ARB Recalls Fuel Abrupt, 'Biologically Implausible' Rise in Cancer Reports

Megan Brooks

August 06, 2019

The tainted "sartan" crisis, which attracted extensive national media coverage last year, led to an abrupt but "biologically implausible" increase in valsartan-associated neoplasms reported by patients and physicians, according to a trends analysis.

Although the lay public appeared to be the most susceptible to the widely covered recall, healthcare providers were also influenced, report Sadeer G. Al-Kindi, MD, and Guilherme H. Oliveira, MD, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center.

"We suspected, from clinical observation, that the public became hyperaware after FDA recalls," Oliveira told theheart.org | Medscape Cardiology. "Therefore, we weren't surprised by being able to confirm that fact. However, what was surprising was the magnitude of the effect and, even more so, that physicians and providers were also influenced by the recall," he said.

"There needs to be a better and stricter way of reporting drug-related associations. As it stands now, the potential for over-reporting and FDA and media-provoked scares puts in question the validity of these reported associations," said Oliveira.

The study was published in the July issue of Circulation: Cardiovascular Quality and Outcomes.

In July 2018, trace amounts of the potential carcinogen N-nitrosodiethylamine were found in some formulations of angiotensin receptor blockers (ARBs), particularly valsartan. This led to recall of valsartan in the United States, an action that received wide media and public attention.

Al-Kindi and Oliveira investigated trends in ARB-associated neoplasm adverse events (AEs) reported to the US Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) between January 1, 2017 and December 31, 2018.

The FAERS data for the study period included 11,112 AEs — 5151 attributed to valsartan and 5961 to other ARBs — of which 920 (8.7%) were due to neoplasms (14.7% out of valsartan AEs, 3.6% out of other ARBs AEs).

The reporting odds ratio (ROR) for neoplasm AEs jumped from 1.7 before the recall to 7.1 after the recall, the researchers report.

On a monthly basis, the ROR jumped from 1.8 in June 2018 (just prior to the recall) to 15.4 in July 2018, 18.2 in August, and 17.2 in September 2018. The ROR then decreased, but remained elevated above baseline.

The steep and transient rise in reporting of ARB-associated cancers was likely associated with "public alarm and fueled mainly by consumer and lay reporting," the researchers say.

They point out that in a previous, similar analysis of the FDA Manufacturer and User Facility Device Experience database, cardiovascular device recalls were linked to increased reporting, "but differently, those preceded the recall, and persisted for a few months."

This study, they conclude, highlights "inherent shortcomings" in the FAERS and suggests that "relying on passive pharmacovigilance analytics to identify risk may result in false signals, especially when relying on reporting by consumers."

A Call to Arms

"This study is a call to arms that we need to have a better mechanism of reporting and/or more education about people reporting in general," Craig Beavers, PharmD, University of Kentucky College of Pharmacy, Lexington, told theheart.org | Medscape Cardiology.

When these things happen, it's equally important to educate the public and health providers about the true risk, said Beavers. "When you put the numbers in relative risk, it may look very high and very scary, but probably the absolute risk is not substantially high, although at any point we should always be concerned about cancer," he said.

Another key issue with the tainted sartan drugs, said Beavers, is it's not exactly clear how long it has been going on, so the true length of exposure is unknown, "but I think we'll continue to learn about it."

Dan Sheehan, PhD, who directs the Gatton Behavioral Research Lab at the University of Kentucky, is not surprised by the findings.

"I would expect that news reports of specific side effects or a recall would enhance consumers' beliefs that they could be suffering from those side effects," he told theheart.org | Medscape Cardiology. "It could lead them to be more likely to report these potential side effects to their doctors. Although situational expertise and knowledge of the bias can curtail this bias, physicians may succumb to the same bias."

Sheehan said the rise in reported valsartan-associated cancers is an example of a common decision-making bias called the availability heuristic, where people overweigh the probability of an event occurring because related information is more accessible (or available) in a person's mind.

"For example, people think the odds of being bitten by a shark is greater after watching a movie about shark attacks," said Sheehan.

The study had no specific funding. The authors, Beavers, and Sheehan have no relevant disclosures.

Circ Cardiovasc Qual Outcomes. 2019;12:e005536. Abstract

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