Effects of imatinib on glycemic and lipid profiles: a retrospective cohort study.

Despite a favorable effect of imatinib on glucose metabolism in animal models, human reports are inconsistent. We retrospectively studied the long-term effect of imatinib on fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), LDL-cholesterol (LDL), and triglycerides (TGs) in a large HMO cohort of patients initiating therapy. In patients with diabetes (n = 118), significant reductions in HbA1c (0.53%, IQR 0.09, 1.19; p < .001) and FPG (10.2 mg/dL, IQR -3.5, 32.2; p < .001), independent of demographics and of glucose-lowering drugs utilization, were observed during the first year of imatinib treatment. Significant reductions in LDL (17.8 mg/dL, IQR -1.3, 34.0; p < .001) and TG (25.0 mg/dL, IQR -2.3, 58.3; p < .001), also independent of demographics and of statin utilization, were evident in the entire cohort (n = 611) during the first imatinib year. All reductions persisted during the second treatment year. To conclude, imatinib is associated with durable metabolic benefits, which may guide TKI choice in patients with cardiovascular co-morbidities.

Concomitant oral potassium chloride and anticholinergic therapy is associated with upper gastrointestinal bleeding: A cohort study.

AIM: To determine whether oral potassium chloride (KCI) therapy with concomitant anticholinergic exposure among hospitalized patients is associated with an excess risk for upper gastrointestinal bleeding (UGIB). METHODS: A retrospective controlled study among hospitalized patients between January 2007 and April 2019 who were treated with oral KCI. Patients were divided into two groups: with or without concomitant exposure to agents with anticholinergic activity. Outcome was defined as any UGIB. RESULTS: The final sample included 13 728 subjects who received oral KCI treatment, of them 3542 (25.8%) had at least one documented overlap with an anticholinergic agent. Mean age was 67.6 (±17.2) and 6893 (50.2%) were females. Median KCI dose was 2.4 g (interquartile range [IQR] 1.2-5.4, n = 9416) with the majority (90.4%) being treated with the wax-matrix form (Slow-K). Twenty-six (0.2%) patients experienced an UGIB event. Univariate analysis demonstrated a significantly higher rate of UGIB among patients concomitantly treated with oral KCI and anticholinergics (0.3%) compared to those without anticholinergic exposure (0.1%, P = 0.018), with median 7 days (IQR 3-16.8) from first KCI dose to bleeding event. Multivariate analysis demonstrated that concomitant anticholinergic exposure (Odds Ratio 2.48, 95% Confidence Interval 1.11-6.51, P = 0.022) and anticoagulation treatment among patients with hemato-oncologic disease (OR 6.61, 95% CI 1.96-22.25, P = 0.002) were significantly associated with UGIB. CONCLUSION: Hospitalized patients treated concomitantly with oral KCI and anticholinergic agents have significantly increased risk for UGIB.

Uninterrupted direct oral anticoagulant treatment during acute illness: Impact on clinical outcomes.

BACKGROUND: Uninterrupted drug therapy during acute illness is often associated with pharmacokinetic and pharmacodynamic variations. Among warfarin treated patients, these changes are reflected in the INR. However, in the case of direct oral anticoagulants (DOACs), given that routine laboratory monitoring is not recommended, these changes may result in unforeseen thromboembolic or bleeding events. OBJECTIVES: To determine the rate of thromboembolic (TEE) and bleeding events associated with uninterrupted DOAC compared to warfarin treatment during acute illness. METHODS: A retrospective cohort study of patients treated with DOACs or warfarin, both at steady state, who were hospitalized for acute illness. Primary outcome was any TEE or major bleeding requiring re-hospitalization within one month from discharge. Secondary outcome was a composite of major bleeding and clinically relevant non-major bleeding (CRNMB) events. RESULTS: A total of 410 patients continued oral anticoagulant treatment during their hospitalization, of whom 191 (46.6%) were on DOACs and 219 (53.4%) on warfarin, with a total of 18 (4.4%) events. Rates of TEE and major bleeding events did not differ between DOACs and warfarin treated patients (0.9% vs. 0.5% and 0.5% vs. 1%, respectively). Similarly, rate of secondary outcome was comparable between DOACs (4.7%) and warfarin (2.7%, p = 0.29). Sub-analyses demonstrated significantly higher rates among rivaroxaban (10.4%) treated patients compared to warfarin (p = 0.03). CONCLUSION: Uninterrupted treatment with DOACs during acute illness is not associated with increased risk for re-hospitalizations due to bleeding or thromboembolic events compared to warfarin. Our results suggest a higher bleeding rate among rivaroxaban treated patients at high bleeding risk.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

