic of King Chulalongkorn Memorial Hospital. TTR was calculated using the Rosendaal linear interpolation method at baseline, and then at 6 and 12 months post-protocol implementation. The primary outcome was the improvement in TTR following the protocol's implementation. The study analyzed 57 patients, with a mean age of 72 years and an even gender distribution. At baseline, 53% of patients had a TTR of less than 65%. However, TTR significantly improved from 65% at baseline to 80% after 12 months of protocol implementation (p < 0.001). Furthermore, there was a significant increase in the proportion of patients with a TTR of 65% or more, from 47 to 88% (p < 0.001). During the follow-up period in the first 12 months, three patients died, but no ischemic or major bleeding events occurred. The significant improvement in TTR after 12 months of protocol implementation suggests that this strategy could provide additional value in improving TTR and outcomes in AF patients receiving Warfarin.

CoaguChek and Coag-Sense PT2 Meter Point of Care INR Device Validation.

OBJECTIVE: To standardize international normalized ratio (INR) measurements and improve data integrity by enabling electronic result transmission for warfarin monitoring, two point-of-care (POC) devices were evaluated against an internal plasma INR reference method. METHODS: A multicenter study was pursued (January 24, 2022, through October 19, 2022) to compare concordance of two commercially available POC devices, Coag-Sense PT2 Meter (Coag-Sense) and CoaguChek XS Pro and Plus devices (CoaguChek), against an internal plasma INR method among patients treated with warfarin. Bias and linear regression analysis were assessed for these devices including dosing decision accuracy compared with plasma INR reference. RESULTS: Two hundred ninety-nine patients treated with warfarin across three Mayo Clinic sites agreed to participate. Atrial fibrillation (n=191, 63.9%), venous thromboembolism (n=65; 21.7%), and heart valve prosthesis (n=46; 15.4%) were common anticoagulant indications with a 2.5 INR target for 280 (93.6%) of patients. For the CoaguChek devices, 243 (81.3%) of values fell within 0.2 INR units with plasma INR referent and 285 (95.3%) within 0.4 units (R2=0.93). For the Coag-Sense device, 102 (34.1%) of values fell within 0.2 INR units and 180 (60.2%) within 0.4 INR units of plasma INR values, (R2=0.83; P<.0001). Using the plasma INR as the gold standard, appropriate dosing recommendations would have occurred for 292 (97.7%) of the CoaguChek and 244 (81.6%) of the Coag-Sense results. CONCLUSION: Compared with a plasma referent, INR values obtained from the CoaguChek devices exhibited less systematic bias compared with Coag-Sense measures. This translates to a greater percentage of concordant management decisions between POC and laboratory INR methods.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Combination anticoagulation strategy in pregnancy with mechanical valves: The KYBELE study.

BACKGROUND: Optimal first-trimester anticoagulation is still challenging in pregnant women with mechanical heart valves (MHVs) requiring high-dose warfarin. This multicenter prospective study aims to determine the optimal anticoagulation regimens for pregnant patients with MHVs. METHODS: All women were allocated to one of three treatment options during first trimester including lone low-molecular-weight heparin (LMWH), combination of LMWH + 2.5 mg warfarin, and LMWH+4 mg warfarin. Primary maternal outcome included a combination of death, thromboembolism, severe bleeding, and need for treatment of mechanical valve thrombosis (MVT). Any fetal loss was determined as primary fetal outcome. RESULTS: The study included 78 pregnancies in 65 women with MHVs. Primary maternal outcome rate was 44%, 12.5%, 3.5%, respectively. The rates of primary maternal outcome (44 vs 3.5%, P < .001), obstructive MVT (16 vs 0%, P = .04), MVT requiring treatment (28 vs 0%, P = .003), and cerebral embolism (24 vs 3.4%, P = .041) were found to be significantly higher in lone LMWH group compared to LMWH + 4 mg warfarin group. Moreover, the rates of primary maternal outcome (12.5 vs 44%, P = .015) and treatment for MHV thrombus (4.2 vs 28%, P = .049) were significantly lower in LMWH + 2.5 mg warfarin group compared to lone LMWH group. The incidences of fetal loss were 8 (32%) in the lone LMWH group, 8 (33.3%) in LMWH + 2.5 mg warfarin group, and 11 (37.9%) in LMWH + 4 mg warfarin group (P = .890 for 3-group).Warfarin related-embryopathy was not observed in any case. CONCLUSIONS: The combined anticoagulation strategy of LMWH plus low-dose warfarin during the first trimester of pregnancy may result in less maternal complications with comparable fetal outcomes in patients with MHVs. CONDENSED ABSTRACT: Low-molecular-weight heparin (LMWH) is thought to be safer for the fetus, however it is suspected to be less protective for the mother. To solve this dilemma, the authors suggested a novel anticoagulation strategy in pregnant women with prosthetic valves. Seventy-eight pregnancies of 65 women (median age 32 [27-35] years) were included in the study. A combination of LMWH and a reduced dose warfarin were associated with low rates of thrombus-related complications in pregnant patients with mechanical heart valves.

