The sole effective and approved drug to treat acute ischemic

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1 Thrombolysis in Stroke Despite Contraindications or Warnings? Benedikt Frank, MD; James C. Grotta, MD; Andrei V. Alexandrov, MD; Erich Bluhmki, PhD; Patrick Lyden, MD; Atte Meretoja, MD; Nishant K. Mishra, MBBS-PhD; Ashfaq Shuaib, MD; Nils G. Wahlgren, MD; Christian Weimar, MD; Kennedy R. Lees, MD, for the VISTA Collaborators Downloaded from by guest on June 14, 2018 Background and Purpose Intravenous thrombolysis with alteplase is approved for acute ischemic stroke, but its use is limited by numerous contraindications and warnings arising from trial selection criteria or expert opinions. We examined outcomes from alteplase-treated versus untreated patients, registered in a trials archive, according to presence or absence of specified contraindications and warnings. Methods We analyzed 90-day modified Rankin Scale across the whole distribution of scores using the Cochran Mantel Haenszel test, with adjustment for age and baseline National Institutes of Health Stroke Score, followed by proportional odds logistic regression analysis to estimate the odds ratios for preferred outcome. Results We used data from 9613 ischemic stroke patients of whom 2755 were treated with thrombolysis. Adjusted odds ratios showed a broad trend of more favorable 3-month outcome associated with alteplase treatment versus no treatment in various subgroups of patients with contraindications and warnings; for example, 1.40 (95% confidence interval [CI], ) in patients aged >80 (n=1805), 1.50 (95% CI, ) in patients with combined history of prior stroke and diabetes mellitus (n=672), 1.42 (95% CI, ) in patients on prior single antiplatelet agent (n=1626), 2.20 (95% CI, ) in patients on oral anticoagulation, and International Normalized Ratio 1.7 (n=157), 1.50 (95% CI, ) in patients with baseline glucose >180 (n=879), and 1.57 (95% CI, ) in patients with pretreatment National Institutes of Health Stroke Score >22 (n=620). Conclusions This comprehensive retrospective analysis of various contraindications and warnings provides reassurance about benefits and risks of intravenous alteplase treatment in common clinical situations. (Stroke. 2013;44: ) Key Words: contraindications exclusion outcomes stroke management thrombolysis The sole effective and approved drug to treat acute ischemic stroke (AIS) can be offered only to a minority of patients, in part, because of the short therapeutic time window of alteplase, as well as numerous additional contraindications. Current contraindications largely derive from the inclusion and exclusion criteria used in the randomized controlled thrombolysis trials, which aimed at selecting patients showing the clearest benefit with optimal safety. 1 4 Additionally, the majority of these criteria were based on expert opinion, with little to no empirical support. A post hoc subgroup analysis of the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial encouraged no further subselection of AIS patients, such as by age or stroke severity. 5 Nevertheless, regulatory approval documents contain several contraindications and warnings that may provide little to no safety benefit. Information about outcome in patients treated outside the approved criteria is mainly restricted to single-case reports and analyses of registry data that lack an untreated control group. 6 8 The recently published third International Stroke Trial (IST-3) provides data from patients treated outside the European license. 9 However, chiefly age and time were the characteristics violating the approval criteria (53% were aged >80, and 72% were treated >3 hours after stroke onset). From neuroprotectant trials within the Virtual International Stroke Trials Archive (VISTA), we have careful recordings of patients, both thrombolyzed and nonthrombolyzed. 10 In these trials, the decision for treatment with alteplase was made independently from the original trial inclusion and exclusion criteria, providing the opportunity to assess the benefits and Received August 22, 2012; final version accepted December 20, From the Department of Medicine and Therapeutics, Faculty of Medicine, University of Glasgow, Western Infirmary, UK (B.F., K.R.L.); Department of Neurology, University of Duisburg-Essen, Essen, Germany (B.F., C.W.); Department of Neurology, University of Texas Medical School at Houston, Houston, TX (J.C.G.); Department of Neurology, University of Alabama at Birmingham Hospital, Birmingham, AL (A.V.A.); Department of Statistics, Boehringer Ingelheim, Bieberach, Germany (E.B.); Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); Florey Neuroscience Institutes and Department of Medicine, Melbourne Brain Centre, University of Melboure, Melbourne, Australia, and Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland (A.M.); Stanford Stroke Center, Stanford University Medical Center, Palo Alto, CA (N.K.M.); Stroke Research Unit, Faculty of Medicine and Dentistry, University of Alberta, Canada (A.S.); and Department of Neurology, Karolinska University Hospital, Stockholm, Sweden (N.G.W.). The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Benedikt Frank, MD, Department of Neurology, University of Duisburg-Essen, Hufelandstr 55, Essen, Germany. benedikt.frank@uni-due.de 2013 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 728 Stroke March 2013 risks of treatment with alteplase in subgroups of trial patients with warnings and contraindications for thrombolysis. We aim at providing valuable information to simplify and expand future guidelines and licences. Methods Data Source and Patients We collected demographics, clinical data, and functional outcome measures from neuroprotectant trials in ischemic stroke conducted from 1998 to 2008 and held within VISTA. 10 Data were anonymized in relation to patients and trials. We excluded trials that had tested effects of thrombolysis or of any drug now known to influence outcome after stroke, and patients who lacked relevant baseline or outcome information: baseline National Institutes of Health Stroke Score (NIHSS), age, alteplase administration as standard of care, occurrence of adverse events or serious adverse events (SAE), and modified Rankin Scale (mrs) at day 90. We collected data from 9613 ischemic stroke patients, of whom 9046 have been enrolled within 6 hours and 567 within 12 hours after symptom onset into a neuroprotectant trial. A total of 8438 out of 9613 (87.8%) were enrolled during a period, and in a country where treatment with intravenous thrombolysis had been approved for use within 3 hours after stroke onset. A total of 2755 out of 8438 (32.6%) were thrombolyzed as per institutional practice at the point of trial conduct. Thrombolyzed patients were on average enrolled in the year 2004 (±2.6 years) and nonthrombolyzed patients in the year 2002 (±3.5 years). Warnings and Contraindications We searched the VISTA database for all available variables providing information on warnings and contraindications for treatment with alteplase. We assigned patients as either having or not having each of these, and excluded patients with missing data from analyses of the corresponding variable. Patients can feature in more than 1 subgroup. The definitions of warnings and contraindications available for analysis within VISTA are given in Table 1. Downloaded from by guest on June 14, 2018 Table 1. Contraindications and Warnings Abbreviation Definition Contraindication Warning Age/Medical History Age >80 Aged over 80 EU-L EU-G, US-L (>75) Stroke & Diabetes History of previous stroke and diabetes mellitus EU-L Hemostasis Single Antiplatelets Use of prior single antiplatelets* EU-L/G Dual Antiplatelets Use of prior dual antiplatelets* EU-L/G OAC Use of prior oral anticoagulation* EU-L, US-L OAC & INR 1.7 Oral anticoagulation and INR 1.7 EU-L, US-L OAC & INR >1.7 Oral anticoagulation and INR > 1.7 EU-L, US-L/G INR >1.7 International Normalized Ratio > 1.7 US-L APTT >39 Activated partial thromboplastin time >39 seconds without recent US-L (stop treatment) use of heparin Platelets <100 Platelet count <100 giga/l EU-L, US-L/G EU-G Glucose/BP Glucose >400 Glucose level >400 mg/dl, respectively, 22.2 mmol/l EU-L EU-G, US-L Glucose >180 Glucose level >180 mg/dl, respectively, 10 mmol/l EU-G Glucose <50 Glucose level <50 mg/dl, respectively, 2.8 mmol/l EU-L, US-G EU-G, US-L BPSYS 185 Systolic blood pressure 185 mm Hg EU-L/G, US-L/G BPDIA 110 Diastolic blood pressure 110 mm Hg EU-L/G, US-L/G IV Antihypertensives Use of intravenous antihypertensives on the day of enrolment EU-L CT Findings Early Changes Edema, dense middle cerebral artery sign, loss of insular ribbon, lenticular hypodensity, acute infarction, sulcal effacement, or ASPECT-score of 8 or 9 Major Early Changes Mass effect, infarction of >1/3 of the middle cerebral artery territory, midline shift, or EU-L, US-G (>1/3) US-L ASPECT-score of 7 ASPECT 7 ASPECT-score of 7 NIHSS NIHSS >22 NIHSS of >22 EU-L (>25) US-L/G NIHSS <6 Minor deficit, arbitrarily defined as NIHSS < 6 EU-L, US-G US-L All Results of all patients were given for reference ASPECT-Score indicates Alberta Stroke Program Early CT-Score; CT, Computer tomograpy; EU-G, European Stroke Organization Guidelines; 11 EU-L, European License; 12 NIHSS, National Institutes of Health Stroke Scale; US-G, American Heart Association/American Stroke Association Guidelines; 13 and US-L, American License. 14 *Within 24 hours of enrolment which was known to be less than 14 hours after stroke event. Baseline variables were recorded at time of enrolment and not necessarily at time of thrombolysis. More detailed timing of intravenous antihypertensives was not available. CT findings were gathered from baseline CT scans with a known scan time of 3 hours from stroke onset. All other CT findings were not considered.

