Higher Warfarin Research Articles

Trajectories of Oral Anticoagulation Adherence and Associated Clinical Outcomes During Long-Term Anticoagulation Among Medicare Beneficiaries With Venous Thromboembolism.

Little is known about anticoagulation medication nonadherence patterns impacting effectiveness and safety outcomes in clinical practice. We identified adherence trajectories of extended therapy with direct-acting oral anticoagulants (DOACs) and warfarin after 6 months initial anticoagulant therapy among Medicare beneficiaries with venous thromboembolism (VTE). We further assessed the associated recurrent VTE and major bleeding risks. Using group-based trajectory models, this retrospective cohort study identified distinct beneficiary subgroups with similar adherence patterns of extended-phase anticoagulant treatment (DOACs or warfarin) for patients with VTE who completed 6 months of initial anticoagulant treatment. We examined associations between adherence trajectories and risks of recurrent VTE and major bleeding using inverse probability treatment weighted Cox proportional hazards models. Compared with no extended treatment, consistently high DOAC adherence was associated with decreased recurrent VTE risk (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21-0.51) without increased major bleeding risk, and consistently high warfarin adherence was associated with decreased recurrent VTE risk (HR = 0.62, 95% CI = 0.40-0.95) and increased major bleeding risk (HR = 1.64, 95% CI = 1.12-2.41). Gradually declining adherence to DOACs (HR = 1.80, 95% CI = 1.07-3.03) or warfarin (HR = 2.34, 95% CI = 1.57-3.47) was associated with increased bleeding risk with no change in recurrent VTE risk. This real-world evidence suggests persistently adhering to extended DOAC therapy is associated with lower recurrent VTE risk without increasing major bleeding among Medicare beneficiaries with VTE. Persistently adhering to extended warfarin therapy was associated with lower recurrent VTE risk but higher major bleeding risk.

Warfarin-Rifampin-Gene (WARIF-G) Interaction: ARetrospective, Genetic, Case-Control Study.

Warfarin is extensively metabolized by cytochrome P450 2C9 (CYP2C9). Concomitant use with the potent CYP2C9 inducer, rifampin, requires close monitoring and dosage adjustments. Although, in theory, warfarin dose increase should overcome this interaction, most reported cases over the last 50 years have not responded even to high warfarin doses, but some have responded to modest doses. To investigate the genetic polymorphisms' impact on this unexplained interpatient variability, we performed genotyping of CYP2C9, VKORC1, and CYP4F2 for warfarin and rifampin concomitant receivers from 2016 to 2022 at Hamad Medical Corporation, Doha, Qatar. We identified and included 36 patients: 22 responders and 14 nonresponders. Warfarin-responders were significantly more likely to have one or more warfarin-sensitizing CYP2C9/VKORC1 alleles than nonresponders (odds ratio=23.2, 95% confidence interval=3.2-195.6; P=0.0001). The mean genetic-based pre-interaction calculated dose was significantly lower for responders than for nonresponders (P < 0.001); and was negatively correlated with warfarin sensitivity index (WSI) (r=-0.58; P=0.0002). The median percentage time in therapeutic range and mean WSI were significantly higher in the warfarin-sensitizing CYP2C9/VKORC1 alleles carriers than noncarriers (P=0.017 and 0.0004, respectively). Whereas the warfarin-sensitizing CYP2C9/VKORC1 genotypes were associated with modest on-rifampin warfarin dose requirements, the noncarriers would have required more than double these doses to respond. Warfarin-sensitizing CYP2C9/VKORC1 genotypes and low genetic-based warfarin calculated doses were associated with higher warfarin sensitivity and better anticoagulation quality in patients receiving rifampin concomitantly.

Trajectories of adherence to extended treatment with warfarin and risks of recurrent venous thromboembolism and major bleeding

