Indications for vitamin K antagonist therapy

Indications for vitamin K antagonist therapy and INR testing


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:

  • Mechanical Heart Valves


Permanent anticoagulation therapy is justified by an increased risk of thromboembolic complications after replacement of any valve with a mechanical prosthesis1,2. Most heart valve defects are acquired later in life and are due to degenerative heart valve disease. Heart valve replacement becomes necessary when hereditary or acquired defects severely limit valve function.

Causes of heart valve defects3:

  • Congenital heart valve defect in the infant.
  • Rheumatic fever - rarely seen now in western industrial nations
  • Changes to the valvular apparatus due to infection, immunological, ischaemic, traumatic or degenerative factors

Acquired valvular stenosis may be a consequence of organic changes to the tissue of the valve; insufficiency may be a secondary consequence of ventricle volume load or congestive heart failure.

Today, the indication for operation and/or interventional treatment of the heart valves is considered earlier4. In Europe, corrective heart valve surgery is performed in approximately 25% of all heart operations: Mechanical heart valves are particularly long-lived, but require that the patient takes life-long oral anticoagulation medication2. Biological heart valve prostheses have the benefit of not requiring prolonged anticoagulation, but calcify sooner and have to be replaced after 10 to 15 years5, with an increased risk linked to the second valve replacement surgery.



All patients with mechanical valves require anticoagulation. For mechanical prostheses in the aortic position, an INR with warfarin therapy should be maintained between 2.0 and 3.0 for bileaflet valves and Medtronic Hall valves. An INR between 2.5 and 3.5 is the target for other disc valves and Starr-Edwards valves. For prostheses in the mitral position, the INR should be maintained between 2.5 and 3.5 for all mechanical valves.

Post-operative mortality and morbidity can be improved through individual adjustment of anticoagulation intensity, involvement of the patient, and the use of the international normalized ratio (INR) as control parameter. Studies such as ESCAT (Early Self Controlled Anticoagulation Trial)6,7have shown that in cases where patients practice self-management they remain within their optimum therapeutic target range for a higher percentage of time and so significantly reduce the rate of complications.

2006 ACC/AHA guidelines (8):


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Risk factors:

Atrial fibrillation, previous thromboembolism, LV dysfunction, hypercoagulable conditions, older-generation thrombogenic valves, mechanical tricuspid valves, or more than 1 mechanical valve.

  • Atrial Fibrillation


Atrial fibrillation is the most common heart rhythm abnormality that people develop. During AF the heart's two upper chambers (the atria) beat chaotically and irregularly. The condition causes poor blood flow and the development of blood clots within the heart which can subsequently release into the arteries of the brain and cause a stroke. It is primarily a problem of the elderly.

AF is often classified as follows:

  • Recurrent AF: two or more episodes of AF
  • Paroxysmal AF: episodes end spontaneously within seven days
  • Persistent AF: pharmacologic or electrical cardio-version is required to terminate the arrhythmia
  • Permanent AF: sustained AF despite treatment to end the arrhythmia or when cardio version is inappropriate

Approximately 15% of strokes occur in patients with atrial fibrillation (AF). The risk of stroke in AF patients increases with age, from a 1.5% annual risk in patients aged 50-59 years to 23.5% in those aged 80-89 years. Indeed, elderly patients with AF are at the highest risk for stroke and the highest risk for hemorrhage. After adjusting for comorbid cardiovascular conditions, AF is associated with a 50% to 90% increase in mortality risk. Furthermore, stroke is a leading cause of serious long-term disability.

It has been recently estimated that around 5.6 million US and around 4.5 million EU citizens suffer from paroxysmal or persistent atrial fibrillation today. This number may increase in the US alone up to 15 Million people.  During the last 20 years there has been a 66% increase in hospitalizations due to atrial fibrillation and atrial fibrillation is regarded as one of the major risk factors for thromboembolic-caused stroke.


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Five landmark clinical trials - AFASAK, SPAF, BAATAF, CAFA, and SPINAF - have demonstrated the unequivocal benefits of warfarin in preventing stroke among patients with AF. Below 2.0, patients have an increased risk for ischemic stroke, and above 3.0, the risk for intracranial bleeding begins to rise.

