Evaluating the Effectiveness of an Additional Risk Minimization Measure to Reduce the Risk of Prescribing Mirabegron to Patients with Severe Uncontrolled Hypertension in Four European Countries

Abstract

Background

Mirabegron, indicated for the treatment of overactive bladder, is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg). In September 2015, a Direct Healthcare Professional Communication (DHPC) letter was disseminated as an additional risk minimisation measure.

Purpose

To assess the effectiveness of the DHPC in reducing the proportions of patients with severe or non-severe uncontrolled hypertension at mirabegron initiation.

Methods

An observational multi-database cohort study was undertaken using routinely collected healthcare data (December 2012–December 2016) from the PHARMO Database Network (Netherlands), SIDIAP database (Spain), CPRD (United Kingdom, UK) and national healthcare registers and electronic medical records from Finland. DHPC effectiveness was evaluated using interrupted time series analyses comparing trends and changes in monthly proportions of severe or non-severe uncontrolled hypertensive mirabegron initiations relative to the timing of the DHPC dissemination.

Results

The study population comprised 52,078 patients. Prior to DHPC dissemination, across the four databases, 0.3–1.3% had severe uncontrolled hypertension. Estimated absolute changes (EAC) in proportions of severe uncontrolled hypertension post-DHPC indicated a tendency towards a lower proportion in the Netherlands (EAC −0.36%, p=0.053), unchanged proportions in Spain and the UK and a higher proportion in Finland (EAC +0.73%, p=0.016). For non-severe uncontrolled hypertension (13–16% pre-DHPC), post-DHPC proportions tended to be lower in the Netherlands (EAC −2.02%, p=0.038) and Spain (EAC −1.04%, p=0.071), and unchanged in the UK and Finland.

Conclusion

Severe uncontrolled hypertension prior to mirabegron initiation was uncommon in these four European countries even before DHPC dissemination. This suggests that other risk minimisation communications (prior to the DHPC dissemination) had worked adequately with respect to minimising mirabegron use among patients with severe uncontrolled hypertension. No strong and consistent evidence of further risk minimisation after the DHPC dissemination was observed in this study.

Keywords:

• drug utilisation study
• direct healthcare professional communication
• risk minimization
• interrupted time series analysis

Acknowledgments

The authors would like to thank all healthcare providers and patients contributing information to the PHARMO Database Network, the CPRD and SIDIAP. In Finland, the following national registers contributed data to the study: the electronic e-Prescription Register, Care Register for Health Care, Register of Primary Health Care Visits, Population Register Centre and Causes of Death Registry, and the cities of Helsinki, Espoo and Vantaa as well as the Hospital District of Helsinki and Uusimaa (HUS). 

Abbreviations

AIC, Akaike Information Criterion; BIC, Bayesian Information Criterion; BP, Blood pressure; DBP, Diastolic blood pressure; DHPC, Direct Healthcare Professional Communication; EAC, Estimated absolute change; EMA, European Medicines Agency; GP, General Practice; SBP, Systolic blood pressure; SD, Standard deviation; SmPC, Summary of product characteristics; UK, United Kingdom.

Data Sharing Statement

The data used for this study were used under license for the current study, and so are not publicly available. The data can however be made available from each of the contributing database partners, upon reasonable request and with permission obtained through required ethics applications and applications to each data holder.

Ethics and Consent Statement

No ethics approval is required for use of anonymized data from the PHARMO Database Network. Scientific approval was obtained from the SIDIAP Scientific Committee and ethical approval was granted by CEIC Idiap Jordi Gol (reference number P17/019). CPRD obtains annual research ethics approval from the UK’s Health Research Authority (HRA) Research Ethics Committee (REC) (East Midlands – Derby, REC reference number 05/MRE04/87) for observational studies using CPRD data for public health research. In Finland, the study protocol was approved by the Coordinating Ethical Review Board of Helsinki University Hospital (Dnro HUS/618/2017). Patient informed consent was not required in any database as only anonymised retrospective data were used for this study.

Disclosure

Edith M. Heintjes, Irene D. Bezemer, Elisabeth Smits and Fernie J.A. Penning-van Beest performed this work as employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and pharmaceutical companies. Daniel Prieto-Alhambra leads the Pharmaco- and Device Epidemiology research group at the Centre for Statistics in Medicine, Oxford University. Daniel Prieto-Alhambra also reports that Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA’s department and open for external participants. This group has received speaker fees and consultancy fees from Amgen and UCB, and research grants from Amgen, UCB, Les Laboratories Servier, Novartis, and Astellas. Ying (Helen) He is a postdoctoral research fellow at the Pharmaco- and Device Epidemiology research group at the Centre for Statistics in Medicine, Oxford University. Minna Vehkala and Fabian Hoti are employees of Statfinn – EPID Research, which performs commissioned pharmacoepidemiological studies; and thus their employees have been and currently are working in collaboration with several pharmaceutical companies. Daniel Dedman and Helen P. Booth are full time employees of CPRD, which provides contract research services for government and related healthcare authorities, and the pharmaceutical industry, including Astellas Pharma. Stefan de Vogel, Noah Jamie Robinson, and Kwame Appenteng are employees of Astellas. The authors report no other conflicts of interest in this work.

Additional information

Funding

This post-authorisation safety study was funded by Astellas Pharma, the market authorisation holder of mirabegron. Astellas Pharma was involved in all stages of this study from protocol development to submission of the manuscript.