BackgroundLittle is published about warfarin therapy adherence patterns beyond 6 months of initial anticoagulant treatment and their association with effectiveness and safety for patients with venous thromboembolism (VTE). ObjectivesTo compare the risks of recurrent VTE and major bleeding during extended treatment between adherence patterns using MarketScan Commercial and Medicare Supplemental databases (2013-2019). MethodsIn a retrospective cohort study, we included patients with incident VTE who completed an initial 6-month anticoagulant treatment and received either warfarin or no extended therapy. Group-based trajectory models were used to identify distinct extended treatment trajectories. Associations between the trajectories and risk of hospitalization due to recurrent VTE and major bleeding were assessed using inverse probability treatment-weighted Cox proportional hazards models. ResultsCompared with no extended treatment, consistently high warfarin adherence was associated with a significantly decreased risk of hospitalization due to recurrent VTE (hazard ratio [HR] = 0.23; 95% CI, 0.12-0.45), but gradually (HR = 0.29; 95CI, 0.08-1.06) or rapidly declining (HR = 0.14; 95% CI, 0.02-1.24) adherence showed no association with the risk of hospitalization due to recurrent VTE. Compared with no extended treatment, warfarin extended therapy was associated with an increased risk of hospitalization due to major bleeding regardless of adherence patterns (consistently high: HR = 2.08; 95% CI, 1.18-3.64, gradually declining: HR = 2.10; 95% CI, 0.74-5.95, and rapidly declining: HR = 9.19; 95% CI, 4.38-19.29). However, compared with rapidly declining adherence, consistently high (HR = 0.23; 95% CI, 0.11-0.47) and gradually declining (HR = 0.23; 95% CI, 0.08-0.64) adherence were associated with decreased risk of hospitalization due to major bleeding. ConclusionThe findings indicated that consistently high adherence to extended warfarin treatment was associated with a decreased risk of hospitalization due to recurrent VTE but an increased risk of hospitalization due to major bleeding compared with no extended treatment.

Coronary Artery Ectasia as a Predictor of Major Adverse Cardiac Events in Patients with Acute ST Elevation Myocardial Infarction

Background: Coronary artery ectasia (CAE) is characterised as localised or widespread non-obstructive lesions of the epicardial coronary arteries with a luminal dilation more than 1.5 times the neighbouring normal segments or vessel diameter. Isolated CAE is CAE in the absence of severe coronary artery stenosis. This aberrant dilatation of coronary arteries can produce angina pectoris and even myocardial infarction in people without coronary artery disease owing to vasospasm, dissection, or thrombus. The purpose of this study was to evaluate the connection between CAE and major adverse cardiac events (MACE) following acute myocardial infarction with ST elevation.&#x0D; Methods: This was a prospective cohort study which was carried out on 300 cases. Cases were divided into two groups: Group I: including about 22 STEMI cases with CAE and Group II: including about 278 STEMI cases without CAE. All cases in this study were subjected to full history taking, clinical examination, laboratory tests, standard 12-leads ECG, resting transthoracic echocardiography (TTE), and coronary angiography.&#x0D; Results: Regarding MACE in the studied groups, Incidence of reinfarction and cardiac death were significant higher in cases with STEMI and CAE than cases with STEMI alone. In univariate regression analysis, CAE (OR: 3.59, p value =0.022) was a significant predictor of cardiac death but age, male sex, and EF were not. Also, in multivariate regression analysis CAE (OR: 3.49, p value =0.029) was a significant predictor of cardiac death but age, male sex, and EF were not smoking with high warfarin consumption. Further, Markis classification 1 and 3 were the most frequent phenotype among cases. In STEMI cases, the incidence of reinfarction and cardiac death were significantly higher in cases with STEMI and CAE than cases with STEMI alone. So, CAE is a significant predictor of cardiac death.

A Multicentre Study on Average Warfarin Dose to Maintain Therapeutic International Normalised Ratio with Time in Therapeutic Range of More than 75% in Atrial Fibrillation Patients

Large interindividual variability and over-anticoagulation resulting bleeding complications due to narrow therapeutic index of warfarin has causes its pharmacodynamic activity to be highly variable. Studies shown that ethnicity, age and gender contribute to warfarin response variability. Good coagulation control of time in therapeutic range (TTR) &gt; 75% was chosen to determine the average warfarin dose in atrial fibrillation (AF) among ethnicity, age and gender. Data from Warfarin Medication Therapy Adherence Clinic of selected Pulau Pinang hospitals were used for the analysis of average warfarin dose in AF among ethnicity, age and gender. Patients who fulfilled the inclusion criteria from 2015–2016 were followed up for a year. Five hundred and seventy-six patients were included. Two hundred and ten patients had good coagulation control of TTR &gt; 75% with mean warfarin dose of 3.05 ± 1.25 mg. Only Chinese and Indian have significant difference in average warfarin dose with 2.86 ± 1.10 mg and 4.11 ± 1.40 mg, respectively (p = 0.008). Average warfarin dose was found not significantly different among gender and age. As for TTR achievement, 210 (36.4%) were able to achieve TTR &gt; 75%, 134 patients achieved TTR 60%–75% and 232 patients has TTR &lt; 60%. The median day to achieve three consecutive targeted international normalised ratio (INR) is 186.5 days for atrial fibrillation patient newly started on warfarin therapy in 2015 until 2016. Indian patients required a higher warfarin dose than Chinese patients. This study found that mean warfarin doses were not affected by age and sex.

