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Statistical analysis plan for the second INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2): a large-scale investigation to solve longstanding controversy over the most appropriate management of elevated blood pressure in the hyperacute phase of intracerebral hemorrhage
(2013)
Craig Anderson
;
Emma Heeley
;
Stephane Heritier
;
Hisatomi Arima
;
Mark Woodward
The Statistical analysis plan (SAP) for the second INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2).
2Scopus© Citations 10
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Validation of the simplified modified Rankin scale for stroke trials: Experience from the ENCHANTED alteplase-dose arm
(2020)
Xiaoying Chen
;
Jingwei Li
;
Craig S Anderson
;
Richard I Lindley
;
Maree L Hackett
<jats:sec><jats:title>Background and aims</jats:title><jats:p> The structured, simplified modified Rankin scale questionnaire (smRSq) may increase reliability over the interrogative approach to scoring the modified Rankin scale (mRS) in acute stroke research and practice. During the conduct of the alteplase-dose arm of the international ENhanced Control of Hypertension ANd Thrombolysis StrokE stuDy (ENCHANTED), we had an opportunity to compare each of these approaches to outcome measurement. </jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p> Baseline demographic data were recorded together with the National Institutes of Health Stroke Scale (NIHSS). Follow-up measures obtained at 90 days included mRS, smRSq, and the 5-Dimension European Quality of life scale (EQ-5D). Agreements between smRSq and mRS were assessed with the Kappa statistic. Multiple logistic regression was used to identify baseline predictors of Day 90 smRSq and mRS scores. Treatment effects, based on Day 90 smRSq/mRS scores, were tested in logistic and ordinal logistic regression models. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> SmRSq and mRS scores had good agreement (weighted Kappa 0.79, 95% confidence interval (CI) 0.78–0.81), while variables of age, atrial fibrillation, diabetes mellitus, pre-morbid mRS (1 vs. 0), baseline NIHSS scores, and imaging signs of cerebral ischemia, similarly predicted their scores. Odds ratios for death or disability, and ordinal shift, 90-day mRS scores using smRSq were 1.05 (95% CI 0.91–1.20; one-sided P = 0.23 for non-inferiority) and 0.98 (95% CI 0.87–1.11; P = 0.02 for non-inferiority), similar to those using mRS. </jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p> This study demonstrates the utility of the smRSq in a large, ethnically diverse clinical trial population. Scoring of the smRSq shows adequate agreement with the standard mRS, thus confirming it is a reliable, valid, and useful alternative measure of functional status after acute ischemic stroke. </jats:p></jats:sec><jats:sec><jats:title>Clinical Trial registration</jats:title><jats:p> URL: http://www.clinicaltrials.gov . Unique identifier: NCT01422616. </jats:p></jats:sec>
Scopus© Citations 9 7
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Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial
(2023)
Chen Chen
;
Menglu Ouyang
;
Sheila Ong
;
Luyun Zhang
;
Guobin Zhang
Scopus© Citations 5 5
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Comparative effects of intensive-blood pressure versus standard-blood pressure-lowering treatment in patients with severe ischemic stroke in the ENCHANTED trial
(2020)
Jatinder S. Minhas
;
Xia Wang
;
Richard I. Lindley
;
Candice Delcourt
;
Lili Song
9Scopus© Citations 16
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Associations of Early Systolic Blood Pressure Control and Outcome After Thrombolysis-Eligible Acute Ischemic Stroke: Results From the ENCHANTED Study
(2022)
Xia Wang
;
Jatinder S. Minhas
;
Tom J. Moullaali
;
Gian Luca Di Tanna
;
Richard I. Lindley
<jats:sec> <jats:title>Background and Purpose:</jats:title> <jats:p>In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150–180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130–140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1–24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71–0.82]; <jats:italic>P</jats:italic> <0.001 and 0.86 [95% CI, 0.76–0.98]; <jats:italic>P</jats:italic> =0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93–1.04]; <jats:italic>P</jats:italic> =0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06–1.31]; <jats:italic>P</jats:italic> =0.002 and 1.34 [1.11–1.62]; <jats:italic>P</jats:italic> =0.002) but not with magnitude of SBP reduction (1.05 [0.98–1.14]; <jats:italic>P</jats:italic> =0.184). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Registration:</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov">https://www.clinicaltrials.gov</jats:ext-link> ; Unique identifier: NCT01422616. </jats:p> </jats:sec>
Scopus© Citations 26 3
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Ethnicity and Other Determinants of Quality of Functional Outcome in Acute Ischemic Stroke
(2020)
Xiaoying Chen
;
Xia Wang
;
Candice Delcourt
;
Jingwei Li
;
Hisatomi Arima
