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The number of non-antiarrhythmic drugs associated with QT
interval prolongation (±TdP) continues to increase. About 50 non-CV and 20 CV non-antiarrhythmic drugs
have been implicated, and the problem may be more frequent with newer drugs. Drugs have either been
withdrawn from the market (prenylamine, terodiline, sertindole and in some countries terfenadine and
astemizole) or attracted severe prescribing restrictions (cisapride, pimozide). Of great concern is the
interval, usually a few years, from the first marketing of these drugs to the first recognition of their
association with QT interval prolongation and TdP.
The clinical and regulatory concerns have been summarised in a recent Editorial by Silvia Priori1. She
has stated that there is concern that “despite this impressive number of reports, the awareness of
this subject is still limited among medical professionals and…” “… it is likely that prevention of drug-induced
torsade de pointes will never be fully successful, because it is a moving target. A patient may not be at
risk when therapy is initiated, and may become at risk 5 days later…”. She recommends that “the
exclusion of potassium-channel-blocking properties might be considered in the future as a requirement
before new molecules are approved for marketing, and more strict warnings in the package insert of
drugs with known repolarization prolonging activity could be enforced”.
The knowledge on the risk factors for TdP are largely based on studies with antiarrhythmic drugs
since the incidence with these is in the range of percents compared to the very much lower incidence
with non-CV drugs but the number of Adverse Drug Reaction (ADR) reports on TdP which are sent to
regulatory agencies has increased during the last years but is still very low.
A Swedish study assessed the incidence of drug associated polymorphic VT in 29 hospitals with a
referring population of about 4 million persons during 28 days. Preliminary analysis showed that
11 pts developed TdP and 50 pts monomorphic ventricular tachycardia. There were more females
(73%) in the TdP group. 8 patients with TdP received sotalol and diuretics but only one patient
was hypokalemic on admission. If one hypotheses that in only one third of these cases, drugs
were either causative or contributed to the arrhythmia, this would mean an annual incidence in
Sweden of more than 100 cases. Calculations like these are speculative but should cause some
concern and warrant further studies.
During the early 90’s, terfenadine and astemizole two antihistaminic drugs were associated with
proarrhythmia. Several quite large epidemiological studies have been performed, looking at terfenadine,
astemizole, sedating and non-sedating antihistamines. The population studied varied from 35000
to more than 1 million. All studies used large medical or spontaneous report databases. The absolute
number of events was low (53 to 317). The risk for ventricular arrhythmias was either lower or identical
for terfenadine compared to other antihistamines or ibuprofen. There was no difference between
astemizole and sedating antihistamines but a markedly increased risk with concomitant use of
terfenadine and ketokonazole, a potent CYP3A4 inhibitor. Thus, although some of these drugs have a
direct effect on potassium channel conduction, they may exert their proarrhythmic potential only when
achieving very high concentrations as may occur when there is an interaction with their metabolism.
In a report from the Monitoring Center of WHO, almost 10000 adverse drug reactions reports on
antihistamines from 17 countries were related to the sales of the five largest antihistamines between
1992 and 1996. The frequency of selected cardiac events, mainly the same as mentioned above, and
deaths were all below 0.1 per million sold defined daily doses. The frequency for loratadine was in the
same range as for astemizole. In July 1996, the FDA reported on 34 pts who had developed
proarrhythmia and on 23 pts with prolonged QT interval on cisapride (for gastroesophageal reflux).
Four patients died and another 16 survived resuscitation. 56% of the patients were on concomitant
treatment with macrolide antibiotics or antifungals, mainly ketokonazole which are known to inhibit
the metabolism of cisapride. 12% were on other drugs known to prolong the QT interval. The incidence of
proarrhythmia or prolonged QT interval has been estimated to 1 in 120000 cisapride treated patients.
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