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It took approximately 3 years of high-dose angiotensin-receptor blocker (ARB) exposure for an increased cancer risk to become evident, according to a large trial-level meta-analysis.

Greater cumulative exposure to these blood pressure-lowering medications correlated with rising risk of all cancers -- lung cancer in particular -- across 15 trials of the ARB Trialists Collaboration. Results persisted regardless of background angiotensin-converting enzyme (ACE) inhibitor treatment and type of control in the trials, reported cardiologist Ilke Sipahi, MD, of Acibadem University Medical School in Istanbul, Turkey.

The risk threshold was a cumulative exposure greater than 3 years of exposure to daily high dose for a statistically significant increase in all cancers combined, whereas the cutoff was 2.5 years for a significant increase in lung cancer alone. Lower exposures showed no relationship to cancer, according to Sipahi's report, published in .

"I think that this new article is providing fundamental proof that these drugs cause cancer," he wrote in an email. He estimated that the antihypertensives are directly responsible for 1.7 million excess cancers (or 430,000 lung cancers) among the more than 200 million ARB users around the world.

The matter of cumulative exposure may offer an explanation as to why prior reports showed conflicting results regarding the safety of ARBs.

In 2010, Sipahi's group published a showing a link between these antihypertensives and cancer. FDA subsequently said it performed its own meta-analysis and found no such result, though there were on how the data were handled in that investigation. Since then, other researchers haven't found definitive evidence leaning one way or another.

The present study suggests that trials with greater cumulative ARB exposure would be the ones to support an increased risk of cancer.

Many lots of ARBs have been recalled since the summer of 2018 -- not for an inherent cancer risk, but because of potentially carcinogenic nitrosamine and azido contamination. Generic valsartan, losartan, and irbesartan were among the first ARBs recalled.

In FDA's probe, the agency estimated that if 8,000 people took the highest valsartan dose (320 mg) containing N-nitrosodimethylamine (NDMA) contamination from the recalled batches daily for 4 years, there may be one additional case of cancer over their lifetimes.

"However, number needed to harm according to the current analysis is remarkably lower; 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis," Sipahi emphasized.

He suggested ACE inhibitors and calcium channel blockers as safer first-line antihypertensives.

Sipahi's present analysis was based on data from the ARB Trialists Collaboration. It comprised 74,021 patients assigned an ARB (for a total cumulative exposure of 172,389 person-years of exposure to daily high dose) and 61,197 patients randomized to control.

"It is highly likely that the ARB Trialists Collaboration data greatly overlaps with the data that the industry provided to the FDA for its official investigation," Sipahi wrote.

"Therefore, given its size, inclusion of data directly provided by the pharmaceutical companies not available elsewhere and detailed public disclosure enabling examination of cumulative exposure-cancer risk relationship, trial-level data from the published report of the ARB Trialists Collaboration was used for the current analysis," he said.

Chief among the limitations of the study was the lack of patient-level data, which prevented Sipahi from making adjustments for age and smoking status, he acknowledged.

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