Racial Differences in Atrial Fibrillation Management Between White Patients and Black Patients in Transthyretin Cardiac Amyloid.

Black patients have higher rates of stroke than White patients. Paradoxically, atrial fibrillation (AF) affects twice as many White patients compared with Black patients. Transthyretin cardiac amyloidosis (ATTR-CA) is associated with both AF and strokes. We hypothesized that although Black patients with ATTR-CA have a lower incidence of AF, when diagnosed with AF, they have increased thromboembolic events. Patients with ATTR-CA (n = 558) at 3 international centers were retrospectively identified. We compared baseline characteristics, presence of AF, outcomes of thromboembolism (stroke, transient ischemic attack, and peripheral embolism), major bleed, and mortality by race. Of all patients, 367 of 488 White patients (75%) were diagnosed with AF compared with 39 of 70 Black patients (56%) (p = 0.001). Black patients with AF had a hazard ratio of 5.78 (95% confidence interval 2.30 to 14.50) for time to first thromboembolic event compared with White patients. There were no racial differences in major bleeding. Black patients with AF more often lacked anticoagulation (p = 0.038) and had higher incidence of labile international normalized ratio (p <0.001). In conclusion, these data suggest that although Black patients with ATTR-CA have lower incidence of AF, they have increased thromboembolic events compared with White patients. These findings may be related to treatment discrepancies, time in therapeutic range for warfarin, and disparities in healthcare.

Genetic Associations With Stable Warfarin Dose Requirements in Han Chinese Patients.

ABSTRACT: Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU, and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anticoagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P = 8 × 10-6 and 9 × 10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust = 0.040 after Bonferroni correction). We discovered that genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.

Correlation between P-selectin rs1800807 and rs1800808 Gene polymorphisms and plasma soluble P-selectin concentrations in patients with atrial fibrillation complicated with thromboembolism in Xinjiang, China.

This study is to investigate the relationship of P-selectin (Ps) gene rs1800807 and rs1800808 polymorphisms with plasma soluble P-selectin (sPs) in Han, Uygur, and Kazakh people with atrial fibrillation (AF) and thromboembolism (TE) in Xinjiang, China.A total of 778 Han patients (including 131 patients with AF and TE, 229 patients with AF and 418 healthy individuals), 660 Uygur patients (including 118 patients with AF and TE, 232 patients with AF and 310 healthy individuals), and 505 Kazakh patients (including 42 patients with AF and TE, 156 patients with AF and 307 healthy individuals) were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis were used to analyze the polymorphisms of rs1800807 and rs1800808 of Ps gene. ELISA was used to determine the plasma sPs level. The association between plasma sPs levels and Ps gene polymorphisms was further analyzed.The sPs concentrations of GG genotype at rs1800807 locus in the Han, Uygur and Kazakh ethnic groups in Xinjiang, China were significantly higher than those of the CC genotype and CG genotype (P < .05). In the rs1800808 locus, plasma sPs concentrations of the heterozygous mutant CT genotypes in Han and Uygur populations were significantly higher than those in the CC and TT genotypes, whereas the plasma sPs concentrations in Kazakh TT genotypes were significantly higher than those in the CC and CT genotypes (P < .05). Among different ethnic groups, there were significant differences in sPs levels of rs1800807 and rs1800808 genotypes (P < .05).Plasma sPs concentrations are associated with Ps genotypes and sPs concentration of the same genotype shows racial differences.

Thromboembolic risks associated with paroxysmal and persistent atrial fibrillation in Asian patients: a report from the Chinese atrial fibrillation registry.

