Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries.

BACKGROUND: This observational safety study used national registers to compare the real world cardiovascular and skeletal safety of zoledronic acid (ZA) against oral bisphosphonates (oBP) and untreated population controls. METHODS: Propensity score matched cohort study in Sweden and Denmark. RESULTS: Matched cohort 1 included 8739 ZA users and 25,577 oBP users while matched cohort 2 included 8731 ZA users and 25,924 untreated subjects. In comparison to oBP users, heart failure risk was higher in ZA users, with an adjusted HR (adj) (95%CI) of 1.17 (1.04;1.32) and a higher all-cause mortality (adj HR 1.24 (1.15; 1.34)), however, there was no increased risk of cardiovascular mortality. In the comparison to untreated subjects, ZA users showed a higher risk of atrial fibrillation, adj HR 1.18 (1.05;1.32), arrhythmias adj HR 1.18 (1.06;1.31), and heart failure, adj HR 1.38 (1.24;1.54). Cardiovascular mortality was lower in ZA users (adj HR 0.87 (0.77; 0.98)) and risk of adverse skeletal outcomes was significantly higher, reflecting more severe osteoporosis in these patients. There was no association of cardiovascular risk with increasing exposure time. Sensitivity analyses produced similar findings with no substantial changes in event rates. CONCLUSIONS: We noted an increased risk of heart failure, fractures and death among ZA users compared with oral BP. The risk of cardiovascular and skeletal outcomes was higher in ZA users than in matched population controls, but there was no increase in cardiovascular mortality in ZA users compared to oral BP or untreated controls. Despite propensity score matching, it is not possible to determine with certainty whether the increased risk of cardiovascular outcomes is consistent with a true drug effect or higher baseline risk in patients who begin ZA treatment.

Addressing limitations in observational studies of the association between glucose-lowering medications and all-cause mortality: a review.

A growing body of observational literature on the association between glucose-lowering treatments and all-cause mortality has been accumulating in recent years. However, many investigations present designs or analyses that inadequately address the methodological challenges involved. We conducted a systematic search with a non-systematic extension to identify observational studies published between 2000 and 2012 that evaluated the effects of glucose-lowering medications on all-cause mortality. We reviewed these studies and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We described these methodological issues and their potential impact on observed associations, providing examples from the reviewed literature, and suggested possible approaches to manage these methodological challenges. We evaluated 67 publications of observational studies evaluating the association between glucose-lowering treatments and all-cause mortality. The identified methodological challenges included trade-offs associated with the outcome of all-cause mortality, incorrect temporal sequencing in administrative databases, inadequate treatment of time-varying hazards and treatment duration effects, unclear definition of the exposure risk window, improper handling of time-varying exposures, and incomplete accounting for confounding by indication. Most of these methodological challenges may be adequately addressed through the application of appropriate methods. Observational research plays an increasingly important role in assessing the clinical effects of diabetes therapy. The implementation of suitable research methods can reduce the potential for spurious findings, and thus the risk of misleading the medical community about benefits and harms of diabetes therapy.

Comparative performance of two drug interaction screening programmes analysing a cross-sectional prescription dataset of 84,625 psychiatric inpatients.

BACKGROUND: Clinical decision support software (CDSS) solutions can automatically identify drug interactions and thereby aim to improve drug safety. However, data on the comparative performance of different CDSS to detect and appropriately classify interactions in real-life prescription datasets is limited. OBJECTIVE: The aim of this study was to compare the results from two different CDSS analysing the pharmacotherapy of a large population of psychiatric inpatients for drug interactions. METHODS: We performed mass analyses of cross-sectional patient-level prescriptions from 84,625 psychiatric inpatients using two CDSS - MediQ and ID PHARMA CHECK(®). Interactions with the highest risk ratings and the most frequent ratings were reclassified according to the Zurich Interaction System (ZHIAS), a multidimensional classification that incorporates the OpeRational ClassificAtion of Drug Interactions (ORCA) and served as a reference standard. RESULTS: MediQ reported 6,133 unique interacting combinations responsible for 270,617 alerts affecting 63,454 patients. ID PHARMA CHECK(®) issued 5,400 interactions and 157,489 alerts in 48,302 patients. Only 2,154 unique interactions were identified by both programmes, but overlap increased with higher risk rating. MediQ reported high-risk interactions in 2.5 % of all patients, compared with 5 % according to ID PHARMA CHECK(®). The positive predictive value for unique major alerts to be (provisionally) contraindicated according to ORCA was higher for MediQ (0.63) than for either of the two ID PHARMA CHECK(®) components (0.42 for hospINDEX and 0.30 for ID MACS). MediQ reported more interactions, and ID PHARMA CHECK(®) tended to classify interactions into a higher risk class, but overall both programmes identified a similar number of (provisionally) contraindicated interactions according to ORCA criteria. Both programmes identified arrhythmia as the most frequent specific risk associated with interactions in psychiatric patients. CONCLUSIONS: CDSS can be used for mass-analysis of prescription data and thereby support quality management. However, in clinical practice CDSS impose an overwhelming alert burden on the prescriber, and prediction of clinical relevance remains a major challenge. Only a small subset of yet to be determined alerts appears suitable for automated display in clinical routine.

Comparative evaluation of the drug interaction screening programs MediQ and ID PHARMA CHECK in neurological inpatients.

