Tuesday, June 12, 2012

Pradaxa: The Science Behind the Medicine—Part One

What is Atrial Fibrillation?

Pradaxa is a prescription drug manufactured by Boehringer Ingelheim which is most commonly prescribed for symptoms of atrial fibrillation. Atrial fibrillation is a condition in which the two upper chambers of the heart slowly begin to fail to rhythmically contract. These chambers then flutter in an irregular manner, which, in some cases, has little effect on the overall health of the patient other than a modest reduction in cardiac output. In other patients these irregular heart contractions can lead to blood clots which can potentially travel to the lungs or brain. Should a clot occur, the results can be irreversible and even potentially life-threatening. As many as two million people per year develop deep vein thrombosis and subsequent blood clots, with over 200,000 of those dying from the clots.

Warfarin Used for Over Half a Century

The anticoagulant Warfarin has been the standard of care in the treatment of atrial fibrillation for fifty-seven years. Warfarin works by preventing the activation of four of the body’s clotting factors which depend on Vitamin K—and in cases of excessive bleeding, a dose of Vitamin K can generally reverse the effects of Warfarin fairly quickly. Even though Warfarin has been shown to reduce the stroke risk caused by clots which form from atrial fibrillation it also has a history of causing incidents of serious bleeding, most particularly intracranial hemorrhage and hemorrhagic stroke. In fact, when Warfarin was compared to an aspirin regimen Warfarin was found to double the risk of intracranial hemorrhage.

The Downside of Warfarin

Warfarin, aside from the risk of excessive bleeding, has a history of negative interactions with other drugs, including antibiotics, anti-depression medications as well as a variety of other drugs. Warfarin has also been found to interact in a negative manner with a variety of foods. Those taking Warfarin are warned to never eat grapefruit or drink grapefruit juice as they can seriously affect the manner in which the body metabolizes Warfarin. Alcohol can change the body’s response to Warfarin as can avocados, dried basil, thyme and oregano, margarine, mayonnaise and Vitamins A, E and C.

Additionally, many herbal supplements can have a negative interaction with Warfarin, so those taking the drug must give their physician a complete list of any supplements and medications they are currently taking. In order to establish appropriate blood serum levels of Warfarin, blood tests must be taken every one to four weeks in order to reach the optimal level of anti-coagulation. Unfortunately, the standard INR blood test fails to provide an entirely accurate measurement of exactly how much anti-coagulation is taking effect in the body. Even with all the downsides, Warfarin remained the drug of choice—and actually the only drug in its class available—largely due to the fact that there is a ready antidote until the advent of Pradaxa.

The Arrival of Pradaxa

When Pradaxa was approved by the FDA in October of 2010, it was the first oral anticoagulant approved as an alternative to Warfarin in 57 years. Unlike Warfarin which prevents clotting factors dependent on Vitamin K, Pradaxa works as a direct thrombin inhibitor. Thrombin is a clotting factor in the blood which is necessary for proper blood clotting and is responsible for converting fibrinogen to fibrin. Heparin and warfarin are the only indirect thrombin inhibitors used in the management of strokes; although heparin works quickly and warfarin is orally available, there are nonetheless limitations in their ability to effectively inhibit thrombin.

For this reason, Pradaxa was hailed an excellent alternative to Warfarin as it eliminated the need for INR blood testing and appeared to have few drug or food interactions. Pradaxa produces a predictable delay in clotting times, typically achieved within two hours of oral ingestion with steady concentrations in the blood reached within two to three days. In fact in patients with normal kidney functions, the anticoagulant effects of Pradaxa are reduced by approximately 50% at twelve hours following oral administration and 25% at twenty-four hours following oral administration. This relatively rapid “drop-off” time is actually the only antidote known for Pradaxa. By the end of 2011, over 272,000 outpatient prescriptions for Pradaxa had been dispensed and Boehringer Ingelheim was riding high on its apparent success.

Efficacy and Bleeding Risk of Pradaxa

A study known as the RE-LY study followed over 18,000 patients for a median period of two years, resulting in the approved 150 mg. of Pradaxa taken twice daily. At this dosage Pradaxa was shown to be highly successful in lowering the risk of strokes in those with atrial fibrillation as compared to Warfarin, however in cases where patients were diligent with their INR monitoring while on Warfarin, the margin for success narrowed between the two drugs. According to the NIH, the rate of intracranial hemorrhage with Warfarin was greater than the rate of Pradaxa, suggesting an important advantage of Pradaxa over Warfarin.

Despite the apparent superiority of Pradaxa, the down side soon became apparent. At the approved rate of 150 mg twice daily, there appeared to be a significant increase in the number of major GI bleeds despite the overall lower incidence of bleeding at other sites. This risk of excessive bleeding appeared to be much more serious in the elderly, especially those who were over the age of 80. Further, it was discovered that there was a greatly increased risk of excess bleeding in patients taking either Pradaxa or Warfarin while also taking aspirin or Plavix. There also appeared to be a difference the location of GI bleeds between Warfarin and Pradaxa patients.

Those patients who experienced serious GI bleeds while taking Warfarin experienced those bleeds in the upper GI tract three-quarters of the time. Pradaxa users experienced upper and lower GI bleeds almost equally. Other adverse symptoms among those taking Pradaxa included dyspepsia and gastritis, leading to a fairly high rate of patient discontinuation. It is believed these GI events are a result of how the drug is delivered. The specific drug-delivery system of Pradaxa will be discussed in greater detail in part two of the discussion of the science behind the medicine of Pradaxa.

Author: Sullo & Sullo Attorneys

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