Symptomatic Intracranial Hemorrhage After Stroke Thrombolysis

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Symptomatic Intracranial Hemorrhage After
                                                                                                          Stroke Thrombolysis
                                                                                                                      Comparison of Prediction Scores
                                                                                    Daniel Strbian, MD, PhD, MSc (Stroke Med); Patrik Michel, MD; David J. Seiffge, MD;
                                                                                                  Jeffrey L. Saver, MD, FAHA; Heikki Numminen, MD, PhD;
                                                                                        Atte Meretoja, MD, PhD, MSc (Stroke Med); Kei Murao, MD; Bruno Weder, MD;
                                                                                          Nina Forss, MD, PhD; Anna-Kaisa Parkkila, MD, PhD; Ashraf Eskandari, RN;
                                                                                   Charlotte Cordonnier, MD, PhD; Stephen M. Davis, MD, PhD; Stefan T. Engelter, MD, PhD;
                                                                                                                  Turgut Tatlisumak, MD, PhD

                                                                            Background and Purpose—Several prognostic scores have been developed to predict the risk of symptomatic intracranial
                                                                              hemorrhage (sICH) after ischemic stroke thrombolysis. We compared the performance of these scores in a multicenter cohort.
                                                                            Methods—We merged prospectively collected data of patients with consecutive ischemic stroke who received intravenous
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                                                                              thrombolysis in 7 stroke centers. We identified and evaluated 6 scores that can provide an estimate of the risk of sICH in
                                                                              hyperacute settings: MSS (Multicenter Stroke Survey); HAT (Hemorrhage After Thrombolysis); SEDAN (blood sugar, early
                                                                              infarct signs, [hyper]dense cerebral artery sign, age, NIH Stroke Scale); GRASPS (glucose at presentation, race [Asian],
                                                                              age, sex [male], systolic blood pressure at presentation, and severity of stroke at presentation [NIH Stroke Scale]); SITS
                                                                              (Safe Implementation of Thrombolysis in Stroke); and SPAN (stroke prognostication using age and NIH Stroke Scale)-100
                                                                              positive index. We included only patients with available variables for all scores. We calculated the area under the receiver
                                                                              operating characteristic curve (AUC-ROC) and also performed logistic regression and the Hosmer–Lemeshow test.
                                                                            Results—The final cohort comprised 3012 eligible patients, of whom 221 (7.3%) had sICH per National Institute of
                                                                              Neurological Disorders and Stroke, 141 (4.7%) per European Cooperative Acute Stroke Study II, and 86 (2.9%) per Safe
                                                                              Implementation of Thrombolysis in Stroke criteria. The performance of the scores assessed with AUC-ROC for predicting
                                                                              European Cooperative Acute Stroke Study II sICH was: MSS, 0.63 (95% confidence interval, 0.58–0.68); HAT, 0.65 (0.60–
                                                                              0.70); SEDAN, 0.70 (0.66–0.73); GRASPS, 0.67 (0.62–0.72); SITS, 0.64 (0.59–0.69); and SPAN-100 positive index, 0.56
                                                                              (0.50–0.61). SEDAN had significantly higher AUC-ROC values compared with all other scores, except for GRASPS where
                                                                              the difference was nonsignificant. SPAN-100 performed significantly worse compared with other scores. The discriminative
                                                                              ranking of the scores was the same for the National Institute of Neurological Disorders and Stroke, and Safe Implementation
                                                                              of Thrombolysis in Stroke definitions, with SEDAN performing best, GRASPS second, and SPAN-100 worst.
                                                                            Conclusions—SPAN-100 had the worst predictive power, and SEDAN constantly the highest predictive power. However,
                                                                              none of the scores had better than moderate performance.   (Stroke. 2014;45:752-758.)
                                                                                                                                Key Word: intracranial hemorrhages

                                                                            T   he only approved clot-busting medical treatment in isch-
                                                                                emic stroke, intravenous thrombolysis (IVT), is not without
                                                                            complications. One of the major reasons for withholding the
                                                                                                                                                           worsening of outcome (≥1 grade on modified Rankin Scale)
                                                                                                                                                           ranges from 29.7 to 40.1.2 There are several scoring systems
                                                                                                                                                           for predicting the risk of sICH.3–8 In an ideal situation, a predic-
                                                                            therapy remains fear of symptomatic intracranial hemorrhage                    tion score could identify patients with very high risk of post-­
                                                                            (sICH), which can worsen patients’ outcomes.1 The number                       thrombolysis sICH. We aimed to compare the performance of
                                                                            needed for IVT to cause fatal sICH is 36.5, and to cause any                   existing risk prediction scores in a large multicenter cohort.

