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BMJ. 2018 Sep 12;362:k3851. doi: 10.1136/bmj.k3851.

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

Author information

1
Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, JB Winsløwsvej 19, 2, 5000 Odense C, Denmark apottegaard@health.sdu.dk.
2
Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, JB Winsløwsvej 19, 2, 5000 Odense C, Denmark.
3
Medical Evaluation and Biostatistics, Danish Medicines Agency, Copenhagen, Denmark.
4
Pharmacovigilance and Medical Devices, Danish Medicines Agency, Copenhagen, Denmark.

Abstract

OBJECTIVE:

To perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products.

DESIGN:

Nationwide cohort study.

SETTING:

Danish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses.

PARTICIPANTS:

5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant's exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag.

MAIN OUTCOME MEASURES:

Association between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined.

RESULTS:

The final cohort comprised 5150 people followed for a median of 4.6 years. In total, 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 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null.

CONCLUSIONS:

The results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

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