Salem L, Malouvier A, Blatchford J, Rivero-Ferrer E, Deltour N, Jacquot E. Ivabradine drug utilization study in five European countries: a PASS to assess effectiveness of risk-minimization measures. Presented at the 35th ICPE International Conference on Pharmacoepidemiology & Therapeutic Risk Management; August 27, 2019. Philadelphia, PA. [abstract] Pharmacoepidemiol Drug Saf. 2019 Aug 20; 28(S2):450. doi: 10.1002/pds.4864.

BACKGROUND: Ivabradine hydrochloride, a pure heart rate lowering agent, was first granted marketing authorization in Europe in October 2005 for the treatment of symptomatic chronic stable angina pectoris. Following the SIGNIFY study, which evaluated ivabradine at higher starting and maintenance doses than the recommended and showed an increase of cardiovascular events in a sub‐group of patients, the benefit–risk ratio of ivabradine was re‐assessed in 2014 and new risk‐minimization measures (RMM) were implemented.

To evaluate prescribers' compliance with the RMMs.

METHODS: This was a multinational (France, Germany, Italy, Spain, and the United Kingdom), retrospective, chart review‐based, drug utilization study with pre‐ and post‐RMM study periods. Patients were identified by general practitioners (GPs) and cardiologists sampled from very large source lists. Data were collected at ivabradine initiation and during ≤6 months of treatment start. The primary outcome was the compliance with the following RMMs: use in patients with a heart rate ≥ 70 bpm at initiation, no doses higher than those recommended in the Summary of Product Characteristics (SmPC) (starting and maintenance doses should not exceed 2.5 and 5 mg twice daily, respectively), and no concomitant use of verapamil or diltiazem. The differences between proportions of the study outcomes in the preand post‐RMM periods were calculated as estimates of the changes using the Newcombe score.

RESULTS: Out of 60,675 contacted sites, 522 were interested in participating and 68 were active. Overall, 711 and 506 eligible patients were included in the pre‐RMM and post‐RMM periods, respectively. The percentage of patients for whom ivabradine prescriptions were compliant with all above mentioned RMMs increased in the post‐RMM period (70.6% pre‐RMM and 78.4% post‐RMM; p‐value = 0.0035). The compliance increased for each individual component: patients with heart rate ≥ 70 bpm at initiation (79.4% pre‐ and 85.2% post‐ RMM; p‐value = 0.0141), no dose higher than the SmPC doses at initiation and during follow‐up (92.8% pre‐ and 94.1% post‐RMM; pvalue = 0.3957), and no concomitance with verapamil or diltiazem (96.1% pre‐ and 99.2% post‐RMM; p‐value = 0.0007). The increase in RMMs compliance was observed in both GPs and specialists and in all countries except Italy.

CONCLUSIONS: The RMMs for ivabradine were well implemented across the participating European countries ensuring a favorable benefit–risk balance of ivabradine in chronic stable angina pectoris.

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