Non-cardiac QTc-prolonging drugs and the risk of sudden
Sabine M.J.M. Straus1,2,3, Miriam C.J.M. Sturkenboom1,2, Gyse `le S. Bleumink1,4,
Jeanne P. Dieleman1,2, Johan van der Lei2, Pieter A. de Graeff3,5, Jan Herre Kingma4,5,
and Bruno H.Ch. Stricker1,4*
1Pharmaco-Epidemiology Unit, Departments of Epidemiology and Biostatistics and Internal Medicine, Erasmus Medical
Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands;2Department of Medical Informatics, Erasmus Medical Center,
3000 DR Rotterdam, The Netherlands;3Medicines Evaluation Board, The Hague, The Netherlands;4Inspectorate for Health
Care, The Hague, The Netherlands; and5Department of Clinical Pharmacology, University of Groningen, Groningen, The
Received 6 February 2005; revised 1 April 2005; accepted 7 April 2005; online publish-ahead-of-print 11 May 2005
Aims To assess the association between the use of non-cardiac QTc-prolonging drugs and the risk of
sudden cardiac death.
Methods and results 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 symp-
toms 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.
Conclusion The use of non-cardiac QTc-prolonging drugs in a general population is associated with an
increased risk of sudden cardiac death.
Sudden cardiac death;
In developed countries, sudden cardiac death is one of the
major causes of cardiovascular mortality.1According to the
most recent definition, sudden cardiac death is a natural
death due to cardiac causes, heralded by abrupt loss of con-
sciousness within 1 h after the onset of acute symptoms or
an unwitnessed, unexpected death of someone seen in a
stable medical condition ,24 h previously with no evidence
of a non-cardiac cause.1–3Probably, the large majority of
cases of sudden cardiac death is due to ventricular fibrilla-
tion.2,4The major unanswered question in sudden cardiac
death, however, is which precipitating event causes arrhyth-
mia in an otherwise stable patient. Probably, it is a complex
interplay among myocardial injury, chronic and acute coron-
ary events, autonomic tone, electrolyte state, drugs, and
genetic factors that determine the occurrence of a life-
In the past decade, one of the most frequent causes of
drug restriction or withdrawal has been prolongation of
the QTc interval associated with fatal cardiac arrhythmias.
Lengthening of QTc interval represents the prolongation of
the action potential and is used as a surrogate marker for
the prediction of this serious adverse drug effect.7The
website of the International Registry for Drug-induced
Arrhythmias maintained by the Georgetown University
htm) provides an up-to-date list of drugs that prolong the
QTc interval and/or induce Torsades de Pointes or ventricu-
lar arrhythmia.8The researchers have classified drugs into
four categories varying from drugs that are generally con-
sidered to confer a risk of Torsade de Pointes (list 1) and
drugs that, when used in usual dosages, are unlikely to
increase the risk (list 4). This potentially fatal adverse reac-
tion is not only associated with cardiovascular drugs, but
also with non-cardiovascular drugs. The risk of arrhythmias
and sudden cardiac death during the use of non-cardiac
QTc-prolonging drugs has attracted considerable clinical
and regulatory attention.7,9
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org
*Corresponding author. Tel: þ31 10 4088229.
E-mail address: email@example.com
European Heart Journal (2005) 26, 2007–2012
by guest on June 6, 2013
Therefore, our objective was to assess the risk of sudden
cardiac death and the use of non-cardiac QTc-prolonging
drugs in a case–control study in a well-defined general popu-
lation with complete coverage of all relevant health care
All data were retrieved from the IPCI project, a longitudinal obser-
vational database, containing data from computer-based medical
records of a group of 150 general practitioners (GPs) in The
Netherlands. In the Dutch health care system, the GP has a
pivotal role by acting as a gatekeeper for all medical care. Nearly
every citizen is enrolled in the practice of a GP independent of
health status.10Details of the database have been described else-
where.10,11Briefly, the database contains the complete medical
records of ?500 000 citizens. The electronic records contain
coded and anonymous data on demographics, symptoms (in free
text), and diagnoses (using the International Classification for
Primary Care12and free text) from GPs and specialists, referrals,
laboratory findings, hospitalizations, and drug prescriptions, includ-
ing their indications and dosage regimen. To maximize completeness
of the data, GPs participating in the IPCI project are not allowed to
maintain a system of paper-based records besides the electronic
medical records. The project complies with European Union guide-
lines on the use of medical data for medical research and has
been proved valid for pharmaco-epidemiological research in
several validation studies that evaluated the quality of the available
information.11The Scientific and Ethics Advisory Board of the IPCI
project approved this study.