                                                                              Received October 9, 2013; final revision received December 4, 2013; accepted December 17, 2013.
                                                                              From the Departments of Neurology and Stroke Units, Helsinki University Central Hospital, Helsinki, Finland (D.S., A.M., N.F., T.T.); Centre
                                                                            Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland (P.M., A.E.); University Hospital Basel, Basel, Switzerland (D.J.S.,
                                                                            S.T.E.); Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (J.L.S.); Tampere University Hospital, Tampere, Finland
                                                                            (H.N., A.-K.P.); The Royal Melbourne Hospital, Parkville, Australia (A.M., S.M.D.); University Lille Nord de France, Lille, France (K.M., C.C.); and
                                                                            Kantonsspital St Gallen, St Gallen, Switzerland (B.W.).
                                                                              Guest Editor for this article was Tatjana Rundek, MD, PhD.
                                                                              The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
                                                                            113.003806/-/DC1.
                                                                              Correspondence to Daniel Strbian, MD, PhD, Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki,
                                                                            Finland. E-mail daniel.strbian@hus.fi
                                                                              © 2014 American Heart Association, Inc.
                                                                              Stroke is available at http://stroke.ahajournals.org                                                       DOI: 10.1161/STROKEAHA.113.003806

                                                                                                                                                     752
Strbian et al   Post-Thrombolytic Hemorrhage Prediction Scores    753

                                                                                                                                                                                      Patients and Methods
                                                                                                                                                              Study Setting
                                                                            Table 1.     Description of the Scores                                            The current analysis comprises data from 7 centers. The study was
                                                                            Score/Derivation             Parameters in the         Cut-Off Values, Score      approved by the relevant authorities in each participating center per
                                                                                                                                                              local requirements. This study was approved in the coordinating cen-
                                                                            Cohort                            Score                     Points, pt
                                                                                                                                                              ter (Helsinki) as a quality registry and did not require review by the
                                                                            MSS (NINDS sICH):                  Age, y                   >60 y, 1 pt           ethical board. All patients were prospectively included in the database.
                                                                            derivation cohort,             NIHSS score                   >10, 1 pt            Data from individual consecutive patients receiving IVT within a 4.5-
                                                                            n=481; validation,                                                                hour time window for acute ischemic stroke were collected using a
                                                                                                      Blood glucose, mmol/L            >8.325, 1 pt           standardized form with predefined variables. For sICH definitions, ra-
                                                                            n=965
                                                                                                        Platelet count/mm3            20, 2 pt
                                                                                                                                                              chymal hemorrhage 1 and 2) was collected and used to prospectively
                                                                                                                                                              assign sICH for the current study by 1 of the study authors in a blinded
                                                                            derivation, n=302;         Blood glucose or DM        >200 mg/dL or DM, 1 pt      fashion. Data from all the centers were compiled in the coordinating
                                                                            validation, n=98
                                                                                                        Hypodensity on CT            75, 1 pt            terior circulation. None of the patients underwent endovascular proce-
                                                                            sICH): derivation,             NIHSS score                   ≥10, 1 pt            dure. None of the patients in the current analysis was included in the
                                                                            n=974; validation,                                                                derivation cohort of any of the scores/indices.
                                                                                                      Blood glucose, mmol/L        8.1–12.0, 1 pt; >12.0,
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                                                                            n=828
                                                                                                                                           2 pt
                                                                                                         Early infarct signs             Yes, 1 pt            Selection Criteria for sICH Risk Scores
                                                                                                      Hyperdense artery signs            Yes, 1 pt            First, we only considered scores and indices but not regression models,
                                                                            GRASPS (NINDS                      Age, y                ≤60, 8 pt; 61–70,        because our aim was to evaluate only tools that are suitable for quick
                                                                                                                                                              bedside calculations without depending on potentially time-consum-
                                                                            sICH): derivation,                                      11 pt; 71–80, 15 pt;
                                                                                                                                                              ing, computer-based systems. Second, we considered only scores and
                                                                            n=7169; validation,                                         >80, 17 pt
                                                                                                                                                              indices based on parameters available shortly after admission, before
                                                                            n=3073                         NIHSS score            0–5, 25 pt; 6–10, 27 pt;
                                                                                                                                   11–15, 34 pt; 16–20,
                                                                                                                                                              Table 2. Demographics, Baseline Characteristics, and
                                                                                                                                     40 pt; >20, 42 pt
                                                                                                                                                              Frequencies of Symptomatic Intracranial Hemorrhage
                                                                                                       Blood glucose, mg/dL
754  Stroke  March 2014

