Medical experts say the results, presented Sunday at the American Heart Association meeting, show there is a lesson to be learned about the effectiveness of small studies over all.
The drug, nesiritide, brand name Natrecor, was approved after small studies in carefully selected patients. It seemed to soothe a terrible heart-failure symptom — patients’ lungs fill with fluid and they feel as if they are drowning.
But the large study, with real-world patients, found no significant effect on that symptom.
A few years after its approval, nesiritide fell out of use because small studies seemed to indicate an increased risk of kidney problems and an increased death rate.
The large study showed those risks, too, were wrong.
“Once again, small studies give us the wrong answers,” said Dr. Robert M. Califf, a Duke cardiologist who directed the large study. “There was no safety issue at all.”
“To me, the really important message is that the drug got very widely used for reasons that are incorrect, and then it got bashed for reasons that are incorrect,” Dr. Califf said. “Unless we do these kinds of large clinical trials we are engaged in a comedy of errors,” he added.
The question of how to evaluate rare side effects that seem to arise in small studies plagues medical researchers. Most drug studies are not designed to assess rare effects, but as more drugs are sold to huge numbers of people who often take them for years, the question has become increasingly pressing.
The nesiritide story began in 2005, four years after the drug was approved. At first it was popular, but then researchers, in two analyses, asked if it was really safe. They had lumped together data from several nesiritide studies. One analysis reported damage to kidney functions, and the other found increased death rates. Sales plummeted.
Johnson & Johnson, the drug’s maker, put together an expert panel that said the only way to answer the safety question was to do a large study. That led to the study that Dr. Califf directed, which enrolled anyone who came to any of 450 participating hospitals around the world with heart failure and complaining of difficulty breathing. Participants were randomly assigned to get an infusion of nesiritide or saline. Researchers asked two main questions: Were the patients still alive a month later? And were they readmitted to the hospital?
The study’s executive committee is still debating what to conclude, Dr. Califf said. No one thinks the drug should be pulled from the market, he added, because some patients may get breathing relief even though the drug was not effective for the participants as a whole.
“But the major message is that if you don’t do the right studies you just don’t know” about risks and benefits, Dr. Califf said. “And you are at risk of making serious errors.”
Cardiologists have similar questions about the effectiveness of Zetia, an eight-year-old cholesterol drug that Dr. Califf is also studying. It has been beset by doubts about whether it improves heart health.
The Food and Drug Administration approved Zetia, which lowers LDL, or “bad” cholesterol, in 2002. In 2004, the agency approved a related drug called Vytorin, which combines Zetia and a statin called simvastatin.
Both are made by Merck. Together, they have had worldwide sales of $26.8 billion, according to IMS Health, a firm that tracks drug sales, and have been taken by millions of Americans.
But eight years after Zetia came on the market, many cardiologists say they still don’t know whether taking Vytorin is better for the heart than using a statin alone.
That is because statins like Crestor, which work by blocking the production of cholesterol in the liver, have proven to cut the risk of cardiovascular problems. Zetia, however, acts differently; it works in the gut, where it inhibits the absorption of cholesterol from food. Zetia alone modestly reduces bad cholesterol, and the combination pill significantly reduces LDL.
But studies so far have failed to demonstrate a cardiac benefit to the drugs. Now there is a new Zetia study, due to be presented this week at a kidney conference in Denver, which looked at whether the combined pill reduces heart attacks and strokes in patients with kidney disease, who are at high risk for heart problems.
But the study is unlikely to resolve the Zetia question because it did not involve a group of patients taking a statin alone. Doctors still won’t know whether the combined pill works better than statins, which are available as inexpensive generics.
To try to answer the health-benefit question, Merck has sponsored one of the largest clinical trials ever conducted on cholesterol drugs. The trial, which started in 2005 and is due to be completed in 2013, involves about 18,000 patients at 1,046 sites around the world. It is taking years to complete because researchers set a goal of tallying 5,200 major cardiovascular problems in order for the project to end, said Dr. Luciano Rossetti, the head of global scientific strategy at Merck Research Laboratories.
“I don’t see a problem with the timing considering what it takes to do a trial like this,” Dr. Rossetti said. “I think it is great that we are committed to finding out that answer.”
Dr. Califf, who is one of two principal investigators on the Zetia trial, said it was common for the main outcomes study to lag years behind the approval of a drug, but he said the practice was a problem for doctors who practice evidence-based medicine.
“F.D.A. by mandate could require studies, but that wouldn’t be necessary if clinical trialists and academic medical centers stuck to their guns and demanded the evidence before they used the drugs on a wide scale,” he said, referring to both Zetia and nesiritide.
Drug makers also bear a responsibility to conduct rigorous studies before they start widely promoting medications, he added.
“Huge amounts are spent on marketing that could have been spent on a clinical trial,” he said.
This article has been revised to reflect the following correction:
Correction: November 15, 2010
???An earlier version of this article misstated the number of trial sites in Merck's study of cholesterol drugs. It is 1,046, not 380.
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