BACKGROUND: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. METHODS: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. RESULTS: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. CONCLUSION: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

Prescriber response to computerized drug alerts for electronic prescriptions among hospitalized patients.

BACKGROUND: Clinical decision support systems (CDSS) reduce prescription errors, but their effectiveness is reduced by high alert rates, "alert fatigue", and indiscriminate rejection. OBJECTIVES: To compare acceptance rates of alerts generated by the SafeRx® prescription CDSS among different alert types and departments in a tertiary care hospital, identify factors associated with alert acceptance, and determine whether alert overrides were justified. METHODS: In a retrospective study, we compared acceptance rates of all prescription alerts generated in 2013 in 18 departments of Israel's largest tertiary care center. In a prospective study in 2 internal medicine departments, we collected data on factors potentially associated with alert override, and an expert panel evaluated the justification for each overridden alert. We used multivariate analyses to examine the association between patient and physician-related factors and alert acceptance. RESULTS: In the retrospective study, of 390,841 prescriptions, 37.1% triggered at least one alert, 5.3% of which were accepted. Acceptance rates ranged from 7.9% for excessive dose alerts to 4.0% for duplicate drug and major drug-drug interactions alerts (p<0.001). In the prospective study, common reasons for alert overriding included "irrelevance to the specific condition" and "medication previously tolerated by the patient". Weekend shifts (incident rate ratio [IRR]=1.50 [95% CI, 1.01-2.22]) and a specific department (IRR=1.87 [1.23-2.87]) were associated with higher alert acceptance, while night shift (IRR=0.47 [0.26-0.85]) was associated with alert override. Most alert overrides (88.6%) were judged justified. CONCLUSIONS: The vast majority of SafeRx® alerts are overridden, and overriding is justified in most cases. Minimizing the number of alerts is essential to reduce the likelihood of developing "alert fatigue". Our findings may inform a rational, department-specific approach for alert silencing.

Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community.

BACKGROUND: In population studies, mild hypomagnesemia, determined by a single measurement, was associated with incident atrial fibrillation, over ~20 years of follow-up. We sought to determine whether mild (≤ 1.7 mg/dL) and moderate (≤ 1.5mg/dL) hypomagnesemia are temporally associated with increased incidence of atrial fibrillation (AF) in the community. METHODS: Health Maintenance Organization (HMO) database cohort study including beneficiaries with ≥ 1 serum magnesium measurement between 2004 and 2013. The follow-up period was defined from the first magnesium measurement to first listing in an AF registry (for cases) and December 2013 or date of death or loss to follow-up (for controls). We analyzed the association between serum magnesium quintiles, as well as the above clinically relevant hypomagnesemia thresholds, and incident AF using Cox proportional hazard regression analysis, adjusting for confounders. The association between serum magnesium and AF occurring within 3 months was also examined. RESULTS: Among 162,162 subjects, 2228 (1.4%) developed AF over a median follow-up of 25.3 months. Compared to the middle quintile the lowest magnesium quintile (≤ 1.9 mg/dL) had a significantly higher risk of AF (HR, 1.21; 95% CI: 1.07-1.37). Increased AF risk was also associated with mild (HR, 1.44; 95% CI: 1.20-1.73) and moderate hypomagnesemia (HR, 1.57; 95% CI: 1.14-2.15). No association was found when limiting the follow-up period to 3 months. CONCLUSIONS: In our study, hypomagnesemia was associated with incident AF over prolonged but not short-term follow-up periods, suggesting that this association may not be causal.

