1Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy, PO Box 80082, 3508 TB Utrecht, The Netherlands
2Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands
3The Uppsala Monitoring Centre, Uppsala, Sweden
Received 22 September 2004; revised 3 November 2004; accepted 25 November 2004; online publish-ahead-of-print 6 January 2005.
* Corresponding author. Tel: +31 30 253 7322; fax:+31 30 253 9166. E-mail address: m.l.debruin{at}pharm.uu.nl
See page 536 for the editorial comment on this article (doi:10.1093/eurheartj/ehi155)
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Abstract |
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Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n=5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.891.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database.
Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.
Key Words: Adverse drug reaction reporting systems Arrhythmia Potassium channels Pre-clinical drug evaluation Sudden death Torsades de pointes
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Introduction |
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In 1997, the Committee for Proprietary Medicinal Products (CPMP) of the European Union adopted a Points to Consider document which made recommendations for non-clinical and clinical approaches to assess the risk of QTc-interval prolongation and TDP for non-cardiovascular drugs.3 The strategies described are now being harmonized by the International Conference of Harmonization (ICH), and a draft version of the Note for Guidance document is currently available.4 Based on these regulatory recommendations, most new drugs are tested nowadays for their ability to block HERG potassium channels and rapid potassium currents (IKr). However, there is still much debate going on within the pharmaceutical industry, as well as regulatory authorities, on the predictive value of HERG channel binding and the risk of cardiac arrhythmias. For example, collaborating researchers from several pharmaceutical industries recently published an extensive overview of 100 QTc-prolonging drugs and their ability to bind to HERG-channels in relation to free-plasma concentrations.5 These authors related this anti-HERG activity to the torsadogenic propensities of the drugs. Drugs were assigned to one of the following five categories of decreasing torsadogenicity: (i) anti-arrhythmic drugs, (ii) drugs withdrawn or suspended due to TDP risk, (iii) drugs with measurable TDP risk in humans or many TDP case reports in published literature, (iv) isolated TDP case reports, and (v) no published reports of TDP in humans, but with a certain degree of suspicion because of, for example, therapeutic class, drug interactions, etc. The clinical relevance of this type of categorization, however, remains to be confirmed.
We therefore studied the magnitude of anti-HERG activity in relation to pro-arrhythmic risk, defined as the occurrence of serious ventricular arrhythmias and sudden death, in day-to-day practice, using drug safety data obtained from the World Health Organization (WHO) adverse drug reactions database.
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Methods |
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For this study all reports up to the first quarter of 2003 of a previously published list of 52 pro-arrhythmic drugs, for which information on both effective free therapeutic plasma concentrations (ETCPunbound) as well as inhibition of HERG/IKr currents were available5 (Appendix 1) were used.
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In the WHO-UMC database the case reports of interest were identified by means of the WHO-ART adverse reaction terms: cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia.7 The anti-HERG activity of the study drugs was regarded as the exposure. Anti-HERG activity was defined as the free plasma concentrations attained during clinical use (ETCPunbound) divided by the concentration which inhibits 50% of the potassium channels (IC50). When multiple HERG-binding properties or free plasma concentrations have been described in the literature, the lowest IC50 and the maximum ETCPunbound were used.5 Per ADR-report, anti-HERG activities of all study drugs which were assigned as suspect were assessed. If multiple study drugs were reported, anti-HERG activities were summed using the following formula:
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The ETCPunbound/IC50 ratio of the study drugs varied from less than 0.0003 to 40, and a log10 transformation was used. This exposure measure can be regarded as the therapeutic/toxic ratio of a drug or drug combination. It was expected that, with increasing ETCPunbound/IC50 ratio, the risk of an adverse event of interest increases.
Potential confounders
The association between anti-HERG activity and the study outcome may be confounded by secondary factors including age, sex, several concomitant diseases (heart disease, pulmonary disease, diabetes mellitus), pharmacokinetic drugdrug interactions (defined as clinically relevant cytochrome P450 interactions by Flockhart et al.8), concomitant use of drugs which may lower blood potassium levels, year of reporting, and time since first marketing. When multiple study drugs were reported, in the analyses, the shortest latency period between marketing and reporting was used.
