Researchers have identified what they call is a modest but significant link between angiotensin receptor blocker (ARB) therapy and the development of new cases of cancer. The Case Western Reserve University School of Medicine team claim that their findings suggest ARB therapy results in a 1.2% absolute risk of any type of cancer developing in patients receiving at least one year of treatment. Lung cancer was the only solid organ cancer that appeared to be significantly increased in patients taking ARBs.
The study didn’t find a significant excess in cancer deaths associated with ARB therapy. However, the authors stress, the process of cancer development, progression, and death is typically slow, particularly after multiple cancer treatments. They noted that conclusions from their meta-analysis of data from trials not geared for longer-term follow-up can’t be drawn.
Moreover, when analysis was limited to the three trials where cancer was a prespecified endpoint and cancer data was collected rigorously, there was a significant increase in risk of cancer associated with ARB therapy. They point out that cancer data was not available in peer-reviewed publications or FDA website documents for several randomized trials of ARBs, “which raises the concern of publication bias.” In fact, most trials did not even collect cancer information.
Results from the Case Western team’s research are published in The Lancet Oncology in a paper titled “Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials.”
Currently, there are no major safety concerns with ARBs apart from their use in pregnancy, renal-artery stenosis, and chronic kidney disease, reports lead author, Ilke Sipahi, M.D., and colleagues. Clinical trials of ARBs have mainly assessed their effects on cardiovascular and renal endpoints and have usually not reported incidence of cancers. Experimental studies, however, have implicated the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cellular proliferation, angiogenesis, and tumor progression.
In addition, the 2003 Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study, which assessed ARBs in heart failure, reported an unexpected finding of significantly higher fatal cancers in the candesartan group than in the placebo group.
“Because the results of several other large ARB trials have become available since the publication of the CHARM trial, we decided to do a meta-analysis of randomized controlled trials of these drugs to examine their effect on occurrence of new cancers,” the Case Western team explains. “Our secondary objectives were to determine whether ARBs affect the occurrence of specific solid organ cancers and cancer deaths.”
The resulting trial included an evaluation of all publicly available data from ARB trials published before November 2009. Dr. Sipahi and colleagues focused on only those trials evaluating one of the seven currently approved ARB drugs. They investigated the incidence of new cancer data in five trials involving nearly 62,000 patients, common types of solid organ cancers in five trials of 68,00 patients, and cancer deaths in eight trials including 93,500 patients. Although new cancer data were available for three of the seven FDA-approved ARBs, over 85% of patients in all the trials were treated using the ARB telmisartan.
The authors stress that given the limited data “it is not possible to draw conclusions about the exact risk of cancer associated with each particular ARB.” They conclude, however, that “the finding of a 1.2 percent increase in absolute cancer risk over an average of four years needs to be interpreted in view of the estimated 41 percent background lifetime cancer risk.”
In an accompanying commentary piece in the same issue of The Lancet Oncology, Steven E. Nissen, M.D., at Cleveland Clinic’s department of Cardiovascular Medicine claims that the findings are “disturbing and provocative, raising crucial drug safety questions for practitioners and the regulatory community.”
He suggests that since full trial data available for developmental drugs are often more detailed than the results presented in published reports, regulatory authorities should request that ARB pharma companies submit complete trial datasets for evaluation.
“Regulators must review the possible association between ARB use and cancer and promptly report their findings,” he notes. “In the interim, we should use ARBs, particularly telmisartan, with greater caution.”