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Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 Pilot Study - TAMI-8
Description:
TAMI-8 was a multicenter, open-label, dose-ranging trial, designed to establish evidence of physiologic activity, as well as to evaluate safety of abciximab among patients receiving recombinant tissue-type plasminogen activator (r-PA) fibrinolysis for ST-segment elevation myocardial infarction (STEMI).
Hypothesis:
Administration of intravenous (IV) abciximab to subjects receiving r-PA will result in inhibition of platelet aggregation, and rate of bleeding among subjects receiving abciximab will be comparable to that in control subjects.
Study Design
Study Design:
Patients Enrolled: 70
Mean Follow Up: 10 weeks
Mean Patient Age: 54 ± 9 years
Female: 27
Patient Populations:
Age 18-76 years, and presentation with STEMI within six hours of symptom onset
Exclusions:
Standard exclusion criteria for fibrinolysis, previous splenectomy, history of vasculitis, percutaneous coronary intervention between the time of administration of r-PA and abciximab, or known hypersensitivity to murine monoclonal antibodies or other murine proteins
Primary Endpoints:
Platelet aggregation inhibition, rate of bleeding complications, and recurrent ischemic events
Drug/Procedures Used:
Subjects presenting with STEMI within six hours of symptom onset were enrolled at six centers. All subjects received fibrinolysis with r-PA 100 mg IV. Subjects then received abciximab as a single bolus IV injection at escalating doses at a different point of time after fibrinolysis, in the following distribution:
• Thirty-two subjects received abciximab 15 hours following fibrinolysis (0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, or 0.25 mg/kg). These subjects received heparin as 5000 U IV bolus, followed by 1000 U/h infusion 90 minutes after initiation of r-PA.
• Fourteen subjects received abciximab six hours following fibrinolysis (0.15 mg/kg, 0.20 mg/kg, or 0.25 mg/kg). These subjects received heparin as 2500 U IV bolus, followed by 800 U/h infusion 90 minutes after initiation of r-PA.
• Fourteen subjects received abciximab three hours following fibrinolysis (0.15 mg/kg, 0.20 mg/kg, or 0.25 mg/kg). These subjects received heparin as 2500 U IV bolus, followed by 800 U/h infusion 90 minutes after initiation of r-PA.
• Ten subjects were studied as controls, and received no abciximab after fibrinolysis.
Subjects underwent a complete neurologic examination twice daily. Blood samples were drawn prior to administration of abciximab, as well as 30 minutes, and 1, 2, 6, 12, 24, and 48 hours after administration. Coronary angiography was performed if clinically indicated. Studies of platelet aggregation to 20 mcmol/l adenosine diphosphate were performed at three of the participating clinical centers. All subjects underwent clinical follow-up after four weeks.
Concomitant Medications:
• r-PA 100 mg IV: 60 mg in the first hour with 10% bolus, followed by an infusion of 40 mg over two hours
• Heparin IV, with goal partial thromboplastin time 65-80 seconds
• Aspirin 160-325 mg/day
• Metoprolol 15 mg IV in three divided doses, unless contraindication existed
Principal Findings:
A total of 70 subjects were enrolled (abciximab, 60; control, 10). Mean age in the treatment group was 54 years, mean body weight was 83 kg, and 26% of subjects were female. Of the 34 subjects in the abciximab group who underwent coronary angiography, 60% had multivessel disease.
Maximal platelet aggregation was found in the two-hour samples, and occurred most consistently at 0.25 mg/kg of abciximab. Aggregation returned to 50% of baseline at six hours, and nearly completely to baseline by 24 hours. Likewise, bleeding time returned to baseline within 24 hours.
Thrombocytopenia occurred in seven subjects treated with abciximab. There were no intracranial bleeds in the study population. Rates of major and minor bleeding were higher with increasing doses of abciximab. Five (50%) of 10 control subjects, and 15 (25%) of 60 subjects in the abciximab group developed a major hemorrhagic event. Of those, 55% were related to an invasive procedure, most commonly, coronary artery bypass surgery. Twelve (20%) of 60 subjects treated with abciximab required blood product transfusions, compared with four (40%) of control subjects.
Overall incidence of recurrent ischemic events was similar in abciximab (8 of 60 subjects) and control (2 of 10 subjects) groups. Of the 42 patients receiving the two highest doses of abciximab, four (9.5%) developed recurrent ischemia.
There was one death from ventricular fibrillation in the trial, in a patient with three-vessel coronary artery disease, who received an abciximab dose of 0.20 mg/kg three hours following fibrinolysis, and was awaiting coronary artery bypass grafting.
Interpretation:
Administration of IV abciximab to patients undergoing r-PA fibrinolysis for STEMI was associated with a profound inhibition of platelet aggregation. Addition of abciximab to r-PA, aspirin, and IV heparin was associated with a low rate of recurrent ischemia and bleeding rates comparable to a control group.
References:
Kleiman NS, Ohman EM, Califf RM, et al. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy. Results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 Pilot Study. J Am Coll Cardiol 1993;22:381-9.
Keywords: Bleeding Time, Myocardial Infarction, Follow-Up Studies, Platelet Aggregation Inhibitors, Ventricular Fibrillation, Body Weight, Heparin, Immunoglobulin Fab Fragments, Fibrinolytic Agents, Neurologic Examination, Coronary Angiography, Platelet Aggregation, Fibrinolysis, Recombinant Proteins, Coronary Artery Bypass, Tissue Plasminogen Activator, Thrombocytopenia
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