Clarithromycin for patients with ischemic heart disease

A Danish study has highlighted concerns regarding the safety of using antibiotics containing clarithromycin for patients with stable ischemic heart disease (AMI (heart attack) and stable angina pectoris (heart cramps)). In Denmark , clarithromycin is sold by the names Klacid®, Klacid Uno®, Clarithromycin "Hexal", Clarithromycin "Sandoz" and Clarithromycin "ratiopharm".

The study was published on the internet by the British Medical journal on 8 December 2005, see fact box to the right.

The Danish Medicines Agency has discussed the study findings with the medicines agencies in other EU countries and the European Medicines Agency (EMEA) as well as with the Food and Drug Administration (FDA) in the US . Following these discussions and in the context of evaluation of the overall data available, the Danish Medicines Agency does not consider that the findings from the newly published study provide a basis to advise against the use of clarithromycin in patients with ischemic heart disease.

13,702 patients, who had been hospitalised with a heart attack or angina pectoris, were asked to participate in the study. 6,116 patients (45 per cent) accepted the invitation, and by lot, 4,373 of these were distributed to 14 days’ treatment with either 500mg clarithromycin a day or an equivalent treatment with placebo. Thereafter, patients were followed via the Danish central national register (CPR) and where possible, the cause was determined in cases of death.

The primary objective of the study was to evaluate the occurrence of a combined endpoint consisting of death (regardless of the cause), heart attack or unstable angina pectoris. Mortality rate and death due to cardiovascular disease were part of several secondary endpoints and likewise, the mortality rate was included in the study to evaluate safety. The patients were followed for a total of 3 years.

The study shows no statistically significant difference in the occurrence of the primary endpoint, but it does show a statistically significant increased mortality rate among patients treated with clarithromycin (9.8 per cent for clarithromycin and 7.8 per cent for placebo). The increased mortality rate is essentially due to an increased mortality rate resulting from cardiovascular disease (5.1 per cent for clarithromycin and 3.5 per cent for placebo) and this did not become evident until after more than a year of monitoring.

The findings of the study are surprising and cannot be explained by known mechanisms of action for clarithromycin or other available data. However, a number of factors in the design of the study may have affected the result.

Previous studies of other antibiotics (including clarithromycin), and studies in which patients with ischaemic heart disease have been exposed to antibiotics over a much longer period than in the present study, have not demonstrated any effect on heart disease (beneficial or harmful), see more information from the fact box to the right. However, it is important to note that the duration of follow up in these studies was shorter than that of the Danish study. The authors of the article conclude that the long-term effect of antibiotics in patients with ischemic heart disease ought to be further investigated.

On the basis of the study findings, the Danish Medicines Agency has attempted to elucidate the mortality from use of clarithromycin by means of data in the Register of Medicinal Product Statistics at the Danish Medicines Agency. The mortality rate among 52,617 patients over 40 years old, who had been treated with antibiotics for a brief period as part of their treatment for ulcer, was compared for two groups that were treated with either clarithromycin or another antibiotic. There was no difference in the mortality rate in the two groups 2, 5 and 9.5 years after end of treatment. Nor were there any difference in the mortality rate 2, 5 and 9.5 years after end of treatment in the subgroup of patients who had cashed a prescription for low-dose aspirin (used as a proxy for ischemic cardiovascular disease: 10,008 patients).

As previously mentioned, the Danish Medicines Agency does not believe it necessary to warn against the use of clarithromycin (or other macrolide antibiotics) for patients with ischemic heart disease.

For further information, please contact Chief Medical Officer Steffen Thirstrup on tel.: +45 4488 9187 / +45 2246 7811 or on sth@dkma.dk.

The Danish Medicines Agency, 8 December 2005