Cases of drug-induced Torsade de Pointes: a review of Belgian cases in the EudraVigilance database

Post-marketing surveillance is very important, especially for rare adverse drug reactions like QTc-prolongation and Torsade de Pointes (TdP). The objective of this study was to investigate the characteristics of Belgian cases of drug-related TdP reported in the EudraVigilance database.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=yacb20status: publishe

Risk factors for QTc-prolongation: systematic review of the evidence

Background QTc-interval prolongation has been associated with serious adverse events, such as Torsade de Pointes and sudden cardiac death. In the prevention of QTc-prolongation, special attention should go to high-risk patients. Aim of the review The aim of this review is to summarize and assess the evidence for different risk factors for QTc-prolongation (demographic factors, comorbidities, electrolytes, QTc-prolonging medication). Methods Potential studies were retrieved based on a systematic search of articles published until June 2015 in the databases Medline and Embase. Both terms about QTc-prolongation/Torsade de Pointes and risk factors were added in the search strategy. The following inclusion criteria were applied: randomized controlled trials and observational studies; inclusion of ≥500 patients from a general population (not limited to specific disease states); assessment of association between QTc-interval and risk factors. For the articles that met the inclusion criteria, the following data were extracted: study design, setting and study population, number of patients and cases of QTc-prolongation, method of electrocardiogram-monitoring, QTc-correction formula, definition of QTc-prolongation, statistical methods and results. Quality assessment was performed using the GRADE approach (for randomized controlled trials) and the STROBE-recommendations (for observational studies). Based on the number of significant results and the level of significance, a quotation of the evidence was allocated. Results Ten observational studies could be included, with a total of 89,532 patients [prospective cohort design: N = 6; multiple regression analyses: N = 5; median STROBE score = 17/22 (range 15-18)]. Very strong evidence was found for hypokalemia, use of diuretics, antiarrhythmic drugs and QTc-prolonging drugs of list 1 of CredibleMeds. Little or no evidence was found for hyperlipidemia, the use of digoxin or statins, neurological disorders, diabetes, renal failure, depression, alcohol abuse, heart rate, pulmonary disorders, hormone replacement therapy, hypomagnesemia, history of a prolonged QTc-interval/Torsade de Pointes, familial history of cardiovascular disease, and the use of only QTc-prolonging drugs of list 2 or 3 of CredibleMeds. Conclusion This systematic review gives a clear overview of the available evidence for a broad range of risk factors for QTc-prolongation.status: publishe

Canine synovial fluid biomarkers for early detection and monitoring of osteoarthritis

Secondary, non-inflammatory osteoarthritis (OA) is a common disorder in dogs. Its silent onset prevents early diagnosis and delays treatment. Synovial fluid biomarkers can detect OA at an early stage, before the presence of radiographic signs. In addition, these local biomarkers can aid prognosis of the disease, monitor the response to treatment and can be used to assess the degree of OA. Currently three groups of canine synovial fluid biomarkers have been the focus of research: proinflammatory mediators, enzymes and their inhibitors, and extracellular cartilage degeneration products. These have been investigated in the elbow, hip and stifle joints of both normal dogs and dogs with naturally occurring and experimentally induced OA. None of these biomarkers are currently used in practice for the detection of canine OA at an early stage. A positive relationship between canine synovial fluid biomarkers and OA has been demonstrated, yet no molecular diagnostic test has been developed so far

Risk management of QTc-prolongation in patients receiving haloperidol: an epidemiological study in a University hospital in Belgium

