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Pharmacotherapeutic group: Antithrombotic agents. ATC code: B01AD02.
Pharmacology: Pharmacodynamics: Mode of Action: The active ingredient of ACTILYSE is alteplase, a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.
Pharmacodynamic effects: Due to its relative fibrin-specificity, alteplase at a dose of 100 mg leads to a modest decrease of the circulating fibrinogen levels to about 60% at 4 hours, which is generally reverted to more than 80% after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20% and 35% respectively after 4 hours and increase again to more than 80% at 24 hours. A marked and prolonged decrease of the circulating fibrinogen level is only seen in few patients.
Clinical efficacy and safety: Acute Myocardial Infarction (AMI) patients: Two ACTILYSE dose regimens have been studied in patients experiencing acute myocardial infarction. The comparative efficacy of these two regimens has not been evaluated.
Accelerated infusion in AMI patients: Accelerated infusion of ACTILYSE was studied in an international, multi-center trial (GUSTO) that randomized 41,021 patients with acute myocardial infarction to four thrombolytic regimens. Administration of 100 mg ACTILYSE over 90 minutes, with concomitant intravenous heparin infusion, led to a lower mortality after 30 days (6.3%) as compared to the administration of streptokinase, 1.5 million IU over 60 minutes, with subcutaneous or intravenous heparin (7.3%). The 1% absolute decrease in 30-day mortality for ACTILYSE compared to streptokinase was statistically significant (p = 0.001).
ACTILYSE-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.
A large scale mortality trial (ASSENT 2) in approx. 17,000 patients showed that alteplase and tenecteplase are therapeutically equivalent in reducing mortality (6.2% for both treatments, at 30 days). The use of tenecteplase was associated with a significantly lower incidence of non-intracranial bleedings compared to alteplase (26.4% versus 28.9%, p = 0.0003). The reduction of the risk of bleeding is likely to be related to the increased fibrin specificity of tenecteplase and to its weight adapted regimen.
3-hour infusion in AMI patients: In a double-blind, randomized trial (5013 patients) comparing ACTILYSE to placebo (ASSET study) patients infused with ACTILYSE within 5 hours of the onset of symptoms of acute myocardial infarction experienced improved 30-day survival compared to those treated with placebo. At 1 month, the overall mortality rates were 7.2% for the ACTILYSE-treated group and 9.8% for the placebo-treated group (p = 0.001). This benefit was maintained at 6 months for ACTILYSE-treated patients (10.4%) compared to those treated with placebo (13.1%, p = 0.008).
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% versus 48.5%, p = 0.01). Patients treated with ACTILYSE had a 19% reduction in infarct size, as measured by cumulative release of HBD (α-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.
In a placebo controlled trial (LATE) in 5711 AMI patients with onset of symptoms between 6 and 24 hours a 100 mg ACTILYSE over 3 hours infusion was compared with placebo. A non-significant reduction of 14.1% (95% CI 0 - 28.1%, p > 0.05) in 35-day-mortality was observed with ACTILYSE. In a pre-specified survival analysis in patients treated within 12 hours of symptom onset, a significant 25.6% reduction in mortality in favour of ACTILYSE (95% CI 6.3 - 45%; p = 0.023) was observed.
Acute massive pulmonary embolism patients: In a comparative randomized trial of alteplase versus urokinase in 63 patients with angiographically documented acute massive pulmonary embolism both treatment groups experienced a significant reduction in pulmonary embolism-induced pulmonary hypertension. Pulmonary haemodynamics improved significantly faster with ACTILYSE than with urokinase.
Acute ischaemic stroke patients: Several studies have been carried out in the field of acute ischaemic stroke. The NINDS study is the only study without an upper age limit, i.e. which also included patients over 80 years. All other randomized trials have excluded patients over 80 years of age. Thrombolysis in AIS patients should be evaluated on individual benefit-risk basis.
Two placebo-controlled, double-blind trials (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 haemorrhage (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.
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 point 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-months outcome associated with ACTILYSE treatment using the following stroke assessment scales: Barthel Index (score ≥ 95), Modified Rank in Scale (score ≤ 1), Glasgow Outcome Scale (score = 1), and the NIHSS (score ≤ 1). A second study (NINDS-Part 2, n = 333) assessed clinical outcome at 3 months as the primary outcome. A favourable outcome was defined as minimal or no disability using the four stroke assessment scales: Barthel Index (score ≥ 95), Modified Rankin Scale (score ≤ 1), Glasgow Outcome Scale (score = 1), and NIHSS (score ≤ 1). The odds ratio for favourable outcome in the ACTILYSE group was 1.7 (95% CI; 1.2 - 2.6). Compared to placebo there was 13% absolute increase in the number of patients with minimal or no disability (mRS 0 - 1) (OR 1.7; 95% CI 1.1 - 2.6). There was also a consistent benefit seen with ACTILYSE on other neurologic and disability scales. Secondary analyses demonstrated consistent functional and neurological improvement within all four stroke scales as indicated by median scores. These results were highly consistent with the 3-months outcome treatment effects observed in the Part 1 study.
