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Practical problems with warfarin therapy in my private cardiology practice 

Date: 02 Apr 2009
The number of very elderly patients in cardiology practices is continually increasing and their specific cardiac problems are more and more common. Together with heart failure, atrial fibrillation (AF) is a good example.

Atrial fibrillation is the most common arrhythmia seen in clinical practice. It is an extremely expensive public health problem costing approximately €3000 [~US $3600] annually per patient. The total cost burden approaches €13.5 billion (~US $15.7 billion) in the European Union.

The risk factors for ischemic stroke and systemic embolism in patients with nonvalvular AF are well established, as are the benefits of anticoagulation treatment. Any patient with atrial fibrillation who has risk factors for stroke (prior stroke or transient ischemic attack, significant valvular heart disease, hypertension, diabetes, age older than 65 years, left atrial enlargement, coronary artery disease, or congestive heart failure) should be treated with warfarin anticoagulation to achieve an international normalized ratio (INR) of 2.0 to 3.0 for stroke prevention, if the individual is a good candidate for oral anticoagulation. Only patients with contraindications to anticoagulation and unreliable individuals should be considered for aspirin treatment.

In very elderly patients (older than 75 years)  with atrial fibrillation, anticoagulation should be used with extra caution and very carefully monitored because of the potentially increased risk of intracranial haemorrhage and their polymorbidism. How could we make warfarin therapy more safe and effective? How could we improve patient management and make it acceptable to most elderly persons ?

In my cardiology practice patients are carefully initiated and educated in detail. If there is a clear indication for anticoagulant therapy, firstly I give them a text concerning the treatment for them to study at home. A week later I interview the patient again to ensure that he or she has understood all aspects of the therapy and that the patient will cooperate. Only then do I decide to start warfarin therapy or not.

Patients are instructed to call whenever they have questions or concerns about their warfarin management or possible side effects or if they begin receiving any new medication. They are warned about significant dietary changes with foods containing vitamin K. I give them a table where they can find the content of vitamin K in the various kinds of foods. But I have found through the years that they don't like big changes in their dietary habits. They receive a "dosing card" where they can find the current dose of warfarin per day and where the current value of INR is noted. The goal is to achieve the highest possible time in therapeutic range (TTR). Some authors suggest that a minimum target for TTR should be 60%-65%, and that medical systems that cannot achieve this target should not prefer anticoagulant therapy to antiplatelet therapy in atrial fibrillation. In such patients I replace warfarin by aspirin.

Theoretical aspects of warfarin therapy are quite well known. Warfarin inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S. Each factor differs in its degradation half-life. The degree of effect on the vitamin K-dependent proteins is dependent upon the dose of warfarin and, to some extent, the patient's VKORC1 genotype (vitamin K epoxide reductase enzyme, which reduces the regeneration of vitamin K epoxide).

Since warfarin reduces the activity of anticoagulant proteins C and S, a hypercoagulable state may be induced for a short period of time after treatment with warfarin is started. The rapid loss of protein C temporarily shifts the balance in favour of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors. How could warfarin treatment be stated more precisely and better tailored to the individual patient?

Although we observe the growth in the area of molecular genetics and pharmacogenetics, and our ability to stratify risk and better guide our therapy theoretically continues to improve, pharmacogenetic testing before starting therapy is not widely available today and still remains too expensive for conventional clinical use. To avoid this problem I always start the therapy slowly with a low dose of 2,5-3 mg of warfarin daily and every week I gradually change the dose according to the INR value. Up to now, I haven´t had any thrombotic complications during this period. In case of emergency the dosage is higher but always combined with LMWH, and INR controls are more frequent. I don´t send patients to hospitals to begin warfarin treatment. Once a stable INR is reached, values are monitored periodically with the frequency based on the indication for anticoagulation and co-existing conditions. Warfarin is stereo-selectively metabolised by hepatic cytochrome P-450 (CYP) isoenzymes. CYP2C9 is the principle enzyme that metabolises S-warfarin and modulates the in vivo activity of warfarin. Genetic polymorphism of CYP2C9 plays a role in the interpatient variability of response to warfarin and predisposition to drug interactions.

After adjusting warfarin dosage, based on INR and clinical response, problems don´t finish but start. Why? Since the number of patients on warfarin treatment are continually growing, I begin to consider the problem of how to take the appropriate time for really responsible management of those patients.

Do you also have a time problem with the long term monitoring of warfarin therapy in your practices? Is the number of your elderly patients adapted to your capacity?
Who helps you with this? GPs? Haematology departments? Is there a place for a new specialisation, such as a "consultant for anticoagulation" or do you believe that new strategies for stroke prevention will soon be developed? Oral thrombin inhibitors? Do you have practical experience with INR home- self-monitoring?


Conclusion I hope that our discussion from the practical point of view will help to improve treatment of increasingly frequent problems such as atrial fibrillation and very elderly patients in general.

Authors: Ivan Kohl

Zlin, Czech Republic