Unlike UFH, direct thrombin inhibitors such as hirudin and bivalirudin do not require a cofactor to inhibit thrombin (66,67). The class prototype, hirudin, is a 65-amino-acid polypeptide derived from the medicinal leech (Hirudo medicinalis), that binds selectively to thrombin in a 1:1 fashion at 2 sites. The 72-amino-acid carboxy terminus binds to the fibrinogen recognition site of thrombin. The amino terminus binds to thrombin's catalytic site. This binding is not covalent but the dissociation rate is so slow that hirudin is essentially an irreversible inhibitor of thrombin. Importantly, it can bind and inactivate both free and bound thrombin. Additionally, PF4, vitronectin, or other plasma proteins do not inactivate it. Finally, direct thrombin inhibitors have a predictable and stable anticoagulant response (66-68).
The antithrombotic effects of hirudin have been demonstrated in animal models. Most notably in the pig model of deep arterial injury (68), where hirudin was a more effective inhibitor of both platelet deposition and thrombus formation than UFH at the site of arterial injury. Furthermore, hirudin completely eliminated macroscopic thrombus formation at an aPTT at least twice that of normal (68).
Given its mechanistic advantages, one might expect hirudin to result in better outcomes in ACS. The TIMI-5 (69) study investigated the efficacy of hirudin compared with UFH as an antithrombotic adjunct in patients with STE who were receiving thrombolytic therapy and aspirin. At 90 min, the primary end point ofTIMI-3 flow at 90 min and 18-36 h was present in 62 and 49% of the hirudin and UFH groups, respectively (p = 0.07). At 18-36 h of therapy, the infarct related artery patency was significantly higher in the hirudin group (98 vs 89%, p = 0.01). Death or reinfarction occurred significantly less in the hirudin group (6.8 vs 16.7%, p = 0.02), while the total incidence of major hemorrhage was not significantly different, with 23.3% for UFH and 17.5% for hirudin.
In another angiographic study, 116 patients with UA and >60% stenosis of a culprit coronary artery or saphenous vein graft were randomized to receive either 1 of 2 doses of UFH or 1 of 4 doses of hirudin (70). After 72-120 h of therapy, patients treated with hirudin had significantly better calibre diameter and minimal cross-sectional area, reflecting thrombus dissolution or prevention of thrombus propagation. Additionally, there was a more consistent and stable elevation of the aPTT with hirudin along with a trend towards an improved composite end point of death, MI, and recurrent angina (14 vs 24%, p = 0.14). This data suggests that resolution of a coronary thrombus as judged by lesion severity might be associated with clinical benefit in UA/NQWMI patients.
The TIMI-7 investigators (71) also randomized UA patients, who were receiving daily aspirin, to 4 different doses of the direct thrombin inhibitor, Hirulog (bivalirudin), in a double-blind study. No differences were observed among the 4 groups of Hirulog dosing for the primary composite end point of death, nonfatal MI, rapid clinical deterioration, or recurrent angina at rest by 72 h. However, the secondary end point of death or nonfatal MI was 10% in the lowest dose group compared with 3.2% in the 3 combined higher dose groups at hospital discharge and persisting for 6 mo. The authors reasoned that the lowest dose could be used as a control group and concluded that Hirulog was effective in preventing adverse outcomes when used in addition to aspirin.
In the GUSTO IIb study (72), 12,142 patients with chest pain associated with STE or depression or T-wave inversion were examined. Patients with STE received tPA, aspirin, and hirudin or UFH, while those without STE were administered aspirin and hirudin or UFH. The total risk of death or MI at 24 h was lower in the hirudin group than the UFH group (1.3 vs 2.1%, p = 0.001). However, this risk was not significantly different between the hirudin and UFH groups at 30 d (9.8 vs 8.9%, p = 0.06). When the UA/NSTEMI group was examined separately, there was no difference between hirudin and UFH therapy. There was also no difference in serious or life-threatening hemorrhage, although hirudin was associated with a higher incidence of moderate bleeding (8.8 vs 7.7%).
In summary, direct thrombin inhibitors have, thus far, failed to live up to their initial billing. One can theorize that although thrombin is an important antagonist of platelet activation, it represents only one pathway of platelet activation among nearly 100.
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