Rivaroxaban and bleeding

Reviewed and revised 10 July 2014 – based on a summary by James Hayes

OVERVIEW

  • an orally active direct Factor Xa inhibitor (a n example of a NOACs or “New Oral Anticoagulants”)
  • Examples of currently available NOACs are:
    • Rivaroxaban (Xarelto)
    • Dabigatran etexilate, (trade name, Pradaxa)
    • Apixaban (Eliquis)

INDICATIONS

  • Prevention of VTE following elective hip or knee replacement
  • Treatment of acute VTE and prevention of subsequent VTE (for pulmonary embolism and deep vein thrombosis)
  • Non-valvular AF and a high risk of stroke or systemic embolism

PREPARATIONS

  • Tablets: 10, 15, 20 mg

MECHANISM OF ACTION

  • orally active direct Factor Xa inhibitor

PHARMACOKINETICS

  • Absorption: rapid oral absorption
  • Distribution: plasma protein binding is high, at around 95%
  • Metabolism: about 2/3 is metabolised by the liver
  • Elimination: About 1/3 is renally excreted unchanged; t1/2 is  5 – 9 h (11-13h in the elderly)

RISK ASSESSMENT

History

  • time of last dose
  • dose taken
  • indication for rivaroxaban

Risk factors for adverse events with rivaroxaban include:

  • Age older than 75 years
  • Low body weight (less than 50kg)
  • Moderate or severe renal impairment (Creatinine Clearance < 50mL/min).

Mild bleeding

  • Local soft tissue hematomas or bleeding from minor wounds to non-life threatening regions

Moderate to severe bleeding

  • Reduction in Hb of 20g/L
  • Transfusion of 2 units of RBCs
  • Bleeding into critical regions
    • Intraocular
    • Intracranial
    • Intrapulmonary
    • Pericardial space
    • GI tract
    • Retroperitoneum
    • Peri or Intraspinal
    • Major muscle group with resulting compartment syndrome.

Life-threatening bleeding

  • uncontrolled progression of the above with worsening symptoms
  • Reduction in Hb of 50 g/L
  • Transfusion of 4 units of RBCs
  • Circulatory shock
  • Bleeding that requires surgical intervention

The above considerations should also take into account comorbidities and other situational facotrs

INVESTIGATIONS

In the patient with clinically relevant bleeding:

  • FBC (Hb, platelets)
  • Coagulation profile
    •  unlike dabigatran rivaroxaban does not prolong the thrombin clotting time
    • prothrombin time (PT) using thromboplastin that is rivaroxaban sensitive (e.g. (such as Triniclot PT Excel S, Neoplastin R and Recombiplastin) is the most sensitive test for detecting rivaroxaban activity, a normal PT suggests the level is not high, but does not exclude it
    • APTT and PT cannot estimate the intensity of rivaroxaban anticoagulation
  • Anti-Factor Xa activity (a drug specific anti-factor Xa chromogenic assay is sensitive for quantitative measurement of rivaroxaban effect)
  • UEC, glucose, Ca
  • Calcium level
  • Blood group and hold or Cross match as clinically indicated.

MANAGEMENT

Attend to life threats and consult a haematologist and/or clinical toxicologist

Mild bleeding

  • Stop rivaroxaban and other anticoagulants
    • recommencement depends on severity of bleeding, ongoing risk factors (e.g. anatomical lesions, persisting renal dysfunction) and the original indication
  • control bleeding using local measures
  • close montioring and observation

Moderate-to-severe bleeding

  • as for mild bleeding plus additional measures
  • activated charcoal if last dose <2h previously and no airway compromise
  • RBC transfusion as indicated
  • platelet transfusion if < 50 x 10E9/ L or on anti-platelet agents

Life-threatening bleeding

  • Consider tranexamic acid 15-30mg/kg IV  then 1 mg/kg/h infusion
  • Consider prothrombinex-VF (efficacy uncertain) 50 U/kg IV (or 8 x 500 unit vials for an average 80kg patient).
  • Consider  FEIBA 50 IU/kg (contains factors 2,7,9 an 10 in predominatly inactivated form as wellas activated factor 7 and 1-6 units of Factor VIII coagulant antigen (FVIII C:Ag) per mL)

COMPARISON WITH DABIGATRAN

  • Different indications for use
  • Different site of action (dabigatran is a direct competitive thrombin inhibitor)
  • Different laboratory investigations required in cases of toxicity (rivaroxaban does not prolong the thrombin clotting time, which dabigatran does)
  • Dialysis has no role in rivaroxaban removal

COMPARISON WITH WARFARIN

Pros

  • Fast onset of action (within 2 hours); thereby potentially negating the need for initial treatment with a rapidly acting injectable anticoagulant.
  • Fast offset of action: anticoagulant effect lasts 12 hours, compared with 48-72 hours
  • Predictable response:  routine coagulation monitoring is not required – avoids the need for repeated blood tests to monitor activity, and adjust dosages that warfarin therapy requires

Cons

  • Routine coagulation monitoring tests (APTT / PT / INR) are not useful indicators of the anticoagulant effect of Rivaroxaban
  • No specific antidote for drug reversal (warfarin has vitamin K and Prothrombin X,  heparin has protamine)
  • Administration of blood clotting products has limited effectives in reversing rivaroxaban effects, s it inhibits factors rather than depletes them (as warfarin does)

References

LITFL

Journal articles

  • Bauer KA. Pros and cons of new oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2013;2013:464-70. doi: 10.1182/asheducation-2013.1.464. PubMed PMID: 24319220. [Free Full Text]
  • Tran H, Joseph J, Young L, McRae S, Curnow J, Nandurkar H, Wood P, McLintock C. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Intern Med J. 2014 Jun;44(6):525-36. doi: 10.1111/imj.12448. PubMed PMID: 24946813.

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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