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Some widely used anti-hypertension drugs may be associated with an increased risk of cancer, researchers said.

In a meta-analysis of nine published studies, angiotensin-receptor blockers were associated with a modest but statistically significant 8% increase in the relative risk of a new cancer, according to Ilke Sipahi, MD, and colleagues at Case Western Reserve University School of Medicine in Cleveland.

On the other hand, there was no increase in the risk of dying from cancer, perhaps because follow-up in the trials was too short, the researchers said online in The Lancet.

Boehringer Ingelheim, maker of telmisartan (Micardis), which was the drug taken by more than 30,000 patients included in the analysis, disputed the findings of the meta-analysis in a statement sent to reporters.

The company said its "comprehensive internal safety data analysis of primary data contradicts the conclusions about an increased risk of potential malignancies mentioned by Sipahi et al."

"Peer-reviewed meta-analyses of aggregate published data like Sipahi et al have their appropriate place in scientific research. However, these analyses have well-recognised limitations, such as combining study summaries rather than analyzing individual patient data," Boehringer Ingelheim said.

The company cited data from published trials of telmisartan to demonstrate the safety of its drug.

"Specifically, in ONTARGET, no statistically significant difference with respect to malignancies was observed in patients treated with telmisartan vs ramipril (HR 1.05, 95% CI 0.94, 1.16). In TRANSCEND, the difference did not reach significance either (HR 1.17, 95% CI 0.97, 1.41). In the PRoFESS trial the placebo arm showed more cases of malignancies than the telmisartan arm (HR 0.92, 95% CI 0.79, 1.06)."

But in a commentary published with the paper, Steven Nissen, MD, of the Cleveland Clinic argued that the findings are "disturbing and provocative" and raise important safety issues both for doctors and regulators.

Nissen said regulators should immediately review the possible association and "promptly report" what they find. In the meantime, he added, doctors should use the drugs with caution, perhaps prescribing angiotensin-converting enzyme inhibitors instead.

The study comes only days after the FDA said it was evaluating data from two clinical trials in which patients with type 2 diabetes taking olmesartan (Benicar) had a higher rate of death from a cardiovascular cause compared to patients taking a placebo. (See Cardiovascular Events Trigger FDA Review of ARB) Olmesartan was not studied by Sipahi and colleagues.

Sipahi told 麻豆传媒 that the study is only a first cut at the issue and needs to be followed by prospective studies aimed at the issue. But, he noted, "tens of millions of patients" use the drugs, so even a small increase in risk could be important.

Other experts, though, challenged the findings, saying the study was flawed. And many said they feared that publicity would lead to patients stopping what are very often life-saving medications.

The study is "unconvincing and irresponsible," charged Henry Black, MD, of New York University School of Medicine and past president of the American Society of Hypertension.

In response to a query from 麻豆传媒/ABC News, Black said the follow-up in the nine studies was so short that "the most you could blame a drug for in such short studies would be that it 'unmasked' a cancer that was already present." Also missing from the analysis, he said, was a plausible biological mechanism by which the drugs could cause cancer.

The researchers "pooled" trials with varying approaches and methods, Black said. "For these sorts of analyses to really be useful, the increase in risk should be at least 500% or more to get my attention," he said.

Black urged "responsible" coverage of the issue, adding "every caution must be taken to avoid patients stopping drugs that undoubtedly save lives."

The finding is "unexpected and certainly warrants scrutiny," said Franz Messerli, MD, of St Luke's-Roosevelt Hospital in New York City. But, he added in an email, "there is little, if any, biological plausibility that a drug exposure of a few years only would increase the risk of new cancer diagnosis."

Messerli noted that most of the patients in the study were being treated with one of the seven available drugs, so that even if the effect is real, the findings may not apply to all of the medications.

Angiotensin-receptor blockers are widely used -- some 82 million prescriptions in 2009, according to IMS Health Inc., which tracks drug sales. And their value is "compelling," according to Clyde Yancy, MD, of Baylor University Medical Center in Dallas.

