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Biomedical subjects

Hillel Halkin

Publications and source records attributed to Hillel Halkin.

16 recordsLinked to original sources
PubMed2006

Brand versus generic alendronate: gastrointestinal effects measured by resource utilization.

BACKGROUND: Adverse reactions related to the upper gastrointestinal tract (UGIT) that are associated with generic alendronate formulations may differ from those associated with the brand drug. OBJECTIVE: To test the hypothesis that adverse UGIT effects of alendronate formulations may differ between generic and brand products. METHODS: We conducted a database health resource utilization analysis of UGIT outcomes in patients who started treatment with generic or brand alendronate formulations during 2001-2005. We included 6962 patients who were treated continuously for 3 months with 1 of 4 alendronate formulations: brand 10 mg/day (Merck, Sharpe & Dohme, n = 1418), generic A 10 mg/day (Teva, Israel, n = 650), generic B 10 mg/day (Unipharm, Israel, n = 628), and brand 70 mg/wk (n = 4266). In these patients, who had neither filled a prescription for alendronate nor had any gastrointestinal problems in the year preceding the study, we compared incidence rates of new use of gastric medications (H2-blockers, proton-pump inhibitors, or antacids), gastroenterology visits, endoscopies, and hospital admissions. RESULTS: Incident rate ratios (IRR) for treatment discontinuation were higher with both daily generic products (IRR 1.3; 95% CI 1.04 to 1.63). Adherence (medication possession ratio [MPR] >80%) was better with brand 10 mg/day (IRR 1.19; 95% CI 1.11 to 1.27). All comparisons were adjusted for use of concurrent corticosteroids, nonsteroidal antiinflammatory drugs, and potassium supplements. Hospitalization rates (2.7-3.2%) were similar in all groups. New use of gastric medications (3.4-4.9%) was lower with brand 10 mg/day (IRR 0.71; 95% CI 0.53 to 0.95). Rates of UGIT endoscopy (n = 49) in patients receiving 10 mg were 0.6% (brand), 1.1% (generic A), and 1.6% (generic B), with generic B higher (IRR 2.88; 95% CI 1.14 to 7.29) in the entire cohort, but not among new users (n = 273) of gastric drugs (IRR 2.46; 95% CI 0.55 to 11.05). Endoscopic findings were normal in 22 patients, hiatal hernia with no mucosal lesion was present in 10 patients, and there was mild-to-moderate esophagitis or gastritis in 17 patients; there were no significant differences among the formulations. CONCLUSIONS: We found insufficient evidence to indicate major differences in UGIT adverse effects related to use of daily generic, as compared with brand, alendronates.

Aged↗
PubMed2006

A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance.

CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin-resistant (dose, 80 to 185 mg/wk) and 8 warfarin-sensitive patients (7 to 13 mg/wk) and 99 unselected controls (8 to 105 mg/wk). We identified a coding VKORC1 Asp36Tyr polymorphism in 7 of 15 resistant compared with 0 of 8 sensitive patients (P = .026) Carriers of Asp36Tyr in the control group (8 of 99) required significantly higher warfarin doses of 80.9 +/- 10.1 mg/wk compared with 42.7 +/- 7.5 mg/wk in noncarriers (F = 9.79, P = .002). Asp36Tyr was significantly associated with doses of more than 70 mg/wk (odds ratio, 13.0; 95% confidence limit, 1.3 to 124.2), while doses of 20 to 70 mg/wk were associated with Asp36Tyr (partial r(2) = .11; P = .004), CYP2C9*2 and *3 (r(2) = .08; P = .01), and VKORC1*2 and *3 markers (r(2) = .05; P = .05). All Asp36Tyr carriers also had VKORC1*1 tag-single nucleotide polymorphisms (tag-SNPs) indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high end of the warfarin dosing range.

Adult↗
PubMed2006

Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin.

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), gamma-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G(1542)C VKORC1 polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p < 0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r(2) = 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G(11)A CALU mutant allele, required an exceptionally high warfarin dose (20 mg/day) and the prevalence of heterozygous (11)A allele carriers in the upper 10(th) dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7.8 +/- 1.5mg/day; n = 9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2.8 +/- 0.3 mg/day; n = 18; p < 0.01). The odds ratio for doses <3mg/day was 5.9 (1.9-18.4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.

