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DOI:10.1111/j.1365-2125.2006.02722.x In-hospital cardiac arrest is associated with use of non-antiarrhythmic QTc-prolonging drugs Marie L. De Bruin,1,2 Pim N. J. Langendijk,3 Richard P. Koopmans,4 Arthur A. M. Wilde,5 Hubert G. M. Leufkens1 &
Arno W. Hoes2
1Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy and 2Julius Centre for
Health Sciences and Primary Care, University Medical Centre, Utrecht,
3Department Hospital Pharmacy, 4Department of Internal Medicine
and Department of Pharmacology and Pharmacotherapy and
5Department of Clinical and Experimental Cardiology, Academic Medical
Centre, Amsterdam, the Netherlands

QTc interval-prolonging drugs have been linked to cardiac arrhythmias, cardiac arrest and sudden death. In this study we aimed to quantify the risk of cardiac arrest associated with the use of non-antiarrhythmic QTc-prolonging drugs in an academic Pharmacotherapy, PO Box 80082, 3508 TB Utrecht, the Netherlands. We performed a case–control study in which patients, for whom intervention of the advanced life support resuscitation team was requested for cardiac arrest between 1995 and 2003 in the Academic Medical Centre, Amsterdam, were compared withcontrols regarding current use of non-antiarrhythmic QTc-prolonging drugs. Oddsratios (OR) and 95% confidence intervals (CI) were calculated using unconditionallogistic regression, adjusting for potential confounding factors.
adverse drug reactions, cardiac arrest,
A statistically significant increased risk of cardiac arrest (OR 2.1, 95% CI 1.2, 3.5)was observed in patients who received QTc-prolonging drugs (42/140). The risk wasmore pronounced in patients receiving doses > 1 defined daily dose (OR 2.5, 95%CI 1.1, 5.9), patients taking > 1 QTc-prolonging drug simultaneously (OR 4.8, 95%CI 1.6, 14) and patients taking pharmacokinetic interacting drugs concomitantly (OR Received
25 July 2005
Use of non-antiarrhythmic QTc-prolonging drugs in hospitalized patients with several Published OnlineEarly
underlying disease is associated with an increased risk of cardiac arrest. The effect is dose related and pharmacokinetic drug–drug interactions increase the risk substan-tially. Physicians caring for inpatients should be made aware of the fact that thesenon-antiarrhythmic drugs may be hazardous, so that potential risks can be weighedagainst treatment benefits and additional cardiac surveillance can be requested, ifnecessary.
de pointes is a polymorphic ventricular arrhythmia, A wide range of QTc-prolonging non-antiarrhythmic which can be self-limiting or degenerate into ventricular drugs have been linked to the occurrence of cardiac fibrillation, cardiac arrest and sudden death [2]. Several arrhythmias, especially torsade de pointes [1]. Torsade population-based epidemiological studies on drug- induced arrhythmias have indicated that the proarrhyth- effects of previously used drugs, patients were eligible mic risk of non-antiarrhythmic drugs is not very high only if the medication records of the present hospital- among the general population [3–6], but can be substan- ization started at least 1 day before the index date.
tial among subgroups of patients with underlying dis- Among current users we evaluated the effect of dose, eases, such as schizophrenia [6] or asthma [3]. In daily measured in defined daily dose equivalents, as defined clinical practice, potential proarrhythmic drugs are by the World Health Organization [8]. One defined daily advised not to be prescribed to patients with pre-existing dose equivalent represents the recommended daily dose risk factors [7]. In a hospital setting, however, and par- for an adult (Appendix 1). In order to evaluate dose– ticularly a university hospital setting, this may be hard response effects, the daily dose of QTc-prolonging to achieve, since virtually all patients have some under- drugs was categorized into ≤1 defined daily dose and lying disease and treatment with potentially hazardous >1 defined daily dose. In addition, the effect of the drugs may be necessary. In this study we aimed to quan- number of different QTc-prolonging drugs taken sim- tify the risk of cardiac arrest associated with the use of ultaneously was assessed. We also evaluated the effect non-antiarrhythmic QTc-prolonging drugs in a univer- of concomitant medication, which can inhibit the metabolism of the study drugs. Patients that used QTc-prolonging drugs which are metabolized through one of the cytochrome P450 isoenzymes according to Flock- heart et al. (Appendix 2) [9] were checked for concom- This study was conducted at the Academic Medical itant use of clinically relevant inhibitors of those Centre, Amsterdam, a tertiary care and university teach- ing hospital (1000 beds, 23 600 admissions per year,mean length of stay 9 days). All patients receiving in- hospital care between 1 January 1995 and 25 December The association between the use of non-antiarrhythmic 2003 with complete computerized medical records on QTc-prolonging drugs and cardiac arrest in this hospi- drug exposure variables and potential confounders were tal-based study may be confounded by secondary factors which were associated with both the exposure and theoutcome, such as confounding by indication [10]. We therefore evaluated the influence of age, gender, several A case–control study was performed. Cases were comorbidities (cardiac arrhythmias, other cardiac dis- defined as patients experiencing circulatory arrest for ease, diabetes mellitus, pulmonary disease, hepatic and whom intervention of the advanced life support resusci- renal impairment), concomitant use of class I and III tation team (including medical doctors in the field of antiarrhythmic drugs, total number of currently used anaesthesiology and cardiology, as well as a Cardiac drugs and electrolyte disturbances (calcium, magne- Care Unit nurse) was requested. Patients in whom the sium, potassium) on the calculated association.
