Antithrombotics

Antithrombotics – Oral anticoagulants

Synopsis of AHA material

Coumarins
are oral vitamin K antagonists that impair the formation and action of anticoagulant proteins-- prothrombin, factor VII, factor IX, factor X, protein C and protein S.

Warfarin
is the oral anticoagulant most widely used in the United States. The mechanism of action, recommendations for monitoring, and drugs that interact with warfarin are discussed at the American Heart Association site accessed using hyperlinks in the frame on the left.

Prothrombin time
is used to monitor anticoagulant dosing and increases with depression of prothrombin and factors VII and X. Reagents used to measure the prothrombin time use thromboplastins that differ in their responsiveness. This means that an individual patient’s prothrombin time measured in one laboratory will differ from that measured in another.

International Normalized Ratio (INR)
is a calculated value base upon the patient’s measured prothrombin time and an International Sensitivity Index determined by comparison of a commercial thromboplastin with a standard reagent. The INR should be used to monitor individual patient’s prothrombin times for clinical purposes.

Recommended INRs
for most conditions that require therapeutic anticoagulation are in the range of 2.0 to 3.0. The major exception is mechanical prosthetic heart valves where the recommended range is 2.5 to 3.5.

Onset of action
requires 2 to 7 days while the normal vitamin K dependent coagulation factors are replaced by decarboxylated derivatives created by the action of warfarin. Warfarin also impairs the activity of the naturally occurring anticoagulants protein C and S. Protein C has a short half (similar to factor VII) which means there is potential for a transient, early, prothrombotic effect. This has been considered a possible cause for warfarin-associated skin necrosis that may occur in patients with protein C or S deficiency.

Dosing
can begin with the anticipated maintenance dose, e.g. 4 mg daily, or with a "loading" dose of twice the anticipated daily oral dose. If anticoagulation is urgent, heparin can be initiated and continued until the prothrombin time has been therapeutic for 2 days. Prothrombin times are ordered daily until therapeutic, 3 times a week for 7 to 14 days then weekly until demonstrated stability permits monthly monitoring.

Reversal of warfarin
effect will begin 24 to 48 hours after discontinuing the drug. If more urgent reversal is required, vitamin K, at doses of 0.5 to 1.0 mg will produce moderate prothrombin time reductions within 6 hours if given subcutaneously. Doses of 5 to 10 mg act more rapidly and completely, but produce warfarin resistance for up to one week. Plasma concentrates can also be used. Intravenous vitamin K can be given, but carries a risk of anaphylaxis.

Warfarin therapy
for most conditions requires a target INR of 2.0 - 3.0.

Condition	Comments
Perioperative DVT prevention	Patients with history of DVT or undergoing major orthopedic procedure.
DVT	Heparin for 5 to 10 days then warfarin for 3 to 6 months.
Acute myocardial infarction	Warfarin for up to three months [also see ACC/AHA AMI practice guidelines. Ed]
Mechanical prosthetic heart valves	Mechanical prosthetic valves, especially in the mitral position, are treated to an INR of 2.5 - 3.5. If systemic embolization occurs, ASA (160 mg/d) or dipyridamole (400 mg/d) can be added. If risk of bleeding is high, INR can be reduced to 2.0 - 3.0.
Bioprosthetic heart valves	Warfarin is given for the first three postoperative months.
Non-valvular atrial fibrillation	Warfarin for patients over the age of 60 or with associated cardiac abnormality. A subset of patients less than age 75 without hypertension, heart disease, previous embolism or abnormality of the left atrium or ventricle can be treated with ASA.
Mitral valve prolapse	Warfarin only for cases complicated by embolic history or atrial fibrillation.
Paradoxical embolization	If a patent foramen ovale [usually identified during echocardiographic contrast study] is complicated by systemic embolization and not treated surgically, warfarin is given.
Rheumatic mitral valve disease	Warfarin is used for patients with very large left atria, history of systemic embolism, or atrial fibrillation. Recurrence during INR of 2.0 to 3.0 can be treated by increasing INR to 2.5 - 3.5 or adding ASA (160 - 325 mg/d).
Dilated cardiomyopathy	Warfarin prophylaxis is reasonable, but not backed by randomized trial data.

Bleeding complications
are increased with INR of 3.5 - 4.5, age over 65, therapeutic aspirin treatment, prior stroke or GI bleeding, chronic renal failure, chronic anemia, and occult GI or GU neoplasm.

Skin necrosis
due to thrombosis of veins and capillaries of the subcutaneous fat is associated with protein S and C deficiency, usually begins at day 3 to 8, and can sometimes be avoided by beginning anticoagulation with heparin and overlapping heparin/warfarin administration for one week.

06/14/98

Send comments to Donald L Vine MD