Accuracy assessment of pharmacogenetic algorithms for warfarin dose prediction in Chinese patients

A few warfarin pharmacogenetic dosing algorithms have been proposed,based on multiethnic or homogeneous populations, to estimate warfarin therapeutic doses. However, it remains to be proven that which algorithm is accurate in predicting warfarin dose in Chinese people. We selected eight warfarin dose predictive pharmacogenetic algorithms and retrospectively assessed the predictive accuracy of each algorithm in a total of 368 eligible outpatients by comparing the actual stable therapeutic dose to the dose predicted by the algorithm. Our results showed that a high level of performance was demonstrated by three algorithms,Gage et al., Anderson et al., and Wu et al., having a similar performance in coefficient of determination (R2) and percentage of patients predicted dose within 20% of actual dose. The Gage et al. algorithm had the lowest mean absolute error (MAE). These results indicated that the algorithm by Gage et al. provided a more accurate prediction than did the others,which suggests that this pharmacogenetic algorithm might be used in clinical practice to guide rational administration of warfarin.     

Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, −1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007. Disclosure: A portion of this article was adapted from an education handout that Dr. Gage has retained copyright of: Gage, B.F. (2006). Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program: 467–473. Dr. Gage has served as a consultant to Bristol-Myers Squibb. Funding: NIH R01 HL074724.     

Therapeutic Endoscopic Ultrasound for Biliary and Pancreatic Disorders

The role of endoscopic ultrasound (EUS) has greatly expanded since the first clinical examination performed nearly 30 years ago. The introduction of linear instruments allowed tissue sampling (Kulesza and Eltoum Clin Gastroenterol Hepatol 5:1248–1254, 2007; Levy and Wiersema Gastrointest Endosc 62:417–426, 2005) and therapeutic interventions applications, including celiac plexus and ganglia blockade and neurolysis (Wiersema and Wiersema Gastrointest Endosc 44:656–662, 1996; Levy and Wiersema Gastroenterol Clin North Am, 35:153–165, 2006; Levy et al. Am J Gastroenterol 103:98–103, 2008), pancreatic fluid drainage (Lopes et al. Arq Gastroenterol 45:17–21, 2008; Norton et al. Mayo Clin Proc 76:794–798, 2001; Kruger et al. Gastrointest Endosc 63:409–416, 2006; Seifert et al.: Endoscopy 32:255–259, 2000), cholecystenterostomy (Kwan et al. Gastrointest Endosc 66:582–586, 2007), and delivery of cytotoxic agents (eg, chemotherapy, radioactive seeds, and gene therapy) (Chang et al.: Cancer 88:1325–1335, 2000; Chang Endoscopy 38(Suppl 1):S88–S93, 2006). The continued need to develop less invasive alternatives to surgical and interventional radiologic therapies drove the development of EUS-guided methods for biliary and pancreatic intervention. This article reviews existing data and focuses on established and emerging EUS techniques for accessing and draining the bile and pancreatic ducts.     

Spontaneous pneumomediastinum secondary to refractory dermatomyositis successfully treated with rituximab

Spontaneous pneumomediastinum has been described in patients with dermatomyositis (DM) and polymyositis (Korkmaz et al., Rheumatology 40:476–478, 2001; Maruoka et al., Mod Rheumatol 16:55–57, 2006; Kono et al., Ann Rheum Dis 59:372–376, 2000; Neves et al., Clin Rheumatol 26:105–107, 2007). Literature reviews suggest that this complication has a mortality of between 27% and 41% ( Kono et al., Ann Rheum Dis 59:372–376, 2000; Neves et al., Clin Rheumatol 26:105–107, 2007; Goff et al., Arthritis Rheum 61:108–118, 2009). This is the first report of rituximab being used successfully as part of the treatment for DM complicated by pneumomediastinum.     