Adolescent↗
PubMed2006

[Generic drug substitution].

The rapidly rising health care expenditures, attributed mainly to the high cost of prescription drugs, have led governments around the world to look to generics as a means of containing costs in the pharmaceutical market. Generic drugs provide a less expensive alternative to brand name drugs due to the elimination of the need to perform lengthy and costly clinical trials, as required for innovative drugs. Essentially, generic substitution of drugs may be performed only after showing unequivocally that the generic formulation is identical in its active ingredients, strength, and route of administration as its innovative counterpart, and that they are bioequivalent to each other. Although the two are in essence the same, generic substitution is occasionally a controversial matter.

Costs and Cost Analysis↗
PubMed2005

The implementation of managed care for diabetes using medical informatics in a large Preferred Provider Organization.

BACKGROUND: It has been demonstrated by meta analysis that if a regular review of patients is guaranteed, the standard of primary care can be as good or better than hospital outpatient care, however, empirical data suggests that compliance with diabetes clinical practice recommendations is inadequate in primary care. This study describes the reorganization of diabetes care using disease management principles in a Preferred Provider Organization (PPO) operating on a country-wide basis in which each diabetes clinic became responsible for the overall care of all patients with diabetes. METHODS: This descriptive pre and post change study was undertaken in a large public-funded PPO insuring over one and half million individuals. The study was possible due the use of a centralized electronic disease registry which enabled the collection of all patient data. Several markers, such as HbA1C and LDC-cholesterol levels, were used to assess the quality of care for the diabetic patients. RESULTS: Mean HbA1C results of the cohort showed a continuous reduction from 8.1% (S.D. = 1.55) in 1999 to 7.68% (S.D. = 1.47) in 2002 and to 7.79 (S.D. = 1.54) in 2004. Improved results were also recorded for LDL-C 126.37 (S.D. = 35.16) in 1999 to 114.74 (S.D. = 34.49) in 2002, and to 113.39 (S.D. = 33.8) in 2004. The number of diabetic patients seen by the diabetologist increased by 62% over this period, despite an increase in diabetologist work hours of only 23%. CONCLUSION: The reorganization of health delivery for diabetic patients within a country-wide PPO, based on the principles of disease management and supported by medical informatics improves quality of care.

Cholesterol, LDL↗
PubMed2005

Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9.

BACKGROUND: Warfarin dose response is partially explained by the polymorphisms in the cytochrome P450 (CYP) 2C9 gene, affecting S -warfarin clearance, as well as by age and body weight. We examined the influence on warfarin dose requirements of candidate genes encoding microsomal epoxide hydrolase (mEH), as well as glutathione S -transferase A1 (GSTA1) components of vitamin K epoxide reductase and the gamma-glutamylcarboxylase (GGCX) gene. METHODS: We studied the effects of CYP2C9, mEH, GSTA1, and GGCX genotypes on warfarin maintenance doses, accounting for age, weight, vitamin K plasma concentrations and concurrent medications, in 100 patients undergoing therapeutic anticoagulation. RESULTS: Allele frequencies were 76.5%, 12.5%, and 11% for CYP2C9*1 , *2 , and *3 , respectively; 75% and 25% for mEH T 612 C; 75.8% and 24.2% for mEH A 691 G; 73.5% and 26.5% for GSTA1 T 631 G; and 70.5% and 29.5% for GGCX G 8762 A. Warfarin doses differed among the CYP2C9 ( 2C9*1 , 2C9*2 , and 2C9*3 ) genotype groups: 6.3 +/- 1.9 mg/d, 5.3 +/- 1.8 mg/d, and 3.8 +/- 1.7 mg/d, respectively (F = 4.83, P < .01). There were no differences in any of the other genotype groups. Among the 62 wild-type CYP2C9 patients, variant mEH T 612 C homozygotes required higher doses than heterozygotes and wild-type patients (7.5 +/- 2.9 mg/d, 6.5 +/- 4.2 mg/d, and 6.0 +/- 2.6 mg/d, respectively [F = 3.57, P = .03]). The odds ratio for requiring greater than 7 mg/d in variant mEH T 612 C patients versus wild-type patients was 3.14 (95% confidence interval, 1.47-6.67), accounting for CYP2C9. CONCLUSIONS: Variant mEH T 612 C genotypes are associated with warfarin doses of greater than 50 mg/wk beyond the effect of CYP2C9.