Incidence of maternal and fetal complications in pregnant with mechanical prosthetic cardiac valves: a cohort study

Abstract Background In developing countries, an unusually large number of women of childbearing age have mechanical valves because rheumatic fever and concomitant valvular heart disease are still common and most severely affect the young. Managing anticoagulation during pregnancy is challenging, and the rate of complications is relatively high. Purpose The aim of this study was to detect the incidence of maternal and fetal complications in pregnant women with prosthetic valve in a high-risk pregnancy unit in one of the developing countries. Methods This study included 106 pregnant women with prosthetic heart valves on oral anticoagulant therapy. Excluded from the study were patients with low ejection fraction (&amp;lt;50%), patients with other comorbidities that may affect the pregnancy outcomes and patients who were not willing to share their data. Patients were followed up since presentation to the high-risk pregnancy unit till delivery. At each visit, women were clinically assessed for the occurrence of complications (heart failure, infective endocarditis, prosthetic valve dysfunction, systemic emboli, new onset arrhythmia, antepartum hemorrhage, or death). Babies were evaluated by an Obstetrician for intrauterine growth retardation or fetal death, abortion, oligo or polyhydramnios, and congenital heart diseases. Results The mean age was 28.5±4.2 years, 58 patients (54.7%) had mitral valve prothesis, 34 (32.1%) had aortic valve prosthesis and 14 patients (13.2%) had double valve prothesis. Fifty-three patients (50%) received warfarin throughout pregnancy and the rest switched to heparin in the first trimester. Cerebrovascular stroke occurred in 4 patients (3.8%), all were on the 1st trimester and all were taking heparins. The mean gestational age at delivery was 36.2±4.8 weeks and the mean fetal birth weight was 2435±791.5 gm. Thirty-three abortions were reported and the mean gestational age for abortion was 13 weeks±6 days while the mean gestational age for intrauterine fetal death was 29±4 weeks, table. Two babies had congenital heart diseases (ventricular septal defect and patent ductus arteriosus) and in both, the mothers were taking warfarin &amp;gt;5 mg/day during the second and third trimesters. Conclusion In this tertiary care centre, the incidence of maternal complications was relatively small while the incidence of fetal complications was high, especially in mothers taking higher warfarin doses. Switching to heparin in the first trimester increased the risk of systemic embolization. Funding Acknowledgement Type of funding sources: None.

Abstract MP23: Neighborhood Disadvantage And Oral Anticoagulant Use In Patients With Atrial Fibrillation

Background: Atrial Fibrillation (AF) is the most common heart rhythm disorder in the US and is treated with anticoagulation to mediate patients’ increased risk of ischemic stroke and death. Direct-acting oral anticoagulants (DOACs) are associated with better patient outcomes than warfarin, but prior studies show disparities in DOAC prescription. AF patients with low socioeconomic status (SES) have an increased risk of AF incidence, adverse outcomes, and mortality. Despite SES disparities in AF outcomes and prescribed medications, the impact of neighborhood SES (ADI) on AF management is unclear. We hypothesized that in comparison to patients with high ADI (e.g. the most disadvantaged), those with low ADI will be more likely to initiate any oral anticoagulants (OACs) and will be more likely to initiate DOACs. Methods: We conducted a retrospective observational study using national data from the Veterans Health Administration (VA) of newly diagnosed AF patients. Our independent variable was ADI, a marker of SES incorporating income, education, employment etc. Our model assessed numerous baseline patient, provider, and system-level covariates. We grouped patients into ADI quintiles, with Q1 being the lowest ADI (e.g., the least disadvantaged) and Q5 being the highest ADI, and used Q5 as a reference value. We used mixed effects logistic regression models, with site as a random effect, to determine the adjusted odds of initiating any OACs and of initiating DOACs by ADI quintile. Results: In our final cohort including 111,666 patients, 10,9386 (98.0%) were male and 2280 (2.0%) were female. The overall mean age at diagnosis was 72.86 (SD 10.4). Patients had the following medical comorbidities: Congestive heart failure: 18212, (16.3%); Hypertension: 84944, (76.1%); Diabetes: 70673, (63.3%); Vascular Disease: 46599, (41.7%). The ADI quintiles included the following patients: Q1: 21570, (20.3%); Q2: 21032, (19.8%); Q3: 21439, (20.2%); Q4: 20974, (19.8%); Q5: 21215, (20.0%). There was no significant difference in the odds of initiating any OAC between ADI quintiles compared to Q5 (Q1: adjusted odds ratio [95% CI], 0.95 [ 0.9, 1.01]; p=0.11). Among patients initiating DOAC, there was a significant association between low ADI and higher odds of initiating DOAC (Q1: 1.39 [1.29, 1.50]); (Q2: 1.18 [1.10, 1.27]); (Q3: 1.13 [1.06, 1.20]); (Q4: 1.09 [1.02, 1.16]). Each ADI quintile had a significantly higher odds of initiating DOACs compared to the highest ADI quintile. Conclusions: Patients with lower ADI are significantly more likely to be prescribed DOACs compared to patients with the highest levels of ADI. We found no significant difference in initiation of any OAC between ADI quintiles, which may result from high Warfarin utilization in the VA compared to the general population. Our data suggests that differences in neighborhood deprivation contribute to disparities in the prescribing DOACs in the VA.

