Bleeding and Anticoagulated, Part 2; Rivaroxaban

Another new and novel anticoagulant that is gaining great traction is Rivaroxaban. This inhibitor of factor Xa is currently approved in Canada for prevention of venous thromboembolism following major hip or knee surgery. It is also gaining ground in off label uses specifically for prophylaxis of stroke in atrial fibrillation, and while this is not yet an approved indication there early studies showing non-inferiority to Coumadin, with similar (possibly better) profile of bleeding risk.

 

Like all anticoagulants the downside is the bleeding risk. A friend of mine, involved with an early trial of Rivaroxaban vs. placebo put it this way; ‘The trial was blinded but the Rivaroxaban patients all had a little trail of blood following them around.’ While this is an exaggeration it is also a reminder that whenever a new anticoagulant becomes available we must also adapt new strategies to treat resulting bleeding complications.

 

Rivaroxaban is the first commercially available oral inhibitor of Factor Xa in Canada. It has excellent GI absorption and it’s inhibition of Xa lasts up to 24 hours allowing easy dosing. Per the manufacturers suggestions there is no need for dose adjustments nor for monitoring of coagulation parameters. Metabolism and excretion are mixed with about half of the drug excreted unchanged in urine and feces and half metabolized prior to excretion. The drug is contraindicated in patients with moderate to severe renal impairment (Creatinine clearance less than 15ml/min) moderate to severe hepatic impairment, elevated INR, or with azole antifungals or HIV protease inhibitors.

 

The bleeding patient who is currently on Rivaroxaban presents a particular challenge. There is limited data suggesting that prothrombin complex concentrate (which contains factor X) and recombinant factor VIIa may have a role in patients with life threatening bleeding.

 

As we discussed in Part 1: Dabigatran, it is imperative that these patients receive early consultation (likely phone consultation) with a hematologist as well as meticulous treatment for all elements of their bleeding. Whenever possible early surgical, endoscopic or interventional radiology control of the bleeding site should be obtained. Resuscitation with balanced blood products rather than crystalloids is likely warranted. Correction of hypothermia and acidosis is of upmost importance, and the presence of other anticoagulants (ASA, clopedigrel, etc.) or auto-anticoagulation (liver disease) should be considered and corrected.

 

In spite of meticulous care and attempted reversal with PCC or rFVIIa some of these patients will continue to bleed and will have poor outcomes.

Bleeding and Anticoagulated, Part 1: Dabigatran

Bleeding patients present all sorts of dilemmas in emergency medicine, but perhaps the most gut wrenching is the patient bleeding on anticoagulant medication. Dabigatran is the latest anticoagulant on the market and is sure to give emergency doctors everywhere headaches.

Dabigatran (Pradaxa) is the most recently released oral anticoagulant. It has become popular as an alternative to Coumadin/Warfarin because there is no need for blood level monitoring. It is a direct thrombin inhibitor (though the suffix-an in other anticoagulants tends to imply Xa inhibition it has no Xa activity). It is approved for prevention of thromboembolism for non-valvular atrial fibrillation, and it is also being used widely for off label indications such as venous thromboembolism, pulmonary embolism, thrombophillias, and post operative prophylaxis.  Dabigatran has a fairly short half life, 7-9 hours initially stretching to 12-17 hours with chronic use. It is therefore taken as a BID medication.

There is no antidote for dabigatran. It has a low volume of distribution and is dialyzable, though this is probably more important in overdose than in life threatening bleeding. Various sources recommend fresh frozen plasma, prothrombin complex concentrates (PCC/Octaplex) and recombinant factor use in the critically bleeding patient on dabigatran.

In general there is not yet a consensus of how to manage the patient taking dabigatran who presents with life threatening bleeding.

My own view is that these patients need prompt and aggressive management including the following steps:

  1. Mechanical control of the bleeding should be attempted by whatever means necessary, including early endoscopy, surgical consultation and interventional radiology consultation.
  2. Specialist consultation should occur very early.
  3. Baseline PT, PTT and INR should be drawn and then monitored. They will be elevated and difficult to interpret due to dabigatran, but further worsening from baseline suggests further coagulopathy (ie. consumptive or dilutional coagulopathy).
  4. Consider early used of balanced blood products rather than crystalloids in in an effort to prevent further coagulopathy.
  5. Consider treatments that will optimize coagulation; prevention of hypothermia and correction of acidosis.
  6. Consider the presence of other anticoagulants especially aspirin, and auto-anticoagulation such as cirrhotic liver disease and correct these.
  7. In life threatening bleeding consider treatments such as fresh frozen plasma 30ml/kg, or prothrombin complex concentrate, but realize that these may not help.