Fuel to the Fire or Flame Retardant? More on ARB Use/Cancer

October 06, 2011

October 6, 2011 (Seoul, Korea) — The use of angiotensin-receptor blockers (ARBs) or ACE inhibitors is not associated with a significantly increased risk of cancer, according to the latest meta-analysis to address this controversy [1]. The findings add yet another wrinkle in a series of published studies attempting to address the cancer issue with the antihypertensive medications, with some studies suggesting there is a cancer link while others finding none.

In this newest meta-analysis published in the October 4, 2011 issue of CMAJ, Dr Chan Yoon (Seoul National University of Medicine, South Korea) and colleagues suggest there was even a beneficial effect of ARBs and ACE inhibitors on the risk of cancer. In a subgroup analysis looking at specific cancer sites, there was a decreased risk of esophageal cancer but an increased risk of melanoma and kidney cancer. Long-term use of the drugs was associated with a decreased risk of smoking-related cancers.

A Food and Drug Administration (FDA) review launched in the wake of a controversial meta-analysis suggesting an increased risk of cancer among patients taking ARBs recently concluded the drugs do not pose a cancer risk to patients. The European Medicines Agency (EMA) is currently performing its own review, but it has not yet reached any conclusions.

How Did the Controversy Begin?

The meta-analysis by Yoon and colleagues included 12 cohort studies and 16 case-control studies and found no significant association between the use of ACE inhibitors or ARBs and the risk of cancer. There was significant heterogeneity across the studies, due mainly to study design and duration of the studies. In a sensitivity analysis, there was a beneficial effect of ACE inhibitors or ARBs on cancer risk when case-control studies were excluded (relative risk 0.90; 95% CI 0.83–0.97), as well as when they included just 11 studies with longer-term follow-up (relative risk 0.89; 95% CI 0.83-0.96).

When the group stratified the studies by site of cancer, there was a reduction in the risk of esophageal cancer and an increased risk of melanoma and kidney cancer. Excluding case-control studies also revealed a decreased risk of prostate cancer, while the reduced risk of esophageal cancer and the increased risk of melanoma persisted.

The cancer question first arose when Dr Ilke Sipahi (University Hospitals Case Medical Center, Cleveland, OH) and colleagues published a 2010 meta-analysis showing that ARBs were associated with a modest 8% increased risk of developing cancer when compared with other agents, usually placebo [2]. Specifically, there was a significant 25% increased risk of lung cancer with the use of this drug class, but no link to breast or prostate cancer was seen.

These data, however, contradict the findings from two other meta-analyses, including a meta-analysis of almost 325 000 individuals from 70 clinical trials [3]. In that study, Dr Sripal Bangalore (New York University School of Medicine, New York) found no excess risk of cancer or cancer death with any single antihypertensive drug, saying the study refuted the findings from earlier meta-analyses and should reassure clinicians about the drug risks.

Asked to comment on the latest findings, Bangalore told heartwire that the initial study by Sipahi and colleagues created "mass hysteria" with regard to the drugs and cancer risks. As reported earlier, many of the leading hypertension experts were critical of the meta-analysis, saying the study should not have been published and that there was no clear pathophysiology suggestive of a mechanistic link. Bangalore said their own study is troubled by short follow-up, just 3.5 years, as are the other studies, and that the present analysis by Yoon and colleagues suffers from selection and ascertainment bias problematic to observational studies. He said he is not surprised that one study showed a protective effect, while another suggested a cancer risk, or that the results from different studies contradict each other in terms of cancers at specific sites.

"I will not be surprised if there will be many more such articles from observational studies, each concluding either for, against, or neutral, that will be published," said Bangalore. "There will be no easy way to separate the wheat from the chaff, given the confounders," said Bangalore.

Also commenting on the findings, Sipahi told heartwire that the "all-clear" message from the FDA and the CMAJ report, as well as from other meta-analyses, can be misleading. In the FDA analysis of ARBs, for example, the trials included were too short, used low doses of ARBs, or had poor patient compliance. "The excess cancer risk coming from trials with appropriate doses and sufficient follow-up were diluted by a plethora of low-dose trials with short follow-ups," he said.

Popular Class of Drugs

Sipahi said the CMAJ report is essentially a meta-analysis of observational studies examining the relationship between ACE-inhibitor therapy and subsequent cancer diagnosis, as only a very small minority of the patients were on ARBs. The results, however, do support another recent meta-analysis that found no link between ACE inhibitors and cancer risk. On the other hand, more studies, including the kidney-transplant study and another analysis suggesting an increased cancer incidence in diabetic patients treated with candesartan and telmisartan, support the ARB-cancer association. Sipahi also noted that since their own meta-analysis was published, the full results of the DIRECT trial became available. This study of long-term, high-dose candesartan therapy in diabetics showed there was a significant 69% increase in cancer incidence in the ARB-treated patients, he noted.

"We need to remember that ARBs are a very popular class of drugs used by approximately a quarter billion patients worldwide," Sipahi told heartwire . "Given the public-health implications, the regulatory agencies should examine the data about the ARBs meticulously and especially analyze the dose-response relationship. When you look at the clinical trials carefully, it is apparent that the cancer risk of ARBs surfaces after maximal daily doses are given for about four years."

To heartwire , however, Bangalore said their own large meta-analysis had 90% power to rule out a 0.5% absolute increase in the risk of cancer with ARBs. In other words, if theirs was a large randomized trial with clinical monitoring, it would have been stopped for futility. In addition, the FDA concurred that there is no cancer risk with ARBs.

"Should a randomized trial be performed?" asked Bangalore. "I don't think so, as currently there are no data, from our analysis and the analysis by ARB Trialists' group, suggesting increased risk. The event rates are so small that this would be trial of massive size with follow-up as long as 20 years, and even a randomized trial may not be able to completely rule out differences due to survivor bias." He added that it takes between two to three years for non–solid-organ tumors, such as leukemia and blood dyscrasia, to turn up following a nuclear disaster and up to 20 years for skin and lung cancers to emerge.

That said, Bangalore believes pharmaceutical companies should be mandated to provide long-term safety data to the FDA, not unlike similar mandates for devices such as drug-eluting stents.