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Medium-dose hirudin was superior to heparin in preventing ischemic events in patients with acute myocardial ischemia
Medium-dose hirudin was superior to heparin in preventing ischemic events in patients with acute myocardial ischemia Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators.
Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with a c u t e myocardial ischemia without ST elevation. A pilot study. Circulation 1997; 96:769-777
Objective To compare the effects of hirudin and heparin on ischemic events in patients with acute MI without ST elevation.
Design Randomized, open pilot study with blinded outcome assessment.
Setting 31 clinical centers in Canada.
Patients 909 patients (mean age 65; 66% men) admitted to hospital within 12 h of the onset of chest pain attributable to UA or MI without ST elevation. Intervention Patients were randomized to 72 h treatment with either heparin (n = 371; 5000 U bolus plus 1000-1200 U/h infusion), low-dose hirudin (n = 271; 0.2 mg/kg bolus plus 0.10 mg/kg/h infusion) or medium-dose hirudin (n = 267; 0.4 mg/kg bolus plus 0.15 mg/kg/h infusion). Adjustments in dosing were permitted to maintain aPTT of 60-100 s. M a i n outcome measures The primary outcome cluster was death, new MI or refractory angina at 7 d; secondary outcome cluster included the primary cluster plus severe angina at 7 d. Safety outcomes included stroke and bleeding events.
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M a i n results There was a trend toward fewer patients allocated to himdin suffering the primary outcome cluster (6.5 vs 4.4 vs 3.0% in heparin, low- and medium-dose hirudin; P = 0.27 for comparison of heparin and lowdose hirudin; P = 0.047 for comparison of heparin and medium-dose hirudin). The trend was also evident when severe angina was added to the outcome cluster (15.6 vs 12.5 vs 9.4% in heparin, low- and mediumdose hirudin; P = 0.27 for comparison of heparin and low-dose hirudin; P = 0.020 for comparison of heparin and medium-dose himdin). There was an increase in the number of ischemic events in the 24 h following cessation of therapy among patients allocated to low-dose hirudin. Patients allocated to medium-dose hirudin experienced fewer ischemic events following cessation of therapy than those allocated to heparin (P = 0.073) or low-dose himdin (P = 0.076) but did experience a sharp increase in the frequency at days 8 or 9. By 35 and 180 d, hirudin was associated with fewer ischemic events, particularly at a medium-dose. The incidence of major bleeding events was low in all groups (1.1 vs 0.7 vs 1.1% in heparin, low- and medium-dose himdin) although minor bleeding events were significantly more common in the hirudin groups (10.5 vs 16.2 vs 21.3%, respectively).
Conclusion Himdin, particularly in a medium-dose, appeared to be superior to heparin in preventing ischemic events in patients with UA or MI without ST elevation.
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
:OMMENTAR~ Although anti-coagulant therapy with heparin combined with aspirin is more effective than aspirin alone in the treatment of patients with acute coronary syndromes (AC5s), heparin has many disadvantages as an anti-coagulant. Heparin is difficult to maintain in the therapeutic range, requires anti-thrombin III as a co-factor, is not effective against clot-bound fibrin, and can readily be inactwated by plasma proteins and platelet factor 4. Hirudm, a naturally occurring anti-coagulant derived from the saliva of the medicinal leech Hirudo medicinalis, does not suffer from these disadvantages, and directly inhibits both free and clot-bound thrombin. In the GUSTO-Ila trial patients with ACS with and without ST-segment elevation were treated with either IV heparin or IV hirudin (0.6 mg/ kg bolus followed by a 0 2 mg/kg/h infusion without aPi-r adjustment)/The trial was stopped prematurely after 2546 patients were enrolled when unacceptably high cerebral hemorrhage rates occurred, even in hirudin patients who had not received thrombolysis (0.5%). The GUSTO-lib trial was completed in 12 142 patients using a much lower dose of hirudm, 0.1 mg/kg bolus followed by a 0A mg/kg/h infusion. There were few data to suggest that the lower dose of hrudin used in GUSTO-JIb (lower even than the low dose in the OASIS trial) was the most appropriate one, and the possibility that too low a dose was used is one explanation of why hirudin provided little benefit in the study. Death and nonfatal MI by 30 d occurred in 9.8% of heparin patients vs 8.9% of hirudm patients (OR 0.89; 95% Cl 0.79-1.00; P = 0.06) with no significant differences in serious bleeding complications, although moderate bleeding occurred more frequently in hirudin patients (8.8 vs 7.7%; P = 0.03). The OASIS pilot study breathes new life into the debate of whether a medium dose of hirudm is superior to heparin in patients with ACS. We await the results of the OASIS2 trial in which 10 000 patients without ST-segment elevation will be randomized to receive either medium-dose hirudin or heparin. Peter B. Berger, MD
The Mayo Clinic Rochester, MN, USA O t h e r sources 1. The Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO) Ila Investigators. Circulation 1994; 90'. 1631-1637 2. The Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO) lib Investigators. N Engl J Med 1996; 335:775-782
MARCH 1998
Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with a c u t e myocardial ischemia without ST elevation. A pilot study. Circulation 1997; 96:769-777
Objective To compare the effects of hirudin and heparin on ischemic events in patients with acute MI without ST elevation.
