The risk of QTc-prolongation and Torsade de Pointes in clinical practice

The risk of QTc-prolongation has become an important issue in drug safety. In rare cases it can lead to serious adverse events like Torsade de Pointes and sudden cardiac death. In the last decades, several drugs have been removed from the market (e.g. cisapride) or restricted in use (e.g. domperidone, (es)citalopram) because of this risk. At the moment, more than 170 drugs are linked with this risk of QTc-prolongation, as defined in the QT-drug lists of CredibleMeds. Furthermore, at lot of other risk factors (e.g. age, female gender, electrolyte disturbances, cardiovascular and other comorbidities, congenital long QT-syndrome) can increase the risk. Due to possible combinations of these factors with additive effect on the QTc-interval, a complex risk estimation is warranted for each individual patient who receives a QTc-prolonging drug. The overall aim of this PhD-project was to study the risk of QTc-prolongation and Torsade de Pointes in clinical practice and to develop tools to help healthcare professionals deal with this risk. To attain this overall aim, specific research questions were defined and investigated in different types of studies. In general, the project can be divided in four major parts. In the first part, epidemiological studies in different settings (psychiatry, University Hospitals of Leuven, community pharmacies) were performed to study the use of QTc-prolonging drugs, concurrent risk factors, and the current risk management of QTc-prolongation in these settings. The second part starts with a systematic review which summarized and assessed the evidence for different risk factors for QTc-prolongation. Further, two clinical studies (in University Hospitals of Leuven and in psychiatric hospitals) were set up to investigate the prevalence of QTc-prolongation in patients starting with a(n) (additional) QTc-prolonging drug, and a preliminary risk score was developed to distinguish between low- and high risk patients. In the third part, Belgian pharmacovigilance data and a diagnostic registry of the University Hospitals of Leuven were screened to select cases of Torsade de Pointes and to analyze the characteristics of these cases. Finally, in the fourth part, tools were developed for clinical practice. On the one hand, the risk score was further optimized and validated, and a first version of an algorithm was proposed that can be translated in an advanced clinical decision support system. On the other hand, an e-learning program was developed for community pharmacists, and the impact on knowledge and clinical practice was investigated. This PhD-thesis starts with a general introduction on QTc-prolongation and Torsade de Pointes and the current guidelines to manage this risk (Chapter 1). The objectives and methods of the project are explained in Chapter 2. The results of the epidemiological studies are presented in Part 2 of the thesis (Chapter 3: psychiatric hospitals; Chapter 4: university hospital; Chapter 5: community pharmacies). All three studies indicated that QTc-prolonging drugs are often prescribed and combined, even in patients who have other risk factors for QTc-prolongation. On top of that, the current risk management and awareness of QTc-prolongation is very limited in all settings. Part 3 consists of a systematic review, two clinical studies and the development of a risk score for QTc-prolongation (the RISQ-PATH score). The systematic review (Chapter 6) gives a clear overview of the available evidence for a broad range of risk factors for QTc-prolongation, including demographic factors, cardiovascular factors, other comorbidities, electrolyte disturbances and QTc-prolonging drugs. Very strong evidence was found for hypokalemia, use of diuretics, antiarrhythmic drugs and QTc-prolonging drugs of list 1 of CredibleMeds. Based on these results, the preliminary RISQ-PATH score was developed. In both clinical studies (Chapter 7: RISQ-PATH study in University Hospitals of Leuven; Chapter 8: QT-study in psychiatry), the mean QTc-intervals did not highly differ between the baseline and follow-up electrocardiograms after the start of a QTc-prolonging drug, but an important number of risk patients did develop QTc-prolongation in a follow-up ECG. The preliminary RISQ-PATH score, with a cut-off of 10 points, was able to distinguish between low- and high-risk patients with a sensitivity of 96% and a negative predictive value of 98%. Consequently, this risk score is promising to identify patients who do not need further ECG follow-up when starting QTc-prolonging drugs. In Part 4, we focused on cases of Torsade de Pointes. In the University Hospitals of Leuven (Chapter 9), a retrospective analysis of a diagnostic registry was performed using the ICD-9 code ‘427.1 paroxysmal ventricular tachycardia’. From 2011 until 2013, 19 cases of Torsade de Pointes secondary to the acquired long QT-syndrome were detected. This number corresponds with an incidence of 0.16 cases of Torsade de Pointes per thousand patients per year, or extrapolated to all Belgian hospitals, approximately 173 possibly lethal cases of Torsade de Pointes in Belgian hospitals each year. The preliminary RISQ-PATH score was able to predict the detected cases. Secondary, with the help of MedDRA preferred terms, the EudraVigilance database was searched for Belgian cases of Torsade de Pointes (Chapter 10). Over 15 years, only 31 cases specifically coded as Torsade de Pointes were identified. These results underline the clear underreporting of QTc-prolongation and Torsade de Pointes to the national authorities in Belgium. Finally, in Part 5, tools for clinical practice were developed. In Chapter 11, the preliminary RISQ-PATH score was further optimized, resulting in the RISQ-PATH model, and validated in a large hospital population (training group: >60,000 patients with an electrocardiogram in 2015 in one of the Nexus hospitals; validation group: >28,000 patients with an electrocardiogram in January-April 2016). With multiple logistic regression analysis, the most optimal prediction model could be designed to predict a QTc-interval ≥450(♂)/470(♀)ms. The RISQ-PATH model, with a cut-off probability of 0.035, could predict a prolonged QTc-interval with an area under the ROC-curve of 0.772, a sensitivity of 87% and a specificity of 45%. These results were confirmed in the validation dataset. A first version of an algorithm was proposed that can be incorporated in a clinical decision support system. As second tool, an e-learning for community pharmacists was developed and implemented in a Flemish pharmacy network (Chapter 12). The e-learning consists of 9 modules, including basic concepts of QTc-prolongation, pharmacovigilance, QTc-prolonging drugs, other risk factors summarized in a risk score, handling drug-drug interactions with an algorithm, communication with physicians and patients, guidelines to plan a local concertation and a library section. The impact and satisfaction of the e-learning was measured with a pre-post knowledge test and a satisfaction questionnaire. The participating pharmacists (response rate of 88.8%) were very satisfied with this training, resulting in a median satisfaction score of 9/10. Furthermore, we found a significant increase in knowledge about this topic immediately after following the e-learning. The pharmacists also indicated that they had more confidence in their own knowledge. In a follow-up study (Chapter 13), we measured the further impact of the e-learning on the activation of drug-drug interaction alerts for QTc-prolongation in the pharmacy software, and the current risk management of QTc-prolongation (by repeating the epidemiological study, see Chapter 5). There was a significant increase in the number of pharmacies in which the drug-drug interaction alerts for QTc-prolonging antibiotics were activated before and after the implementation of the e-learning. Moreover, in comparison with 2014, more actions were taken to deal with this risk (gathering more information of the patient, reviewing the risk factors of the patient, contacting the physician, warning the patient for the risk of QTc-prolongation, replacing one of the concerning QTc-prolonging drugs by an alternative). However, the community pharmacists still have to be encouraged to further improve this risk management. In the closing part of this PhD-thesis (Part 6), a general discussion of the findings is provided, including methodological considerations and a SWOT-analysis of the RISQ-PATH model. In addition, recommendation for the implementation of the proposed tools (clinical decision support and training) and further research perspectives are discussed.nrpages: 314status: publishe