BACKGROUND: Several studies have reported on atrial fibrillation (AF) outcomes, including thromboembolism in patients with paroxysmal and non-paroxysmal AF; however the findings still remain controversial on whether risks differ between these clinical subtypes and limited data are available in Asian cohorts. METHODS: We compared the risk of thromboembolism between paroxysmal and persistent AF patients, in a large contemporary Chinese cohort study. A total of 8529 non-valvular atrial fibrillation (NVAF) patients from the Chinese Atrial Fibrillation Registry (CAFR) study were enrolled. The study subjects were divided into two groups: paroxysmal AF (PaAF, defined as AF lasting within 7 days, n = 4642) and persistent AF (PeAF, lasting over 7 days, n = 3887) groups. RESULTS: In non-anticoagulated patients, PeAF group demonstrated a higher risk of stroke, all-cause death, cardiac/ non-cardiac death and composition of stroke/ transient ischemic attack (TIA)/peripheral thromboembolism (PT)/all-cause death, compared to the PaAF group. No significant difference was found in anticoagulated subjects. On multivariate analysis in non-anticoagulated patients, age ≥ 75 years (P = 0.046) and prior stroke/TIA/PT (P = 0.018) but not AF type (P = 0.63) were significantly associated with the risk of stroke/TIA/PT events. CONCLUSIONS: Stroke, all-cause death and cardiac/non-cardiac death in Chinese NVAF population was increased in non-anticoagulated PeAF patients compared with PaAF group, but same between anticoagulated PeAF and PaAF patients. After adjustment, AF type was not an independent predictor of thromboembolism in NVAF patients. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-OCH-13003729. Registered 22 October 2013.

Predictive role of CHA2DS2-VASc score for cardiovascular events and death in patients with arterial hypertension and stable sinus rhythm.

Background The CHA2DS2-VASc score well stratifies the risk for thromboembolic events in non-valvular atrial fibrillation (NVAF) patients. This score may also predict thromboembolic events in sinus rhythm populations. Purpose The purpose of this study was to assess the prognostic role of CHA2DS2-VASc in a Caucasian community population of patients with arterial hypertension and sinus rhythm. Methods A total of 12,599 arterial hypertension residents not receiving anticoagulation were selected from a community population in Trieste between November 2009 and October 2014: 11,159 sinus rhythm and 1440 NVAF patients. We considered thromboembolic events, cardiovascular hospitalisation and all-cause death in all patients divided according to CHA2DS2-VASc. Results Sinus rhythm patients were 74 (interquartile range 65-81) years old, 50% were women, 32% with CAD, mean CHA2DS2-VASc 3.68 ± 1.47 points, significantly lower than NVAF patients (4.26 ± 1.50, P < 0.001). After 37 months follow-up, an increasing CHA2DS2-VASc corresponded to a higher rate of thromboembolic events in sinus rhythm patients, ranging from 0% in patients with a score of 1 or 2 to 2.6% in those with a score of 6 or greater ( P < 0.0001). A similar trend was found in the reference NVAF group. At Cox multivariable analysis, CHA2DS2-VASc predicted thromboembolic events (hazard ratio (HR) 2.12), cardiovascular hospitalisation (HR 1.55) and all-cause death (HR 1.57). The predictive accuracy of CHA2DS2-VASc was similar in sinus rhythm and NVAF patients for thromboembolic events, cardiovascular hospitalisation and all-cause death (area under the curve statistic 0.76 vs. 0.76, 0.68 vs. 0.66, 0.64 vs. 0.64, respectively). Conclusions In a community population of Caucasian arterial hypertension patients in sinus rhythm, CHA2DS2-VASc rather well stratifies for adverse clinical events at mid-term follow-up with a similar accuracy to NVAF patients. These results might be clinically relevant in this setting of sinus rhythm patients.

Predictors of warfarin dose requirements in South African patients attending an anticoagulation clinic.