arrest occurred either prior to hospital admission, in the Data on potential confounders were retrieved from emergency room (ER) or during an outpatient visit were the medical records through computerized searches.
excluded. Per case, four controls from all other patients Cardiac arrhythmias were defined by hospital discharge receiving inhospital care were selected at the date the diagnosis for the disease (ICD code 427). Antiarrhyth- mic proarrhythmic drug use was defined as current useof class I or III antiarrhythmic drugs. Other cardiac disease was defined as either a prescription for other Current inhospital exposure to non-antiarrhythmic QTc- cardiac drugs and/or a hospital discharge diagnosis (ICD prolonging drugs with a clinically relevant proarrhyth- code) for ischaemic heart disease (410–414), heart fail- mic risk (published clinical evidence for torsade de ure (428), cardiomyopathy (425), valvulopathy (4240, pointes or ventricular arrhythmias) was assessed for 4241, 4242, 4243), artificial heart (valve) (V421, V422, cases and controls (see Appendix 1 [1]). A patient was V432, V433) and/or a hospital procedure for coronary defined as a current user if the index date fell between artery bypass graft (5361, 5362, 5363) or percutaneous the prescription date and the end date of the prescription.
transluminal coronary angioplasty (88370, 88378, Exposure was assessed through the automated phar- 88379). Diabetes mellitus was defined as either a macy database in which all prescribed medication of prescription for antidiabetic drugs and/or a hospital dis- patients receiving inhospital care is collected. To ensure charge diagnosis for diabetes (ICD code 250).
knowledge of all currently used drugs and exclude Pulmonary disease was defined as either a prescription for antiasthmatic drugs and/or a hospital discharge diag- 4.8, 95% CI 1.6, 14) and was twice as high when QTc- nosis (ICD code) for asthma (493), chronic bronchitis prolonging drugs were taken concomitantly with other (491) or emphysema (492). Normal serum electrolyte drugs that inhibit the metabolism (adjusted OR 4.0, 95% levels, based on the criteria used in the Academic Med- CI 1.2, 13). Of the individual drugs, domperidone and ical Centre, were defined as calcium between 2.1 and haloperidol appeared to have the greatest risks (Table 2).
2.55 mmol l−1, magnesium between 0.7 and 1 mmol l−1,potassium between 3.5 and 5 mmol l−1. Hepatic and Discussion
renal impairment were defined by an expert panel The results of our study indicate that current use of non- consisting of an internist and a cardiologist as serum antiarrhythmic QTc-prolonging drugs is associated with total bilirubin concentrations >50 µmol l−1 and serum a doubled risk of cardiac arrest in a hospital setting.
creatinine concentrations >110 µmol l−1 (males) or From previously published data it is known that QTc- 100 µmol l−1 (females), respectively. Serum concentra- prolonging drugs increase the risk of arrhythmias such tions had to be measured during the 7 days previous to as torsade de pointes and sudden death [1, 2]. Further- the index date. If multiple measurements were taken, the more, population-based epidemiological studies indi- value closest to the index date was used.
cate that the proarrhythmic risk of these drugs in thegeneral population is not very high [3–6], but can be substantial among subgroups of patients with underly- The relative risk, estimated by the odds ratio (OR) and ing diseases, such as schizophrenia [6] or asthma [3].