中国患者华法林抗凝治疗剂量的药物基因组学相关性及药物基因组学方程的比较分析

目的药物基因组学方程对华法林剂量的预测作用的重要性日益受到重视。但是,其准确性仍受到种族和包括华法林剂量在内的多种临床因素的影响。本文旨在接受低剂量华法林抗凝治疗的中国患者中,验证遗传因素对华法林治疗剂量的影响,并分析药物基因组学方程对华法林不同剂量范围的预测效果。方法在接受低强度华法林抗凝治疗（目标INR为1．6～2．5）的中国患者队列（n=282）人群中,检测CYP2C93、VKORC1-1639A／G和CYP4F2＊3基因多态性与华法林稳定治疗剂量的关系。根据华法林剂量将患者分为低剂量组（≤1．5mg／d）,中间剂量组（1．5～4．5mg／d）和高剂量组（≥4．5mg／d）,分别评估8个药物基因组学方程在各组患者中的预测效果。预测效果评估指标包括,剂量预测值位于实际值20％界限内的患者比例（20％内患者比例）,预测值与实际值之间绝对误差的平均值（MAE）。结果华法林的稳定治疗剂量在各个基因的变异基因型携带者和野生基因型携带者之间均存在显著差异（CYP2C9-3：P〈0．00l;VKORC1-1639A／G：P〈0．001;CYP4F2＊3：P=0．025）。来自白种人群和混合人群的药物基因组学方程在华法林高剂量组中预测效果最好,而来自亚洲人群的方程在中间剂量组中的预测效果更好。所有方程对低剂量患者的剂量预测效果均不佳。结论CYP2C93、VKORC1-1639A／G和CYP4F2＊3基因多态性均与中国人群华法林稳定治疗剂量相关。已有的药物基因组学方程尚不能有效的预测华法林各个剂量组患者的稳定治疗剂量。     

药物基因组学方程对中国患者低强度华法林抗凝治疗剂量的预测效果分析

目的在接受低强度华法林抗凝治疗的中国患者人群中,验证华法林药物基因组学剂量预测方程的效果。方法在接受低强度华法林抗凝治疗（目标国际标准化比值INR为1．6至2．5）的226例中国患者人群中,分别比较已公开发表并符合本研究入选标准的药物基因组学方程的效果。效果评估指标包括剂量预测值位于实际值20％界限内的患者比例（20％界限内的患者比例）以及剂量预测值与实际值之间绝对误差的平均值（MAE）。结果8个入选的药物基因组学方程的平均MAE为（0．87±0．17）mg／d[（0．73-1．17）mg／d],平均20％界限内的患者比例为（43．8％±8．1％）（29．1％-52．1％）。配对比较显示,来自亚洲人群的方程的预测效果明显优于来自高加索人群的方程（OR：1．61-3．36,P≤0．02）;加入INR值或CYP4F2＊3的方程较未加入的方程预测效果更好[加入INR的OR：1．71（1．08-2．72）,P=0．029;加入CYP4F2＊3的OR：2．67（1．41-5．05）,P=0．004]。结论来自亚洲人群,或者整合3个基因变异型和INR反应性的药物基因组学方程能更好地预测接受低强度抗凝治疗的中国患者人群的华法林剂量。     

Paper-based dosing algorithms for maintenance of warfarin anticoagulation

We examined the quality of anticoagulation produced by two paper-based warfarin dosing algorithms in a randomized clinical trial of warfarin therapy. Fifty-eight patients were randomized to receive warfarin at a target international normalized ratio (INR) range of 2.1–3.0 and were followed for an average of 2.7 years. As a proportion of total patient-time, the percentage of time spent above, within, and below the therapeutic range was 11%, 71%, and 19% respectively. Fifty-six patients were randomized to receive warfarin at a higher target INR range (3.1–4.0) and had INRs within the therapeutic range for 40% of total patient time. We conclude that the performance, minimal cost, and ease-of-use of these algorithms make them well-suited for patient management within primary-care and research settings. Dr Crowther is a Career Investigator of Heart and Stroke Foundation of Canada This study was supported by the Canadian Institutes for Health Research.     