INTRODUCTION: Warfarin is the most common oral anticoagulant for the treatment and prevention of thromboembolic disease. However, it has a wide interpatient variability in dose requirements due to various genetic and clinical factors. MATERIALS AND METHODS: This study investigated the effect of clinical and genetic factors on the variability of warfarin dose requirements in 147 South African patients (81 white and 66 black). The study was performed at a University Hospital Anticoagulation Clinic managed by nursing sisters at the Charlotte Maxeke Johannesburg Academic Hospital. RESULTS: The most common indication for anticoagulation was atrial fibrillation (n = 55, 37.4%). The mean warfarin dose was significantly higher in black patients as compared to white patients (5.4 ± 2.9 mg/day and 3.8 ± 2.1 mg/day, respectively; P < 0.001). Older age was significantly associated with a lower maintenance warfarin dose (P < 0.001). Drugs which decreased the international normalized ratio (INR) were significantly associated with a higher maintenance warfarin dose of 6.4 ± 3.4 mg/day (P < 0.034). In contrast, there was no significant difference in warfarin dosage requirements in the presence of CYP2C9 and VKORC1 variant alleles (P > 0.05). Patients, however, homozygous for CYP2C9 *1,*3, and VKORC1 required less than 5 mg/day of warfarin to maintain the INR within the therapeutic range. CONCLUSION: In conclusion, this study indicates that clinical characteristics including; age, ethnic group, and drugs which decrease the INR might help to predict better dose requirements in this population group and thereby reduce the risk of bleeding and thrombotic complications.

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation. SUMMARY: Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (ß = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (ß = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research.

Atrial fibrillation in New Zealand primary care: Prevalence, risk factors for stroke and the management of thromboembolic risk.

Background Atrial fibrillation is a major risk factor for stroke and heart disease but there is limited information on its prevalence in New Zealand primary care or the treatment provided to manage thromboembolic risk. Our aim was to estimate the prevalence of atrial fibrillation, assess patient risk for thromboembolism and evaluate the appropriateness of risk reduction using antiplatelet and oral anticoagulation therapy. Design A retrospective cohort study utilising electronic medical records for 739,000 patients registered with 170 general practices in 2014. Methods Patient diagnoses and prescriptions from 2010-2014 were analysed to identify patients with atrial fibrillation in 2014 and co-morbidities included in the CHA2DS2-VASc algorithm. Adjusted prevalence of atrial fibrillation by patient demographic group and the proportion of patients following recommended antithrombotic therapy were calculated. Results 12,712 patients were identified with AF (1.72%, 95% confidence interval 1.69%-1.75%). Prevalence was significantly higher for Maori (odds ratio 1.91, 95% confidence interval 1.80-2.03) than Europeans after adjusting for age, sex, deprivation and clinical risk factors. Stroke risk for Maori and Pacific Island patients was higher than for Europeans across all age groups. Of the 10,406 patients (81.9%) at high risk for thromboembolism, 60.5% were using anticoagulants, 24.1% aspirin monotherapy and 15.4% neither anticoagulants nor aspirin. Oral anticoagulants were used by 31.5% of patients at low risk (CHA2DS2-VASc <2). Conclusions Oral anticoagulants are under-utilised in the management of thromboembolic risk in high risk patients with atrial fibrillation. Better promotion of guideline recommendations for the treatment of patients with atrial fibrillation may be required to improve clinician and patient decision-making.

A comparative analysis of clinical characteristics of patients with paroxysmal nocturnal hemoglobinuria between Asia and Europe/America.

To accurately analyze the clinical characteristics of paroxysmal nocturnal hemoglobinuria (PNH) in different ethnic backgrounds, we retrieved all retrospective studies on clinical characteristics of PNH with a median follow-up period >60 months published after 2000, analyzed the clinical characteristics of PNH patients in Asia and European/America, and statistically compared enumeration data in these studies. We included 1665 patients in this analysis. The proportion of female patients in Asia was significantly lower than that in Europe/America (P = 0.000). Incidence rates of hemoglobinuria and thromboembolism in Asia were significantly lower than in Europe/America (both P values were 0.000). Within the subgroups of patients with thromboembolism, Asian patients had a higher proportion of arterial thrombosis while Western patients had a higher proportion of abdominal venous thrombosis. Bone marrow failure was not clearly defined in most studies. The proportion of patients with pancytopenia was higher in China than in France (P = 0.048). The total death rates were similar in both ethnic groups (P > 0.05). In Europe/America the major cause of death was thromboembolism and in Asian countries was serious infections. Differences in population characteristics of PNH patients among different ethnic groups indicate the possibility of differential pathogenesis and may be informative for treatment decisions.