95% confidence interval (CI) of the association between Our most important finding is that these results indicate exposure to QTc-prolonging drugs and cardiac arrest, that the risk of inhospital cardiac arrest is doubled when was calculated using unconditional logistic regression currently using non-antiarrhythmic QTc-prolonging analysis. All potential confounders were univariately drugs. This is, to our knowledge, the first report to quan- associated with cardiac arrest (at a P < 0.1 level) and tify the inhospital relative risk factor on cardiac arrest, included in the multivariate regression analyses. All sta- a hard outcome parameter, in this setting.
tistical analyses were performed using SPSS 10.0 (SPSS Although the study was not designed to investigate individual drugs risks, or to study effects in subgroups,it is interesting to see that the risks were highest among patients taking two medications mainly used in pallia- During the study period, 140 patients were resuscitated tive care: domperidone and haloperidol. Domperidone for cardiac arrest in the Academic Medical Centre and is used to treat gastrointestinal discomfort [11]. In a fulfilled the eligibility criteria. The mean age of cases hospital setting haloperidol is mainly used to treat delir- was significantly higher (59.6 years) than of controls ium [12]. Both drugs are known for their potential proar- (47.5 years) and cases were more often male than were rhythmic effects [12, 13] and warnings are included in controls (65.7% vs. 48.9%). All known potential risk the Summary of Product Characteristics. Apparently, the factors for cardiac arrest were associated with an potential benefits of treatment outweigh the adverse increased risk, notably cardiac arrhythmias, other cardiac effects in a clinical setting. Another interesting finding disease, diabetes mellitus, pulmonary disease, electrolyte is the fact that the association between non- disturbances and hepatic as well as renal impairment.
antiarrhythmic QTc-prolonging drugs and cardiac arrest As expected, the use of antiarrhythmic drugs and the appears to be greater among the 93 patients with total number of currently used drugs were also associated hypokalaemia (adjusted OR 3.3, 95% CI 0.7, 15).
with cardiac arrest (Table 1). The most pronounced were Hypokalaemia is one of the main risk factors for drug- the associations between cardiac arrhythmias (adjusted OR 6.6, 95% CI 3.7, 12) as well as hyperkalaemia The magnitude of the potential problem in a hos- (adjusted OR 4.1, 95% CI 1.6, 10) and cardiac arrest.
pital setting such as this is reflected in the fact that Current use of non-antiarrhythmic QTc-prolonging almost 20% of the source population is using non- drugs was associated with a twofold increased risk of antiarrhythmic QTc-prolonging drugs. This prevalence cardiac arrest (crude OR 1.8, 95% CI 1.2, 2.8). This risk in much higher than that of exposure to one of the drugs increased slightly after adjustment for confounders from this same list in the general population, which is (adjusted OR 2.1, 95% CI 1.2, 3.5). The risk of cardiac arrest increased with dose (adjusted OR >1 defined daily The number of cases included in our study may seem dose 2.5, 95% CI 1.1, 5.9) and number of QTc-prolong- low in a university hospital for a period of almost 9 years ing drugs taken simultaneously (adjusted OR >1 drug [15]. The total number of cardiac arrests for whom inter- vention of the advanced life support resuscitation team A finding consistent with other studies on the associ- was requested, in this study period, exceeded 1200.
