Drugs that don't work: a tough pill to swallow

What's a patient to do when top-selling meds fail the test? By JoNel Aleccia

Health writer


updated 5:07 a.m. PT, Fri., April. 4, 2008

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 board about 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.

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?’”

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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.

Drug Poisoning Deaths on the Rise

By Kathleen Fackelmann,

USA Today

Posted: 2008-04-03 10:23:59

Filed Under: Health News, Nation News

(April 3) -- Poisoning continues to be the second-leading cause of injury deaths in the USA, outstripping deaths caused by firearms for the second year in a row, a federal report says.

For 40 years, deaths caused by car crashes and firearms have topped the list of injury deaths in the USA. Poisoning edged into the No. 2 position in 2004, and the report shows the trend continues for 2005, the latest year for which numbers are available. The report is published in the March Health E-Stats.

Death rates for automobile accidents and firearms did not change much from 1999 to 2005, but the latest analysis shows that the rates for fatal poisonings increased at a dramatic pace and that narcotic drugs are responsible for the majority of the increase.

"When most people think of poisoning, they think of a kid getting under the sink and drinking Drano," says researcher Lois Fingerhut of the National Center for Health Statistics. "That does happen, but it doesn't cause most of the deaths we're talking about now."

A second study, this one published in February, blames one narcotic drug specifically for the lethal trend: methadone, a drug often prescribed to treat chronic pain.

Fingerhut's report shows methadone deaths are up from 786 in 1999 to 4,462 in 2005 for an increase of almost 500%.

The spike in deaths does not appear to be linked to the liquid form of methadone taken by heroin addicts to control cravings, says Leonard Paulozzi of the National Center for Injury Prevention and Control.

Fingerhut's research and other evidence suggests most of the methadone deaths are caused by an overdose of prescription pills.

In the late 1990s, doctors treating patients for pain started to shy away from frequently abused drugs such as OxyContin and turned to methadone pills, Paulozzi says.

But methadone has some properties that make it tricky to prescribe: Its painkilling properties can fade after a few hours, yet the drug can stay in the bloodstream for days, Fingerhut says.

Doctors sometimes prescribe too much methadone, or patients hoping to get more pain relief will take an additional dose. The drug builds up in the bloodstream to a lethal level, and the patient stops breathing, she says.

Robert Lubran of the Substance Abuse and Mental Health Services Administration says people also take methadone along with other drugs to get high. They can buy methadone from street dealers, or they get prescription pills from a friend, he says.

Fingerhut says there's an urgent need for public education about the dangers of prescription drug overdose - especially those caused by methadone. Drugs can kill easily, she says: "People die at home or on the street."

****************DRUG ERRORS HURT 1 IN 15 HOSPITALIZED KIDS: *******APRIL 08    

CHICAGO - Medicine mix-ups, accidental overdoses and bad drug reactions harm roughly one out of 15 hospitalized children, according to the first scientific test of a new detection method.

That number is far higher than earlier estimates and bolsters concerns already heightened by well publicized cases like the accidental drug overdose of actor Dennis Quaid's newborn twins last November.

“These data and the Dennis Quaid episode are telling us that... these kinds of errors and experiencing harm as a result of your health care is much more common than people believe. It's very concerning,” said Dr. Charles Homer of the National Initiative for Children's Healthcare Quality. His group helped develop the detection tool used in the study.

Researchers found a rate of 11 drug-related harmful events for every 100 hospitalized children. That compares with an earlier estimate of two per 100 hospitalized children, based on traditional detection methods. The rate reflects the fact that some children experienced more than one drug treatment mistake.

The new estimate translates to 7.3 percent of hospitalized children, or about 540,000 kids each year, a calculation based on government data.

Simply relying on hospital staffers to report such problems had found less than 4 percent of the problems detected in the new study.

‘Triggers’ reveal drug mistakes
The new monitoring method developed for the study is a list of 15 “triggers” on young patients' charts that suggest possible drug-related harm. It includes use of specific antidotes for drug overdoses, suspicious side effects and certain lab tests.

By contrast, traditional methods include nonspecific patient chart reviews and voluntary error reporting.

The researchers said their findings highlight the need for “aggressive, evidence-based prevention strategies to decrease the substantial risk for medication-related harm to our pediatric inpatient population.”

The study is being released Monday in the April issue of the journal Pediatrics.

It involved a review of randomly selected medical charts for 960 children treated at 12 freestanding children's hospitals nationwide in 2002. Triggers mentioned in the charts promoted an in-depth review of the patients' care.

Patient safety experts said the problem is likely even bigger than the study suggests because it involved only a review of selected charts. Also, the study didn't include general community hospitals, where most U.S. children requiring hospitalization are treated.

Study author Dr. Paul Sharek said evidence is needed to show whether a big push to prevent medical errors in recent years has put a dent in the problem since 2002, when the data were gathered.

Homer, of the children's healthcare initiative, said some hospitals have started using trigger methods similar to those in the study. But he added, “we still have a long way to go.”

Painkillers cause overdoses, reactions
Among triggers on the list was use of the drug naloxone, an antidote for an overdose of morphine and related painkillers. Symptoms include breathing difficulty and very low blood pressure.

