Has prolonged QT-interval or T-wave inversion in ECG been associated with sumatriptan?/nBackground:

Fråga: Has prolonged QT-interval or T-wave inversion in ECG been associated with sumatriptan?

Background: A 40-year-old woman and previous smoker, has taken oral sumatriptan against sporadic migraine for several years. Last year, ECG was normal. Recently, her intake of sumatriptan increased to eight 100 mg-tablets in 16 days, as migraine attacks became more frequent due to emotional stress. At the end of this period, she experienced a heavy pressure in her chest and at medical examination the same day (just after intake of another tablet) the above-mentioned ECG-changes were evident. However, blood samples including cardiac enzymes showed no abnormalities. The QT-prolongation (maximally 520 ms) disappeared over the next few days in contrast to the T-wave inversions that remained unchanged. Exercise stress testing, coronary arteriography and ultrasound investigation of the heart were all normal. The manufacturer could not exclude a possible association between sumatriptan and the pathological ECG.

Sammanfattning: In contrast to several reports on other types of serious adverse cardiac reactions to sumatriptan, there is no documentation that sumatriptan could cause long-QT or Torsade de pointes, except for two reports without further clinical details in the WHO-database. However, in the present case, the temporal relationship between the intake of sumatriptan and a reversible QT-prolongation, speaks in favour of a causal association. The reason for T-wave inversion is very unclear when biochemical tests do not support an ischemic injury to the myocardium. Taken together, it seems appropriate to stop further treatment with sumatriptan in the present case, until a better understanding of underlying mechanisms has been reached.

Svar: We have made an extensive search in the scientific literature. It is evident that sumatriptan is not listed among drugs associated with long QT-syndrome (LQTS) or the highly related ventricular tachyarrhythmia Torsade de pointes (1-3). Moreover, we found no such reports in the Swedish register of adverse drug reactions (Swedis), and neither any reports about isolated T-wave inversions (4). However, according to the Questioner (working in the ADR-reporting centre), there are two cases of QT-prolongation listed in the International Drug Information System at WHO, as well as one case of T-wave inversion.

It is clear from the literature that sumatriptan in very rare cases may trigger other cardiac arrhythmias, such as ventricular and supraventricular fibrillation, but the mechanism is unknown (5-10). Even a case of ventricular tachycardia is described briefly, however without any mention of Torsade de pointes (5). According to these reports, symptoms usually develop soon (immediately, or within the first hour) after administration of sumatriptan, similar to the temporal relationship in the present case.

The mechanism of LQTS involves disturbances in the sodium-potassium balance in myocardial cells, which leads to a delay in ventricular repolarisation (3). Drugs frequently associated with LQTS, like quinidine or sotalol, are believed to act directly on ion channels involved in this sodium-potassium exchange, but there is no documentation that sumatriptan could have similar effects.

Concerning the T-wave inversion in the present case, it should be mentioned that biphasic T-waves sometimes are evident in LQTS (3). Inverted T-waves are also the first sign of ischemic damage to the myocardium (11). Interestingly, there are several reports both in Swedis and in the scientific literature indicating that sumatriptan, has a potential to trigger angina and myocardial infarction. In some of these reported cases, an underlying pathology of the heart was evident, such as advanced coronary arteriosclerosis (4-10). Perhaps relevant to the present case, sumatriptan has been suspected to trigger spasm angina in very rare cases (6). This suspicion was in part strengthened by experimental findings that sumatriptan triggered a contraction of human coronary arteries in vitro, even though this was seen at concentrations that were 5-10 fold higher than plasma concentrations in subjects on single oral doses of sumatriptan (12).

In the present case, however, myocardial infarction was excluded by normal plasma biochemistry tests. The major symptom that led to medical investigation of the patient in question was chest pain. Sumatriptan is the most common drug reported to cause chest pain (9). This symptom, or a related discomfort, occurs in 4-8 per cent of treated patients and is not believed to be myocardial in origin (1, 13). According to data from the manufacturer, 99 per cent of patients with sumatriptan-related chest pain had normal ECG, and less than 1 per cent showed abnormalities of serious nature, such as myocardial ischemia (1). Rather, chest pain has been suggested to originate from the thorax or esophagus (13).

Finally, it seems unlikely that the increased use of sumatriptan in the present case would mean a risk of drug accumulation. Even though the pharmacokinetics of sumatriptan has been reported to exhibit a significant interindividual variability, especially after oral administration, the half-life is short with a mean half-life of 2h (14). Sumatriptan is subject to extensive hepatic metabolism by MAO-A where an inactive metabolite, indolacetic acid, is formed (7, 14). 1 Stewart Hillis W, MacIntyre PD:Sumatriptan and chest pain. Lancet 1993; 341: 1565-1566

2 Ben-David J, Zipes ZP: Torsades de pointes and proarrhythmia. Lancet 1993; 341: 1578-1582
3 Viskin S: Long QT syndromes and torsade de pointes. Lancet 1999; 354: 16251633
4 Swedis (The Swedish Drug Information System)

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