Dr. Steve Wong (biography and disclosures)
What I did before
I recognized that atrial fibrillation is the most common arrhythmia in the world, affecting nearly 3-5% of patients older than 70. Most are asymptomatic, yet atrial fibrillation can account for up to 30% of strokes in patients > 80 years old. In addition, strokes from atrial fibrillation tend to be larger and more prone to hemorrhagic transformation.
I routinely recommend warfarin for stroke prophylaxis for patients with a CHADS score ≥ 2 (see below) given its much greater stroke reduction vs aspirin (~66% relative risk reduction with warfarin vs. ~33% relative risk reduction with ASA). Warfarin, although very effective, is hardly anyone’s favorite drug: its narrow therapeutic window is a challenge, and the need for laboratory testing (patient & clinician time, lost productivity), dose adjustment, accounting for food and drug interactions are huge challenges. The low cost of warfarin itself belies its larger cost to society and the health care system in general.
What changed my practice
Over the years, several different agents to replace warfarin were disappointing: they were associated with major adverse bleed risks, liver failure or were inferior. Dabigatran is the first oral direct thrombin inhibitor to make it to the market. This drug does not require monitoring, has few food & drug interactions, and is currently being used in the post-orthopedic surgery prophylaxis arena as an alternative to low molecular weight heparin.
In late 2009, the RE-LY study was published. This was the largest-ever trial of anticoagulation in atrial fibrillation (n=18,113), comparing warfarin against dabigatran at doses of 110 mg bid or 150 mg bid. Patients were followed for 2 years, comparing the primary endpoint of stroke & systemic embolization as well as bleeding rates.
RE-LY demonstrated that dabigatran 110 mg bid was noninferior to warfarin (relative risk (RR) 0.91 (CI 0.74-1.11)) yet had a 22% reduction in total bleeding (RR 0.78, p <0.001) and a 32% reduction in life-threatening bleeding (RR 0.68, P <0.001). At 150mg BID, dabigatran was actually superior to warfarin, achieving a 34% reduction in the primary endpoint (RR 0.66, NNT 200, p<0.001) and met criteria for superiority over warfarin (not ‘just’ non-inferiority). At the 150 mg bid dose, dabigatran was associated with a 9% reduction in total bleeding (RR 0.91, p=0.002) and a 19% reduction in life-threatening bleeding (RR 0.81, P=0.037).
It should be noted that RE-LY did show more GI side effects with dabigatran (dyspepsia, ~11-12% vs 5.8% on warfarin) and GI bleeding (1.12% per year at 110 mg bid, 1.51% per year at 150 mg bid vs 1.02%/yr warfarin). Again, note that life-threatening bleeding was lower in both dabigatran groups.
Although not in the scope of this article, the RE-COVER trial looked at dabigatran 150mg bid vs warfarin in thromboembolic disease with very similar findings (equal to warfarin, lower bleed rate).
What I do now
I now strongly consider using dabigatran instead of warfarin in patients with a CHADS score of 2 or higher (see below). The 2 doses allow a choice of efficacy vs bleeding with both doses (110mg bid vs 150 mg bid) being either much safer or somewhat safer than warfarin.
CHADS score in non-valvular Atrial Fibrillation:
1 point for: CHF, Hypertension, Age >75, Diabetes,
2 points for prior Stroke.
Suggest warfarin or dabigatran for CHADS score ≥2, Warfarin or dabigatran > ASA for CHADS score = 1, ASA for CHADS score = 0.
|Annual Stroke risk %
I feel the time savings to patients and clinicians (no monitoring required), clinical efficacy and safety vs warfarin and fewer drug interactions make this a huge innovation in clinical practice.
Although not specifically studied, given its cost, dabigatran may be a very reasonable option for patients who need a temporary refrain from testing (eg. traveling abroad). I’ve had many patients express anxiety over how they would monitor their INRs when traveling – a special challenge given costs, time constraints, lack of access to medical care and changing diet and bowel habits.
While my opinion may seem enthusiastic for a new drug based on a single trial, it should be noted that the RE-LY study is the largest ever done, encompassing more patients than all the warfarin studies to date. It will not be repeated.
In addition, a preview of the Canadian Cardiovascular Society’s new 2011 Atrial fibrillation guidelines endorses dabigatran in preference to warfarin (we await the final publication):
- Based on its safety and efficacy profile, dabigatran is preferred over warfarin. Overall, the 150-mg dose of dabigatran is preferred over the 110-mg dose (conditional recommendation, high-quality evidence).
- For patients at low risk of stroke (CHADS2 score=1), treatment should include either warfarin or dabigatran (strong recommendation, high-quality evidence). However, based on individual risk/benefit considerations, aspirin is a reasonable alternative (conditional recommendation, moderate-quality evidence).
- For patients at moderate to high risk of stroke (CHADS2>2), treatment should include either warfarin or dabigatran (strong recommendation, high-quality evidence).
Dabigatran just received approval for use in Canada for atrial fibrillation at the end of October 2010. The monthly cost will be around $100 at either dose (not currently covered by Pharmacare nor via special authority).
References: (Note: Article requests require a login ID with UBC)
- RE-LY trial (dabigatran in AFib). N Engl J Med 2009;361. (10.1056/NEJMoa0905561) (View article with UBC or http://www.nejm.org/doi/pdf/10.1056/NEJMoa0905561)
- RE-COVER trial (dabigatran in PE & DVT). N Engl J Med 2009;361.(10.1056/NEJMoa0906598) (View article with UBC or http://www.nejm.org/doi/pdf/10.1056/NEJMoa0906598)
- CCS guideline preview: http://www.theheart.org/article/1141079.do
- Dabigatran cost-effectiveness: http://www.theheart.org/article/1142417.do
Article request form with CPSBC Library: https://www.cpsbc.ca/library/library-article-requests