<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>Patient-centered outcomes are important. We aimed to determine predictors of health-related quality of life (HRQoL) and develop utility-weighted modified Rankin Scale (mRS) scores in thrombolyzed acute ischemic stroke patients from both arms of ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p>ENCHANTED was an international quasi-factorial clinical trial of different doses of intravenous alteplase and intensities of blood pressure control in acute ischemic stroke patients, with outcomes on the 5-Dimensional European Quality of Life Scale and mRS assessed at 90 days post-randomization. Logistic regression models were used to identify baseline predictors of poor HRQoL (≤mean 5-Dimensional European Quality of Life Scale utility scores). Ordinary least squares regression derived utility-weighted mRS scores.</jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p>In 4016 acute ischemic stroke patients with complete 5-Dimensional European Quality of Life Scale and mRS data, independent predictors of poor HRQoL were older age (odds ratio, 1.19 [95% CI, 1.12–1.27], per 10-year increase), non-Asian ethnicity (1.91 [1.61–2.27]), greater stroke severity on the National Institutes of Health Stroke Scale (1.11 [1.09–1.12]), diabetes mellitus (1.41 [1.18–1.69]), premorbid disability (mRS score 1 versus 0; 1.62 [1.33–1.97]), large vessel atheromatous pathogenesis (1.32 [1.12–1.54]), and proxy respondent (2.35 [2.01–2.74]). Sensitivity analyses indicate the ethnicity influence on HRQoL was driven by the high proportion of Chinese (62.9% of Asian) participants with better HRQoL compared with non-Chinese or other Asian groups. Derived utility values across mRS scores 0 to 5 were 0.977, 0.885, 0.748, 0.576, 0.194, and −0.174, respectively. Correlations between mRS and 5-Dimensional European Quality of Life Scale scores were stronger in Asians.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>HRQoL is worse after thrombolyzed acute ischemic stroke in the elderly, non-Asians, with greater initial severity, diabetes mellitus, premorbid disability, due to large vessel atheroma, and proxy assessment. The broader significance of better HRQoL in Asians is tempered by Chinese participants dominating analyses. From utility-weighted mRS scores indicating the greatest steps in mRS scores are between 5 and 3, treatments to avoid major disability provide the greatest benefits for patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Registration—</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov">https://www.clinicaltrials.gov</jats:ext-link> . Unique identifier: NCT01422616. </jats:p> </jats:sec>
6Scopus© Citations 8
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Mannitol and Outcome in Intracerebral Hemorrhage Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results
(2015)
Xia Wang
;
Hisatomi Arima
;
Jie Yang
;
Shihong Zhang
;
Guojun Wu
<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>Mannitol is often used to reduce cerebral edema in acute intracerebral hemorrhage but without strong supporting evidence of benefit. We aimed to determine the impact of mannitol on outcome among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p>INTERACT2 was an international, open, blinded end point, randomized controlled trial of 2839 patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure allocated to intensive (target systolic blood pressure, <140 mm Hg within 1 hour) or guideline-recommended (target systolic blood pressure, <180 mm Hg) blood pressure–lowering treatment. Propensity score and multivariable analyses were performed to investigate the relationship between mannitol treatment (within 7 days) and poor outcome, defined by death or major disability on the modified Rankin Scale score (3–6) at 90 days.</jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p> There was no significant difference in poor outcome between mannitol (n=1533) and nonmannitol (n=993) groups: propensity score–matched odds ratio of 0.90 (95% confidence interval, 0.75–1.09; <jats:italic>P</jats:italic> =0.30) and multivariable odds ratio of 0.87 (95% confidence interval, 0.71–1.07; <jats:italic>P</jats:italic> =0.18). Although a better outcome was suggested in patients with larger (≥15 mL) than those with smaller (<15 mL) baseline hematomas who received mannitol (odds ratio, 0.52 [95% confidence interval, 0.35–0.78] versus odds ratio, 0.91 [95% confidence interval, 0.72–1.15]; <jats:italic>P</jats:italic> homogeneity <0.03 in propensity score analyses), the association was not consistent in analyses across other cutoff points (≥10 and ≥20 mL) and for differing grades of neurological severity. Mannitol was not associated with excess serious adverse events. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Mannitol seems safe but might not improve outcome in patients with acute intracerebral hemorrhage.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trial Registration—</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</jats:ext-link> . Unique identifier: NCT00716079. </jats:p> </jats:sec>
6Scopus© Citations 53
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Prognostic Significance of Hyperglycemia in Acute Intracerebral Hemorrhage The INTERACT2 Study
(2016)
Anubhav Saxena
;
Craig S. Anderson
;
Xia Wang
;
Shoichiro Sato
;
Hisatomi Arima
<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>We aimed to determine associations of baseline blood glucose and diabetes mellitus with clinical outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p>INTERACT2 was an international prospective, open, blinded end point, randomized controlled trial of 2839 patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure randomly assigned to intensive (target systolic blood pressure <140 mm Hg) or guideline-based (systolic blood pressure <180 mm Hg) BP management. Associations of hyperglycemia at presentation (>6.5 mmol/L) and combined and separate poor outcomes of death and major disability (scores of 3–6, 3–5, and 6, respectively, on the modified Rankin scale) at 90 days were determined in logistic regression models.</jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p> In 2653 patients with available data, there were 1348 (61%) with hyperglycemia and 292 (11%) with diabetes mellitus. Associations of baseline blood glucose and poor outcome were strong and near continuous. After adjustment for baseline variables, the highest fourth (7.9–25.0 mmol/L) of blood glucose was significantly associated with combined poor outcome (adjusted odds ratio 1.35, 95% confidence interval 1.01–1.80; <jats:italic>P</jats:italic> trend 0.015). Diabetes mellitus also predicted poor outcome (adjusted odds ratio 1.46, 95% confidence interval 1.05–2.02; <jats:italic>P</jats:italic> =0.023), though more important for residual disability than death on separate analysis. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Hyperglycemia and diabetes mellitus are independent predictors of poor outcome in patients with predominantly mild to moderate severity of intracerebral hemorrhage. These data support guideline recommendations for good glycemic control in patients with intracerebral hemorrhage.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trial Registration—</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</jats:ext-link> . Unique identifier: NCT00716079. </jats:p> </jats:sec>
