Global Utilization of Streptokinase and TPA for Occluded Arteries IIb - GUSTO IIB

Description:

Hirudin vs. heparin for death/reinfarction in acute MI.

Hypothesis:

Potent, direct inhibition of thrombin improves clinical outcomes. Because thrombin plays a pivotal role in the pathogenesis of acute coronary thrombosis, a direct thrombin inhibitor such as recombinant hirudin may be more effective in reducing the risk of nonfatal myocardial infarction (MI) than the indirect thrombin inhibitor heparin.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 12,142
Mean Follow Up: not given
Mean Patient Age: 65
Female: 30
Mean Ejection Fraction: not given

Patient Populations:

Chest discomfort within the previous 12 hours associated either with transient or persistent ST-segment elevation or depression of more than 0.5mm or with persistent, definite T-wave inversion of more than 1mm

Exclusions:

Warfarin at the time of enrollment
Active bleeding
History of stroke
Renal insufficiency (serum creatinine >2.0 mg/dL (177 æmol/L)
Relative contraindication to hirudin therapy
Systolic blood pressure >200 mmHg
Diastolic blood pressure >110 mmHg
Women of child-bearing potential
If a patient were enrolled and was subsequently found to have a serum concentration > 2.0 mg/dL at base line, the study-drug infusion was discontinued

Secondary Endpoints:

Composite endpoint of death, MI, or disability from stroke. Bleeding complications were classified as follows: severe or life-threatening bleeding was defined as intracranial hemorrhage or bleeding that caused hemodynamic compromise requiring intervention. Moderate was defined as bleeding that required transfusion, but was not associated with any hemodynamic compromise.

Drug/Procedures Used:

The study medication (hirudin or heparin) was infused for a minimum of three and a maximum of five days. Each patient received either heparin and hirudin placebo or hirudin and heparin placebo on a double-blind basis.
Desulfated form of recombant hirudin was initially given in a bolus dose of 0.1 mg/kg of body weight IV, followed by a continuous infusion of 0.1 mg/kg/h.
Heparin was initially given in a bolus dose of 5000 U IV, followed by a continuous infusion of 1000 U per hour.

The activated partial-thromboplastin time was determined before the study drug was infused, at 6 hours, 12 hours, and 24 hours. Then a minimum of once a day during its administration. The activated partial-thromboplastin time was adjusted by using a standard nomogram to maintain the value between 60 and 85 seconds. In patients undergoing coronary intervention during the administration of the study drug, specific guidelines allowed the use of a bolus infusion of heparin or placebo and hirudin or placebo to achieve an activated clotting time of at least 300 to 350 seconds and to preserve the double-blind nature of the study.

Concomitant Medications:

For patients with ST-segment elevation, thrombolytic therapy included either streptokinase (SK) or a regimen of accelerated tissue plasminogen activator (tPA) in which tPA is infused rapidly over a period of 1-1/2 hours so that two thirds of the dose is given in the first 30 minutes. Other adjunctive medications given and procedures performed during hospitalization included aspirin, nitrates (oral, topical, IV), calcium-channel blockers, beta blockers (oral, IV), angiotensin-converting enzyme (ACE) inhibitors, coronary arteriography, percutaneous transluminal coronary angioplasty (PTCA), and coronary-artery bypass grafting (CABG).

Coronary angiography, percutaneous coronary revascularization, and CABG were discouraged for the duration of the study-drug infusion unless there was evidence of recurrent ischemia. For patients undergoing elective CABG, it was recommended that the study drug be stopped six to eight hours before surgery, with heparin therapy initiated (if indicated) on an open basis. In cases of emergency CABG, unblinding of the study drug was permitted to avoid the inappropriate use of protamine and to facilitate the control of hemostasis.

Principal Findings:

Infusing clinically effective hirudin while maintaining an acceptable rate of bleeding complications is very dependent on dosage level (GUSTO IIb = bolus dose of 0.1 mg/kg of body weight IV, followed by a continuous infusion of 0.1 mg/kg/h).

During the infusion, 94.6% of patients assigned to heparin required an adjustment in the dosage compared with 71.5% of those assigned to hirudin (P <0.001).

After 24 hours of therapy, the risk of death or MI was significantly lower in the group assigned to hirudin (1.3% for hirudin vs. 2.1% for heparin; odds ratio, 0.61; 95% confidence interval, 0.46 to 0.81; P = 0.001).

The difference in this risk between groups was also significant 48 hours after the initiation of therapy (2.3% and 3.1% respectively; odds ratio, 0.73; 95% confidence interval, 0.59 to 0.91; P = 0.001).

At 30 days, 8.9% of the hirudin group and 9.8% of the heparin group had reached the primary endpoint (odds ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P = 0.06).

The effect of hirudin was not affected by ST-segment status.

However, there were no significant differences between hirudin and heparin for other clinical events such as recurrent ischemia, heart failure, arrhythmias, or cardiogenic shock.

The secondary composite endpoint of death, MI, or disability from stroke was reached in 9.2% of the hirudin group and 10.2% of the heparin group (P = 0.07).

Although not a statistically significant difference, there was a higher incidence of intracranial bleeding among patients without ST-segment elevation who were treated with hirudin, as compared with those treated with heparin (0.2% [6 events] vs. 0.02% [1 event]). Also, there was a higher overall rate of moderate bleeding in the group treated with hirudin (8.8% vs. 7.7%, P = 0.03).

After adjustment for baseline differences between thrombolytic groups, the rates of 30-day death or reinfarction were 9.1% for SK with hirudin, 10.3% for t-PA with hirudin, 10.5% for t-PA with heparin and 14.9% for SK with heparin (for treatment heterogeneity: chi-square 4.5, df 1, p = 0.03), suggesting that the beneficial treatment effect of hirudin was limited to the SK-treated patients.

Interpretation:

The higher doses of heparin and hirudin used in the GUSTO IIa trial were associated with an unacceptable rate of bleeding complications, resulting in the early termination of GUSTO IIa and initiation of GUSTO IIb with a redesigned protocol.

Although hirudin improves the clinical outcomes of death and MI at 30 days after infusion, the extent of the benefit was small (11% reduction in risk) and of marginal statistical significance. The small benefit at 30 days was similar in patients with ST-segment elevation and those without ST-segment elevation.

However, hirudin significantly reduced the risk of death and MI at 24 and 48 hours.
There appear to be significant favorable interactions between hirudin and SK. Similar interactions between concomitant agents and thrombolytic therapies have been observed for gp IIb/IIIa antagonists.

References:

1. N Engl J Med 1996;335:775-782. Design and final results
2. New Engl J Med 1997;336:1621-8. PTCA vs tPA analysis
3. J Am Coll Cardiol 1998;31:1493-8.Thrombolytic interactions

Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Stable Ischemic Heart Disease, Lipid Metabolism, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Stroke, Myocardial Infarction, Thrombin, Body Weight, Heparin, Hirudins, Platelet Membrane Glycoprotein IIb, Nomograms, Shock, Cardiogenic, Streptokinase, Thromboplastin, Heart Failure, Coronary Thrombosis, Tissue Plasminogen Activator


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