ACTILYSE®

Efficacy

Acute myocardial infarction (AMI)

Accelerated dose regimen of ACTILYSE® significantly reduced mortality rate compared with streptokinase

A multinational multicenter trial, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO), which studied the therapeutic effects of accelerated dose regimen of ACTILYSE®, included total of 41,021 patients with AMI randomized into receiving 4 types of thrombolytic treatments. The 30-day mortality rate of patients who received 100 mg of ACTILYSE® infusion over 90 minutes with concomitant intravenous heparin infusion (6.3%) was lower than those who received 1.5 million IU of streptokinase infusion over 60 minutes with subcutaneous or intravenous heparin (7.3%). The 1% absolute reduction in the 30-day mortality rate in the ACTILYSE® group was statistically significant compared with the streptokinase group (p=0.001).

ACTLYSE®-treated patients showed higher infarct related vessel patency rates at 60 and 90 minutes after thrombolysis than the streptokinase-treated patients. No differences in patency rates were noted at 180 minutes or longer.¹

Three-hour dose regimen of ACTILYSE® significantly improved mortality rate up to 6 months and reduced adverse cardiac outcomes

In a double-blind, randomized trial (n =5,013) comparing 3-hour infusion of ACTILYSE® to placebo (Anglo-Scandinavian Study of Early Thrombolysis [ASSET] study), patients infused with ACTILYSE® within 5 hours of AMI symptom onset experienced improved 30-day survival compared to the placebo arm. At 1 month, the overall mortality rates were 7.2% for the ACTILYSE® group and 9.8% for the placebo group (p=0.001). At 6 months, the benefit of reducing overall mortality rate for ACTILYSE®-treated patients was unchanged compared to the placebo arm (10.4% vs. 13.1%, p=0.008).¹

In a double-blind, randomized trial (721 patients) comparing ACTILYSE® to placebo, patients infused with ACTILYSE® within 5 hours of the onset of symptoms experienced improved ventricular function 10–22 days after treatment compared to the placebo group, when global ejection fraction was measured by contrast ventriculography (50.7% vs 48.5%, p=0.01). Patients treated with ACTILYSE® had a 19% reduction in infarct size, as measured by cumulative release of HBD (⍺-hydroxybutyrate dehydrogenase) activity compared to placebo treated patients (p=0.001). Patients treated with ACTILYSE® had significantly fewer episodes of cardiogenic shock (p=0.02), ventricular fibrillation (p<0.04) and pericarditis (p=0.01) compared to patients treated with placebo. Mortality at 21 days in ACTILYSE® treated patients was reduced to 3.7% compared to 6.3% in placebo treated patients (1-sided p=0.05). Although these data do not demonstrate unequivocally a significant reduction in mortality for this study, they do indicate a trend that is supported by the results of the ASSET study.¹

Acute massive pulmonary embolism (PE)

ACTILYSE® improved pulmonary hemodynamics significantly faster than urokinase

A randomized trial comparing therapeutic effects of alteplase and urokinase in 63 patients with confirmed acute massive PE assessed by pulmonary angiography. Both groups had significantly reduced PE-induced pulmonary hypertension. The ACTILYSE® treatment group had significantly faster improvement in the lung hemodynamic profile than that of the urokinase group.¹

Acute ischemic stroke

ACTILYSE® significantly improved bodily and neurological functions in patients with symptom onset within 3 hours

Two placebo-controlled, double-blind trials (The National Institute of Neurological Disorders and Stroke [NINDS] t-PA Stroke Trial, Part 1 and Part 2) enrolled patients with measurable neurological deficit who could complete screening and begin study treatment within 3 hours from symptom onset. A cranial computerized tomography (CT) scan was performed prior to treatment to rule out the presence of symptomatic intracranial hemorrhage (SICH). Patients were also excluded for the presence of conditions related to risks of bleeding, for minor neurological deficit, for rapidly improving symptoms prior to initiating study treatment, or for blood glucose of < 50 mg/dL or > 400 mg/dL. Patients were randomized to receive either 0.9 mg/kg ACTILYSE® (maximum of 90 mg), or placebo. ACTILYSE® was administered as a 10% initial bolus over 1 minute followed by continuous intravenous infusion of the remainder over 60 minutes.¹