BACKGROUND: Many drugs, including haloperidol, are linked with a risk of QTc-prolongation, which can lead to Torsade de Pointes and sudden cardiac death. OBJECTIVE: To investigate the prevalence of concomitant risk factors for QTc-prolongation in patients treated with haloperidol, and the use of safety measures to minimize this risk. SETTING: University Hospitals of Leuven, Belgium. Methods A retrospective epidemiological study was performed. On 15 consecutive Mondays, all patients with a prescription for haloperidol were included. A risk score for QTc-prolongation, inspired by the pro-QTc score of Haugaa et al., was calculated based on gender, comorbidities, lab results and concomitant QTc-prolonging drugs (each factor counting for one point). Available electrocardiograms before and during the treatment of haloperidol were registered. MAIN OUTCOME MEASURE: Management of the risk of QTc-prolongation. RESULTS: Two hundred twenty-two patients were included (59.0 % men, median age 77 years) of whom 26.6 % had a risk score of ≥4 (known to significantly increase the mortality). Overall, 24.3 % received haloperidol in combination with other drugs with a known risk of Torsade de Pointes. Half of the patients had an electrocardiogram in the week before the start of haloperidol; only in one-third a follow-up electrocardiogram during haloperidol treatment was performed. Of the patients with a moderately (n = 41) or severely (n = 14) prolonged QTc-interval before haloperidol, 48.8 % and 42.9 % respectively had a follow-up electrocardiogram. In patients with a risk score ≥4, significantly more electrocardiograms were taken before starting haloperidol (p = 0.020). CONCLUSIONS: Although many patients had risk factors for QTc-prolongation (including the use of other QTc-prolonging drugs) or had a prolonged QTc on a baseline electrocardiogram, follow-up safety measures were limited. Persistent efforts should be taken to develop decision support systems to manage this risk.status: publishe

Which correction formula for QT should be implemented in a computer based hospital wide QT monitoring system?

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Which correction formula for the QT-interval should be implemented in a computer based hospital wide QT-monitoring system?

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Incidence of Torsade de Pointes in a tertiary hospital population

BACKGROUND: Multiple risk factors play a role in the development of QTc-prolongation and Torsade de Pointes (TdP). Cases of TdP are underreported and data on the incidence of TdP is scarce. The aim of this study was to investigate the incidence of TdP in a Belgian university hospital and describe the characteristics of TdP-cases using a risk score. METHODS: All cases from 2011 till 2013 coded with the ICD-9 code 427.1 in the University Hospitals of Leuven were selected. The medical files were reviewed and demographical, medical, medication and electrocardiographic data were collected. We focused on TdP-cases that were probably caused by the acquired long QT-syndrome. The RISQ-PATH score was used to quantify the risk in these cases (≥10 points as high risk for QTc-prolongation/TdP). RESULTS: Over three years, 41 TdP-cases were identified of which 19 cases were secondary to the acquired long QT-syndrome (52.6% females, mean age of 74±12years). This corresponds with an incidence of 0.16‰/year in a hospital population. Most of the patients (N=17) were treated with at least one QTc-prolonging drug (most frequently amiodarone, sotalol and furosemide) of whom 12 patients with ≥1 QTc-prolonging drug of list 1 of CredibleMeds. Fifteen patients had an electrocardiogram in a 24-hours interval before the TdP with a prolonged QTc-interval (≥450/470ms). All the patients had a RISQ-PATH score≥10. CONCLUSIONS: Although the incidence of 0.16‰/year might seem low, this means that approximately 173 possibly lethal TdP-cases can be expected in Belgian hospitals each year. All TdP-cases were associated with a high RISQ-PATH score.status: publishe