Alleles↗
PubMed2004

Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland.

Many patients with cardiac arrhythmias require concomitant therapy with warfarin and amiodarone. Beyond the predictable pharmacokinetic drug-drug interaction requiring a significant warfarin dose reduction, the iodine-rich amiodarone affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%-18% of cases. In turn, thyroid disorders may affect warfarin sensitivity, with hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin requirements, respectively. We describe 3 patients on concomitant amiodarone and warfarin who developed amiodarone-induced thyrotoxicosis heralded by a significant decrease in warfarin requirements. We review the literature on the mechanisms of the complex drug-drug and drug-disease interactions within the thyroid gland, warfarin, and amiodarone triad. Given that significant thyroid disorders may be only mildly symptomatic and thus may escape clinical detection, we suggest that thyroid function should be tested in any patient with otherwise unexplained changes in warfarin dose requirements, particularly if concomitantly treated with amiodarone.

Adult↗
PubMed2004

Over-the-counter vitamin K1-containing multivitamin supplements disrupt warfarin anticoagulation in vitamin K1-depleted patients. A prospective, controlled trial.

Most multivitamin supplements contain far less vitamin K(1) than thought to affect warfarin anticoagulation. Having described 3 patients with multivitamin-warfarin interactions, we hypothesized that vitamin K(1)-depleted patients are sensitive to even small increments. Therefore, we compared the effect of a vitamin K(1)-containing multivitamin on warfarin anticoagulation between patients with low versus normal vitamin K(1) status. We screened 102 warfarin-treated patients and recruited nine with "low" (< 1.5 mcg/L, 10(th) percentile) (group 1) and 7 with "normal" (>4.5 mcg/L, median) (group 2) total vitamin K(1) plasma levels (vitamin K(1) + vitamin K(1) 2,3-epoxide). Patients received one multivitamin tablet containing 25 mcg of vitamin K(1) daily, for 4 weeks (period 1). A predefined algorithm was used to adjust warfarin doses if the INR was outside the therapeutic range. Patients requiring warfarin increments were then switched to 4 weeks of a vitamin K(1)-free multivitamin supplement (period 2). During period 1, subtherapeutic INRs occurred in 9/9 and 1/7 patients in group 1 and 2, respectively (p <0.001). In group 1, INR decreased by a median of 0.51 (p <0.01), and warfarin dose had to be raised by 5.3% (p <0.01), whereas INR and warfarin dose did not change significantly in group 2. During period 2 (7 patients), there were trends towards decreased total vitamin K(1) and rising INRs associated with significantly lower warfarin doses. We conclude that vitamin K(1)-containing multivitamins reduce INR in patients with low vitamin K(1) status. Our study suggests that vitamin K-depleted patients are sensitive to even small changes in vitamin K(1) intake.

Adult↗
PubMed2004

Applying an artificial neural network to warfarin maintenance dose prediction.

BACKGROUND: Oral anticoagulation with warfarin can lead to life-threatening events as a result of either over-anticoagulation or undertreatment. One of the main contributors to an undesirable warfarin effect is the need to adjust its daily dose for a specific patient. The dose is adjusted empirically based on the experience of the clinician, a method that is often imprecise. There is currently no other well-accepted method for predicting the maintenance dose of warfarin. OBJECTIVE: To describe the application of an artificial neural network to the problem of warfarin maintenance dose prediction. METHODS: We designed a neural network that predicts the maintenance dose of warfarin. Data on 148 patients attending a large anticoagulant clinic were collected by file review. Using correlational analysis of the patients' data we selected the best input variables. The network was trained by using the back-propagation algorithm on a subset of our data and the results were validated against the rest of the data. We used a multivariate linear regression to create a comparable model. RESULTS: The neural network generated reasonable predictions of the maintenance dose (r = 0.823). The results of the linear regression model were similar (r = 0.800). CONCLUSION: Neural networks can be applied successfully for warfarin maintenance dose prediction. The results are promising, but further investigation is needed.

Adolescent↗
PubMed2003

Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study.

