Ivabradine drug utilization study in five European countries: A multinational, retrospective, observational study to assess effectiveness of risk‐minimization measures

Abstract Purpose This drug utilization study of ivabradine evaluated prescriber compliance with the new risk minimization measures (RMMs), communicated starting 2014 following preliminary results from the SIGNIFY study. Methods This was a multinational (five European countries) chart review study with two study periods: pre‐RMM and post‐RMM. Patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice were identified across general practitioners and specialists. The primary outcome analysis evaluated the compliance with the new RMMs, ie, use in patients with a heart rate greater than or equal to 70 bpm at initiation, no doses higher than those recommended in the summary of product characteristics (SmPC) at initiation and during 6 months of follow‐up, and no concomitant use of verapamil or diltiazem. Results Overall, 711 and 506 eligible patients were included in the pre‐RMM and post‐RMM periods, respectively. The percentage of patients prescribed ivabradine according to the new RMMs increased significantly in the post‐RMM period (70.6% and 78.4% in the pre‐ and post‐RMM periods respectively; P value = .0035). The compliance to RMMs increased for all the criteria assessed independently: the proportions of patients with (a) heart rate ≥ 70 bpm at initiation (79.4% and 85.2%, respectively; P value = .0141), (b) no dose higher than the SmPC doses at initiation and during follow‐up (92.8% and 94.1%, respectively; P value = .3957), and (c) no concomitance with verapamil or diltiazem (96.1% and 99.2%, respectively; P value = .0007). Conclusions The RMMs for ivabradine were well implemented across the five participating European countries confirming a favorable benefit‐risk balance of ivabradine in chronic stable angina pectoris.


| INTRODUCTION
Ivabradine hydrochloride (Procoralan/Corlentor) is a selective inhibitor of the cardiac pacemaker if current, with corresponding reductions in cardiac workload and myocardial oxygen consumption. 1 Ivabradine is indicated in Europe from 2005 for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm and a contraindication to, or intolerance of beta blockers. Extensions of the indication were subsequently approved in combination with beta-blockers in patients inadequately controlled despite an optimal beta-blocker dose and heart rate (HR) > 60 bpm (October 2009) and in chronic heart failure (HF) in patients with sinus rhythm and HR ≥ 75 bpm (February 2012).
The recommended ivabradine starting dose for these indications was 5-mg bid, with consideration of 2.5-mg bid for patients aged 75 years and older. The recommended maintenance dose was 7.5-mg bid.
The SIGNIFY study 2  Ivabradine benefit-risk ratio was reassessed by the Pharmacovigilance Risk Assessment Committee (PRAC) in November 2014 and was found to remain positive for its authorized indications. 4 The PRAC recommended to increase the resting HR threshold of patients with angina pectoris from greater than 60 to greater than or equal to 70 bpm before treatment initiation, contraindicate concomitant use of ivabradine with verapamil or diltiazem, and reinforce current posology including initial (5-mg bid) and maintenance (7.5-mg bid) maximal doses. Previous information found in the summary of product characteristics (SmPCs) regarding HR monitoring and warning of use in patients with atrial fibrillation was also reinforced. As routine and additional risk minimization measures (RMMs), the SmPC was updated accordingly, and a second DHPC was distributed to inform prescribers in Europe from December 2014.
Following the PRAC recommendations, a drug utilization study (DUS) was conducted to evaluate how ivabradine is used in patients with chronic stable angina pectoris in routine clinical practice and the consistency of ivabradine prescribing with the aforementioned PRAC recommendations.

| Study design overview
This retrospective cohort study collected data from medical records (chart review) of patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice in five European countries. Data, from start of treatment until 6 months, describing ivabradine new users' characteristics and ivabradine patterns of use were collected retrospectively from patients' charts by the physicians.
The study design included two study periods: pre-and post-RMM  For each study period, ivabradine initiation was defined as the first date in which a patient was treated with ivabradine in the considered study period, provided that the patient had not received ivabradine during the previous 6 months.
The targeted countries were France, Germany, Italy, Spain, and the United Kingdom (UK). Countries' selection was based on ivabradine volume sales, geographic representation of the European Union (EU), and ability to represent a variety of medical practices, in term of specialty and practice settings.
A pilot study was conducted to identify potential challenges in the study design such as the shared-care management (SCM) (ie, when patient care was shared between different physicians and not only the participating physician), to evaluate practical aspects of implementation, and test the data collection form. The protocol was registered and made publicly available on the European Medicine Agency electronic Register of Post-Authorization Studies (EU PASS 19522).

| Physician and patient enrollment
A total of 600 patients per study period were targeted taking into account the clustering effect and other contingencies such as missing