Abstract 14379: Implementation of Pharmacist-led Antithrombotic Medication Management for Elective Endoscopic Procedures

Introduction: Mismanagement of antithrombotic medications often leads to cancelled elective procedures. Pharmacist-led anticoagulation management prior to elective procedures is not well studied. Methods: We implemented a best practice advisory (BPA) that offered referral to a pharmacist-led medication management service prior to elective outpatient gastrointestinal endoscopies. Eligible patients were taking warfarin, a direct oral anticoagulant, and/or a P2Y12 inhibitor for management of atrial fibrillation (AF), venous thromboembolism (VTE), coronary artery disease (CAD), peripheral arterial disease (PAD), and/or mechanical heart valve. Patients referred to the antithrombotic service were compared to those managed by the ordering provider. Outcomes assessed included documentation of a medication management plan, guideline-appropriateness of drug cessation prior to endoscopy, and guideline-appropriate rates of enoxaparin bridging for high risk warfarin patients. Results: Seventy-four percent of patients (448/645) were referred to the antithrombotic service. These patients were more likely to have had VTE (33.0% vs. 18.2%), less likely to have CAD (31.9% vs. 40.9%; p=0.009 for indication category), and more likely to be prescribed warfarin (32.8% vs 20.9%, p&lt;0.001). After adjusting for baseline differences, patients referred to the antithrombotic service were more likely to have had pre-procedure medication plan documentation (98.7% vs 56.1%, p &lt;0.001), and pre-procedure antithrombotic management was more likely to follow guidelines (97.5% vs. 91.5%, p=0.024). Guideline-appropriate use of bridging enoxaparin for warfarin patients was not different (10/16 [62.5%] vs. 2/6 [33.3%], p=0.221). Conclusion: Pre-procedural antithrombotic medication management by a pharmacist-led team for elective endoscopies was associated with more guideline-adherent management and better documentation of the medication plans.

Genetic influence on bleeding and over-anticoagulation risk in patients undergoing warfarin treatment after heart valve replacements

ABSTRACTBackground: Warfarin acts in heart valve replacement patients to minimize thromboembolic complications. We investigated whether patients can be distinguished based on their genotypes to efficiently and safely administer warfarin therapy after heart valve replacements.Research design and methods: A retrospective analysis was conducted in patients with warfarin therapy who underwent elective heart valve replacements between January 2013 and September 2018. The patients were divided into normal, sensitive, and highly sensitive bins based on their CYP2C9 and VKORC1 genotypes. The primary endpoints were over-anticoagulation and overt bleeding.Results: 375 patients were enrolled, with 65 classified as normal, 281 as sensitive, and 29 as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent more time on over-anticoagulation in the first 28 (P < 0.001) and 90 (P = 0.001) days; experienced more frequent bleeding events in the first 28 days (P = 0.029; OR, 2.18; 95% CI, 1.15–4.13); required lower warfarin doses to obtain stable INR (P < 0.001); had higher warfarin sensitivity indices (P < 0.001).Conclusion: Predicting evidence have been obtained with CYP2C9 and VKORC1 genotypes in identifying heart valve replacement patients with higher efficient sensitivity and with a higher risk of bleeding and over-anticoagulation.

