Drug products: Actilyse, Actilyse Cathflo, Actilyse®, Activase, Cathflo, Cathflo Activase
ATC code: B01AD02
Alteplase is mainly used in ischemic stroke but also in some cases of myocardial infarction and pulmonary embolism.
The risk of symptomatic intracranial hemorrhage after thrombolysis of ischemic stroke has in observational studies been found to be slightly higher in men. In treatment of myocardial infarction women were shown to have a higher risk of bleeding complications. In myocardial infarction a standard dose is used while the dosage in ischemic stroke is calculated by per kilogram body weight usually resulting in lower doses for women.
Pharmacokinetics and dosing
No studies with a clinically relevant sex analysis regarding pharmacokinetics of alteplase have been found. Dosing is done after weight [1, 2]. Compared to other countries, a lower dose is registered for both men and women in Japan .
Meta-analyses of sex differences in placebo-controlled trials of i.v. rt-PA with alteplase 0-6 h after onset of ischemic stroke have been conducted. In one  (1 190 men, 980 women) the odds of good outcome, defined as independence in daily living, was found to be better in men than in women on placebo, while there was no sex difference in patients treated with alteplase [2, 3]. Another meta-analysis of observational studies on outcomes after i.v. rt-PA (12 620 men, 5 221 women) found no sex difference in alteplase treated patients , a finding which has been confirmed in other studies [5-7].
Studies not included in the meta-analyses, analyzing sex differences in outcome after i.v. thrombolysis with alteplase for acute ischemic stroke, report contradictory results. Some studies suggest that women benefit more than men from alteplase treatment [8-12], while others suggest a worse outcome in women [13-16], or no sex differences [6, 17-22].
Using the Safe Implementation of Stroke (SITS), a register of thrombolysis with alteplase in ischemic stroke, several analyses on sex differences have been performed. Based on this material (25 777 men, 19 302 women) multivariate analysis showed male sex to be correlated to symptomatic intracranial hemorrhage and higher mortality (OR 1.19) . In another analysis (43 056 men, 18 412 women) women were found to have a higher adjusted odds ratio for remote intracranial hemorrhage than hemorrhages in the infarction area (adjusted OR 1.23) .
The Global Utilization of Streptokinase and t-PA in Occluded Coronary Artery (GUSTO-I) study (30 600 men, 10 292 women) investigated accelerated alteplase combined with heparin as one of several thrombolytic substances used in acute myocardial infarctions. In contrast to the findings in SITS, female sex together with lower body weight and older age were found in multivariate analyses to be the independent strongest predictors of bleeding complications after thrombolysis [24, 25]. Higher doses of alteplase have in general been used in myocardial infarctions . In ischemic stroke the dose used is 0.9 mg/kg and never >90 mg , in myocardial infarctions an alteplase dose of 100 mg is normally used and in the GUSTO trial the accelerated dose regiment was <100 mg or 100 mg.
A retrospective study of alteplase in ischemic stroke (59 men, 54 women) found no sex differences in the incidence of intracranial or peripheral bleeding .
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
An older meta-analysis study found women to be less likely to be treated with i.v. rt-Pa for ischemic stroke (OR 0.7) . The heterogeneity of the studies in this analysis was large. Possible explanations are the time at which the study was performed and whether thrombolysis had indication in patients > 80 years. Women are in general older at onset of stroke and indication in patients >80 years was unclear until 2012 when the randomized, placebo-controlled, unblinded study IST-3 (1 465 men, 1 570 women, in all 53% >80 years) could show a positive effect also in older stroke patients .
