Published online before print November 29, 2004, doi: 10.1161/01.STR.0000150515.15576.29
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2005;36:62.)
© 2005 American Heart Association, Inc.
Original Contributions |
Sex-Based Differences in Response to Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke
A Pooled Analysis of Randomized Clinical Trials
From the Institute for Clinical Research and Health Policy Studies (D.M.K., L.L.P., H.P.S.), Tufts–New England Medical Center Boston, Mass; the Department of Neurology (P.R.), University of Heidelberg, Germany; and the Department of Clinical Neuroscience (M.D.H.), Foothills Medical Centre, University of Calgary, Canada.
Correspondence to Dr David M. Kent, Institute for Clinical Research and Health Policy Studies, Tufts–New England Medical Center, 750 Washington Street, #63, Boston, MA, 02111. E-mail dkent1{at}tufts-nemc.org
Background and Purpose— Women experience worse outcomes after stroke compared with men. Prior work has suggested sex-based differences in coagulation and fibrinolysis markers in subjects with acute stroke. We explored whether sex might modify the effect of recombinant tissue plasminogen activator (rtPA) on outcomes in patients with acute ischemic stroke.
Methods— Using a combined database including subjects from the National Institute of Neurological Disorders and Stroke (NINDS), Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) A and B, and the Second European Cooperative Acute Stroke Study (ECASS II) trials, we examined 90-day outcomes in patients randomized to rtPA versus placebo by sex. We used logistic regression to control for potential confounders.
Results— Among 988 women treated between 0 and 6 hours from symptom onset, patients receiving rtPA were significantly more likely than those receiving placebo to have a modified Rankin Score 
1 (40.5% versus 30.3%, P<0.0008). Among 1190 men, the trend toward benefit in the overall group did not reach statistical significance (38.5% versus 36.7%, P=0.52). An unadjusted analysis showed that women were significantly more likely to benefit from rtPA compared with men (P=0.04). Controlling for age, baseline National Institutes of Health Stroke Scale, diabetes, symptom onset to treatment time, prior stroke, systolic blood pressure, extent of hypoattenuation on baseline computed tomography scan and several significant interaction terms (including onset to treatment time–by-treatment and systolic blood pressure–by treatment) did not substantially change the strength of the interaction between gender and rtPA treatment (P=0.04).
Conclusions— In this pooled analysis of rtPA in acute ischemic stroke, women benefited more than men, and the usual gender difference in outcome favoring men was not observed in the thrombolytic therapy group. For patients presenting at later time intervals, when the risks and benefits of rtPA are more finely balanced, sex may be an important variable to consider for patient selection.
Key Words: clinical trials • outcome • thrombolytic therapy • sex factors • stroke, acute
This article has been cited by other articles:
 |
|
 |
|
  S. Prabhakaran and M. S.V. Elkind Vive la difference!: On potential sex differences in response to thrombolysis Neurology, September 30, 2008; 71(14): 1048 - 1049. [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kent, A. M. Buchan, and M. D. Hill The gender effect in stroke thrombolysis: Of CASES, controls, and treatment-effect modification Neurology, September 30, 2008; 71(14): 1080 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Saposnik, M. D. Hill, M. O'Donnell, J. Fang, V. Hachinski, M. K. Kapral, and on behalf of the investigators of the Registry of Variables Associated With 7-Day, 30-Day, and 1-Year Fatality After Ischemic Stroke Stroke, August 1, 2008; 39(8): 2318 - 2324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Reid, D. Dai, G. J. Gubitz, M. K. Kapral, C. Christian, and S. J. Phillips Gender Differences in Stroke Examined in a 10-Year Cohort of Patients Admitted to a Canadian Teaching Hospital Stroke, April 1, 2008; 39(4): 1090 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Saposnik, A. Baibergenova, M. O'Donnell, M. D. Hill, M. K. Kapral, V. Hachinski, and On behalf of the Stroke Outcome Research Canada (S Hospital volume and stroke outcome: Does it matter? Neurology, September 11, 2007; 69(11): 1142 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Saver Hemorrhage After Thrombolytic Therapy for Stroke: The Clinically Relevant Number Needed to Harm Stroke, August 1, 2007; 38(8): 2279 - 2283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P A Ringleb, C. Schwark, M Kohrmann, S Kulkens, E Juttler, W Hacke, and P D Schellinger Thrombolytic therapy for acute ischaemic stroke in octogenarians: selection by magnetic resonance imaging improves safety but does not improve outcome J. Neurol. Neurosurg. Psychiatry, July 1, 2007; 78(7): 690 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Foerch, B. Misselwitz, M. Humpich, H. Steinmetz, T. Neumann-Haefelin, M. Sitzer, and for the Arbeitsgruppe Schlaganfall Hessen Sex Disparity in the Access of Elderly Patients to Acute Stroke Care Stroke, July 1, 2007; 38(7): 2123 - 2126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rundek Do Women Have Worse Outcome After Stroke Caused by Intracranial Arterial Stenosis? Stroke, July 1, 2007; 38(7): 2025 - 2027. [Full Text] [PDF]
