Mean Warfarin Dose Research Articles

Interaction between Warfarin and Linezolid in Patients with Left Ventricular Assist System in Japan.

The purpose of this study was to investigate the possible interaction between warfarin and linezolid in patients with a left ventricular assist system (LVAS) for the treatment of severe heart failure. Patients with LVAS who were treated with linezolid for the treatment of infections from January 2003 to March 2013 were identified from medical records. The impact of linezolid on the clotting function, as well as the dose of warfarin during the first 10 days of linezolid therapy, was investigated. The mean prothrombin time-international normalized ratio (PT-INR) and mean doses of warfarin during 7 days before and 10 days after the initiation of linezolid therapy were calculated for individual patients. The PT-INR per mg of WF dose on the previous day (X) was calculated. The warfarin dose, PT-INR, and warfarin sensitivity index (WSI) value before and after the initiation of linezolid were compared to evaluate the impact of linezolid on the effect of warfarin. Sixteen patients were enrolled in the study. Although the mean PT-INR increased from 3.74 to 4.06, no significant difference was observed (p=0.05). A significant difference was observed in the mean dose of warfarin before and after the initiation of linezolid administration, with a decrease from 3.23 to 2.69 mg/day (p=0.001). In contrast, the mean WSI value significantly increased from 1.37 to 1.82 (p=0.014). After 10 days of linezolid administration, the mean X values increased over the baseline value by 31.7%. These findings suggest that co-administration of linezolid results in increased PT-INR in patients with LVAS treated with warfarin.

The potential drug-drug interaction between proton pump inhibitors and warfarin.

Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values. The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test. We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63-78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5-2.8) and 2.6 (95%CI 2.5-2.7) in the period 1-3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs. We found no evidence of a clinically meaningful drug-drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to "cautiously monitor" users of warfarin initiating PPI treatment.

Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome.

Warfarin is the most widely prescribed anticoagulant drugs. Cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase-oxidaxe complex subunit 1 (VKORC1) contribute significantly to the variability of warfarin dose requirements among patients. We investigated the impact of CYP2C9 and VKORC1 polymorphisms on the variability of warfarin dosage requirements in Egyptian patients with acute coronary syndrome and their association with other nongenetic factors. Eighty participants with acute coronary syndrome were enrolled in this cross-sectional study. Associations between CYP2C9 and VKORC1 gene variants together with daily warfarin dose, demographic data, clinical status of patients and time to target international normalized ratio were assessed. Mean warfarin dose among patients with wild-type CYP2C91/1 genotype was significantly higher than heterozygous CYP2C91/2 and CYP2C91/3 variants (P ≤ 0.001). Patients with wild VKORC1 (G/G) genotype were treated with significantly higher daily warfarin dosages than homozygous (A/A) and heterozygous (G/A) genotypes. Patients carrying VKORC1 (G/G) genotype in combination with the CYP2C91/1 type alleles had the highest daily warfarin dosage, whereas the lowest daily warfarin dosage to achieve the required clinical effect was found among patients having CYP2C91/2 and CYP2C91/3 genotypes combined with VKORC1 (A/A) genotype (P ≤ 0.001). Regression analysis revealed that age, height, CYP2C9 and VKORC1 genotypes were significantly associated with warfarin dose. Genetic polymorphisms in VKORC1, CYP2C9 along with age and height are determinants of warfarin dose requirements in Egyptian population acute coronary syndrome. Higher warfarin loading dose is required for both wild CYP2C9 and VKORC1 gene variants which may contribute to warfarin-resistant cases.

Prevalence of Warfarin Genotype Polymorphisms in Patients with Mechanical Circulatory Support.