Anticoagulation intensity of rivaroxaban for stroke patients at a special low dosage in Japan.

OBJECTIVES: In Japan, low-dose rivaroxaban [15 mg QD/10 mg QD for creatinine clearance of 30-49 mL/min] was approved for clinical use in NVAF patients partly because of its unique pharmacokinetics in Japanese subjects. The aim of the study was to determine the anticoagulation intensity of rivaroxaban and its determinant factors in Japanese stroke patients. METHODS: Consecutive stroke patients with NVAF admitted between July 2012 and December 2013 were studied. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and estimated plasma concentration of rivaroxaban (Criv) based on an anti-factor Xa chromogenic assay were measured just before and 4 and 9 h after administration at the steady state level of rivaroxaban. Determinant factors for Criv were explored using a linear mixed-model approach. RESULTS: Of 110 patients (37 women, 75±9 years old), 59 took 15 mg QD of rivaroxaban and 51 took 10 mg QD. Criv at 4 h was 186 ng/mL for patients taking 15 mg QD and 147 ng/mL for those taking 10 mg QD. Both PT and aPTT were positively correlated with Criv. Criv was 72% lower at 4 h in 15 patients receiving crushed tablets than in the other patients, and tablet crushing was significantly associated with lower Criv (adjusted estimate -0.43, 95% CI -0.60 to -0.26) after multivariate-adjustment. CONCLUSION: The anticoagulation effects of rivaroxaban in the acute stroke setting for Japanese NVAF patients were relatively low as compared with those in the ROCKET-AF and J-ROCKET AF trials. Tablet crushing, common in dysphagic patients, decreased Criv.

Association of PS gene polymorphism and soluble P-selectin levels in atrial fibrillation thromboembolism population in Xinjiang.

UNLABELLED: To investigate the association between the polymorphism of P choose element (p. selectin, PS) and soluble P-selectin levels in atrial fibrillation (AF) thromboembolism in Han and Uigur population of Xinjiang. METHOD: Using ELISA method determination of plasma level of sPs. The frequency distributions of SNP sP-selectin gene promoter (-2123C/G) and SNP in exon region (Thr715Pro) were investigated by polymerase chain reaction (PCR)-restriction fragment length polymorphism and direct DNA sequence analysis among 302 Xinjiang Uigur and 340 age- and sex-matched Han people. RESULTS: Cases sPs exist significant difference serum level and the control group. The frequencies of the -2123C/G allele among the Uigur population had no significant differences from those of the Han population. Thr715Pro did not show any polymorphism in the two populations. CONCLUSIONS: The sP-selectin gene polymorphisms are associated with serum sP-selectin levels or thromboembolic events, suggesting that the patients with nonvalvular AF and thromboembolic events may have genetic susceptibility.

Oral anticoagulants for Asian patients with atrial fibrillation.

Anticoagulation is the most-important intervention to prevent stroke in patients with atrial fibrillation (AF). Despite a lower point prevalence of AF in Asian communities and Asian countries than in other populations, individuals of Asian ethnicity are at a disproportionately high risk of stroke and have greater consequent mortality. Warfarin and other vitamin K antagonists are conventionally used for anticoagulation, and demonstrably reduce the risk of stroke and all-cause mortality in patients with AF. The use of warfarin in Asian countries is suboptimal, primarily owing to the universal challenge of achieving controlled anticoagulation with an unpredictable drug as well as concerns about the particularly high-risk of haemorrhage in Asian patients. Instead, antiplatelet therapy has been favoured in Asian communities, this strategy is neither safe nor effective for stroke prevention in these individuals. The non-vitamin K antagonist, oral anticoagulant drugs offer a solution to this challenge. The direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have demonstrated noninferiority to warfarin in the prevention of stroke and systemic embolism in international, randomized, controlled trials. Importantly, some of these drugs are also associated with a significantly lower incidence of major haemorrhage, and all result in lower rates of intracranial haemorrhage and haemorrhagic stroke than warfarin. In this article, we review the use of the non-vitamin K antagonist anticoagulants in the management of AF in Asian populations.

