Research Influence of racial differences on outcomes after thrombolytic therapy in acute ischemic stroke Nishant K. Mishra1,2,3*†, Pitchaiah Mandava4†, Christopher Chen5, James Grotta3, Kennedy R. Lees2, and Thomas A. Kent4, on behalf of the VISTA collaboration‡ Background The National Institutes of Neurological Disorders and Stroke and the European Co-operative Acute Stroke III trials enrolled a largely Caucasian population, but the results are often extrapolated onto non-Caucasians. A limited number of nonrandomized studies have proposed that non-Caucasian patients show differential response to tissue plasminogen activator. Aims and/or hypothesis We examined if non-Caucasian patients of mixed national origin within the Virtual International Stroke Trials Archives neuroprotection trials responded differently to tissue plasminogen activator compared with Caucasians. Methods We matched patients within each race-subtype for age, baseline National Institutes of Health Stroke Scales, and diabetes status, and excluded outliers. We tested for an interaction of race ethnicity with tissue plasminogen activator on predicting outcomes at α = 0·05. We compared 90-day ordinal outcome (modified Rankin Scale; primary analysis) and dichotomized outcomes (modified Rankin Scale 0–1; modified Rankin Scale 0–2; survival) within individual race ethnicity. Results One thousand nine hundred forty-six thrombolysed patients (125 Blacks, 39 Asians, and 1821 Caucasians) were matched with 1946 non-thrombolysed patients in each race ethnicity group. Postmatching, there were no imbalances in baseline National Institutes of Health Stroke Scales and age between the groups (P > 0·05). The interaction of tissue plasminogen activator with race ethnicity was nonsignificant in ordinal (P = 0·4) and in dichotomized outcome models (P > 0·05). Ordinal odds for improved outcomes were 1·5 for Correspondence: Nishant K. Mishra, MBBS, PhD.*†, Stanford Stroke Center, 1215, Welch Road, Modular D, Stanford, CA 94305, USA. Tel: 650 391 4511. E-mail: [email protected] 1 Stanford Stroke Center, Stanford University Medical Center, Palo Alto, CA, USA 2 Western Infirmary and Faculty of Medicine, University of Glasgow, Glasgow, Scotland 3 Department of Neurology, University of Texas Health Sciences Centre, Houston, TX, USA 4 Stroke Outcomes Laboratory, Department of Neurology, Baylor College of Medicine, and the Michael E. DeBakey VA Medical Center Comprehensive Stroke Program, Houston, TX, USA 5 Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore Received: 19 December 2012; Accepted: 22 May 2013; Published online 22 October 2013 Conflict of interest: NKM reports no conflict of interest. Drs Mandava and Kent are copyright holders of pPAIRS© and have no commercial interest in its use. †

Shared first authors.



VISTA-acute steering committee: K.R. Lees (Chair), A. Alexandrov, N. Bornstein, P.M. Bath, E. Bluhmki, L. Claesson, S.M. Davis, G. Donnan, H.C. Diener, M. Fisher, B. Gregson, J. Grotta, W. Hacke, M.G. Hennerici, M. Hommel, M. Kaste, P. Lyden, J. Marler, K. Muir, G. Rosenberg, R. Sacco, A. Shuaib, P. Teal, N.G. Wahlgren, S. Warach, and C. Weimar. DOI: 10.1111/ijs.12162 © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization

all patients (P < 0·05). Ordinal odds for Caucasians were 1·5 (P < 0·05); for Blacks, 2·1 (P < 0·05); and for Asians, 1·2 (P > 0·05; 1·6 after 1:2 matching with nonthrombolysed, because of small numbers). Dichotomized functional outcomes improved after thrombolysis overall, in Caucasians, in Blacks (modified Rankin Scale 0–2 only), and in Asians (after 1:2 matching; P > 0·05). Odds for survival were consistent across all groups. Conclusions These results do not suggest a differential response to tissue plasminogen activator based on race ethnicity. Among Asians, data were particularly sparse, and results should be interpreted with caution. Key words: tPA, race ethnicity, clinical trials, Asian, African American/ Black, Caucasian

