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Oral Anticoagulation Therapies

Vitamin K antagonists

Oral anticoagulants, also called vitamin K antagonists (VKAs), are used to prevent the occurrence or increase of unwanted blood clots. They inhibit enzymes called vitamin K epoxide reductase and vitamin K reductase. These enzymes are required for chemical reduction of oxidized vitamin K.1

The main VKAs are:

  • Warfarin/coumarin (Coumadin®)2
  • Nicoumalone/acenocoumarol (Sintrom®)2
  • Phenprocoumon (Marcumar®; Falithrom®)2
  • Fluindione (Previscan®)3

 

Relevant indications for oral anticoagulation therapy

 

While hemostasis is necessary for survival, the pathological formation of a blood clot, or thrombosis, poses significant health risks. The main indications for a patient to receive vitamin K antagonists (VKAs) are the following:1,2,4,5

 

  • Mechanical heart valves
  • Atrial fibrillation
  • Venous thromboembolism, i.e. deep vein thrombosis and pulmonary embolism
  • Myocardial infarction
  • Acute ischemic stroke

 

Oral anticoagulants are effective for primary and secondary prevention of venous thromboembolism; for prevention of systemic embolism in patients with prosthetic heart valves or atrial fibrillation; for prevention of acute myocardial infarction (AMI) in patients with peripheral arterial disease and patients otherwise at high risk, for prevention of stroke, recurrent infarction and to reduce mortality in patients with AMI.

Physicians are reluctant to prescribe warfarin, in part because they fear that the drug will cause bleeding. Patients treated with warfarin do require close monitoring to avoid bleeding.6 It has been shown that the drug significantly reduces stroke rates and for these indications, a moderate anticoagulant intensity (range, INR 2.0-3.0) is recommended.7

Remarks

  • Some countries use warfarin, while others use different VKAs, such as acenocoumarol or phenprocoumon. These VKAs have a shorter (acenocoumarol) or longer (phenprocoumon) half-life, and are not completely interchangeable with warfarin.
  • Generic VKAs are sold in some countries; these are also not totally interchangeable to warfarin
  • VKAs can be administered orally. They have a narrow therapeutic window, have a slow onset of action and may have unpredictable pharmacology. In addition, many foods and drugs interact with VKAs. As a result, periodic blood tests and dose adjustments are necessary to maintain the optimal degree of anticoagulation.1
New anticoagulants on the market

In the last few years, several new drugs have been approved for anticoagulation use that offer the following benefits:2,4

 

  • Do not require monitoring
  • Wider therapeutic index
  • Simplified kinetics
  • More rapid onset/offset
  • Fewer or absent drug and food interactions

 

Dabigatrain, Rivaroxaban and Apixaban demonstrated non-inferiority with warfarin in prevention of stroke and systemic embolism.  Secondary analyses demonstrated superiority for apixaban and dagibatran 150mg dose. 

In each of these studies the warfarin group were monitored using the Usual Care model.  As seen elsewhere in this site, warfarin patients that self-monitor once per week or every other week experience dramatic increases in TTR with decreases in adverse events compared to patients managed in under Usual Care.

Considerations for choosing an anticoagulant regimen

The following patient related factors are important.

  • Risk of bleeding8,9
    • HAS-BLED score (≥ 3 points = high risk)9
  • A mechanical heart valve or hemodynamically significant valve disease10
  • Renal function, advanced liver disease, body weight8,10
  • Risk of coronary events or propensity to dyspepsia8
  • Patient compliance and preferences9
  • Ability to safely sustain adjusted chronic anticoagulation9
  • Success on existing anticoagulation therapy10

 

For patients in the following sub-groups therefore, warfarin plus monitoring remains the standard of care:

  • There is a risk of non-compliance11,12
  • There are co-morbidities (hypertension, heart failure, diabetes)12
  • Patients with renal impairment and mechanical heart valve11,12
  • The patient is a child or adolescent or an elder (>75 years)12
  • Where cost is an issue13
  • Patient is intolerant to the new drugs13

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    References

    1. Ansell et al. (2008). Chest 133, 160S-198S 
    2. Singer et al. (2008). Chest 133, 546S-592S 
    3. Chen et al. (2018). Blood 132, 1974-1984
    4. Kearon et al. (2008). Chest 133, 454S-545S
    5. Coumadin® package insert. Bristol-Myers Squibb:2010
    6. Lane and Gregory. (2008). Stroke 39, 7-9
    7. Hirsh et al. (2003). J Am Coll Cardiol 41, 1633-1652
    8. Cairns et al. (2011). Can J Cardiol 27, 74–90
    9. Camm et al. (2010). Eur Heart J 31, 2369-2429
    10. Fuster et al. (2011). Circulation 123, 269-367
    11. Wann et al. (2011). J Am Coll Cardiol 57, 1330-1337
    12. Canadian Agency for Drugs and Technology in Health. (2012). Report available from https://www.cadth.ca/media/pdf/OP0508_warfarin-science-report-1_clinical_e.pdf [Accessed November 2019]
    13. Connolly et al. (2009). N Engl J Med 361, 1139-1151