Management of deep vein thrombosis with oral vitamin K antagonist (pp. 97-124)
Authors: (Pinjala Ramakrishna)
Abstract: Oral vitamin K antagonist therapy is useful for prevention and treatment of thromboembolic disease. The fear of medication errors and medication related adverse events limit the appropriate use of oral vitamin k antagonist therapy. The beneficial effectiveness of oral vitamin K antagonist therapy depends on the adequate dose and its long term management. Acenocoumarol and warfarin are the commonly used vitamin K antagonists (VKAs) in our practice. Long term management (6 months) of the DVT patients with vitamin K antagonists has increased in recent years with improvement in the diagnostic methods of DVT detection and increasing age of the population. The pharmacokinetic and pharmacodynamic properties of the vitamin K antagonists along with the narrow therapeutic range make the management of oral anticoagulation
for thromboembolic complications complex. Patients receiving oral anticoagulants are likely to attend emergency department due to bleeding from the medication errors. So, this is a serious concern in many countries and one would like to avoid the medication errors by maintaining the high quality of anticoagulation in DVT patients. During the initiation of oral anticoagulation therapy injection of heparin and oral anticoagulants are overlapped till the therapeutic INR values are achieved with the vitamin K antagonists. This overlap is maintained till two consecutive INR values are above 2.0. We generally start oral anticoagulation with 5mgs of tablet warfarin or 4mgs of tablet Acitrom as the higher doses are known to precipitate early hemorrhages. In the elderly people, undernourished, heart failure, liver disease and postoperative patients the anticoagulation is initiated with smaller doses (<5 mgs) due to the fear of bleeding. CYP2C9 is the principal enzyme to metabolize the oral anticoagulants and polymorphisms of the gene coding CYP2C9 can result in abnormalities. Recent studies are showing the advantages of pharmacogenetic based dosing to overcome these abnormalities, but it is not yet widely accepted or recommended. The warfarin inhibits the vitamin K oxide reductase complex (VKORC) and mutation of the genes coding this enzyme complex (VKORC1) can increase the sensitivity or resistance to warfarin inhibition. The adequate therapeutic dose to maintain INR shows variability due to these mutations. The therapeutic anticoagulation (INR>2) should be maintained to get maximum benefit. That means the time in therapeutic range (TTR) correlates with the clinical outcomes of hemorrhage and thrombosis. Increased TTR has also been associated with decreased mortality. INR test is performed at regular intervals of 7-14 days depending on the stable dose response in a given patient. Management of non-therapeutic INR is difficult in patients with complex life styles and variable dietary habits. Non-compliance and concomitant medications makes this more difficult to manage and maintain the therapeutic INRs. The target therapeutic INRs can be achieved by adjusting the warfarin doses with up or down increments of 5-20% and frequent monitoring. When the INR is between 4-10 without bleeding it is better to stop the medication and monitor the INR daily and restart with the reduced weekly dose of INR after it has fallen to the therapeutic range. Abnormally elevated INRs with or without bleeding would need attention and careful follow up adjustment of doses. We are cautious in correcting the abnormally high INRs associated with bleeding with Vitamin K injections which can increase the vitamin K resistance to warfarin later. Correction dose requirements are dependent on age, race, BMI, concomitant medications, co-morbidities and gene mutations. Systematic reviews of the patients on warfarin have shown bleeding rates of 8.9% per patient year in first 3 months, only 2.5% after 3 months of initiation of anticoagulation therapy. When patients are actively bleeding while they are on oral vitamin K antagonists one would
target rapid lowering of the INRs with infusion of fresh frozen plasma (FFP), Prothrombin concentrates or recombinant factor VIIa along with injection vitamin K to facilitate the endogenous coagulation factor production. Quality patient education is necessary to achieve the safe and effective oral anticoagulation with Vitamin K antagonists under the supervision of the treating teams. It is indeed a challenge for the teams providing the oral anticoagulation therapies to prevent the recurrent thrombosis and thromboembolism in deep vein thrombosis in patients in many countries through quality education of patients to achieve the maximum time in therapeutic range.