Key Points
• Following the SIGNIFY study, the benefit-risk ratio of ivabradine was reassessed in 2014, and risk minimization measures (RMM) were recommended.
• Compliance to RMM was evaluated in a drug utilization study (DUS) across five European countries.
• The study results show that the heart rate at treatment initiation, ivabradine dosing at initiation and during follow-up, and concomitant use of verapamil or diltiazem were in line with the updated summary of product characteristics (SmPC). To avoid a cluster effect and to ensure a sufficient number of participating sites allowing to assess different practice modalities, the physicians were informed that they could not include greater than 20 patients by period for a specialist and greater than 10 patients by period for a GP. To avoid selection bias, if a site had a larger number of patients than the maximum threshold, physicians had to organize the eligible patients in alphabetical order by surname and to start patient data abstraction in ascending or descending order whether the last number of the site ID was odd (eg, XX1) or even (eg, XX2).

| Analysis
Primary outcome was the compliance with the composite of the four criteria in the SmPC assessed before and after RMMs implementation: (1) use in patients with a HR threshold greater than or equal to 70 bpm at initiation; (2) no doses higher than 5-mg bid at treatment initiation; (3) no doses higher than 7.5-mg bid during 6-month follow-up; and (4) no concomitant use of verapamil or diltiazem at treatment initiation or Primary and secondary analyses were stratified by study period.
Primary analyses were also performed by country and by specialty.
The primary analysis was conducted in the patients' set with complete data. However, a patient who was not compliant with one of the four SmPC criteria was deemed noncompliant, regardless of the completeness of data for the other criteria. Confidence intervals (CI) and P values for the difference in proportions of patients satisfying each

| Disposition
Of the 138 741 physicians in the source list with relevant contact information, 60 675 physicians were contacted. The percentage of interested physicians overall was 0.86%. Of these, 13% participated in the study. A total of 68 physicians were active (included at least one eligible patient). Active physicians' distribution by country and specialty is presented in Table 1.  Active physicians were participating physicians who had included at least one eligible patient in the study.

| Concomitant medication use
The

| HR at initiation
The

| Overall patterns of use pre-and post-RMM
The overall proportion of patients treated with ivabradine according to the composite of the four criteria of SmPC increased in the post-RMM period (70.6% in the pre-RMM period and 78.4% in the post-RMM period, difference: 7.8; 95% CI, 2.5-12.9; P value = .0035) ( Table 3).  (Table 4).

| DISCUSSION
The overall objective of this PASS was to assess in five European countries how ivabradine is used in patients with chronic stable angina pectoris in routine clinical practice and to evaluate the compliance  with the new RMMs. Patients were identified across a variety of physician specialties, including specialists from private and hospital settings, as well as GPs. Overall, the RMMs were well implemented across the participating countries and among both specialists and GPs.
One of the specific study aims was to check that appropriate ivabradine doses were prescribed. These recommended doses had not This study aimed to ensure selection of a diverse and generally representative physicians' sample and their treated patients. However, as for most studies conducted for regulatory reasons, 6 this study faced a very low interest rate among physicians and recruitment challenges.
Having a total of 68 active physicians across the five countries needs to be considered when interpreting the results. The study was not powered to assess compliance with RMMs at country and specialty levels. This is particularly true for Italian GPs and UK specialists (one and two active physicians, respectively). The assessment of any potential difference between participating and nonparticipating physicians was not possible because data on nonparticipating physicians were  A review of 29 studies in the European Union electronic Register of Post-Authorization Studies found that only four studies used retrospective medical files review-others were surveys-and only 10 studies were conducted within a 12-18-month timeframe after RMM implementation. 17 The main strength of this PASS remains its conclusiveness on the effectiveness of RMMs on the prescribing of ivabradine since EU marketing authorization. A review of studies registered in EU PAS Register showed that only half of the effectiveness indicators were reported as successful and conclusive. 18 In addition, the current study did examine the compliance with each individual component of the RMMs and the composite.
Overall, although most patients were already prescribed ivabradine according to RMMs, the study was able to show a significant improvement in compliance to these RMMs in the post-RMM period.

| CONCLUSION
Overall, the study results show that the RMMs for ivabradine were well implemented across the participating European countries.
Ivabradine prescribing patterns have significantly changed to be in line with newly implemented RMMs and the updated SmPC, confirming a favorable benefit-risk balance of ivabradine in chronic stable angina pectoris and maintaining the ivabradine EU marketing authorization. Note. The denominator is patients who reported information for each of the criteria (patients with no subsequent prescriptions are included in the denominator).
Abbreviations: GP, general practitioner; N, total number of patients in the strata; RMM, risk minimization measures; SmPC, summary of product characteristics. a Corresponds to patients prescribed ivabradine according to the heart rate recommendation, no doses higher than the SmPC doses at treatment initiation and during follow-up (if available) and no concomitant use of verapamil or diltiazem during the study period.