Adverse drug reaction-related hospitalisations: a population-based cohort study

Purpose To evaluate the extent, characteristics and determinants of adverse drug reaction (ADR)-related hospitalisations on a population-based level in 2003. Methods We performed a cohort study in the Integrated Primary Care Information (IPCI) database, a general practitioners (GPs) research database with longitudinal data from electronic patient records of a group of 150 GP throughout the Netherlands. Hospital discharge letters and patient records were reviewed to evaluate ADR-related hospitalisations applying WHO causality criteria. The prevalence of ADR-related hospitalisations per total admissions and the incidence per drug group were calculated. Avoidability and seriousness of the ADRs causing admission were assessed applying the algorithm from Hallas. Results We identified 35 15 hospital admissions, 1277 elective and 2238 acute. Of the acute admissions, 115 were caused by an ADR giving a prevalence of 5.1% (95% confidence intervals (CI): 4.3-6.1%). The prevalence of ADR-related acute admissions increased with age up to 9.8% (95%CI: 7.5-12.7) for persons > 75 years. The ADRs that most frequently caused hospitalisations were gastro-intestinal bleeding with anti-thrombotics, bradycardia/hypotension with cardiovascular drugs and neutropenic fever with cytostatics. The incidence rate of ADR-related hospitalisations per drug group was highest for anti-thrombotics and anti-infectives and was relatively low for cardiovascular drugs. Fatality as a direct consequence of the ADR-related admission was 0.31%. In elderly patients 40% of the ADRs causing hospitalisation were judged to be avoidable. Conclusions The extent and potential avoidability of ADR-related hospitalisations is still substantial, especially in elderly patients. Measures need to be put into place to reduce the burden of ADRs. Copyright (c) 2008 John Wiley & Sons, Ltd

Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea

Objective The single nucleotide polymorphism rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene is associated with QTc prolongation, through an effect on the intracellular Ca2+ levels. As sulfonylurea stimulate insulin secretion by an increased 21 influx of Ca2+ we hypothesized that this polymorphism is associated with the glucose-lowering effect and mortality risk in sulfonylurea users. Methods Associations between the NOS1AP polymorphism, prescribed doses, and mortality rates in sulfonylurea, metformin, and insulin users were assessed in the Rotterdam Study, a population-based cohort study of 7983 elderly people. Results We identified 619 participants who were prescribed oral antidiabetic drugs during follow-up. In glibenclamide users carrying the TG genotype, the prescribed doses were higher compared with the glibenclamide users carrying the TT genotype [0.38 defined daily dose units, 95% confidence interval (Cl) 0.14-0.63]. Glibenclamide users with the TG or GG genotype had an increased mortality risk compared with glibenclamide users with the TT genotype [hazard ratio (H R) 2.80, 95% Cl: 1.09-722]. Tolbutamide users with the TG or GG genotype HR: 0.30, 95% Cl: 0.14-0.63) and glimepiride users with the TG or GG genotype (H R: 0.18, 95% Cl: 0.04-0.74) had a decreased mortality risk compared with tolbutamide and glimepiride users with the TT genotype. Conclusion In participants with the TG or GG genotype at rs10494366 in the NOS1AP gene, glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared with glibenclamide users with the TT genotype. In tolbutamide and glimepiride users, the TG and GG genotype were associated with a reduced mortality rate. Pharmacogenetics and Genomics 18:591-597 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation

Objectives To study whether NOS1AP single nucleotide polymorphisms (SNPS), rs10494.366 T>G and rs10918594 C>G, modify the heart-rate-corrected QT (QTc) prolonging effect of calcium channel blockers. Background Common variation in the NOS1AP gene has been associated with QT interval variation in several large population samples. NOS1 is presumed to influence intracellular calcium. Methods The prospective population-based Rotterdam Study includes 16 603 ECGs from 7565 participants (>= 55 years), after exclusion of patients with left ventricular hypertrophy, left and right bundle branch block, as well as carriers of pacemakers. The endpoint was the length of the QTc interval in calcium channel blocker users and non-users with the minor alleles compared with the major alleles (wild type). We used a repeated-measurement analysis, adjusted for all known confounders. Results Use of verapamil was associated with a significant QTc interval prolongation [6.0 ms 95% confidence interval (CI) 1.7; 10-2] compared with non-users. Furthermore, users of verapamil with the rs 10494366 GG genotype showed significantly more QTc prolongation than users with the TT genotype [25.4 ms (95% Cl: 5.9-44.9)] (P value for multiplicative interaction 0.0038). Users of isradipine with the GG genotype showed more QTc prolongation than users with the TT genotype [19.8 ms (95% CI: 1.9-37.7)]; however, SNP rs10494366 did not modify the effect on QTc interval on a multiplicative scale (P=0.3563). SNP rs10918594 showed similar results. Conclusion In conclusion, we showed that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil. Pharmacogenetics and Genomics 19:260-266 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Psychotropic Drugs Associated With Corrected QT Interval Prolongation

Aims: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drue effect. we conducted a prospective population-based cohort study. Methods: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (>= 55 years) who had triennial electrocardiograms (ECGs). The primary end point,; of the study were the length of the QTc interval at each ECG. the difference in QTc interval between consecutive ECGs within one person, and the risk of ail abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age. sex, diabetes mellitus. hypertension, myocardial infarction, heart failure. and use of class I QTc-prolonging drugs. Results: Of the 8222 participants. 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison With Consecutive ECGs of participants not using tricyclic antidepressants. in particular starting amitriptyline (8.5 milliseconds: 95% CI. 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds: 9 % CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds: 95% CI. 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% Cl 4.8-32.4 milliseconds). Conclusions: In this population-based prospective cohort Stud),, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect