ACE-Inhibitor Related Angioedema Is Not Sufficiently Reported to the Danish Adverse Drug Reactions Database

Abstract

Purpose

The primary objective of this study was to calculate the report rate of angiotensin-converting enzyme inhibitor-related angioedema (ACEi-AE). Secondary objectives were to determine factors suspected to affect the likelihood of ACEi-AE being reported and to investigate potential differences in angioedema risks between different ACEis.

Patients and methods

Patient data from two cohorts comprising 176 patients with ACEi-AE were compared with report data from the Danish Adverse Drug Reactions Database, administered by the Danish Medicines Agency (DKMA). The study period was 1994–2015. Data were linked using unique personal identification numbers and birth dates. Cohort data and report data were compared with ACEi sales numbers from MedStat, an official database containing annual pharmaceutical drug sale data in Denmark.

Results

ACEi-AE was reported in two out of 176 cases resulting in a report rate of 1.1%, meaning that 98.9% of the cases were not reported. Since 1994, a total of 417 ACEi-AE reports were made to the DKMA. Fifty-eight percent of these were made by general practitioners or physicians with unknown workplaces and 35% by hospital staff. Enalapril and ramipril were the most sold ACEi’s in the study period (40.3% and 42.6%, respectively). Enalapril was associated with 54.7% of ACEi-AE reports while ramipril was associated with 14.2%. ACEi substance received was known for 141 cohort patients, of which 53.9% were prescribed enalapril and 17.0% received ramipril.

Conclusion

ACEi-AE was found to be severely underreported in Denmark, greatly limiting the available incidence data for this potentially life-threatening adverse reaction.

Keywords:

• edema
• side-effect
• adverse-effect
• pharmacovigilance
• antihypertensive
• agent

Acknowledgments

The adverse drug reaction reports and related figures and tables referred to in this article originate from the Danish ADR Database administered by the DKMA. The cases have been forwarded to all relevant pharmaceutical companies and to the EudraVigilance Database. The pharmaceutical companies are not to report these cases to the DKMA. The authors thank Shire and CLS Behring for their contribution to AE research. Data regarding cohort 2 were stored by OPEN, Open Patient data Explorative Network, Odense University Hospital, Odense, Denmark (www.sdu.dk/ki/open). Study data were collected and managed using REDCap electronic data capture tools hosted at Odense University Hospital.³⁰ We thank DKMA Special Advisor Mai Frederiksen Raun, who was responsible for the data export from the Danish ADR Database. Her constructive comments and feedback on the manuscript are greatly appreciated and contribute to the quality of this article.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. All authors fulfilled the authorship criteria in the IMCJE guidelines and have approved the final version of the manuscript. JC has written the manuscript, performed literature research and produced figures and tables. AB has provided data, performed data linkage, performed literature research and critically revised the manuscript, figures and tables. ER has conceived the idea for the study, provided data, performed data linkage, produced figures, performed literature research and critically revised the manuscript, figures and tables.

Disclosure

Johan Cornwall declares that he has no conflicts of interest. Dr. Eva Rye Rasmussen has previously performed scientific work in cooperation with Shire/Takeda. She has also received personal fees for educational seminars from MSD Norway and Shire/Takeda. CLS Behring and Viropharma have previously supported AE research performed by Dr. Eva Rye Rasmussen. Anette Bygum has received research grant support and/or speaker/consultancy fees from CSL Behring, Viropharma, SOBI and Shire/Takeda and participated in clinical trials for Jerini AG, Shire/Takeda and BioCryst. She is an advisor for the HAE Scandinavian Patient Organization. She participates in a clinical study in collaboration with BioCryst. Viropharma is now part of Shire/Takeda.