They reduce the risk of stroke and the risk of death from left ventricular dysfunction after heart attack, they slow progression in chronic kidney disease, and they improve outcomes in heart failure, Yancy said in an email.

Yancy said he applauds Sipahi and colleagues but cautioned that the results are far from solid evidence of risk. "We usually describe these kinds of findings as a 'signal' but given the modest result," he said, "perhaps this is more of a 'hint'."

Above all, he said, patients on the drugs -- Yancy said he's included in that number -- should not stop treatment with what he called a "cornerstone of cardiovascular care."

Sipahi and colleagues said their analysis was prompted by the result of a 2003 trial of one of the drugs, which showed an unexpected increase in the proportion of fatal cancers among those getting the medication.

Since several other large randomized controlled trials have since reported, they decided to perform a meta-analysis. Literature searches turned up five trials with data on the occurrence of new cancers in a total of 61,590 patients. As well, five trials had data on specific solid tumors and eight trials had data on cancer-related deaths.

All told, nine randomized controlled trials were included in the analysis, with a total of 94,210 patients, they reported. The studies included data on four of the seven available angiotensin-receptor blockers -- losartan (Cozaar), candesartan (Atacand), telmisartan (Micardis), and valsartan (Diovan).

For the primary endpoint of the study -- new cancers -- 30,014 patients (or 85.7% of those in the five studies with data on the issue) were treated with telmisartan, the researchers said.

Analysis showed that the meta-analytic relative risk of a new cancer in those five trials was 1.08, with a 95% confidence interval from 1.01 to 1.15, which was significant at P=0.016. The absolute risk increase was 1.2% over four years, Sipahi and colleagues said, which should be put in the context of an estimated 41% lifetime risk of cancer.

Three trials had new cancer as a pre-specified endpoint, the researchers said, and in those the meta-analytic relative risk of cancer was 1.11, with a 95% confidence interval from 1.04 to 1.18, which was significant at P=0.001.

Using the data from those three trials, Sipahi and colleagues calculated that one excess cancer diagnosis would be made for every 105 patients treated with angiotensin-receptor blockers -- the so-called "number needed to harm."

Combined with the large number of patients taking the drugs, that figure "is a very scary way of looking at it," Sipahi told 麻豆传媒.

Eight trials reported cancer-related deaths, but there was no significant difference between treated and control groups, they found.

Sipahi and colleagues said a strength of the study is that all of the data comes from randomized controlled trials, which should reduce the effect of confounding variables.

On the other hand, they said, the findings come from pooled data from trials not specifically designed to assess cancer, and cancer data was not available from several large trials of the drugs, which could lead to publication bias.

As well, they said, "meta-analyses are generally considered less convincing than a large prospective trial."

Nonetheless, Sipahi and colleagues concluded, the modest but significant safety signal warrants more investigation.

In the meantime, many doctors said, prescribing patterns will probably not change.

"I do not believe that this study as a single source should drive clinical practice at this time," said Randy Wexler, MD, of Ohio State University Medical Center in Columbus. "My prescribing pattern will not change."

Wexler noted in an email that meta-studies are only as good as the trials they include. "A meta-analysis may point in the direction of a problem," he said, but that problem then has to be confirmed. He said a meta-analysis once showed that calcium channel blockers increase the risk of stroke -- but subsequent studies showed that in fact some calcium channel blockers reduce that risk.

Scott Wright, MD, of the Mayo Clinic in Rochester, Minn., called the finding "interesting and potentially concerning" but said he would wait for further studies.

And John Messmer, MD, of Penn State College of Medicine in Hershey, Pa., said a "possible, inconclusive increased risk of cancer is not going to change" his use of the drugs.

On the other hand, he and several other doctors questioned said they prefer to use the less expensive angiotensin-converting enzyme (ACE) inhibitors and rely on the angiotensin-receptor blockers only when patients are intolerant of ACE inhibitors.

This article was developed in collaboration with ABC News.

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