Antihypertensive Treatment Of Acute Cerebral Hemorrhage Research Articles

Intensive Blood Pressure Lowering in Patients with Moderate to Severe Grade Acute Cerebral Hemorrhage: Post Hoc Analysis of Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 Trial

Objective: To study the effect of intensive blood pressure reduction in patients with moderate to severe intracerebral hemorrhage (ICH) within the subjects recruited in Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. Design: Randomized, multicenter, 2 group, open-label clinical trial. Setting: A total of 110 sites in the USA, Japan, China, Taiwan, South Korea, and Germany. Patients: A total of 1,000 patients underwent randomization from May 2011 till September 2015. Interventions: We analyzed the effect of intensive (goal 110–139 mm Hg) over standard (goal 140–179 mm Hg) systolic blood pressure (SBP) reduction using intravenous nicardipine within 4.5 h of symptom onset in moderate to severe grade subjects with ICH in a non-prespecified analysis. Moderate to severe grade was defined by Glasgow Coma Scale score <13 or baseline National Institutes of Health Stroke Scale score ≥10 or baseline intraparenchymal hemorrhage volume ≥30 mL or presence of intraventricular hemorrhage. The primary outcome was death or disability (score 4–6 on the modified Rankin scale) at 3 months after randomization ascertained by a blinded investigator. Measurements and Main Results: Of a total of 682 subjects who met the definition of moderate to severe grade (mean age 61.9 ± 13.1 years, 62.5% men) with a mean baseline SBP of 174.7 ± 24.8 mm Hg, the frequency of hematoma expansion was significantly lower among subjects randomized to intensive SBP reduction than among subjects randomized to standard SBP reduction (20.4 vs. 27.9%, relative risk [RR]: 0.7; 95% confidence interval [CI]: 0.55–0.96). The primary endpoint of death or disability was observed in 52.5% (170/324) of subjects receiving intensive SBP reduction and 48.9% (163/333) of subjects receiving standard SBP reduction (RR: 1.1; 95% CI: 0.9–1.2). Conclusions: Intensive SBP lowering reduced the frequency of hematoma expansion but did not reduce the rate of death or disability in patients with moderate to severe grade ICH.

Rate and Predictors of Unanticipated Surgical Evacuation in Patients with Intracerebral Hemorrhage: Post Hoc Analysis of ATACH 2 Trial

We performed this analysis to identify the rates, predictors, and associated outcomes of unexpected neurosurgical evacuation in a multicenter randomized clinical trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)2. The ATACH 2 trial determined the efficacy of antihypertensive treatment in patients with spontaneous supratentorial intracerebral hemorrhages (ICHs) with a Glasgow Coma Scale (GCS) score of ≥5 and intraparenchymal hematoma volume of <60 cm3 on initial computed tomographic scan. We determined the proportion of ICH patients requiring unanticipated surgical evacuation and identified baseline factors associated with evacuation. Among the 992 subjects analyzed, 44 (4.4%) subjects required unanticipated surgical evacuation of hematoma. The proportion of subjects with initial GCS score of 13 or less was significantly higher among those who required surgical evacuation (43.2% vs. 26.8%, P < 0.001). In the logistics regression analysis, hematoma volume ≥18 cm3 (odds ratio, 4.3; 95% confidence interval, 2.1-8.8) and right-sided hematoma (odds ratio, 2.8; 95% confidence interval, 1.3-5.9) were significantly associated with surgical evacuation. Age, location, GCS score strata, and allocated treatment (intensive vs. standard systolic blood pressure reduction) were not associated with surgical evacuation. Among the 44 patients who underwent surgical evacuation, death or disability at 3 months postrandomization was seen in 32 (73%) of 44 subjects. In the large cohort of ATACH 2 subjects with good grade ICH, the rates of unanticipated surgical evacuation were low and were associated with relatively high rates of death or disability at 3 months.