Introduction Thrombolysis with tissue plasminogen activator (tPA) is the only proven therapy available to treat acute ischemic stroke (AIS) patients (1,2). The National Institutes of Neurological Disorders and Stroke (NINDS) study demonstrated the efficacy of tPA in AIS patients at a dose of 0·9 mg/kg administered within threehours of symptom onset (1). The European Co-operative Acute Stroke III (ECASS III) study demonstrated the efficacy of tPA, administered at a standard dose (0·9 mg/kg) in a 3–4·5 hours’ time window (2). Although both these studies enrolled a largely Caucasian population, the findings are often extrapolated onto non-Caucasian populations. A small number of non-randomized studies have claimed that the response to tPA differs with a patient’s race ethnicity (3,4). For example, a single-arm open-labeled prospective study, the Japan Alteplase Clinical Trial (J-ACT), demonstrated better outcomes with a lower dose of tPA (0·6 mg/kg) compared with a predetermined threshold obtained from the tPA trials with predominantly Caucasian subjects [modified Rankin Scale (mRS) 0–1 on day 90: 36·9% vs. 33·9%; symptomatic ICH 5·8% vs. 9·6%] (5). The lower dose was chosen in J-ACT because Japanese trials had earlier demonstrated better outcomes (greater recanalization rates and lower risks for hemorrhagic transformation) with a lower dose of duteplase (6,7). Based on the J-ACT findings, the Japanese Ministry of Health approved the lower dose, 0·6 mg/kg, in October 2005· (8) Chinese patients have also shown better outcomes with the lower dose instead of the standard dose (hemorrhage rate: per NINDS definition: 5·2% vs. 10·4%; 90-day mortality: 6·9% vs. 12·8%) (9). Cardiology studies have shown that compared with Caucasians, African American patients have a greater fibrinolytic activity and a higher hemorrhage risk (4,10,11). Despite the possibility of a differential response of tPA because of racial differences, we are unaware of any randomized controlled trials that examined thrombolysis outcomes in Asians or Blacks. In the absence of such randomized thrombolytic trials, we interrogated Vol 9, July 2014, 613–617

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the Virtual International Stroke Trials Archives (VISTA) with respect to race ethnicity and baseline variables.

was performed in the combined dataset and then in each racial subtype; only the resulting matched patients were considered for subsequent comparison of outcomes.

Aims and/or hypothesis

Comparison of outcomes between thrombolysed and nonthrombolysed patients

We examined if matched non-Caucasian patients of mixed national origin within the VISTA neuroprotection trials respond differently to treatment with tPA owing to racial differences.

Methods Data source and patients We collected anonymized data from the VISTA randomized neuroprotection trials [http://www.vistacollaboration.org; duration: 1998–2007] that included demographics, baseline National Institutes of Health Stroke Scales (NIHSS), risk factors, measures of functional outcomes (NIHSS on day 90 and Rankin Scores on day 90), race ethnicity information, and tPA use. VISTA is a collaborative, not-for-profit, register of stroke trials. VISTA policy precludes the disclosure of the source trials that contributed data to this analysis (12). Matching VISTA patients for baseline characteristics Imbalances in baseline factors such as age and stroke severity are typically observed in stroke trials especially in subgroup analysis (13–15). Hence, in the present analysis, we used pPAIRS©, software developed for matching patients in both large and small samples (16,17). The pPAIRS algorithm matches patients in Euclidean space by identifying a patient in one group who is in close proximity to a patient in the other group. Using pPAIRS, two authors (P. M. and T.A.K.) matched thrombolysis and nonthrombolysis patients blinded to outcome, matching them for their baseline NIHSS, age, and diabetes status (16). Diabetes status was defined per the criteria used in the randomized controlled trials that contributed data to VISTA. The pPAIRS method is a variation of the weighted-Euclidean method, and it can match subjects on both dichotomous (e.g. race ethnicity) and continuous (e.g. NIHSS, age) variables (16–18). The software weights individual variables so that their influence on the final match is not skewed by a larger range, and it considers poorly matched patients as outliers, excluding them using Tukey’s method (16,19). Matching