The source population comprised all subjects of 18 years and older,
who were registered with a GP participating in the IPCI project for
at least 1 year. Subjects with a diagnosis of cancer were excluded
from the source population, because in these patients the cause
of death is often difficult to assess and usually not unexpected.
The study period started on 1 January 1995 and ended on 1
September 2003. All subjects were followed until death, transferal
out of practice, date of last data collection, or end of the study
period, whichever came first.
Case and control definition
The computerized medical and demographic data were screened for
deaths that occurred during the study period. The medical records
of identified cases of death were reviewed manually to assess
whether death could be classified as sudden cardiac death.
Validation was performed independently by two physicians who
were blinded to exposure (S.M.J.M.S. and G.S.B.) and in the case
of discrepancy, a third expert (B.H.Ch.S.) arbitrated. Case assess-
ment was based on the most recent definition of sudden cardiac
death: a natural death due to cardiac causes heralded by abrupt
loss of consciousness within 1 h after the onset of acute symptoms
or an unwitnessed, unexpected death of someone seen in a stable
medical condition ,24 h previously with no evidence of a non-
cardiac cause.1–3Cases were classified as (probable) sudden
cardiac death if the medical record indicated that death occurred
within 1 h after the onset of cardiovascular symptoms, and if the
following wording was found in the free text: ‘sudden cardiac
death’, ‘acute cardiac death’, ‘mors subita’, ‘sudden death’,
‘died suddenly’, ‘died unexpectedly’, or if this was an unwitnessed,
unexpected death of someone seen in ‘good health’ or in a stable
medical condition ,24 h previously and without evidence of a
non-cardiac cause (e.g. pneumonia, convulsion, choking, or
stroke). Suicides were excluded. To each case of sudden cardiac
death, up to 10 controls were randomly drawn from the source
population matched for age (year of birth), gender, and practice.
If less than 10 controls were available, all of them were included.
The index date was defined as the date on which sudden cardiac
death occurred in the cases. This date was also the index date for
The exposure of interest was the use of non-cardiac QTc-
prolonging drugs, as specified in the most recent version of list 1
(drugs that are generally accepted by authorities to have a risk of
causing Torsades de Pointes) from the International Registry for
lists.htm)8and comprise the following non-cardiac QTc-prolonging
drugs: chloroquine, chlorpromazine, cisapride, clarithromycin, dom-
peridone,droperidol,erythromycin, halofrantine, haloperidol, levo-
methadyl, mesoridazine, pentamidine, pimozide, sparfloxacin, and
thioridazine. As not all drugs are licensed, marketed, or prescribed
in The Netherlands, some of these drugs were not included in our
analyses. Our analyses included gastro-intestinal QTc-prolonging
medication: cisapride, domperidone; antibiotic QTc-prolonging
medication: erythromycin, clarithromycin; and antipsychotic QTc-
prolonging medication: chlorpromazine, haloperidol, pimozide,
and thioridazine. In order to classify the use at the index date,
we calculated the duration of each prescription, as the total
number of units issued per prescription divided by the number of
units prescribed daily. Exposure at the index date was categorized
into three mutually exclusive groups of current-, past-, and non-
use. To account for the differences in prescription patterns of
non-cardiac QTc-prolonging drugs, different risk windows were
specified. For non-cardiac QTc-prolonging drugs, normally pre-
scribed for shorter periods of time (gastro-intestinal medications
and antibiotics), use was defined as current if the index date fell
within a period of use or within a maximum of 7 days after the
end of the last prescription (to account for carry-over effects).