Implementation of a clinical decision support system for computerized drug prescription entries in a large tertiary care hospital.

BACKGROUND: Prescription errors are common in hospitalized patients and result in significant morbidity, mortality and costs. Electronic prescriptions with computerized physician order entry systems (CPOE) and integrated computerized decision support systems (CDSS providing online alerts) reduce prescription errors by approximately 50%. However, the introduction of CDSS is often met by opposition due to the flood of alerts, and most prescribers eventually ignore even crucial alerts ("alert fatigue"). OBJECTIVES: To describe the implementation and customization of a commercial CDSS (SafeRx) for electronic prescribing in Internal Medicine departments at a tertiary care center, with the purpose of improving comprehensibility and substantially reducing the number of alerts to minimize alert fatigue. METHODS: A multidisciplinary expert committee was authorized by the hospital administration to customize the CDSS according to the needs of six internal medicine departments at Sheba Medical Center. We assessed volume of prescriptions and alert types during the period February-August 2012 using the statistical functions provided by the CDSS. RESULTS: A mean of 339 +/- 13 patients per month per department received 11.2 +/- 0.5 prescriptions per patient, 30.1% of which triggered one or more CDSS alerts, most commonly drug-drug interactions (43.2%) and dosing alerts (38.3%). The review committee silenced or modified 3981 alerts, enhancing comprehensibility, and providing dosing instructions adjusted to the patient's renal function and recommendations for follow-up. CONCLUSIONS: The large volume of drug prescriptions in internal medicine departments is associated with a significant rate of potential prescription errors. To ensure its effectiveness and minimize alert fatigue, continuous customization of the CDSS to the specific needs of particular departments is required.

The association of proton pump inhibitors and hypomagnesemia in the community setting.

Evidence for the association between hypomagnesemia and proton pump inhibitors (PPIs), highlighted by the 2011 FDA Drug Safety Communication, rests mainly on studies in hospitalized patients. Our objectives were to determine the prevalence of hypomagnesemia and its association with PPIs in the community setting. We performed a retrospective cross-sectional analysis of a large health maintenance organization administrative database, including ambulatory patients with ≥1 serum magnesium concentrations between 2008 and 2011, the lowest referred to as "index magnesium." In cases with any (index magnesium ≤0.7 mmol/L) or severe (≤0.55 mmol/L) hypomagnesemia, we analyzed (vs. controls, >0.7 mmol/L) the association with PPI or H2 -blocker use during the 4-12 months preceding the index magnesium by logistic regression analysis, adjusting for confounders. Among 95,205 subjects, 5,696 (6.0%) had any hypomagnesemia, which was severe in 454 (0.5%), with twofold higher prevalences in those with established risk factors. PPI use during the 4 months preceding the index magnesium was more common in cases of any hypomagnesemia (adjusted OR = 1.66; 95% CI, 1.55-1.78) and severe hypomagnesemia (adjusted OR = 3.79; 2.99-4.82) than in controls without acid suppression. Hypomagnesemia remained significantly associated with PPI use when using H2 -blocker-users as reference (adjusted OR = 1.25 [P = 0.003] and 2.65 [P < 0.001] for any and severe hypomagnesemia, respectively). We conclude that hypomagnesemia is associated with PPI use in ambulatory patients.

The VKORC1 Asp36Tyr variant and VKORC1 haplotype diversity in Ashkenazi and Ethiopian populations.