A Simplified Understanding of the Black Swan: Anti-phospholipid Antibody Syndrome

Anti-phospholipid Antibody Syndrome or Hugh's syndrome is a heterogeneous disorder, first fully described in 1980s. The syndrome is caused by the presence of specific antibodies against phospholipid binding plasma proteins in the serum of the patient, with or without underlying autoimmune diseases, that causes prolongation of tests of coagulation. High index of clinical suspicion is required for diagnosis of Anti-phospholipid Antibody Syndrome. Stroke or myocardial infarction in young, unprovoked recurrent deep vein thrombosis and recurrent pregnancy loss are typical scenarios where Anti-Phospholipid Antibody Syndrome should be suspected. Presence of non-criteria manifestations like livedo reticularis, skin ulcers, nephropathy, valvular heart disease and thrombocytopenia adds to diagnostic clue for presence of Anti-Phospholipid Antibody Syndrome. Treatment of Anti-Phospholipid Antibody Syndrome has preventive and therapeutic aspects that usually focus on thrombotic and obstetric manifestations of the disease. Therapeutic anti-coagulation with heparin followed by warfarin is required for patients presenting with acute thrombosis. Those with venous thrombosis are given moderate intensity warfarin International Normalized Ratio, 2-3), whereas those with arterial thrombosis or recurrent venous thrombosis even on warfarin are treated with high intensity warfarin (International Normalized Ratio, 3-4). Similarly, anticoagulation with heparin is advised in patients with obstetric Anti-Phospholipid Antibody Syndrome throughout pregnancy and up to six weeks postpartum. Treatment recommendations are still not clear for asymptomatic Anti-Phospholipid Antibody Syndrome positive patients and in those with non-criteria manifestations of the disease. Steroids, intravenous immunoglobulin and immunosuppressant are reported to be effective in severe cases of catastrophic antiphospholid syndrome characterized by rapid small vessel thrombotic involvement of multiple organ systems. Studies are evaluating the efficacy of direct thrombin inhibitors in the management of refractory cases. Keywords: anticoagulants; anti-phospholipid syndrome; obstetric APS; thrombotic APS.

Abstract 16902: The Effect of Kidney Function on Antithrombotic Regimen Among Patients With Atrial Fibrillation and Acute Myocardial Infarction: Insights From the National Cardiovascular Disease Registry’s Acute Coronary Treatment and Intervention Outcomes Network Registry

Introduction: The impact of kidney function in selecting antithrombotic therapy at hospital discharge for patients with atrial fibrillation (AF) who survive an acute myocardial infarction (AMI) is uncertain. Hypothesis: We hypothesized that kidney dysfunction is associated with decreased oral anticoagulant (OAC) use in AF patients who survive AMI. Methods: We studied 30,308 AF patients at 791 hospitals who survived AMI and were hospitalized between January 2015 and December 2017 (Acute Coronary Treatment and Intervention Outcomes Network Registry). We separated patients into 4 mutually exclusive groups: triple antithrombotic therapy (TAT), dual-antiplatelet therapy (DAPT), dual antithrombotic therapy excluding DAPT (DAT), and single therapy. Logistic regression was used to explore the trend for each antithrombotic strategy across CKD stage. Results: Of the 30,308 patients included in this analysis, 6,618 were on TAT (22%), 12,920 on DAPT (43%), 6,148 on DAT (20%), and 4,622 were on single therapy (15%). Overall, 46% of patients were discharged on an OAC (warfarin 22%; apixaban 14%; rivaroxaban 8%; dabigatran 2%). Patients with higher CHA 2 DS 2 -VASC scores (≥4) were more likely to be discharged on oral anticoagulation, except patients with GFR &lt; 15 ml/min/1.73m 2 . Compared to patients with normal kidney function, patients with GFR &lt; 30 ml/min/1.73m 2 had lower rates of TAT use (23% vs. 18%) despite higher warfarin use (20% vs. 27%). Within each antithrombotic discharge strategy, there was no significant trend across GFR strata among patients with in-hospital PCI ( Figure ). Conclusion: Significant heterogeneity in antithrombotic discharge strategy was seen among AF patients who survived AMI, however, the trend of each strategy across CKD stage was not significant among patients with in-hospital PCI. More research is needed to understand whether a particular antithrombotic strategy has improved outcomes in this population.

