Pradaxa: More Concerns. More Myocardial Infarctions?

Pradaxa is part of a new group of anticoagulants (thrombin X inhibitors) that eventually will allow anticoagulation by the pill route without requiring patients to alter their food and medication intake and avoid foods and medications that interfere with the anticoagulant as patients must do with Warfarin. Pradaxa additionally eliminates the need to take blood tests (INR/ PT) to monitor the dosage as one has to do with Warfarin (Coumadin).

There is a large commercial advertising campaign underway on TV and print media to encourage patients with atrial fibrillation to ask their doctors to switch them from Coumadin to Pradaxa (Dabigatrin).  The campaign bases its claims on the RE-LY trial of 18,000 patients at 80 medical centers throughout the world who took the 150 mg dosage and had significantly fewer strokes than patients taking Warfarin.  The original study was criticized because many of the patients in the Warfarin (Coumadin) group were not on enough Warfarin or at a therapeutic PT/INR to prevent embolic strokes so the comparison with Pradaxa may not be valid. Another criticism involved the fact that Pradaxa can cause major bleeding and there is no antidote to stop the bleeding. Patients on Pradaxa who are bleeding are advised to undergo hemodialysis to remove the drug from their system because there are no medications or treatments available to stop Pradaxa related bleeding.

One wonders how the Food and Drug Administration approved this product for general use under these circumstances without conducting further testing?  The issue becomes even more confusing with the addition of data presented by Ken Uchino, MD, and Adrian Hernandez MD, PhD of the Cleveland Clinic in the online version of the Archives of Internal Medicine. They claim that by reviewing the RE-LY data there is a 38% relative increase in the risk of a myocardial infarction (MI) or heart attack in the Pradaxa group. In an accompanying editorial in the same journal, clinicians at the Hadassah- Hebrew University Medical Center in Jerusalem wrote, “The robust finding that Dabigatran is associated with increased rates of MI (heart attack) is alarming and emphasizes the need for continued critical appraisal of new drugs after phase III trials.”

In my practice I generally will not switch to a new or controversial medication until it has been on the US market for at least one year. I make exceptions for orphan drugs, products to treat incurable diseases with no other choices available. The 12 months gives the medical and scientific community a chance to see how the medication performs and what unexpected adverse effects may be associated with it.

Thrombin X inhibitors are the wave of the future. With no way to stop the bleeding, and data on their safety and efficacy still accumulating, they are just not ready for prime time yet.

Coumadin versus Pradaxa

Coumadin (Warfarin) is a blood anticoagulant which prevents clotting by inhibiting Vitamin K dependent clotting factors.  It is taken orally and becomes effective after several days of administration when the Vitamin K dependent clotting factors have been depleted.  It is inexpensive and has been used for years to prevent clots from forming in patients with the irregular heart rhythm known as atrial fibrillation.  These clots can form in the chambers of the heart and break off and travel to the brain causing embolic strokes.

Coumadin is additionally used to prevent recurrent blood clots in patients who have had phlebitis (or inflammation of a blood vessel) and in certain postoperative conditions such as joint replacements. Physicians monitor your ability to clot by drawing blood for a test called “the prothrombin time or INR (International Normalized Ratio).  The blood can be drawn from a vein and sent to a lab or performed by a finger stick method in a doctor’s office.  Based on the blood test result we adjust your medication dose up or down. Coumadin’s effect on blood clotting can be easily affected by certain foods rich in Vitamin K (green leafy vegetables in particular) and by medicines which either enhance or limit Coumadin’s effect on clotting.

The major complication of Coumadin is excessive bleeding. We stop the bleeding by administering Vitamin K and infusing blood products intravenously containing active blood clotting factors.

Pradaxa and the new wave of direct thrombin inhibitors that are now being released are designed to do the same job as Coumadin without requiring monitoring by blood test of your ability to clot. This new class of medications should have many fewer interactions with food and other prescription and over the counter medicines. Its two major drawbacks are bleeding and expense.  The drug was tested extensively in Europe and proved to be safe but it has been on the US market for less than six months. While Coumadin costs pennies per tablet, Pradaxa costs about $300 per month. It requires taking a pill twice per day.

It is clear that thrombin inhibitors like Pradaxa will one day replace Coumadin. For now I prefer to have other physicians’ patients use it and compile a safety record before I try it on my patients. We know the pros and cons of Coumadin.  Let Pradaxa survive the test of use on the US market, and time, and show a clear cut safety advantage before giving it to our patients locally.