A bitter pill for older patients

By Steve Sternberg, USA TODAY

If medical research mirrored reality, promising drugs would be tested extensively in patients who need them most: frail, elderly people who also take other drugs.

But that’s not the way the research world works.

Medical trials are complex and pose unpredictable risks, especially for people in shaky health. Older people with overlapping chronic illnesses and medicine cabinets resembling small pharmacies often can’t qualify for medical research.

With Americans reaching old age in unprecedented numbers, the problem is becoming even more acute. By 2030, 24 million baby boomers will span the ages of 75 to 84, twice as many as today, according to Census Bureau projections. A shortage of elderly patients in clinical studies equals a shortage of evidence. Doctors say the elderly data gap is one of the more challenging medical problems that an aging America must confront.

“This is precisely the group for which we lack evidence, especially for those who are taking multiple medications and have a high risk of adverse consequences of heart disease,” says Yale University’s Harlan Krumholz, author of The Expert Guide to Beating Heart Disease: What You Absolutely Must Know

Alastair Wood, professor of pharmacology at Vanderbilt University, puts it this way: “The traditional criticism is that we study young, fit, male volunteers and then give the drugs to elderly, sick women.”

An exaggeration? Maybe, but one based on fact. For example, 27% of patients treated for a common type of massive heart attack are older than 75, yet 75-year-olds account for 15% of those in clinical trials of drugs designed to minimize damage to the heart, says cardiologist Karen Alexander of Duke University.

Drug companies don’t exclude patients from drug trials just because they’re too old. They exclude them because they may be more likely to suffer potentially dangerous side effects or because their presence would make it harder for researchers to interpret the study’s results. Did the patient get worse because the drug didn’t work? Or because he also had heart failure and diabetes? Did the drug have dangerous side effects or did it clash with another medication?

Doctors need information

Gertrude Possick, 89, of Brookline, Mass., is just such a patient. “I’ve had a quadruple bypass, I have a pacemaker, and I’ve had angioplasty. I take about 10 medicines. The worst part is (figuring out) what to take at what time. I take six in the morning, two at dinner and one before bed. I’ve had a seizure, too. I take three pills for that.”

But what doctors don’t know can hurt their patients, as a study released in March demonstrates. The study, called COMMIT, involved 46,000 patients in China. Its aim: to test whether two drugs, clopidogrel and metoprolol, could limit damage from severe heart attacks typically caused by a complete blockage of the coronary artery.

Clopidogrel, which blocks blood from clotting, proved it could save about 5,000 lives for every 1 million patients treated. Metoprolol, a medication that slows the heart rate and lowers blood pressure, sent 16% of people whose damaged hearts were failing into potentially fatal shock, compared with 10% of those given a placebo.

The study sent tremors through the medical world, because metoprolol and its cousins in the beta blocker family are proven lifesavers.

The Joint Commission for Accreditation of Hospitals and the U.S. Center for Medicare and Medicaid Services have established regulations meant to encourage wider use of these drugs.

Metoprolol had never been studied in elderly patients with heart failure until COMMIT, says cardiologist Magnus Ohman of the University of North Carolina at Chapel Hill, a member of an American Heart Association committee that is drafting a scientific statement on acute cardiac care in elderly patients.

That’s true for many drugs, not just beta blockers, says UNC-CH’s Sidney Smith, a co-chairman of the joint American Heart Association-American College of Cardiologists’ committee that writes patient-care guidelines. “White men in their 60s, that’s where the greatest evidence lies,” Smith says.

The lack of evidence from patients 75 and older has tied the hands of doctors such as Smith, who write guidelines other doctors use to guide their decisions. Doctors must use their best judgment to decide whether to use beta blockers to treat heart attack patients whose hearts are failing, because the guidelines are silent.

The Food and Drug Administration never has formally examined the representation of the elderly in clinical trials, but officials say heart studies include many patients in their 60s and 70s.

“I don’t think there are a lot of studies involving people in their 80s,” says Robert Temple, associate director of medical policy. “That’s probably something to look into and think about.”

The lack of data means:

• Doctors, drugmakers and federal regulators can’t always predict how a drug or procedure will affect older patients.

• Doctors prescribing certain drugs for people 75 and older must base their decisions partly on results from studies in younger patients, partly on their clinical experience and partly on guesswork.

• Problems may emerge, as with non-steroidal painkillers and Baycol, only after the drugs reach the market.

“The elderly are basically unstudied guinea pigs in the post-market approval phase of drug distribution,” says Alta Charo, University of Wisconsin professor of medicine and bioethics.

Women and minorities also have been poorly represented in drug trials. In the mid-1990s, the National Institutes of Health began requiring researchers to actively recruit women, minorities and children into clinical trials. But there’s no such mandate for the elderly. And, if there were, it wouldn’t necessarily apply in drug-company-financed trials.

Recent studies on women and blacks demonstrate that drugs affect populations differently.

The Women’s Health Study, released last month, showed that aspirin doesn’t prevent heart attacks in low-risk women, as it does in men. And the African-American Heart Failure Trial showed that a two-drug combination that didn’t work in a racially mixed population cut deaths in blacks by 43%.

On the strength of that study, a fixed-dose combination of the two drugs, trade-named BiDil, may soon become the first drug approved by the government to treat patients of a specific race.

Older people often have a problem that younger patients don’t. Their kidneys don’t work as efficiently, and drugs may build up in their blood.

One recent study of nearly 12,000 patients in Italy showed that drugs that healthy kidneys would wash out of the body accounted for about one-third of the dangerous drug reactions that occurred in elderly patients.

“We just don’t think enough about how many people have hidden kidney disease,” says Christopher Cannon of Brigham and Women’s Hospital. “The medicines we have traditionally given have been one size fits all, but we’re realizing dosing is trickier than that.”

‘Shared’ decisions

Doctors never will be able to answer every question about every drug for every patient, even if they succeed in enrolling more elderly patients in drug trials.

“We need to talk openly to patients about the strength of the evidence that’s available and what all the options are,” says Krumholz, whose book focuses on the importance of what he calls “shared decision-making.”

Possick and her doctor had such a discussion when he discovered that her cholesterol was high and suggested she take a cholesterol-lowering drug. But the decision wasn’t a slam-dunk. No guideline directly addressed Possick’s situation, which she expresses best.

“I’m 89 years old. I’ve had a good life,” Possick says. “My cholesterol is very high, no one questions that, but they say the ratio of one to the other is fine. They tried to give me Lipitor. I don’t want it. I don’t react well to most medications. The heck with it. It’ll just make me sicker.”

Krumholz says that’s the way medical decisions ought to be made. “Let’s talk about the pros and cons of what we’re trying to accomplish and what it’s costing you,” he says. “If you’re saying, ‘This drug is making my life miserable,’ I’m saying we need to find another way. If you’ve had a couple of heart attacks, you need to be aware of the dangers involved in what you’re doing.

“The honest truth is, if we don’t do that, you’re unlikely to follow the regimen, anyway.”