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Feeling the Pressure

After reports of a link between common blood pressure drugs and increased cancer risk, researchers caution patients not to get their heart rates up.

Some are hailing it as a life-saving find. Others are calling it a rash judgment. But amid the compliments and the controversies, what's the course of action for the 10 million U.S. patients who have just learned their blood pressure medication could cause cancer?


One in three adults in the United States has high blood pressure. Because there are no symptoms, it often goes undetected. Left untreated, however, it can lead to heart disease, heart failure, stroke, kidney failure and more.

Treatment starts with a healthful habit makeover: a low-fat diet, a moderate exercise program, quitting smoking, managing stress and the like. About 70 percent of patients, however, require medication to lower their blood pressure, and drug options abound.

Physicians tend to call upon well-established diuretics and calcium channel blockers for simple cases.

For more complicated cases, such as a patient who also suffers from diabetes or kidney disease, doctors turn to various drug combinations and newer medications, such as ACE inhibitors and angiotensin II receptor blockers (ARBs).

This summer ARBs caused a stir in the medical community and in the national news when researchers at Case Western Reserve University and University Hospitals Case Medical Center reported their apparent connection to cancer, leading already-high blood pressures to skyrocket in panic. Though their results are noteworthy and clearly distressing, the scientists are quick to calm the nerves of those who rely on the popular drugs.

Disparate Data

Persuading patients to continue taking blood pressure drugs is one of the biggest hurdles to treating the condition. In an effort to keep patients taking their medications faithfully, ACE inhibitors, with their tendency to cause a persistent cough for some patients, are being replaced by ARBs.

Almost 80 million prescriptions for ARBs are administered every year. They've been proved effective at treating high blood pressure and reducing the risk of stroke and death after a heart attack. They slow the progression of chronic kidney disease and improve heart failure outcomes-all with fewer chances of side effects.

But for all their virtues, researchers say the drugs have a dark side.

This July, researchers at Case Western Reserve reported the gravity of a danger they say was suggested years before, though it was largely ignored at the time.

The positive track record of ARBs, it seemed, had made the world turn a blind eye to the drugs' potential risk.

A 2003 study of heart failure patients treated with one ARB showed the drug was linked to a significantly higher risk of developing fatal cancers. This finding was largely ignored because it was just a single study and wasn't primarily looking at cancer outcomes. Later, two trials by the manufacturer of another ARB showed their medication also caused an increased risk of cancer. The pharmaceutical company responsible for the drug, however, called the findings "inconsistent."

To better understand the data, cardiology experts Ilke Sipahi, MD, Daniel Simon, MD, and James Fang, MD, of Case Western Reserve's School of Medicine and University Hospitals Case Medical Center; and Sara M. Debanne, PhD, and Douglas Y. Rowland, PhD, of the School of Medicine, conducted a meta-analysis of all publicly available data from randomized controlled trials of ARBs published before November 2009. In total, they analyzed new cancer data in trials involving more than 60,000 patients.

Those taking ARBs, the researchers say, were 8 percent to 11 percent more likely to develop a new cancer over a four-year period than those in the control groups. Lung cancer occurrence was significantly higher-25 percent.

Modest but Significant

The researchers published their findings in the journal The Lancet Oncology, describing the risk of cancer as "modest but significant." The lung cancer statistic stands out, but the overall increase in new cancers cannot be overlooked, they say.

The results were widely reported by ABC News, Reuters, The New York Times, The Wall Street Journal and other national outlets. However, researchers caution against overreaction and media hype.

"The risk for the individual patient is not very high," says Sipahi, the study's lead investigator. "You have to treat about 105 patients to cause one excess cancer. That may not seem like much. However, more than 10 million patients take these drugs. While our findings are robust, they need to be replicated in other studies before they can be considered definitive."

The researchers were careful to note the shortcomings of their study. "Given the limited data," they wrote, "it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug."

As for the course of action for those who currently take the drugs, Sipahi says he's happy to see most media outlets have effectively communicated his message that patients should not discontinue the drugs on their own, but rather should consult their physician to determine the appropriate course of action. This is especially important, he says, because abandoning the medications can leave patients at a higher risk for cardiovascular and renal complications.

Co-author Simon agrees. "In medicine, physicians must balance the benefits and risks of all drug and device therapies. We recommend that patients discuss the findings of this study with their physicians."

Compliments and Criticisms

Steven E. Nissen, MD, chair of cardiovascular medicine at Cleveland Clinic and a professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, described the research findings in the journal's accompanying comment section as "disturbing and provocative, raising crucial drug safety questions for practitioners and the regulatory community."

Nissen is an FDA adviser and is well-known for his own drug safety research. In 2001, he linked COX-2 inhibitors, such as Vioxx, with an increased risk of heart attack and stroke. Three years later, the arthritis drug was pulled from shelves. In 2007, his meta-analysis on the diabetes drug Avandia revealed high cardiovascular risks, resulting in an FDA warning-and a sales loss of about 75 percent for the drug.

He wrote, "We should use ARBs...with greater caution. These drugs are often over-prescribed, as a result of aggressive marketing, and in the absence of evidence that they are better than ACE inhibitors. ARBs can be reserved for patients with intolerance to ACE inhibitors."

Reactions among the medical community are varied. The European Medicines Agency and the FDA each announced they would begin investigations regarding the risk of cancer in patients taking ARBs.

Others—including doctors from the University of Chicago, Hannover Medical School in Germany and the University of Oslo in Norway—took to theheart.org, an online cardiology news site, to express concern. They called the study "a very bad example of science," "irresponsible," "skewed" and "noise and rubbish," among other unflattering remarks.

The researchers, however, were unaffected.

"The public has the right to know these research findings," Sipahi says. "They are the ones taking the drugs and taking the risks."

He adds that the swift and dissenting reaction is to be expected by some in the field.

"The financial implications are tremendous," he says. "There are some who are conflicted. They are paid by the pharmaceutical industry to promote their drugs and they are swearing at our analysis in any medium they can find. I am still waiting to hear criticism of any real and useful content."

Critics like William B. White, MD, president-elect of the American Society of Hypertension, argue that the meta-analysis is limited because the majority of the trials were not designated to look at cancer risk, that some large trial results were not available for inclusion and that study participants had other risk factors. Other criticisms are that the study follow-up was too short to detect cancer and that there was no biological explanation for how the drugs could cause cancer.

Nissen counters saying, "Meta-analysis is not a perfect tool, but it is a very useful tool.

All you can ask of independent investigators is that they provide a careful, ethical and appropriate discussion of both the values and limitations of their studies. That's what Dr. Sipahi and his colleagues did."

Sipahi concedes the team would have preferred to review individual-level data, but he calls on government agencies to help out. "That's why the FDA has to get involved," he says. "It has the authority to collect such data from the drug companies in order to obtain additional information about this cancer risk."

In the end, some will continue to wonder: Why cause a scare about ARBs when patients are already bad about taking their medicine-especially when the results are small and the study not definitive?

Nissen asserts it's in the public's best interest to know their risks. "It's never irresponsible to pose a serious question that involves a patient's safety," he says.

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