Can enoxaparin reduce thromboembolism related events after primary TKA in Asian patients?

The purpose of this study was to investigate the efficacy and safety of enoxaparin in preventing venous and arterial thromboembolism related events after primary total knee arthroplasty (TKA) in Asian patients. Four hundred twenty nine patients (621 TKAs) did not receive thromboprophylaxis after TKA and 907 patients (1,336 TKAs) received enoxaparin after the procedure. We assessed clinically significant venous and arterial thromboembolism related events and bleeding complications. Total thromboembolism related events occurred in 13 patients (3.03%) without thromboprophylaxis and 17 patients (1.87%) with enoxaparin (P = 0.183). Our study showed that the incidence of clinically significant thromboembolism related events after TKA was very low in Asian patients. Enoxaparin had no benefits in reducing thromboembolism related events in Asian patients.

Evaluation of the safety and efficacy of warfarin in Taiwanese patients.

OBJECTIVE: The safety and efficacy of warfarin therapeutic range in Asians remain to be ascertained. Physicians in Taiwan consider Asians are more likely to have bleeding complications rather than thromboembolic events from warfarin. The aim of this study was to determine if the proper INR range for patients in Taiwan is different. METHODS: A retrospective study was conducted with 161 patients on warfarin therapy for more than 24 consecutive months during March 1, 2006 to Sepember 30, 2008. Total follow-up time was 3,504 patient-months. The incidence rates of thromboembolic and bleeding events for INR categories were calculated. RESULTS: The overall incidence rates of INR ranges of < 1.5, 1.5 - 1.9, 2.0 - 2.4, 2.5 - 2.9, 3.0 - 3.4, and ≥ 3.5 were 8.1, 5.6, 2.0, 7.6, 33.3, and 121.2 per 1,000 patientmonths, respectively. The overall incidence rate at INR of > 3 is higher than that at INR of < 2 or 2 - 3 (p < 0.001), with the lowest incidence rate at INR between 2.0 and 2.4. When INR was maintained at a level < 2, patients taking warfarin for secondary prevention had a significantly higher event rate compared to the primary prevention group (p < 0.05). Age greater than 73 years was a risk factor for thromboembolic events before and after covariate adjustment. CONCLUSION: An INR range of 2 - 2.4 appeared to be associated with lower complications and better clinical outcomes in Taiwanese patients treated with warfarin. Lowering the intensity of anticoagulant therapy further does not decrease the number of events.

Correlation of CHADS2 and CHA2DS2-VASc scores with transesophageal echocardiography risk factors for thromboembolism in a multiethnic United States population with nonvalvular atrial fibrillation.

