Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Cost-Effectiveness of Low-Dose Compared to Standard-Dose Alteplase for Acute Ischemic Stroke in China: A Within-Trial Economic Evaluation of the ENCHANTED Study.

INTRODUCTION: The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) showed that a low-dose alteplase was safe but not clearly non-inferior to standard-dose alteplase in acute ischemic stroke (AIS). Given the significant cost of this medicine, we undertook a cost-effectiveness analysis to determine the probability that low-dose is cost-effective relative to standard-dose alteplase in China. METHODS: For ENCHANTED participants in China with available health cost data, cost-effectiveness and cost-utility analyses were undertaken in which death or disability (modified Rankin scale scores 2-6) at 90 days and quality-adjusted life-years (QALYs) were used as outcome measures, respectively. There was adherence to standard guidelines for health economic evaluations alongside non-inferiority trials and according to a health-care payer's perspective. The equivalence margin for cost and effectiveness was set at USD 691 and -0.025 QALYs, respectively, for the base-case analysis. Probabilistic sensitivity analyses were used to evaluate the probability of low-dose alteplase being non-inferior. RESULTS: While the mean cost of alteplase was lower in the low-dose group (USD 1,569 vs. USD 2,154 in the standard-dose group), the total cost was USD 56 (95% confidence interval [CI]: -1,000-1,113) higher compared to the standard-dose group due to higher hospitalization costs in the low-dose group. There were 462 (95% CI: 415-509) and 410 (95% CI: 363-457) patients with death or disability per 1,000 patients in the low-dose and standard-dose groups, respectively. The low-dose group had marginally lower (0.008, 95% CI: -0.016-0.001) QALYs compared to their standard-dose counterparts. The low-dose group was found to have an 88% probability of being non-inferior based on cost-effectiveness versus the standard-dose group. CONCLUSIONS: This health economic evaluation alongside the ENCHANTED indicates that the use of low-dose alteplase does not save overall healthcare costs nor lead to a gain in QALYs in the management of Chinese patients with AIS compared to the use of standard dose. There is little justification on economic grounds to shift from standard-of-care thrombolysis in AIS.

Off-Hour Admission and Outcomes in Patients with Acute Intracerebral Hemorrhage in the INTERACT2 Trial.

BACKGROUND: Conflicting data exist of an association between off-hour (weekend, holiday, or night-time) hospital admission and adverse outcome in intracerebral hemorrhage (ICH). We determined the association between off-hour admissions and poor clinical outcome, and of any differential effect of early intensive blood pressure (BP) lowering treatment between off- and on-hour admissions, among participants of the Intensive BP Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). METHODS: Subsidiary analysis of INTERACT2, a multinational, multicenter, clinical trial of patients with spontaneous ICH with elevated systolic BP, randomly assigned to intensive (target systolic BP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Primary outcome was death or major disability (modified Rankin scale of 3-6) at 90 days. Off-hour admission was defined as night-time (4:30 p.m. to 8:30 a.m.) on weekdays, weekends (Saturday and Sunday), and public holidays in each participating country. RESULTS: Of 2,794 patients with information on the primary outcome, 1,770 (63%) were admitted to study centers during off-hours. Off-hour admission was not associated with risk of poor outcome at 90 days (53% off-hour vs. 55% on-hour; p = 0.49), even after adjustment for comorbid risk factors (odds ratio 0.92; 95% CI 0.76-1.12). Consistency exists in the effects of intensive BP lowering between off- and on-hour admission (p = 0.85 for homogeneity). CONCLUSIONS: Off-hour admission was not associated with increased risks of death or major disability among trial protocol participants with acute ICH. Intensive BP lowering can provide similar treatment effect irrespective of admission hours.

Rapid Blood Pressure Lowering According to Recovery at Different Time Intervals after Acute Intracerebral Hemorrhage: Pooled Analysis of the INTERACT Studies.