BACKGROUND: Treatment of patients with excessive anticoagulation is routinely done by intravenous phytonadione (vitamin K1). Oral administration of phytonadione has been shown to be an effective alternative to the intravenous route, but these methods have never been compared directly. Our objective was to compare efficacy and safety of intravenous vs oral phytonadione treatment in patients with excessive anticoagulation without bleeding. METHODS: The study was a prospective randomized controlled trial of consecutive patients presenting with excessive anticoagulation without major bleeding. Patients with a baseline international normalized ratio (INR) of 6 to 10 (n = 44, 47 episodes) received either intravenous or oral phytonadione (0.5 mg or 2.5 mg, respectively), and patients with an INR greater than 10 (n = 17, 19 episodes) received 1 mg or 5 mg, respectively. Efficacy and safety end points were sequential INR changes and the proportion of patients achieving therapeutic range (INR, 2-4), overcorrection (INR<2.0), or undercorrection (INR>4.0) INR values. RESULTS: Sixty-six episodes of excessive anticoagulation were studied. In patients with baseline INR 6-10 the response to intravenous phytonadione was more rapid than in the oral group, and the proportion of patients reaching therapeutic range INR at 6 hours (11/24 vs 0/23) and at 12 hours (16/24 vs 8/23) was significantly higher. However, mean +/- SD INR values were similar for both groups at 24 hours (2.9 +/- 0.8 vs 2.6 +/- 0.8). Patients in the intravenous group tended to be more often (7/24 vs 2/23) overcorrected (INR<2). In patients with baseline INR values greater than 10 efficacy and safety were comparable for both routes of administration. CONCLUSION: Oral administration of phytonadione had similar efficacy and safety as intravenously administered phytonadione and may be suitable for treatment of patients with excessive anticoagulation.

Administration, Oral↗
PubMed2003

Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching.

OBJECTIVE: Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998. METHODS: In the computerized records of a health maintenance organization database, we identified 975 patients who took warfarin continuously over two 6-month periods, before (period 1) and after (period 2) the generic switch. In this sample we performed a retrospective, between-period paired comparison of warfarin doses dispensed and international normalized ratio (INR) levels maintained, as well as of the apparent warfarin sensitivity index (calculated as INR/Warfarin dose [in milligrams per day]). RESULTS: Overall, for period 2, doses were 26.5% higher and INR 4.2% lower, with a 14.7% reduction in warfarin sensitivity index (P <.001). The findings were strongest in the 61 of 975 patients (6.3%) dispensed the lowest maintenance doses (<1.0 mg/d), with minimal change at greater than 3 mg/d. In 94 other patients (9.6%) in whom doses were unchanged, INR (median with 5th and 95th percentiles) dropped to subtherapeutic levels, from 2.2 (1.8, 3.0) to 1.7 (1.3, 1.8) (P <.001). There were no adverse events, expressed as no change in hospital admissions. Apparent warfarin sensitivity was reduced in period 2 by 15% to 20% (P <.001) across all period 1 INR levels. CONCLUSION: Because a general unidirectional change in INR response per unit warfarin dose cannot be explained by biologic mechanisms or confounding, we conclude that slightly reduced bioavailability (within the acceptable bioequivalence range) of the new formulation led to overestimated period 2 doses and reduced apparent warfarin sensitivity in all patient subgroups (by period 1 dose or INR), which was most prominent in those individuals with the lowest maintenance dose requirements.

Anticoagulants↗
PubMed2003

Potential dosing errors using portable prothrombin time monitoring devices.

Portable prothrombin time (PT) monitors facilitate the control of warfarin therapy. Few studies have compared the influence of using different monitors on dosage decisions. We determined the comparability of data generated by two portable PT monitors, Coaguchek S, (Roche Diagnostics Boehringer-Mannheim) and Hemochron Jr (International Technidyne Corporation Ltd.), with that of a reference laboratory. Simultaneous International Normalized Ratio (INR) measurements (portable monitor and laboratory) were performed in 193 consecutive patients receiving warfarin for at least 3 months. Agreement of measurements was assessed by both regression analysis and influence on dosage decisions in accordance with pre-defined criteria. The Coaguchek S versus laboratory INR regression line (n = 111; r2 = 0.88; P < 0.001) was close to the line of identity, while that of the Hemochron Jr (n = 82; r2 = 0.61; P < 0.001) was not. The overall proportion of dual INR measurements that fulfilled the clinical criteria of agreement was 90% for the Coaguchek S compared with 62% for the Hemochron Jr (P < 0.0001). For laboratory INRs 2.0-2.5, 2.6-4.0 and > 4.0, the proportions of portable measurements that satisfied the clinical criteria for the Coaguchek S versus the Hemochron Jr were 96 versus 63% (P < 0.001), 81 versus 45% (P < 0.04), and 67 versus 17% (P < 0.85), respectively. Warfarin dosing based solely on the portable devices would have resulted in unjustified dose increments in 22% of the patients with the Hemochron Jr device compared with 8% with the Coaguchek S monitor (chi2 = 4.43; P = 0.035). The Coaguchek S monitor provides measurements for INR values within the therapeutic range that agree well with the standard laboratory. The Hemochron Jr measurements result in different dosage adjustments even within the therapeutic range, but especially for INR values > 4.0. For both monitors, agreement of INR measurements with the standard decreases with increasing INR values.

