Dr. Bryan A. Cotton, a trauma surgeon in Houston, had not heard much about the new anti-clotting drug Pradaxa other than the commercials he had seen during Sunday football games.

Then people using Pradaxa started showing up in his emergency room. One man in his 70s fell at home and arrived at the hospital alert and talking. But he rapidly declined.

“We pretty much threw the whole kitchen sink at him,” recalled Cotton, who works at Memorial Hermann-Texas Medical Center. “But he still bled to death on the table.”

Unlike warfarin, an older drug, there is no antidote to reverse the blood-thinning effects of Pradaxa.

“You feel helpless,” Cotton said. The drug has contributed to the bleeding deaths of at least eight patients at the hospital. “And that’s a very bad feeling for us.”

Pradaxa has become a blockbuster drug in its two years on the market, bringing in more than $1 billion in sales for its maker, the privately held German drug maker Boehringer Ingelheim.

But Pradaxa has been linked to more than 500 deaths in the United States and a chorus of complaints has risen from doctors, victims’ families and others in the medical community, who worry that the approval process was not sufficiently rigorous because it allowed a potentially dangerous drug to be sold without an option for reversing its effects.

Pradaxa is an example, some critics say, of what can happen when a drug that performs well in tightly controlled trials is released into the messy world of real-life medicine. Boehringer Ingelheim said it was working on developing an antidote but that even without one, patients in a large clinical trial died at roughly the same rate as those who were taking warfarin.

The Food and Drug Administration released a report Friday that found the drug did not show a higher risk of bleeding than for patients taking warfarin, and the report did not address the lack of an antidote for Pradaxa.

“The evolving spontaneous reporting patterns do not indicate a change in the favorable benefit-risk profile of Pradaxa, when used correctly according to the approved label,” Boehringer Ingelheim said in a statement. In other words, the drug is still safe. But some reports have indicated that doctors are not sufficiently cautious when prescribing Pradaxa, giving the drug to older people or those with kidney problems even though there is evidence that the bleeding risks are higher in those groups. The company recommends testing patients’ kidney function before prescribing Pradaxa and notes that the risk of bleeding increases with age.

“The problem is that the people that prescribe this, as a general rule, are cardiologists and family practitioners,” said Dr. Mark L. Mosley, director of the emergency room at Wesley Medical Center in Wichita, Kan. “The people that see the harm are your ER docs and your trauma docs.”

Critics say that at least until an antidote is found, better disclosure or more limited use of Pradaxa may be preferable. Patients’ lawyers have begun turning their attention to the drug. More than 100 lawsuits have been filed in federal courts and lawyers say thousands more are expected.

When the FDA approved Pradaxa in October 2010, the drug was hailed as the first in a new category of replacements for warfarin, the nearly 60-year-old drug used to prevent strokes in people with a heart-rhythm disorder known as atrial fibrillation.

Warfarin requires careful monitoring of a patient’s diet and drug regimen, and frequent blood tests to ensure that it is working. Pradaxa required no such monitoring and, compared with warfarin, appeared to be better at preventing strokes.

Sales of the drug took off. By the end of 2011, after just over a year on the market, 17 percent of patients with atrial fibrillation were being prescribed Pradaxa, compared with 44 percent for warfarin, according to a study released in September. About 725,000 patients in the United States have used the drug, according to the FDA. But almost as soon as doctors started prescribing Pradaxa, concerns surfaced about its safety. Pradaxa was identified as the primary suspect in 542 patient deaths reported to the FDA in 2011, and was linked to more reports of injury or death than any of the more than 800 drugs regularly monitored by the Institute for Safe Medication Practices, a nonprofit based in Pennsylvania that monitors medicine safety.

Mosley said he found it “shocking, just shocking” that the FDA approved Pradaxa, which is also called dabigatran, even though no antidote was available.

In a statement, the FDA said, “the lack of an antidote notwithstanding, dabigatran was superior to warfarin in preventing strokes in a large clinical trial. The rates of bleeding were similar.” The study released Friday examined health insurance claims and hospital data and reached a similar conclusion.

Warfarin, which is also known by the brand name Coumadin, can often be reversed by giving a patient vitamin K or other substances. Warfarin, too, can be deadly but, doctors said, they at least have options.

“The practical experience is that once hemorrhagic complications occur in this drug, it is much more likely to be a catastrophe than with Coumadin,” said Dr. Richard H. Schmidt, an associate professor of neurosurgery at the University of Utah, who treated an 83-year-old man who died from bleeding and was using Pradaxa.

Boehringer Ingelheim recommends treating bleeding patients with dialysis to help flush the drug from the body, although it notes that “the amount of data supporting this approach is limited.”

Several doctors said that option was not realistic.

“People that are bleeding to death aren’t going to tolerate being put on dialysis,” Cotton said.

Two other new drugs intended as warfarin replacements also lack antidotes. Doctors said they had not seen as many bleeding deaths associated with Xarelto, which was approved in 2011 and is sold by Bayer and Johnson & Johnson. On Friday, the FDA approved Xarelto to also treat deep vein thrombosis and pulmonary embolism, two kinds of blood clots. Pradaxa is approved in the United States only to prevent stroke in patients with atrial fibrillation. A third drug, Eliquis, by Bristol-Myers Squibb and Pfizer, has not yet been approved by the FDA. Representatives for both drugs said trials showed their products were safe, adding that the companies were investigating different antidotes.

Boehringer Ingelheim is expected to present several new studies of Pradaxa’s safety and efficacy — Including one that examines potential antidotes — at the American Heart Association scientific conference next week in Los Angeles.

Some cardiologists have said that Pradaxa and the other new drugs represent real advances over warfarin. Around 40 percent of people with atrial fibrillation do not take any drugs for it, a recent study showed, putting them at risk for strokes.

“I think the benefit of the drug clearly exceeds the risk because to me, a disabling stroke has a greater weight than a bleeding complication,” said Dr. Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles and a member of the FDA committee that voted to approve Pradaxa.

But those calculations make little sense to Walter Daumler, who said he watched his 78-year-old sister, Doris, bleed to death in May. Daumler, who lives in Wisconsin, has hired a lawyer and is considering suing. He said the doctors told him that because she was on Pradaxa, there was nothing they could do.

“My No. 1 goal is to stop this insidious drug,” Daumler said. “To get this off the market, so others will not undergo or witness what I saw.”
 

© 2012 The New York Times Company