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Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study

BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3851 (Published 12 September 2018) Cite this as: BMJ 2018;362:k3851

Linked editorial

Regulatory response to contaminated valsartan

Linked opinion

Fast-tracked pharmacoepidemiology in drug safety issues

Authors’ reply: A large sample size is needed to find one case of cancer caused by contaminated valsartan - FDA reports

Dear Dr. Zhou

We appreciate your response to our study and would like to address the two key issues that you highlight, i.e. the statistical power and potential for residual confounding.

The estimate from the FDA corresponds to one additional cancer for each 32 000 person years, i.e. an absolute risk increase of 0,03/1000 person years.1 Compared to the incidence rate of cancer among unexposed in our study (14.2 incident cancers per 1000 person years), this would correspond to a relative risk of 1.002 for use of NDMA contaminated valsartan compared to no use. Importantly, however, our objective was not to detect or rule out a risk increase of that magnitude. Given the fact that no human data is available, the above estimates are based on animal studies and several assumptions regarding the extrapolation of animal studies to humans. We therefore aimed to assess whether exposure to contaminated valsartan was associated with a markedly increased short-term cancer risk. While we cannot rule out a small risk increase, even several magnitudes larger than the one estimated by the FDA, our estimates do provide some reassurance that no major increase in cancer incidence could be detected.

With regards to confounding, we do agree that smoking, alcohol, body mass index are risk factors for a range of cancers.2-4 However, a noteworthy feature of this study was that users of contaminated valsartan were compared to users of non-contaminated valsartan. As such, no comparison was made to non-users. As patients and physicians were unaware of the NDMA contamination during the study period, we considered it highly unlikely that, within this cohort, smoking, body mass index, or alcohol consumption would be associated with the exposure, i.e., choosing a contaminated over a non-contaminated valsartan product for a given patient. As such, we do not agree that residual confounding from lifestyle factors is a major concern in the interpretation of our results.

References
1. U.S. Food and Drug Adminsitration. Analysis of N-nitrosodimethylamine (NDMA) Levels in Recalled Valsartan in the U.S. Update 7/27/2018. https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm
2. Anderson AS, Key TJ Norat T et al. European Code against Cancer 4th edition: Obesity, body fatness and cancer. Cancer Epidemiol. 2015;39 Suppl 1:S34-45. doi: 10.1016/j.canep.2015.01.017
3. Leon ME, Peruga A, McNeill A et al. European Code against Cancer 4th edition: Tobacco and cancer. Cancer Epidemiol. Cancer Epidemiol. 2015;39 Suppl 1:S20-33. doi: 10.1016/j.canep.2015.06.001
4. Scoccianti C, Cecchini M, Anderson AS et al. European Code against Cancer 4th edition: Alcohol drinking and cancer. Cancer Epidemiol. 2016;45:181-188. doi: 10.1016/j.canep.2016.09.011

Competing interests: No competing interests

25 September 2018
Anton Pottegård
associate professor
Kasper Bruun Kristensen, Martin Thomsen Ernst, Nanna Borup Johansen, Pierre Quartarolo, Jesper Hallas,
Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark
JB Winsløwsvej 19, 2, 5000 Odense C, Denmark