Adult↗
PubMed2003

Multivitamin supplements may affect warfarin anticoagulation in susceptible patients.

OBJECTIVE: To report an interaction of a multivitamin preparation containing small amounts of vitamin K(1) (25 microg) with warfarin in a case series and to assess the prevalence of vitamin K(1) deficiency in ambulatory anticoagulated patients. CASE SUMMARIES: We describe 3 patients whose anticoagulation was stabilized with warfarin in whom initiation or cessation of a self-prescribed multivitamin supplement delivering 25 microg of vitamin K(1) daily was associated with an otherwise unexplained significant fall or rise in international normalized ratio (INR), respectively, with major thrombosis or hemorrhage in 2. This interaction was rated probable on the Naranjo probability scale. Suspecting vitamin K(1) deficiency as an explanation for this oversensitivity, we assessed the prevalence of vitamin K(1) deficiency in our clinic by determining plasma vitamin K(1) levels in 179 stable consecutive patients, finding very low levels (<0.1 ng/mL) in 22 of 179 (12%). DISCUSSION: Vitamin K(1) supplements of 25 microg daily are far below the dose thought to affect anticoagulant control. We hypothesize that, in our patients, unsuspected vitamin K(1) deficiency caused an oversensitivity to small vitamin K(1) supplements. In patients with low vitamin K(1) status, even such low doses represent a significant increment in daily intake, thus lowering the sensitivity to warfarin. Our analysis suggests that low vitamin K(1) status exists in a small, but important, minority of ambulatory patients undergoing anticoagulation. CONCLUSIONS: Clinicians should instruct anticoagulated patients to report the use of multivitamin supplements and inquire about it in cases of unexplained INR changes.

Adult↗
PubMed2003

Impact of pre-treatment INR level on the effect of intravenous low dose vitamin K in patients with excessive anticoagulation.

Administration of vitamin K is the common mode of treatment in excessively anticoagulated patients. However, patient's response to vitamin K varies, depending on the vitamin K dose and the route of administration. Another potential source of variation is the pre-treatment INR which has not been accounted for in most previous studies. In the present study the effect of baseline INR on the response to a single dose of intravenous vitamin K (0.5 mg) was studied in 95 episodes of excessively anticoagulated patients (n = 76). In 67 episodes of moderately excessive baseline INR (6-10) mean INR declined from 8.0 +/- 1.2 to 2.6 +/- 0.9 at 24 hours, 59/67 (88%) responding within the first 12 hours and not requiring a second dose. In contrast, in 28 episodes with highly excessive baseline INR (> 10) response was slower; mean INR declining from 13.6 +/- 2.7 to 4.0 +/- 2.1 at 24 hours. In 14/28 of these episodes, patients failed to respond to vitamin K in the first 12 hours and required a second vitamin K dose. We conclude that INR at presentation affects the response to vitamin K and that this INR value should be considered in determining appropriate vitamin K doses.

Acenocoumarol↗
PubMed2003

[Computerized physician order entry--an urgently required modality].

Misread or misinterpreted hand-written prescriptions or medication orders are the most important cause of life-threatening or serious drug related adverse effects occurring in hospital in-patients. There is convincing evidence in the literature showing that computerized systems for physician order entry, with on-line screening of drug related orders for compatibility with patient characteristics (e.g. age, renal function), drug information (e.g. dose limits, drug-drug interactions) and sets of institutional rules of performance can reduce rates of medication related errors by 80% and more. Reduction of error-related hospital costs would generate the funding required for implementation of such systems, a need that must be met without delay.

Decision Support Systems, Clinical↗