BACKGROUND AND PURPOSE: Early intensive blood pressure (BP) lowering has been shown to improve functional outcome in acute intracerebral hemorrhage (ICH), but the treatment effect is modest and without a clearly defined underlying explanatory mechanism. We aimed at more reliably quantifying the benefits of this treatment according to different time periods in the recovery of participants in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies. METHODS: Pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2,839) involving patients with spontaneous ICH (<6 h) and elevated systolic BP (SBP 150-220 mm Hg) who were randomized to intensive (target SBP <140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP lowering treatment. Treatment effects were examined according to repeated measures analysis of an ordinal ('shift') across all 7 levels of the modified Rankin Scale (mRS) assessed during follow-up at 7, 28, and 90 days, post-randomization. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov, NCT00226096 and NCT00716079. RESULTS: Intensive BP lowering resulted in a significant favorable distribution of mRS scores for better functioning (odds ratio 1.13, 95% confidence interval 1.00-1.26; p = 0.042) over 7, 28 and 90 days, and the effect was consistency for early (7-28 days) and later (28-90 days) time periods (p homogeneity 0.353). Treatment effects were also consistent across several pre-specified patient characteristic subgroups, with trends favoring those randomized early, and with higher SBP and milder neurological severity at baseline. CONCLUSIONS: Intensive BP lowering provides beneficial effects on physical functioning that manifests consistently through the early and later phases of recovery from ICH.

Older age is a strong predictor for poor outcome in intracerebral haemorrhage: the INTERACT2 study.

BACKGROUND AND PURPOSE: Global ageing contributes greatly to the burden of stroke. We investigated the influence of age on the baseline profile and on outcomes in acute intracerebral haemorrhage (ICH) among participants of the INTERACT2 study. METHODS: INTERACT2 was an international, randomised controlled trial in 2839 patients with spontaneous ICH within 6 h of onset and elevated systolic blood pressure (SBP; 150-220 mmHg) who were allocated to receive intensive (target SBP <140 mmHg within 1 h) or guideline-recommended (target SBP <180 mmHg) blood pressure lowering treatment. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Poor outcome was defined as death or major disability ('dependency', modified Rankin Scale scores 3-6) at 90 days. Health-related quality of life (HRQoL) was assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Associations between age and outcomes were analysed in multivariable logistic regression models. RESULTS: Stroke severity increased in categories of older age (P-trend 0.002). Stroke patients over 75 years old were four times more likely to die or be disabled at 90 days than those <52 years when other confounders were accounted for (odds ratio 4.36, 95% confidence interval 3.12-6.08). Older age was also associated with decreasing HRQoL, across mobility, self-care, usual activities and depression (all P-trend <0.001), and pain or discomfort (P-trend 0.022). CONCLUSION: In the INTERACT2 cohort, older people had more severe ICH and worse outcomes (death, major disability and HRQoL). These data will help guide clinicians manage older people with haemorrhagic stroke. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT00716079).

Urate-lowering drugs for chronic kidney disease with asymptomatic hyperuricemia and hypertension: a randomized trial.

INTRODUCTION: Xanthine oxidase (XO) inhibitors may slow down chronic kidney disease (CKD) progression. The comparative effectiveness of the different urate-lowering drugs is unknown. The aim of this study was to determine whether urate-lowering therapy with an XO inhibitor (febuxostat) and that with a uricosuric drug (benzbromarone) are comparable in slowing renal function decline in patients with CKD complicated with hypertension and hyperuricemia. METHODS: This study was an open-label randomized parallel-group clinical trial of 95 patients with stage G3 CKD in Japan. The patients had hypertension and hyperuricemia without a history of gout. They were randomized to receive febuxostat ( n  = 47; febuxostat group) or benzbromarone ( n  = 48; benzbromarone group) and titrated to reduce their serum urate level to <6.0 mg/dl. The primary end-point was change in estimated glomerular filtration rate (eGFR) from baseline to 52 weeks. The secondary end-points included changes in uric acid level, blood pressure, urinary albumin-to-creatinine ratio, and XO activity. RESULTS: Of the 95 patients, 88 (92.6%) completed the trial. There were no significant differences in change in eGFR (in ml/min/1.73 m 2 ) between the febuxostat [-0.23, 95% confidence interval (CI), -2.00 to 1.55] and benzbromarone (-2.18, 95% CI, -3.84 to -0.52) groups (difference, 1.95; 95% CI, -0.48 to 4.38; P  = 0.115) nor in the secondary end-points, except for XO activity. Febuxostat significantly reduced XO activity ( P  = 0.010). There were no significant differences in primary and secondary outcomes between the groups. A decrease in eGFR was significantly less in the febuxostat group than that of the benzbromarone group in the CKDG3a, but not in CKDG3b, in the subgroup analysis. There were no adverse effects specific to either drug. CONCLUSIONS: No significant differences were found in the effects of febuxostat and benzbromarone in renal function decline in stage G3 CKD complicated with hyperuricemia and hypertension.

