Dabigatran and Bleeding

Sara Dempsey, PharmD Candidate; Kathryn Samai, PharmD, BCPS

After the approval of the new oral anticoagulant, dabigatran, practitioners raised concerns regarding the bleeding risk. The FDA noted a large number of post-marketing reports regarding bleeding among patients treated with dabigatran. Since dabigatran’s FDA approval, clinicians are eager to know whether or not the post-marketing data is congruent with the rates of bleeding that were published in the preapproval trial (RE-LY trial). Because patients with renal dysfunction were excluded from the RE-LY trial, another concern is whether the use of dabigatran increases their risk of bleeding.

Dabigatran is an oral anticoagulant that acts by inhibiting thrombin. It is FDA approved for the prevention of stroke in nonvalvular atrial fibrillation.¹ In the United States, dabigatran’s approved dosing is 150 mg twice daily in patients with creatinine clearance (CrCl) > 30 ml/min and 75 mg twice daily in patients with CrCl 15-30 ml/min.

In the RE-LY trial, dabigatran was shown to be non-inferior and then later updated showing superiority in reducing ischemic and hemorrhagic strokes relative to warfarin. The incidence of stroke was less with dabigatran (1.5% for 110 mg and 1.1% for 150 mg) than with warfarin (1.7%). Dabigatran also had less patients experience major bleeding than warfarin.  Rates of major bleeding were 3.11 % for dabigatran 150 mg (p= 0.31) and 2.71% for dabigatran 110 mg (p= 0.003) compared to 3.36% for warfarin.⁴

Post-marketing studies have shown a substantial amount of bleeding episodes associated with dabigatran, as evidenced by the number of reports to the Institute for Safe Medication Practices (ISMP). In the first quarter of 2011, there were 505 cases of hemorrhage associated with use of dabigatran,³ exceeding the hemorrhage rate of any other therapeutic agent, including warfarin.  The FDA has investigated reported bleeding events associated with dabigatran, and in November 2012 released a position statement that dabigatran’s bleeding rates appear to be no higher than that of warfarin. The position statement is based on post-marketing data reported to the FDA from October 19, 2010 through December 31, 2011. Both gastrointestinal bleeding and intracranial hemorrhage rates were analyzed. New warfarin users had a 1.6 to 2.2 times higher risk of gastrointestinal bleeding and 2.1 to 3.0 times higher risk of intracranial hemorrhage than new dabigatran users. These calculations were performed using insurance claims and the FDA’s Sentinel Initiative. Rates were calculated by using the number of patients that had a diagnosis of intracranial or gastrointestinal hemorrhage and were new users of warfarin or dabigatran.²

In addition to concerns of post-marketing bleed rates, it is important to address the lack of safety outcomes data in patients with renal dysfunction. Originally, patients with severe renal impairment were excluded from the RE-LY trial.⁴ The renal adjustment recommendation of a dose reduction to 75 mg twice daily for patients with CrCl between 15-30 ml/min is  based on a single-dose, pharmacokinetic modeling and data demonstrating that dabigatran is approximately 80% renally excreted.^1,2

There is no dosing adjustment recommended for patients with mild to moderate kidney function, but somewhat reassuringly, 19% of patients in the RE-LY trial had moderate renal insufficiency (CrCl= 30-49 ml/min). There is still a concern that elderly patients with moderate renal dysfunction may have an increased risk of bleeding with the 150 mg twice daily dosing.¹ A lower dose of 110 mg twice daily for patients older than 80 years has been approved in other countries.³ Canada has also updated their recommendations to contraindicate use of dabigatran in patients with CrCl below 30 ml/min.  One study evaluated case reports of patients that had impaired renal function (CrCl ranging from 15-43 ml/min) and had a bleeding event while receiving dabigatran. It found that these patients had plasma concentrations and coagulation parameters that were higher than what was reported in the RE-LY trial. In addition, two of the five patients sustained bleeding events that were fatal.¹

Although dabigatran has been associated with increased risk of bleeding, it does not appear that this is occurring at rates greater than those seen with warfarin, according to the FDA. To date, practitioners should follow the approved package labeling and reported updates.²

· Continue use of dabigatran 150 mg twice daily in patients with CrCl >30 ml/min

· Continue use of dabigatran 75 mg twice a day in patients with CrCl 15-30 ml/min

· Avoid use of dabigatran in patients with CrCl <15 ml/min or requiring hemodialysis 

More randomized, controlled studies need to be performed, especially studies that specifically look at subpopulations such as elderly patients and those with renal dysfunction. When choosing between starting a patient on warfarin or dabigatran, the decision should be patient specific and many factors need to be taken into account. Patients should be monitored closely for renal function and signs and symptoms of bleeding, especially those that are of advanced age or with renal insufficiency. Reevaluation of anticoagulation management is key as further reports of bleeding with dabigatran become available. A long-term safety trial is anticipated soon (RELY-ABLE).

References:

1. Mack et al. Pharmacokinetic and Clinical Implications of Dabigatran use in severe renal impairment for Stroke Prevention in Nonvalvular Atrial Fibrillation. The Annals of Pharmacotherapy. 2012; 46: 1105-1110.
2. Food and Drug administration. Pradaxa: Drug safety communication-Safety review of post market reports of serious bleeding events. November 2nd 2012. http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm
3. Institute for Safe Medication Practices. QuarterWatch. Monitoring FDA Medwatch Reports Signals for Dabigatran and Metoclopramide. Data from 2011 Quarter 1. January 12, 2012  http://www.ismp.org/quarterwatch/pdfs/2011Q1.pdf
4. Connolly et al. Dabigatran versus warfarin in patients with atrial fibrillation (RELY Trial) New England Journal of Medicine 2009; 361:1139-1151.
5. Beasley et al. Anticoagulant Options — Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran. New England Journal of Medicine 2011; 364:1788-1790