Rivastigmine and QT interval prolongation

Walsh & Dourish (2002) reported that a 78-year-old man, receiving a number of medications and with a history of myocardial infarction and hypokalaemia, developed an abnormal QTc interval a week after starting rivastigmine treatment. I have performed an extensive review of the tolerability and safety of cholinesterase inhibitors (Inglis, 2002), in which I described the favourable cardiac safety profile of rivastigmine. Therefore, I contacted Novartis for more information. This case, which was initially submitted to the authorities in June 2001, included further clinically relevant information.

Primarily, the patient's pre-rivastigmine QTc (3 weeks before starting treatment) was 431 ms rather than 397 ms as suggested by Walsh & Dourish (C. Videbaek (Novartis), personal communication, 2002). The reported QTc of 397 ms was obtained a week after starting rivastigmine treatment, indicating that during this week the patient's electrocardiogram (ECG) ‘normalised’. The following week (2 weeks post-rivastigmine) it increased to 477 ms. The QTc prolongation (pre-rivastigmine to 2 weeks post-rivastigmine) was less than 11%. Nevertheless, since this change was above the 30 ms usually considered relevant, it is important to assess in an unbiased manner whether it was drug-induced.

The patient was already at risk of cardiac abnormalities owing to: previous increased QTc; hypokalaemia (a risk factor for QTc change; De Ponti et al, 2002) 2 weeks before starting rivastigmine treatment (no potassium values were reported at the time of the ECG finding); concomitant use of diltiazem, which is known to cause atrio-ventricular blockade and brady-cardia (risk factors for QTc change; De Ponti et al, 2002); a history of hypertension, ischaemic heart disease, myocardial infarction and cerebrovascular accident, reflecting the presence of clinically significant heart disease (another risk factor for QTc change; De Ponti et al, 2002): concurrent Lewy body dementia, which is associated with autonomic failure (McKeith, 2000) and frontal lobe deficits that may influence QT intervals (Kubota et al, 2001).

My review of the cholinesterase inhibitors (Inglis, 2002) included an analysis of 2791 patients involved in pivotal studies of rivastigmine in Alzheimer's disease (Morganroth et al, 2002). About 30% and 10% of these patients had cardiovascular disorders and heart rate/rhythm disorders, respectively. About 35% were receiving concomitant cardiovascular treatments. Even in this relatively at-risk population, heart rate, PQ, PR, QT and QRS intervals were very similar in rivastigmine- and placebo-treated patients, indicating that rivastigmine did not produce adverse effects on cardiac function as assessed by ECG. The lack of cardiac effects associated with rivastigmine may be explained by its selectivity for central over peripheral cholinesterases, and an apparent brain-region selectivity that may avoid areas such as the medullary cardiorespiratory nucleus (Enz et al, 1993).

Case reports are an important means of communicating clinical observations. However, it is important that the facts are presented clearly to allow a balanced judgement on the available evidence. I would suggest that the prolonged QTc described in this single case report is more likely to be due to the confounding factors described above than to a causal association with rivastigmine treatment. The cholinesterase inhibitors form an invaluable part of our limited armamentarium in managing patients with dementia. It would be unfortunate if patients who might benefit from these treatments were deprived of them because of false-positive associations with cardiotoxicity.