Impact of VKORC1, CYP4F2 and NQO1 gene variants on warfarin dose requirement in Han Chinese patients with catheter ablation for atrial fibrillation

BackgroundThe anticoagulation of atrial fibrillation catheter ablation during the perioperative stage does matter and should be treated with discretion. We aimed to assess impact of three important genes participating in vitamin K cycle (i.e. VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566) on the daily stable warfarin dose requirement in Sichuan Han Chinese patients with catheter ablation of atrial fibrillation.MethodsA total of 222 atrial fibrillation patients taking stable warfarin therapy after catheter ablation operation were enrolled in this study. The study population included had high (≥2) risk according to the CHA2DS2-VASc risk score. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 were analyzed by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Multiple linear regression analysis was applied to depict the impact of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 on the daily stable warfarin dose requirement.ResultsCarriers of VKORC1 rs9923231 AG/GG genotypes required significantly higher warfarin dose (3.03 ± 0.28 mg/day, 7.19 mg/day, respectively) than AA carriers (2.52 ± 0.07 mg/day; P < 0.001). Carriers of CYP4F2 rs2108622 CT/TT genotypes required significantly higher warfarin dose (3.38 ± 0.22 mg/day, 2.79 ± 0.19 mg/day, respectively) than CC carriers (2.41 ± 0.08 mg/day; P < 0.001). However, the warfarin dose for carriers of NQO1 rs1800566 CT/TT genotypes (2.46 ± 0.24 mg/day, 3.01 ± 0.27 mg/day, respectively) was not significantly higher than that for the CC carriers (2.33 ± 0.1 mg/day). The multiple linear regression model including genotypes and demographic characteristics, could explain 20.1% of individual variations in the daily stable warfarin dose in Sichuan Han Chinese. VKORC1 rs9923231 contributed most (15%) to the individual variations in daily stable warfarin dose, while CYP4F2 rs2108622 contributed least (3%).ConclusionNQO1 rs1800566 is not a significant genetic factor of warfarin dose for Han Chinese, whereas VKORC1 rs9923231 and CYP4F2 rs2108622 are significant genetic factors, which could explain 15% and approximately 3% of individual variations in the daily stable warfarin dose respectively.

Identification of gene modules associated with warfarin dosage by a genome-wide DNA methylation study.

To identify warfarin dose-associated DNA methylation changes, we conducted the first genomewide DNA methylation association study. A total of 22 patients who required an extreme warfarin dosage from VKORC1 -1639AA & CYP2C9*1*1 genotype group were enrolled in this study. The Illumina Infinium HumanMethylation450 platform was used to perform genome-scale DNA methylation profiling, identifying differentially methylated CpG sites by a nonparametric test. WGCNA was used to analyze the association between gene modules and extreme warfarin dosage. For a total of 378,313 CpG sites that passed the quality control processes, we identified eight differentially methylated CpG probes (p<0.05) showing altered DNA methylation level (>20%) between two extreme dose groups. Though the WGCNA method we identified two gene modules, Turquoise and Light-cyan, with high methylation level were significantly correlated with high warfarin doses (P-values were 0.036 and 0.022 respectively). Both gene modules exhibited good warfarin dosage prediction performance (77% for the Turquoise module and 79% for the Light-cyan module). This study showed for the first time that DNA methylation level changes are significantly associated with warfarin dosage, providing a novel idea for understanding warfarin dose various and laying the groundwork for further related studies.

Trends in warfarin use and its associations with thromboembolic and bleeding rates in a population with atrial fibrillation between 1996 and 2011.

AimWarfarin is a cornerstone for the prevention of thromboembolism in atrial fibrillation (AF), and several efforts have been taken to increase its usage and safety, including risk stratification schemes. Our aim was to investigate the temporal trends in initiation of warfarin and its effects on incidence of bleeding and thromboembolism in patients with new-onset atrial fibrillation 1996–2011.MethodsAll patients with a first-time diagnosis of non-valvular atrial fibrillation were identified from nationwide administrative registries. Trends were determined by linear regression.ResultsIn total 153,682 patients were included. Initiation of warfarin increased from 14% to 41% (p<0.0001). Events of thromboembolism decreased from 3.9% to 2.6% annually (p<0.0001). The greatest decline in thromboembolic events was observed for patients with a CHA2DS2VASc score >1, where the annual decline was -0.12% (95%CI: -0.161; -0.084)) for those treated with warfarin and -0.073% (95%CI: -0.116;-0.030)) for those not treated with warfarin. Bleeding increased from 3.3% to 3.9% (p = 0.043). For those with a CHA2DS2VASc score >1 annual bleeding rates increased by 0.095% (95%CI: -0.025; -0.165) in warfarin treated and by 0.056% (95%CI: -0.013; -0.100) in patients not treated with warfarin.ConclusionWarfarin use increased by nearly a 3-fold between 1996 and 2011. During the same period, thromboembolic events declined by a third and bleeding increased by a fifth, suggesting a beneficial effect associated with higher warfarin use. Notably, a small decline in thromboembolic events and increase in bleeding events was observed for the untreated population, suggesting a changing risk profile of AF patients.

