Hirudin (desirudin) and Hirulog (bivalirudin) in acute ischaemic syndromes and the rationale for the Hirulog/Early Reperfusion Occlusion (HERO 2) Study

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Abstract

Unlike unfractionated heparin, direct thrombin inhibitors such as hirudin and Hirulog inhibit clot-bound as well as fluid-phase thrombin, escape neutralisation by platelet secretion products, do not require monitoring, and are unassociated with immune thrombocytopenia. They have been shown to have modest advantages over heparin when given after thrombolytic therapy, reducing reinfarction by 14%. In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO 2b) trial, 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, p = 0.004). In the Hirulog Early Reperfusion/Occlusion (HERO 1) trial, 48% of patients who received Hirulog as adjunctive therapy with streptokinase had Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 flow in the infarct-related artery, compared with 35% of patients who received heparin with streptokinase (p < 0.05). The HERO 2 study, involving 17,000 patients, will test the hypothesis that Hirulog and aspirin given before streptokinase will reduce mortality compared with aspirin plus heparin. Early administration of direct thrombin inhibitors may potentially improve the outcome of patients treated with thrombolytic therapy.

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Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.

J Chesebro, G. Knatterud, R. Roberts … (1987)

Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

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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.

EJ Topol (1996)

Thrombin has a pivotal role in the pathogenesis of acute coronary thrombosis. We compared the clinical efficacy of a potent, direct thrombin inhibitor, recombinant hirudin, with that of heparin (an indirect antithrombin agent) in patients with unstable angina or acute myocardial infarction. At 373 hospitals in 13 countries, 12,142 patients with acute coronary syndromes were randomly assigned to 72 hours of therapy with either intravenous heparin or hirudin. Patients were stratified according to the presence of ST-segment elevation on the base-line electrocardiogram (4131 patients) or its absence (8011 patients), with the latter characteristic considered to indicate unstable angina or non-Q-wave myocardial infarction. At 24 hours, the risk of death or myocardial infarction was significantly lower in the group assigned to hirudin therapy than in the group assigned to heparin (1.3 percent vs. 2.1 percent, P = 0.001). The primary end point of death or nonfatal myocardial infarction or reinfarction at 30 days was reached in 9.8 percent of the heparin group as compared with 8.9 percent of the hirudin group (odds ratio for the risk of the end point in hirudin group,0.89; 95 percent confidence interval, 0.79 to 1.00; P = 0.06). The predominant effect of hirudin was on myocardial infarction or reinfarction and was not influenced by ST-segment status. There were no significant differences in the incidence of serious or life-threatening bleeding complications, but hirudin therapy was associated with a higher incidence of moderate bleeding (8.8 percent vs. 7.7 percent, P = 0.03). For acute coronary syndromes, recombinant hirudin provided a small advantage, as compared with heparin, principally related to a reduction in the risk of nonfatal myocardial infarction. The relative therapeutic effect was more pronounced early (at 24 hours) but dissipated over time. The small benefit was consistent across the spectrum of acute coronary syndromes and was not associated with a greater risk of major bleeding complications.

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Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators.

B Chaitman, John A Bittl, J Maraganore … (1995)

Heparin is often administered during and after coronary angioplasty to prevent closure of the dilated vessel. However, ischemic or hemorrhagic complications occur in 5 to 10 percent of treated patients. We studied whether these complications could be prevented when the direct thrombin inhibitor bivalirudin (Hirulog) was used in place of heparin. We performed a double-blind, randomized trial in 4098 patients undergoing angioplasty for unstable or postinfarction angina. Patients were assigned to receive either heparin or bivalirudin immediately before angioplasty. The primary end point were death in the hospital, myocardial infarction, abrupt vessel closure, or rapid clinical deterioration of cardiac origin. In the total study group, bivalirudin did not significantly reduce the incidence of the primary end point (11.4 percent, vs. 12.2 percent for heparin) but did result in a lower incidence of bleeding (3.8 percent vs. 9.8 percent, P < 0.001). In the prospectively stratified subgroup of 704 patients with postinfarction angina, bivalirudin therapy resulted in a lower incidence of the primary end point (9.1 percent vs. 14.2 percent, P = 0.04) and a lower incidence of bleeding (3.0 percent vs. 11.1 percent, P < 0.001), but in a similar cumulative rate of death, myocardial infarction, and repeated revascularization in the six months after angioplasty (20.5 percent vs. 25.1 percent, P = 0.17). Bivalirudin was at least as effective as high-dose heparin in preventing ischemic complications in patients who underwent angioplasty for unstable angina, and it carried a lower risk of bleeding. Bivalirudin, as compared with heparin, reduced the risk of immediate ischemic complications in patients with postinfarction angina, but this difference was no longer apparent after six months.