                                                                            administration of thrombolysis. Finally, we included scores that had      University of Southampton). A 2-tailed P value
Strbian et al   Post-Thrombolytic Hemorrhage Prediction Scores    755
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                                                                            Figure 2. Frequencies of symptomatic intracranial hemorrhage according to the criteria of European Cooperative Acute Stroke Study II
                                                                            for each point level of the predictive scores. Number in parentheses represents patients who reached that specific score points. Because
                                                                            of the complexity of GRASPS, not all n for particular score points are shown. GRASPS indicates glucose at presentation, race (Asian),
                                                                            age, sex (male), systolic blood pressure at presentation, and severity of stroke at presentation (NIH Stroke Scale); HAT, Hemorrhage
                                                                            After Thrombolysis; MSS, Multicenter Stroke Survey; SEDAN, blood sugar, early infarct signs, (hyper)dense cerebral artery sign, age, NIH
                                                                            Stroke Scale; SITS, Safe Implementation of Thrombolysis in Stroke; and SPAN, stroke prognostication using age and NIH Stroke Scale.

                                                                            9.3% (ECASS-II criteria), from 4.4% to 9.9% (NINDS), and               highest nominal predictive performance in all comparisons,
                                                                            from 2.2% to 5.1% (SITS).                                              most of which were statistically significant, except for the com-
                                                                               Frequencies of sICH, according to the 3 criteria,1 per point        parison with GRASPS, which showed the second highest AUC-
                                                                            increase of the scores are outlined in Figures 1–3 and Figure I in     ROC values. In 2-way comparisons, the differences between
                                                                            the online-only Data Supplement. Based on the logistic regres-         GRASPS and other scores were frequently nonsignificant.
                                                                            sion analysis, all scores were associated with sICH according to          We observed rather low frequencies of post-thrombolytic
                                                                            all 3 criteria (Table I in the online-only Data Supplement). The       sICH in the current merged cohort with considerable inter-
                                                                            results of the Hosmer–Lemeshow test showed worst model fit             center differences. This contributes to the relatively low risk
                                                                            for GRASPS in case of ECASS-II sICH. Because SPAN-100 is               of sICH even with the worst scores compared with the original
                                                                            a binary index, the test could not have been calculated.               reports (perhaps with the exception of MSS and HAT, rela-
                                                                               Score comparisons by means of AUC-ROCs are presented                tively smaller number of patients scored the highest points).
                                                                            separately for each sICH definition (Table 3). SEDAN had               Nonetheless, what is crucial is that the relative risk of high-risk
                                                                            the highest absolute values of AUC-ROC in all analyses, and            patients compared with low-risk patients remained similar.
                                                                            except for the comparison with GRASPS, these differences               For example, according to the original report,5 a patient with
                                                                            were statistically significant. SPAN-100 positive index had the        SEDAN of 5 had almost 4-fold higher risk of sICH (33.3%)
                                                                            lowest AUC-ROC values in all comparisons.                              compared with SEDAN of 2 (8.5%) and >20-fold higher risk
                                                                                                                                                   compared with SEDAN of 0 (1.4%). Here, the magnitude of
                                                                                                     Discussion                                    these relative risks remained similar, 4 and 18, respectively.
                                                                            With comprehensive data from several dedicated stroke centers,            Taken together, the scores consist of parameters related to
                                                                            we had a unique opportunity to perform a head-to-head compari-         (1) underlying parenchymal injury, microangiopathy (age,
                                                                            son of the existing sICH prediction scores. In general, SPAN-          history of hypertension and diabetes mellitus, blood glucose
                                                                            100 showed poor predictive power, and all other scores moderate        as a marker of diabetes mellitus history), (2) degree of acute
                                                                            predictive power. Of all scores, SEDAN had constantly the              parenchymal injury (CT findings and, to certain level, also the
756  Stroke  March 2014
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                                                                            Figure 3. Frequencies of symptomatic intracranial hemorrhage according to the criteria of Safe Implementation of Thrombolysis in Stroke
                                                                            for each point level of the predictive scores. Number in parentheses represents patients who reached that specific score points. Because
                                                                            of the complexity of GRASPS, not all n for particular score points are shown. GRASPS indicates glucose at presentation, race (Asian),
                                                                            age, sex (male), systolic blood pressure at presentation, and severity of stroke at presentation (NIH Stroke Scale); HAT, Hemorrhage
                                                                            After Thrombolysis; MSS, Multicenter Stroke Survey; SEDAN, blood sugar, early infarct signs, (hyper)dense cerebral artery sign, age, NIH
                                                                            Stroke Scale; SITS, Safe Implementation of Thrombolysis in Stroke; and SPAN, stroke prognostication using age and NIH Stroke Scale.