Abstract WP396: Analysis of Patients With Excessively High Pre-Randomization Systolic Blood Pressure and Effect of Intensive Systolic Blood Pressure Reduction in Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) 2

Background: Current guidelines recommend for intracerebral hemorrhage (ICH) patients with the systolic blood pressure (SBP) &gt;220 mmHg, unlike those with initial SBP 150-220 mm, Hg, the efficacy of aggressive reduction of SBP is less well established and further studies are recommended. Methods: We analyzed data from ATACH 2 trial which randomized patients with initial SBP &gt;180 mm Hg to intensive (goal 110-139 mmHg) and standard (goal 140-179 mmHg) SBP reduction using IV nicardipine within 4.5 hours of symptom onset. We compared the characteristics and outcomes between patients with pre- randomization SBP ≥220 mm Hg and those with initial SBP &lt;220 mm Hg. We analyzed the modifying effect (interaction test) of pre-randomization SBP ≥220 mm Hg on treatment effect (intensive versus standard) on death or disability (score 4-6 on modified Rankin scale) at 3-months post-randomization ascertained by a blinded investigator. Results: Of 1000 randomized subjects, 48 subjects had a pre-randomization SBP ≥ 220 mm Hg (mean age 57.8 years, 65% men); 24 were assigned to intensive-treatment and standard-treatment each. The rate of death or disability at 3 months (47.9% versus 37.7%, odds ratio (OR): 1.52, 95% confidence interval (CI): 0.43 to 1.5, 0.85 to 2.72) and hematoma expansion within 24 hours (30.0% versus 21.2%, OR: 1.60; 95% CI: 0.80 to 3.20) was not different among subjects with SBP≥220 mm Hg SBP and those with SBP &lt; 220 mm Hg. Rates of hematoma expansion (19% and 27.3%, OR: 0.63; 95% CI: 0.15 to 2.6) and neurological deterioration (8.7% versus 17.4%, OR: 0.45; 95% CI: 0.07 to 2.8) within 24 hours were not different between those randomized to intensive treatment and those to standard treatment in patients with SBP≥220 mm Hg. The interaction between initial SBP ≥220 mm Hg and treatment effect on death or disability was significant (p=0.0111). Conclusions: Patients with pre-randomization SBP ≥220 mm Hg did not have higher rates of hematoma expansion or death or disability compared to those with SBP &lt;220 mm Hg. The interaction of pre- randomization SBP ≥220 mm Hg with the treatment effect and a non-significantly higher rate of death or disability associated with intensive treatment requires further studies.

Abstract WP398: Occurrence of Acute Kidney Injury in Patients With Intracerebral Hemorrhage Undergoing Systolic Blood Pressure Reduction

Background: Aggressive systolic blood pressure (SBP) reduction may precipitate acute kidney injury (AKI) because of underlying hypertensive nephropathy, in subjects with intracerebral hemorrhage (ICH). Rate and determinants of AKI during acute hospitalization among ICH subjects were analyzed using a post hoc analysis of randomized, multicenter, two-groups, open-label clinical trial. Methods: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) 2 trial data was analyzed. Subjects with ICH (volume &lt;60 cm 3 ) and a Glasgow Coma Scale (GCS) score of 5 or more were randomized to a SBP target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment). IV nicardipine was given within 4.5 hours of symptom onset to lower SBP. Serum creatinine was ascertained at baseline, 24, 48 and 72 hours after randomization. AKI was classified based on increase in serum creatinine levels from baseline, stage 1 ≥ 0.3 mg/dl (≥ 26.4umol/L) or (&gt;1.5 to 2-fold), stage 2 (&gt;2 to 3-fold) and stage 3 (&gt;3-fold) were identified. Results: Of 1000 randomized subjects, 158 developed AKI (65% were men; mean age of 61.5±13.2 years). Severity of AKI was grade I, II, III in 15.3%, 0.1%, and 0.4% patients, respectively. The rate of AKI was similar in intensive and standard treatment group (16.4% versus 15.2%, P=N.S). AKI incidence was significantly higher in subjects with baseline creatinine greater than 1.2 mg/dl (36% compared to 14%, OR 3.4, 95% CI 2.3-4.9, P= &lt;0.0001). There was no significant association between subjects with AKI and hypertension (RR 1.1, 95% CI 1-1.2, P=0.15) or diabetes mellitus type 2 (RR 0.72, 95% CI 1.5-1.1, P=0.12). Patients with GCS ≤ 12 had significantly lower chances of developing AKI (RR 0.5, 95% CI 0.4-0.9, P=0.01). The incidence of hematoma expansion (OR 2.5, 95% CI 0.6-11, P=0.2) was not significantly higher in the subjects with AKI. No significant association was observed between occurrence of AKI and death or disability (modified Rankin score 4-6) at 3 months post randomization (RR 1.1, 95% CI 0.9-1.3, P=0.44). Conclusions: Mild AKI is frequent among intracerebral hemorrhage subjects undergoing SBP reduction. However, the rate of AKI was not different between subjects who were randomized to intensive or standard treatments.

