Editor's note: This story was updated Nov. 5, 2014, with information on two new studies regarding Pradaxa.
July 25, 2014 -- Two recent studies that compare the newer blood-thinner drug Pradaxa (dabigatran) with the old standby drug, warfarin, have found that people on higher doses of Pradaxa have a greater risk of gastrointestinal bleeding.
The recent research follows an investigation in the BMJ published in July that suggested more frequent blood testing with Pradaxa might help prevent major bleeding problems. When Pradaxa was approved by the FDA in 2010 to prevent stroke in people at high risk, a major selling point was that it didn't require frequent blood tests as warfarin (Coumadin, Jantoven) does.
WebMD turned to experts and Pradaxa's maker, Boehringer Ingelheim, to explain further.
What did the two new studies find?
In one study, published Oct. 30 in Circulation, researchers looked at more than 134,000 patients, all on Medicare, who took either Pradaxa or warfarin for their atrial fibrillation, a heart rhythm problem that increases stroke risk.
They found that Pradaxa was linked with a lower risk of ischemic stroke (in which an artery to the brain is blocked), hemorrhage within the brain, and death, compared with warfarin. But it had an increased risk of major stomach bleeding or brain hemorrhage. The higher risk was more pronounced in those treated with the 150-milligram doses of Pradaxa twice daily. The 75-mg dose twice daily was comparable to warfarin in terms of pros and cons, except Pradaxa had a lower risk of hemorrhage within the brain than warfarin.
In another study, published online Nov. 3 in JAMA Internal Medicine, researchers compared the use of Pradaxa in more than 1,300 Medicare patients and warfarin in more than 8,000 Medicare patients to determine the risk of bleeding as a side effect.
While 9% of the Pradaxa group had major bleeding, 5.9% of the warfarin group did. The risk of hemorrhage within the brain was higher among warfarin users. Those on Pradaxa had an increased risk of major bleeding and GI bleeding. That risk was especially high for those with chronic kidney disease and for African-Americans.
What does the maker of Pradaxa say?
In a statement issued by Boehringer Ingelheim Pharmaceuticals, the company says that "real-world studies are important to support understanding of the safety and effectiveness of approved medicines in routine clinical use."
It points to an FDA statement issued after the larger study, noting that Pradaxa is still considered to have more benefits than risks, and no changes have been made to recommendations for its use or to its label.
What do experts say about the findings?
Both of the new studies are observational, so they have built-in limitations compared to clinical trials, says Rita Redberg, MD. She's a professor of medicine at the University of California, San Francisco, and editor of JAMA Internal Medicine. When she looks at findings from both the clinical trials and the new observational studies, Redberg says, she thinks the ''overall risk-benefit ratio is more favorable on warfarin."
While she understands that patients like the convenience of not having to get regular blood tests on the newer drugs as they have to on warfarin, she says: "I am very concerned about the bleeding risk with the newer oral anticoagulants, and the fact that there is no reversal agent [to undo excess bleeding]."
She is talking about all three of the newer oral medicines, including Xarelto (rivaroxaban) and Eliquis (apixaban), although the recent studies focused on Pradaxa.
New guidelines on how to manage atrial fibrillation were released in March 2014 by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society, in collaboration with the Society of Thoracic Surgery. In them, all three new oral drugs are viewed as options, with pros and cons. The benefits and risks sometimes vary by dosage, according to the guidelines.
The guidelines state that deciding whether to use warfarin or the newer blood thinners should be based on clinical factors, patient preference and costs, among other things. If someone is on warfarin and doing well, there is no need to switch, according to the guidelines.
People on the Pradaxa should ask their doctors about their risks and benefits, Redberg says.
If you take an anticoagulant, don't stop taking it without talking to your doctor. Stopping it can raise your stroke risk.
What else is important to know about how Pradaxa compares to warfarin?
Both drugs are prescribed for people with atrial fibrillation. More than 3 million Americans have the condition, the FDA says. The drugs are also used to treat deep vein thrombosis, or blood clots in a vein, although they're not approved for that purpose.
Blood thinners work to prevent strokes by keeping the blood thin enough to prevent clots. If the blood becomes too thin, the risk is serious bleeding.
According to the FDA, Pradaxa -- as well as Xarelto (rivaroxaban) and Eliquis (apixaban) -- were found either equal to or better than warfarin at preventing strokes. The drugs were approved based on clinical trials including more than 50,000 patients, the FDA says.
More than 850,000 patients have been prescribed Pradaxa since its approval, according to Boehringer Ingelheim.
A typical dose of Pradaxa costs about $300 a month, compared to $4 a month for a typical dose of generic warfarin.
What were the major concerns raised in the July report on Pradaxa?
Safety is the major one, says Thomas J. Moore, senior scientist at the Institute for Safe Medication Practices. He wrote an analysis to accompany the investigation.
Any anticoagulant treatment carries risks, he says. "Anticoagulant treatment for people with atrial fibrillation ranks as one of the highest-risk treatments in older Americans," he says. More than 15% of older patients treated for atrial fibrillation with blood thinners for 1 year have bleeding, he says.
Concerns about Pradaxa surfaced 2 years ago, he says, when doctors began reporting a larger number of serious and sometimes fatal bleeding problems in older patients on the drug.
The claim by the company that the drug needs no blood-level monitoring is misguided, Moore says. "It turns out the company has had data for several years, showing the amount of anticoagulation [blood thinning] varied [from patient to patient] more than fivefold."
That means, Moore says, that "the same dose could produce widely varying effects on blood clotting. Some patients would be at extremely high risk of bleeding. Others would not get a strong enough ... effect to serve its purpose, reduce the risk of stroke."
According to the BMJ report, the company re-analyzed drug information in 2012, finding that blood-level monitoring and adjusting the dose could lower major bleeding problems by 30% or 40% compared to warfarin -- but regulators and doctors weren't informed, the report says. The company refutes this.
"The concerns are that Pradaxa was approved on the basis that it did not require monitoring," Redberg said after the July report was published. She wrote an editorial to accompany the analysis. "There is now new evidence that has come to light suggesting it is not safe to use it without monitoring, particularly in the elderly and those with kidney failure. The bleeding risk is higher than we first thought and the effectiveness is basically equivalent to warfarin.''
What's needed, Moore says, is for doctors to pinpoint a patient's ideal blood level and regularly check it.
What does the drug maker say?
In a press release issued in response to the July report, Boehringer Ingelheim says it did study the effect of blood-level testing and dose adjusting and concluded it was not needed.
"The truth is the totality of scientific evidence does not support dosing decisions for Pradaxa based on blood levels," the statement reads in part.
Other factors, such as how well the kidneys work, affect the risk of bleeding, too, the company says.
What are the symptoms of internal bleeding?
Bleeding that can turn serious is a complication of all blood thinners, according to the FDA. People on a blood thinner who have certain symptoms of bleeding should seek immediate medical help, the FDA says. These include:
- Bleeding from the gums that is unusual
- Frequent nose bleeds
- Urine that is pink or brown
- Stools that are black or red
- Coughing up blood or blood clots
- Vomiting blood
- Vomit that looks like coffee grounds
- Heavier than normal vaginal bleeding