This July, it was discovered that some valsartan products (used for treatment of hypertension and heart failure) sold in Europe and the United States had been contaminated with a potent carcinogen called N-nitrosodimethylamine (NDMA). This contamination was specific to valsartan substances manufactured by Zhejiang Huahai Pharmaceuticals, a company in Linhai, China.
Medical agencies across Europe as well as the US Food and Drug Administration immediately withdrew all contaminated products from the market. However, it is believed that the contamination began six years ago as it seems to be related to a change in the manufacturing process that was implemented in 2012. From animal studies, we know that NDMA is a potent carcinogen, but unfortunately, no human data are available.
In collaboration with the Danish Medicines Agency, we decided to address this issue using the nationwide Danish health registries. Due to the public health implications, we aimed to provide answers as quickly as possible. That sense of urgency was shared by our collaborators at the Danish Medicines Agency, the Danish Health Data Authority, and the reviewers and editorial board at The BMJ, who all contributed greatly to expediting the process. Thus, we could publish these findings in The BMJ only ten weeks after the NDMA contamination was first announced. We think of this study as a proof-of-concept study in that expedited pharmacoepidemiologic assessment is possible and has its place in such urgent public health matters.
We are able to provide some reassurance with this study, as NDMA contaminated valsartan products showed no association with an increased risk of cancers in general compared with exposure to non-contaminated valsartan products. An interesting feature of our study was that we were able to compare patients who had unknowingly taken NDMA contaminated valsartan products with patients who had taken non-contaminated valsartan products, thus ensuring a high degree of comparability. Although our results are generally reassuring, uncertainty remains regarding both individual cancer outcomes and long-term cancer risk. For individual cancers, we observed increases in risk of colorectal and uterine cancer, however, with wide confidence intervals that included the null. Further, the limited follow-up time (median of 4.6 years) constitutes the main limitation to the study. As such, we are not able to infer anything about later carcinogenic effects. Our results do not imply an increase in short-term overall cancer risk from use of valsartan products contaminated with NDMA. We plan to follow up on these findings with regards to exposure classification once data on actual NDMA content become available and eventually to assess long-term risks.
Anton Pottegård, associate professor, Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark
Kasper Bruun Kristensen, research fellow, Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark
Martin Thomsen Ernst, data manager, Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark
Nanna Borup Johansen, senior medical officer, Medical Evaluation & Biostatistics, Danish Medicines Agency, Copenhagen, Denmark
Pierre Quartarolo, director of division, Pharmacovigilance and Medical Devices, Danish Medicines Agency, Copenhagen, Denmark
Jesper Hallas, professor, Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark
Competing interests: Please see full details on the research paper.