Real world adherence to oral anticoagulant in non-valvular atrial fibrillation patients in China

Background and objective: Adherence to oral anticoagulants is crucial for the prevention of ischemic stroke in atrial fibrillation patients; however, evidence of oral-anticoagulant adherence from developing countries is still lacking. This study aimed to evaluate the current situation and predictors of oral-anticoagulant adherence in non-valvular atrial fibrillation (NVAF) patients in China.Methods: Records of NVAF patients were obtained from a regional claims database. Both initiation and adherence to oral anticoagulants were calculated from linked records. Factors of oral-anticoagulant initiation were identified using Cox regression.Results: Among 33,463 NVAF patients, only 13.9% initialized warfarin treatment after the indexed hospital visit. Stratified by CHA2DS2-VASc scores, 20.9% of patients in the low-risk group were on warfarin, followed by 15.3% and 10.7% from the middle and high-risk groups, respectively. Among patients who initialized warfarin, only 40.4% filled the first repeat prescription within 3 months. Concurrent statin use, hypertension and heart failure were associated with higher warfarin initiation rate. Factors such as age above 75, female sex, manufacture workers, discharge from the primary-care center, antiplatelet use, and diabetes, ischemic and hemorrhagic stroke were associated with lower rate of warfarin initiation. Additionally, initiating warfarin treatment reduced risk of ischemic stroke in middle and high-risk patients.Conclusion: Oral anticoagulation was significantly under-used in NVAF patients in China. Age, sex, concurrent drug usage, and disease history were associated factors. Improving warfarin adherence was promising to reduce ischemic stroke risk of NVAF patients.

Warfarin and Flavonoids Do Not Share the Same Binding Region in Binding to the IIA Subdomain of Human Serum Albumin.

Human serum albumin (HSA) binds a variety of xenobiotics, including flavonoids and warfarin. The binding of another ligand to the IIA binding site on HSA can cause warfarin displacement and potentially the elevation of its free concentration in blood. Studies dealing with flavonoid-induced warfarin displacement from HSA provided controversial results: estimated risk of displacement ranged from none to serious. To resolve these controversies, in vitro study of simultaneous binding of warfarin and eight different flavonoid aglycons and glycosides to HSA was carried out by fluorescence spectroscopy as well as molecular docking. Results show that warfarin and flavonoids do not share the same binding region in binding to HSA. Interactions were only observed at high warfarin concentrations not attainable under recommended dosing regimes. Docking experiments show that flavonoid aglycons and glycosides do not bind at warfarin high affinity sites, but rather to different regions within the IIA HSA subdomain. Thus, the risk of clinically significant warfarin–flavonoid interaction in binding to HSA should be regarded as negligible.

Polymorphisms of VKORC1 and CYP2C9 are associated with warfarin sensitivity in Chinese population

ObjectiveWarfarin is a commonly prescribed anticoagulant for prevention of thromboembolic events. Wide inter-individual dose variation, narrow therapeutic range and risk of serious bleeding result in difficulties in achieving the therapeutic effect. The present study was designed to clarify the real biological significance of the polymorphisms of VKORC1 and cytochrome P450 2C9 (CYP2C9) in warfarin metabolism.MethodsA total of 214 patients with warfarin anticoagulant therapy were selected. During follow-up of anticoagulation, warfarin dosage and associated international normalized ratio values were recorded. Genetic polymorphisms of VKORC1 promoter and from exon 1 to exon 3 and CYP2C9 exon 4 sequence were detected by polymerase chain reaction and gene sequencing.ResultsFive polymorphisms were identified in this research, which were VKORC1 1173C>T (intron 1), 1542G>C (intron 2), 2255C>T (intron 2), 3730C>T (3′-downstream) and CYP2C9 exon 4 −65G>C. VKORC1 1173CT, 1542GC, 2255CT and 3730CT polymorphisms were detected in same patients, but CYP2C9 exon 4 −65GC carriers were different from them. VKORC1 1173CT, 1542GC, 2255CT, 3730CT carriers and CYP2C9 exon 4 −65GC carriers had significantly higher warfarin daily dosage than others (3.2±0.6 vs 3.1±1.1 vs 2.6±0.8 mg/day). Logistic regression analysis revealed VKORC1 1173CT, 1542GC, 2255CT, 3730CT carrier status (odds ratio [OR] =3.233, 95% confidence interval [CI]: 1.259–8.303, P=0.015) and obesity with body mass index >27 kg/m2 (OR =1.223, 95% CI: 1.097–1.363, P<0.001) to have independent and statistically significant contributions to high warfarin dosage.ConclusionIn general, in VKORC1 1173CT, 1542GC, 2255CT and 3730CT carriers and in obese patients, warfarin maintenance doses were significantly higher than in the others.