                                                                            National Institutes of Health Stroke Scale [NIHSS] and onset-­         calculation of HAT and SEDAN) seem to improve the perfor-
                                                                            to-treatment time), (3) coagulation process (platelet count, use       mance of outcome prediction scores.12 Although their assess-
                                                                            of antiplatelet agents, and perhaps patient’s weight determin-         ing requires training, we think it is readily achievable with
                                                                            ing the dose of alteplase), (4) physical factors (systolic blood       continuous education in centers delivering IVT. Interestingly,
                                                                            pressure), and (5) sex and ethnicity. In fact, modest differ-          platelet count was included in 1 score only (MSS), but it did
                                                                            ences in the AUC-ROC values among the scores reflect that              not, for example, improve the model of SEDAN (data not
                                                                            most of the scores include similar components: age, NIHSS,             shown). One possible explanation is the fact that a vast major-
                                                                            and baseline glucose level being the most common (Tables 1             ity of patients in its derivation cohort had similar platelet
                                                                            and 3). The differences are often in the relative weighting            counts, being in the physiological range.
                                                                            given to individual components. SPAN-100 (consisting of age               Another source of differences in the performances of scores
                                                                            and NIHSS) had rather low AUC-ROC values according to all              may reflect the fact that they were derived to predict particular
                                                                            sICH criteria (0.55–0.56) as compared with 0.73 per NINDS              definitions of sICH. For example, SITS had higher ­AUC-ROC
                                                                            criteria in the original report.8 Potential explanations may           values than for ECASS-II or NINDS criteria (Table 3).
                                                                            be that SPAN-100 was postulated rather than derived from               SEDAN had the highest AUC-ROC value for sICH per
                                                                            a specific cohort. Also, validation was performed in a rather          ECASS-II definition, for which it was developed. Whereas,
                                                                            small cohort of 312 patients with IVT from the NINDS trial.            GRASPS had almost identical AUC-ROC values for each def-
                                                                            Furthermore, the timing of treatment in the present study was,         inition. Another aspect influencing the performance of scores
                                                                            on average, somewhat later than in the NINDS patients, half of         is the number of component items. Scores derived from larger
                                                                            whom were treated
Strbian et al   Post-Thrombolytic Hemorrhage Prediction Scores    757

                                                                            Table 3.     Areas Under the Curves (AUC) and P Values for Their Comparisons
                                                                                                          MSS                       HAT                     SEDAN                    GRASPS                      SITS                  SPAN-100
                                                                            sICH NINDS study
                                                                             AUC (95% CI)        0.62 (0.58–0.66)          0.65 (0.62–0.69)         0.69 (0.66–0.73)          0.67 (0.63–0.70)         0.61 (0.58–0.65)          0.55 (0.51–0.59)
                                                                             MSS                        …                        0.10
758  Stroke  March 2014