For drugs usually prescribed for longer periods of time (antipsycho-
tics), use was defined as current if the index date fell within a
period of use or within a maximum of 30 days after the end of
the last prescription. Past use was defined as discontinuation of a
non-cardiac QTc-prolonging drug before the index date or discon-
tinuation .7 days (gastro-intestinal or antibiotic medication) or
.30 days before the index date (antipsychotic medication). If
patients had no prescription for any type of non-cardiac QTc-
prolonging drug prior to the index date they were considered
non-exposed. Among current users, we evaluated the effect of dur-
ation (?90 and .90 days continuous use), type of non-cardiac QTc-
prolonging drug, and the current daily dose used in defined daily
Organization.13One DDD-equivalent represents the recommended
daily dose for an adult for the main indication. To evaluate dose
response effects, the current daily dose of a non-cardiac QTc-
prolonging drug was categorized into less than one DDD equivalent
and one or more DDD equivalents.
Co-variates and risk factors
co-variates were gathered from the medical records through compu-
terized searches and manual validation. The co-variates that were
evaluated included cerebrovascular and cardiovascular ischaemia
(history of myocardial infarction, stroke, and angina pectoris),
hypercholesterolaemia, smoking, and alcohol abuse. Cerebrovas-
cular ischaemia, cardiovascular ischaemia, and heart failure were
assessed, based on the diagnoses provided by the GP and specialists
in the medical records. Hypertension was identified through the
diagnoses in the medical records, the use of antihypertensive
2008S.M.J.M. Straus et al.
by guest on June 6, 2013
medication and/or the blood pressure measurements, meeting the
guidelines of the World Health Organization (a blood pressure
exceeding 140 mmHgsystolic
Diabetes mellitus, arrhythmias, and hypercholesterolaemia were
identified through diagnoses in the medical records from GPs and
specialists and/or the use of antidiabetic, antiarrhythmic, or
lipid-lowering medication. Information on smoking and alcohol
abuse was obtained from the free text in the medical records. As
concomitant medication, we considered among other diuretics,
angiotensin-converting enzyme inhibitors, and other cardiovascular
medication. Current use of concomitant medication was defined as
use at the index date. We evaluated the effect of social-
economic status(SES), byincluding
care insurance, which is a proxy for income (all below an income
of about $25 000 per year have sick fund insurance and those
above have a private insurance).
and/or90 mmHg diastolic).14
a variableon health
The relative risk for sudden cardiac death during the use of non-
cardiac QTc-prolonging drugs was estimated by calculation of the
odds ratios (95% CI) using conditional logistic regression analyses.
We evaluated risk factors and confounders one by one, by including
one factor with the exposure variable. Subsequently, we performed
a bivariate evaluation for potential multicollinearity of confoun-
ders. Thereafter, co-variates that were univariately associated
with sudden cardiac death (at a P , 0.1 level) were included in
the regression analyses. After doing this for each factor separately,
we retained a list of all factors that changed the point estimate of
the association between non-cardiac QTc-prolonging drugs and
sudden cardiac death by .5%, which were included in the final
model.15We investigated potential effect modification by age and
gender and performed sub-analyses to evaluate potential misclassi-
fication of sudden cardiac death by splitting the outcome between
witnessed and unwitnessed deaths. To evaluate a possible dose-
effect relation, a trend test was performed. We calculated the
population attributable risk (PAR) per cent.16
In the source population, 806 cases of sudden cardiac death
were identified, representing an incidence rate of sudden
cardiac death of almost one per 1000 person-years. As we
adhered strictly to the matching criteria to ensure internal
validity, the 31(4%) cases for whom no controls could be
found were excluded from further analyses. Hence, the
study population comprised 775 cases of sudden cardiac
death and 6297 matched controls (approximate case:control
ratio, 1:8). The median age of the study population was 72
years and ?61% were male. Despite the matching for age
(year of birth), the median age of cases was higher than
the median age of all controls (74 and 72 years, respect-
ively) because more controls were available for younger
cases than for elderly cases (Table 1). There were
437(56.4%) witnessed and 338(43.6%) unwitnessed cases of
sudden cardiac death reported. All known potential risk
factors were associated with an increased risk for sudden
cardiac death, notably ischaemic cerebrovascular and
cardiovascular disease, hypertension, arrhythmia, diabetes
mellitus, heart failure, hypercholesterolaemia, smoking,
and alcohol abuse. As expected, use of cardiovascular medi-
cation was associated with sudden cardiac death as well
(Table 1). There was no association between SES and sudden
Current use of non-cardiac QTc-prolonging drugs was
associated with an almost three-fold increased risk of
sudden cardiac death (Table 2). Past use of non-cardiac
QTc-prolonging drugs was not associated with an increased
risk of sudden cardiac death. The risk was higher among
recent starters (?90 days) of non-cardiac QTc-prolonging
drugs (Table 2). The risk was significantly increased in
users of gastro-intestinal medication and antipsychotics.
