Pradaxa Bleeding and Higher Heart Attack Risk?

Higher heart attack risk from Pradaxa, study shows: Here’s a note of caution for those who are taking blood thinners to manage atrial fibrillation or prevent stroke after a hip or knee replacement.

Patients taking the new anti-clotting drug Pradaxa have a higher risk—from 22 percent to 33 percent—of heart attack or severe symptoms of heart disease than do patients taking the older blood thinner, warfarin, a meta-analysis of various reports says.

That’s the range of relative increase in risk compared to other blood thinners—but the absolute risk increase for suffering a heart attack was only 0.27 percent, clarify the authors of the meta-analysis published online in the Archives of Internal Medicine Jan. 9 issue.

The findings, from Cleveland Clinic researchers Dr. Ken Uchino and Dr. Adrian V. Hernandez, is based on data from seven clinical trials that involved more than 39,500 patients and compared those on Pradaxa to others in control groups, who received either warfarin, Lovenox (enoxaparin) or a placebo. [

Pradaxa, known chemically as dabigatran, is approved in the United States for stroke prevention in patients suffering from an irregular heartbeat known as atrial fibrillation.

In Europe, Pradaxa is used to prevent strokes caused by blood clots in patients who have undergone hip and knee replacements. It’s also known as Pradaxa in Australia, but Pradax in Canada and Prazaxa in Japan.

The drug, produced by Germany’s Boehringer Ingelheim, has been touted as an alternative to warfarin, the blood thinner that has been used effectively for many decades, but which doctors say is hard to use.

Pradaxa was expected to compete with two other new blood clot and stroke preventers—Xarelto (rivaroxaban) from Bayer AG and Johnson & Johnson, and Eliquis (apixaban) from Bristol-Myers Squibb Co and Pfizer Inc. Approved by health regulators only in recent years, use of these three new anticoagulants was expected to rise in recent months, generating billions of dollars in sales.

Since October 2010, when it was approved by the U.S. Food and Drug Authority’s, until August 2011, doctors wrote about 1.1 million Pradaxa prescriptions and about 371,000 patients received Pradaxa prescriptions from U.S. outpatient retail pharmacies, Forbes reports.

Only a small increased risk of heart attack was linked to the use of Pradaxa compared to warfarin in the original study Boehringer used to gain the health regulator’s approval. At the same time, the study found that the drug slashed the risk of strokes by 35 percent.

But the new meta-analysis by the Cleveland Clinic researchers shows that Pradaxa boosts the risk of a heart attack and acute coronary syndrome (ACS), the umbrella term covering conditions of angina and chest pain typically caused by a blocked coronary artery.

Uchino, the study’s lead researcher and a neurologist, clarified that the actual increase in the number of heart attacks and ACS events was very small and is outweighed by the benefits—mainly, the drug’s ability to reduce the number of strokes.

“The overall benefit and risk balance of dabigatran use appears to be favorable in patients with atrial fibrillation because of reduction in ischemic stroke,” the study authors wrote. However, they caution, “clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.”

The meta-analysis also found that these events occurred in 1.19 percent of Pradaxa patients and in 0.79 percent of control-group patients. The rate of death was also found to be lower for patients who received Pradaxa than those who got other medicines in clinical trials—4.83 percent versus 5.02 percent in control groups.

Dr. Uchino’s team called for more study of the drug’s potential to increase heart-attack risk.

In an editorial accompanying the study Archives of Internal Medicine, journal editor Dr. Rita Redberg notes that this isn’t the first safety warning issued for Pradaxa.

FDA probes Praxada bleeding reports
European regulators recently warned that due to reports of fatal bleeding, Pradaxa should be used with caution and at low doses in people over 75 years of age and in those with moderate kidney impairment. Pradaxa is not recommended for those with severe kidney function problems, the regulators said.

Last month, the FDA said it was conducting a safety review of Pradaxa, prompted by reports of serious bleeding events in people taking the drug.

But the FDA acknowledges that all blood thinners increase the risk of bleeding, saying that it was “working to determine whether reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected.”

In January, the FDA also said that it was looking at the heart-attack issue and using other data to compare Pradaxa users to warfarin users.

Many doctors were hoping to switch patients to the newer medicines that don’t cause as much monitoring as Warfarin requires.

Pradaxa provides an important health benefit when used as directed, the FDA said, advising healthcare professionals who prescribe Pradaxa to follow the recommendations in the approved drug label.

The agency also said patients with AF shouldn’t stop taking Pradaxa without talking to their healthcare professional. Stopping use of blood thinning medications can increase their risk of stroke—and strokes can lead to permanent disability and death.

Currently, Pradaxa’s drug label already contains a warning about significant and sometimes fatal bleeds. In a large clinical trial (18,000 patients) comparing Pradaxa and warfarin, major bleeding events occurred at similar rates with the two drugs.

FDA is also working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa. FDA is working closely with Pradaxa’s maker to evaluate the post-market reports of bleeding.

The agency listed additional information for patients:

  • Pradaxa is an anticoagulant medicine that reduces the risk of blood clots forming in your body and causing a stroke. Having a stroke can cause permanent disability and death.
  • Do not stop taking Pradaxa without talking to your healthcare professional. Stopping use of your blood thinner suddenly can put you at risk of a stroke.
  • Be aware that while taking Pradaxa you may bruise more easily and it may take longer for any bleeding to stop.
  • Discuss any questions or concerns about Pradaxa with your healthcare professional.
  • Call your healthcare professional and seek immediate care if you develop any signs or symptoms of bleeding such as:

o unusual bleeding from the gums
o nose bleeding that happens often
o menstrual or vaginal bleeding that is heavier than normal
o bleeding that is severe or you cannot control
o pink or brown urine
o red or black stools (looks like tar)
o bruises that happen without a known cause or that get larger
o coughing up blood or blood clots
o vomiting blood or vomit that looks like coffee grounds.

The FDA also enjoined patients to report any side effects you experience to your healthcare professional and the FDA MedWatch program at 1-800-332-1088 or 1-800-FDA-0178 (Fax)

It also advised healthcare professionals to follow carefully the approved indication and other recommendations in the professional drug label regarding dosage and administration when prescribing

“Make sure your patients know the signs and symptoms of bleeding and when to seek care,” the FDA said.

It said it is working with the manufacturer to analyze the post-market reports for evidence of inappropriate dosing, use of interacting drugs, or other clinical factors that might lead to a bleeding event.

Boehringer disagrees
The meta-analysis combined trial data from different patient populations and various comparator medicines or placebo—and Boehringer said it did not agree with this method used.

“Based on the totality of the data, we concluded that myocardial infarction (heart attack) is not an adverse consequence of Pradaxa treatment,” said John Smith, Boehringer’s senior vice president for clinical development and medical affairs.

When medicines become widely used in the general population, they often turn up additional safety issues not seen in carefully controlled clinical trials.

In her editorial, Dr. Redberg wrote: “These additional concerns deserve serious consideration in weighing the risks and benefits of dabigatran and highlight the importance of continued collective analysis of data after drug approval.”

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