The discovery of Valsartan products that were contaminated with NDMA, in July 2018, in drug products manufactured in China, triggered the withdrawal of all affected products by medical agencies across Europe and the United States. Being one of the most well characterized and potent animal carcinogens known, Pottegard and his colleagues conducted an expedited observational cohort study using the nationwide Danish healthcare registry. They aimed to quantify the potential effects of NDMA contaminated valsartan products in terms of increased cancer risk, in order to provide timely information for regulatory bodies evaluating its carcinogenic effects. Results from this Danish cohort study, published in the BMJ, however, failed to show a significant increase in overall short-term cancer risk due to consumption of NDMA contaminated valsartan.
The investigators enrolled 5150 Danish patients with no history of cancer, aged 40 years or older, who were using valsartan in 2012 or initiating use in the period between 2012 and 2017. The follow-up period was one year after cohort entry (lag time period) until the occurrence of a cancer outcome, death, migration, or the end of the study period (30 June 2018). Each participant’s exposure to NDMA was mapped out as a time-varying variable while also applying a one year lag. The primary composite endpoint comprised of all cancers except non-melanoma skin cancer. The risk of individual cancers was determined in the supplementary analyses.
[perfectpullquote align=”full” bordertop=”false” cite=”” link=”” color=”” class=”” size=””]“We have assessed the potential cancer risk associated with exposure to NDMA through contaminated valsartan products and found no evidence of a markedly increased short-term overall risk of cancer. However, we cannot exclude a modest association.”- Dr. Anton Pottegård, M.D.[/perfectpullquote]
The study population consisted of 50 individuals who were followed for a median of 4.6 years. A total of 3625 cohort participants contributed 7344 person-years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person-years classified as ever exposed to NDMA. With 104 and 198 cancer outcomes reported among NDMA unexposed and exposed participants respectively, the adjusted hazard ratio for overall cancer was 1.09 (95% CI 0.85 to 1.41). Furthermore, there was no evidence of a dose-response relation (P=0.70). In the supplementary analysis for single cancer outcomes, increases in risk for colorectal cancer (HR 1.46, 95% CU 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90) that did not reach significance were reported by Anton Pottegard, PhD, of University of Southern Denmark in Roskilde, and his colleagues.
The investigators concluded that this study was not a testament to the carcinogenic effects of NDMA, stating, “We have assessed the potential cancer risk associated with exposure to NDMA through contaminated valsartan products and found no evidence of a markedly increased short-term overall risk of cancer. However, we cannot exclude a modest association.” Additionally, they acknowledged that the limited follow-up period and inability to assess the long-term effects, coupled with the low number of events could have made the interpretation of estimates for single cancer outcomes difficult. While these findings were reassuring for NDMA, they were quickly succeeded by an FDA warning for a second cancer-related impurity, N-nitrosodiethylamine (NDEA), in valsartan products. Both NDMA and NDEA were thought to arise as part of certain manufacturing steps for valsartan. While investigations for NDEA are ongoing, only future research can fully elucidate the health effects of these impurities in contaminated valsartan products.
Rita Banzi, PharmD, Ph.D., and Vittorio Bertelé, MD, both of Istituto di Ricerche Farmacologiche Mario Negri in Milan, wrote in an accompanying BMJ editorial, “The study alone cannot dispel doubts about the potential risk for patients in the long term, but it helps inform decision making around this episode. It also illustrates the usefulness of national registries for examining relations between risk factors and health problems and how research can give a prompt response whenever public health concerns emerge.”
Source: https://www.bmj.com/content/362/bmj.k3851