Polymorphisms for VKORC1 and CYP2C9 are associated with increased warfarin sensitivity. The prevalence of these polymorphisms in patients with mechanical circulatory support (MCS) is unknown. Polymorphisms for VKORC1 and CYP2C9 were determined in 65 patients undergoing MCS surgery. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). A total of 67.7% (44/65) had at least one polymorphism: VKORC1 (44.6%), CYP2C9*2 (7.7%), CYP2C9*3 (4.6%), CYP2C9*2 and VKORC1 (3.1%), or CYP2C9*3 and VKORC1 (7.7%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.21 ± 1.47 vs. 5.57 ± 3.72 mg, p = 0.015) and achieved a similar mean INR (2.20 ± 0.67 vs. 2.19 ± 0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). One or more polymorphisms for VKORC1 or CYP2C9 (associated with warfarin sensitivity) were found in 67.7% of MCS patients. By using a warfarin genotype-guided approach, MCS patients with polymorphisms received a lower warfarin dosage to achieve a similar INR, with similar bleeding rates, in comparison with no polymorphisms. A warfarin genotype-guided approach avoided excessive anticoagulation and its attendant bleeding risks.

Interethnic variability of CYP4F2 (V433M) in admixed population of Roma and Hungarians

AimsPharmacogenetic based dosing recommendations are provided in FDA-approved warfarin label for Caucasians. Evidence of notable difference in dosing algorithms of under-represented populations forced us to explore the genetic variability of CYP4F2 gene in Roma and Hungarian populations. Patients and methods484 Roma, 493 Hungarian untreated subjects were genotyped for the CYP4F2*3 (rs2108622) variant by PCR-RFLP assay. Results and discussionWe firstly report, that frequencies of the CYP4F2 rs2108622 GG, GA, AA genotypes and A allele in the Roma population were 46.5%, 42.6%, 10.9% and 32.2%; in Hungarians 50.1%, 42.2%, 7.7% and 22.8%, respectively. Bearing of two minor alleles of CYP4F2 missense variant (AA genotype) modestly explains inter-ethnic differences of studied populations (p<0.08). CYP4F2*3 (V433M) risk allele frequency of Roma (0.32) was in higher range, and of Hungarians (0.23) in lower range, as compared with other world populations. ConclusionsRoma have an elevated chance for higher mean warfarin dose, besides a decreased risk of major bleeding events in long-term warfarin use.

VKORC1 and CYP2C9 genotypic data-based dose prediction alone does not accurately predict warfarin dose requirements in some Malaysian patients.

VKORC1 and CYP2C9 genetic polymorphisms may not accurately predict warfarin dose requirements. We evaluated an existing warfarin dosing algorithm developed for Malaysian patients that was based only on VKORC1 and CYP2C9 genes. Five Malay patients receiving warfarin maintenance therapy were investigated for their CYP2C9*2, CYP2C9*3, and VKORC1-1639G>A genotypes and their vitamin K-dependent (VKD) clotting factor activities. The records of their daily warfarin doses and international normalized ratio (INR) 2 years prior to and after the measurement of VKD clotting factors activities were acquired. The mean warfarin doses were compared with predicted warfarin doses calculated from a genotypic-based dosing model developed for Asians. A patient with the VKORC1-1639 GA genotype, who was supposed to have higher dose requirements, had a lower mean warfarin dose similar to those having the VKORC1-1639 AA genotype. This discrepancy may be due to the coadministration of celecoxib, which has the potential to decrease warfarins metabolism. Not all patients' predicted mean warfarin doses based on a previously developed dosing algorithm for Asians were similar to the actual mean warfarin dose, with the worst predicted dose being 54.34% higher than the required warfarin dose. Multiple clinical factors can significantly change the actual required dose from the predicted dose from time to time. The additions of other dynamic variables, especially INR, VKD clotting factors, and concomitant drug use, into the dosing model are important in order to improve its accuracy.

