番茄社区

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Valsartan contaminated with N-nitrosodimethylamine (NDMA) did not appear to put patients at a greater short-term risk for cancer, a Danish cohort study found.

Out of all 5,150 Danish patients filling a valsartan prescription during the study period of January 2012 through June 2018, there were 104 cancer cases among 7,344 patients taking NDMA-unexposed valsartan and 198 cases among 11,920 taking valsartan later found to have been contaminated with NDMA, for an adjusted hazard ratio of 1.09 for overall incidence of cancer (95% CI 0.85-1.41).

There was also no evidence of a dose-response relation between cancer and NDMA exposure (P=0.70), reported Anton Pottegard, PhD, of University of Southern Denmark in Roskilde, and colleagues in .

The data related to early cancer risk connected to use of valsartan-contaminated NDMA should not, however, be viewed as an indication that NDMA is not carcinogenic to people, the researchers emphasized.

"[L]evels of NDMA exposure achieved through valsartan products do not translate into a substantially increased short term cancer risk," the investigators concluded.

While those findings may be reassuring, they were quickly followed by an FDA warning of a second cancer-related impurity, N-nitrosodiethylamine (NDEA), in valsartan products. The agency has an ongoing investigation, as the impurity is known to be carcinogenic for animals and suspected to be one for humans. Both NDMA and NDEA are thought to arise as part of certain manufacturing steps for valsartan.

"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," Rita Banzi, PharmD, PhD, and Vittorio Bertelé, MD, both of Istituto di Ricerche Farmacologiche Mario Negri in Milan, wrote in an accompanying BMJ editorial.

"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," they added.

The study "underscores how we need to remain vigilant for such impurities in pharmaceuticals due to the manufacturing process," commented John Bisognano, MD, of University of Rochester Medical Center, in New York, in an interview with 番茄社区.

"Fortunately, valsartan containing the impurity is off the shelves in the USA, but patients need to be sure that they don't have any old stock at home from the manufacturer of concern. Similarly, valsartan is one of several drugs in the ARB class that can be easily replaced by other ARBs, some of which may even be preferable," added Bisognano, who was not involved in the study.

The investigators evaluated 5,150 Danish patients (age 40 years old or older), all of whom had never had cancer before. After a one year lag period, the study participants were followed up until there was a cancer outcome, death, migration or end of study. Researchers evaluated each participant's exposure to NDMA.

Moreover, the researchers also assessed individual cancer outcomes. They noted nonsignificant increases in risk for colorectal cancer (HR 1.46, 95% CI 0.79-2.73) and for uterine cancer (HR 1.81, 95% CI 0.55-5.90).

"The study was reassuring to me in that the overall incidence of cancer was not statistically significantly different in the people who were on valsartan compared to those who were off," noted Bisognano.

"There were some sub groups suggestive of more colon and uterine cancer that were worrisome, but not reaching statistical significance. One always worries about a carcinogen in a place where one would not normally expect it, even if the concentration is really low," Bisognano added.

Apart from those two types of cancer, the researchers found no other cancer outcomes linked with NDMA, the investigators explained. Moreover, "analyses of other cancer outcomes were not possible owing to low numbers," the investigators wrote.

Taking into account their study's limited follow-up, low single outcome numbers, and assessment of long term effects, the investigators concluded, "further studies are needed to fully elucidate the health effects of NDMA contaminated valsartan products."