Abstract TP440: Predictors and Associated Outcomes With Unanticipated Surgical Evacuation in Patients With Intracerebral Hemorrhage: Post Hoc Analysis of ATACH 2 Trial

Background: We performed this analysis to identify the rates, predictors and associated outcomes of unexpected neurosurgical intervention in a multicenter clinical trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2, involving good grade patients with intracerebral hemorrhage (ICH). Methods: The ATACH 2 Trial determined the relative efficacy of intensive versus standard antihypertensive treatment in subjects with spontaneous supratentorial ICHs with a Glasgow Coma Scale (GCS) score of ≥5 and intraparenchymal hematoma volume of &lt; 60 cm3 on initial computed tomographic (CT) scan in whom surgical evacuation was not anticipated. We performed logistic regression analyses to determine the effect of unanticipated surgical intervention on death or disability at 3 months, death within 3 months, after adjusting for age and initial hematoma volume presence of intraventricular hemorrhage, and initial GCS score strata (14-15,9-13,8 or less). Results: Among the 992 subjects analyzed, 44 (4.4%) subjects required unanticipated surgical evacuation of hematoma. The mean time interval between randomization and surgical intervention was 1.6 days (±SD 3.7 days). In multivariate analyses, subjects who underwent unanticipated surgical evacuation had a significant higher risk of death or disability (OR 3.6, 95% confidence interval [CI] 1.6 - 8.3; p-value .002) at 3 months and mortality (OR 2.9, 95% CI 1.1 - 7.6; p-value .03) within 3 months after adjusting for potential confounders. Conclusions: In the large cohort of ATACH-2 subjects with good grade ICH, the rates of unanticipated surgical evacuation were low and associated with high rates of death or disability at 3 months.

Abstract 52: Global Cerebral Edema in Patients With Primary Intracerebral Hemorrhage: Results From Brain Edema at Cerebral Hemorrhage (BEACH) Study

Background: Recent data supports presence of neuronal injury and blood brain barrier breakdown in brain regions distant to hematoma in patients with intracerebral hemorrhage (ICH). We determined the prevalence of global cerebral edema and its impact on clinical outcome in patients with ICH recruited in a multicenter clinical trial. Methods: BEACH was a pre-planned prospective observational study (N=278) nested in the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 clinical trial which randomized ICH patients with SBP ≥ 180 mmHg who presented within 4.5 hours of symptom onset. The aim of the ATACH-2 was to ascertain whether SBP reduction to &lt; 140 mmHg would yield reduction in death and disability (defined as modified Rankin Scale 4-6) at 90 days compared to the current guideline. Total brain volume, parenchymal hematoma volume, and peri-hematoma edema volume were measured on CT scans acquired on admission and at 24 (±8) hours (and later intervals when available) post-randomization using computerized image analysis software(Analyze. Inc). Global cerebral edema was defined as 5% or greater increase in the brain volume (excluding parenchymal hematoma and peri-hematoma edema volumes) on follow up CT scan compared with baseline scan. Results: A total of 48 (17%) of 278 patients had global cerebral edema by 24 hours CT scan. The median increase in total brain volume was 9 cm3 (range 5 - 20 cm3). Additional occurrence of global cerebral edema was seen in 3% and 1% of patients by 48 hours and 72 hours, respectively. Baseline characteristics were similar, but median NIHSS was higher and median GCS score was lower in patients with global cerebral edema. The prevalence of global cerebral edema was significantly lower in intensive SBP reduction group compared to standard SBP reduction group (12% vs 23%, p-value: 0.02). While not statistically significant, higher rates of death or disability at 90 days were observed among subjects with global cerebral edema within 24 hours (48% vs 36%, p-value: 0.12) Conclusion: Global cerebral edema at 24 hours occurred in 17% of the BEACH subgroup of ATACH 2 subjects. Global cerebral edema was associated with higher level of clinical severity of disease and its prevalence was significantly lower among intensive SBP reduction group.

