An alternative to warfarin for A. fib? ; The Great Influenza

Dabigatran for atrial fibrillation

The NEJM recently published a lead article (http://content.nejm.org/cgi/content/full/361/12/1139) which compared dabigatran to warfarin in patients with atrial fibrillation. Dabigatran belongs to a new class of oral anticoagulants known as DTI’s (direct thrombin inhibitors) which are in development. (See my Heme-O-Gram of Dec. 14 ’08 http://adrounysheme-o-gram.blogspot.com/2009/03/new-oral-anticoagulant-drugs-report.html )

While the effectiveness of warfarin for stroke prevention in atrial fibrillation is in little doubt, warfarin is probably underutilized because of a number of reasons primarily relating to inconvenience and risk of bleeding. Drugs like dabigatran offer several advantages over warfarin: fixed dose, shorter half-life, no need for monitoring, wide therapeutic index, oral administration, general convenience. The question is whether it meets non-inferiority with a tried and true agent like warfarin. Previously, dabigatran was shown to be as effective and safe as enoxaparin (Lovenox) in reducing VTE after orthopedic surgery.

The RE-LY (Randomized Evaluation of Long-Term Anticoagulation) trial, which accrued and randomized over 18,000 patients, the standard of non-inferiority for atrial fibrillation appears to have been met with respect to the primary outcome, either stroke or systemic embolism. The study was funded by Boehringer Ingelheim, the manufacturer of dabigatran. Two doses of dabigatran were studied: 110 mg and 150 mg each given b.i.d. The 18,000 patients were evenly matched across the three study groups.

The lowest rate of stroke/systemic embolism occurred in the group receiving dabigatran 150 mg bid (1.11. % per year compared to 1.69% for warfarin and 1.53% for dabigatran 110 mg bid.) Both dabigatran doses were non-inferior to warfarin but only the higher dose was superior. Bleeding rate was highest in the warfarin group (3.36% per year) and lowest in the dabigatran 110 mg bid group (2.71% per year). In the dabigatran 150 mg bid group, the rate was 3.11% per year.

The only significantly increased adverse effect in the dabigatran treated patients was dyspepsia. There were higher rates of myocardial infarction in the dabigatran groups, but not statistically significant. The authors hypothesize that warfarin may have a more protective effect in coronary disease than dabigatran.

There were also higher rates of discontinuation in both dabigatran groups, apparently because of GI symptoms and other unspecified serous adverse events. The authors do not go into any detail to explain the latter.

The quality of warfarin administration was good, as evidenced by a 64% rate of therapeutic INR in the warfarin treated group.

In conclusion: dabigatran appears to be non inferior to warfarin both in terms of efficacy and complications for prophylaxis of stroke and systemic embolism in patients with atrial fibrillation. As part of a new class of oral anticoagulants, dabigatran appears to be headed towards approval for use in a variety of settings. Keep yours eye open for this new drug.

Hemorrhagic complications of influenza

“Then there was the blood, blood pouring from the body. To see blood trickle, and in some cases spurt, from someone’s nose, mouth, even from the ears or around the eyes, had to terrify.

“One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred.

“One German investigator recorded ‘hemorrhages occurring in different parts of the interior of the eye’ with great frequency. An American pathologist noted: ‘Fifty cases of subconjunctival hemorrhage were counted. Twelve had a true hemoptysis, bright red blood with no admixture of mucus…Three cases had intestinal hemorrhage…’

These frightening descriptions of “the flu” come from the book The Great Influenza by John M. Barry, an outstanding treatise on the history of the 1918 flu pandemic and the history of American medicine and its response to the medical emergency posed by the pandemic. With current concerns about H1N1 virus, it made me wonder if we might expect similar dramatic clinical manifestations.

But surprisingly (and happily), clinical descriptions of the current H1N1 flu outbreak, which conceivably has the potential to reach pandemic levels, are surprisingly tame with respect to hematologic complications. Both mild leukocytosis and leucopenia have been seen according to reports. A substantial incidence of pulmonary embolism was reported in five of 10 ICU patients hospitalized with H1N1 and ARDS in Michigan and “hypercoagulable state” was reported to be evident in two additional patients. Otherwise, there seems little to report. I will keep watch on this.