The initial study (NINDS-Part 1, n=291) evaluated neurological improvement at 24 hours after stroke onset. The primary endpoint, the proportion of patients with a 4 or more points improvement in the National Institutes of Health Stroke Scale (NIHSS) score or complete recovery (NIHSS score = 0), was not significantly different between treatment groups. A secondary analysis suggested improved 3-month outcome associated with ACTILYSE® treatment using the following stroke assessment scales: Barthel Index, Modified Rankin Scale (mRS), Glasgow Outcome Scale, and the NIHSS. A second study (NINDS-Part 2, n=333) assessed clinical outcomes at 3 months as the primary outcome. A favorable outcome was defined as minimal or no disability using the four stroke assessment scales: Barthel Index (score ≥ 95), mRS (score ≤1), Glasgow Outcome Scale (score = 1) and NIHSS (score ≤1). Compared with the placebo-treated patients, the patients treated with ACTILYSE® had an odds ratio (OR) of 1.7 to reach a favorable outcome (95% confidence interval [CI]: 1.2-2.6). Compared with placebo, the absolute increase in the number of ACTILYSE®-treated patients with very low or no disability (mRS 0-1) was 12.6%. In other neurological function scales and energy loss scales, ACTILYSE® also has a fairly consistent benefit. The results of the secondary analysis from the median scores of four stroke scales demonstrated fairly consistent improvements in physical function and neurological function. These results are consistent with the 3-month treatment effect observed in the first part of the study.¹

ACTILYSE® used at 3 to 4.5 hours from symptom onset significantly increased patients with favorable outcome without increasing SICH risk

A meta-analysis included total of 6,756 patients in 9 global clinical trials administering alteplase intravenously was done by the Stroke Thrombolysis Trialists’ collaborative group (STT). Total of 2,812 patients were treated at 3 to 4.5 hours from the onset of their symptoms (1,375 received alteplase and 1,437 were in the controlled group). The alteplase group had significantly higher portion of patients with favorable outcome of mRS 0-1 compared to the controlled group (35.3% vs. 30.1%; OR 1.26; 95% CI 1.05-1.51). Further analysis showed that compared with patients who were treated within 3 hours from symptoms onset, patients treated at 3 to 4.5 hours with alteplase would not have increased risk for SICH (by Safe Implementation of Thrombolysis in Stroke-Monitoring Study [SITS-MOST] definition, 3.1% vs. 3.0%).²

A clinical study in Taiwan published in 2018 reviewed patients from 16 hospitals for the past 10 years. Compared with the controlled patients, 374 patients who received alteplase at 3 to 4.5 hours from onset had significantly more ratio of favorable outcome (mRS 0-1) after 3 months (OR 1.75; 95% CI 1.27-2.42), slightly higher risk of SICH (by NINDS definition) (OR 1.96; 95% CI 0.93-4.13) and no significantly different risk of mortality within 3 months (OR 1.04; 95% CI 0.61-1.78).²

Low-dose ACTILYSE® led to lower risk for symptomatic intracranial hemorrhage

An observational study using data from Taiwan Stroke Registry by A-Ching Chao, et al showed that the SICH (by NINDS definition) rate were 12.41% in 71-to-80-year-old population and 7.35% in the overall population after alteplase treatment of 0.9 mg/kg body weight for acute ischemic stroke. The 3-month mortality rate was 12.41% in the 71-to-80-year-old population and 8.3% in the overall population.¹

According to the results of Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial involving Asian patients with acute ischemic stroke, the use of low-dose alteplase could not reach non-inferiority in the endpoint of 90-day mortality and disability rates when compared with the standard dose. However, the results of ENCHANTED trial and the observational study by A-Ching Chao, et al showed that patients who received low-dose alteplase had a lower chance of developing SICH.¹