Acute Basilar Artery Occlusion in the Basilar Artery International Cooperation Study
Does Gender Matter?
Background and Purpose—Randomized trials suggested a different benefit of intravenous thrombolysis (IVT) and intra-arterial thrombolysis (IAT) between men and women with anterior circulation stroke because of a worse outcome of women in the control group.
Methods—We compared outcome and recanalization in men and women with basilar artery occlusion treated with antithrombotic treatment alone, IVT or combined IVT–IAT, or IAT in the Basilar Artery International Cooperation Study.
Results—Overall, 389 male and 226 female patients were analyzed. In the antithrombotic treatment group, 68 of 111 (61%) men and 47 of 70 (67%) women had a poor outcome defined as a modified Rankin Scale score of 4 to 6 (adjusted risk ratio [aRR], 0.96; 95% CI, 0.75 to 1.24), in the IVT/combined IVT–IAT group, 47 of 77 (61%) men and 24 of 43 (56%) women (aRR, 1.19; 95% CI, 0.89 to 1.60), and in the IAT group, 142 of 185 (77%) men and 71 of 102 (70%) women (aRR, 1.01; 95% CI, 0.88 to 1.17). Mortality was not different between men and women in the antithrombotic treatment group (aRR, 0.80; 95% CI, 0.55 to 1.16), the IVT/combined IVT–IAT group (aRR, 1.11; 95% CI, 0.72 to 1.73), or in the IAT group (aRR, 1.01; 95% CI, 0.75 to 1.36). Insufficient recanalization after combined IVT–IAT or IAT was similar in men and women (23% versus 22%; aRR, 0.92; 95% CI, 0.58 to 1.46).
Conclusions—In patients with acute basilar artery occlusion, no significant gender differences for outcome and recanalization were observed, regardless of treatment modality.
In previous studies on patients with acute stroke, gender-based differences have been observed with respect to clinical presentation, management, and outcomes.1 Studies on patients with ischemic stroke not treated with thrombolysis reported less favorable outcomes for women than for men.2 Further, it has been reported that women benefited more from intravenous thrombolysis (IVT) and intra-arterial thrombolysis (IAT) than men.3,4 The main reason for this difference in favor of women was that nonthrombolyzed women in the control group had a worse outcome than nonthrombolyzed men, whereas in patients undergoing IAT or IVT, outcome was similar in men and women.3,4
Large studies on differences between men and women with acute basilar artery occlusion (BAO) are lacking. The Basilar Artery International Cooperation Study (BASICS) is the largest observational study of consecutive patients with acute BAO and provides multicenter data for secondary analyses.5,6
The aim of this study was to determine the association between gender and outcome in patients from the BASICS registry.
BASICS was a prospective, observational, international registry of consecutive patients presenting with an acute symptomatic and radiologically confirmed BAO. Details of the protocol have been published previously.5,6
For the analyses of gender differences in outcome and mortality, patients were divided into 3 groups: (1) antithrombotic treatment (AT; antiplatelets or systemic anticoagulation) alone, (2) IVT or combined IVT–IAT (cIVT-IAT), and (3) IAT (including thrombolysis, mechanical thrombectomy, stenting, and a combination of these). Risk ratios and corresponding 95% CIs were calculated according to gender for poor clinical outcome (modified Rankin scale score 4 to 6), for death within the 3 treatment subgroups, and for insufficient vessel recanalization (Thrombolysis in Myocardial Infarction grade 0 or 1) after cIVT-IAT and after IAT. Adjusted risk ratios (aRRs) were calculated with Poisson regression. Simultaneous adjustments for the 3 and 4 factors that affected the crude risk ratio most were performed. Missing baseline data (<5% for each variable) were imputed with regression imputation for optimal adjustment for differences between men and women.7
A total of 619 patients from 48 centers were included in BASICS. Four patients were not included because of missing data for gender, and 27 were excluded for further analysis because they did not receive any AT, IVT, or IAT. Of these 27 patients, 26 died and 1 survived, with a modified Rankin Scale score of 5. Of the remaining 588 patients (373 [63%] men; 215 [37%] women), 181 received AT alone, 120 IVT (n=79) or cIVT-IAT (n=41), and 287 IAT. Table 1 shows baseline characteristics of men and women.