The vitamin K epoxide reductase (VKORC1) is a key enzyme in the vitamin K cycle impacting various biological processes. VKORC1 genetic variability has been extensively studied in the context of warfarin pharmacogenetics revealing different distributions of VKORC1 haplotypes in various populations. We previously identified the VKORC1 Asp36Tyr mutation that was associated with warfarin resistance and with distinctive ethnic distribution. In this study, we performed haplotype analysis using Asp36Tyr and seven other VKORC1 markers in Ashkenazi and Ethiopian-Jewish and non-Jewish individuals. The VKORC1 variability was represented by nine haplotypes (V1-V9) that could be grouped into two distinct clusters (V1-V3 and V4-V9) with intra-cluster difference limited to two nucleotide changes. Phylogeny analysis suggested that these haplotypes could have developed from an ancestral variant, the common V8 haplotype (40 % in all population samples), after ten single mutation events. Asp36Tyr was exclusive to the V5 haplotype of the second cluster. Two haplotypes V5 and V4, distinguished only by Asp36Tyr, were prevalent in both Ethiopian population samples. The V2 haplotype, belonging to the first cluster, was the second most prevalent haplotype in the Ashkenazi population sample (15.8 %) but relatively uncommon in the Ethiopian origin (4.5-4.7 %). We discuss the genetic diversity among studied populations and its potential impact on warfarin-dose management in certain populations of African and European origin.

"Body packers" in Israel: a case series.

BACKGROUND: "Body packers" swallow multiple packets filled with illicit drugs, mainly cocaine, in order to smuggle them across international borders. In recent years, an increasing number of body packers have been hospitalized after their detention by the police upon arrival in Israel. OBJECTIVES: To characterize the clinical features and outcomes of body packers hospitalized at the Sheba Medical Center. METHODS: We conducted a retrospective case series of body packers hospitalized between January 2010 and October 2012 in our medical center. Electronic medical records and imaging files were reviewed to extract clinical, laboratory and radiological data as well as details on medical treatments. RESULTS: We identified 23 body packers (mean age 38 +/- 10 years), 20 of whom smuggled cocaine from South America. The number of packets transported ranged from 1 to 242 (median 42) and duration of hospitalization from 1 to 14 days (median 2). Two subjects required surgical intervention. All others were treated conservatively by polyethylene glycol-electrolyte lavage solution, laxatives, or watchful waiting. Ten patients underwent a urinary screen for illicit drugs, 7 of whom tested positive for cocaine and 2 for cannabinoids. Abdominal X-rays were performed in all patients at admission, and 14 had follow-up imaging, including abdominal CT scans without contrast media in 8. CONCLUSIONS: The main treatment goals for body packers are the rapid excretion of drug packets and early detection of complications, i.e., drug intoxication and bowel obstruction. We suggest the use of a structured treatment approach for the in-hospital management of body packers.

Effect of the VKORC1 D36Y variant on warfarin dose requirement and pharmacogenetic dose prediction.

Pharmacogenetic dosing algorithms help predict warfarin maintenance doses, but their predictive performance differs in different populations, possibly due to unsuspected population-specific genetic variants. The objectives of this study were to quantify the effect of the VKORC1 D36Y variant (a marker of warfarin resistance previously described in 4% of Ashkenazi Jews) on warfarin maintenance doses and to examine how this variant affects the performance of the International Warfarin Pharmacogenetic Consortium (IWPC) dose prediction model. In 210 Israeli patients on chronic warfarin therapy recruited at a tertiary care centre, we applied the IWPC model and then added D36Y genotype as covariate to the model (IWPC+D36Y) and compared predicted with actual doses. Median weekly warfarin dose was 35 mg (interquartile range [IQR], 24.5 to 52.5 mg). Among 16 heterozygous D36Y carriers (minor allele frequency = 3.8%), warfarin weekly dose was increased by a median of 43.7 mg (IQR, 40.5 to 47.2 mg) compared to non-carriers after adjustment for all IWPC parameters, a greater than two-fold dose increase. The IWPC model performed suboptimally (coefficient of determination R²=27.0%; mean absolute error (MAE), 14.4 ± 16.2 mg/week). Accounting for D36Y genotype using the IWPC+D36Y model resulted in a significantly better model performance (R²=47.2%, MAE=12.6 ± 12.4 mg/week). In conclusion, even at low frequencies, variants with a strong impact on warfarin dose may greatly decrease the performance of a commonly used dose prediction model. Unexpected discrepancies of the performance of universal prediction models in subpopulations should prompt searching for unsuspected confounders, including rare genetic variants.

Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins.

OBJECTIVE: Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin-induced myalgia, which was ameliorated by high-dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin-induced myalgia and elevation of serum creatine kinase (CK). DESIGN: Retrospective cohort study, based on the electronic database of a health maintenance organization. PATIENTS: Six thousand eight hundred and eight patients (71·5% women) to whom statins were dispensed during 2008 and who had ≥1 CK and 25-hydroxy vitamin D (25OHD) levels measured during statin exposure. Of these, 376 patients (5·5%) had switched from a first-line statin to atorvastatin because of muscle pain (n = 220) or other reasons (n = 156). Measurements; In the entire cohort, we compared serum CK levels among serum 25OHD quartiles. In addition, we compared CK and 25OHD levels among patients with myalgia, other switchers and nonswitchers. RESULTS: The median 25OHD level in the entire cohort was 21·8 ng/ml [interquartile range (IQR), 16·3-27·4]. CK levels were marginally lower in patients in the lowest 25OHD quartile [median CK (IQR) in 25OHD quartiles 1-4, 87 (61-130), 90 (65-131), 91 (65-132) and 91 (67-131) IU/ml, respectively; P = 0·007]. 25OHD levels in statin switchers were similar to those in nonswitchers; moreover, there were no differences in 25OHD among switchers with muscle pain and other switchers. CONCLUSION: Our findings do not support an association between low 25OHD levels and statin-induced myalgia or CK elevation.

Hyperkalemia and renal function during monotherapy and dual renin-angiotensin blockade in the community setting.

BACKGROUND: In controlled trials, dual therapy with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) is associated with hyperkalemia and decreased renal function, but there is no information about these adverse effects in clinical practice. OBJECTIVE: The aim of this study was to assess the incidence of hyperkalemia and decreased renal function during dual therapy (ACE-I plus ARB) in a community-based setting. METHODS: In a retrospective cohort database study, we identified patients who received ARBs added to ongoing ACE-I therapy and who had at least 1 measurement of serum creatinine and potassium during each treatment period. We compared rates of hyperkalemia (>5.5 mmol/L) during equal periods of monotherapy and dual therapy and the rate of a significant rise in serum creatinine (≥0.5 mg/dL) between study periods. We assessed the impact of potential confounders on outcomes by logistic regression analysis. RESULTS: Among 425 patients (median follow-up 19 months for each treatment period), hyperkalemia was 2-fold more common during dual therapy than monotherapy (11.1% and 5.6% of patients, respectively) (relative risk = 1.96; 95% CI, 1.22-3.14; P < 0.001). In 77 patients with reduced renal function on monotherapy (serum creatinine ≥1.5 mg/dL), the rate of hyperkalemia was 20.8/100 patient-years, resulting in a number needed to harm of 10.1 patients, compared with 52.6 patients among those with preserved renal function. Mean serum creatinine between treatment periods increased >0.5 mg/dL in 7.5% of patients, more commonly in patients with decreased (18.2%) than with preserved (5.2%) baseline renal function (P < 0.001). CONCLUSION: In the community setting, dual therapy was associated with hyperkalemia and a decrease in renal function. The absolute risks were especially high among patients with reduced baseline renal function.

Database evaluation of the effects of long-term rosiglitazone treatment on cardiovascular outcomes in patients with type 2 diabetes.