Significance of hyponatremia in heart failure

Heart failure is one of the most common, costly, disabling and growing diseases (McMurray and Pfeffer in Lancet 365(9474):1877–1889, 2005). Hyponatremia, conventionally defined as a serum-sodium concentration equal or less than 135 mmol/l (American Heart Association in Heart disease and stroke statistics—2007 update. American Heart Association, Dallas, 2007; Stewart et al. in Eur J Heart Fail 4:361–371, 2002), is a common phenomenon in patients with heart failure, with an incidence of 20–25% (Krumholz et al. in Arch Intern Med 157:e99–e104, 1997; Rosamond et al. in Circulation 117(4):e25–e146, 2008; Adrogue and Madias in N Engl J Med 342:1581–1589, 2000) and seems to be of prognostic importance in patients with heart failure (Luca et al. in Am J Cardiol 96:19L–23L, 2005; Gheorghiade et al. in Eur Heart J 28:980–988, 2007; Gheorghiade et al. in Arch Intern Med 167:1998–2005, 2007). So far treatment strategies have been limited and burdened by side effects. The development of hyponatremia in the setting of heart failure is related to the arginine vasopressin (AVP) dysregulation. Thus, AVP receptor antagonists are a promising approach to treatment. However, several questions remain: whether there is a cause-and-effect mechanism, if the correction of hyponatremia improves outcomes, and defining the specific cut-off level of serum-sodium that should be used to define hyponatremia. In this review, we aim to summarize the literature on hyponatremia in patients with heart failure within several aspects: incidence in clinical trials and registries, prognostic value, underlying mechanisms, therapeutic options, and possible future perspectives.     

Genetic Testing Before Anticoagulation? A Systematic Review of Pharmacogenetic Dosing of Warfarin

Background  Genotype-guided initial warfarin dosing may reduce over-anticoagulation and serious bleeding compared to a one-dose-fits-all dosing method. Objective  The objective of this review was to investigate the safety and efficacy of genotype-guided dosing of warfarin in reducing the occurrence of serious bleeding events and over-anticoagulation. Data Sources  The authors searched PubMed, EMBASE and International Pharmaceutical Abstracts through January 23, 2009, without language restrictions. Selected articles were randomized trials comparing pharmacogenetic dosing of warfarin versus a “standard” dose control algorithm in adult patients taking warfarin for the first time. Review Methods  Two reviewers independently extracted data and assessed study quality using a validated instrument. The primary outcomes were major bleeding and time spent within the therapeutic range International Normalized Ratio (INR). Secondary outcomes included minor bleeding, thrombotic events and other measures of anticoagulation quality. Results  Three of 2,014 studies (423 patients) met the inclusion and exclusion criteria. Differences in study quality, dosing algorithms, length of follow-up and outcome measures limited meta-analysis. Summary estimates revealed no statistically significant difference in bleeding rates or time within the therapeutic range INR. The highest quality study found no significant difference in primary or secondary outcomes, although there was a trend towards more rapid achievement of a stable dose (14.1 vs. 19.6 days, p = 0.07) in the pharmocogenetic arm. Conclusions  We did not find sufficient evidence to support the use of pharmacogenetics to guide warfarin therapy. Additional clinical trials are needed to define the optimal approach to use warfarin pharmacogenetics in clinical practice. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

A case report of acute lymphoblastic leukemia complicated by lactic acidosis

Type B lactic acidosis (LA) is a distinct form of metabolic acidosis characterized by low blood pH (≤7.35) accompanied by accumulation of lactate (blood concentration ≥ 5 mmol/L) (Luft et al. in Am J Clin Pathol 80:484–489, 1983). There are two types of LA that are caused by different mechanisms. Type A is more common, and is caused by the lack of oxygen (tissue hypoxia or hypoperfusion). In this case, impaired cellular respiration leads to lower pH level and at the same time the cells are forced to metabolize glucose anaerobically, which leads to increased production of lactate. The other type, Type B, is relatively rare, and is occasionally found in patients with hematological malignancies, such as leukemia or lymphoma. The molecular mechanism of Type B LA is not fully understood. Here, we report a case of precursor B cell acute lymphoblastic leukemia who initially shows manifestations of Type B LA and bilateral renal enlargement.     

Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study

Background Warfarin has a narrow therapeutic range and wide inter-individual dosing requirements that may be related to functional variants of genes affecting warfarin metabolism (i.e., CYP2C9) and activity (i.e., vitamin K epoxide reductase complex subunit 1-VKORC1). We hypothesized that variants in these two genes explain a substantial proportion of variability in stable warfarin dose and could be used as a basis for improved dosing algorithms.Methods Consecutive consenting outpatients (n = 213) with stable INR (2–3) for >1 month were enrolled. Buccal DNA was extracted using a Qiagen mini-column and CYP2C9*2 and VKORC1 genotyping performed by the Taqman 3′ nuclease assay. Sequencing for CYP2C9*3, genotyping was done using Big Dye v3.1 terminator chemistry Dose by genotype was assessed by linear regression.Results Weekly warfarin dose averaged 30.8 ± 13.9 mg/week; average INR was 2.42 ± 0.72. CYP2C9*2/*3 genotype distribution was: CC/AA (wild-type [WT]) = 71.4%, CT/AA = 18.3%, CC/AC = 9.4%, and CT/AC = 1%; VKORC1 genotypes were CC (WT) = 36.6%, CT = 50.7%, and TT = 12.7%. Warfarin doses (mg/week) varied by genotype: for CYP2C9, 33.3 mg/week for WT (CC/AA), 27.2 mg/week for CT/AA (P = 0.04 vs. WT), 23.0 mg/week for CC/AC (P = 0.003), and 6.0 mg/week for CT/AC (P < 0.001), representing dose reductions of 18–31% for single and 82% for double variant carriers; for VKORC1: 38.4 mg/week for WT (CC), 28.6 mg/week for CT (P < 0.001 vs. WT), 20.95 mg/week for TT (P < 0.001). In multiple linear regression, genotype was the dominant predictor of warfarin dose (P = 2.4 × 10⁻¹⁵); weak predictors were age, weight, and sex. Genotype-based modeling explained 33% of dose-variance, compared with 12% for clinical variables alone.Conclusion In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18–72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications.     

Initiation of warfarin therapy

In a prospective, randomized study at two university hospitals, the authors examined how effectively housestaff physicians (n=36) managed the initiation of warfarin therapy compared with a computer-assisted dosing regimen (n=39) using the software program Warfcalc, which was managed by one of the authors. Target prothrombin time ratios were selected by the physicians. Study endpoints included: the time to reach a therapeutic prothrombin ratio, the time to reach a stable therapeutic dose, the number of patients transiently overanticoagulated, the number of bleeding complications, and the accuracy of the predicted maintenance dose, which was assessed at steady-state 10–14 days later. Computer-assisted dosing consistently outperformed the physicians: a stable therapeutic dose was achieved 3.7 days earlier (p=0.002), fewer patients were overanticoagulated (10% versus 41%), and the predicted maintenance dose was in the therapeutic range in 85% of the computer-dosed patients versus 42% of the physician group (p<0.002). For physicians who did not routinely manage warfarin therapy, computer-assisted dosing improved the accuracy of dosing and shortened the time required to achieve a stable therapeutic dose. Presented at the annual meeting of the Society for Research and Education in Primary Care Internal Medicine, Washington, D.C., May 2, 1986.     

Oral anticoagulation in the hospital: analysis of patients at risk

Warfarin is one of the most commonly used medications associated with adverse events. Warfarin therapy is often initiated or continued in the hospital, yet hospitalization increases the risk of poor anticoagulation control with warfarin. To help understand this, we retrospectively reviewed the records of patients admitted to our hospital during a 6-month period who were given at least one dose of warfarin. To explore factors that may have contributed to poor anticoagulation control, we compared characteristics of patients with an international normalized ratio (INR) ≥5 at some point during hospitalization with those of a group of matched controls who also received warfarin and had INR <5. Among the 35 patients identified who had an INR ≥5, concomitant use of antibiotics was more common than among 105 matched controls; improper warfarin dosing also appeared to contribute to the high INRs. These findings indicate possible targets for intervention to improve patient safety.     