Unadjusted risk ratios and aRRs for poor outcome at 1 month according to gender for each treatment group are shown in Table 2. In the AT group, 68 of 111 (61%) men and 47 of 70 (67%) women had a poor outcome (aRR, 0.96; 95% CI, 0.75 to 1.24), in the IVT/cIVT-IAT group, 47 of 77 (61%) men and 24 of 43 (56%) women (aRR, 1.19; 95% CI, 0.89 to 1.60), and in the IAT group, 142 of 185 (77%) men and 71 of 102 (70%) women (aRR, 1.01; 95% CI, 0.88 to 1.17). The Figure shows detailed clinical outcomes in men and women.
Mortality did not differ between men and women in any group (AT group [aRR, 0.80; 95% CI, 0.55 to 1.16]; IVT/cIVT-IAT group [aRR, 1.11; 95% CI, 0.72 to 1.73]; IAT group [aRR, 1.01; 95% CI, 0.75 to 1.36]).
Recanalization was investigated in 37 of 44 (91%) patients after cIVT-IAT and in 252 of 287 (88%) patients after IAT. Insufficient recanalization (Thrombolysis in Myocardial Infarction score of 0 or 1) after cIVT-IAT or IAT was similar in men and women (23% versus 22%; aRR, 0.92; 95% CI, 0.58 to 1.46). The rate of symptomatic intracranial hemorrhage was equal in men (30 of 343; 8%) and women (17 of 215; 8%).
In this secondary analysis of BASICS, no significant gender differences in clinical outcome were observed, regardless of treatment modalities. Recanalization rates after IAT and cIVT-IAT were similar for men and women.
The lack of an association between gender and outcome for patients treated with IVT, IAT, or cIVT-IAT is in line with the results of previous studies.3,4,8 However, the similar outcome of men and women with BAO in the AT group is in contrast with previous studies performed on patients with mainly or exclusively anterior circulation stroke. In a pooled analysis of randomized trials of acute stroke patients, women treated with IV recombinant tissue plasminogen activator derived a greater benefit than men independently of other variables.3 This effect of gender on outcome was caused primarily by a worse outcome of women among the control patients who were not treated with thrombolysis.
Similar results were reported in patients treated with intra-arterial pro-urokinase for acute ischemic stroke resulting from M1 or M2 segment occlusion of the middle cerebral artery.4 In a secondary analysis of the PROACT-2 study, an association between gender and treatment effect was demonstrated, with women showing a larger benefit (20% absolute risk reduction for achieving a modified Rankin Scale score ≥2) compared with men (10% absolute risk reduction).4 Again, the reason for this difference was that in the control group, women had a worse outcome than men, whereas in the thrombolytic group, outcome was similar in men and women. This gender-based effect in the PROACT-2 trial was not attributable to differences in vessel recanalization rates between women and men, and the reasons for these differences remained unexplained. An observational study including patients with middle cerebral artery or internal carotid artery occlusion showed no difference between men and women of recanalization rate and clinical outcome after IAT with urokinase and is in line with the PROACT-2 data.9 In contrast, a smaller observational study showed higher recanalization rates and more frequent early clinical neurological improvements after intravenous recombinant tissue plasminogen activator among women than men.10
The Canadian Alteplase for Stroke Effectiveness Study reported similar clinical outcome and mortality for men and women treated with IVT.11
The reasons for the differences between the gender-based analyses of BASICS with regard to treatment effect of AT therapy and those of previous studies are difficult to explain. Differences in coagulation and endogenous fibrinolysis between men and women were reported previously and might contribute to different outcomes according to gender in patients with acute stroke treated with AT.12,13 Higher factor VII:C levels in women than men have been described in healthy persons and in patients with noninsulin-dependent diabetes mellitus.14,15 Moreover, plasminogen activator inihibitor-1 levels were shown to be higher in women than men with diabetes mellitus.15 However, it is difficult to understand why such gender differences would have different effects in acute ischemic stroke in the anterior and posterior circulation, and it seems unlikely that differences of coagulation and the fibrinolytic system exist between patients with anterior and posterior circulation stroke. In the absence of a pathophysiological explanation of the contrary, we believe our study suggests a lack of a difference in treatment response between men and women with BAO.
BASICS was an observational registry and has the inherent limitations of a nonrandomized study. Therefore, our results are prone to known and unknown biases that limit the strength of the evidence and preclude definite conclusions on gender differences in patients with BAO. However, we did adjust for age, National Institutes of Health Stroke Scale score at time of treatment, location of occlusion, and deficit at time of treatment in multivariable analyses, whereas no major imbalance was found among other patient characteristics between men and women overall and in the AT group specifically.
In conclusion, in this observational study, men and women with acute BAO did not show any significant differences in clinical outcome and vessel recanalization regardless of treatment modalities.
Participating centers (with number of patients and names of investigators) were as follows. Australia (6): University of Melbourne (A.M. Weber, G.A. Donnan); Belgium (21): University Hospital, Leuven (11; V. Thijs), University Hospital St. Luc, Brussels (10; A. Peeters); Brazil (18): University of Rio de Janeiro (11; G. de Freitas), University of Sao Paolo, Hospital das Clinicas (5; A.B. Conforto), Federal University of Sao Paolo (2; M. Miranda-Alves, A. Massaro); Finland (14): University of Helsinki (14; P. Ijäs, T. Bogoslovsky, P.J. Lindsberg); Germany (224): German Stroke Database (77; C. Weimar, J. Benemann, K. Kraywinkel), University Hospital Freiburg (20; C. Haverkamp), Leipzig University (15; D. Michalski), University Hospital Essen (10; C. Weimar), Medical University Hannover (8; K. Weissenborn), 6; University Hospital, Magdeburg (M. Goertler), 4; University Hospital Rostock (A. Kloth), Kliniken Neuruppin (3; A. Bitsch), Bürger Hospital, Stuttgart (3; T. Mieck), Heinrich Braun Krankenhaus, Zwickau (2; J. Machetanz), Sofien and Hufeland Hospital, Weimar (2; P. Möller), University Hospital, Ulm (2; R. Huber), Hospital Heidenheim (2; S. Kaendler), St. Elisabeth Hospital, Ravensburg (47; C. Rueckert), TEMPiS Network Bavaria (38; H. Audebert, R. Müller, B. Vatankhah), University of Munich (26; T. Pfefferkorn, T.E. Mayer), Universitätsklinikum Mannheim (19; K. Szabo), Dresden University (13; C. Disque), Klinikum Minden (2; O. Busse), University of Heidelberg (2; C. Berger, W. Hacke); Israel (19): Sheba Medical Center (19; Y. Schwammenthal, D. Orion, D. Tanne); Italy (6): University of Turin (5; M. Bergui), University of Bologna (1; E. Pozzati); Netherlands (82): St. Antonius Hospital, Nieuwegein (40; W.J. Schonewille), University Medical Center Utrecht (22; W.J. Schonewille, A. Algra, L.J. Kappelle), University Medical Center Groningen (6; G.J. Luijckx, P. Vroomen), Academic Medical Center, Amsterdam (5; M.D. Vergouwen, Y. Roos, J. Stam), Gelre Hospital (4; P. Bienfait), University Medical Center Nijmegen (3; F.E. de Leeuw), St. Elisabeth Hospital, Tilburg (1; P. de Kort), Erasmus Medical Center, Rotterdam (1; D. Dippel); Scotland (23): Southern General Hospital, Glasgow (23; T. Baird, K. Muir); Spain (25): Hospital Val ‘d Hebron, Barcelona (13; J. Pagola, M. Ribo, C. Molina), Hospital Virgen del Rocio, Sevilla (12; A. Gonzales, A. Gil-Peralta); Sweden (3): Lund University (3; B. Norrving); Switzerland (127): Inselspital, Bern (52; M. Arnold, U. Fischer, J. Gralla, H. Mattle, G. Schroth), Centre Hospitalier Universitaire Vaudois, Lausanne (39; P. Michel), University Hospital, Basel (24; S.T. Engelter, S. Wetzel, P. Lyrer), University Hospital Zurich (8; J. Gandjour, N. Michael, R. Baumgartner), Kantonsspital, St. Gallen (2; B. Tettenborn), Kantonsspital, Aarau (2; H. Hungerbuehler); United States (51): Stanford Stroke Center, Palo Alto, Calif (29; C.A. Wijman, A. Finley Caulfield, M. Lansberg, N. Schwartz, C. Venkatasubramanian), University of Texas, Houston (22; Z. Garami, S. Bogaard, F. Yatzu, J. Grotta).