BACKGROUND: The aims of this study were to evaluate the relationship of the CHA(2)DS(2)-VASc score and risk categories with transesophageal echocardiographic (TEE) risk factors for thromboembolism and to compare the CHA(2)DS(2)-VASc and CHADS(2) risk stratification schemes with respect to their ability to predict these risk factors in a multiethnic US population with nonvalvular atrial fibrillation. METHODS: Transesophageal echocardiograms of 167 patients (mean age, 66.3 ± 11.6 years; 146 men [87%]; 100 whites [60%]; 40 Hispanics [24%]; 27 blacks [16%]) with nonvalvular atrial fibrillation were retrospectively reviewed for smoke, sludge, thrombus, and left atrial appendage (LAA) emptying velocity ≤20 cm/sec. The patients' CHA(2)DS(2)-VASc and CHADS(2) risk scores and categories were also calculated. RESULTS: Any LAA abnormality, smoke, sludge, thrombus, and abnormal LAA emptying velocity were present in 45%, 38%, 13%, 3%, and 22% of patients, respectively. Heart failure (P < .001), age (P < .001 for age ≥75 vs ≤64 years, P = .013 for age 65-74 vs ≤64 years), and diabetes (P = .019) were independent predictors of LAA abnormalities, while ethnicity was not. The prevalence of TEE risk factors for thromboembolism increased with increasing CHA(2)DS(2)-VASc score and risk category. The CHADS(2) risk categories of 35 patients (21%) were upgraded by the CHA(2)DS(2)-VASc scheme. Using the latter scheme, fewer patients were classified as at intermediate risk compared with the CHADS(2) system (21 [13%] vs 46 [28%]). Patients classified as at low risk by either scheme had almost no TEE risk factors. Of 30 intermediate-risk patients by CHADS(2) score upgraded to high risk using CHA(2)DS(2)-VASc score, eight (27%) had at least one TEE risk factor for thromboembolism. C-statistics, sensitivity, and specificity for predicting any LAA abnormality were 0.607 (95% confidence interval, 0.549-0.665), 92.0%, and 28.9% for CHA(2)DS(2)-VASc score and 0.685 (95% confidence interval, 0.615-0.755), 81.3%, and 54.2% for CHADS(2) score. CONCLUSIONS: CHA(2)DS(2)-VASc score is associated with TEE risk factors for thromboembolism in a multiethnic US population. Compared with CHADS(2) score, it has increased sensitivity, decreased specificity, and lower ability for predicting TEE risk factors in this population.

Low incidence of thromboembolism in relapsed/refractory myeloma patients treated with thalidomide without thromboprophylaxis in Taiwan.

Thromboembolism (TE) is a common complication in patients with multiple myeloma (MM). Immunomodulatory agents, e.g., thalidomide, have expanded the therapeutic options for treating myeloma; however, Western countries report a high incidence of thrombosis in thalidomide-treated MM patients who lack thromboprophylaxis. A Korean trial reported low TE incidence in thalidomide-treated myeloma patients (39% were given aspirin prophylactically). We aimed to elucidate the TE frequency in MM patients in Taiwan who were treated with thalidomide without TE prophylaxis. We retrospectively collected the records of MM patients who had used thalidomide from a single institute between 2004 and 2010, combined these records with two other Taiwanese studies, and compared all three with the Korean trial. In the current Taiwanese series, five of 144 patients (3.5%) developed TE as follows: three (2.1%) were venous and two (1.3%) were arterial. Only 6.1% of the patients had undergone TE prophylaxis, which is less than in the Korean trial (38.9%, p < 0.05). Of the patients in the relapsed/refractory cohort (n = 114) who were given thalidomide alone, none (0/52) developed venous TE (VTE); however, two patients (2/35, 5.7%) who were given thalidomide-dexamethasone as a salvage treatment developed VTE. In the thrombosis cohort, four patients (80%) were treated with thalidomide plus dexamethasone. In conclusion, the frequency of thalidomide-related TE in myeloma patients without effective TE prophylaxis was low in Taiwan. In relapsed/refractory myeloma patients, the VTE frequency was slightly lower compared with Western patients irrespective of treatment with thalidomide alone or combined with dexamethasone. Even in low TE incidence areas, thalidomide combined with dexamethasone was more thrombogenic compared with others.

A new algorithm to predict warfarin dose from polymorphisms of CYP4F2 , CYP2C9 and VKORC1 and clinical variables: derivation in Han Chinese patients with non valvular atrial fibrillation.