Design Randomized, open pilot study with blinded outcome assessment.
Setting 31 clinical centers in Canada.
Patients 909 patients (mean age 65; 66% men) admitted to hospital within 12 h of the onset of chest pain attributable to UA or MI without ST elevation. Intervention Patients were randomized to 72 h treatment with either heparin (n = 371; 5000 U bolus plus 1000-1200 U/h infusion), low-dose hirudin (n = 271; 0.2 mg/kg bolus plus 0.10 mg/kg/h infusion) or medium-dose hirudin (n = 267; 0.4 mg/kg bolus plus 0.15 mg/kg/h infusion). Adjustments in dosing were permitted to maintain aPTT of 60-100 s. M a i n outcome measures The primary outcome cluster was death, new MI or refractory angina at 7 d; secondary outcome cluster included the primary cluster plus severe angina at 7 d. Safety outcomes included stroke and bleeding events.
12
M a i n results There was a trend toward fewer patients allocated to himdin suffering the primary outcome cluster (6.5 vs 4.4 vs 3.0% in heparin, low- and medium-dose hirudin; P = 0.27 for comparison of heparin and lowdose hirudin; P = 0.047 for comparison of heparin and medium-dose hirudin). The trend was also evident when severe angina was added to the outcome cluster (15.6 vs 12.5 vs 9.4% in heparin, low- and mediumdose hirudin; P = 0.27 for comparison of heparin and low-dose hirudin; P = 0.020 for comparison of heparin and medium-dose himdin). There was an increase in the number of ischemic events in the 24 h following cessation of therapy among patients allocated to low-dose hirudin. Patients allocated to medium-dose hirudin experienced fewer ischemic events following cessation of therapy than those allocated to heparin (P = 0.073) or low-dose himdin (P = 0.076) but did experience a sharp increase in the frequency at days 8 or 9. By 35 and 180 d, hirudin was associated with fewer ischemic events, particularly at a medium-dose. The incidence of major bleeding events was low in all groups (1.1 vs 0.7 vs 1.1% in heparin, low- and medium-dose himdin) although minor bleeding events were significantly more common in the hirudin groups (10.5 vs 16.2 vs 21.3%, respectively).
Conclusion Himdin, particularly in a medium-dose, appeared to be superior to heparin in preventing ischemic events in patients with UA or MI without ST elevation.
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
:OMMENTAR~ Although anti-coagulant therapy with heparin combined with aspirin is more effective than aspirin alone in the treatment of patients with acute coronary syndromes (AC5s), heparin has many disadvantages as an anti-coagulant. Heparin is difficult to maintain in the therapeutic range, requires anti-thrombin III as a co-factor, is not effective against clot-bound fibrin, and can readily be inactwated by plasma proteins and platelet factor 4. Hirudm, a naturally occurring anti-coagulant derived from the saliva of the medicinal leech Hirudo medicinalis, does not suffer from these disadvantages, and directly inhibits both free and clot-bound thrombin. In the GUSTO-Ila trial patients with ACS with and without ST-segment elevation were treated with either IV heparin or IV hirudin (0.6 mg/ kg bolus followed by a 0 2 mg/kg/h infusion without aPi-r adjustment)/The trial was stopped prematurely after 2546 patients were enrolled when unacceptably high cerebral hemorrhage rates occurred, even in hirudin patients who had not received thrombolysis (0.5%). The GUSTO-lib trial was completed in 12 142 patients using a much lower dose of hirudm, 0.1 mg/kg bolus followed by a 0A mg/kg/h infusion. There were few data to suggest that the lower dose of hrudin used in GUSTO-JIb (lower even than the low dose in the OASIS trial) was the most appropriate one, and the possibility that too low a dose was used is one explanation of why hirudin provided little benefit in the study. Death and nonfatal MI by 30 d occurred in 9.8% of heparin patients vs 8.9% of hirudm patients (OR 0.89; 95% Cl 0.79-1.00; P = 0.06) with no significant differences in serious bleeding complications, although moderate bleeding occurred more frequently in hirudin patients (8.8 vs 7.7%; P = 0.03). The OASIS pilot study breathes new life into the debate of whether a medium dose of hirudm is superior to heparin in patients with ACS. We await the results of the OASIS2 trial in which 10 000 patients without ST-segment elevation will be randomized to receive either medium-dose hirudin or heparin. Peter B. Berger, MD
The Mayo Clinic Rochester, MN, USA O t h e r sources 1. The Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO) Ila Investigators. Circulation 1994; 90'. 1631-1637 2. The Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO) lib Investigators. N Engl J Med 1996; 335:775-782
MARCH 1998