Sudden, ‘Biologically Implausible’ Rise in Valsartan-Linked Neoplasms After 2018 Recall

After the US Food and Drug Administration announced a voluntary recall of several valsartan-containing drugs in mid-2018, citing reports of potentially cancerous impurities, there was an “abrupt and biologically implausible” rise in the number of cancers reported by patients and providers, according to new research.

The report, published as a research letter in Circulation: Cardiovascular Quality Outcomes, mapped out patterns in valsartan-associated adverse events (AEs) reported to the FDA’s Adverse Events Reporting System (FAERS). Investigators focused on reports to FAERS from January 1, 2017, to December 31, 2018, and calculated a reporting odds ratio (ROR), which captures the proportion of all reported adverse events (AEs) that were said to be neoplasms. This number ballooned from 1.8 in June 2018, just prior to the recall, to 15.4 in July and 18.2 in August before beginning to decline. As of December, the ROR for valsartan-connected neoplasm AEs remained higher than in June, the last month prior to recall.

“Given the very, very tiny amount of impurities that were discovered in valsartan, we don’t exactly know what the risk [of cancer] is,” Sadeer G. Al-Kindi, MD, who co-authored the letter along with Guilherme H. Oliveira, MD, MBA (both from University Hospitals Cleveland Medical Center, OH), observed to TCTMD. “Patients felt as though the problem was much bigger than it is.”

Patients felt as though the problem was much bigger than it is. Sadeer G. Al-Kindi

The FAERS data included 11,112 AEs in total, with 5,151 attributed to valsartan and 5,961 to other angiotensin-receptor blockers (ARBs). While neoplasms comprised just 8.7% of the overall AEs for ARBs, this figure rose to 14.7% for valsartan.

“Although consumer reporting appeared to be the most susceptible to the widely covered recall, healthcare providers were also influenced,” Al-Kindi and colleagues note, citing both media and public attention. For example, in Q3 of 2018, the ROR for consumer-reported cancers had increased to 16.5, compared to just 1.0 in Q2.

Some of these issues are related to inherent shortcomings of FAERS, such as “inaccurate, voluntary, and delayed reporting,” they say. “Our findings not only underscore these limitations but also illustrate how an increase in drug AE reporting can be associated with drug recalls and the media.”

Commenting on the results for TCTMD, Franz Messerli, MD (University of Bern, Switzerland), said: “The risk [of cancer] is exceedingly low. It corresponds to about one cigarette a day. [But] once there is public alarm, everybody thinks all of a sudden that they have some malignancies that are related to valsartan.” Messerli said he not optimistic that such effects can be contained, similarly finding them to be inherent to widespread adverse event reporting.

Craig Beavers, PharmD (University of Kentucky, Lexington), however, marked a distinction between events that receive widespread attention—like the valsartan recall—and other upticks in FAERS’ reports that fly under the radar. “If we have registries or real live insurance claims or anything like that, at least you can do some case control or [cohort studies] to help observe when we’re having these events,” Beavers suggested to TCTMD. In such cases, he added, reports to the FDA “can help you understand if there are signals that need to be investigated.”

We should educate not just the medical community—but the public—about what the risk means. Craig Beavers

Of course, there will always be high-profile events like the valsartan recall that fuel intense public concern, Beavers acknowledged.

“When these things start occurring, we should educate not just the medical community—but the public—about what the risk means. I’m not saying cancer isn’t a big deal. . . . Relative risk can sound really scary, but realistically when you look at the actual true incidence of what the increase of cases [could] be it may not be that dramatic. Trying to put some context about what risk truly means” should be a paramount goal of health professionals, he advised.

Concern fueled by adverse event reports can have real-world consequences, Al-Kindi emphasized. “Once we discovered that a lot of patients are discontinuing these medications [such as valsartan] in our large health system, we’re [now] looking into the impact of this valsartan recall on heart-failure outcomes,” he said. “Valsartan is not only used for blood pressure. It’s also one of the medications that’s been proven to reduce death in patients with heart failure.”