Low Dose Oral Vitamin K Does Not Increase Time in Therapeutic Range: Results of a Multicentre Clinical Trial

Warfarin remains the most commonly used oral anticoagulant. Its efficacy is closely correlated with the time in therapeutic range (TTR) of the international normalized ratio (INR). Excellent anticoagulant management systems can achieve TTRs in excess of 80%: however, in day-to-day clinical practice TTR values in the range of 50 to 60% are more commonly seen. Strategies to increase TTR are widely sought; one such intervention is the daily administration of low dose vitamin K (VK) administered to reduce variations in VK intake and thus reduce fluctuations in the INR due to such variability. In this multicentre, blinded, randomized controlled trial we allocated patients on chronic warfarin therapy to receive either 0.150 mg of daily oral VK, or matching placebo. After a one month “run in period” to allow adjustment of the warfarin dose, patients were followed for a maximum of 9 months (mean 6 months), their INR was determined, their TTR calculated and their mean warfarin dose calculated. A total of 253 patients were enrolled at 4 clinical centres between Aug 19, 2010 and Aug 30, 2013; 18 (9 in each group) were excluded from this analysis due to inadequate follow-up data, mostly as a result of withdrawal from the study during the run in period. Of the 117 analyzable patients allocated to VK, 66 were male (average age 66.9 yrs). Of the 118 analyzable patients allocated to placebo 59 were male (average age 65.7 yrs). Indications for warfarin were similar between the two groups, as was the frequency of renal insufficiency and the presence of cancer. Patients allocated to placebo were more likely to report a history of bleeding (7% vs 3%). Mean TTR over the 6 months prior to enrollment to the study was 54.6% in the placebo group, and 51.8% in the VK group. Mean TTR over an average follow-up of 6 months after completion of the 1 month run-in period was 66% in the placebo group, and 65.1% in the VK group. We conclude that inclusion in this study resulted in a statistically (and likely clinically) significant improvement in the TTR. The improvement in the TTR we observed appeared to be predominately as a result of attentive clinical management, rather than administration of VK. Our findings do not support the use of daily, low dose oral vitamin K administered in an effort to improve TTR. DisclosuresCrowther:Portola: Consultancy; Leo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; AKP America: Consultancy; Heart and Stroke Foundation: Career Investigator award Other; Celgene: Honoraria; Shire: Honoraria; CSL Behring: Honoraria. Lazo Langer:Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Alexion: Research Funding; Daichii Sankyo: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Yeo:Bayer: Honoraria. Schulman:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding.

An evaluation of the potential drug interaction between warfarin and levothyroxine

Drug interaction references report that initiation of levothyroxine potentiates the effects of warfarin, and recommend more frequent International Normalized Ratio (INR) monitoring, but the mechanism is not well understood. To assess the impact of levothyroxine initiation on INR response. A retrospective, self-controlled study was performed on patients aged ≥ 18 years receiving chronic warfarin therapy who were started on levothyroxine between 1 January 2006 and 30 June 2013, and who were followed for 90 days prior to and after levothyroxine initiation. The included patients had at least one elevated thyroid-stimulating hormone laboratory value in the pre-period, continuous warfarin therapy for 100 days prior to levothyroxine initiation, no purchases of medications known to interact with warfarin, no procedures requiring warfarin interruption, and no bleeding or thromboembolic event during the study period. The primary outcome was a comparison of the warfarin dose/INR ratio recorded before the initiation of levothyroxine with the ratio recorded during the post-period after two consecutive INRs with no warfarin dose change. One hundred and two patients were included in the primary outcome. The mean warfarin dose/INR ratios in the pre-period and post-period were equivalent (P = 0.825). Although the mean warfarin dose was numerically lower in the post-period than in the pre-period, this difference did not reach statistical significance (P = 0.068). No difference in the mean warfarin dose/INR ratio before and after initiation of levothyroxine was detected. The results suggest that there is not a clinically significant interaction between warfarin and levothyroxine, and so additional monitoring may not be necessary.