The risk of sudden cardiac death was not significantly
increased in antibiotic users, probably due to the limited
number of exposed cases. Antibiotics were only used for
,90 days and only in a dosage of one or more DDD equiva-
lents. Therefore, we could not assess duration and dose–
response relationships (Table 2). The risk of sudden
cardiac death was increased to a larger extent in users of
a higher daily dose of gastro-intestinal or of antipsychotic
medication. The risk was highest in subjects using antipsy-
chotics, predominantly haloperidol. In users of gastro-intes-
tinal medication, the risk of sudden cardiac death was
significantly increased in users of domperidone in contrast
to cisapride users, although a three-fold higher risk of
sudden cardiac death in cisapride users could not be
excluded (Table 2).
For witnessed cases of death, the association with current
use of non-cardiac QTc-prolonging drugs was higher (OR: 2.9;
95% CI: 1.5–5.9) than those for unwitnessed cases (OR: 2.3;
95% CI: 1.0–5.4), but this difference was not statistically sig-
nificant. Stratified analyses showed that the risk of sudden
cardiac death in users of non-cardiac QTc-prolonging medi-
cations tended to be higher in women (OR: 3.1; 95% CI:
1.5–6.4) than in men (OR: 2.3; 95% CI: 1.0–5.1) and higher
in patients older than 65 years (OR: 2.7; 95% CI: 1.5–4.9)
than in patients 65 years or younger (OR: 2.3; 95% CI:
0.6–8.1), but none of these differences were statistically sig-
nificant. The incidence of sudden cardiac death in our popu-
lation was almost one per 1000 person-years.17On the basis
of the findings in this study, the PAR per cent of non-cardiac
QTc-prolonging medication could be calculated as 2%.16
The results of our study indicate that current use of non-
cardiac QTc-prolonging drugs in a general population is
associated with a significantly increased risk of sudden
cardiac death. After adjustment for known confounding
factors, current use of non-cardiac QTc-prolonging drugs
was associated with an almost three-fold increased risk of
sudden cardiac death. The risk was higher in women than
in men. This is in line with earlier findings that women
seem to be more susceptible to drug-induced cardiac
arrhythmias than men.7,18
Drug-induced Torsades de Pointes is a significant cause of
morbidity and mortality and non-cardiac drugs have been
Prolongation of the QTc interval, ventricular arrhythmias
and Torsades de Pointes have been associated with cisapride
use in anecdotal reports. These case reports raised concern,
but could not be confirmed in cohort and case–control ana-
lyses in the UK and Canada and in some studies no substan-
tial increase in the QTc interval could be identified.7Our
results are in line with these findings.22This is not surprising
because life-threatening arrhythmias during cisapride use in
adults are believed to occur predominantly, when there is
concurrent use of inhibitors of cytochrome P450 CYP3A4,
such as itraconazole, ketocaonazole, or macrolides. This
number of cases.7,19–21
Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death 2009
by guest on June 6, 2013
was not the case in our population. Domperidone seemed an
attractive, safer alternative to cisapride. Our findings of a
significantly increased risk of sudden cardiac death in dom-
peridone users, however, suggest that domperidone should
not be viewed as a low risk alternative to cisapride and
are in line with earlier results.23
number of exposed cases in our study prohibited us from
analysing the macrolides individually. At an FDA advisory
committee meeting, therelative
Torsades de Pointes was increased in clarithromycin users
and the risk was highest shortly after initiating therapy, as
was also the case in our data.24Case reports have suggested
for long that erythromycin is associated with an increased
risk of Torsades de Pointes and recent research has shown
a two-fold increase in the rate of sudden cardiac death in
current erythromycin users.25
sudden cardiac death has been reported with antipsychotic
use in case reports and epidemiological studies.26–28Also
in our study, the use of antipsychotics, particularly haloper-
idol is associated with a significant increase in the risk of
sudden cardiac death.