Optimal blood pressure target to prevent severe hypertension in pregnancy: A systematic review and meta-analysis.

Severe hypertension in pregnancy is a hypertensive crisis that requires urgent and intensive care due to its high maternal and fetal mortality. However, there is still a conflict of opinion on the recommendations of antihypertensive therapy. This study aimed to identify the optimal blood pressure (BP) levels to prevent severe hypertension in pregnant women with nonsevere hypertension. Ovid MEDLINE and the Cochrane Library were searched, and only randomized controlled trials (RCTs) were included if they compared the effects of antihypertensive drugs and placebo/no treatment or more intensive and less intensive BP-lowering treatments in nonsevere hypertensive pregnant patients. A random effects model meta-analysis was performed to estimate the pooled risk ratio (RR) for the outcomes. Forty RCTs with 6355 patients were included in the study. BP-lowering treatment significantly prevented severe hypertension (RR, 0.46; 95% CI, 0.37-0.56), preeclampsia (RR, 0.82; 95% CI, 0.69-0.98), severe preeclampsia (RR, 0.38; 95% CI, 0.17-0.84), placental abruption (RR, 0.52; 95% CI, 0.32-0.86), and preterm birth (< 37 weeks; RR, 0.81; 95% CI, 0.71-0.93), while the risk of small for gestational age infants was increased (RR, 1.25; 95% CI, 1.02-1.54). An achieved systolic blood pressure (SBP) of < 130 mmHg reduced the risk of severe hypertension to nearly one-third compared with an SBP of ≥ 140 mmHg, with a significant interaction of the BP levels achieved with BP-lowering therapy. There was no significant interaction between the subtypes of hypertensive disorders of pregnancy and BP-lowering treatment, except for placental abruption. BP-lowering treatment aimed at an SBP < 130 mmHg and accompanied by the careful monitoring of fetal growth might be recommended to prevent severe hypertension.

Intensive or standard blood pressure control in patients with a history of ischemic stroke: RESPECT post hoc analysis.

The Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study and its pooled analysis showed that intensive blood pressure (BP) lowering reduced recurrent stroke risk by 22% in patients with a history of stroke. Here, we report the effect of intensive BP lowering on the risk of recurrent stroke subtypes in patients with a history of ischemic stroke. RESPECT was a randomized clinical trial among 1280 people with a history of cerebral infarction or intracerebral hemorrhage. Participants were assigned to the intensive blood pressure control group (blood pressure < 120/80 mmHg) or standard blood pressure control group (blood pressure < 140/90 mmHg). In this post hoc analysis, we analyzed 1074 patients with a history of cerebral infarction. The mean BP at baseline was 140.7/81.4 mmHg. Throughout the follow-up period, the mean BP was 133.4/77.5 (95% CI, 132.7-134.1/76.9-78.2) mmHg in the standard group and 126.7/74.1 (95% CI, 126.0-127.4/73.5-74.8) mmHg in the intensive group. During a mean follow-up of 3.9 years, 78 first recurrent strokes occurred. Intensive treatment tended to reduce overall annual stroke recurrence (1.74% in intensive vs. 2.17% in standard; P = 0.351 by log-rank test) and did not change the risk of ischemic stroke (1.74% vs. 1.75%, P = 0.999) but markedly reduced the risk of hemorrhagic stroke (0.00% vs. 0.39%, P = 0.005). Beneficial effects of intensive BP control were observed for the risk of hemorrhagic stroke in patients with a history of ischemic stroke. The findings of this study indicate the benefit of intensive BP control for patients with a history of ischemic stroke at high risk of hemorrhagic stroke.

