The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.
Although hirudin is better than heparin at preventing recurrent ischemia in patients with unstable angina, hirudin produces more bleeding. The purpose of this study was to use a rabbit arterial thrombosis prevention and ear bleeding model to determine whether for equivalent efficacy, melagatran, a synthetic direct thrombin inhibitor, is safer than hirudin. A combination of balloon injury and stasis was used to induce thrombosis in the distal aorta, and patency and blood flow were continuously monitored with ultrasonic flow probes. Rabbits were randomized to melagatran (in total doses of 78-313 nmol kg(-1)), hirudin (in total doses of 18-107 nmol kg(-1)), or saline over 90 min. To assess safety, blood loss from standardized ear incisions was measured. Both melagatran and hirudin produced dose-dependent increases in patency and blood flow. At doses that maintained the highest levels of patency, however, melagatran produced 2-3-fold less bleeding than hirudin. Thus, at maximally effective doses, melagatran causes less bleeding than hirudin in this model. These findings raise the possibility that some direct thrombin inhibitors are safer than others.
Klement
P
P
McMaster University and Henderson Research Center, Hamilton, Ontario, Canada.
Carlsson
S
S
Rak
J
J
Liao
P
P
Vlasin
M
M
Stafford
A
A
Johnston
M
M
Weitz
J I
JI
D000818:Animals; D001158:Arteries; D001384:Azetidines; D001596:Benzylamines; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D006470:Hemorrhage / Q000188:drug therapy / Q000517:prevention & control*; D024764:Hirudin Therapy; D006629:Hirudins / Q000494:pharmacology*; D008297:Male; D011817:Rabbits; D018570:Risk Assessment; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*
D001384:Azetidines; D001596:Benzylamines; D005343:Fibrinolytic Agents; D006629:Hirudins; C109573:melagatran; D005337:Fibrin; D013917:Thrombin; D005998:Glycine