8.3.5 Anti vitamin K agents

In the 1920s, massive haemorrhages among livestock after eating mouldy hay led to the discovery of warfarin. Initially used as rat poison, it was later adapted for clinical use in humans as an oral anticoagulant (Coumadin® ). Coumarins such as phenprocoumon (Marcoumar® ) or acenocoumarol (Sintrom® ) have been used since the 1950s (see Tables 8.1, 8.2 and 8.3 , 8.11 and 8.12).

Anti-vitamin K drugs (AVKs) work by blocking the hepatic synthesis of the vitamin-dependent factors: factors II (prothrombin), VII, IX and X, protein C and S (see Figure 8.9). At the start of treatment, protein C and S depletion is faster than coagulation factor depletion, which temporarily induces a hypercoagulable state, since both proteins have an inhibitory effect on the coagulation cascade [1]. The half-life is 8-11 hours for Sintrom® and 90-160 hours for Marcoumar® . As these drugs are mainly eliminated via the liver, they are not influenced by renal function. The initial dose is 5-10 mg per day, adjusted thereafter according to INR response. In the elderly, it is advisable to keep the dose below 5 mg/d [2]. The incidence of bleeding on AVKs varies from 0.5% to 3.4% per year according to studies, depending on the INR sought [5].

Although anti-vitamin K agents have been used for some 60 years, they have major drawbacks [4,6].

  • Response is slow; peak action is reached after several days (4 days for Sintrom, 7 days for Marcoumar); in venous thromboembolism, the AVK is started during the first 2-5 days of intravenous heparin treatment.
  • Treatment requires continuous monitoring by INR / PT.
  • The therapeutic range is narrow; the therapeutic INR is between 2.0 and 3.0. However, individual response is highly variable for several reasons: high genetic and ethnic polymorphism, strong binding to certain foods, fluctuations in vitamin K intake, interaction with many other drugs.
    • Potentiation: azole antifungals, cephalosporins, erythromycin, amoxicillin, amiodarone, diltiazem, clofibrate, fluvastatin, simvastatin, phenylbutazone, cimetidine, omeprazole, acetaminophen, alcohol, NSAIDS.
    • Inhibition: rifampicin, barbiturates, carbamazepine, azathioprine.

When interrupted preoperatively, the time to INR ≤ 1.5 averages 5 days, but varies considerably between patients depending on maintenance dose, liver function, diet and concomitant medications. The routine is to discontinue AVKs 5 days before surgery and resume them on the first postoperative day (see Surgery in anticoagulated patients) [3]. As patients cannot be left without anticoagulation for such a long time, temporary substitution with heparin is recommended (see Bridging).

 

Anti-vitamin K  agents 
AVKs block hepatic synthesis of vitamin K-dependent factors: factors II (prothrombin), VII, IX and X, protein C and S. Peak action is reached after several days (4 days for Sintrom® , 7 days for Marcoumar® ); the half-life is long: 11 hours for Sintrom® , 40 hours for Coumadin® and 140 hours for Marcoumar® . Response is highly variable individually, hence the need for regular monitoring of PT/INR (therapeutic level: INR 2.5-3.0). Initial dose: 5-10 mg/d; maintenance: 2-5 mg/d.
 
When interrupted preoperatively, the time to INR < 1.5 averages 5 days, but varies considerably between patients depending on maintenance dose, liver function, diet and concomitant medications. The routine is to discontinue AVKs ≥ 5 days before surgery and resume them on the first postoperative day; substitution with a heparin is usually required.

 

 © CHASSOT PG, MARCUCCI Carlo, last update November 2019.

 

References

 

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  2. AGENO WA, GALLUS AS, WITTKOWSKY A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl 2):e44S-e88S
  3. DOUKETIS JD, BERGER PB, DUNN AS, et al. The perioperative management of antithrombotic therapy. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133:299S-339S
  4. HOLBROOK A, SCHULMAN S, WITT DM, et al. Evidence-based management of anticoagulant therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl 2):e152S-e184S
  5. JACKSON SL, PETERSON GM, VIAL JH, et al. Outcomes in the management of atrial fibrillation: clinical trials results can apply in practice. Intern Med J 2001; 31:329-36
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