Medical experts have reacted with caution to the publication of a meta-analysis suggesting that use of angiotensin receptor blockers (ARBs) to treat hypertension, heart failure or diabetic kidney disease could lead to a small but significant increase in the risk of new cancers.
The researchers themselves, from Case Western Reserve University in Cleveland, US, acknowledge that their findings need further investigation and that patients on ARBs should not stop taking their medication without first discussing the risks and benefits with their doctor – a view backed up by other cardiology and cancer experts.
The research team led by Dr Ilke Sipahi, associate director of heart failure and transplantation at Case Western Reserve University School of Medicine, found that the risk of new cancer diagnoses associated with ARBs was 8-11% higher, with a 25% increase in the risk of lung cancer.
The vast bulk of the patients in the studies analysed were taking telmisartan, marketed by Boehringer Ingelheim (BI) as Micardis. The company issued a strong rebuttal of the meta-analysis published in Lancet Oncology, questioning the study design and citing BI’s own “comprehensive internal safety data analysis”, which found no significant association between telmisartan and malignancies.
Meta-analysis
Noting that experimental studies implicate the renin-angiotensin system, and particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis and tumour progression, Sipahi and his colleagues conducted a meta-analysis of randomised controlled trials (RCTs) with ARBs to see whether the drugs had any effect on cancer occurrence.
In 2003, an increase in fatal cancers was observed in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) study with the angiotensin II blocker candesartan (AstraZeneca’s Atacand), but this was viewed as almost certainly a chance finding.
The researchers looked at studies published before November 2009 that included any of the seven currently marketed ARBs. These had to involve RCTs with an ARB given in at least one group, with a follow-up of at least one year and a minimum100 patients enrolled.
New cancer data were available for 68,402 patients from five trials, while data on common types of solid organ cancers were collated for 68,402 patients from five trials. The researchers also examined data on cancer deaths for 93,515 patients from eight RCTs.
In 30,014 or 85.7% of the patients who were given ARBs as part of trials with new cancer data, the study drug was telmisartan, Sipahi et al noted. The risk of new cancer occurrence in patients randomly assigned to ARBs was 7.2% compared with 6.0% for patients in control groups, giving a risk ratio of 1.08. When the analysis was limited to trials where cancer was a prespecified endpoint, the risk ratio was 1.11%, the meta-analysis found.
Among the solid organ cancers analysed, only new lung cancer occurrence was significantly higher in patients assigned to ARBs versus those in control groups, with rates of 0.9% and 0.7% respectively and a risk ratio of 1.25. No statistically significant increase in the risk of cancer deaths was observed.
“Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug,” the study authors stated, while adding that their findings “warrant further investigation”.
Dr Daniel Simon, director of the Harrington-McLaughlin Heart and Vascular Institute at University Hospitals Case Medical Center, concurred. “Meta-analyses are a powerful tool to look at low-frequency safety signals but require confirmation with other approaches, such as large national health and managed care registries,” he commented.
He recommended that patients “discuss the findings of this study with their physicians since ARBs are effective agents in the treatment of high blood pressure and heart failure”.
Disturbing and provocative
In an editorial for Lancet Oncology, Dr Steven Nissen, chairman of the Department of Cardiovascular Medicine at Cleveland Clinic and scourge of GlaxoSmithKline’s Avandia (rosiglitazone), described the findings of the meta-analysis as “disturbing and provocative”.
Regulators should demand more detailed data from manufacturers for a review of the potential association between ARB use and cancer, Nissen suggested.
According to Boehringer Ingelheim, a “rigorous assessment” of safety data from three long-term outcome trials with telmisartan, following some patients for up to five years (ONTARGET, PRoFESS and TRANSCEND), had found no association with an increased risk of cancer in the telmisartan arms.
In ONTARGET, a trial involving more than 25,000 patients, no statistically significant difference was observed in the rate of malignancies between patients treated with telmisartan and ramipril, the company noted. There was, though, a “modestly” increased risk of cancer in the one treatment arm combining telmisartan and ramipril.
Pointing out that product labelling for telmisartan does not recommend taking the drug with ACE-inhibitors such as ramipril, BI said the findings in the meta-analysis by Sipahi et al were “mainly based on the combination arm of telmisartan and ramipril …and not on the trial arms of each compound separately”.
Differences in malignancies between patients who did and did not take telmisartan failed to reach significance in the 6,000-patient TRANSCEND trial, BHI added. And in the PRoFESS trial, which enrolled more than 20,000 patients, the telmisartan arm showed fewer cases of malignancies than the placebo arm.
“Peer-reviewed meta-analyses of aggregate published data like Sipahi et al have their appropriate place in scientific research,” BI stated. “However, these analyses have well-recognised limitations, such as combining study summaries rather than analysing individual patient data.”