Effect of CYP2C9 and VKORC1 genetic variations on warfarin dose requirements in Indian patients

BackgroundWarfarin, an oral anticoagulant is used in patients who are at increased risk of developing blood clots. The management of warfarin therapy is challenging because it shows large inter and intra individual variability in patient response due to factors like age, gender, diet, concurrent drug interactions and variations in CYP2C9 and VKORC1 genes. Studies implicate that polymorphisms in VKORC1 and CYP2C9 genes are associated with reduced doses of warfarin. The aim of our current study was to characterize the effects of VKORC1 and CYP2C9 gene variations that contribute to variability in warfarin dosing in Indian patients. MethodsGenomic DNA was extracted from 103 patients undergoing warfarin therapy. Their mean daily warfarin dose, INR and demographics were recorded and genotyping of VKORC1 and CYP2C9 gene was performed by PCR-RFLP method. ResultsIndividuals with wild type genotypes required highest mean warfarin dosage of 4.72mg/day while VKORC1 variants required 3.6mg/day to maintain their therapeutic INR. CYP2C9*2 genotype was not found to affect the warfarin maintenance dosages. The odds ratio for developing supra therapeutic INR in patients carrying VKORC1 variant allele when compared to wild types was 13.96 (95% CI; 4.85 – 44.65. Other factors affecting warfarin dosages were age and weight. ConclusionInclusion of pharmacogenetic data along with clinical parameters would help better predict warfarin doses in Indian patients.

Setting an International Normalized Ratio (INR) Target Range doesn’t Guarantee Good Achievement of that Range-A Study in Omani Patients and Review of Literature

Abstract Background: Effective management of warfarin dose to get therapeutic range of International Normalized Ratio (INR) is complex. The present study was designed to know the quality of warfarin control. Methods: We consecutively enrolled 113 patients taking warfarin. Two groups of patients were divided according to different settings of therapeutic INR. We compared their time in therapeutic range in these two groups. Results: Totally 113 patients, with 1976 INR tests, were enrolled. Total follow-up period was 188.4 patient-years. Group A included 25 patients, with mean age 43.4 ± 16.0 years, mean INR 2.96 ± 1.61, and mean warfarin dose 4.69 ± 2.03 mg. Group B included 88 patients with mean age 52.7 ± 16.7 years, mean INR 2.67 ± 2.16, and mean warfarin dose 4.80 ± 2.44 mg. One hundred fifty-four (32.8%) INRs were within the target range of 2.5-3.5 in Group A; whereas 533 (35.4%) INRs were within the target range of 2-3 in Group B. Although the target INR in Group A was set in 2.5 to 3.5, 187 (39.8%) INRs were found in the range of 2-3, which was more than those in the range of 2.5 to 3.5 (39.8% vs 32.8%) in the same group. Moreover, the percentage of INR range from 2-3 in Group A, which was originally set with INR range of 2.5-3.5, was more than the percentage found in Group B (39.8% vs 35.4%) whose INR range was set in 2-3. Conclusions: Setting an INR target range followed by monitoring it in a specialist clinic is not enough to achieve the ideal target range.

CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism Regulates mRNA Expression in Human Livers

CYP2C9 is involved in metabolism of nearly 25% of clinically used drugs. Coding region polymorphisms CYP2C9*2 and *3 contribute to interperson variability in drug dosage and clinical outcomes, whereas the role of a regulatory polymorphism remains uncertain. Measuring allelic RNA expression in 87 human liver samples, combined with genotyping, sequencing, and reporter gene assays, we identified a promoter variable number tandem repeat polymorphism (pVNTR) that fully accounted for allelic CYP2C9 mRNA expression differences. Present in three different variant forms [short (pVNTR-S), medium (pVNTR-M), and long (pVNTR-L)], only the pVNTR-S allele reduced the CYP2C9 mRNA level compared with the pVNTR-M (reference) allele. pVNTR-S is in linkage disequilibrium with *3, with linkage disequilibrium r(2) of 0.53 to 0.75 in different populations. In patients who were taking a maintenance dose of warfarin, the mean warfarin dose was associated with the copies of pVNTR-S (p = 0.0001). However, in multivariate regression models that included the CYP2C9*3, pVNTR-S was no longer a significant predictor of the warfarin dose (p = 0.60). These results indicate that although pVNTR-S reduced CYP2C9 mRNA expression, the in vivo effects of pVNTR-S on warfarin metabolism cannot be separated from the effects of *3. Therefore, it is not necessary to consider pVNTR-S as an additional biomarker for warfarin dosing. Larger clinical studies are needed to define whether the pVNTR-S has a minimal effect in vivo, or whether the effect attributed to *3 is really a combination of effects on expression by the pVNTR-S along with effects on catalytic activity from the nonsynonymous *3 variant.

