Sunday, June 10, 2012

A Review of Pradaxa: Part 2 - Questionable Efficacy and Study Limitations

Pradaxa is a drug which is a newcomer into the pharmaceutical marketplace, used in the treatment of atrial fibrillation and the subsequent prevention of strokes. The only drug of its kind, Warfarin, has been in use as an anticoagulant and to treat atrial fibrillation for over half a century—since 1957. Although Pradaxa’s manufacturer, Boehringer Ingelheim, boasts Pradaxa is far superior to Warfarin in the prevention of stroke as well as prevention of systemic embolism, a flurry of adverse reports have come into the FDA regarding the incidence of excessive bleeding, particularly in the GI tract. It appears that especially in those over the age of 75, Pradaxa can have some very serious side-effects.

Warfarin works by preventing the activation of four major clotting factors in the blood, all of which are dependent upon Vitamin K. For this reason, in the event that Warfarin creates an excessive bleed in a patient, Vitamin K can be administered to reverse the anticoagulant effects and halt the bleeding. Warfarin, while reducing the risk of blood clots caused by atrial fibrillation can cause excessive bleeding, but doctors are much more likely to be able to stop the bleeding. Pradaxa, on the other hand, has no known antidote, therefore if a patient presents in an ER with severe bleeding as a result of Pradaxa, there is little the doctors can do. In recent months the limitations of the various Pradaxa studies have been questioned, as well as its overall efficacy as compared to Warfarin.

RE-LY Study

The study which gained Pradaxa its FDA approval in October, 2010, was called the RE-LY study, and included over 18,000 patients being treated for atrial fibrillation. Patients were randomized to receive one of three treatments for twenty-four months, including 110 mg. of Pradaxa twice daily, 150 mg. of Pradaxa twice daily or adjusted dose Warfarin. Stroke or embolism occurred in 182 patients on the lower dosage of Pradaxa, 134 patients on the higher dosage of Pradaxa and 199 patients who were receiving Warfarin. The rates of myocardial infarction was higher in both Pradaxa groups than in the Warfarin group, and both the Warfarin group and the group taking 150 mg of Pradaxa showed increased risks of major bleeds. Over 11% of both Pradaxa groups suffered gastrointestinal problems as compared to 5.8% in the Warfarin group.

Limitations of the RE-LY Study

The patients in the RE-LY study were allowed to use other anticoagulants during the study such as aspirin, however the use of such drugs were not noted at the baseline or follow-up to the study. Further, the study was entirely funded by the manufacturer of Pradaxa, Boehringer Ingelheim. Many experts feel this is a clear conflict of interest. The final results of the study showed that treatment with the higher dosage of Pradaxa resulted in lower rates of stroke and embolism as well as intracranial bleeding, but higher rates of gastrointestinal bleeding as compared to Warfarin.

The American Journal of Cardiology Study

A 2007 double blind, randomized trial comparing Pradaxa with or without accompanying use of aspirin to Warfarin alone. The study reported in the American Journal of Cardiology was performed with 502 patients in Denmark, the Netherlands, Sweden and the United States. Three dosages of Pradaxa—50 mg. twice daily, 150 mg. twice daily and 300 mg. twice daily—were combined with no aspirin, 81 mg. of aspirin or 325 mg. of aspirin, then compared to Warfarin. The study only lasted 12 weeks and the goal was to determine whether there was a dose-related incidence of bleeding. Major hemorrhages were seen in those taking the highest does of Pradaxa plus both strengths of aspirin, leading the Safety Monitoring Board to remove aspirin from those taking the highest doses of Pradaxa. Total bleeding events were higher in both the 150 and 300 mg. Pradaxa users, regardless of aspirin ingestion. The limitations were the duration of the trial and the fact that the trial was largely comprised of men. Almost 2/3 of the participants had a history of coronary artery disease, almost 75% were smokers and 70% were younger than 75. Again, this study was funded by Boehringer, creating a conflict of interest.

RE-COVER Study

A six-month, randomized, double blind parallel group study was performed on 2564 patients with deep-vein thrombosis from 29 different countries. About half of those were given Pradaxa while the other half were given Warfarin for six months. Twenty patients in the Pradaxa group suffered major bleeding episodes while 24 patients in the Warfarin group had major bleeding episodes. 115 patients in the Pradaxa group as compared to 86 patients in the Warfarin group suffered an adverse event which led them to discontinue taking the drug. The limitations in this study were that over 95% of the participants were white meaning efficacy in other ethnic groups was not tested. Once more, Boehringer Ingelheim funded the study, also employing many of the investigators and authors.

Conclusions

It is clear that a major hindrance to all three studies comparing Warfarin to Pradaxa suffered under the fact that they were funded and carried out by the manufacturer of Pradaxa. The conclusions regarding the two anticoagulant drugs are that Warfarin, although still carrying a risk of excessive bleeding events, has a ready antidote meaning that in the event of uncontrolled bleeding, Vitamin K can be administered to stop the bleeding. Pradaxa has no such antidote. Warfarin suffers under the problem of full patient compliance due to the necessity of constant monitoring as well as the fact that there are many other drugs as well as foods and herbal supplements which can have an adverse reaction with Warfarin.

Pradaxa doesn’t require monitoring and has few known interactions to other prescription drugs, foods or herbal supplements. While intracranial bleeds appear to decrease with Pradaxa, gastrointestinal bleeds increase. There is a high rate of drug discontinuation in Pradaxa users, and those with any sort of renal impairment, should use caution when taking Pradaxa. Those who are tolerating a Warfarin drug regimen should likely remain on this therapy, while for select others, Pradaxa may be a viable alternative.

**Study Facts and Results taken From: http://pharmacy.hsc.wvu.edu/wvcdhi/MediaLibraries/Pharmacy-WVCDHI/Media/Documents/PDF/Monographs/Pradaxa-Monograph-final-version1.pdf

Author: Sullo & Sullo Attorneys

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