Impact of angiotensin receptor blocker product recalls on antihypertensive prescribing in Germany

Ulrich Laufs,Michael Böhm,Ulrike Maria Rudolph,Felix Mahfoud,Martin Schulz,Marita Kieble,Salka Enners

doi:10.1038/s41371-020-00425-z

Abstract

In Germany, ~8 million patients take angiotensin receptor blockers (ARBs) and 2.25 million of them valsartan. In 2018, contamination of generic ARBs with probable carcinogenic nitrosamines resulted in more than 30 recalls. The impact of such a huge recall has never been explored in Europe. We analyzed the utilization of valsartan, all ARBs, and other alternative antihypertensive drugs in Germany. We used our database of anonymized dispensing data from >80% of community pharmacies at the expense of the statutory health insurance (SHI) funds from January 2017 to December 2019. We analyzed 290.8 million prescriptions, including all oral mono- and fixed-dose combinations of ARBs and plausible alternatives, i.e. ACE inhibitors (ACEi), beta-blockers (BB), and calcium channel blockers (CCB). Utilization was calculated by defined daily doses per 1000 SHI-insured persons per day (DID). Valsartan use decreased substantially after the recalls in July 2018 from 39.0 to 14.2 DID (−64%) in the second quarter of 2019 and to 16.9 DID (−57%) in the fourth quarter of 2019. Simultaneously, the use of alternative ARBs increased from 77.7 DID in the second quarter of 2018 to 121.9 DID (+57%) in the fourth quarter of 2019, mainly due to an increase of candesartan dispensing to 99.8 DID (+73%). There were no changes in the utilization of ACEi, BB, or CCB. The majority of recalled generic valsartan products were replaced by other ARBs, predominantly candesartan, despite documented drug shortages. In contrast to previous safety warnings/recalls, our data do not suggest an under-prescription of antihypertensives during this period.

Highlights

Angiotensin receptor blockers (ARBs) are the most commonly used drugs for the treatment of arterial hypertension, heart failure, and chronic kidney disease [1]
Non-recalled and recalled valsartan products together had a market share of 35% of all ARBs, which decreased to 26% (−26%) in the second half of 2018 and to 12% (−66%) in the second half of 2019
Our analyses suggests that only a minority of patients received new prescriptions for other ARBs than candesartan, such as losartan, telmisartan, irbesartan, olmesartan, azilsartan, or eprosartan

Summary

Introduction

Angiotensin receptor blockers (ARBs) are the most commonly used drugs for the treatment of arterial hypertension, heart failure, and chronic kidney disease [1]. In accordance with the European Medicines Agency, the German Federal Institute for Drugs and Medical Devices announced recalls of generic valsartan products on July 4th, 2018 [3]. The drugs were recalled due to high concentrations of probable carcinogenic nitrosamines found in selected lots of ARB substances and generic drugs, primarily valsartan from Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, China. These impurities were most likely related to a change in the manufacturing process of the valsartan substance implemented in 2012 [4]. Other manufacturers and other drug classes were recognized to be contaminated with nitrosamines and were recalled worldwide [5]. Previous safety warnings and medication recalls were associated with gaps in prescriptions and often associated with adverse health outcomes, due to drug shortages [7,8,9,10]

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Discussion

Conclusion