Recent meta-analyses suggest an increased risk of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) treated with rosiglitazone. These meta-analyses have drawn considerable criticisms. Retrospective observational studies do not consistently support this association. The objective of this study was to compare rates of adverse cardiovascular outcomes in T2DM patients treated with rosiglitazone alone or combined with metformin or metformin alone. This retrospective study, using the health maintenance organization database, included patients who were dispensed rosiglitazone (alone or with metformin) for at least 6 months as follows: rosiglitazone alone (n = 745), rosiglitazone and metformin (n = 2753), and metformin alone (n = 11 938). Adverse cardiovascular outcomes were new diagnosis of AMI, acute coronary syndrome (ACS), coronary revascularization (CRV), congestive heart failure (CHF), and all-cause mortality. Mean on-treatment follow-up was 30 months. After adjustment for covariates found to be significant in univariate analyses, rosiglitazone was associated only with CHF (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.41-1.95) with no increase of risk for AMI (HR = 1.13; 95%CI: 0.60-2.12), ACS (HR = 0.85; 95% CI: 0.57-1.26), coronary revascularization (HR = 1.22; 95% CI:0.82-1.54), or all-cause mortality (HR = 1.15; 95% CI: 0.85-1.56). In this community-based cohort, 30 months of therapy with rosiglitazone treatment was associated with increased risk of CHF but was not associated with increased risk of AMI, ACS, coronary revascularization, or all-cause mortality.

Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination.

High-dose busulfan (Bu) is frequently used in preparative myeloablative conditioning (MAC) regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). MAC and reduced-intensity conditioning (RIC) protocols for i.v. Bu infusion have been developed to achieve reliable systemic exposure while minimizing toxicity and treatment failure (relapse). The objectives of the present study were to (1) compare the pharmacokinetics (PK) of i.v. Bu in different dosing protocols, (2) compare intrasubject variability of Bu PK over repeated administrations; (3) examine the effect of concomitant administration of fludarabine on Bu PK, and (4) examine the effect of plasma concentrations of glutathione (GSH), the cosubstrate in Bu metabolism, on Bu clearance. We studied Bu PK twice in each of 46 HSCT patients (after the first and then after the middle dose of the treatment cycle) receiving one of 4 dosing protocols, 2 MAC (cumulative dose, 12.8 mg/kg) and 2 RIC (cumulative dose, 6.4 mg/kg), with daily doses administered either as an individual infusion (3.2 mg/kg) or as 4 infusions of 0.8 mg/kg each. Blood samples were obtained for 6-24 hours after dosing for measurement of Bu plasma concentrations. PK parameters were estimated using compartmental analyses. In a subgroup of patients (n = 14), GSH blood concentrations were determined before Bu administration. Dose- and weight-corrected Bu PK parameters (clearance, 0.173 ± 0.051 L/hour · kg; volume of distribution, 0.71 ± 0.17 L/kg; half-life time, 3.0 ± 0.7 hours) did not differ among treatment protocols (all P >.14) and remained stable between the first and mid-cycle doses. Fludarabine did not affect Bu PK. Blood GSH concentrations before Bu dosing were positively correlated with Bu clearance (adjusted R(2) = 0.45; P = .009). Our data indicate that Bu PK parameters are linear, stable, and predictable in different i.v. protocols and are unaffected by coadministration of fludarabine. Differences in whole blood GSH might contribute to variability in Bu clearance.

Warfarin and vitamin K intake in the era of pharmacogenetics.

The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.

10 years of oral anticoagulant pharmacogenomics: what difference will it make? A critical appraisal.

Since the first report on warfarin pharmacogenetics in 1999, genetic variants have emerged as an important predictor of warfarin maintenance doses before therapy is initiated, raising expectations of greatly improved clinical outcomes. However, much of the information on warfarin sensitivity conveyed by genetic variants is captured by early international normalized ratio values traditionally used to guide dose titration. Thus, inclusion of early international normalized ratios in prediction models reduces the contribution of genetics. Moreover, in large population cohorts, genetics explained only 20-30% of variance in warfarin doses. Finally, even pharmacogenetic prediction models did not predict doses reliably in the majority of at-risk patients with warfarin requirements at the low or high end of the dose range. Currently, the clinical utility and cost-effectiveness of pharmacogenetic-based dosing are being assessed in large prospective trials in various settings. In the interim, enthusiasm for warfarin pharmacogenetics should not supersede strict adherence to traditional measures used to optimize coumarin anticoagulation.