Few pharmacogenomic dosing regimens of warfarin have been developed for Chinese patients with non valvular atrial fibrillation (NVAF). The objective of this study was to develop a new algorithm by polymorphisms of CYP2C9, VKORC1 and CYP4F2 to predict the daily stable dose of warfarin in Chinese patients with NVAF. A total of 325 Chinese NVAF patients on stable dose of warfarin with a target international normalised ratio of 1.5 to 3.0 were recruited and divided randomly into two cohorts. CYP2C9*3, VKORC1-1639, VKORC1 1173 and CYP4F2 were detected by ligase detection reaction method. The new algorithm was developed with multivariate linear regression in cohort 1 (260 patients) and assessed with Pearson Correlation Analysis (PCA) in cohort 2 (65 patients). From 260 enrolled patients, the model (R2 = 51.7%) was developed as: Dose = 3.47 - 0.022 (AGE) + 0.017 (WT) + 0.189 (PTE) - 0.283 (ß-blocker) - 0.471 (AMIO) - 0.586 (CYP2C9 *1/*3) - 0.296 (VKORC1 CT) - 0.648 (VKORC1 TT) + 0.219 (CYP4F2 TT). PCA displayed that the algorithm was good (r = 0.658). The residual plots revealed that the predicted doses by the algorithm tend to be overestimated when lower doses were administered to patients and to be underestimated in higher doses. The algorithm developed by us might predict warfarin dose used by Chinese NVAF patients.

The effect of CYP2C9, VKORC1 genotypes and old age on warfarin pharmacologic sensitivity in korean patients with thromboembolic disease.

The therapeutic dose of warfarin is dependent upon intrinsic patient characteristics that are highly variable. We assessed the effects of CYP2C9, VKORC1 1173 C/T polymorphisms, and old age on warfarin dosing and sensitivity by measuring plasma S-/R-warfarin levels in Korean patients. INR and the plasma S-/R-warfarin concentrations were determined in 58 patients who had the VKORC1 1173C/T CYP2C9 genotypes, were on a long-term anticoagulation regimen with warfarin, and took a daily dose of warfarin. The pharmacokinetic sensitivity of warfarin was significantly higher in the CYP2C9 *1/*3 genotypes than in the CYP2C9 *1/*1 genotypes [ratio of S-warfarin concentration/dose, 0.53 vs. 0.21; p=0.01]. Pharmacodynamic sensitivity in older patients (≥ 75 years) with the CYP2C9 *1/*1 and VKORC1 1173 TT genotypes was significantly higher as compared to younger patients (<75 years) [Ratio of INR/S-warfarin concentration, 4.88 vs. 3.41; p = 0.026]. The CYP2C9*3 allele and old age (≥ 75 years) with the VKORC1 1173 T allele were also associated with increased risk of over-anticoagulation. The increase of over-anticoagulation risk and warfarin sensitivity is related to the CYP2C9*3 allele and old age with the VKORC1 1173 T allele in Korean patients with thromboembolic disease. These findings suggest that a lower initial and maintenance dose should be considered for the patients with CYP2C9 *3 allele and advanced age in this patient population. However, due to the limited number of patients in the study population, our finding needs to be confirmed by a larger, well-controlled study.

Practical management approaches to anticoagulation non-compliance, health literacy, and limited English proficiency in the outpatient clinic setting.

Warfarin is a widely used oral anticoagulant. It is highly efficacious for the treatment and prevention of thromboembolic disorders despite its narrow therapeutic window. Poor compliance with warfarin is common and a major contributor to poor anticoagulation control. A number of psychosocial issues (e.g. depressive symptoms, attitudinal and behavioral factors, cognitive function, lack of social support, limited English proficiency, health illiteracy) have been associated with warfarin non-compliance among patients in anticoagulation clinics. Patient-specific features, such as these, are important to identify in order to develop appropriate and practical interventions. Health literacy and limited English proficiency are the extension of issues related to culture, language, and ethnicity. A better understanding of patients' functioning level and health utilization factors may help to develop and target interventions for high risk patients and reduce complications from suboptimal therapy and poor warfarin management due to non-compliance. Four patient case scenarios will be used to illustrate these issues and identify potential interventions to optimize warfarin therapy.