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:k3851Linked editorial
Regulatory response to contaminated valsartan
Linked opinion
Fast-tracked pharmacoepidemiology in drug safety issues
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Dear Drs. Etminan and Mansournia.
Thank you for taking interest in our study and for your considerations regarding exposure definition, follow-up time, and statistical precision.
We analysed whether ever-use of NDMA contaminated valsartan was associated with increased cancer risk compared to use of non-contaminated valsartan. This does indeed compare to an intention-to-treat like approach. Exposed follow-up time began after the first filled prescription for contaminated valsartan (applying a 1-year lag-time). The follow-up time as NDMA ever-exposed was on average 3.5 years (11 920/3450) and the median follow-up time was 3.8 years. Importantly, the ever-user analyses do not introduce exposure misclassification. By definition, a patient is considered an ever-user after the first NDMA contaminated prescription fill regardless of whether the patient uses non-contaminated valsartan later.
We fully agree that relying solely on ever-use is insufficient in this as well as other drug-cancer association studies.1 Hence, we carried out dose-response analyses for cumulated dose of contaminated valsartan as well. For the dose-response analyses, the follow-up time for each stratum of cumulated dose cannot be calculated by dividing person years for each stratum with the total number of ever-exposed, because not all the 3450 ever-exposed patients reached the highest dose category. Although this was not supplied in the article, the median follow-up time of individuals was 3.1 years after having entered the highest dose category (excluding the 1-year lag-time we applied), among those that entered this category. Importantly, however, we fully agree that our results only pertain to short-term risk given the limited follow-up time and latency of most cancers. Accordingly, we emphasized that long-term risk is unknown and should be addressed in future studies in the manuscript. Similarly, we have already, as suggested, highlighted the upper bounds of the confidence intervals in the discussion section of our manuscript.
Lastly, Drs. Etminan and Mansournia suggest that death should be considered as a competing event. There were 425 deaths in our sample, corresponding to a rate of 0.036 per 1000 person years. We have performed a competing risk analysis based on Fine and Gray’s proportional subhazards model for our main estimate, using all-cause death as the competing event. This yielded subhazard ratios that were virtually identical to the hazard ratios reported in our paper: The estimate for ever exposure to NDMA was changed from 1.09 (0.85 to 1.41) to 1.12 (0.88 to 1.43), while the estimates for the three strata in the dose response analysis was changed from 1.15, 0.99, and 1.11 to 1.14, 1.00, and 1.17, respectively. As such, we conclude that there is no reason to suspect bias from informative censoring by death.
References:
1. Pottegård A, Friis S, Stürmer T, Hallas J, Bahmanyar S. Considerations for Pharmacoepidemiological Studies of Drug-Cancer Associations. Basic Clin Pharmacol Toxicol 2018;122:451-9. doi:10.1111/bcpt.12946. pmid:29265740
Competing interests: No competing interests
Editor,
We enjoyed reading the study by Pottegard et al.1 that examined the risk of NDMA contaminated valsartan and the risk of cancer. We commend the authors for addressing an important and timely question. A number of methodological issues must be addressed to better put the results into context.
First, an intention-to-treat approach used in this study is the not the optimal analytical approach to examine diseases with long latency like cancer. This is especially important with this particular study question as it is possible that patients taking NDMA valsartan may switch to other generic formulations during follow up increasing the possibility of exposure misclassification. The strongest analysis in the study is the dose response analysis which demonstrates adequate exposure over time. However, from the person time information provided the cumulative exposure follow up time spans from less than one year to 1.5 years for the lowest and highest dose categories respectively. These follow up times are not particularly sufficient for the initiation and detection of a malignant process that might result from NDMA contaminated valsartan use. Furthermore, since a competing risk bias analysis was not presented it is not known how many patients died of other causes and were not at risk of developing cancer.
All these reasons might have contributed to a small number of cancer events and the possibility of sparse data bias2. In their conclusion the authors state that there was a non-statistically significant risk with colorectal and uterine cancers. However, according to Figure 3 the upper bounds of the confidence intervals with all solid tumor risks presented are high and cannot exclude the possibility of an increased risk. The increase in the risk of cancer with incident users is concerning and studies with a larger sample and longer follow up that can also address competing risk bias are needed to better answer this question.
References:
1. Pottegård A, Kristensen KB, Ernst MT, Johansen NB, Quartarolo P, Hallas J. 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.
2. Greenland S, Mansournia MA, Altman DG. Sparse data bias: a problem hiding in plain sight.BMJ 2016;352:i1981.
Competing interests: No competing interests
I read with great interest this Danish nationwide cohort study by Pottegård and his colleagues (1), in which they investigated whether the use of N-nitrosodimethylamine (NDMA) contaminated valsartan products is associated with the risk of cancer in Danes.
It should be noted that, in an updated official report from FDA (2) related to contaminated valsartan, FDA scientists estimated that one additional case of cancer may be found among eight thousand people who keep taking the highest contaminated valsartan dose every day for the full four year. This claim gives us an intuitive impression that the risk of cancer caused by the problematic valsartan is extremely minimal. Given only 6000+ subjects who had taken this contaminated drug in the last 4.6 years were included this cohort study, I am afraid that this sample size seems far from big enough to detect the hypothesized association in this study.
Furthermore, I noticed that Pottegård and his colleagues (1) only adjusted the covariates including age, sex, medication history and disease-related factors in their study. In this case, potential bias would likely to be introduced because of many other well-known important covariates that were unadjusted such as patients lifestyle (smoking, alcohol et al.) and other environmental factors (eg. occupation-related exposure). These confounders can largely distort and even reverse the association between contaminated valsartan and cancer, especially when the association is assumed to be extremely low.
In conclusion, the interpretation of the results from this study should be done with caution.
References:
1. Pottegård A, Kristensen KB, Ernst MT, Johansen NB, Quartarolo P, Hallas J. 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.
Competing interests: No competing interests
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