According to a large European fibrillation study from Hart et al., involving more than 1,000 patients, a risk reduction for stroke from 12% to 4% was achieved for this clinical picture. In other words, the number of stroke events can be reduced by 80 in every 1,000 patients treated with anticoagulants.
This was confirmed recently by the BAFTA study showing that stroke risk is lowered by 64 % and death by 25 % with VKA compared to no treatment, and stroke is reduced by 22 % with antiplatelet agents.
Warfarin is 40 % more efficacious than antiplatelet therapy and is appropriate in elderly population

Where oral anticoagulation is indicated, a risk stratification (e.g. using the CHADS2 score) must be performed. The CHADS2 scoring system assigns 1 point to each of four risk factors for stroke: Congestive Heart Failure, Hypertension, Age ≥75 years, and Diabetes. In addition, 2 points are assigned for prior Stroke, TIA, or systemic embolus. The annual risk for stroke is directly related to CHADS2 score, ranging from 1.9% for a CHADS2 score of 0 to 18.2% for a CHADS2 score of 6.


The latest ACC/AHA/ESC AF guidelines confirm the need and benefits of oral anticoagulation in most patients. For patients with a CHADS2 score >1, the guidelines recommend warfarin therapy (INR 2.0-3.0) for long-term risk management.


Open questions:

  • Limited Compliance
    Despite considerable evidence supporting the use of anticoagulation therapy in the management of AF, warfarin is under-utilized across treatment settings. In a survey of community and academic hospitals in the US, nearly half of high-risk AF patients (47%) were not being treated with warfarin therapy.  In a European survey, only 54% of high-risk AF patients were receiving warfarin therapy.
    Long-term adherence to warfarin therapy is also low among patients with AF. Up to 25% of patients aged 80 years or older discontinued therapy within 90 days for reasons excluding death or return to normal sinus rhythm.  Factors associated with decreased use of oral anticoagulation include perceived bleeding risk, lack of proximity to an INR monitoring site, patient preference, and the innate difficulties of warfarin use.
  • Elderly patients
    The recent prospective randomised BAFTA trial assessed whether warfarin reduced the risk of major stroke or embolism without impacts on major haemorrhages as compared to acetylsalicylic acid in elderly patients.
    Findings indicated the benefit of warfarin over acetylsalicylic acid for stroke prevention (70% reduction in risks with warfarin use vs. acetylsalicylic acid) with significantly lower complication rates and similar risks of major haemorrhage (1.9% vs. 2.0% haemorrhage risk per year). Therefore, anticoagulation therapy is recommended for people with AF over 75 years old, unless there are contraindications.
    The safety and efficacy of oral anticoagulation self-management in elderly patients was confirmed by a randomized controlled trial from Siebenhofer et al. in 2007.
  • New anticoagulants
    New anticoagulants which do not require continuous monitoring are currently under evaluation for stroke prevention in AF.
    Presently, there are nevertheless no alternatives better than vitamin K antagonists for stroke prevention in atrial fibrillation (SPAF)



  • Deep Vein Thrombosis and Pulmonary Embolism
  • Myocardial infarction
  • Acute Ischemic Stroke


Some physicians are reluctant to prescribe a VKA, in part because they are not familiar with techniques for administering the drug safely and fear that the drug will cause bleeding. Patients treated with a VKA, such as warfarin, do require close monitoring to avoid bleeding. However, it has been shown that the drug prevents 20 strokes for every bleeding episode it causes. For most of these indications, a moderate anticoagulant intensity (INR 2.0 to 3.0) is appropriate.

Medical information

  1. Vongpatanasin W, Hillis LD, Lange RA. Prosthetic Heart Valves. N Engl J Med 1996; 335:407-416.
  2. Gohlke-Barwolf C. [Current recommendations for prevention of thromboembolism in patients with heart valve prostheses] (german article). Z Kardiol 2001; 90 Suppl 6:112-117.
  3. Braunwald E. Valvular heart disease. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's principles of internal medicine. New York: McGraw-Hill, 2001; 1343-1355.
  4. Carabello BA, Crawford FA. Valvular Heart Disease. N Engl J Med 1997; 337:32-41.
  5. Ennker Jr, Lauruschkat A. Mechanische vs. biologische Herzklappen. Z Kardiol 2001; 90.
  6. Koertke H, Korfer R. International normalized ratio self-management after mechanical heart valve replacement: is an early start advantageous? Ann Thorac Surg 2001; 72:44-48.
  7. Koertke H, Zittermann A, Minami K, et al. Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement. Ann Thorac Surg 2005; 79:1909-1914; discussion 1914.
  8. From: ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease Journal of the American College of Cardiology Vol. 48, No. 3, 2006 Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr., Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Valvular Heart Disease), American College of Cardiology Web Site: index.pdf