DIRECT THROMBIN INHIBITORS
The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin’s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMWH (see above), which act through antithrombin. Hirudin and bivaliru-din are bivalent DTIs in that they bind at both the catalytic oractive site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only atthe thrombin active site.
Leeches have been used for bloodletting since the age of Hippocrates. More recently, surgeons have used medicinal leeches (Hirudo medicinalis) to prevent thrombosis in the fine vessels of reattached digits. Hirudin is a specific, irreversible thrombin inhibitor from leech saliva that is now available in recombinant form as lepirudin. Its action is independent of antithrombin, which means it can reach and inactivate fibrin-bound thrombin in thrombi. Lepirudin has little effect on platelets or the bleeding time. Like heparin, it must be administered parenterally and is monitored by the aPTT. Lepirudin is approved by the FDA for use in patients with thrombosis related to heparin-induced thrombo-cytopenia. Lepirudin is excreted by the kidney and should be used with great caution in patients with renal insufficiency as no anti-dote exists. Up to 40% of patients who receive long-term infusions develop an antibody directed against the thrombin-lepirudin com-plex. These antigen-antibody complexes are not cleared by the kidney and may result in an enhanced anticoagulant effect. Some patients re-exposed to the drug have developed life-threatening anaphylactic reactions.
Bivalirudin, another bivalent inhibitor of thrombin, is admin-istered intravenously, with a rapid onset and offset of action. The drug has a short half-life with clearance that is 20% renal and the remainder metabolic. Bivalirudin also inhibits platelet activation and has been FDA-approved for use in percutaneous coronary angioplasty.
Argatroban is a small molecule thrombin inhibitor that isFDA-approved for use in patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by continuous intravenous infusion, and is monitored by aPTT. Its clearance is not affected by renal disease but is dependent on liver function; dose reduction is required in patients with liver disease. Patients on argatroban will demonstrate elevated INRs, rendering the transition to warfarin difficult (ie, the INR will reflect contributions from both warfarin and argatroban). (INR is discussed in detail in the discussion of warfarin administration.) A nomogram is supplied by the manu-facturer to assist in this transition. No properly designed head-to-head trials have been performed to determine whether argatroban or lepirudin is superior in the treatment of HIT. However, in practice, the choice of which DTI to use in a patient with HIT is usually dictated by the condition of the clearing organ. If the patient has severe renal insufficiency, then argatroban would be preferred. If there is severe hepatic insufficiency, then lepirudin would be a better choice.
Advantages of oral direct thrombin inhibitors include predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable anticoagulant response, and make routine coagu-lation monitoring unnecessary. In addition, these agents do not interact with P450-interacting drugs, and their rapid onset and offset of action allow for immediate anticoagulation, thus avoid-ing the need for overlap with additional anticoagulant drugs.
Dabigatran etexilate mesylate is the first oral direct thrombininhibitor approved by the FDA. Dabigatran was approved in 2010 to reduce risk of stroke and systemic embolism with nonval-vular atrial fibrillation. In the EU, dabigatran is approved for prevention of venous thromboembolism in patients who have undergone hip or knee replacement surgery. The pivotal trial lead-ing to FDA approval was a study of > 18,000 patients with non-valvular atrial fibrillation and at least one other defined risk factor. Dabigatran at a dose of 150 mg bid was shown to be superior to warfarin with an INR target of 2–3 in preventing stroke and sys-temic embolization.
Dabigatran and its metabolites are direct thrombin inhibitors. Following oral administration, dabigatran etexilate mesylate is converted to dabigatran. The oral bioavailability is 3–7% in nor-mal volunteers. The drug is a substrate for the P-glycoprotein efflux pump; however, P-glycoprotein inhibitors or inducers do not have a significant effect on drug clearance. Concomitant use of ketoconazole, amiodarone, quinidine, and clopidogrel increases the effect of dabigatran. The half-life of the drug in normal volun-teers is 12–17 hours. Renal impairment results in prolonged drugclearance and may require dose adjustment; the drug should be avoided in patients with severe renal impairment.
For prevention of stroke and systemic embolism in nonvalvular atrial fibrillation, 150 mg should be given bid to patients with creatinine clearance > 30 mL/min. For decreased creatinine clear-ance of 15–30 mL/min, the dose is 75 mg bid. No monitoring is required. Dabigatran will prolong the PTT and thrombin time, which can be used to estimate drug effect if necessary.
As with any anticoagulant drug, the primary toxicity of dabigatran is bleeding. In the RE-LY study, there was an increase in gastroin-testinal adverse reactions and gastrointestinal bleeding compared to warfarin. There was also a trend toward increased bleeding with dabigatran in patients older than 75 years. There is no antidote for dabigatran. In a drug overdose situation, it is important to main-tain renal function or dialyze if necessary. Use of recombinant factor VIIa or prothrombin complex concentrates may be consid-ered as an unproven, off-label use in cases of life-threatening bleeding associated with dabigatran use.
Oral direct thrombin inhibitors and oral direct Xa inhibitors offer significant advantages over warfarin (discussed next), which has a narrow therapeutic window, is affected by diet and many drugs, and requires monitoring for dosage adjustment. It appears that the oral anti-Xa drugs and oral direct thrombin inhibitors are poised to challenge warfarin’s dominance in the prevention and therapy of thrombotic disease.