Clinical background
Intravenous thrombolysis with alteplase is the only approved pharmacological reperfusion treatment in acute ischaemic stroke. The dose is weight-based and the regimen specific: a bolus over one minute followed by an infusion over one hour. A dosing error may mean either underdosing with failure to recanalise or overdosing with an increased risk of bleeding. The calculator eliminates arithmetical errors during the acute assessment, when the time from symptom onset to treatment is the single most important determinant of outcome and every minute counts.
The dosing was established in the NINDS trial (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group) published in 1995, the first randomised double-blind study to show that intravenous alteplase within three hours of symptom onset improved clinical outcome at three months [1]. Since then the regimen, at 0.9 mg/kg up to a maximum of 90 mg, has remained unchanged in all major thrombolysis trials and is the dose stated in current guidelines.
Calculating the dose
The total dose is calculated from the patient's weight as follows:
The weight is given in kilograms, with a lower limit of 30 kg and an upper limit of 200 kg in the calculator. At a weight of 100 kg or more the total dose is capped at 90 mg, of which the bolus is 9 mg and the infusion 81 mg.
The derivation cohort consisted of 624 patients with acute ischaemic stroke randomised to either alteplase (0.9 mg/kg, max 90 mg) or placebo within three hours of symptom onset in the NINDS trial [1]. The study population was adult; the median patient had a mild to moderate stroke with an NIHSS (National Institutes of Health Stroke Scale) score of around 8 to 14. The primary outcome measure was global clinical outcome at 90 days, measured with a composite of four scales (the Barthel index, the modified Rankin scale, the Glasgow Outcome Scale and the NIHSS). Alteplase increased the probability of a favourable outcome with a global odds ratio of 1.7 (95% CI 1.2 to 2.6) [1].
The dosing regimen was validated in ECASS III (European Cooperative Acute Stroke Study), which extended the treatment window to 3 to 4.5 hours from symptom onset [2]. In that study, 821 patients were randomised to alteplase 0.9 mg/kg or placebo. Alteplase gave a favourable outcome at 3 to 4.5 hours: 52.4% had a modified Rankin scale score of 0 or 1 at 90 days compared with 45.2% for placebo (OR 1.34; 95% CI 1.02 to 1.76) [2]. The rate of symptomatic intracranial haemorrhage was 2.4% with alteplase and 0.2% with placebo, but mortality did not differ significantly (7.7% and 8.4% respectively) [2].
Interpretation in practice
The calculation gives three values to be administered in sequence. In a patient weighing 70 kg, the total dose is 63 mg, of which 6.3 mg is given as a bolus over one minute and the remaining 56.7 mg is infused over 60 minutes. In a patient weighing 120 kg, the total dose is capped at 90 mg, of which 9 mg is given as a bolus and 81 mg as an infusion. The upper dose limit of 90 mg must not be exceeded whatever the patient's weight.
The bolus and the infusion should follow one another immediately, without interruption. The infusion should be started immediately after the bolus and completed exactly 60 minutes after it is begun. The blood pressure should be kept below 185/110 mmHg before and during the infusion, and monitored closely during and after it.
Treatment should be started as early as possible within the approved window, that is, within 4.5 hours of symptom onset. Time to treatment is strongly linked to outcome; the shorter the time from symptom onset to thrombolysis, the better the outcome. Where large-vessel occlusion is suspected, thrombolysis should be combined with mechanical thrombectomy according to current criteria.
Validation and performance
The regimen of 0.9 mg/kg with a maximum of 90 mg has been used consistently in every large thrombolysis trial since NINDS and is the dose recommended in the 2019 AHA/ASA guidelines [3]. In ECASS III, which extended the window to 3 to 4.5 hours, both safety and efficacy were confirmed with the same dose [2]. Symptomatic intracranial haemorrhage occurred in 2.4% of the alteplase group in ECASS III, compared with 6.4% in the NINDS trial, which partly reflects differences in study population and time window [1, 2].
A meta-analysis of three phase III trials with a total of 4,094 patients showed that tenecteplase 0.25 mg/kg was non-inferior to alteplase 0.9 mg/kg for an excellent functional outcome (mRS 0 or 1) at 90 days, with a pooled risk difference of 0.03 (95% CI −0.00 to 0.06) against a non-inferiority margin of −4% [4]. The risk of symptomatic intracranial haemorrhage (RD 0.00; 95% CI −0.01 to 0.01) and mortality at 90 days (RD 0.01; 95% CI −0.01 to 0.02) did not differ significantly between the agents [4]. Tenecteplase has the advantage of being given as a single bolus, which simplifies management, particularly during transfer to another hospital ("drip and ship").
The question of capping the dose at 90 mg for patients over 100 kg has been discussed in the light of increasing obesity in the population. A retrospective single-centre study of 301 patients, of whom 21% received a dose below 0.9 mg/kg because of the cap, found a significant association between a higher dose per kilogram and a favourable outcome (mRS 0 to 1 at 90 days) with an adjusted odds ratio of 1.7 (p = 0.027) [5]. The study was retrospective and single-centre, and the results should be interpreted with caution, but they highlight that capping the dose at 90 mg for patients over 100 kg may potentially result in suboptimal treatment.
Limitations
This dosing applies only to acute ischaemic stroke. Alteplase in acute myocardial infarction uses a different regimen (usually an accelerated regimen up to 100 mg over 1.5 hours), and the doses must not be confused. In pulmonary embolism a different dose is used (100 mg over two hours), and in central retinal artery occlusion a lower dose may be used.
The regimen should not be used without first confirming that the patient meets the criteria for thrombolysis: the time window, the absence of contraindications (for example recent surgery, active bleeding, anticoagulant treatment at higher intensity), a controlled blood pressure and the exclusion of haemorrhage on CT of the brain. The dose reflects not the severity of the illness but the patient's weight; a low dose in a light patient is not a sign that the stroke is mild.
For patients over 100 kg, capping the dose at 90 mg means that the actual dose per kilogram of body weight is below 0.9 mg/kg. There is no strong evidence that a higher dose would be safer or more effective in this group, but the question has not been definitively answered [5]. In clinical practice, 90 mg is retained as the upper limit in line with current guidelines [3].
Tenecteplase may be an alternative to alteplase within 4.5 hours and is given as a single bolus of 0.25 mg/kg (max 25 mg), but it is not universally approved for the stroke indication in every regulatory setting and may require specific approval or off-label use [4].
References
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995. PMID: 7477192
- Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008. PMID: 18815396
- Powers WJ, Rabinstein AA, Ackerson T et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019. PMID: 31662037
- Xiong Y, Wang L, Li G et al. Tenecteplase versus alteplase for acute ischaemic stroke: a meta-analysis of phase III randomised trials. Stroke Vasc Neurol 2024. PMID: 37640500
- Garavaglia J, Sherman J, Yetzer H et al. Impact of Tissue Plasminogen Activator Dosing on Patients Weighing More Than 100 kg on 3-Month Outcomes in Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2017. PMID: 28129994