3 Frank et al Thrombolysis Despite Contraindications or Warnings 729 Downloaded from by guest on June 14, 2018 Outcome Measures The primary outcome measure was the distribution of mrs at 90 days using the full scale. 15 The mrs was available for all patients (n=9613). For comparison with prior trials and reports, dichotomized outcomes at 90 days (mrs 0 1, mrs 0 2, NIHSS 0 1, and mortality) were also reported. NIHSS at 90 days was recorded in 8608 patients. Additionally, information on occurrence of intracranial hemorrhages (ICH) within the first 4 days after stroke was retrieved from adverse events and SAE data, as raw computerized tomography (CT) data are available for few trials held within VISTA, and as only thrombolyzed patients received routine follow-up CTs. Although adverse events and SAE reporting was rigorous in the included trials, asymptomatic ICH are likely to be underreported in nonthrombolyzed patients. In approximation to the definition of symptomatic ICH (SICH) used in the second European Cooperative Acute Stroke Study (ECASS II), 4 we report the rates of SICH, defined as any ICH with neurological deterioration, as indicated by an NIHSS increase of 4 points from baseline; or any ICH leading to death within 7 days thereafter. As NIHSS was not required to be recorded on every subsequent day, some SICH might be missed by this definition, SICH was additionally defined as any ICH that has been recorded to be the cause of an SAE. As information on exact onset timing of adverse events or SAE is not available for all patients within VISTA, information on occurrence of SICH could only be presented for 7326 patients. However, by analyzing the mrs across the full scale, we take into account any effects of serious bleeding in our primary outcome. Statistical Analysis Nonrandomized adjusted comparisons of outcomes were conducted within each subgroup, differentiating patients who received alteplase versus patients who did not (controls). All outcome analyses were adjusted for age and baseline NIHSS, as previously justified. 15 We did not adjust for time to treatment, as this variable was incompletely available. Unadjusted baseline comparisons were conducted using the 2 sample t test, the Mann Whitney U test, or the χ 2 test depending on the distribution and nature of the data. The primary outcome measure was the mrs at 90 days, analyzed across the whole distribution of scores with the use of the Cochran Mantel Haenszel test, with adjustment for stratification variables (age: 30, 31 40, 41 50, 51 60, 61 70, 71 80, 81; baseline NIHSS: 4, 5 8, 9 12, 13 16, 17 20, 21 24, 25). Odds ratio (OR) and 95% CI were computed using ordinal logistic regression. Whereas ordinal logistic regression gives an estimate of treatment effect, the Cochran Mantel Haenszel test gives a more conservative probability value based on fewer assumptions. 16 Dichotomized outcome measures were assessed using binary logistic regression. Analyses were undertaken using SAS 9.2. Results A total of 4793 out of 9613 patients (49.6%; 1281 thrombolyzed, 3512 nonthrombolyzed) had at least one known contraindication, and 6231 out of 9613 (64.8%; 1946 thrombolyzed, 4285 nonthrombolyzed) had at least one known contraindication or warning for treatment with alteplase. Detailed information about relevant baseline characteristics is given in Table 2. Results for our primary outcome measure, distribution of mrs at 90 days, in patients with specified warnings and contraindications for thrombolysis are presented in Figure 1. Rates of SICH within the first 4 days after stroke are presented in Figure 2. Additional detailed information about dichotomized outcomes in these subgroups, as well as for all outcomes in subgroups without having specified warnings and contraindications are presented in the online-only Data Supplement. Discussion Age/Medical History The present results are consistent with previous analyses of registry data 17,18 and an updated meta-analysis of thrombolysis trial data, including IST-3, 9 showing that thrombolysis is effective in patients aged >80, at least up to 3 hours after stroke onset. In an analysis of 5 thrombolysis trials, history of prior stroke and diabetes mellitus was found to be a predictor of poor clinical outcome in patients with AIS treated within 0 to 6 hours. 19 Although alteplase treatment in AIS patients with combined history of prior stroke and diabetes mellitus has not been approved in Europe, 12 subsequent registry analyses showed no statistical justification for the exclusion of these patients from treatment. 20,21 Corroborating, the present analysis showed a significant benefit from thrombolysis in the Stroke & Diabetes subgroup; note that the present dataset partly overlaps with reports in previous publications, however. 18,20,21 Table 2. Baseline Characteristics of Patients Control Alteplase P-Value All Sex (male) 3655/6858 (53.3%) 1557/2755 (56.5%) /9613 (54.2%) Age (years) 70.3 (12.1)/ (12.9)/2755 < (12.3)/9613 NIHSS score 12 (9)/ (8)/2755 < (9)/9613 Atrial fibrillation 1715/5918 (29.0%) 607/2516 (24.1%) < /8434 (27.5%) Diabetes mellitus 1593/6588 (24.2%) 537/2718 (19.8%) < /9306 (22.9%) Glucose (mg/dl) (57.9)/ (50.6)/2247 < (55.6)/6451 Hypertension 4326/5918 (73.1%) 1778/2516 (70.7%) /8434 (72.4%) BPSYS (mm Hg) (26.8)/ (25.2)/2367 < (26.4)/8980 BPDIA (mm Hg) 84.1 (16.1)/ (16.1)/2367 < (16.1)/8980 Myocardial infarction 905/5918 (15.3%) 378/2516 (15.0%) /8434 (15.2%) Ischemic heart disease 1070/2572 (41.6%) 533/1850 (28.8%) /4422 (36.3%) BPDIA indicates diastolic blood pressure; BPSYS, systolic blood pressure; and NIHSS, National Institutes of Health Stroke Scale. Data are number of observations/total number of cases with available information (%), mean (SD)/total number of cases with available information, median (inter quartile range)/total number of cases with available information.

4 730 Stroke March 2013 Hemostasis An analysis of International Stroke Thrombolysis Registry (SITS-ISTR) data showed an increased risk for SICH after thrombolysis in patients with prior combination of Aspirin and Clopidogrel, whereas patients with prior single antiplatelet agent use were not at higher risk than antiplateletnaive patients. 22 IST-3 trialists detected no significant effect of treatment with antiplatelets prior to thrombolysis on functional outcome. 23 The primary outcome of the present study corroborates the effectiveness of thrombolysis in the subgroup of patients with Single Antiplatelets, whereas it shows discouraging results in the Dual Antiplatelets subgroup. The rate of SICH in patients with prior Dual Antiplatelets was the highest among all patients receiving thrombolysis, but with small numbers of patients remains statistically indistinguishable from the control group. A prior study also found no association between prior antiplatelet use and the likelihood of recanalization and good outcomes. 24 Although the European and American licences exclude AIS patients with prior anticoagulation from alteplase treatment, 12,14 the American Heart Association/American Stroke Association guidelines relaxed this restriction by recommending treatment with alteplase if oral anticoagulation has been taken, but the International Normalized Ratio (INR) is below Additionally, the AHA/ASA guidelines recommend not to delay initiation of treatment with alteplase by waiting for blood and coagulation tests in patients without suspected bleeding abnormality. Only limited and partly contradictory data are mrs ordinal Downloaded from by guest on June 14, 2018 Age/Medical History Age >80 Stroke &Diabetes Hemostasis Single Antiplatelet DualAntiplatelets OAC OAC &INR 1.7 OAC &INR >1.7 INR >1.7 APTT >39 Platelets <100 Glucose/BP Glucose >400 Glucose >180 Glucose <50 BPSYS 185 BPDIA 110 IV Antihypertensives CT Findings Early Changes Major Early Changes ASPECT 7 NIHSS NIHSS >22 NIHSS <6 All Control Alteplase OR (95% CI) CMH p-value ( ) ( ) Favours Control FavoursAlteplase 1.42 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) < ( ) ( ) ( ) ( ) ( ) < dead Control (top) and Alteplase(bottom) Figure 1. Odds of more favorable outcome for thrombolyzed patients compared with controls, adjusted for age, and baseline National Institutes of Health Stroke Scale (NIHSS), within subgroups of patients with specified warnings and contraindications. Number of thrombolyzed (intravenous alteplase) and control patients within these subgroups is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and Cochran Mantel Haenszel (CMH) test probability values are presented in the middle. As multivariate ordinal logistic regression uses a different algorithm to the adjusted CMH test, a discrepancy between 95% CI and CMH probability value of 0.05 can occur. The CMH probability value was prespecified as our primary measure of significance. The unadjusted modified Rankin Scale (mrs) distribution at 90 days in controls (top) and treated patients (bottom) within each subgroup is presented on the right.