Date of litterature search: 2019-03-04
- Acheampong P, Ford GA. Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012;8:271-81. PubMed
- Reeves MJ, Wilkins T, Lisabeth LD, Schwamm LH. Thrombolysis treatment for acute stroke: issues of efficacy and utilization in women. Womens Health (Lond Engl). 2011;7:383-90. PubMed
- Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke. 2005;36:62-5. PubMed
- Meseguer E, Mazighi M, Labreuche J, Arnaiz C, Cabrejo L, Slaoui T et al. Outcomes of intravenous recombinant tissue plasminogen activator therapy according to gender: a clinical registry study and systematic review. Stroke. 2009;40:2104-10. PubMed
- Kent DM, Buchan AM, Hill MD. The gender effect in stroke thrombolysis: of CASES, controls, and treatment-effect modification. Neurology. 2008;71:1080-3. PubMed
- Förster A, Gass A, Kern R, Wolf ME, Ottomeyer C, Zohsel K et al. Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis. Stroke. 2009;40:2428-32. PubMed
- Nathanson, DP, C; Nyström, T; von Euler, M. Sex, Diastolic Blood Pressure, and Outcome after Thrombolysis for Ischemic Stroke. Stroke Research and Treatment. 2014 sep;-:7. PubMed
- Savitz SI, Schlaug G, Caplan L, Selim M. Arterial occlusive lesions recanalize more frequently in women than in men after intravenous tissue plasminogen activator administration for acute stroke. Stroke. 2005;36(7):1447-51. PubMed
- Buijs JE, Uyttenboogaart M, Brouns R, de Keyser J, Kamphuisen PW, Luijckx GJ. The Effect of Age and Sex on Clinical Outcome after Intravenous Recombinant Tissue Plasminogen Activator Treatment in Patients with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis. 2016;25(2):312-6. PubMed
- Clua-Espuny JL, Ripolles-Vicente R, Forcadell-Arenas T, Gil-Guillen VF, Queralt-Tomas ML, González-Henares MA et al. Sex Differences in Long-Term Survival after a First Stroke with Intravenous Thrombolysis: Ebrictus Study. Cerebrovasc Dis Extra. 2015;5(3):95-102. PubMed
- Lasek-Bal A, Puz P, Kazibutowska Z. Efficacy and safety assessment of alteplase in the treatment of stroke - gender differences. Neurol Res. 2014;36(9):851-6. PubMed
- Lorenzano S, Ahmed N, Falcou A, Mikulik R, Tatlisumak T, Roffe C et al. Does sex influence the response to intravenous thrombolysis in ischemic stroke?: answers from safe implementation of treatments in Stroke-International Stroke Thrombolysis Register. Stroke. 2013;44:3401-6. PubMed
- Spaander FH, Zinkstok SM, Baharoglu IM, Gensicke H, Polymeris A, Traenka C et al. Sex Differences and Functional Outcome After Intravenous Thrombolysis. Stroke. 2017;48(3):699-703. PubMed
- Elkind MS, Prabhakaran S, Pittman J, Koroshetz W, Jacoby M, Johnston KC et al. Sex as a predictor of outcomes in patients treated with thrombolysis for acute stroke. Neurology. 2007;68(11):842-8. PubMed
- Martínez-Sánchez P, Fuentes B, Alonso de Leciñana M, Masjuan J, Simal P, Egido J et al. Female gender is a factor of worse outcome in acute stroke even after thrombolytic treatment. Int J Stroke. 2011;6(4):371-2. PubMed
- Niewada M, Kobayashi A, Sandercock PA, Kamiński B, Członkowska A, International Stroke Trial Collaborative Group. Influence of gender on baseline features and clinical outcomes among 17,370 patients with confirmed ischaemic stroke in the international stroke trial. Neuroepidemiology. 2005;24(3):123-8. PubMed
- Lincoff AM, Califf RM, Ellis SG, Sigmon KN, Lee KL, Leimberger JD et al. Thrombolytic therapy for women with myocardial infarction: is there a gender gap? Thrombolysis and Angioplasty in Myocardial Infarction Study Group. J Am Coll Cardiol. 1993;22(7):1780-7. PubMed
- Shah SH, Liebeskind DS, Saver JL, Starkman S, Vinuela F, Duckwiler G et al. Influence of gender on outcomes after intra-arterial thrombolysis for acute ischemic stroke. Neurology. 2006;66(11):1745-6. PubMed
- Shobha N, Sylaja PN, Kapral MK, Fang J, Hill MD, Investigators of the Registry of the Canadian Stroke Network. Differences in stroke outcome based on sex. Neurology. 2010;74(9):767-71. PubMed
- Tafreshi GM, Raman R, Ernstrom K, Meyer BC, Hemmen TM. Gender differences in acute stroke treatment: the University of California San Diego experience. Stroke. 2010;41(8):1755-7. PubMed
- Al-hussain F, Hussain MS, Molina C, Uchino K, Shuaib A, Demchuk AM et al. Does the sex of acute stroke patients influence the effectiveness of rt-PA?. BMC Neurol. 2014;14(1):60. PubMed
- Hametner C, Kellert L, Ringleb PA. Impact of sex in stroke thrombolysis: a coarsened exact matching study. BMC Neurol. 2015;15(1):10. PubMed
- Mazya MV, Ahmed N, Ford GA, Hobohm C, Mikulik R, Nunes AP et al. Remote or extraischemic intracerebral hemorrhage--an uncommon complication of stroke thrombolysis: results from the safe implementation of treatments in stroke-international stroke thrombolysis register. Stroke. 2014;45:1657-63. PubMed
- Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simoons M et al. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Circulation. 1997;95:2508-16. PubMed
- Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guerci A et al. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy GUSTO-I investigators. JAMA. 1996;275:777-82. PubMed
- IST-3 collaborative group. Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. Lancet Neurol. 2013;12:768-76. PubMed
- Concise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2019-03-14.] länk
- Riksstroke - The Swedish Stroke Register. 2018 [cited 2019-03-25].
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson