Modest Lung-Cancer Signal With Angiotensin-Receptor Blockers

June 14, 2010

June 14, 2010 (Cleveland, Ohio) Angiotensin-receptor blockers (ARBs) have been associated with a modest increased risk of developing cancer, in a new meta-analysis [1]. 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.

On a population level, I think these are very concerning signals.

"This is a modest increase, similar to that seen with passive smoking; it's not a massive increase," lead author of the study, Dr Ilke Sipahi (University Hospitals Case Medical Center, Cleveland, OH), told heartwire . Nevertheless, this is the first time such an association has been made, he said. And although the number needed to treat to cause one excess cancer was calculated to be 105 patients for four years, meaning the risk for the individual patient is not huge, "given the millions of patients on these drugs, this is an important number, because it gives us an idea of potentially how many excess cancers could be caused by these medications. On a population level, I think these are very concerning signals."

Dr Michael D Peake (Glenfield Hospital, Leicester, UK), a spokesperson for the UK Lung Cancer Coalition, who was not involved in this research, told heartwire that the increase in lung cancer seen in this meta-analysis with ARBs "is fairly small." The risk of lung cancer is around 200% to 300% higher in a smoker than in a nonsmoker and is increased by about 60% in a person with a family history of lung cancer compared with an individual with no family history, he said.

It's a relatively small risk . . . [and] would not stop me personally from taking an ARB if I needed one.

"In this context, it's a relatively small risk, but if applied to large numbers of people, it might be quite important," he explained. The data are interesting but "would not stop me personally from taking an ARB if I needed one; it's not sufficiently powerful to influence prescribing at this point," he added.

Preliminary Data, More Studies Needed, But Use ARBs With Caution

Sipahi is aware that many will view this meta-analysis as "inconclusive or hypothesis-generating," and he himself admits the data "could be viewed as preliminary, so we need more studies in this area." First, this should involve "the US FDA [Food and Drug Administration] looking at the individual patient-level data, which they have and we don't have, to clarify this cancer risk with ARBs. According to those analyses, they should act," he stated.

Peake agrees that more studies are needed: "This is interesting work, but it needs a randomized controlled prospective piece of work rather than a retrospective trawl of trials done for other purposes." In the meantime, he said he would support the call made by Sipahi and colleagues for further analyses by the FDA or other regulatory bodies.

In an accompanying comment [2], Dr Steven E Nissen (Cleveland Clinic, OH) calls the meta-analysis "disturbing and provocative, raising crucial safety questions for practitioners and the regulatory community." Nissen says that until more work can be completed on this subject, ARBs, which "are often overprescribed as a result of aggressive marketing," should be used "with greater caution."

Continue using [ARBs] but more cautiously until we have additional studies.

Sipahi told heartwire : "Patients should not discontinue these medications on their own. They have beneficial effects in the control of blood pressure, heart failure, and certain types of kidney disease. Patients should have a discussion with their physician to look at the risks and benefits of these drugs in their particular case and their specific situation." For physicians, Sipahi said his message is "to continue using these medications but more cautiously until we have additional studies and more thorough individual-level analyses of these data."

Most Cancer Data Are With Telmisartan

ARBs are a class of blood-pressure–lowering drug that is widely used for the treatment of heart failure and diabetic nephropathy; there are currently seven on the market in the US, and they are "multibillion-dollar-revenue medications," Sipahi said. He explained that a significant excess of fatal cancers was observed in the CHARM study with the ARB candesartan (Atacand, AstraZeneca), published in 2003, but that the investigators concluded this finding was likely due to chance. In the past few years there have been several other multicenter trials with ARBs, so he and his colleagues decided to perform a meta-analysis of all the available literature and all of the data publicly available on the FDA website.

New cancer data were available for 61 950 patients from five trials, including only three of the seven FDA-approved ARBs; most patients in this meta-analysis (85.7%) received telmisartan (Micardis, Boehringer Ingelheim) as the study drug; the other patients received losartan or candesartan. The five trials with new cancer data were ONTARGET, PROFESS, LIFE, TRANSCEND, and CHARM-Overall. In addition, data were available for cancer deaths in LIFE, TRANSCEND, VALIANT, and Val-HeFT.

