RESUMEN
BACKGROUND AND PURPOSE: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide. METHODS: CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 µg/kg bolus and 2-hour infusion at 0.75 µg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients. RESULTS: From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34-85; interquartile range, 65-80) and median National Institute of Health stroke scale score was 12 (range, 6-26; interquartile range, 9-16). One sICH (3.7%; 95% confidence interval, 0.7%-18%) was observed. CONCLUSIONS: These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Fibrinolíticos/efectos adversos , Péptidos/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica/efectos adversos , Activador de Tejido Plasminógeno/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada/efectos adversos , Eptifibatida , Femenino , Fibrinolíticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Péptidos/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Activador de Tejido Plasminógeno/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial demonstrated safety of recombinant tissue-type plasminogen activator (r-tPA) plus eptifibatide in acute ischemic stroke (AIS). CLEAR-ER randomized AIS patients (5:1) to 0.6 mg/kg r-tPA plus eptifibatide versus standard r-tPA (0.9 mg/kg). Interventional Management of Stroke III randomized AIS patients to r-tPA plus endovascular therapy versus standard r-tPA. Albumin in Acute Stroke Part 2 randomized patients to albumin±r-tPA versus saline±r-tPA. Our aim was to compare outcomes in CLEAR-ER combination arm patients to propensity score-matched r-tPA only subjects in Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III. METHODS: The primary outcome was 90-day severity-adjusted modified Rankin score (mRS) dichotomization based on baseline National Institutes of Health Stroke Scale. Secondary outcomes were 90-day mRS dichotomization as excellent (mRS, 0-1); mRS dichotomization as favorable (mRS, 0-2); and nonparametric analysis of the ordinal mRS. RESULTS: Eighty-five combination arm CLEAR-ER subjects were matched with 169 Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III trials' r-tPA only patients (controls). Median age in CLEAR-ER and control subjects was 68years; median National Institutes of Health Stroke Scale in the CLEAR-ER subjects was 11 and in control subjects 12. At 90 days, CLEAR-ER subjects had a nonsignificantly greater proportion of patients with favorable outcomes (45% versus 36%; unadjusted relative risks, 1.24; 95% confidence intervals, 0.91-1.69; P=0.18). Secondary outcomes were 52% versus 34% excellent outcomes (relative risks, 1.51; 95% confidence intervals, 1.13-2.02; P=0.007); 60% versus 53% favorable outcome (relative risks, 1.13; 95% confidence intervals, 0.90-1.41; P=0.31); and ordinal Cochran-Mantel-Haenszel P=0.10. CONCLUSION: r-tPA plus eptifibatide showed a favorable direction of effect that was consistent across multiple approaches for AIS outcome evaluation. A phase III trial to establish the efficacy of r-tPA plus eptifibatide for improving AIS outcomes is warranted.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Péptidos/administración & dosificación , Puntaje de Propensión , Accidente Cerebrovascular/tratamiento farmacológico , Activador de Tejido Plasminógeno/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/diagnóstico , Método Doble Ciego , Quimioterapia Combinada , Eptifibatida , Femenino , Fibrinolíticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Accidente Cerebrovascular/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator (rt-PA) in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial found that intravenous rt-PA plus eptifibatide (combination arm) in acute ischemic stroke (AIS) was safe and had a direction of effect that would justify a phase III trial. CLEAR-ER had unanticipated imbalances between treatment groups. We compared the rates of symptomatic intracranial hemorrhage (sICH) and good outcomes for combination therapy patients in the CLEAR-ER trial to a matched cohort of rt-PA patients from the National Institute of Neurological Disorders and Stroke (NINDS) trial. METHODS: CLEAR-ER was a multicenter, double-blind, randomized study; rt-PA-eligible AIS patients were randomized to .6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and .75mcg/kg/min two-hour infusion) versus standard rt-PA (.9 mg/kg). For this analysis, we matched 1:1 CLEAR-ER combination therapy patients with rt-PA arm NINDS trial patients. Patients were matched by age, gender, race, baseline modified Rankin Scale score, baseline National Institutes of Health Stroke Scale (NIHSS) score, and stroke onset to rt-PA time. RESULTS: Fifty-four matches were made. One (1.8%) sICH occurred in each group (odds ratio [OR] 1.00, 95% confidence interval [CI] .01-78.50). At 90 days, 51.8% of the CLEAR-ER group had good outcomes versus 46.3% in the NINDS rt-PA group (OR 1.30, 95% CI .57-2.96). For subjects with baseline NIHSS score > 12 (CLEAR-ER median NIHSS score), 38.5% of the CLEAR-ER group had good outcomes versus 23.1% in the NINDS group (OR 2.33, 95% CI .60-9.02). CONCLUSIONS: The safety and direction of effect of eptifibatide plus rt-PA were confirmed. A phase III trial is needed to determine the efficacy of eptifibatide plus rt-PA for improving long-term outcomes after AIS.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Péptidos/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica , Activador de Tejido Plasminógeno/administración & dosificación , Anciano , Isquemia Encefálica/diagnóstico , Evaluación de la Discapacidad , Método Doble Ciego , Quimioterapia Combinada , Eptifibatida , Femenino , Fibrinolíticos/efectos adversos , Humanos , Infusiones Intravenosas , Hemorragias Intracraneales/inducido químicamente , Masculino , Persona de Mediana Edad , Péptidos/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Proteínas Recombinantes/administración & dosificación , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/diagnóstico , Terapia Trombolítica/efectos adversos , Factores de Tiempo , Activador de Tejido Plasminógeno/efectos adversos , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND AND PURPOSE: In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial. METHODS: CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression. RESULTS: Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52). CONCLUSIONS: The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00894803.