Department of Cardiology
CharitéCampus Virchow Clinic
Augstenburger Platz 1
13353 Berlin
Germany
E-mail address:
wilhelm.haverkamp{at}charite.de
Department of Cardiology and Angiology
Hospital of the University of Münster
Münster
Germany
We have read with great interest the paper which was recently published by Straus et al.1 on the association between the use of non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death (SCD). On the basis of their findings, which were drawn from a large population-based case-control study, the authors concluded that the use of certain non-cardiac drugs that prolong myocardial repolarization is indeed associated with an increased risk of SCD.
This study seems to represent an extension of a methodologically almost identical study published in 2004 by the same group.2 This previous study reviewed all cases of death in the Integrated Primary Care Information study between 1 January 1995 and 1 April 2001 (in the recently published paper, the time of observation was extended to 1 September 2003) and concentrated on the association between current use of antipsychotics and SCD. The results of the studies are similar. In the earlier paper, the current use of an antipsychotic drug was associated with a three-fold increase in risk of SCD. In the present article, current use of non-cardiac QTc-prolonging drugs was associated with a similar increase in risk of SCD (adjusted OR: 2.7), although gastrointestinal drugs and antibiotic drugs were included in the analysis. In their final conclusion, the authors extrapolate their results by emphasizing that 320 cases of sudden death per year can be attributed to the use of non-cardiac QTc-prolonging medication in the Netherlands. The authors stress the role of regulatory authorities in the evaluation of the clinical significance of QTc prolongation induced by drugs.
We believe that extrapolation of these findings has to be made with greatest caution. The authors themselves extensively discuss some of the potential limitations of their study (e.g. the chance of misclassification of events and also misclassification of drug exposure). In addition, the cases occurring during treatment with antipsychotics seem to have made a significant contribution to the study results obtained. The finding that conventional antipsychotics may increase mortality is not new. Epidemiological studies have confirmed a direct relationship between the conventional antipsychotics and the risk of sudden death.35 The newer, so called atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) are considered to be safer.5
A further limitation may result from the methodology of case-control matching. Patients were matched for age, gender, and practice, but the severity of disease was not included. The data of this study suggest that patients who died suddenly had more frequent co-morbidities and usually more frequent use of concomitant cardiovascular drugs. Also, patients on antipsychotics may have been sicker than control patients. Patients with schizophrenia are at higher risk for medical illnesses than people in the general population. The risk of atherosclerosis and cardiac death in these patients is markedly higher and parallels the severity of the disease.6
Last but not least, one should mention the role of the treating physician in the unwanted occurrence of abnormal QTc prolongation and SCD, mostly resulting from torsade de pointes (TdP). There is no question that the most effective way of preventing complications due to drug-induced QTc prolongation is to avoid the use of these drugs. However, there are many QTc-prolonging drugs which have certain therapeutic advantages which the physician usually does not want to miss. In these cases, a systematic approach seems advisable. First of all, the physician prescribing such a drug must be familiar with the problem of drug-induced TdP. Moreover, the physician should also know that the risk for abnormal QTc prolongation and TdP varies between patients; although some patients may have a high propensity to the development of drug-associated TdP, the risk may be low in others. Risk factors for the occurrence of the arrhythmia have been identified (e.g. female gender, bradycardia, and hypokalaemia). Thus, although the role of regulatory authorities in pharmacology is crucial, we should not forget the role of the prescribing physician.
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