Risk of bleeding amongst warfarin and direct oral anticoagulant users prescribed immediate antibiotics for respiratory tract infection: Cohort study.

PURPOSE: Incidence of bleeding amongst warfarin and direct oral anticoagulant (DOAC) users is greater following a respiratory tract infection (RTI). It is unclear whether immediate antibiotics modify this association. We estimated the risk of bleeding amongst warfarin and DOAC users with RTI by antibiotic treatment. METHODS: This retrospective cohort study used data from the Clinical Practice Research Datalink (CPRD) GOLD for adults in England prescribed warfarin or a DOAC, who sought primary care for an RTI between 1st January 2011 and 31st December 2019. Outcomes were major bleeding (hospital admission for intracranial or gastrointestinal bleeding), and non-major bleeding (hospital admission or General Practice consult for epistaxis, haemoptysis, or haematuria). Cox models derived hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, adjusting for confounders using inverse probability of treatment weighting. RESULTS: Of 14 817 warfarin and DOAC users consulting for an RTI, 8768 (59%) were prescribed immediate antibiotics and 6049 (41%) were not. Approximately 49% were female, and median age was 76 years. Antibiotics were associated with reduced risk of major bleeding (adjusted HR 0.38, 95% CI 0.25 to 0.58). This was consistent across several sensitivity analyses. Antibiotics were also associated with a reduced risk of non-major bleeding (adjusted HR 0.78, 95% CI 0.61 to 0.99). CONCLUSIONS: Immediate antibiotics were associated with reduced risk of bleeding amongst warfarin and DOAC users with an RTI. Further work is needed to understand mechanisms and confirm whether a lower threshold for antibiotic use for RTI in this population may be beneficial.

Effect of different oral anticoagulants on cognitive function in patients with atrial fibrillation: A Bayesian network meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is 1 of the most common types of arrhythmias. At present, the treatment for patients with AF mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation; however, there is a lack of relevant evidence. This study used Bayesian network meta-analysis (NMA) to investigate the effects of different oral anticoagulants on cognitive decline in patients with AF. METHODS: We systematically searched for clinical studies on oral anticoagulants in patients with AF in PubMed, Web of Science, Embase, and the Cochrane Library as of July 3, 2023. Cochrane's randomized controlled trial bias risk assessment tool and the Newcastle-Ottawa Scale were used to assess the bias risk of the included studies. The main outcome measure was decreased cognitive functioning. RESULTS: Ten studies were included, including 2 RCTs and 7 RCSs, including 882,847 patients with AF. Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel. The results of the mesh meta-analysis showed that VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = -1.19, 95% CI (-2.35, -0.06), P < .05) (Table 5). The top 3 drugs in terms of the probability of reducing the incidence of cognitive impairment in patients with AF with different oral anticoagulants were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%). CONCLUSION: Based on the results of this study, VKAs may be the best intervention measure for reducing the risk of cognitive decline in patients with AF. Owing to the limitations of this study, more high-quality randomized controlled trials with large sample sizes and multiple centers are required to provide more evidence.

On-X aortic valve replacement patients treated with low-dose warfarin and low-dose aspirin.

OBJECTIVES: To assess if warfarin targeted to international normalized ratio (INR) 1.8 (range 1.5-2.0) is safe for all patients with an On-X aortic mechanical valve. METHODS: This prospective, observational registry follows patients receiving warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus daily aspirin (75-100 mg) after On-X aortic valve replacement. The primary end point is a composite of thromboembolism, valve thrombosis and major bleeding. Secondary end points include the individual rates of thromboembolism, valve thrombosis and major bleeding, as well as the composite in subgroups of home or clinic-monitored INR and risk categorization for thromboembolism. The control was the patient group randomized to standard-dose warfarin (INR 2.0-3.0) plus daily aspirin 81 mg from the PROACT trial. RESULTS: A total of 510 patients were enroled at 23 centres in the UK, USA and Canada. Currently, the median follow-up duration is 3.4 years, and median achieved INR is 1.9. The primary composite end point rate in the low INR patients is 2.31% vs 5.39% (95% confidence interval 4.12-6.93%) per patient-year in the PROACT control group, constituting a 57% reduction. Results are consistent in subgroups of home or clinic-monitored, and high-risk patients, with reductions of 56%, 57% and 57%, respectively. Major and total bleeding are decreased by 85% and 73%, respectively, with similar rates of thromboembolic events. No valve thrombosis occurred. CONCLUSIONS: Interim results suggest that warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus aspirin is safe and effective in patients with an On-X aortic mechanical valve with or without home INR monitoring.

