Winter
2011

Research Feature

Dilemma

> WHAT HAPPENS WHEN THE DRUGS THAT ARE SUPPOSED TO HELP END UP PUT TING PATIENTS AT RISK?

by Linda Formichelli

Dilemma

Antibiotics can knock out a nasty infection. Chemotherapy can save a life. Modern drugs sometimes seem like miracles in pill form.
But sometimes, it turns out that the drugs that are supposed to help us can end up causing even more harm.

In June, the journal Lancet Oncology published a meta-analysis by researchers at Case Western Reserve University School of Medicine showing that the popular class of blood-pressure drugs angiotensinreceptor blockers (ARBs), which include Diovan®, Cozaar®, Micardis® and Atacand®, cause a modest but statistically significant increase in the risk of cancer: The absolute risk is 1.2 percent higher in people using ARBs, and the relative risk is 8 to 11 percent higher.

"My life changed in the last couple of months since publishing the study," says lead author Ilke Sipahi, MD, assistant professor of medicine at the School of Medicine and associate director of heart failure and transplantation at University Hospitals (UH) Case Medical Center. "The reaction was huge because these drugs are extremely popular."

While the absolute risk of cancer increased only modestly, it was the number needed to harm—the number of patients that need to be treated to cause one adverse reaction—that made the discovery big news. "We found that number to be 105," says Sipahi. "If there are 10 million patients on these drugs in the United States, we could be potentially causing more than 100,000 excess cancers by preferring these medications over others." Sipahi and his colleagues are careful to say that more research needs to be done to determine whether ARBs are too risky to be used, and the FDA is now reviewing the cancer data relating to these drugs.

Other cases of drugs causing harm have been hitting the news in recent years as well. First there was the well-publicized link between COX-2 inhibitors like Vioxx® and Celebrex® with heart attacks; Vioxx was pulled from the market, but Celebrex is still available.

"Pfizer is holding on to the fact that a 200 mg dose instead of a 400 mg dose may be safe, and this lower dose is being compared with the non-selective NSAIDs naproxen and ibuprofen in a clinical trial," says Daniel Simon, MD, the Herman K. Hellerstein Professor of Cardiovascular Research at the School of Medicine and director of the Harrington- McLaughlin Heart and Vascular Institute at UH Case Medical Center. And most recently, researchers had to shut down one arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which was designed to determine whether intensively lowering blood sugar would reduce the risk of heart attacks and stroke in people with type 2 diabetes. Because 257 people in the more intense group died compared with 203 in the standard treatment group, researchers determined that the risk of the intensive treatment was too high to continue.

A NUMBERS GAME

It seems the number of cases like these is exploding. This is partly because the number of studies conducted has been increasing. "Fifty years ago, it was very uncommon to do a clinical trial," says Faramarz Ismail-Beigi, MD, PhD, professor of medicine, physiology and biophysics at the school, endocrinologist at UH Case Medical Center and a principal investigator for the Ohio-Michigan network of the ACCORD trial. "When you have 50 studies, if one of them has a negative outcome, you'll hear it every now and then. But if you have 500 studies with the same ratio, there would be 10 that have a negative outcome, and you're apt to hear about it more."

Increased reporting of adverse events has also helped bump up the amount of bad news; Steven Nissen, MD, the patient advocate who discovered the link between COX-2 inhibitors and heart attacks, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve and chair of cardiovascular medicine at Cleveland Clinic, says, "Historically, pharmaceutical companies would only publish clinical trials that showed the benefits of their drugs and they would bury the results of any studies that were not favorable. That has come under increasing scrutiny by Congress and by the medical profession so that more studies showing adverse effects of drugs are being published."

In addition, more new drugs equals more adverse reactions, says Nissen. Pharmaceutical companies lose money when drugs go generic, so as more and more medications go generic, drug companies are rushing to revamp the drugs so they can be sold at a higher price, notes Nissen.

WHAT IS RISK?

Every drug has side effects, points out James C. Fang, MD, professor of medicine and medical director of the Heart Failure, Transplant and Mechanical Circulatory Support Program at UH Case Medical Center, who was the senior author on the ARB/cancer study. "Everything in medicine is a risk/benefit ratio," he says. "Everything that we do in medicine has a downside. Whenever we prescribe anything, for example an antibiotic for a patient's cough, there is an inherent risk." Unfortunately, though, figuring out when a drug's risks outweigh the benefits is a fuzzy science at best.

Decision-makers—from patients to the doctors who treat those patients to the FDA, which approves drugs—have to keep in mind the severity of the patient's health issue plus how immediate and how strong the benefits of the drug are. "We can treat people for cancer with chemotherapy, but those drugs themselves make patients more vulnerable to cancer in the future," says Stuart Youngner, MD, the Susan E. Watson Professor of Bioethics and chair of the Department of Bioethics. "Is it worth it? Most cancer patients say, 'Well, I am either going to die now or I have a 30 percent chance of developing a cancer in 10 years.' They are going to say that the benefits outweigh the burdens."

Another consideration is whether there are other drugs that work as well as the medication in question. If a drug is truly the best in its class, patients, doctors and the FDA might tolerate more risks. But if a drug isn't any better than its competitors, there's no point in putting patients at risk of adverse reactions. For example, COX-2 inhibitors like Vioxx were developed to provide pain relief with reduced risk of gastrointestinal bleeding. According to Simon, Vioxx was pulled from the market because not only was there a clear adverse safety signal, but its pain relief was no better than the COX-1 inhibitor drugs currently on the market and its touted benefit of reducing GI bleeding was actually short-lived.

As another example, ARBs can reduce blood pressure in people with hypertension who can't tolerate ACE inhibitors—another popular class of high-blood-pressure drugs—but there are plenty of other drugs that battle hypertension just as well as ARBs. "I continue to prescribe ARBs to heart-failure patients if they are truly intolerant to ACE inhibitors," says Sipahi. "But if the reason to give an ARB is simply high blood pressure, then that's a completely different story, because there are so many different classes of drugs for high blood pressure."

Finally, when determining whether to prescribe a drug that has risks, doctors have to take into account questions that go beyond the issue of side effects, says Fang. For example, doctors need to ask: What other health problems does the patient have? What drugs can he tolerate? What can the patient afford? What is the magnitude of benefit of the drug?

While the FDA is in charge of whether drugs are pulled from the market, and doctors decide which medication to prescribe to a patient, the final defense lies with the patient himself; once the doctor fills the patient in on the risks and benefits of a drug, the patient needs to decide whether it's worth it for him to take any risks there may be. Says Youngner, "That's what informed consent is about. We can give statistics, but we can't say whether a chance is worth taking. This is something that individuals have to decide."

> WHAT IS THE FDA DOING TO HELP?

The Adverse Event Reporting System is a computerized database the FDA uses to track reactions and errors that occur with already-approved drugs. However, while it's mandatory to report adverse events in clinical trials, medical professionals aren't obligated to report events that happen during routine medical practice, says GQ Zhang, PhD, division chief of medical informatics in the university's Clinical and Translational Science Collaborative. However, because reporting is voluntary, according to Steven Nissen, MD, only 1 to 10 percent of adverse drug reactions are ever reported to the FDA.

It's the job of the FDA's Center for Drug Evaluation and Research to make sure that available drugs are safe and effective; the same people who approve drugs are also in charge of post-marketing monitoring. Says Nissen, "I've recommended that the FDA separate the drug approval process from the post-marketing surveillance and drug safety process. There is an inherent conflict of interest in asking the people who approved a drug in the first place to be the ones to take it off the market."