                                                                            for ≥1 of the scores, but they did not differ from the included        fees from Boehringer-Ingelheim (modest), and advisory board com-
                                                                            patients in demographics and baseline characteristics. Each            pensation from Boehringer-Ingelheim (modest). Dr Davis received
                                                                                                                                                   travel grants from EVER Neuropharma (modest) and Sanofi (mod-
                                                                            center performed its imaging read. However, our study rep-             est), as well as speakers fees from Boehringer-Ingelheim (modest).
                                                                            resents a large sample size with patients from several cen-            Dr Tatlisumak received honoraria from Boehringer-Ingelheim (mod-
                                                                            ters operating under different conditions. Unfortunately, we           est) and advisory board compensations from Boehringer-Ingelheim
                                                                            could not analyze the scores separately in men and women               (modest) and H Lundbeck A/S (modest). The other authors have no
                                                                            or in patients treated
Symptomatic Intracranial Hemorrhage After Stroke Thrombolysis: Comparison of
                                                                                                                 Prediction Scores
                                                                               Daniel Strbian, Patrik Michel, David J. Seiffge, Jeffrey L. Saver, Heikki Numminen, Atte
                                                                               Meretoja, Kei Murao, Bruno Weder, Nina Forss, Anna-Kaisa Parkkila, Ashraf Eskandari,
                                                                                 Charlotte Cordonnier, Stephen M. Davis, Stefan T. Engelter and Turgut Tatlisumak
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                                                                                         Stroke. 2014;45:752-758; originally published online January 28, 2014;
                                                                                                        doi: 10.1161/STROKEAHA.113.003806
                                                                                  Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
                                                                                                Copyright © 2014 American Heart Association, Inc. All rights reserved.
                                                                                                           Print ISSN: 0039-2499. Online ISSN: 1524-4628

                                                                            The online version of this article, along with updated information and services, is located on the
                                                                                                                   World Wide Web at:
                                                                                                             http://stroke.ahajournals.org/content/45/3/752

                                                                                                                  Data Supplement (unedited) at:
                                                                                        http://stroke.ahajournals.org/content/suppl/2014/01/28/STROKEAHA.113.003806.DC1

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SUPPLEMENTAL MATERIAL

    Symptomatic intracranial hemorrhage after stroke thrombolysis: comparison of prediction scores
1
  Daniel Strbian, MD, PhD; 2Patrik Michel, MD; 3David J Seiffge, MD; 4Jeffrey L. Saver, MD, FAHA; 5Heikki
Numminen, MD, PhD; 1,6Atte Meretoja, MD, PhD, MSc (Stroke Med); 7Kei Murao; 8Bruno Weder, MD;
1
  Nina Forss, MD, PhD; 5Anna-Kaisa Parkkila, MD, PhD; 2Ashraf Eskandari, RN; 7Charlotte Cordonnier, MD,
PhD; 6Stephen M Davis, MD, PhD; 3Stefan T Engelter, MD, PhD; 1Turgut Tatlisumak, MD, PhD
Supplementary Table I. Logistic regression coefficients per score point and the Hosmer-Lemeshow

test.

                           OR (95% CI)      Hosmer-Lemeshow test        P

sICH (NINDS)

                  MSS    1.72 (1.47-2.02)            0.85              0.66

                  HAT    1.75 (1.54-1.98)            0.67              0.72

              SEDAN      1.72 (1.54-1.92)            0.94              0.82

              GRASPS     1.07 (1.05-1.09)            9.44              0.31

                  SITS   1.24 (1.15-1.32)            3.78              0.71

        SPAN-100 +       2.43 (1.70-3.48)
Supplementary Figure I

a)

b)
c)

Legend: Frequencies of symptomatic intracranial hemorrhage according to the criteria of a) NINDS, b)
       ECASS-II, and c) SITS for each point level of the predictive scores. Number in the brackets repre-
       sent patients who reached the particular score points. In addition to the full range of possible
       GRASPS points presented in the main text of the manuscript, we show here 10 categories of the
       GRASPS score (45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, 85-89, 90-94).
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