|
|
|
|
|
|
M. Arnold, L. Kappeler, K. Nedeltchev, C. Brekenfeld, U. Fischer, B. Keserue, L. Remonda, G. Schroth, and H. P. Mattle Recanalization and Outcome After Intra-Arterial Thrombolysis in Middle Cerebral Artery and Internal Carotid Artery Occlusion: Does Sex Matter? Stroke, April 1, 2007; 38(4): 1281 - 1285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.S.V. Elkind, S. Prabhakaran, J. Pittman, W. Koroshetz, M. Jacoby, K. C. Johnston, and for the GAIN Americas Investigators Sex as a predictor of outcomes in patients treated with thrombolysis for acute stroke Neurology, March 13, 2007; 68(11): 842 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Benchenane, H. Castel, M. Boulouard, R. Bluthe, M. Fernandez-Monreal, B. D. Roussel, J. P. Lopez-Atalaya, S. Butt-Gueulle, V. Agin, E. Maubert, et al. Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory J. Cell Sci., February 15, 2007; 120(4): 578 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kent, H. P. Selker, R. Ruthazer, E. Bluhmki, and W. Hacke Can Multivariable Risk-Benefit Profiling Be Used to Select Treatment-Favorable Patients for Thrombolysis in Stroke in the 3- to 6-Hour Time Window? Stroke, December 1, 2006; 37(12): 2963 - 2969. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nedeltchev, U. Fischer, M. Arnold, P. Ballinari, T. Haefeli, L. Kappeler, C. Brekenfeld, L. Remonda, G. Schroth, and H. P. Mattle Long-Term Effect of Intra-Arterial Thrombolysis in Stroke Stroke, December 1, 2006; 37(12): 3002 - 3007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Reid, G. J. Gubitz, S. J. Phillips, M. J. Reeves, Y. Deng, and J. Gargano IV tissue plasminogen activator use in acute stroke: experience from a statewide registry. Neurology, November 14, 2006; 67(9): 1724 - 1725. [Full Text] [PDF]
|
|
|
|
 |
|
 M.D. Hill, A.M. Demchuk, T.A. Tomsick, Y.Y. Palesch, J.P. Broderick, and on behalf of the IMS-1 Investigators Using the Baseline CT Scan to Select Acute Stroke Patients for IV-IA Therapy. AJNR Am. J. Neuroradiol., September 1, 2006; 27(8): 1612 - 1616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Hill, D. M. Kent, J. Hinchey, H. Rowley, A. M. Buchan, L. R. Wechsler, R. T. Higashida, N. J. Fischbein, W. P. Dillon, M. Gent, et al. Sex-Based Differences in the Effect of Intra-Arterial Treatment of Stroke: Analysis of the PROACT-2 Study Stroke, September 1, 2006; 37(9): 2322 - 2325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sandercock and S. Lewis Sex-Based Differences in the Effect of Intra-Arterial Treatment of Stroke: A Plea to Stop Torturing the Old Data and Do Large Trials! Stroke, September 1, 2006; 37(9): 2198 - 2198. [Full Text] [PDF]
|
|
|
|
|
|
S. D. Legge, G. Saposnik, Y. Nilanont, and V. Hachinski Neglecting the Difference: Does Right or Left Matter in Stroke Outcome After Thrombolysis? Stroke, August 1, 2006; 37(8): 2066 - 2069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Shah, D. S. Liebeskind, J. L. Saver, S. Starkman, F. Vinuela, G. Duckwiler, R. Jahan, D. Kim, N. Sanossian, P. Vespa, et al. Influence of gender on outcomes after intra-arterial thrombolysis for acute ischemic stroke Neurology, June 13, 2006; 66(11): 1745 - 1746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stramba-Badiale, K. M. Fox, S. G. Priori, P. Collins, C. Daly, I. Graham, B. Jonsson, K. Schenck-Gustafsson, and M. Tendera Cardiovascular diseases in women: a statement from the policy conference of the European Society of Cardiology Eur. Heart J., April 2, 2006; 27(8): 994 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kent, M. D. Hill, S. I. Savitz, and M. Selim Gender Differences in tPA-Related Arterial Recanalization * Response: Stroke, December 1, 2005; 36(12): 2529 - 2530. [Full Text] [PDF]
|
|
|
|
|
|
G. Saposnik, S. Di Legge, F. Webster, and V. Hachinski Predictors of major neurologic improvement after thrombolysis in acute stroke Neurology, October 25, 2005; 65(8): 1169 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ovbiagele and J. L. Saver The smoking-thrombolysis paradox and acute ischemic stroke Neurology, July 26, 2005; 65(2): 293 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. I. Savitz, G. Schlaug, L. Caplan, and M. Selim Arterial Occlusive Lesions Recanalize More Frequently in Women Than in Men After Intravenous Tissue Plasminogen Activator Administration for Acute Stroke Stroke, July 1, 2005; 36(7): 1447 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mann, D. M. Kent, L. L. Price, H. P. Selker, P. Ringleb, and M. D Hill Sex-Based Differences in Response to Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke * Response: Stroke, May 1, 2005; 36(5): 929 - 929. [Full Text] [PDF]
|
|