Marie Louise De Bruin drug induced arrhythmias Quantifying the problem Cover design: Tom Frantzen CIP-gegevens Koninklijke Bibliotheek, Den Haag De Bruin, Marie Louise Drug-induced arrhythmias, quantifying the problem / Marie Louise De Bruin Thesis Utrecht - with ref.- with summary in Dutch ISBN: 90-808203-3-4 © Marie Louise De Bruin drug-induced arrhythmias, quantifying the problem Geneesmiddel-geïnduceerde hartritmestoornissen, kwantificering van het probleem (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit van Utrecht op gezag van de Rector Magnificus Prof. dr W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op woensdag 1 december 2004 des namiddags om 14.30 uur door Marie Louise De Bruin Geboren op 1 april 1974 te Haarlem promotores Prof. dr H.G.M. Leufkens Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaco- epidemiology and Pharmacotherapy, Utrecht University, Utrecht, the Netherlands Prof. dr A.W. Hoes Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands The work in this thesis was performed at the Department of Pharmacoepidemiology and Pharmacotherapy of the Utrecht Institute for Pharmaceutical Sciences (Utrecht) and the Julius Center for Health Sciences and Primary Care (Utrecht), in collabo- ration with the PHARMO Institute (Utrecht), the Netherlands Pharmacovigilance Centre Lareb (‘s-Hertogenbosch), the WHO-Uppsala Monitoring Centre (Uppsala, Sweden) and the Academic Medical Center (Amsterdam). The research presented in this thesis was funded by the Utrecht Institute for Pharmaceutical Sciences, and an unrestricted grant from the Dutch Medicines Evaluation Board. The study presented in chapter 3.1 was funded by an unrestricted grant from Janssen Pharmaceutica NV, Beerse, Belgium. Financial support from the Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged. Voor mijn ouders contents 1 Introduction 9 2 Quantification of the risk of drug-induced arrhythmias 2.1 Nonsedating antihistamine drugs and cardiac arrhythmias, 25 biased risk estimates from spontaneous reporting systems? 2.2 QTc-prolonging drugs and hospitalisations for cardiac arrhythmias 37 2.3 Proarrhythmic drugs and cardiac arrest, a hospital based case- 49 control study 3 Special focus on high-risk groups 3.1 Use of cisapride with contraindicated drugs in the Netherlands 63 3.2 Predicting arrhythmias and sudden death in diabetic patients taking 79 non-antiarrhythmic proarrhythmic drugs 4 Molecular strategies 4.1 Pharmacogenetics of drug-induced arrhythmias, a feasibility study 97 using spontaneous adverse drug reaction reporting data 4.2 Anti-HERG activity and the risk of drug-induced arrhythmias and 111 sudden death 5 Methodological issues 5.1 Validation of hospital discharge diagnosis for cardiac arrhythmias 131 5.2 Non-differential misclassification in pharmacoepidemiological 143 studies, the example of drug-induced arrhythmias 6 General discussion On the search for clinically relevant drug-induced arrhythmias, 165 options in study design 7 Summary 189 8 Samenvatting 197 Appendix 1 205 Appendix 2 209 Appendix 3 211 Dankwoord 213 List of publications 217 Chapter 1 introduction introduction A 59-year-old man presented himself to the emergency department after playing handball, complaining of shortness of breath for 45 minutes associated with dizziness and upper extremity tingling. His medical history was significant only in relation to hypertension. He had had palpitations 10 years ago and was prescribed verapamil with complete resolution of symptoms. He still was taking verapamil 40mg twice daily, and two days previously he had taken two tablets of terfenadine 60mg for one day, for nasal congestion associated with hay fever. Initial physi- cal examination revealed a well-developed, well-nourished man in mild distress. The patient was placed on a cardiac monitor, which revealed three episodes of Torsade de Pointes associated with shortness of breath and dizziness, but without loss of consciousness. He was given 2g magnesium which led to resolution of the arrhythmia. The QT-interval reverted to 0.36ms from 0.46ms during the episodes of Torsade de Pointes. The possibility of the arrhythmia being caused by a myocardial infarction, silent ischemia, electrolyte disturbance or liver disease was excluded. It was considered likely that the terfenadine lengthened the patient’s QT-interval sufficiently to allow the increased sympathic tone produced from playing handball to trigger Torsade de Pointes [1]. This publication in 1997 was probably a pivotal case report that triggered public awareness about the seriousness of drug-induced arrhythmias. Syncope during initiation of quinidine therapy was already recognised in the 1920s [2], and cardiac effects of first-generation antihistamines [3, 4], antidepressants [5] as well as anti- psychotics [6] had been described in the 1960s and 1970s. In addition, in the late 1980s and early 1990s the first few drugs had already been withdrawn from the market for their proarrhythmic potential (Table 1). However, this case report was the first proof that an apparently harmless drug, being sold without prescription, and used to treat a mild condition such as hay fever could cause a potentially fatal adverse reaction, even when the drug is taken in the recommended therapeutic dose, and without concomitant use of metabolism inhibiting drugs. Since the publication of this case report, seven drugs, including terfenadine, have been taken off the market in parts of the world or worldwide, because of their potential to prolong the QTc-interval or even cause Torsade de Pointes arrhythmias 11 introduction (Table 1). Over the last decade QTc-interval prolongation and Torsade de Pointes have been the single most common cause of withdrawal from or restriction of the use of drugs on the market, and it appears to be the latest ‘epidemic’ in drug regulatory affairs [7]. Although they have gained much attention during recent years, drug-induced arrhythmias have been in existence for centuries. Recently, Mari et al [8] hypothesised that Napoleon may have died from Torsade de Pointes arrhythmias. At the time of his death, the Emperor was exposed to three agents that could block cardiac potassium channels (arsenic, quinidine and antimony) as well as to two agents (mercury chloride and antimony potassium tartrate) which may cause gastrointestinal potassium loss predisposing to Torsade de Pointes. Table 1 Reasons for regulatory action of drugs with proarrhythmic potential [7] Drug Indication Year Reason(s) for regulatory action Prenylamine Angina pectoris 1988 TdP* Terodiline Bladder instability 1991 QTc-prolongation and TdP Encainide Cardiac arrhythmia 1991 Proarrhythmic effects Flosequinan Heart failure 1993 Excess mortality, possibly due to arrhythmias Terfenadine Allergy 1998 QTc-prolongation and TdP Sertindole Schizophrenia 1998 QTc-prolongation and potential for TdP Astemizole Allergy 1999 QTc-prolongation and TdP Grepafloxacin Infection 1999 QTc-prolongation and TdP Cisapride Gastroparesis 2000 QTc-prolongation and TdP Droperidol Psychosis 2001 QTc-prolongation and TdP Levacetylmethadol Opioid dependence 2001 QTc-prolongation and TdP *TdP: Torsade de Pointes 12 introduction why are drug-induced arrhythmias of concern? Although drug-induced arrhythmias are very rare [9], they are nevertheless of concern. The following facts are central to the regulatory concern: • Drug-induced arrhythmias are potentially fatal [10] • They concern a broad range of widely used drugs, from different therapeutic classes [11, 12], and the number of drugs concerned continues to increase • For the majority of the drugs, proarrhythmic potential was recognised only after approval [13], at a time when the drugs were already widely prescribed • Most of the drugs are prescribed for otherwise relatively benign or low risk conditions, and some of the drugs are even available without prescription [14] • Drug-drug interactions may substantially increase the proarrhythmic risk in some instances [15] Regulators usually have to weigh the potential proarrhythmic risks of treatment against the benefits in the context of the potentially large numbers of exposed patients and availability of therapeutic alternatives, and have to estimate the public health impact of their decisions. When therapeutic alternatives are available, or the drugs causing concern are used to treat mild diseases (as in the case of astemizole and terfenadine), the decision to withdraw a drug from the market may be straight- forward. Nevertheless, when the therapeutic equality of the alternatives is debatable (for example in the case of sertindole), or the disease treated is much worse than the potential adverse reaction (such as arsenic trioxide [16]), regulatory decision-making is much more complex. In order to take appropriate regulatory measures, it is essential to have detailed information about several relevant aspects of the adverse reaction. The clinical pro- blem should be described while some understanding of the physiological mechanism underlying the drug-induced disease would be useful, although this often remains unknown. In addition, epidemiological research is needed to quantify the magnitude of the problem and to identify patient groups at increased risk of the adverse reaction. 13 introduction Figure 1 ECG of an 83 year old female who developed Torsade de Pointes while