Direct Thrombin Inhibitors
Direct thrombin inhibitors such as hirudin, bivalirudin (formerly known as hirulog), and argatroban have several theoretical advantages over unfractionated heparin. Heparin does not inhibit clot-bound thrombin, due to the stoichiometry of the heparin-antithrombin-III complex, and is neutralized by platelet factor-4, which is secreted by activated platelets. While direct antithrombins avoid these clot-specific problems they also do not require monitoring, and are not associated with immune thrombocytopenia. In clinical trials, acute complications after routine angioplasty were reduced by 39% when hirudin was used rather than heparin while hirulog had no effect 1,2. Neither drug had any effect on restenosis rates. This benefit did not seem to extend to the use of hirudin in infarct angioplasty 3. Despite early trials suggesting greater benefit 4, they have only modest advantages over heparin when given after thrombolytic therapy in the GUSTO-IIb trial, reducing reinfarction by 14% 5. However, patients treated with streptokinase and adjunctive hirudin had a reduction in death or myocardial infarction of 40% at 30 days (8.6% with hirudin versus 14.4% with heparin,) 6. In the HERO-1 trial, 48% of patients who received hirulog as adjunctive therapy with streptokinase had TIMI-3 flow in the infarct-related artery, compared with 35% of patients who received heparin with streptokinase 7. In the OASIS trial hirudin also reduced events compared to heparin in patients with unstable angina or non-Q-wave MI 8.
Argatroban is a synthetic reversible competitive thrombin inhibitor with a half-life of 46 minutes. In the ARGAMI-2 trial, argatroban was administered with thrombolytic therapy for acute myocardial infarction to assess safety and efficacy. The lower dose of argatroban (60 mg IV bolus followed by 2 mg/kg/min for 72 hours) was stopped at an interim analysis because of excess mortality. The higher dose (120 mg bolus with 4 mg/kg/min) in the final analysis of 1001 patients showed no significant benefit over standard heparin dosing (5000 U IV bolus then 1000 U/hr) in terms of 30-day major adverse cardiac events (15.1% vs. 13.0%; p=NS) or in bleeding events (5.9 vs. 8.3%; p=NS).
Direct antithrombins are not yet routinely used for any acute ischemic syndromes. Further work is clearly needed to advance the use of these agents in acute coronary syndromes.
References
1. Serruys PW, Herrman JP, Simon R, Rutsch W, Bode C, Laarman GJ, van Dijk R, van den Bos AA, Umans VA, Fox KA, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators. N Engl J Med. 1995; 333:757-63.
2. Bittl JA, Strony J, Brinker JA, Ahmed WH, Meckel CR, Chaitman BR, Maraganore J, Deutsch E, Adelman B. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med. 1995; 333:764-9.
3. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. N Engl J Med. 1997; 336:1621-8.
4. Antman EM. Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial [see comments]. Circulation. 1996; 94:911-21.
5. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med. 1996; 335:775-82.
6. Metz BK, White HD, Granger CB, Simes RJ, Armstrong PW, Hirsh J, Fuster V, MacAulay CM, Califf RM, Topol EJ. Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators. J Am Coll Cardiol. 1998; 31:1493-8.
7. White HD, Aylward PE, Frey MJ, Adgey AA, Nair R, Hillis WS, Shalev Y, Brown MA, French JK, Collins R, Maraganore J, Adelman B. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Circulation. 1997; 96:2155-61.
8. Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Circulation. 1997; 96:769-77.
Michael Ward, M.B.B.S.