PURPOSE: The comparative evaluation of clinical decision support software (CDSS) programs regarding their sensitivity and positive predictive value for the identification of clinically relevant drug interactions. METHODS: In this research, we used a cross-sectional study that identified potential drug interactions using the CDSS MediQ and the ID PHARMA CHECK in 484 neurological inpatients. Interactions were reclassified according to the Zurich Interaction System, a multidimensional classification that incorporates the Operational Classification of Drug Interactions. RESULTS: In 484 patients with 2812 prescriptions, MediQ and ID PHARMA CHECK generated a total of 1759 and 1082 alerts, respectively. MediQ identified 658 unique potentially interacting combinations, 8 classified as "high danger," 164 as "average danger," and 486 as "low danger." ID PHARMA CHECK detected 336 combinations assigned to one or several of 12 risk and management categories. Altogether, both CDSS issued alerts relating to 808 unique potentially interacting combinations. According to the Zurich Interaction System, 6 of these were contraindicated, 25 were provisionally contraindicated, 190 carried a conditional risk, and 587 had a minimal risk of adverse events. The positive predictive value for alerts having at least a conditional risk was 0.24 for MediQ and 0.48 for ID PHARMA CHECK. CONCLUSIONS: CDSS showed major differences in the identification and grading of interactions, and many interactions were only identified by one of the two CDSS. For both programs, only a small proportion of all identified interactions appeared clinically relevant, and the selected display of alerts that imply management changes is a key issue in the further development and local setup of such programs.

Evaluation of drug interactions and dosing in 484 neurological inpatients using clinical decision support software and an extended operational interaction classification system (Zurich Interaction System).

PURPOSE: The current study aimed at identifying and quantifying critical drug interactions in neurological inpatients using clinical decision support software (CDSS). Reclassification of interactions with a focus on clinical management aimed to support the development of CDSS with higher efficacy to reduce overalerting and improve medication safety in clinical practice. METHODS: We conducted a cross-sectional study in consecutive patients admitted to the neurology ward of a tertiary care hospital. We developed a customized interface for mass analysis with the CDSS MediQ, which we used for automated retrospective identification of drug interactions during the first day of hospitalization. Interactions were reclassified according to the Zurich Interaction System (ZHIAS), which incorporates the Operational Classification of Drug Interactions (ORCA). Dose adjustments for renal impairment were also evaluated. RESULTS: In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "average danger," and 1233 "low danger" interaction alerts. According to ZHIAS, 6 alerts involved contraindicated and 33 alerts involved provisionally contraindicated combinations, and 327 alerts involved a conditional and 1393 alerts involved a minimal risk of adverse outcomes. Thirty-five patients (6.2%) had at least one combination that was at least provisionally contraindicated. ZHIAS also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 13 prescriptions without recommended dose adjustment for impaired renal function. CONCLUSIONS: MediQ detected a large number of drug interactions with variable clinical relevance in neurological inpatients. ZHIAS supports the selection of those interactions that require active management, and the effects of its implementation into CDSS on medication safety should be evaluated in future prospective studies.

Evaluation of medication safety in the discharge medication of 509 surgical inpatients using electronic prescription support software and an extended operational interaction classification.

PURPOSE: Our aim was to study drug interactions and dose adjustments in patients with renal impairment in the discharge medication of surgical inpatients and to evaluate the strengths and limitations of clinical decision support software (CDSS) for this task. METHODS: This was a cross-sectional study involving 509 surgical patients of a primary care hospital. We developed a customized interface for the CDSS MediQ, which we used for automated retrospective identification of drug interactions in the patients' discharge medication. The clinical relevance of the interactions was evaluated based on the Zurich Interaction System (ZHIAS) that incorporates the operational classification of drug interactions (ORCA). Prescriptions were further analyzed for recommended dose adjustments in patients with a glomerular filtration rate <60 ml/min. RESULTS: For the total of 2,729 prescriptions written for the 509 patients enrolled in the study, MediQ generated 2,558 interaction alerts and 1,849 comments. Among these were ten "high danger" and 551 "average danger" alerts that we reclassified according to ORCA criteria. This reclassification resulted in ten contraindicated combinations, 77 provisionally contraindicated combinations, and 310 with a conditional and 164 with a minimal risk of adverse outcomes. The ZHIAS classification also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 56 prescriptions without a recommended dose adjustment for impaired renal function. CONCLUSIONS: CDSS identified a large number of drug interactions in surgical discharge medication, but according to ZHIAS criteria only a minor fraction of these appeared to involve a substantial risk to the patient. CDSS should therefore aim at reducing over-alerting and improve usability in order to become more efficacious in terms of the prevention of adverse drug events in clinical practice.

Trace amine associated receptor 1 and movement control.

The recently discovered trace amine associated receptors (TAARs) represent attractive potential mediators of certain aspects of movement control. The TAAR that is best characterized, TAAR1, is particularly interesting because it can be activated by a variety of monoaminergic compounds including trace amines, amphetamines and dopamine metabolites. By using an experimental paradigm developed in our laboratory that involves a novel model of acute dopamine deficiency (DDD mice), and mice lacking TAAR1 (TAAR1 knockout mice), we explored the role of TAAR1 in movement control and actions of antiparkinsonian drugs. These investigations may eventually bring novel approaches to the pharmacology of Parkinson's disease.