It remains unknown whether other ARBs--irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Aventis), valsartan (Diovan, Novartis), olmesartan (Benicar, Daiichi Sankyo), and eprosartan (Teveten, Abbott)--are linked to a higher risk of new cancer incidence, the investigators say. "Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each ARB," they observe.

In the meta-analysis, patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence, compared with those in the control groups (7.2% vs 6.0%; risk ratio [RR] 1.08; p=0.016). When analysis was limited to trials where cancer was a prespecified end point, the RR was 1.11 (p=0.001).

Among the malignancies examined--lung, breast, and prostate--only new lung-cancer occurrence was significantly higher in those randomly assigned to ARBs than in control subjects (0.9% vs 0.7%; RR 1.25; p=0.01). There was also a "weak trend" for an increased risk of prostate cancer with ARB use, Sipahi said.

There was no significant difference in cancer deaths observed in the meta-analysis between those who took ARBs and control subjects (1.8% vs 1.6%; RR 1.07; p=0.183). But the researchers note that cancer death "is typically a slow process and, with the present trials, it is not possible to make conclusions regarding the effect of ARBs on cancer-related deaths."

Boehringer Ingelheim Contests Findings

Sipahi and colleagues speculate on mechanisms that could be responsible for the possible increase in new cancer cases associated with ARBs. In animal models, blockade of the angiotensin 1 receptor and direct stimulation of angiotensin 2 receptors--both of which are affected by ARBs--are capable of stimulating tumor angiogenesis, they state. But the relevance of these observations in human malignancy "is largely unknown," they add.

Peake said that the lung "is very rich in angiotensin 2 receptors. It's the only organ with a huge surface area in blood vessels, which have very high numbers of these receptors, but I don't know how important this is. I have no idea what this means."

Boehringer Ingelheim, which markets telmisartan, says it "strongly disagrees" with the conclusions of the study [3]. The finding of a modestly increased risk of new cancer diagnosis in the analysis by Sipahi and colleagues is "mainly based on the combination arm of telmisartan and ramipril [Altace, King Pharmaceuticals], an ACE [angiotensin-converting enzyme] inhibitor, in ONTARGET and not on the trial arms of each compound separately," it asserts, noting that the product labelling for telmisartan does not recommend combining it with ACE inhibitors.

A "rigorous assessment" of the data from ONTARGET, PROFESS, and TRANSCEND show no increased risk of cancer in the telmisartan arms, the company adds.

"In preclinical trials, clinical trials, and day-to-day patient exposure with telmisartan we have not seen any significant finding related to malignancies," says Dr Klaus Dugi, corporate senior vice president, medicine, at Boehringer Ingelheim, in the company statement.

Regulatory Authorities Must Review Data on ARBs and Cancer

Nissen writes that although there are "clearly some important strengths" of the analysis, "there are also important weaknesses, which the investigators acknowledge. Based on these limitations, the investigators are appropriately cautious in their interpretation of the results."

Nevertheless, questions remain as to whether ARBs are associated with malignancies and whether there should be concern about a single drug, telmisartan, or all ARBs, he says.

"We should recognize that additional data exist that were not available for this current meta-analysis," Nissen asserts. "How do we access additional, unpublished data on ARBs and cancer safety? Fortunately, pharmaceutical companies routinely submit data from clinical trials to regulatory agencies, including the FDA. These data are often more detailed than the results in published reports, allowing more sophisticated approaches for determining hazard ratios from survival analyses.

"When important safety questions arise, regulatory authorities can order drug makers to submit a complete data trial set. This is precisely what should happen in the case of ARBs. Regulators must review the possible association between ARB use and cancer and promptly report their findings," he states.

In the interim, ARBs, particularly telmisartan, should be used selectively, he urges. They can be reserved for patients with intolerance to ACE inhibitors, "which will also save money for healthcare systems, since nearly all ARBs are proprietary and ACE inhibitors are generic."

Sipahi has received an educational grant and lecture honoraria from Pfizer and lecture honoraria from AstraZeneca and Ranbaxy. Disclosures for the coauthors are listed in the paper. Peake reports no conflicts of interest. Nissen reports receiving support for clinical trials from Pfizer, AstraZeneca, Novartis, Novo Nordisk, Roche, Daiichi-Sankyo, Takeda, Sanofi-Aventis, Resverlogix, and Eli Lilly. He consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor tax deductions.