5 Frank et al Thrombolysis Despite Contraindications or Warnings 731 Downloaded from by guest on June 14, 2018 Control Alteplase Age/Medical History Age >80 22/957 (2.3%) 29/389 (7.5%) Stroke &Diabetes 9/404 (2.2%) 4/98 (4.1%) Hemostasis Single Antiplatelet 23/970 (2.4%) 41/656 (6.3%) DualAntiplatelets 4/83 (4.8%) 6/71 (8.5%) OAC 14/380 (3.7%) 5/68 (7.4%) OAC &INR 1.7 4/119(3.4%) 2/38 (5.3%) OAC &INR >1.7 2/134 (1.5%) 0/14 (0.0%) INR >1.7 3/197 (1.5%) 7/138 (5.1%) APTT >39 4/137 (2.9%) 6/139 (4.3%) Platelets <100 4/102 (3.9%) 0/10 (0.0%) Glucose/BP Glucose >400 1/14 (7.1%) 0/5 (0.0%) Glucose >180 18/552 (3.3%) 11/222 (5.0%) Glucose <50 0/3 (0.0%) 0/3 (0.0%) BPSYS /636 (2.5%) 14/225 (6.2%) BPDIA 110 5/290 (1.7%) 5/109 (4.6%) IV Antihypertensives 12/307 (3.9%) 33/465 (7.1%) CT Findings Early Changes 12/211 (5.7%) 38/627 (6.1%) Major Early Changes 4/39 (10.3%) 7/137 (5.1%) ASPECT 7 2/26 (7.7%) 5/89 (5.6%) NIHSS NIHSS >22 17/317 (5.4%) 9/159 (5.7%) NIHSS <6 0/156 (0.0%) 0/28 (0.0%) All 90/4773 (1.9%) 113/2553 (4.4%) SICH (%) available on this subject. 8,25,26 Although in most subgroups of patients with disturbed hemostasis, rates of SICH were higher in thrombolyzed patients (eg, OAC), OR point estimates for our primary outcome measure favored alteplase treatment. Cochran Mantel Haenszel estimates were significant for benefit in patients with OAC & INR 1.7 and APTT >39. These results may have implications for trials adding further antithrombotic drugs to intravenous thrombolysis to improve clot lysis, in that combinations of thrombolysis with anticoagulants may prove safer than combining with potent antiplatelet agents. This is relevant with the ongoing Argatroban+Alteplase and CLEARER (Eptifibatide+Alteplase) studies. Glucose/Blood Pressure Previous analyses have reported significantly increased rates of SICH in thrombolyzed stroke patients with only mildly elevated baseline glucose levels. 27,28 Although the rate of SICH was slightly increased in our subgroup of patients with Glucose >180, functional outcome significantly favored treatment with alteplase. Subgroups of patients with Glucose >400 and <40 were small, but none of these patients treated with alteplase experienced a SICH. High initial systolic blood pressure was found to predict less benefit from thrombolysis in an analysis of 5 thrombolysis trials. 19 Although OR in our primary analysis of subgroups with BPSYS 185, BPDIA 110, and IV Antihypertensives significantly favored alteplase treatment, rates of SICH were increased in thrombolyzed patients. Thus, caution should be Control Alteplase Figure 2. Proportion of controls (white bars) and thrombolyzed patients (intravenous alteplase; grey bars) having a symptomatic intracranial hemorrhage (SICH) in the first 4 days after stroke, within subgroups of patients with specified warnings and contraindications. The incidence of SICH was too low for reliable assessment of odds ratios, but their estimates are displayed in the online-only Data Supplemental Figure V. exercised, as violations of pretreatment blood pressure parameters are associated with an increased risk of bleeding. 29 CT Findings Analyses of baseline imaging data from NINDS showed that early ischemic changes were not associated with increased risk of adverse outcome, 30 whereas observational data has suggested increased risk of SICH with early imaging findings. 27 IST-3 trialists found no significant association of recent ischemic changes at randomization with benefit from thrombolysis. 23 Accordingly, present analyses in subgroups of patients with CT Findings favored thrombolysis treatment, despite marginally increased risk of SICH. NIHSS A pooled analysis of 6 thrombolysis trials showed no evidence to exclude AIS patients from treatment based on their initial NIHSS. 31 The IST-3 trialists observed a significant trend for greater benefit from thrombolysis, with increasingly severe strokes. 23 Interaction tests in the subgroups of IST3 patients should be interpreted with caution, as overall benefit for their primary outcome was nonsignificant. Although in the present study a clear benefit for thrombolysis in patients with NIHSS >22 is evident, benefit was not confirmed in the subgroup of patients with NIHSS <6. However, the size of the latter subgroup was small, leaving residual uncertainty.