For the assessment of concomitant diseases, proxies derived from the available information provided by the reporters were used (Table 1). Time since marketing was calculated as the year of reporting minus the year of first marketing (Appendix 1).
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Different case-definitions
Since we used a composite study outcome, we also looked at the five different endpoints separately. Cardiac arrest, sudden death, TDP, ventricular fibrillation, and ventricular tachycardia are the most precisely defined serious outcomes which may result from drug-induced QTc-prolongation in the WHO-ART terminology. Other, less well-defined terms, such as cardiac fibrillation, and ventricular arrhythmias, however, may also include study outcomes of interest. We therefore also calculated RORs using these two latter case definitions. The association of anti-HERG activity with QTc-prolongation, a precursor for drug-induced arrhythmias, and syncope, one of the clinical symptoms, were also assessed. As a negative control, we studied the association between anti-HERG activity and two randomly picked study outcomes, without proven association with HERG: hepatitis and skin ulcer.
Missing values
The WHO-UMC data are summaries of case reports of suspected ADRs, originally submitted to national pharmacovigilance centres. However, reports such as these often do not contain a full medical history, and data on confounders may be incomplete or lacking. To assess the presence of concomitant diseases, use was made of the information in the field predisposing or contributing conditions (shown in 2% of the reports), as well as known co-medication (shown in 50% of the reports).
Age and gender of the patient were unknown in 20% and 9% ADR reports respectively. Unknown gender was analysed as a separate category. Missing ages were imputed based on the mean age of patients of the same gender, using the same drugs.
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Results |
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When taking an IC50/ETCPunbound ratio of 30, corresponding to a ETCPunbound/IC50 ratio of 0.033, as a cut-off point, as suggested by Redfern et al.,5 the adjusted ROR for a ratio over 0.033 vs. a ratio below 0.033 was 3.68 (95% CI 3.473.91). This indicates that drugs which bind to HERG potassium channels at levels less than 30 times the therapeutic levels, have a three to four times stronger association with serious ventricular arrhythmias and sudden death as an adverse reaction, compared with drugs which bind to HERG potassium channels at concentrations more than 30 times the therapeutic levels.
In Figure 1, anti-HERG activities of the study drugs were grouped into five categories. Adjusted RORs were calculated for these categories using an ETCPunbound/IC50 ratio of < 1/1000 as the reference category. The ROR of 5.97 indicates that for drugs for which the IC50 is 1 to 10 times higher than the ETCPunbound the risk of reporting serious ventricular arrhythmias and sudden death is six times higher compared with drugs for which the IC50 is more than 1000 times higher than the ETCPunbound (reference category).
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Discussion |
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Our findings support the hypothesis that anti-HERG activity is associated with risk of serious ventricular arrhythmias, and sudden death, in daily clinical practice. As expected, drugs which bind to HERG potassium channels in concentrations close to therapeutic plasma concentrations, have a high risk of reports of serious ventricular arrhythmias and sudden death, probably indicating a pro-arrhythmic effect. The smaller the margin between IC50 (toxic drug level) and ETCPunbound value (therapeutic drug level), the higher the risk (Figure 1). The ORs in this study represent a relative risk, but do not estimate the actual pro-arrhythmic risk in day-to-day practice. They reflect the disproportionality of serious ventricular arrhythmias, and sudden death, as an ADR among all possible ADRs of a certain drug. The overall OR of 1.93 indicates that for every single unit increase in the log10 (e.g. from 1/1000 to 1/100, from 1/100 to 1/10, etc) of the therapeutic/toxic ratio of a drug, the risk of reporting serious ventricular arrhythmias, and sudden death, doubles.
Previously, several studies have shown that female gender is a rather strong predictor for drug-induced TDP, since 70% of the published case reports concerned women.12,13 In the present study, we found that (of the ADR reports with known gender of the patient) 56% of the case patients were female, compared with 58% of the patients experiencing other ADRs. We used, however, a composite endpoint which included, apart from TDP: cardiac arrest, sudden death, ventricular fibrillation, and ventricular tachycardia. When we focused solely on the ADR-reports of TDP, we found that more than 68% of these reports concerned females.