More than half the problems the study found were related to these powerful painkillers, including overdoses and allergic reactions.

While 22 percent of the problems were considered preventable, most were relatively mild. None were fatal or caused permanent damage, but some “did have the potential to cause some significant harm,” said Sharek, who is medical director of quality at Stanford University's Lucile Packard Children's Hospital.

Other triggers included use of vitamin K, an antidote for an overdose of the blood thinner Coumadin; use of a blood test that detects insulin overdoses; and a lab test that identifies blood-clotting problems that can come from an overdose of the blood thinner heparin and other drugs.

Quaid's twins got accidental life-threatening heparin overdoses in a Los Angeles hospital shortly after they were born last November. The actor and his wife, Kimberly, have since formed a foundation to prevent medical errors. The babies recovered and Quaid said in an interview with The Associated Press on Saturday that “they appear to be normal kids, very happy and healthy.”

Monitor caregivers, Quaid urges
Quaid praised the new study for raising awareness about an under-recognized problem, and said he'd never envisioned having to play the role of public health advocate before the harrowing experience. He called it “the most frightening time” of his life.

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Quaid's advice to parents of hospitalized children?

“Every time a caregiver comes into the room, I would check and ask the nurse what they're giving them and why,” Quaid said.

Allen Vaida of the Institute for Safe Medication Practices said trigger methods like those used in the study can help. Still, amore comprehensive approach is needed, he said, to detect the most serious, least common errors like those involving the Quaids.

Voluntary reporting by hospital staffers is still needed, along with methods to detect errors in time to prevent or lessen any harm to patients, Vaida said.

How meds in water could impact human cells

Ingesting scant amounts could have powerful effect, experiment shows

updated 8:23 a.m. PT, Mon., March. 10, 2008

Troubled by drugs discovered in European waters, poisons expert and biologist Francesco Pomati set up an experiment: He exposed developing human kidney cells to a mixture of 13 drugs at levels mimicking those found in Italian rivers.

There were drugs to fight high cholesterol and blood pressure, seizures and depression, pain and infection, and cancer, all in tiny amounts.

The result: The pharmaceutical blend slowed cell growth by up to a third — suggesting that scant amounts may exert powerful effects, said Pomati, who works at the University of New South Wales in Sydney, Australia.

Story continues below ↓



Taken alone, this was a modest study. But in fact Pomati’s work is part of a body of emerging scientific studies that indicate that over time, humans could be harmed by ingesting drinking water contaminated with tiny amounts of pharmaceuticals.

In another recently published study, Pomati discovered that some of those pharmaceuticals could amplify — or reverse — the effects of some others.

For example, the cholesterol drug bezafibrate and asthma drug salbutamol each seem to stimulate cell growth. Combined in the laboratory, they slowed it way down. The same cholesterol drug appeared to make cells more sensitive to harm from the antibiotic fluoroquinolone.

And Pomati’s work indicates some drugs cause cellular effects at scant concentrations that — strangely — cannot be seen at higher levels.

Such findings are preliminary; they alone cannot demonstrate the same effects within the human body. But they provide scientific hints, just like cellular experiments that routinely guide discovery of new drugs.

Estrogen risks
They also heighten worry about the possible effects on especially vulnerable groups, like the very young, old or sick. “My wife is pregnant, and I don’t let my wife drink the water ... where I know that there are pollutants like pharmaceuticals in concentrations that are detectable and in mixtures that are complex,” said Pomati.

Elsewhere in the world, other researchers are finding results similar to Pomati’s.

In research awaiting publication, human breast cancer cells grew twice as fast when exposed to estrogens taken from catfish caught near untreated sewage overflows in Pennsylvania, compared with other fish.

The University of Pittsburgh researchers didn’t calculate how much effect came from pharmaceuticals instead of natural hormones, but their earlier work points to birth-control pills and hormone treatments as important contributors, said lead researcher Conrad Volz.

“There is the potential for an increased risk for those people who are prone to estrogenic cancer,” said Volz, who studies environmental hazards at the university’s Cancer Institute.

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He said people who regularly drink water containing low levels of hormones may be at higher risk, since they would presumably consume more of these drugs than those who only occasionally eat such fish.

'Kaleidoscope of chemicals'
Scientists at the Helmholtz research center in Leipzig, Germany, linked low levels of the pain reliever diclofenac to an inflammatory-like response in human blood cells, according to biologist Kristin Schirmer. Inflammation at the wrong time and place plays a role in conditions ranging from infections and arthritis to heart disease.

Sandra Steingraber, a biologist at New York’s Ithaca College, adds that many efforts to determine how trace drugs affect humans don’t fully consider the whole range of pharmaceuticals in the environment and whether someone has been exposed at more susceptible times, like during childhood or old age.

“The timing makes the poison as much as the dose,” she said. “And the dose itself is not the dose from just any one thing — it’s from this whole kaleidoscope of chemicals.”

Taking notice of accumulating evidence, the drug industry has backed studies of its own in recent years that have found very slight, if any, risk to humans.

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