Primary analysis Using generalized estimation equation ordinal models, we compared distribution of Rankin scores at three-months in each racial subgroup between the matched thrombolysis [Treatment (T)] and nonthrombolysis [Controls (C)] groups. Secondary analyses We compared dichotomized outcomes, defined as excellent functional outcome (mRS 0–1), good functional outcome (mRS 0–2), and survival on day 90 in each racial group using conditional logistic regression model. Ordinal analysis was chosen for our primary analysis because it has been shown to be an efficient method for outcome analysis in stroke trials data (20–22). The choice of mRS cut points in the dichotomized outcomes was based on the previous t-PA trials (2,21,23). We report P for the interaction test (tPA use*race) from the outcome prediction models. For this, we used generalized estimation equation ordinal models and dichotomized Rankin outcomes using conditional logistic regression model. We also report odds ratio (OR) for outcomes in the combined dataset and within each racial subtype. Other statistical tests Wilcoxon Rank-Sum test was used to compare the median NIHSS of two populations. Means of populations were compared by Student’s t-test.

Results Matching procedure We report patients’ prematch and postmatch characteristics in Tables 1–3. Matched pairs were well balanced in terms of baseline NIHSS and age (postmatch P > 0·05; Tables 1–3). Functional outcome data were unavailable for 217 patients (17 Blacks, 6

Table 1 Baseline characteristics of the Asians in the Virtual International Stroke Trials Archives (VISTA) data: prematch denotes the patient characteristics without matching; the postmatch denotes the patient characteristics after matching Prematch

Postmatch (1:1)

Postmatch (1:2)

Asians

tPA

Control

P*

tPA

Control

P*

tPA

Control

P*

Median NIHSS Mean NIHSS + SD Mean age +SD Diabetes (n) Number of patients

17 15·9 ± 5·76 69·3 ± 12·6 11 40

11 12·5 ± 7·28 68·1 ± 12·3 42 127

0·004 0·009 0·612

17 15·6 ± 5·59 70·2 ± 11·1 11 39

16 15·3 ± 5·50 70·0 ± 10·2 11 39

0·771 0·823 0·924

17 15·9 ± 5·76 69·3 ± 12·6 11 40

15·5 15·4 ± 5·88 69·9 ± 11·1 19 72

0·629 0·681 0·767

For the Asian subgroup, the 1:1 matching resulted in a small sample size of 78 patients. In order to increase the sample size, we undertook 1:2 matching that led to a sample size of 112 patients. *Median NIHSS were compared using Wicoxon Rank-Sum test, and mean NIHSS and age were compared using Student’s t-test. tPA, tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scales; SD, standard deviation.

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Table 2 Baseline characteristics of the Blacks in the Virtual International Stroke Trials Archives (VISTA) data: prematch denotes the patient characteristics without matching; the postmatch denotes the patient characteristics after matching Prematch

Postmatch (1:1)

Blacks

tPA

Control

P*

tPA

Control

P*

Median NIHSS Mean NIHSS + SD Mean age + SD Diabetes (n) Number of patients

13 13·7 ± 6·04 61·0 ± 14·9 46 132

13 13·6 ± 5·96 64·1 ± 15·0 75 223

0·933 0·869 0·065

12 13·3 ± 5·74 62·0 ± 14·3 44 125

12 13·4 ± 5·73 62·3 ± 14·3 44 125

0·939 0·938 0·835

Before matching, there were 46 diabetes patients in tPA group and 75 diabetes patients in control group. After matching, there were 44 diabetes patients in both groups. *Median NIHSS were compared using Wicoxon Rank-Sum test, and mean NIHSS and age were compared using Student’s t-test.

Table 3 Baseline characteristics of the Caucasians in the VISTA data: pre-match denotes the patient characteristics without matching; the post-match denotes the patient characteristics after matching Prematch

Postmatch (1:1)

Caucasians

tPA

Control

P*

tPA

Control

P*

Median NIHSS Mean NIHSS+STD Mean age +STD Diabetes Number of patients

14 14·2 ± 5·13 68·7 ± 12·6 397 2131

12 12·9 ± 5·57 70·8 ± 11·8 791 3273

Influence of racial differences on outcomes after thrombolytic therapy in acute ischemic stroke.

The National Institutes of Neurological Disorders and Stroke and the European Co-operative Acute Stroke III trials enrolled a largely Caucasian popula...
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