Outcomes of non-vitamin K oral anticoagulants for secondary prevention in ischemic stroke with atrial fibrillation.

Previous studies have rarely investigated the role of non-vitamin K oral anticoagulants (NOAC) and warfarin in the secondary prevention of ischemic stroke patients with nonvalvular atrial fibrillation (NVAF). In this study, we compared the effectiveness and safety of NOAC and warfarin for secondary prevention in Korean ischemic stroke patients with NVAF. Based on the Korean National Health Insurance Service Database, this study included 21,064 oral anticoagulants-naïve acute ischemic stroke patients with NVAF between July 2015 and June 2019. The main study outcomes included ischemic stroke, systemic embolism, major bleeding, and death. During the observational periods, NOAC users had a significantly decreased risk of ischemic stroke + systemic embolism (adjusted hazard ratio [aHR] 0.86; 95% confidence interval [CI] 0.78-0.95), ischemic stroke (aHR 0.89; 95% CI 0.81-0.99), major bleeding (aHR 0.78; 95% CI 0.68-0.89), and all-cause death (aHR 0.87; 95% CI 0.81-0.93). Standard-dose NOAC users had a lower risk of ischemic stroke, systemic embolism, and major bleeding events than warfarin users. In contrast, low-dose NOAC users did not differ in risk from warfarin users for all outcomes. In conclusion, NOACs were associated with a lower risk of secondary thromboembolic events and bleeding complications in Korean ischemic stroke patients with NVAF than warfarin.

Warfarin dosage in a postpartum woman while breastfeeding: A case report.

Warfarin is the only oral anticoagulant recommended in women who are breastfeeding. Although warfarin is a compatible and recommended agent in the postpartum period and during lactation, little is known regarding changes to warfarin dose requirements in this patient population. Here, we report the case of a 40-year-old woman who transitioned from enoxaparin monotherapy back to warfarin at 2 months postpartum, while she was breastfeeding. Despite resuming warfarin at her previously therapeutic dose, her international normalized ratio (INR) remained subtherapeutic and required multiple dose increases. She ultimately required a 100% increase in her warfarin dose postpartum, compared to pre-pregnancy, to achieve a therapeutic INR. This case suggests patients may require higher warfarin doses postpartum, compared to pre-pregnancy, especially if breastfeeding. Clinicians should closely monitor these patients and adjust warfarin doses as necessary.

Trends in Oral Anticoagulant Use and Individual Expenditures Across the United States from 2014 to 2020.

BACKGROUND: Landmark clinical trials have expended the indications for the direct oral anticoagulants (DOACs), but contemporary data on usage and expenditure patterns are lacking. OBJECTIVE: This study aimed to assess annual trends in oral anticoagulant (OAC) utilization and expenditure across the United States (US) from 2014 to 2020. METHODS: We utilized the Medical Expenditure Panel Survey (MEPS) to study the trends of use and expenditures of warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban between 2014 and 2020 in the US. Survey respondents reported OAC use within the past year, which was verified against pharmacy records. Payment information was obtained from the respondent's pharmacy and was categorized as third-party or self/out-of-pocket. Potential indications and medical conditions of interest for OAC therapy were identified from respondent-reported medical conditions. We estimated the national number of OAC users and total expenditures across age, sex, race, ethnicity, insurance, and medical condition subgroups. Trends of OAC users' characteristics, expenditure, and number of prescriptions were evaluated using the Mann-Kendall test for trends. RESULTS: Between 2014 and 2020, the number of warfarin users decreased from 3.8 million (70% of all OAC users) to 2.2 million (p = 0.007) [29% of all OAC users], while the number of DOAC users increased from 1.6 million (30% of all OAC users) to 5.4 million (p = 0.003) [70% of all OAC users]. The total expenditure of OACs in the US increased from $3.4 billion in 2014 to $17.8 billion in 2020 (p = 0.003), which was driven by the increase in DOAC expenditures (p = 0.003). CONCLUSIONS: DOACs have replaced warfarin as the preferred OAC in the US. The increased costs associated with DOAC use may decline when generic formulations are approved.

Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage ( P  < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P  = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications ( P  < 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.