Influence of CYP4F2 rs2108622 (V433M) on Warfarin Dose Requirement in Asian Patients

Warfarin exhibits wide interpatient variability in dosing requirements. Recent studies have shown a novel polymorphism (rs2108622, V433M) in the CYP4F2 gene to be associated with variability in warfarin requirements in Caucasians. The purpose of this study was to evaluate the impact of rs2108622 on warfarin dose requirements in the Asian population. The mean warfarin dose was found to be significantly lower in patients carrying homozygous wild-type allele CC when compared with patients carrying variant alleles CT and TT (CC vs CT+TT: 3.0 mg/day vs 3.75 mg/day, p = 0.033). In patients harboring VKORC1 diplotypes associated with low warfarin requirements, a linear regression model which included age, weight, CYP2C9 and CYP4F2 variants accounted for 38% of the variability in warfarin dose. Approximately 11% of the dose variation was explained by CYP4F2 rs2108622 (p = 0.004). The influence of rs2108622 in patients harboring VKORC1 diplotypes associated with high warfarin requirements was not significant. This study suggests that CYP4F2 rs2108622 may significantly affect warfarin dose requirements in carriers of VKORC1 low-dose-associated diplotypes.

Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations

Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p < 0.001). VKORC1 GG genotype was more commonly seen in Indian patients. The mean warfarin dose in patients with GG genotype required a significant higher warfarin dose compared with those with AG and AA genotype (4.9 vs. 3.7 vs. 3.1 mg, respectively; p < 0.001). CYP2C9*2 and *3 is associated with a lower maintenance dose, 2.9 versus 3.7 mg in CYP2C9*1; p < 0.01. In multivariate analysis, age, ethnic groups, and genotypes had a significant influence on the required warfarin dose. In conclusion, VKORC1 and CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.

The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: A cross-sectional study in Iran

Background: Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and treatment of venous and arterial thromboembolic disorders. Its anticoagulant effect is widely variable between patients because of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors. Objective: This study was conducted to identify the associations between demographic characteristics, warfarin maintenance dose, and genetic polymorphisms of cytochrome P450 (CYP) 2C19, CYP2C9, and vitamin K epoxide reductase complex subunit 1 (VKORC1). Methods: This study was conducted from April 2005 to April 2008 at 3 warfarin clinics affiliated with Shiraz University of Medical Sciences. Blood samples were collected from patients with stable warfarin maintenance dose and a stable target international normalized ratio of 2 to 3. Patients who had a condition (including use of an interacting medication) affecting the metabolism of warfarin were excluded. CYP2C9, CYP2C19, and VKORC1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. The associations between demographic characteristics (eg, age, sex, body surface area, weight, height), genetic factors, and maintenance warfarin dose were examined by multiple linear regression. The probability of F as a criterion for removal of a variable from the multiple linear regression was set at 0.1. Results: One hundred patients were enrolled in the study; complete data were available for 55, who were included in the regression analysis. Among this smaller group, the mean (SD) age was 53 (11) years (range, 25–80 years) and mean weight was 72 (15) kg (range, 42–125 kg); the mean warfarin dose was 27.2 (13.4) mg/week. The allelic frequencies of CYP2C9*2 and CYP2C9*3 were 27% and 9%, respectively. The allelic frequencies of CYP2C19*2 and CYP2C19*3 were 11% and 1%, respectively. Fifteen percent of our patients carried a VKORC1 genotype GG, whereas the AA and GA genotypes were seen in 18% and 58% of patients, respectively. Multiple linear regression analysis found that sex ( P = 0.045), height ( P = 0.024), age ( P = 0.081), and VKORC1 ( P = 0.004) and CYP2C9 ( P = 0.011) polymorphism had significant influence on the maintenance dose of warfarin. They were associated with 41.3% of the variability in warfarin maintenance dose requirement. VKORC1 polymorphism (partial R 2 = 20.3%) and height (partial R 2 = 20.3%) had the greatest effects on warfarin maintenance dose requirement. Conclusion: Among the demographic and genetic factors evaluated in these Iranian patients, sex, height, age, CYP2C9, and VKORC1 had significant effects on warfarin maintenance dose requirements.

