Oral Anticoagulation Therapies

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(3):

  • Warfarin/coumarin (Coumadin®)
  • Nicoumalone/acenocoumarol (Sintrom®)
  • Phenprocoumon (Marcumar®; Falithrom®)

Not a VKA, but same mode of action:

  • Fluindione (Previscan®)

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)

  • 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. 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.(5)

 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 cleared for anticoagulation use that offer the following benefits:2,3

  • Do not require monitoring
  • Wider therapeutic index
  • Simpler 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 bleeding7,8
    • HAS-BLED score (≥ 3 points = high risk)8
  • A mechanical heart valve or hemodynamically significant valve disease6
  • Renal function6,7
  • Advanced liver disease6
  • Body weight7
  • Risk of coronary events7
  • Propensity to dyspepsia7
  • Patient compliance and preferences8
  • Ability to safely sustain adjusted chronic anticoagulation8
  • Success on existing anticoagulation therapy6

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

  • There is a risk of non-compliance9,10,11
  • There are co-morbidities (hypertension, heart failure, diabetes)11
  • Patients with renal impairment10
  • Patients with a mechanical heart valve11
  • Elderly patients (>75 years)11
  • Patients with an increased risk of bleeding12
  • Where cost is an issue12
  • The patient is a child or adolescent12
  • Patient is intolerant to the new drugs13
References
  1. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K
    antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S-198S.
  2. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous
    thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:454S-545S.
  3. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:546S-592S.
  4. Coumadin® package insert. Bristol-Myers Squibb:2010.
  5. Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 2003; 41:1633-1652.
  6. Fuster et al (2011). Circulation 123:e269-e367
  7. Cairns et al (2011). Can J Cardiol 27: 74–90
  8. Camm et al (2010). Eur Heart J 31:2369-2429
  9. United Kingdom Clinical Pharmacy Association"Position statement on introduction of the new oral anticoagulant"
  10. Wann et al (2011). J Am Coll Cardiol 57:1330-1337
  11. Fuster et al (2011). Circulation 123:269-367
  12. Market research with 288 GPs and 29 experts from Australia, Germany, UK, USA; Q2 2011
  13. Connolly et al (2009). N Engl J Med 361:1139-1151
  14. 2. Schwatrz & Albers (2010). Stroke 41:1307-1309
  15. 3. Moualla & Garcia (2011). Thromb Res 128:210-215