Effects of blood pressure lowering on major vascular events among patients with isolated diastolic hypertension: the perindopril protection against recurrent stroke study (PROGRESS) trial.

BACKGROUND AND PURPOSE: Despite clear evidence that blood pressure (BP) lowering is effective for prevention of cardiovascular events among patients with isolated systolic hypertension and systolic-diastolic hypertension, there is ongoing uncertainty about its effects in those with isolated diastolic hypertension. The objective of the present analysis is to determine whether BP lowering provides benefits to patients with isolated diastolic hypertension. METHODS: Patients with cerebrovascular disease and hypertension at baseline (n=4283) were randomly assigned to either active treatment (perindopril in all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). The primary outcome was total major vascular events. RESULTS: There were 1923 patients with isolated systolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP < 90 mm Hg), 315 with isolated diastolic hypertension (systolic BP <140 mm Hg and diastolic BP ≥ 90 mm Hg), and 2045 with systolic-diastolic hypertension (systolic BP ≥ 140 mm Hg and diastolic BP ≥ 90 mm Hg) at baseline. Active treatment reduced the relative risk of major vascular events by 27% (95% CI, 10% to 41%) among patients with isolated systolic hypertension, by 28% (-29% to 60%) among those with isolated diastolic hypertension, and by 32% (17% to 45%) among those with systolic-diastolic hypertension. There was no evidence of differences in the magnitude of the effects of treatment among different types of hypertension (P homogeneity=0.89). CONCLUSIONS: BP lowering is likely to provide a similar level of protection against major vascular events for patients with isolated diastolic hypertension as for those with isolated systolic hypertension and systolic-diastolic hypertension. Clinical Trial Registration Information- This trial was not registered because patients were enrolled before July 1, 2005.

Cluster-randomized controlled trial for the early promotion of clinic visits for untreated hypertension.

Despite clear evidence of the benefits of lowering blood pressure among patients with hypertension, the treatment rate remains <40% worldwide. In the present trial, we aimed to investigate the effects of the early promotion of clinic visits among patients with untreated hypertension detected during annual health checkups. This was a worksite-based, parallel group, cluster-randomized trial with blinded outcome assessment. Employees of 152 Japanese supermarket stores found to have untreated hypertension (blood pressure levels ≥ 160/100 mmHg) during health checkups were assigned to an early promotion group (encouraged to visit a clinic in face-to-face interviews and provided with a referral letter to a physician as well as a leaflet) or a control group (received usual care), according to random assignment. The primary outcome was the completion of a clinic visit within 6 months. Odds ratios with 95% confidence intervals for the early promotion group versus the control group were estimated using multilevel logistic regression with random effects of clusters. A total of 273 participants (mean age 50.3 years, 55% women) from 107 stores were assigned to the early promotion group (138 from 55 stores) or control group (135 from 52 stores). During the 6-month follow-up, 47 (34.1%) participants in the early promotion group visited a clinic, as did 26 (19.3%) in the control group (odds ratio 2.33, 95% confidence interval 1.12-4.84, P = 0.024). Early promotion using a referral letter during health checkups significantly increased the number of clinic visits within 6 months completed by participants with untreated hypertension (UMIN000025411).

Smoking influences outcome in patients who had thrombolysed ischaemic stroke: the ENCHANTED study.

BACKGROUND AND PURPOSE: As studies vary in defining the prognostic significance of smoking in acute ischaemic stroke (AIS), we aimed to determine the relation of smoking and key outcomes in patient participants who had thrombolysed AIS of the international quasi-factorial randomised Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: Post-hoc analyses of ENCHANTED, an international quasi-factorial randomised evaluation of intravenous alteplase-dose comparison and levels of blood pressure control in patients who had thrombolysed AIS. Multivariable logistic regression models with inverse probability of treatment weighting (IPTW) propensity scores were used to determine associations of self-reported smoking status and clinical outcomes, according to 90-day modified Rankin Scale (mRS) scores and symptomatic intracerebral haemorrhage (sICH). RESULTS: Of 4540 patients who had an AIS, there were 1008 (22.2%) current smokers who were younger and predominantly male, with more comorbidities of hypertension, coronary artery disease, atrial fibrillation and diabetes mellitus, and greater baseline neurological impairment, compared with non-smokers. In univariate analysis, current smokers had a higher likelihood of a favourable shift in mRS scores (OR 0.88, 95% CI 0.77 to 0.99; p=0.038) but this association reversed in a fully adjusted model with IPTW (adjusted OR 1.15, 95% CI 1.04 to 1.28; p=0.009). A similar trend was also apparent for dichotomised poor outcome (mRS scores 2-6: OR 1.18, 95% CI 1.05 to 1.33; p=0.007), but not with the risk of sICH across standard criteria. CONCLUSION: Smoking predicts poor functional recovery in patients who had thrombolysed AIS. TRIAL REGISTRATION NUMBER: NCT01422616.

Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT).

BACKGROUND AND PURPOSE: The Intensive Blood Pressure Reduction In Acute Cerebral Haemorrhage Trial (INTERACT) study suggests that early intensive blood pressure (BP) lowering can attenuate hematoma growth at 24 hours after intracerebral hemorrhage. The present analyses aimed to determine the effects of treatment on hematoma and perihematomal edema over 72 hours. METHODS: INTERACT included 404 patients with CT-confirmed intracerebral hemorrhage, elevated systolic BP (150 to 220 mm Hg), and capacity to start BP-lowering treatment within 6 hours of intracerebral hemorrhage. Patients were randomly assigned to an intensive (target systolic BP 140 mmHg) or standard guideline-based management of BP (target systolic BP 180 mm Hg) using routine intravenous agents. Baseline and repeat CTs (24 and 72 hours) were performed using standardized techniques with digital images analyzed centrally. Outcomes were increases in hematoma and perihematomal edema volumes over 72 hours. RESULTS: Overall, 296 patients had all 3 CT scans available for the hematoma and 270 for the edema analyses. Mean systolic BP was 11.7 mm Hg lower in the intensive group than in the guideline group during 1 to 24 hours. Adjusted mean absolute increases in hematoma volumes (mL) at 24 and 72 hours were 2.40 and 0.15 in the guideline group compared with -0.74 and -2.31 in the intensive group, respectively, an overall difference of 2.80 (95% CI, 1.04 to 4.56; P=0.002). Adjusted mean absolute increases in edema volumes (mL) at 24 and 72 hours were 6.27 and 10.02 in the guideline group compared with 4.19 and 7.34 in the intensive group, respectively, for an overall difference of 2.38 (95% CI, -0.45 to 5.22; P=0.10). CONCLUSIONS: Early intensive BP-lowering treatment attenuated hematoma growth over 72 hours in intracerebral hemorrhage. There were no appreciable effects on perihematomal edema.

Sex differences in treatment and outcome after stroke: Pooled analysis including 19,000 participants.

OBJECTIVE: To explore the sex differences in outcomes and management after stroke using a large sample with high-quality international trial data. METHODS: Individual participant data were obtained from 5 acute stroke randomized controlled trials. Data were obtained on demographics, medication use, in-hospital treatment, and functional outcome. Study-specific crude and adjusted models were used to estimate sex differences in outcomes and management, and then pooled using random-effects meta-analysis. RESULTS: There were 19,652 participants, of whom 7,721 (40%) were women. After multivariable adjustments, women with ischemic stroke had higher survival at 3-6 months (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.70-0.97), higher likelihood of disability (OR 1.20, 95% CI 1.06-1.36), and worse quality of life (weighted mean difference -0.07, 95% CI -0.09 to 0.04). For management, women were more likely to be admitted to an acute stroke unit (OR 1.17, 95% CI 1.01-1.34), but less likely to be intubated (OR 0.58, 95% CI 0.36-0.93), treated for fever (OR 0.82, 95% CI 0.70-0.95), or admitted to an intensive care unit (OR 0.83, 95% CI 0.74-0.93). For preadmission medications, women had higher odds of being prescribed antihypertensive agents (OR 1.22, 95% CI 1.13-1.31) and lower odds of being prescribed antiplatelets (OR 0.86, 95% CI 0.79-0.93), glucose-lowering agents (OR 0.86, 95% CI 0.78-0.94), or lipid-lowering agents (OR 0.85, 95% CI 0.77-0.94). CONCLUSIONS: This analysis suggests that women who had ischemic stroke had better survival but were also more disabled and had poorer quality of life. Variations in hospital and out-of-hospital management may partly explain the disparities.

Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment.

RATIONALE: Controversy exists over the optimal dose of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. AIMS: The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) i.v. rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) i.v. rt-PA; and (ii) early intensive BP lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). DESIGN: The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. STUDY OUTCOMES: The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. RESULTS: Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. CONCLUSIONS: Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial.

BACKGROUND: High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079). METHODS: INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150-220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2-7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles. FINDINGS: We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05-1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14-2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14-1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13-1·88; ptrend=0·0044). INTERPRETATION: Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure. FUNDING: National Health and Medical Research Council of Australia.

Shoulder taping reduces injury and pain in stroke patients: randomized controlled trial.

OBJECTIVES: We aimed to study the effectiveness of shoulder taping and conventional treatment vs sham taping and conventional treatment in prevention of shoulder injuries in patients with acute stroke. METHODS: This study was a multicenter, interventional, prospective, randomized, outcome-blinded trial (PROBE design). All first-ever stroke patients were included within 48 hours of stroke onset (August 2009-October 2011). The treatment group included shoulder taping and conventional treatment, and the control group received sham taping and conventional treatment. Primary outcomes were changes in visual analog scale (VAS) and shoulder pain and disability index (SPADI), and secondary outcomes were changes in shoulder range of motion (flexion and abduction) at days 14 and 30. Clinical trials registration no. NCT 01062308. RESULTS: There were 80 patients in the treatment arm and 82 in the control arm. There was a better reduction of VAS (on day 14: mean difference 3.7 mm, p = 0.45; on day 30: 11.9 mm, p = 0.03) and SPADI scores (on day 14: mean difference 3.5, p = 0.33; on day 30: 9.3, p = 0.04) in the treatment arm. CONCLUSIONS: Although there was a trend toward pain reduction and functional improvement associated with shoulder taping for 2 weeks after acute stage of stroke, this did not reach statistical significance. The long-term effects of taping need to be studied in large trials. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that tri-pull shoulder taping was ineffective in significantly reducing shoulder pain in patients with acute stoke.

Effects of the endpoint adjudication process on the results of a randomised controlled trial: the ADVANCE trial.

BACKGROUND: Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925). METHODS AND FINDINGS: The ADVANCE trial was a multicentre, 2 × 2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (-1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6). CONCLUSIONS: The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment.

Hematoma growth and outcomes in intracerebral hemorrhage: the INTERACT1 study.

OBJECTIVE: Uncertainty exists over the size of potential beneficial effects of medical treatments targeting hematoma growth in intracerebral hemorrhage (ICH). We report associations of hematoma growth parameters on clinical outcomes in the pilot phase, Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1) (ClinicalTrials.gov NCT00226096). METHODS: In randomized patients with both baseline and 24-hour brain CT (n = 335), associations between measures of absolute and relative hematoma growth and 90-day poor outcomes of death and dependency (modified Rankin Scale score 3-5) were assessed in logistic regression models, with data reported as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: A total of 10.7 mL (1 SD) increase in hematoma volume over 24 hours was strongly associated with poor outcome (adjusted OR 1.72, 95% CI 1.19-2.49; p = 0.004). An association was also evident for relative growth (adjusted OR 1.67, 95% 1.22-2.27; p = 0.001 for 1 SD increase). The analyses were adjusted for age, sex, achieved systolic blood pressure, elevated NIH Stroke Scale score (≥ 14), hematoma location, baseline hematoma volume, intraventricular extension, antithrombotic therapy, baseline glucose, time from ICH to baseline CT scan, and time from baseline to repeat CT scan. A 1 mL increase in hematoma growth was associated with a 5% (95% CI 2%-9%) higher risk of death or dependency. CONCLUSION: Medical treatments, such as rapid intensive blood pressure lowering, could achieve ∼2-4 mL absolute attenuation of hematoma growth. There is hope that this could translate into modest but still clinically worthwhile (∼10%-20% better chance) outcome from ICH.