For prevention of stroke and systemic embolism in nonvalvular atrial fibrillation, the dosage is 150 mg twice daily for patients with creatinine clearance greater than 30 mL/min. For decreased creatinine clearance of 15–30 mL/min, the dosage is 75 mg twice daily. No monitoring is required.
Assessment of and Reversal of Antithrombin Drug Effect
As with any anticoagulant drug, the primary toxicity of dabigatran is bleeding. Dabigatran will prolong the PTT, thrombin time, and ecarin clotting time, which can be used to estimate drug effect if necessary. The ecarin clotting time [ECT] is another clotting test based on the use of a protein isolated from viper venom. Idarucizumab is a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect. The drug is approved for use in situations requiring emergent surgery or for life-threatening bleeding. The recommended dose is 5 g given intravenously. If bleeding re-occurs a second dose may be given. The drug is primarily excreted by the kidneys. The half-life in patients with normal renal function is approximately 1 hour.
Summary of the Direct Oral Anticoagulant Drugs
The direct oral anticoagulant drugs have consistently shown equivalent antithrombotic efficacy and lower bleeding rates when compared with traditional warfarin therapy. In addition, these drugs offer the advantages of rapid therapeutic effect, no monitoring requirement, and fewer drug interactions in comparison with warfarin, which has a narrow therapeutic window, is affected by diet and many drugs, and requires monitoring for dosage optimization. However, the short half-life of the newer anticoagulants has the important consequence that patient noncompliance will quickly lead to loss of anticoagulant effect and risk of thromboembolism. Given the convenience of onceor twice-daily oral dosing, lack of a monitoring requirement, and fewer drug and dietary interactions documented thus far, the new direct oral anticoagulants represent a significant advance in the prevention and therapy of thrombotic disease.
Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin from its precursor zymogen, plasminogen (Figure 34–3). These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down. The Box: Thrombolytic Drugs for Acute Myocardial Infarction describes the use of these drugs in one major application.
Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors (antiplasmins) in plasma prevent its effects. However, the absence of inhibitors for urokinase and the streptokinase-proactivator complex permits their use clinically. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins; this allows it to lyse the thrombus from within.