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      Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson's disease

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          Abstract

          Aim

          Domperidone is preferentially used over other antiemetic agents to treat digestive symptoms in Parkinson's disease (PD). Concerns have been raised regarding an increased risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD) associated with domperidone in the general population. However, the risk in PD is unknown.

          Methods

          We conducted a multicentre retrospective cohort study using administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink. Using a nested case–control analysis, we estimated the rate ratios (RRs) of VT/SCD associated with domperidone use compared to no use in patients newly‐diagnosed with PD. VT/SCD events were identified using administrative medical records and vital statistics with a manual review of all potential cases. Meta‐analytic methods were used to estimate overall effects across sites.

          Results

          Among 214 962 patients with PD, 2907 cases of VT/SCD were identified during 886 581 person‐years of follow‐up (incidence rate 3.28 per 1000 persons per year). Current use of domperidone was associated with a non‐statistically significant 22% increased risk of VT/SCD (RR 1.22; 95% CI 0.99–1.50) compared with no use. The risk was significantly elevated in those with a history of cardiovascular disease (RR 1.38; 95% CI 1.07–1.78), but not in those without (RR 1.21; 95% CI 0.81–1.81). Dose and duration of use did not affect the magnitude of the risk.

          Conclusion

          Domperidone use may increase the risk of VT/SCD in patients with PD, particularly those with a history of cardiovascular disease. This risk may be underestimated because of imprecision in identifying VT/SCD events.

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          Most cited references19

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          Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death.

          To assess the association between the use of non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. A population-based case-control study was performed in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from more than 500,000 persons. All deaths between 1 January 1995 and 1 September 2003 were reviewed. Sudden cardiac death was classified based on the time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, gender, date of sudden death, and general practice. The exposure of interest was the use of non-cardiac QTc-prolonging drugs. Exposure at the index date was categorized into three mutually exclusive groups of current use, past use, and non-use. The study population comprised 775 cases of sudden cardiac death and 6297 matched controls. Current use of any non-cardiac QTc-prolonging drug was associated with a significantly increased risk of sudden cardiac death (adjusted OR: 2.7; 95% CI: 1.6-4.7). The risk of death was highest in women and in recent starters. The use of non-cardiac QTc-prolonging drugs in a general population is associated with an increased risk of sudden cardiac death.
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            Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study.

            Limited information from spontaneous reports and results of two case-control studies raised concern about the cardiotoxicity of oral domperidone therapy. This case-control study nested in a retrospective cohort evaluated the combined risk of serious ventricular arrhythmia (SVA) and sudden cardiac death (SCD) in users of domperidone compared with users of proton pump inhibitors (PPIs), or non-users of these medications.
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              Immeasurable time bias in observational studies of drug effects on mortality.

              Observational studies suggesting that some drugs are effective at reducing mortality may have been subject to "immeasurable time bias" arising from the unidentified presence of hospitalizations when defining drug exposure with computerized health databases. The author illustrates the bias using a case-control study of 1,313 deaths and 1,313 controls selected from a cohort of 2,049 patients with chronic obstructive pulmonary disease from Saskatchewan, Canada, identified from 1990 and followed up through 1999. Different approaches were used to estimate the rate ratio of death associated with inhaled corticosteroid exposure, defined by a prescription dispensed in the 30-day period prior to the index date. More cases had been hospitalized during the 30-day exposure period (72%) than controls (26%), with lower durations of stay for cases who received an inhaled corticosteroid prescription (9.9 vs.16.2 days), thus introducing variations in measurable exposure times. The raw analysis that did not consider hospitalization found a rate ratio of 0.60 (95% confidence interval (CI): 0.50, 0.73). Alternatively, analyses accounting for variations in measurable times resulted in a rate ratio of 0.93 (95% CI: 0.76, 1.14) when weighted by measurable time, while use of the Kaplan-Meier estimator of the 30-day cumulative incidence of exposure found a rate ratio of 1.35 (95% CI: 1.14, 1.60). In conclusion, immeasurable time bias may be present in several observational database studies suggesting that certain drugs are effective at reducing mortality.
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                Author and article information