Use of Pharmacogenetic Information in the Treatment of Cardiovascular Disease.

In 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine. In this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants. These genetic variations have pharmacodynamic and pharmacokinetic effects and have been shown to explain differences in drug response such as lipid lowering, prevention of cardiovascular disease, and prevention of stroke, as well as incidence of adverse events such as musculoskeletal side effects and bleeding. Several groups have begun to implement pharmacogenetics testing as part of routine clinical care with the goal of improving health outcomes. Such strategies identify both patients at increased risk of adverse outcomes and alternative strategies to mitigate this risk as well as patients with "normal" genotypes, who, armed with this information, may have increased confidence and adherence to prescribed medications. While much is known about the genetic variants that underlie these effects, translation of this knowledge into clinical practice has been hampered by difficulty in implementing cost-effective, point-of-care tools to improve physician decision-making as well as a lack of data, as of yet, demonstrating the efficacy of using genetic information to improve health. Many genetic variants that affect individual responses to drugs used in cardiovascular disease prevention and treatment have been described. Further study of these variants is needed before successful implementation into clinical practice.

Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population.

BackgroundWarfarin is a widely prescribed anticoagulant with narrow therapeutic window for thromboembolic events. Warfarin displays large individual variability in dose requirements. The purpose of this study is to assess the contribution of patient-specific and genetic risk factors to dose requirements of patients on either high or low warfarin maintenance dose in Ghana. Blood samples were collected from 141 (62 males, 79 females) Ghanaian patients on stable warfarin dose to determine their INR. Influence of patient specific factors and gene variations within VKORC1, CYP2C9 and CYP4F2 were determined in patients on either high or low warfarin maintenance dose.ResultsOne hundred and forty-one patients took part in the study with 79 (56%) participants being Female. The median age of the study participants was 48 years [IQR: 34–58]. The median duration for patients to be on warfarin therapy was 24 months [IQR: 10–72]. Majority of the study participants (80.9%, n = 114) did not have any side effects to warfarin. CYP2C9*2 and CYP2C9*3 variant alleles were not detected. VKORC1 variant allele was observed at 6% and CYP4F2 variant allele was observed at 41%. Duration of patients on warfarin therapy was marginally associated with high warfarin dose (adjusted OR = 1.01 [95% CI 1.00–1.02], p = 0.033) while the odds of heterozygous individuals (G/A) for VKORC1 gene to have high warfarin dose compared to persons with homozygous (G/G) (adjusted OR = 0.06 [95% CI 0.01–0.63], p = 0.019). Age, gender, diagnosis, presence of side effects and other medications were not associated with warfarin dose (p = 0.05).ConclusionThis study provides data on VKORC1 and CYP4F2 variants among an indigenous African population. Duration of patients on warfarin therapy was marginally associated with high warfarin dose. CYP2C9*2 and *3 variants were not detected and may not be the most important genetic factor for warfarin maintenance dose among Ghanaians.

Strain differences in intestinal toxicity of warfarin in rats.

Intestinal hemorrhage characterizes effectiveness of warfarin (WF) as rodenticide and is among adverse effects of therapy in humans. Having in mind genetic variations in the effectiveness of WF in wild rats and in the doses required for therapeutic effect, strain differences in the intestinal toxicity of oral warfarin in rats were examined in this study. High WF dose (3.5mg/l) led to mortality in Albino Oxford (AO) rats, with no lethality in Dark Agouti (DA) rats. Higher values of prothrombin time were noted at low WF dose (0.35mg/l) in the former strain. Leukocyte infiltration in intestine noted at this dose in both strains was associated with oxidative injury and more pronounced anti-oxidative response in AO rats. Suppression of mesenteric lymph node cell proliferation and IFN-γ and IL-10 production in AO rats and lack of these effects in DA rats, represent different strategies to protect vulnerable intestine from harmful immune responses.