Rheumatoid arthritis in patient with homozygous haemoglobin C disease

To date, few cases of hemoglobinopathies in patients with rheumatoid arthritis (RA) have been reported (Marino and Mcdonald in J Rheumatol 17:970–972, 1990; Gladman and Bombardier in Arthritis Rheum 30:1065–1068, 1987; Michel et al. in Semin Arthritis Rheum 38:228–240, 2008). These haemoglobin diseases are associated with characteristics abnormalities of the skeleton. Haemoglobin C disease is a benign hemoglobinopathy rarely associated with skeletal disorders [Piéron et al. in la semaine des h?pitaux 57(1–2):22–25, 1981]. We report a case of RA in a 60-year-old woman with homozygous haemoglobin C disease. This coexistence may be a pure coincidence, although we discuss the difficulties with RA treatment in this case due to the unknown effect of anti-rheumatic drugs on the progression of haemoglobin C disease.     

影响中国汉族≥75岁老年口服华法林病人IWPC预测模型准确性的相关因素

目的 探讨影响≥75岁老年病人国际华法林药物基因组协会(IWPC)预测模型准确性的相关因素,为≥75岁病人更合理地应用华法林提供参考.方法 收集≥75岁口服华法林抗凝治疗的老年病人的临床资料,根据预测剂量与实际剂量间的差异率分为差异轻微组、差异一般组和差异显著组,比较各组性别、年龄、BMI、血压、心率、合并疾病及合并用...     

Pharmacogenetics of warfarin treatment for potential clinical application

Warfarin anticoagulation therapy requires extensive medical supervision and empirical adjustments of dose to achieve the narrow therapeutic window and avoid complications. Developments in understanding the genetic basis for interindividual differences in warfarin dose requirements have led to the discovery of polymorphisms in two genes: cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1). Genotyping these variants in patients who use warfarin could possibly help guide dosing. Numerous retrospective clinical studies have shown these polymorphisms to have large, independent effects on the pharmacokinetic and pharmacodynamic warfarin pathways, stabilized dose, and other clinical outcomes. From these studies, dosing algorithms based on patient, clinical, and genetic factors have been developed. Multicenter, randomized clinical studies are planned to further validate these findings and determine the utility of prospective genetic testing as a central component of warfarin management. Pending these results, warfarin genetic testing could be the first example of the widespread application of pharmacogenetics in the era of “personalized medicine.”     

Validity of current recommendation for peri-operative interruption of warfarin in Asians

Temporary interruption of anticoagulation therapy is usually recommended for anticoagulated patients undergoing invasive procedures to minimize their bleeding risks. We validated the current consensus recommendation on warfarin interruption which were based on Western population studies to determine if they could safely be applied to Asians. The international normalized ratios (INR) in twenty warfarinised patients with a stable INR of 2–3 were prospectively measured at days 0, 3 and 5 after stopping warfarin for procedures or at completion of treatment. The median INR at days 0, 3 and 5 were 2.30 (95% CI 2.16–2.43), 1.32 (95% CI 1.22–1.57) and 1.06 (95% CI 1.05–1.13) respectively (P < 0.001 for trend). All patients were below therapeutic INRs by day 3 with 14 patients (70%, 95% CI 49.92–90.08) achieving INR readings below 1.5. By day 5, all INRs were below 1.5 and only 2 patients (10%, 95% CI −3.15 to 23.15) had INRs above 1.2. There were no significant peri-procedure bleeding or thrombotic events in the 1 month following interruption of warfarin. Our results suggest that the current international recommendation of stopping warfarin for 5 days prior to procedure can safely be applied to Asians without compromising risk of bleeding or thrombosis.