                Journal
                Br J Clin Pharmacol
                Br J Clin Pharmacol
                10.1111/(ISSN)1365-2125
                BCP
                British Journal of Clinical Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                0306-5251
                1365-2125
                19 May 2016
                August 2016
                : 82
                : 2 ( doiID: 10.1111/bcp.v82.2 )
                : 461-472
                Affiliations
                [ 1 ] Centre for Clinical Epidemiology, Lady Davis Institute for Medical ResearchJewish General Hospital Montréal QCCanada
                [ 2 ] Department of Neurology and NeurosurgeryMcGill University Montréal QCCanada
                [ 3 ] Department of Epidemiology and BiostatisticsMcGill University Montréal QCCanada
                [ 4 ] Montreal Heart Institute Adult Congenital CenterUniversité de Montréal Montréal QCCanada
                [ 5 ] Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital and the Edmond J. Safra Program in Parkinson's Disease Research University of Toronto Toronto ONCanada
                [ 6 ] Faculty of Health Sciences, College of PharmacyUniversity of Manitoba Winnipeg MBCanada
                [ 7 ] Department of Family Medicine, Cumming School of MedicineUniversity of Calgary, Health Sciences Centre Calgary ABCanada
                [ 8 ] Faculty of PharmacyUniversity of Montreal Montreal QCCanada
                [ 9 ] School of Kinesiology and Health ScienceYork University Toronto ONCanada
                [ 10 ] Department of Community Health and EpidemiologyDalhousie University Halifax NSCanada
                [ 11 ] College of Pharmacy and NutritionUniversity of Saskatchewan Saskatoon SKCanada
                [ 12 ] Department of Mathematics and StatisticsMcGill University Montréal QCCanada
                [ 13 ] Anesthesiology, Pharmacology & TherapeuticsUniversity of British Columbia Vancouver BCCanada
                [ 14 ] Department of Medicine, Pulmonary DivisionJewish General Hospital Montreal QCCanada
                Author notes
                [*] [* ] Correspondence Dr Christel Renoux, Centre for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, 3755 Cote Ste‐Catherine, Montreal, Quebec H3T 1E2, Canada. Tel.: +1 (514) 340 ‐ 8222 ext 4561; Fax: +1 (514) 340 ‐ 7564; E‐mail: christel.renoux@ 123456mcgill.ca
                [*]

                The Canadian Network for Observational Drug Effect Studies (CNODES) investigators are: Samy Suissa (Principal Investigator); Colin R. Dormuth (British Columbia); Brenda R. Hemmelgarn (Alberta); Gary F. Teare (Saskatchewan); Patricia Caetano and Dan Chateau (Manitoba); David A. Henry and J. Michael Paterson (Ontario); Jacques LeLorier (Québec); Adrian R. Levy (Nova Scotia); Pierre Ernst (UK Clinical Practice Research Datalink (CPRD)); Robert W. Platt (Methods); and Ingrid S. Sketris (Knowledge Translation). CNODES, a collaborating centre of the Drug Safety and Effectiveness Network (DSEN), is funded by the Canadian Institutes of Health Research (Grant Number DSE‐111845).

                Article
                BCP12964 MP-00087-16.R2
                10.1111/bcp.12964
                4972162
                27062307
                26ece121-d059-4b26-8dcf-4e104455aa87
                © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 27 January 2016
                : 15 March 2016
                : 02 April 2016
                Page count
                Pages: 12
                Funding
                Funded by: Canadian Institutes of Health Research
                Award ID: DSE‐111845
                Categories
                Drug Safety
                Drug Safety
                Custom metadata
                2.0
                bcp12964
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:17.07.2016

                Pharmacology & Pharmaceutical medicine
                domperidone,parkinson's disease,sudden cardiac death,ventricular arrhythmia

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