Development of a risk score for QTc-prolongation: the RISQ-PATH study

Background More than 170 drugs are linked with QTc-prolongation, which in extreme cases can lead to Torsade de Pointes. Monitoring of this potential side effect is an important challenge in clinical practice. Objective To investigate the risk of QTc-prolongation in hospital patients who started a QTc-prolonging drug, and to develop a risk score to identify patients at high/low risk for QTc-prolongation. Setting University Hospitals Leuven, Belgium. Method All patients starting with haloperidol or a QTc-prolonging antibiotic/antimycotic were eligible for this observational study. Twelve-lead electrocardiograms were recorded at baseline and follow-up (steady state). Demographic, medical and drug data were collected. The obtained data were used to calculate the performance characteristics of a preliminary risk score (RISQ-PATH score), based on a systematic review of risk factors. ROC analysis determined a score of <10 points as a low risk for QTc-prolongation. Main outcome measure QTc-interval in a baseline and follow-up electrocardiogram. Results 178 patients (46.6% female; mean age 69 ± 14 years) were included (levofloxacin: N = 80; haloperidol: N = 41; fluconazole: N = 41). Overall, no significant difference between the mean QTc-values at baseline (425.7 ± 31.7 ms) and follow-up (428.0 ± 30.7 ms) was found (p = 0.328). However, 26 patients (14.6%) did develop a prolonged QTc-interval (≥450(♂)/470(♀) ms) of whom 25 with a RISQ-PATH score ≥10. This score had a sensitivity of 96.2% (95% CI 78.4-99.8%) and a negative predictive value of 98.0% (95% CI 88.2-99.9%). Conclusion This RISQ-PATH score is able to rule out low-risk patients with a negative predictive value of 98.0% and is promising to exclude patients from further follow-up when starting QTc-prolonging drugs. Clinicaltrials.gov Registration Number: NCT02068170.status: publishe

Frequency of use of QT-interval prolonging drugs in psychiatry in Belgium

INTRODUCTION: Drug-induced QT-prolongation is an established risk factor for Torsade de pointes and sudden cardiac death. The list of QT-prolonging drugs is extensive and includes many drugs commonly used in psychiatry. AIM: In this study we performed a cross-sectional analysis of medication profiles to assess the prevalence of drug interactions potentially leading to QT-prolongation. SETTING: 6 psychiatric hospitals in Flanders, Belgium. METHODS: For each patient, the full medication list was screened for the presence of interactions, with special attention to those with an increased risk for QT-prolongation. Current practice on QT monitoring and prevention of drug-induced arrhythmia was assessed. MAIN OUTCOME MEASURE: Number of drug interactions with risk of QT-prolongation. RESULTS: 592 patients (46 % female; mean age 55.7 ± 17.1 years) were included in the analysis. 113 QT-prolonging interactions were identified in 43 patients (7.3 %). QT-prolonging interactions occurred most frequently with antidepressants (n = 102) and antipsychotics (n = 100). The precautions and follow-up provided by the different institutions when combining QT-prolonging drugs were very diverse. CONCLUSION: Drug combinations that are associated with QT-prolongation are frequently used in the chronic psychiatric setting. Persistent efforts should be undertaken to provide caregivers with clear guidelines on how to use these drugs in a responsible and safe way.status: publishe

Impact of training on pharmacists’ counseling of patients starting antidepressant therapy

OBJECTIVE: To measure the impact of a one-day depression-related training program on pharmacists' counseling of unannounced "mystery shoppers" (MS) starting antidepressant therapy. METHODS: Clustered RCT pharmacies; intervention group pharmacists received communication skills training related to depression (n=21); control pharmacists did not (n=19). Eight months after training, the 40 community pharmacies were visited by MS with a first prescription for antidepressants. The pharmacy interactions were recorded and analyzed using the Roter Interaction Analysis System (RIAS). Mann-Whitney U tests were used to evaluate the impact of training on pharmacy interactions and MS evaluations of the pharmacists' skills and attitudes. RESULTS: Interactions of intervention group pharmacists were significantly longer and consisted of more education and counseling statements about lifestyle and psychosocial concerns. Intervention group pharmacists asked more questions about medical condition and therapeutic regimen, as well as socioemotional concerns. MS gave more socioemotional information to intervention group pharmacists and were more positive in their assessment of these pharmacists' skills and attitudes (p values<0.05). CONCLUSION: Pharmacist training in depression care can positively affect the quality of patient care. PRACTICE IMPLICATIONS: Postgraduate training in depression related services is a worthwhile approach to improve the quality of pharmaceutical care.publisher: Elsevier articletitle: Impact of training on pharmacists’ counseling of patients starting antidepressant therapy journaltitle: Patient Education and Counseling articlelink: http://dx.doi.org/10.1016/j.pec.2013.09.023 content_type: article copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.status: publishe