M.A. and U.F. had the idea for this study, wrote the first draft of the manuscript and the final report, and contributed equally to this study. W.J.S. had the idea for the BASICS registry, developed the Internet database, encouraged international colleagues to contribute data to the study, analyzed and interpreted data, and contributed to subsequent versions of the manuscript. A.A. and A.C. performed the statistical analyses and contributed to subsequent versions of the manuscript. J.G., O.F., D.T., L.J.K., and H.P.M. assisted in the recruitment of patients and contributed to the design of the study and to subsequent versions of the manuscript.
Sources of Funding
BASICS was an independent, investigator-initiated registry. No external support was received. Development of the BASICS database was supported by the Department of Neurology of the University Medical Center Utrecht, The Netherlands.
Participating centers and the number of patients recruited per center are listed in the Appendix.
- Received June 18, 2010.
- Accepted July 29, 2010.
Di Carlo A, Lamassa M, Baldereschi M, Pracucci G, Basile AM, Wolfe CD, Giroud M, Rudd A, Ghetti A, Inzitari D; European BIOMED Study of Stroke Care Group. Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital-based registry. Stroke. 2003; 34: 1114–1119.
Niewada M, Kobayashi A, Sandercock PA, Kaminski B, Czlonkowska A. International Stroke Trial Collaborative Group. Influence of gender on baseline features and clinical outcomes among 17 370 patients with confirmed ischemic stroke in the International Stroke Trial. Neuroepidemiology. 2005; 24: 123–128.
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: 62–65.
Hill MD, Kent DM, Hinchey J, Rowley H, Buchan AM, Wechsler LR, Higashida RT, Fischbein NJ, Dillon WP, Gent M, Firszt CM, Schulz GA, Furlan AJ; PROACT-2 investigators. Sex-based differences in the effect of intra-arterial treatment of stroke: analysis of the PROACT-2 study. Stroke. 2006; 37: 1322–1325.
Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H, Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra A; BASICS Study Group. Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study. Lancet Neurol. 2009; 8: 724–730.
Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol. 1995; 142: 1255–1264.
Messeguer E, Mazighi M, Labreuche J, Arnaiz C, Cabrejo L, Slaoui T, Guidoux C, Olivot JM, Abboud H, Lapergue B Raphaeli G, Klein IF, Lavallée PC, Amarenco P. Outcomes of intravenous recombinant tissue plasminogen activator therapy according to gender. A clinical registry study and systematic review. Stroke. 2009; 40: 2104–2110.
Arnold M, Kappeler L, Nedeltchev K, Brekenfeld C, Fischer U, Keserue B, Remonda L, Schroth G, Mattle HP. Recanalization and outcome after intra-arterial thrombolysis in middle cerebral artery and internal carotid artery occlusion: does sex matter? Stroke. 2007; 38: 1281–1285.
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: 1447–1451.
Kent DN, Buchan AN, Hill MD. The gender effect in stroke thrombolysis: of CASES, controls and treatment-effect modification. Neurology. 2008; 71: 1080–1083.
Baliesen L, Bailey J, Epping PH, Schulte H, Van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body weight, smoking, alcohol, pill-using and menopause. Thromb Haemost. 1985; 54: 475–479.
Mansfield MW, Heywood DM, Grant PJ. Sex differences in coagulation and fibrinolysis in white subjects with non-insulin dependent diabetes mellitus. Arterioscler Thromb Vasc Biol. 1996; 16: 160–164.