The incidences of all-cause 90-day mortality, SICH, and new ischemic stroke following ACTILYSE treatment compared to placebo indicated a significant increase in symptomatic SICH (according to NINDS definition) following ACTILYSE treatment within 36 hours (ACTILYSE 6.4%; Placebo 0.65%). In ACTILYSE-treated patients, there were no increases compared to placebo in the incidences of 90-day mortality or severe disability (ACTILYSE 20.5%; Placebo 17.3%).
A pooled analysis of 2775 patients from 6 major randomized clinical trials (NINDS part 1 and 2, two ECASS trial and ATLANTIS part A and B) evaluated the disability status of patients treated with ACTILYSE or placebo. In this analysis, the odds of a favourable outcome at 3 months increased as the time to treatment with ACTILYSE decreased. A SICH rate was seen in 5.9% of patients treated with ACTILYSE versus 1.1% of controls (p < 0.0001) This analysis strongly confirms that rapid treatment with ACTILYSE is associated with better outcomes at 3 months. It also provides evidence that the therapeutic window may extend as far out as 4.5 hours.
In a large observational study (SITS-MOST: The Safe Implementation of Thrombolysis in Stroke-Monitoring Study) the safety and efficacy of ACTILYSE for acute stroke treatment within 3 hours in a routine clinical setting was assessed and compared with results from randomised clinical trials (RCTs). All patients had to be compliant with the European summary of the product characteristics of ACTILYSE. Treatment and outcome data of 6483 patients from 285 centres in 14 European countries were collected. Primary outcome were symptomatic intracranial haemorrhage within 24 hours and mortality at 3 months. The rate of SICH found in SITS-MOST was comparable with the SICH rate as reported in randomized trials 7.3% (95% CI 6.7 - 8.0) in SITS-MOST versus 8.6% (95% CI 6.1 - 11.1) in RCTs. Mortality was 11.3% (95% CI 10.5 - 12.1) in SITS-MOST versus 17% (95% CI 13.9 - 20.7) in RCTs. The results of SITS-MOST indicate that, the routine clinical use of ACTILYSE within 3 hours of stroke onset is as safe as reported in randomized clinical trials.
The ECASS III trial as a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3 to 4.5 hours. The study enrolled patients with measurable neurological deficit compliant with the European summary of product characteristics (SmPC) except the time-window. After exclusion of brain haemorrhage or major infarction by computed tomography, patients with acute ischemic stroke were randomized in a 1:1 double-blind fashion to intravenous alteplase (0.9 mg/kg bodyweight) or placebo. The primary end point was disability at 90 days, dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6) outcome. The principal secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included mortality, SICH, and serious adverse events. A total of 821 patients were (418 alteplase/403 placebo) randomized. More patients achieved favourable outcome with alteplase (52.4%) versus placebo (45.2%; odds ratio [OR], 1.34; 95% CI 1.02 - 1.76; p = 0.038). On the global analysis, outcome was also improved (OR, 1.28; 95% CI 1.00 - 1.65; p = 0.048). The incidence of any ICH/SICH was higher with alteplase versus placebo (any SICH 27.0% versus 17.6%, p = 0.0012; SICH by NINDS definition 7.9% versus 3.5%, p = 0.006; SICH by ECASS III definition 2.4% versus 0.2%, p = 0.0008). Haemorrhagic transformations were seen in 22.24% of patients in the alteplase group versus 16.13% in the placebo group. Parenchymatous haemorrhages occurred in 4.78% with alteplase versus 1.49% with placebo.
Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; p = 0.681). The results of ECASS III show that ACTILYSE between 3 and 4.5 hours after symptom onset significantly improves clinical outcomes in patients with acute ischeamic stroke. Since generally, the net clinical benefit for alteplase decreases over time, the benefits and risks need to be carefully weighed and earlier treatment increases the probability of a favourable outcome. Pooled data demonstrate that the net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours.
The safety and efficacy of ACTILYSE for acute ischaemic stroke treatment up to 4.5 hours time onset to treatment (OTT) has been assessed by an ongoing AIS registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke registry). Primary outcome and mortality data of 21,566 patients in the 0 to 3 hours time window were compared with data from 2,376 patients treated between 3 to 4.5 hours after onset of AIS (data from 2010). The incidence of symptomatic intracerebral haemorrhage (according to the NINDS definition) was found to be slightly higher in the 3 to 4.5 hours time window (7.4%) as compared with the up to 3 hours time window (7.1%; adjusted odds ratio 95% CI :1.18 (0.99-1.41) p = 0.06). Mortality rates at 3 months were similar for the 3 to 4.5 hours time window (12.0%) with the 0 to 3 hours time window 12.3%.
Pharmacokinetics: ACTILYSE is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma clearance 550 - 680 ml/min.). The relevant plasma half-life T½ alpha is 4 - 5 minutes. This means that after 20 minutes less than 10% of the initial value is present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-life of about 40 minutes was measured.