6 732 Stroke March 2013 Downloaded from by guest on June 14, 2018 General The present retrospective analysis shows a broad trend of more favorable outcome, as well as lower mortality associated with alteplase treatment across all subgroups of patients. Our analysis was based on observational rather than trial data. Thus, selection bias is inevitable. Additionally, the general standard of care may have been different in patients receiving alteplase than in controls, as time of enrolment differed on average by 2 years and information on duration of stroke unit care is not available within VISTA. Nevertheless, all patients were participants in clinical trials and thereby received similar attention and a careful follow-up. The presented patient population may have had a better baseline functional status prior to stroke than the general stroke population encountered in clinical practice, but in this respect, they will be comparable with thrombolysis trial patients. Although early complications are rare after thrombolysis, and although the delay between initiating alteplase and enrolment in the VISTA trials was generally short, there is a possibility that a few patients with contraindications who suffered early complications could have been excluded from enrolment, and thus from our sample, leading to underestimation of the complication rate. It is also possible that early improvers were excluded, with an opposite effect. However, randomized controlled trials are simply not feasible for many of the subgroups analyzed here, so these data provide valuable guidance on the risks and benefits of thrombolysis in numerous subgroups of patients, where equipoise exists and guidelines and treatment practices vary. Many of the warnings and contraindications of alteplase may not be justified and licences, guidelines, and protocols should be adjusted to accommodate recent data from registries and real-world experience. Contributors See the online-only Data Supplement. Disclosures BF has received modest honoraria for participation in clinical trials (Sanofi-Aventis). AVA has served as PI of CLOTBUST trial partially funded by Genentech, and currently serves as PI of CLOTBUSTER funded by Cerevast Therapeutics and consultant to Genentech. EB is an employee of Boehringer Ingelheim. JCG, CW, PL, and NKM have no relevant conflicts of interest. AM has served as a consultant for Boehringer Ingelheim, received speaker s honoraria from Boehringer Ingelheim, and congress expenses from Lundbeck. NW has received expenses from Boehringer Ingelheim for his role as member of the steering committee in relation to the ECASS III trial with alteplase and served as a consultant to Thrombogenics as chairman of the DSMB. SITS International (chaired by NW) received a grant from Boehringer Ingelheim and from Ferrer for the SITS-MOST/SITS-ISTR. His institution has also received grant support toward administrative expenses for coordination of the ECASS III trial. NW has also received lecture fees from Boehringer Ingelheim and from Ferrer. AS and KRL have received research grants, modest honoraria for participation in clinical trials, and have a consultancy or advisory board relationship with manufacturers from drugs (including Boehringer Ingelheim). KRL administered the grant from Genentech for support of this study. Acknowledgments Genentech sponsored the costs of VISTA access and analysis for this report, although the views presented here do not necessarily reflect those of Genentech. The authors were fully responsible for all content and editorial decision, were involved at all stages of the manuscript development, and have approved the final version that reflects the authors personal interpretation and conclusion. Appendix VISTA-Acute Steering committee members: A.V. Alexandrov, P.W. Bath, E. Bluhmki, L Claesson, J. Curram, S.M. Davis, G. Donnan, H. C. Diener, M. Fisher, B. Gregson, J. Grotta, W. Hacke, M.G. Hennerici, M. Hommel, M. Kaste, K.R. Lees (chair), P. Lyden, J. Marler, K. Muir, R. Sacco, A. Shuaib, P. Teal, N.G. Wahlgren, S. Warach, and C. Weimar. References 1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med. 1995;333: Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al.; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359: Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274: Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. 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7 Frank et al Thrombolysis Despite Contraindications or Warnings 733 Downloaded from by guest on June 14, 2018 from the Virtual International Stroke Trials Archive (VISTA). Stroke. 2010;41: Mishra NK, Diener HC, Lyden PD, Bluhmki E, Lees KR; VISTA Collaborators. Influence of age on outcome from thrombolysis in acute stroke: a controlled comparison in patients from the Virtual International Stroke Trials Archive (VISTA). Stroke. 2010;41: Ford GA, Ahmed N, Azevedo E, Grond M, Larrue V, Lindsberg PJ, et al. Intravenous alteplase for stroke in those older than 80 years old. Stroke. 2010;41: Mishra NK, Ahmed N, Andersen G, Egido JA, Lindsberg PJ, Ringleb PA, et al.; VISTA collaborators; SITS collaborators. Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive. BMJ. 2010;341:c Kent DM, Selker HP, Ruthazer R, Bluhmki E, Hacke W. The strokethrombolytic predictive instrument: a predictive instrument for intravenous thrombolysis in acute ischemic stroke. Stroke. 2006;37: Mishra NK, Ahmed N, Davalos A, Iversen HK, Melo T, Soinne L, et al.; SITS and VISTA collaborators. Thrombolysis outcomes in acute ischemic stroke patients with prior stroke and diabetes mellitus. Neurology. 2011;77: Mishra NK, Davis SM, Kaste M, Lees KR; VISTA Collaboration. Comparison of outcomes following thrombolytic therapy among patients with prior stroke and diabetes in the Virtual International Stroke Trials Archive (VISTA). Diabetes Care. 2010;33: Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. 2010;41: Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379: Ibrahim MM, Sebastian J, Hussain M, Al-Hussain F, Uchino K, Molina C, et al.; CLOTBUST Investigators. Does current oral antiplatelet agent or subtherapeutic anticoagulation use have an effect on tissue-plasminogen-activator-mediated recanalization rate in patients with acute ischemic stroke? Cerebrovasc Dis. 2010;30: Brunner F, Tomandl B, Schröter A, Mellinghoff C, Haldenwanger A, Hildebrandt H, et al. Hemorrhagic complications after systemic thrombolysis in acute stroke patients with abnormal baseline coagulation. Eur J Neurol. 2011;18: Prabhakaran S, Rivolta J, Vieira JR, Rincon F, Stillman J, Marshall RS, et al. Symptomatic intracerebral hemorrhage among eligible warfarintreated patients receiving intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2010;67: Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012;71: Ahmed N, Dávalos A, Eriksson N, Ford GA, Glahn J, Hennerici M, et al.; SITS Investigators. Association of admission blood glucose and outcome in patients treated with intravenous thrombolysis: results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Register (SITS-ISTR). Arch Neurol. 2010;67: Tsivgoulis G, Frey JL, Flaster M, Sharma VK, Lao AY, Hoover SL, et al. Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke. 2009;40: Patel SC, Levine SR, Tilley BC, Grotta JC, Lu M, Frankel M, et al.; National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA. 2001;286: Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al.; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-pa Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-pa stroke trials. Lancet. 2004;363:

8 Downloaded from by guest on June 14, 2018 Thrombolysis in Stroke Despite Contraindications or Warnings? Benedikt Frank, James C. Grotta, Andrei V. Alexandrov, Erich Bluhmki, Patrick Lyden, Atte Meretoja, Nishant K. Mishra, Ashfaq Shuaib, Nils G. Wahlgren, Christian Weimar and Kennedy R. Lees for the VISTA Collaborators Stroke. 2013;44: ; originally published online February 6, 2013; doi: /STROKEAHA Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Stroke is online at:

9 Contributors: JCG and KRL conceptualised the project. KRL prepared a proposal, including a preliminary analysis plan, which was approved by the VISTA steering committee. BF collected the data and performed statistical analyses after discussing the descriptive statistics and final analysis plan with KRL. BF drafted the report and all authors critically revised the manuscript. 1

10 Figures for subgroups of patients with specific contraindications or warnings Figure1 MRS 0 to 1 at 90 days Odds of having a mrs at 90 days of 0 or 1 for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients with specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. NA = not applicable 2

11 Figure2 MRS 0 to 2 at 90 days Odds of having a mrs at 90 days of 0 to 2 for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients with specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. 3

12 Figure3 NIHSS 0 to 1 at 90 days Odds of having a NIHSS at 90 days of 0 or 1 for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients with specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. NA = not applicable 4

13 Figure4 Mortality at 90 days Odds of mortality at 90 days for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients with specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. NA = not applicable 5

14 Figure5 SICH within the first four days Proportion of controls (white bars) and thrombolysed patients (Alteplase, grey bars) having a symptomatic intracranial haemorrhage (SICH) in the first four days after stroke, within subgroups of patients with specified warnings and contraindications. Numbers of proportion are presented in the middle. Odds ratio (OR), adjusted for age and baseline NIHSS, with 95% confidence interval (95% CI) and p-value are presented on the right. NA = not applicable 6

15 Figures for subgroups of patients without specific contraindications or warnings Figure6 ordinal MRS at 90 days Odds of more favourable outcome for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients without specified warnings and contraindications. Number of thrombolysed (Alteplase) and control patients within these subgroups is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and Cochran-Mantel-Haenszel (CMH) test p-value are presented in the middle. The unadjusted mrs distribution at 90 days in controls (top) and treated patients (bottom) within each subgroup is presented on the right. 7

16 Figure7 MRS 0 to 1 at 90 days Odds of having a mrs at 90 days of 0 or 1 for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients without specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. 8

17 Figure8 MRS 0 to 2 at 90 days Odds of having a mrs at 90 days of 0 to 2 for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients without specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. 9

18 Figure9 NIHSS 0 to 1 at 90 days Odds of having a NIHSS at 90 days of 0 or 1 for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients without specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. 10

19 Figure10 Mortality at 90 days Odds of mortality at 90 days for thrombolysed patients compared to controls, adjusted for age and baseline NIHSS, within subgroups of patients without specified warnings and contraindications. Number of treated (Alteplase) and control patients within these subgroups with available outcome information is presented on the left. Odds ratio (OR) with 95% confidence interval (95% CI) and p-value are presented on the right. 11

20 Figure11 SICH within the first four days Proportion of controls (white bars) and thrombolysed patients (Alteplase, grey bars) having a symptomatic intracranial haemorrhage (SICH) in the first four days after stroke, within subgroups of patients without specified warnings and contraindications. Numbers of proportion are presented in the middle. Odds ratio (OR), adjusted for age and baseline NIHSS, with 95% confidence interval (95% CI) and p-value are presented on the right. 12