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

Antimicrobial prescribing by Belgian dentists in ambulatory care, from 2010 to 2016

OBJECTIVES: To describe antimicrobial prescribing by Belgian dentists in ambulatory care, from 2010 until 2016. MATERIALS AND METHODS: Reimbursement data from the Belgian National Institute for Health and Disability Insurance were analysed to evaluate antimicrobial prescribing (WHO ATC-codes J01/P01AB). Utilisation was expressed in defined daily doses (DDDs), and in DDDs and packages per 1000 inhabitants per day (DID and PID, respectively). Additionally, the number of DDD and packages per prescriber was calculated. RESULTS: In 2016, the dentistry-related prescribing rate of 'Antibacterials for systemic use' (J01) and 'Antiprotozoals' (P01AB) was 1.607 and 0.014 DID, respectively. From 2010 to 2016, the DID rate of J01 increased by 6.3%, while the PID rate declined by 6.7%. Amoxicillin and amoxicillin with an enzyme inhibitor were the most often prescribed products, followed by clindamycin, clarithromycin, doxycycline, azithromycin and metronidazole. The proportion of amoxicillin relative to amoxicillin with an enzyme inhibitor was low. The narrow-spectrum antibiotic penicillin V was almost never prescribed. CONCLUSIONS: Antibiotics typically classified as broad- or extended-spectrum were prescribed most often by Belgian dentists during the period 2000-2016. Although the DID rate of all 'Antibacterials for systemic use' (J01) increased over the years, the number of prescriptions per dentist decreased since 2013. The high prescription level of amoxicillin with an enzyme inhibitor is particularly worrying. It indicates that there is a need for comprehensive clinical practice guidelines for Belgian dentists.status: publishe

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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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