Editor's Note: Dr. Ganetsky and colleague  published a very well written article this week in the Journal of Medical Toxicology. Dabigatran’s dosing and management is important for kidney doctors to be aware of – as Dr. Ganetsky discusses in the post below.


Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral Anticoagulant.

Michael Ganetsky, MD
Director, Medical Toxicology Consult Service,
Department of Emergency Medicine, Beth Israel Deaconess Medical Center
Instructor, Harvard Medical School
 

Case Study

He is a 66 year old male with ischemic cardiomyopathy, diverticulosis and paroxysmal atrial fibrillation for which he was prescribed Pradaxa (dabigatran etexilate), a novel oral anticoagulant which received FDA approval in October 2010 for prevention of embolic stroke in patients with non-valvular atrial fibrillation.

This patient had been aggressively diuresed for weight gain and presented to me hypotensive, having rectal bleeding, an acute hematocrit drop and acute on chronic renal failure. After transfusion of 2 units of PRBC's, crystalloid and close observation in the ICU, his blood pressure, hematocrit, lower GI bleeding and creatinine had all improved after 24 hours.

So what precipitated this patient's bleeding?

To answer this, we need to take a closer look at the pharmacology and pharmacokinetics of dabigatran. Dabigatran is a reversible, potent, competitive direct thrombin inhibitor. Dabigatran exhibits predictable and linear dose-dependent anticoagulation, leading to both the fixed dose regimen and lack of required hematologic monitoring as compared to warfarin. It is not metabolized by nor does it affect the cytochrome P450 system so drug-drug interactions are minimal. In patients with normal renal function, approximately 80% of an intravenous dabigatran dose is excreted in urine with an elimination half-life of 12-17 hours. Renal impairment increases the elimination half-life to 15-34 hours and dabigatran accumulates in acute renal failure and moderately increases bleeding risk.

In a pharmacokinetic study of patients with end stage renal disease, hemodialysis removes 62% of dabigatran at 2 hours and 68% at 4 hours.  In patients with a creatinine clearance of 15-30 mL/min, it is recommended that daily dosing be cut in half (to 75mg BID) and it is not 
recommended in patients with a creatinine clearance less than 15 mL/min.

Dabigatran differs from conventional warfarin-based anticoagulation therapy in several important ways. The stable hematologic response to dabigatran makes frequent laboratory monitoring of clotting parameters unnecessary, an appealing feature for many patients and providers. In large clinical trials, patients taking dabigatran had either similar or less rates of major bleeding as compared to warfarin. In the RE-LY trial, dabigatran actually produced a non-significant dose-response improvement in mortality. On a population basis, dabigatran clearly seems superior to warfarin and it received a class I recommendation as an alternative to warfarin from the American College of Cardiology and the American Heart Association in February 2011.However when taking care of an individual with dabigatran-induced bleeding, we have little clinical experience and no therapeutic agent reliably reverses hemorrhagic complications of dabigatran therapy as FFP and vitamin K do with warfarin.

Management of dabigatran-induced bleeding complications should start with local control if possible and transfusion of PRBC's if needed. Transfusion of FFP and Vitamin K administration is generally considered ineffective, but may be given if a concomitant factor deficiency is suspected. 

Both recombinant activated Factor VII and activated prothrombin complex concentrates  have shown promising results in animal models of dabigatran-induced bleeding, however human experience is both mixed and lacking.

rFVIIa and APCC should be considered as rescue therapy for active bleeding even though data is limited and potential exists for ischemic complications.
Fortunately, the half-life of dabigatran is short-enough that most bleeding can be managed supportively.

Although a duration of bleeding that corresponds to dabigatran's elimination half-life of 12 to 17 hours may not be lethal in gastrointestinal hemorrhage, this duration of bleeding into the intracranial or spinal spaces would be devastating. As such, several authors have recommended hemodialysis for situations where supportive care would not be sufficient. The goal of hemodialysis would be to rapidly increase serum dabigatran elimination; although published human experience is lacking, pharmacokinetic evidence suggests that hemodialysis would provide significant benefit since the degree of anticoagulation is correlated with serum concentrations. Let's revisit the patient discussed earlier. Most likely he developed pre-renal azotemia from increased diuretic use, leading to dabigatran accumulation and diverticular bleeding. As he was resuscitated, his renal function improved, he was able to clear the dabigatran and his bleeding stopped. He required no other blood product transfusions and did well.

As the use of this novel oral anticoagulant grows, we are going to see many more patients with dabigatran-induced bleeding and we need to develop greater clinical experience and further study management of bleeding complications.

__________

Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral

Anticoagulant. J Med Toxicol. 2011 Sep 2. [Epub ahead of print] Link