Uptick in ‘Implausible’ Cancers Reported After ARB Recalls

Three ARBs were recalled by the US Food and Drug Administration in 2018 because of trace amounts of the potential carcinogen nitrosamine, but a sudden spike in reports of cancers among ARB users was overwhelmingly attributed to the least used of the three, a new investigation of the FDA Adverse Event Reporting System (FAERS) data concludes.

The agency recalled valsartan first. That was followed by a global voluntary recall, and by the end of 2018, the recalls expanded to include irbesartan and losartan.

Cynthia A. Jackevicius, PharmD, MSc (Western University of Health Sciences, Pomona, CA), senior author of the new study published in Circulation: Cardiovasc Quality and Outcomes, explained that while the logical expectation would be that losartan would have the most cancer reports associated with it because it is the most widely used, the distinction belonged to valsartan.

“The first ARB recalled had the most-extreme increase in the neoplasms that were reported,” she told TCTMD.

At 1 year after the recall, cancer reports made to the database were significantly more common for valsartan compared with irbesartan (OR 1.77; 95% CI 1.47-2.13) or losartan (OR 2.07; 95% CI 1.85-2.32). Additionally, when the researchers looked at the types of cancer signals that had been identified from animal models and epidemiological studies as being associated with nitrosamine compounds, there was no excess of those types of cancers reported by ARB users and/or their physicians.

“This is likely a false signal and can be reassuring to patients,” Jackevicius noted. “It’s still something that should be on the radar. I hope through this lesson there can be more work done to improve production processes and enhance the quality of the drug products based on what we've learned.”

Their study adds to a growing picture of the recalls’ impact on patients and their physicians. Jackevicius and co-authors Robert Cohen Sedgh, PharmD, and Jungyeon Moon, PhD, PharmD (both Western University of Health Sciences), note that “despite regulatory authorities’ warnings and advice not to abruptly stop ARB therapy, there were sudden declines in Medicaid prescriptions for both contaminated and noncontaminated ARBs in the United States after the initial FDA recalls, along with an immediate increase in emergency department visits for hypertension and a delayed increase in emergency department visits and hospitalizations for stroke/transient ischemic attack in Ontario, Canada, after similar ARB recalls by Health Canada.”

A previous study looking at the months after the valsartan recall similarly found an “abrupt and biologically implausible” rise in the number of cancers reported to FAERS, with those researchers concluding that the increase was “likely associated with public alarm and fueled mainly by consumer and lay reporting.” Jackevicius and colleagues reached the same conclusion even when expanding to all three recalled ARBs and extending the time window to include neoplasm reports prior to the recall and more than a year later.

Call for Better Communication

Beginning in July and August 2018, which were the month of the recall and the month after, cancer reports for valsartan showed a sudden, transient increase followed by a decrease in September 2018, although the average number of these types of reports for valsartan remained higher than normal through 2019. In contrast, neoplasm adverse events reported by irbesartan users or their physicians did not peak until 5 months after the recall date. Neoplasm adverse events associated with losartan also peaked at 5 months after the recall date, but they then rose sharply again 11 months after the initial recall date.

To TCTMD, Jackevicius said while it’s unclear why there were delays in the reporting of these events for irbesartan and losartan, it may be related to them getting less media attention, or having less of an acute reaction, than the valsartan recall.

She and her colleagues say one of the takeaways from the ARB experience should be to improve the quality of the communication that reaches patients by having the FDA work closer with clinicians, prescribers, and pharmacists when a major recall happens.

“We’d like to see them give some notice and have some sort of organized rollout before there is a very broad recall,” she said. “That way, prescribers and pharmacists can plan a little bit more around this and contact patients in a concerted manner. It will decrease the public alarm to a certain extent, and allow for communication among healthcare professionals and patients when these non-life-threatening kinds of recalls happen.”