Newly Released Data Stirs Naproxen Debate

(HealthDay News) -- Just-released data from a trial that was stopped early in 2004 for safety reasons is re-igniting debate on the safety of two popular painkillers.

The trial suggested the over-the-counter painkiller Aleve boosted heart risks, while another controversial prescription painkiller known as Celebrex did not.

Now, the data from that trial has finally been made available. But that has not silenced one critic, who says this early data is unreliable and questions the reasons the trial was stopped prematurely.

"The trial was improperly stopped by what appears to be political considerations. When you do that, you generate data which we know is unreliable," said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic Foundation.

Nissen is author of an accompanying commentary in the Nov. 17 online edition of PLoS Clinical Trials, which has published the data from the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT).

Specifically, Nissen charges that ADAPT was cut short not on the advice of its safety-review board but by nervous officials at the U.S. National Institutes of Health, which had funded the trial. Those officials were worried about the media furor over the safety of now-withdrawn painkiller Vioxx, Nissen claims.

The medications in question all fall into the class of nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin, naproxen, ibuprofen and cox-2 inhibitor medications such as Celebrex and the now-withdrawn Bextra and Vioxx.

Beginning in late 2004, major studies began to show that heart risks to users rose with long-term use of cox-2s. This led to the eventual withdrawal from the market of Vioxx and Bextra, and the U.S. Food and Drug Administration slapping a "black box" cardiovascular warning on the remaining cox-2, Celebrex.

In December of 2004, officials at the NIH announced the premature termination of the ADAPT trial, which had been set up to look at the possible usefulness of NSAIDs in preventing Alzheimer's disease.

Early results from that trial came as a surprise to many, because they suggested that long-term use of Celebrex did not significantly boost heart risks, while the use of an over-the-counter rival, naproxen (Aleve), did.

"We ended up stopping the trial early, when another trial brought up some safety concerns about these drugs," said study author Barbara Martin, an assistant professor of epidemiology at Johns Hopkins Bloomberg School of Public Health.

"We found a small but not statistically significant risk with celecoxib, and a larger and statistically significant increased risk with naproxen," Martin said.

But the actual data from the trial was not released at the time, adding to the confusion. It has now been published.

The 2,500 elderly participants in the ADAPT trial took either celecoxib, naproxen or placebo for up to 3.5 years.

Compared to those taking placebo, people taking celecoxib had a 10 percent increased risk of heart attack and stroke, while those taking naproxen had a 63 percent increase risk, the researchers found.

Martin said she wasn't sure why these drugs might have different risk profiles. Other trials have suggested that naproxen was actually cardioprotective, but these results indicated that it is not, she said.

Martin believes that the ADAPT results would also apply to people who take the painkillers over the long-term to help relieve arthritis.

"As yet, the specifics of the risks aren't really well-defined, but the clinical benefits of the drug are established," Martin said. "What is most clear is that when you take NSAIDs for a long period of time, there is a risk associated with them. What exactly it is, how big it is, is still not clear, but there is no completely safe NSAID."

There did not seem to be any protective effect from the drugs in terms of warding off Alzheimer's, she added. "Part of the reason we stopped was that there was some evidence of risk, and there wasn't any overwhelming evidence of benefit to counter that," Martin said.
But Nissen strongly disagreed with the findings, noting that they run counter to the results of other large trials.

"The published results of the ADAPT trial with regard to cardiovascular risk are completely unreliable," said Nissen. In his editorial, he explained that because the trial was stopped early, the data lacks the statistical power to deliver any clear verdict on either Celebrex or naproxen.
"These results cannot be used in any way to assess the relative risks of naproxen," Nissen said.

He added that he is not surprised that the premature termination of the trial in late 2004 -- coming at the height of the Vioxx debacle -- caused such a media uproar. Newspapers at the time trumpeted headlines such as "Heart Risk Seen in Naproxen" (Wall Street Journal) and "Patients, Doctors Agonize Over Risks of Painkillers", (Los Angeles Times).

"A warning was issued to the public that we now know was wrong," he said.

But Martin said she blames the media for creating a false impression of why the trial was stopped. "All of the publicity when the trial was stopped -- it was not what we intended," she said. "It's difficult in a political maelstrom of events to have the true rationale come through."

According to Martin, the trial was stopped because of data from another major trial was raising questions about the safety of Celebrex, triggering the premature closure of that arm of the ADAPT trial. When that happened, the researchers decided against continuing with the naproxen arm alone.

"We weren't seeing a risk with celecoxib (Celebrex), so it put us in a very uncomfortable position. We were imagining three years later if the adverse effects with naproxen were really real getting roundly criticized for not having stopped it earlier," she said.

Martin agreed, then, that there were political as well as safety concerns in stopping the trial.
"There was this domino effect and we felt that even though the results in and of themselves would not have led us to stop the trial, this domino effect made it necessary," she said.

Despite all the controversy, Martin feels that the trial data remains valid. She also believes it was right to have stopped the trial early. As to the safety of naproxen, Martin said there's not yet enough data to answer that question.

But Nissen said the accumulated evidence on NSAIDS supports the notion that the drug is, on the whole, safe.

"There is overwhelming evidence that of all the drugs in the class, the safest drug is naproxen," he said. "Analyses involving millions of patients have shown, consistently, that it is probably the safest drug."

Nissen doesn't believe naproxen actually protects against heart attack, however. "It's neutral," he said.

More information
There's more on NSAIDs at the U.S. National Library of Medicine.