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application

Warfarin is a widely used oral anticoagulant with broad within- and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice. We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations. The mean maintenance dose of warfarin in 105 patients was 4.1 +/-1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3+/-0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r(2)=0.259, P<0.001) was higher than that with INR (r(2)=0.029, P=0.072). There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment.

Prediction of the warfarin maintenance dose after completion of the 10 mg initiation nomogram: do we really need genotyping?

Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients. Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule. Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose (r = 0.88, P < 0.0001). The mean difference between observed and predicted dose was not clinically significant: -0.1 +/- 1.1 mg. In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.

Relationship between VKORC1-1639G/A, CYP2C9-2 and -3 polymorphisms and warfarin dosage in Chinese

Objective To investigate the relationship between the VKORC1-1639G/C polymorphism and warfarin dosage in Chinese. Methods VKORC1-1639G/A and CYP2C9-2 and -3 polymorphisms were detected by Taqman real time PCR technology in 92 warfarin-treated patients. The mean warfarin dosage was compared according to different VKORC1genotypes. Results The frequencies of the VKORC-1639 AA, AG, and GG genotypes in the patient group were 8.8%, 14.1%, and 1.1% respectively. Due to low numbers of participants, the mean warfarin dosage was not significantly different among the VKORC1 genotypes, but the warfarin dosage/INR of G carriers (1.67±0.93 mg/INR) is much higher than those of A carriers (1.19±0.49 mg/INR). The frequencies of the CYP2C9 AA, AC, and CC genotypes in the patient group were 93.5%, 6.5%, and 0 respectively. There is one CT genotype in the CYP2C9-2 polymorphism. All genotypings are in HWE. Conclusions The high frequency of the VKORC1-1639 AA genotype might be a main cause of lower warfarin dosage in Chinese. For the polymorphism of CYP2C9-2, there are T carriers in the Chinese Han cohort. Objective To investigate the relationship between the VKORC1-1639G/C polymorphism and warfarin dosage in Chinese. Methods VKORC1-1639G/A and CYP2C9-2 and -3 polymorphisms were detected by Taqman real time PCR technology in 92 warfarin-treated patients. The mean warfarin dosage was compared according to different VKORC1genotypes. Results The frequencies of the VKORC-1639 AA, AG, and GG genotypes in the patient group were 8.8%, 14.1%, and 1.1% respectively. Due to low numbers of participants, the mean warfarin dosage was not significantly different among the VKORC1 genotypes, but the warfarin dosage/INR of G carriers (1.67±0.93 mg/INR) is much higher than those of A carriers (1.19±0.49 mg/INR). The frequencies of the CYP2C9 AA, AC, and CC genotypes in the patient group were 93.5%, 6.5%, and 0 respectively. There is one CT genotype in the CYP2C9-2 polymorphism. All genotypings are in HWE. Conclusions The high frequency of the VKORC1-1639 AA genotype might be a main cause of lower warfarin dosage in Chinese. For the polymorphism of CYP2C9-2, there are T carriers in the Chinese Han cohort.

