Effectiveness of risk minimization measures for the use of cilostazol in United Kingdom, Spain, Sweden, and Germany

Abstract Purpose The purpose of the study is to evaluate the effectiveness of risk minimization measures—labeling changes and communication to health care professionals—recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe. Methods Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002‐2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of ≥2 antiplatelet agents, concurrent use of potent CYP3A4/CYP2C19 inhibitors and high‐dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk. Results We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high‐dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron). The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction). Conclusions This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement.


| INTRODUCTION
Cilostazol is a platelet aggregation inhibitor approved in Europe in 2002 to improve walking distances in patients with intermittent claudication. Cilostazol has been associated with spontaneous reports of serious bleeding and cardiovascular effects including heart attacks, angina, and arrhythmias. The European Medicines Agency (EMA) evaluated the benefits and risks of cilostazol in a referral and recommended implementation of risk minimization measures to restrict the use of cilostazol to patients that could benefit from treatment and in which important risks are minimized. 1 Risk minimization measures included labeling changes (Table 1) and educational communications directed to health care professionals through the Otsuka Europe website and "Dear Doctor" letters implemented in 2013.
To evaluate the impact of these risk minimization measures, we compared the prevalence of cilostazol use and of the conditions targeted by these risk minimization measures before and after these measures were implemented.

| Data sources
The study was conducted in The Health Improvement Network (THIN), UK [2][3][4] ; the EpiChron cohort (EpiChron) from the Aragon Institute of Health Sciences (IACS), Aragon, Spain 5,6 ; the Information System for Research in Primary Care (SIDIAP), Catalonia, Spain 7 ; the Swedish National Registers 8,9 ; and the German Pharmacoepidemiological Research Database (GePaRD). 10 The main features of the study databases are presented in Table S1, online supporting information. The baseline characteristics of users of cilostazol before implementation of risk minimization measures have been published elsewhere. 11

| Study population
New users of cilostazol were identified before and after implementa- the time of the baseline assessment. 11 The period after implementation was the year 2014. New users were defined as patients who received a first-ever prescription of cilostazol during each study period after having at least 6 months of continuous enrollment in the database. The date of the first cilostazol prescription was defined as the start date. Patients with a recorded prescription of cilostazol at any time before the start date were excluded. New users were followed from the start date until the first of the following: end of enrollment in the database, death, or end of the study period.

| Evaluation of the effectiveness of risk minimization measures
We compared the prevalence of new users of cilostazol and the frequency of conditions targeted by risk minimization measures included in the labeling (Table 1)   In GePaRD, a twice-daily dosage was also assumed. In SIDIAP, evaluation of daily dose was not conducted, as information on dosage instructions was not available. Medical diagnoses and use of medications were ascertained through the coding system specific to each database (Table S1, online supporting information).

| Analysis
The annual prevalence of cilostazol use was calculated in each data-

| Prevalence and patterns of use
We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively ( Table 2).

| Comorbidity and comedications
The most frequent comorbidities and comedications before and after implementation of risk minimization measures are presented in Tables   (Table S4, online supporting information).

| Evaluation of the effectiveness of risk minimization measures
Results of the assessment of the risk minimization measures are presented in Table 3 (Table S5, online supporting information). After labeling changes, the prevalence of old contraindications decreased in THIN (10.0% before, 8.7% after) and EpiChron (6.2%, 5.5%), increased in SIDIAP (39.1%, 51.5%) and GePaRD (51.8%, 54.7%), and was the same as before labeling changes in Sweden (12.2%, 12.1%).

| DISCUSSION
In this study, we evaluated the effectiveness of risk minimization mea-  The terms before and after refer to the periods before and after the implementation of risk minimization periods. the concern is not great because it does not impact the Spanish data  • Maria Giner-Soriano and Albert Roso-Llorach, as employees of IDIAP Jordi Gol, worked on other projects funded by pharmaceutical companies in their institution that were not related to this study and without personal profit.
• Marie Linder is employed at the Centre for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, and contract research organizations) for performance of drug safety and drug utilization studies.
• Oliver Scholle is an employee of the nonprofit scientific organization Leibniz Institute for Prevention Research and Epidemiology-BIPS, which is, among others, conducting studies financed by pharmaceutical companies based on data provided by German statutory health insurance agencies.

SOURCES OF SUPPORT
The study was funded by Otsuka Pharmaceutical Europe Ltd., Gallions,