A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty

The likelihood of restenosis is a major limitation of coronary angioplasty. We studied whether hirudin, a highly selective inhibitor of thrombin with irreversible effects, would prevent restenosis after angioplasty. We compared two regimens of recombinant hirudin with heparin. We randomly assigned 1141 patients with unstable angina who were scheduled for angioplasty to receive one of three treatments: (1) a bolus dose of 10,000 IU of heparin followed by an intravenous infusion of heparin for 24 hours and subcutaneous placebo twice daily for three days (382 patients), (2) a bolus dose of 40 mg of hirudin followed by an intravenous infusion of hirudin for 24 hours and subcutaneous placebo twice daily for three days (381 patients), or (3) the same hirudin regimen except that 40 mg of hirudin was given subcutaneously instead of placebo twice daily for three days (378 patients). The primary end point was event-free survival at seven months. Other end points were early cardiac events (within 96 hours), bleeding and other complications of the study treatment, and angiographic measurements of coronary diameter at six months of follow-up. At seven months, event-free survival was 67.3 percent in the group receiving heparin, 63.5 percent in the group receiving intravenous hirudin, and 68.0 percent in the group receiving both intravenous and subcutaneous hirudin (P = 0.61). However, the administration of hirudin was associated with a significant reduction in early cardiac events, which occurred in 11.0, 7.9, and 5.6 percent of patients in the respective groups (combined relative risk with hirudin, 0.61; 95 percent confidence interval, 0.41 to 0.90; P = 0.023). The mean minimal luminal diameters in the respective groups on follow-up angiography at six months were 1.54, 1.47, and 1.56 mm (P = 0.08). Although significantly fewer early cardiac events occurred with hirudin than with heparin, hirudin had no apparent benefit with longer-term follow-up. Platelet aggregation, the generation of thrombin, and the release of growth factors at the site of angioplasty have all been implicated in the process of restenosis.¹,² Consequently, anticoagulants, antiplatelet agents, and specific antithrombin agents have been considered for the prevention of restenosis.³ Thrombin is the most potent platelet activator known, stimulating the production of platelet-derived growth factor and the secretion of prostacyclin, platelet-activating factor, and plasminogen-activator inhibitor. Thrombin has apparent mitogenic effects on lymphocytes and vascular smooth-muscle cells.⁴,⁵ Hirudin, a 65-amino-acid compound originally extracted from the salivary gland of the leech, is a specific inhibitor of thrombin. The.