Predisposing Preventable Factors in Patients With Bleeding due to Warfarin Usage: Evaluation of 114 Patients

Warfarin is one of the commonly used oral anticoagulant. The aim of our study is to evaluate the predisposing preventable factors among patients with bleeding due to warfarin usage. This study was performed on 114 cases who were admitted to emergency service for bleeding and whose ages range between 27 and 89 years. The mean time between the onset of the bleeding and admission to the hospital was 2.9 ± 3.4 days. The mean dose of warfarin being used at the time of admission was 31.2 ± 10.8 mg weekly. Only 37 cases were being controlled regularly. The mean number of the drugs being used other than warfarin was 4.8 ± 2.5 drugs. Forty-eight cases were using aspirin, 28 nonsteroidal anti-inflammatory drugs other than aspirin and 18 cases were using various antibiotics. Forty eight patients knew that they had to use this drug under the regular follow-up of a physician and 43 knew that during monitoring a laboratory test had to be done while using the drug named as warfarin. Only 39 patients knew that this drug may cause bleeding. It was also surprising that only 9 patients knew that there may be drug interaction and 1 knew that this drug may be affected from the dietary factors. As a result, it may be concluded that most of the patients admitting to the emergency service had a lack of basic knowledge about this drug, which might invite bleeding.

VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients

The objective of this study was to determine the quantitative influence of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP 2C9) polymorphisms on warfarin dose requirements in Turkish patients. A total of 205 patients taking warfarin for >2 months were enrolled in the study. Deoxyribonucleic acid (DNA) samples from these patients were genotyped for polymorphisms in VKORC1 and CYP2C9 genes. A linear regression analysis was used to determine the independent effects of genetic and non-genetic factors on mean warfarin dose requirements. The VKORC1 promoter polymorphism (3673 G>A) was associated with differences in weekly mean varfarin dose: for GG genotype the dose was 43.18 mg/week, for GA genotype 33.78 mg/week and for AA genoype 25.83 mg/week (P < 0.0001). Patients who carried VKORC1 and CYP2C9 variants needed a 40% lower mean weekly warfarin dose compared to wild types. Variables associated with lower warfarin dose requirements were VKORC1 3673 AA or GA genotype (both P < 0.0001), one or two CYP2C9 variant alleles (both P < 0.0001), increasing age (P < 0.0001) and non-indication of venous thromboembolism for warfarin therapy (P = 0.002). Polymorphisms in VKORC1 and CYP2C9 genes were important determinants of warfarin dose requirements in Turkish patients.

W1041 Using Patient Narratives Improves Awareness and Knowledge of Celiac Disease Amongst Physicians

history of SIBO; use of antimicrobial agents within the previous 3 months; no use of drugs potentially interacting with warfarin before or during the observation period. All pts were instructed to follow a standard dietological regimen to ensure constant oral vitamin K intake. Daily warfarin dosage was recorded in all pts during the month after enrolment. The weekly mean dose of warfarin was calculated. All pts underwent hydrogen lactulose breath test (LBT) in order to assess SIBO presence. Results: A total of 28 pts were enrolled. Eleven (11) out 28 pts showed positivity to LBT (39%). The weekly mean dosage of warfarin was significantly lower in SIBO-positive pts with respect to SIBO-negatives (43,9 daily mg vs 29,6 daily-mg, p<0.05). Conclusion: Our data suggest that SIBO is associated to a lower mean dosage of warfarin. These results appear hard to be clarified since the complex interaction between intestinal microflora and vitamin K. Previous studies show that SIBO results in the synthesis of MNQ but without consistent resistance to the effect of warfarin. However SIBO is a well known cause of malabsorption of several nutrients including vitamin K both consuming them and above all decreasing their absorption through the damaged small bowel mucosa. Further larger studies are needed to confirm these preliminary data and to assess the effects of SIBO decontamination on warfarin dosage.