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Consumers who assume that widely used drugs are both safe and effective have more and more reasons to think again.
By JoNel Aleccia Health writer
updated 4/4/2008 8:07:28 AM ET 2008-04-04T12:07:28

When C.W. MacLeod’s cholesterol shot sky-high, the Texas businessman was only too happy to find a drug to bring it down.

For two years, the 57-year-old Houston resident dutifully took Vytorin, relying on his doctor’s assurance that as his levels of so-called "bad" cholesterol dropped, so would his risk of heart attack.

But MacLeod’s confidence was shaken this week, when he and millions of other Vytorin users learned that it and its component drug, Zetia, failed to work as widely expected. Final results of a clinical trial showed the drugs reduced LDL cholesterol, but failed to slow the buildup of artery-clogging plaque, suggesting they’ll do little or nothing to prevent heart attacks.

“It hasn’t hurt my body, but apparently it hasn’t done any good either,” said MacLeod, who wonders why he’s been shelling out $100 a month in co-payments for a brand-name drug that doesn’t work.

“If lowering your cholesterol doesn’t reduce your risk, then what’s the point?” another Vytorin user wrote on an message boardabout the issue. “Maybe I’m dense, but I just don’t understand.”

Those questions are on the minds of millions of consumers in the wake of a string of startling findings about some of the nation’s best-selling — and most heavily promoted — drugs.  In less than a year, patients have learned that a popular diabetes drug, Avandia, may raise the risk of heart attack , and that antidepressants, the most widely prescribed drugs in America , may work no better than placebo.

They’ve watched as the federal Food and Drug Administration expanded use of a top cancer drug, Avastin , to treat breast cancer, on basis of a trial that showed that while the drug slowed the disease, it didn’t impact overall survival.

And now they’ve seen the results on Vytorin and Zetia, which account for more than 15 percent of the cholesterol-lowering drug market in the U.S.  — and more than $5 billion in annual sales.

It’s a confusing situation for consumers who assume that widely used drugs are both safe and effective, said Fran Visco, president of the National Breast Cancer Coalition and a 20-year survivor of the disease.

“You want drugs that save lives, that have a significant impact on the quality of life,” said Visco, whose agency helps patients make treatment decisions.  “The drugs do not show these things.”

Time for docs to pause and say ‘Whoa’
And it’s not just patients who’ve been stumped. The chain of surprises began in late 2006, said Dr. Harlan M. Krumholz, a professor of medicine at Yale University. That’s when an apparent increase in patient deaths abruptly halted development of torcetrapib, a promising cholesterol drug that boosted “good” HDL cholesterol, a new approach in the fight against heart disease.

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When that was followed by Avandia, which raised questions about the assumed benefits of lowering blood sugar, and later by Vytorin and Zetia, which challenged the benefits of lowering LDL cholesterol — it rocked the medical world, Krumholz said.

“It was a time to pause and say ‘Whoa,’’’ he said. “It has caused us to take a step back and say ‘How much do we really know?’”

The situation has renewed debate about the ways drugs are tested and approved in the U.S. and whether they’re being released to market too soon.

It also has raised doubts about the FDA’s practice of accepting “surrogate endpoints” for drug approval. Instead of relying on ultimate outcomes — a reduction in heart attacks or strokes, for instance, or a decrease in deaths — many studies measure a drug’s effectiveness by using interim markers, such as decreasing blood pressure levels or lowering LDL cholesterol.

The FDA long has allowed use of such markers because waiting for the results of large-scale outcome trials would cost too much and take too long, possibly delaying life-saving advances for millions of people, said Dr. Robert Temple, director of the agency’s office of medical policy.

But the practice has been called into question by the surprises of recent research, said Dr. Nortin M. Hadler, a professor of medicine at the University of North Carolina.

“In our zeal to do modern medicine ... we’ve managed to lose our way,” he said. “We’ve forgotten to ask: ‘Does this matter to the patient?’”

Temple argued that surrogates do matter because they allow faster development of advanced drugs. Many of the popular cholesterol-lowering drugs known as statins have been proven to reduce heart disease, but they were originally approved based on surrogate measures, he said.

“If we’d taken that position on Lipitor and Crestor, all of those people would not have gotten that benefit for years and years,” he said. “They would have lost heart, brain — and life.”

It could be six months before the FDA finishes a review of the final Vytorin study, known as Enhance, and decides whether the findings will change the way the agency regards lowering LDL cholesterol, Temple said.

"Nobody I know thinks the Enhance study is definitive," he said.

Temple and others noted that there's no medical debate that in general lowering cholesterol helps heart patients or that decreasing blood sugar benefits diabetics.  

But the question of what constitutes a suitable surrogate is debatable. Visco and others criticized the FDA’s expansion of Avastin for breast cancer treatment because it didn’t extend survival. However, the study’s lead author, Dr. Kathy Miller, an associate professor of medicine at Indiana University, said that wasn’t the main goal.

“Progression-free survival was an endpoint valuable in and of itself,” she said. “If you double the period of time for these women that their disease remains under control without symptoms, it gives them more time with their families without side effects from a different therapy.”

A larger window of remission also offered a chance, however remote, that new treatments might be developed in the interim, said Christina Koenig, 45, who was a single mother of a young child when she was diagnosed with breast cancer in 2002.

"I'm just thinking of that hope," said Koenig, who now works as a spokeswoman for the Y-ME National Breast Cancer Organization in Chicago. "Although, of course, we would not want to give people false hope."

Visco, on the other hand, said there was no reason to rush approval of a new, expensive drug when existing treatments were available.  In addition, she worries that the FDA move set a precedent for approving drugs without proof that they extend life.

It provides a new market for drug sales, she said, but little benefit for patients.

“I feel like we took many, many steps backward,” she said.

With so much friction and so many questions among experts, it can be difficult for consumers to know what to do about issues that have profound effects on individual health, said Kimberly Thompson, an associate professor of risk analysis and decision science at the Harvard School of Public Health.

No easy answer for patients
The key, she said, is for patients to give up the notion that they’re going to get an easy answer from their doctors — or anywhere else.

“The main thing is you have to go beyond the sound bite or the headline,” she said. “Patients need to dig deeper and physicians need to push them to do that.”

It’s important to find a trusted source of information, said Visco. She recommends patient advocacy agencies, whose staff members are trained in the latest research with an eye on consumer interests.

On their own, patients need to invest the time and energy necessary to understand the issues, whether it’s the effectiveness of Vytorin or the potential dangers of Avandia, said Hadler, who has written several articles and books on consumer medical issues. And they shouldn't be shy about talking to their doctors.

That can be difficult in today’s medical climate, acknowledged Hadler. “It takes about two minutes to prescribe a statin and 20 minutes to explain why it’s the right one for you,” he said.

But consumers should insist on those 20-minute conversations, preferably when they’re well, Hadler said. They should ask doctors for detailed information, such as the number of patients who would have to be treated to prevent a serious outcome or death from a drug.

When people suggest that many consumers might not be savvy enough for risk-benefit discussions, Hadler disagrees.

“They can handle the discussion because they do when they buy a car,” he said.

MacLeod, an oil company executive, said he plans to call his doctor soon to weigh the merits of continuing with Vytorin.

“I’m an educated person. I understand the risks and rewards,” he said. “Should I be any more concerned with that than with living in Houston around all these refineries?”

That’s exactly the kind of question to ask, Thompson said.

“Basically people need to realize that all treatments come with both risks and benefits and you can’t believe that it’s all going to be benefit.”

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