ation between QTc-prolonging drugs and cardiac However, almost 50% of the interventions took place in arrhythmias is that there appears to be a positive dose– the ER. No information on current medication use could response relationship [3, 6, 16–19]. In accordance with be retrieved through computerized searches in these out- Ray et al. [20], we found that cytochrome P450 phar- of-hospital cardiac arrest cases. Furthermore, the inclu- macokinetic drug–drug interactions apparently play an sion of inhospital cardiac arrest cases was relatively low (140/600). This was due to the fact that the hospital was The data we used were not recorded for research implementing a computerized physician drug order entry purposes, but to support medical and pharmaceutical system (CPOE) starting in 1996 with two wards and care, to improve medication safety and for administra- gradually increasing the number of wards until mid tive reasons. The main advantage of these data is the fact 2001. Eventually, all wards used this CPOE with the that they were collected prospectively and are unlikely exception of the ER, operation rooms and intensive care to be subject to differential misclassification [21]. How- units. Exclusion of inhospital cardiac arrest cases was ever, we cannot exclude the possibility that some non- mainly because not all requested information, especially differential misclassification of outcome and exposure concerning prescribed drugs, could be retrieved through may have occurred or that some residual confounding may still be present. First, some control patients with a Table 1
Characteristics of cases and controls
Creatinine < 110 µmol l−1 (M),100 µmol l−1 (F) Creatinine > 110 µmol l−1 (M),100 µmol l−1 (F) Table 2
Risk of cardiac arrest and non-antiarrhythmic QTc-prolonging medication
Type of QTc-prolonging drug used† *Adjusted for age, gender, cardiac arrhythmias, other cardiac disease, diabetes mellitus, pulmonary disease, total number ofcurrent drugs, concomitant use of antiarrhythmic drugs, serum potassium, calcium, magnesium, creatinine, and bilirubine.Somepatients used >1 QTc-prolonging drug, numbers do not add up. do-not-attempt-resuscitation order may have actually controls. Third, we may not have been able to control experienced cardiac arrest, without intervention of the fully for disease severity. Patients appeared to be more advanced life support resuscitation team. The proportion severely ill than controls. This was reflected in the higher of patients with a do-not-attempt-resuscitation order was number of prescribed drugs, a higher prevalence of found to depend on age and comorbidity in the Academic comorbidity as well as electrolyte disturbances and the Medical Centre [22]. According to the age distribution, fact that serum levels for electrolytes and renal and we expect that 57 of the 560 control patients in our study hepatic function were measured more often during the may have had a do-not-attempt-resuscitation order.
week before the index date. We took all these factors Assuming that 10% of these patients actually experi- into account in our analyses, but were not able to adjust enced a cardiac arrest implies that only 1% of our control for a standardized measure of disease severity such as patients were misclassified. This may have resulted in a minor underestimation of the true effect. Second, mis- Another factor which may have influenced our results classification of exposure may have occurred, but was is that doctors refrain from prescribing QTc-prolonging minimized, because patients were included only if the drugs to high-risk patients, so-called ‘confounding by medication records of the present hospitalization started contraindication’ [10]. This may have resulted in an at least 1 day before the index date. In addition, it is apparently absent association between use of cisapride likely that any such exposure misclassification will be and cardiac arrest on the one hand and a large associa- random and will be evenly distributed between cases and tion between use of domperidone and cardiac arrest on the other hand, when physicians prescribe domperidone observational design of our research, our findings instead of cisapride in high-risk patients. Cisapride- indicate merely associations and not necessary causal induced arrhythmias have received much greater attention in recent years than domperidone-induced In conclusion, the results of our study indicate arrhythmias [13]. This hypothesis is strengthened by the that current use of non-antiarrhythmic QTc- fact that until 2001 cisapride was taken twice as often prolonging drugs in hospitalized patients with several as domperidone, whereas after 2001 domperidone was underlying disease is associated with an increased taken twice as often as cisapride. The overall awareness risk of cardiac arrest. The effect is dose related and of risks associated with prescribing non-antiarrhythmic pharmacokinetic drug–drug interactions increase the QTc-prolonging drugs to patients is not very high con- observed risk substantially. Hospital specialists sidering the fact that even in the control population should be made aware of the fact that these non- almost one-fifth of the patients were taking these drugs.
antiarrhythmic drugs may be hazardous, so that Since March 2005 physicians and pharmacists have potential risks can be weighed up against treatment been warned by the hospitals’ CPOE when non- benefits and additional cardiac surveillance can be antiarrhythmic QTc prolonging drugs are prescribed. It would be interesting to see if the percentage of patientsprescribed these classes of drugs will decrease over time Competing interests: None declared. This research was funded by Utrecht University, and Although we emphasize above the causative factors an unrestricted grant from the Dutch Medicines Evalu- that explain at least some of our findings, it should be borne in mind that due to the non-experimental, Appendix 1
QTc-prolonging drugs having a clinically relevant proarrhythmic risk and defined daily dose (mg) [1]*
*Clinical data do not provide a strong signal for fexofenadine, fluoxetine, clindamycin, levofloxacin, spiramycin and fluconazole[1]. These drugs are excluded from the original selection. DDD, Defined daily dose. Appendix 2
Clinically relevant P450 interactions according to Fockhart et al. [9]
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