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Initial experience with a direct antithrombin, Hirulog, in unstable angina. Anticoagulant, antithrombotic, and clinical effects.

AbstractBACKGROUND:
Currently available antithrombotic therapy for unstable angina is unwieldy and occasionally ineffective. This study was designed to investigate the potential of Hirulog, a new synthetic specific antithrombin agent, for the management of this condition.
METHODS AND RESULTS:
A total of 55 patients in the acute phase of unstable angina received intravenous Hirulog according to one of two protocols. In an acute dose-escalating study, 0.02, 0.05, 0.1, 0.25, and 0.5 mg.kg-1 x h-1, each for 30 minutes, were infused in 15 patients. Prolongation of activated partial thromboplastin time (aPTT) (r = .95), fibrinopeptide A inhibition (r = .96), and Hirulog plasma levels (r = .91) correlated closely with the dose infused, with significant changes compared with baseline appearing at doses of 0.25 mg.kg-1 x h-1 and higher. The purposes of the second protocol were to determine whether the anticoagulant and antithrombotic effects of the drug were sustained during a 72-hour infusion and to assess whether such treatment prevented the complications of unstable angina. Based on the initial study, we planned to give a dose of 0.25 mg.kg-1 x h-1 to each patient until 2 patients failed therapy, then successively higher doses until a 95% success rate was achieved or adverse effects intervened, increasing the dose after two failures had occurred at each level. Five patients received the 0.25-mg.kg-1 x h-1 dose and 14 the 0.5-mg.kg-1 x h-1 dose before two failures occurred. Failure was observed in only one of 21 patients at the dose of 1 mg.kg-1 x h-1. aPTT (+/- SEM) levels increased to 62 +/- 5, 76 +/- 2, and 98 +/- 3 seconds at the three doses, with minimal intraindividual variation, and Hirulog plasma levels to 1050, 2100, and 4200 mg/mL, respectively. Fibrinopeptide A plasma levels decreased at all doses but more consistently at the dose of 1 mg.kg-1 x h-1. The overall clinical success rate was 87.5%: 60% (3/5) at the low dose, 86% (12/14) at the intermediate dose, and 95% (20/21) at the high dose. No deaths, myocardial infarctions, or bleeding complications occurred.
CONCLUSIONS:
In unstable angina patients, Hirulog infusions quickly and reproducibly yield stable, dose-dependent anticoagulant and antithrombotic effects with a favorable clinical efficacy profile.
AuthorsR M Lidón, P Théroux, M Juneau, B Adelman, J Maraganore
JournalCirculation (Circulation) Vol. 88 Issue 4 Pt 1 Pg. 1495-501 (Oct 1993) ISSN: 0009-7322 [Print] United States
PMID8403297 (Publication Type: Clinical Trial, Comparative Study, Journal Article)
Chemical References
  • Hirudins
  • Peptide Fragments
  • Recombinant Proteins
  • Fibrinopeptide A
  • Thrombin
  • bivalirudin
Topics
  • Angina, Unstable (blood, drug therapy)
  • Dose-Response Relationship, Drug
  • Female
  • Fibrinopeptide A (analysis)
  • Hirudin Therapy
  • Hirudins (administration & dosage, analogs & derivatives)
  • Humans
  • Male
  • Middle Aged
  • Partial Thromboplastin Time
  • Peptide Fragments (administration & dosage, therapeutic use)
  • Recombinant Proteins (administration & dosage, therapeutic use)
  • Thrombin (antagonists & inhibitors)

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