5Scopus© Citations 118
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Prophylactic heparin in acute intracerebral hemorrhage: a propensity score-matched analysis of the INTERACT2 study
(2016)
MUÑOZ VENTURELLI, PAULA ANDREA
;
Xia Wang
;
Pablo M Lavados
;
Christian Stapf
;
Thompson Robinson
<jats:sec><jats:title>Background</jats:title><jats:p> Indication and timing of pharmacological venous thromboembolism prophylaxis in intracerebral hemorrhage patients is controversial. </jats:p></jats:sec><jats:sec><jats:title>Aims</jats:title><jats:p> To determine whether use of subcutaneous heparin during the first 7 days after spontaneous intracerebral hemorrhage increases risks of death and disability. </jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p> Data are from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) study. Patients with acute intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure were included; patients received subcutaneous heparin following local best practice standards of care. Multivariable logistic regression and propensity score matched analysis were used to determine associations of heparin use on death and disability (modified Rankin scale) at 90 days. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> In 2525 patients with available data, there were 465 (22.5%) who received subcutaneous heparin. They had higher death or major disability at 90 days in crude (odds ratio 2.29, 95% confidence interval 1.85–2.84; p < 0.001), adjusted (odds ratio 1.62, 95% confidence interval 1.26–2.09; p < 0.001) and propensity score matched (odds ratio 2.06, 95% confidence interval 1.53–2.77; p < 0.001) analyses. In propensity score matched analysis, heparin-treated patients had significant lower mortality (odds ratio 0.55, 95% CI 0.35–0.87; p = 0.01) but greater major disability (odds ratio 1.68, 95% confidence interval 1.25–2.28; p < 0.001) at 90 days. However, no mortality difference was found in analysis restricted to 48-hour survivors. </jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p> Use of subcutaneous heparin is associated with poor outcome in acute intracerebral hemorrhage, driven by increased residual disability. Despite the limitations of this study, and no clear relation of heparin with bleeding risk, we recommend careful consideration of the need for venous thromboembolism prophylaxis with heparin in intracerebral hemorrhage patients. </jats:p></jats:sec><jats:sec><jats:title>Trial registration</jats:title><jats:p> http://www.clinicaltrials.gov NCT00716079. </jats:p></jats:sec>
Scopus© Citations 14 1
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Significance of Intraventricular Hemorrhage in Acute Intracerebral Hemorrhage Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Results
(2015)
Edward Chan
;
Craig S. Anderson
;
Xia Wang
;
Hisatomi Arima
;
Anubhav Saxena
<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>Intraventricular hemorrhage (IVH) with spontaneous intracerebral hemorrhage indicates a poor prognosis but uncertainty exists over the pattern of association. We aimed to elucidate risk associations of IVH and outcome in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) data set.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p>INTERACT2 was an international prospective, open-blinded end point, randomized controlled trial in 2839 patients with intracerebral hemorrhage (<6 hours) with elevated systolic blood pressure randomly assigned to intensive (target systolic blood pressure <140 mm Hg) or guideline-based (systolic blood pressure <180 mm Hg) blood pressure management. Associations of baseline IVH in 740 of 2613 (28%) patients and poor outcomes (death and major disability defined on the modified Rankin Scale) at 90 days were determined in linear and logistic regression models.</jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p> Patients with IVH were significantly older and with greater neurological impairment, history of ischemic stroke, and larger hematomas more often deep hemisphere located at presentation, after adjustment for other baseline variables. Death or major disability occurred in 66% with IVH versus 49% in intracerebral hemorrhage–alone patients (adjusted odds ratio, 1.68; 95% confidence interval, 1.38–2.06; <jats:italic>P</jats:italic> <0.01). Associations of IVH volume and clinical outcomes were strong and near continuous. Adjusted analyses by thirds of IVH volume indicate thresholds of ≈5 and 10 mL for significantly increased odds of death and death or major disability, respectively. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>A strong association exists between the amount of IVH and poor outcome in intracerebral hemorrhage. An IVH volume of 5 to 10 mL emerges as a significant threshold for decision making on prognosis in these patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trial Registration—</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</jats:ext-link> . Unique identifier: NCT00716079. </jats:p> </jats:sec>
1Scopus© Citations 50

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