June 14, 2010— -- Some widely used blood pressure drugs may be associated with an increased risk of cancer, researchers found in a new study.
In a meta-analysis of nine published studies the blood pressure drugs called angiotensin-receptor blockers were associated with a modest but statistically significant 8 percent increase in the relative risk of a new cancer, according to Dr. Ilke Sipahi, and colleagues at Case Western Reserve University School of Medicine in Cleveland, Ohio.
Angiotensin-receptor blockers, or ARBs, are a drug class that includes Diovan, Cozaar, Micardis, and Atacand.
A full list of the study drugs can be found at the bottom of the story.
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 medical journal The Lancet.
The findings are "disturbing and provocative" and raise important safety issues both for doctors and regulators, argued Dr. Steven Nissen, of the Cleveland Clinic, in an accompanying Comment article in the journal.
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 U.S. Food and Drug Administration said it was evaluating data from two clinical trials in which patients with type 2 diabetes taking the blood pressure drug olmesartan (Benicar) had a higher rate of death from a cardiovascular causes compared to patients taking a placebo. Olmesartan was not studied by Sipahi and colleagues in the recent article.
Sipahi told MedPage Today 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," said Dr. Henry Black, of New York University School of Medicine and past president of the American Society of Hypertension.
In response to a query from ABC News and MedPageToday, 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 percent 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 Dr. Franz Messerli, of St Luke's-Roosevelt Hospital in New York City. But, he added in an e-mail, "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 were written in 2009, according to IMS Health Inc., which tracks drug sales. And their value is "compelling," according to Dr. Clyde Yancy, 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 e-mail.
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).
The absolute risk increase for caner in the study was 1.2 percent over four years, Sipahi and colleagues said, which should be put in the context of an estimated 41 percent lifetime risk of cancer.
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 said in an interview.
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 Dr. Randy Wexler of Ohio State University Medical Center in Columbus. "My prescribing pattern will not change."
Wexler noted in an e-mail 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.
Dr. Scott Wright, of the Mayo Clinic in Rochester, Minn., called the finding "interesting and potentially concerning" but said he would wait for further studies.
And Dr. John Messmer, 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 (ARBs) only when patients are intolerant of ACE inhibitor.
FULL LIST OF STUDY DRUGS:MicardisTargitBlopressAtacandAmiasRatcandCozzar