General limitations of the dataset should be discussed. First, the study was restricted to drugs for which HERG binding properties as well as therapeutic free plasma concentrations have been studied, and published. The number of drugs being tested for HERG-activities is still increasing and these analyses should be repeated when more data are available. Secondly, the ETCPunbound/IC50 ratios were based on therapeutic plasma levels at recommended doses. The case reports in the WHO-UMC database, however, do not disclose in sufficient detail the doses used by these patients. Plasma levels may increase when pharmacokinetic drugdrug interactions occur or alternative routes of administration are used. Specific anti-HERG activities were only known for terfenadine plus CYP3A4 inhibitors, and iv erythromycin. Uncertainty of actual plasma levels may have influenced our results.
The method of reaction proportion signalling has several drawbacks. ADRs were reported on a voluntary basis, and therefore represented only a fraction (<10%) of the actual adverse events that occurred.14,15 Selective under- and over-reporting of particular ADRs within the overall under-reporting can lead to misinterpretations when comparing drugs with respect to ADRs. ADRs which are more likely than others to be reported are ADRs of relatively new drugs10,16 severe ADRs,14,16 and ADRs which are not listed in the summary of product characteristics.14 All these aspects can be seen in the subgroup analyses we performed. The association was stronger shortly after marketing, and it was less well pronounced among patients taking anti-arrhythmic drugs, for which the pro-arrhythmic side-effects have been already described (Table 4). The association weakens when the study event is less severe (syncope vs. ventricular arrhythmia). Another factor which may have influenced our results is selective reporting as a result of media attention. This factor has been described previously for the association between cardiac arrhythmias and the use of anti-histamine drugs,11 and similarly in our study the association between exposure and outcome is stronger after 1 January 1998 than before.
We did not, of course, study the effects of individual drugs, but the in vitro anti-HERG activities of drugs, and combinations of drugs. These molecular properties of drugs are unlikely to be known by healthcare providers in daily practice. We therefore think that we have used a more objective exposure measure, which is less susceptible to recognized bias. Moreover, all sub-group analyses point in a similar direction and negative control outcomes which should not be related to anti-HERG activity (hepatitis, skin ulcer) are indeed unrelated to the exposure. We therefore believe that our findings represent a true connection.
There were several drugs that appeared not to follow the predicted association. Their observed cases/non-cases ratios were relatively high or low compared with the ratios fitted by our logistic model (Appendix 1, Figure 2). For ibutilide, bepridil, amiodarone, sotalol, and flecainide, the cases/non-cases ratio is higher than expected. These drugs are prescribed to patients with cardiac diseases and therefore confounding by indication may have caused this relatively high fraction of case-events. In addition, only less than 200 case reports were used to estimate the ratio for ibutilide and bepridil. Slightly more than 300 case reports were used to estimate the cases/non-cases ratio for combination of terfenadine and CYP3A4 inhibiting drugs. This relatively high ratio may have been caused by selective reporting of ADRs due to media attention for cardiac arrhythmias associated with the combined use of these drugs. For ketoconazole, mefloquine, and aprindine the fraction of case-events in the WHO-UMC database is much lower than expected, based on anti-HERG activity. These drugs could be regarded as drugs with false positive anti-HERG activities. For ketoconazole this effect was described before.5 However, the low ratio may also be explained by the fact that there were relatively many ADR reports of skin and appendages disorders as well as liver and biliary system disorders, competing with the ADRs of our interest to stand out disproportionately against all other case reports. Both ADRs counted for 23% of all ADRs that were reported for ketoconazole, whereas the percentages among the case reports of all studied drugs together were 12 and 4%, respectively. Similarly the relatively high proportion of case reports of psychiatric disorders (31% for mefloquine vs. 13% overall) and central and peripheral nervous system disorders (25% for mefloquine vs. 14% overall) could have competed with the ADRs of our interest.
Drugs that bind to HERG potassium channels in concentrations close to or lower than therapeutic plasma concentrations (i.e. have a high log10 ETCPunbound/IC50 ratio) have a high risk of reports of serious ventricular arrhythmias, and sudden death, in the WHO-UMC database, indicating a higher pro-arrhythmic risk. The higher the IC50 (toxic drug level) compared with the ETCPunbound value (therapeutic drug level), the higher this risk. These findings support the value of pre-clinical HERG testing for predicting pro-arrhythmic effects of medicines.
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Acknowledgements |
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References |
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