Risk of digoxin intoxication caused by clarithromycin-digoxin interactions in heart failure patients: a population-based study.

OBJECTIVE: To quantify the effect of exposures to digoxin–clarithromycin interactions on the risk of digoxin toxicity requiring hospitalizations in a population-based manner in a Taiwanese population.

METHODS: This is a retrospective population-based nested case–control study. Data were retrieved from the National Health Insurance Research Database. Heart failure (HF) patients newly treated with digoxin between 1 January 2001 and 31 December 2004 were retrieved from the database as the study cohort. Case patients, admitted to the hospitals with the diagnosis of digoxin intoxication (ICD-9 code 972.1) were identified from the study cohort and compared with the matched controls for the receipt of clarithromycin.

RESULTS: A total of 154,058 patients were identified as the study cohort; from these, 595 cases and 27,020 matched controls were selected for study. The prescription of clarithromycin at 7, 14, and 30 days prior to the index date was associated with a 4.36- (95% CI 1.28–14.79), 5.07- (95% CI 2.36–10.89), and 2.98-fold (95% CI 1.59–5.63) increase in hospitalization for digoxin intoxication, respectively. The results of the dose–response relationship also indicated that clarithromycin prescribed with a prescribed daily dose (PDD)/defined daily dose (DDD) ratio >2 led to a 55.41-fold (95% CI 9.31–329.9) increase of the risk, which is significantly greater than that prescribed with a 1–2 PDD/DDD ratio (adjusted OR  4.81; 95% CI 1.88–12.30) or with a <1 PDD/DDD ratio (adjusted OR  0.78; 95% CI 0.19–3.20).

CONCLUSION: This study provides empirical evidence that digoxin–clarithromycin interactions do increase the risk of hospitalization for digoxin intoxication in HF patients and that this risk could reach as high as 55.4-fold. We strongly recommend that the combined use of digoxin with clarithromycin should be avoided and that digoxin concentrations should be monitored closely in situations where the combination can not be avoided.