Many drugs can prolong the QTc interval.19,21,29,30QT pro-
longation, however, is a surrogate marker with an imperfect
predictive value for fatal cardiac arrhythmias and sudden
cardiac death and it is difficult to predict whether a drug
Since the early 1960s,
will cause Torsades de Pointes.21For the vast majority of
drugs known to induce QTc prolongation, it has been demon-
strated that the slowing of the action potential is a conse-
quence of the blockage of the rapid component of the
delayed rectifier potassium channel (Ikr) through blockade
of the human ether a go-go related gene (HERG).21,31–33
The extent to which blocking of this channel results in
Torsades de Pointes or sudden cardiac death, however, is
concept ‘reduced repolarization reserve’ has been used to
explain this variable risk.36Current evidence also suggests
that 5–10% of persons in whom cardiac arrhythmias occur
carry a (silent) mutation in one of the genes responsible
for the congenital long QT syndrome.37,38
In our population, we were able to take advantage of the
fact that in the Dutch health care system, all medical infor-
mation (including specialist and hospital care) are collected
at practices that cover the general population instead of
selected socio-economic groups. As a consequence, there
was extensive information available on drug use, potential
confounders, and all the circumstances surrounding death.
Nevertheless, our study has some potential limitations.
First, we cannot exclude that some misclassification of
outcome occurred. We may have missed some deaths
although this will be minimal, since death is consistently
Demographics, distribution of covariates, and use of concomitant medication in cases and controls
(n ¼ 775)
(n ¼ 6297)
OR (95% CI)a
Age (mean+SD) (Years)
71 years, 13
69 years, 13
Sudden cardiac death
Ischaemic cerebro-/cardiovascular disease
Concomitant cardiovascular drugs
Lipid lowering agents
Ca, Calcium; ATII, angiotensin II receptor antagonist. Values in 1st and 2nd columns represented as n(%).
aAll ORs are calculated taking matching for age, gender, practice, and calendar time into consideration.
2010S.M.J.M. Straus et al.
by guest on June 6, 2013
registered by GPs. Secondly, not all acute deaths may have
been of cardiac origin. We determined sudden cardiac
death, however, on the basis of the full medical records
and all circumstances surrounding the death were available.
Recently, an evaluation comparing different methods to
determine the incidence of sudden cardiac death suggested
that this method provides a very reliable way of determining
sudden cardiac death cases.3In addition, we could reduce
misclassification by differentiating between witnessed and
unwitnessed cases of sudden cardiac death. The percent of
unwitnessed deaths in our population was 43.6% which is
in line with earlier findings.3,39The risk of witnessed
sudden cardiac death associated with the use of non-
cardiac QTc-prolonging drugs was higher than the risk of
unwitnessed sudden cardiac death. This may be consistent
with the fact that misclassification will occur more often
in unwitnessed cases. In addition, slight misclassification
of exposure may have occurred because we used outpatient
prescription data and we had no information as to whether
the prescription was actually filled and taken. It is likely,
however, that such exposure misclassification will be
random and will be evenly distributed among cases and con-
trols. Although we adjusted for all known confounders,
residual confounding may exist, but is unlikely to explain
the strong association we have observed.
In conclusion, our findings suggest that the current use of
non-cardiac QTc-prolonging drugs in a general population is
associated with an increased risk of sudden cardiac death.
Although prolongation of the QTc interval by non-cardiac
drugs is not an unusual finding, potentially fatal arrhythmias
and sudden cardiac death are relatively uncommon. Our
results suggest that 320 cases of sudden cardiac death can
be attributed to the use of non-cardiac QTc-prolonging
medication in The Netherlands on a yearly basis.16,17This
is important because regulatory authorities have to evaluate
the clinical significance of QTc prolongation observed in
relatively small clinical trials without cases of sudden
Risk of sudden cardiac death and the use of non-cardiac QTc-prolonging medication
Use of non-cardiac QTC-
(n ¼ 775)
(n ¼ 6297)
OR (95% CI)a
OR (95% CI)b
Current use of different
Duration of use in current
aOdds ratios matched for age, gender, practice, and calendar time.
bOdds ratio matched for age, gender, practice, and calendar time and adjusted for diabetes mellitus, arrhythmias, heart failure, hypertension, smoking,
alcohol abuse, and cerebrovascular and cardiovascular ischaemia, current use of diuretics and cardiac glycosides.
cSince one patient used domperidone and cisapride concomitantly, numbers do not add up.
dTest for trend P , 0.005.
Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death2011
by guest on June 6, 2013
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