Abstract 128: Intensive Blood Pressure Lowering in Patients with Moderate to Severe Grade Acute Cerebral Hemorrhage: Post Hoc Subgroup Analysis of Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 Trial

Background: The intent to treat analysis of ATACH-2 trial did not demonstrate any difference in rates of death or disability with intensive systolic blood pressure (SBP) reduction compared with standard SBP reduction in patients with intracerebral hemorrhage (ICH). The benefit may have been obscured due to relatively high proportion of good grade patients (ceiling effect) in both treatment groups. Methods: We evaluated the effect of intensive (goal 110-139 mmHg) over standard (goal 140-179 mmHg) SBP reduction using intravenous nicardipine within 4.5 hours of symptom onset in a subgroup of moderate to severe grade subjects with ICH. Moderate to severe grade was defined by Glasgow coma scale score &lt;13 or baseline National Institutes of Health Stroke Scale score ≥10 or baseline intraparenchymal hemorrhage volume ≥30cm 3 or presence of intraventricular hemorrhage. The primary outcome was death or disability (score 4-6 on modified Rankin scale) at 3-months post-randomization ascertained by a blinded investigator. Results: A total of 682 subjects (336 in intensive and 346 in standard groups) met the definition of moderate to severe grade. The primary endpoint of death or disability was observed in 52.5% of subjects receiving intensive treatment and 48.9% subjects receiving standard treatment (relative risk: 1.07; 95% confidence interval: 0.86 to 1.33). Serious adverse events were significantly higher (relative risk: 1.38; 95% confidence interval: 1.04 to 1.84), among patients randomized to intensive treatment (32.7% and 23.7% for intensive and standard treatment groups, respectively). Conclusions: Similar to the conclusion from the overall ATACH-2 Trial sample, the rate of death or disability in the moderate to severe ICH subjects was similar, but significantly higher rate of serious adverse events were observed in subjects randomized to intensive SBP reduction.

Abstract TP337: Did Pre-Randomization Use of Intravenous Nicardipine Adversely Affect the Results of Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 Trial?

Background: The design of the ATACH-2 trial permitted use of intravenous (IV) nicardipine to maintain systolic blood pressure (SBP) &lt;180 mm Hg prior to randomization. We performed an analysis to determine if pre-randomization use of IV nicardipine modified the treatment effect of intensive SBP reduction (compared with standard SBP reduction) in patients with intracerebral hemorrhage (ICH). Methods: ATACH-2 evaluated the treatment effect of intensive (goal 110-139 mmHg) over standard (goal 140-179 mmHg) SBP reduction using IV nicardipine within 4.5 hours of symptom onset in subjects with ICH in a generalized linear (GLM) model. The outcome was death or disability (modified Rankin scale 4-6) at 3-months post-randomization ascertained by a blinded investigator. The interaction between pre-randomization use of IV nicardipine and treatment was tested in the model at p&lt;0.15 level. Additional variables included were age, Glasgow coma scale score category (3-11, 12-14, and 15), and presence of intraventricular hemorrhage. Results: Pre-randomization IV nicardipine was used in 517 of 1000 subjects who were randomized. The baseline SBP of those who did and did not receive pre-randomization nicardipine were similar. The interaction term in the GLM was significant (p=0.133). The outcome for each subgroup (with or without pre-randomization nicardipine) is given below. Conclusions: A small modifying effect of treatments effect with pre-randomization use of IV nicardipine was observed in ATACH-2 trial which may have implications for future clinical trial design.

Effect of Intensive Systolic Blood Pressure Lowering on Hematoma Expansion in Patients with Intracerebral Hemorrhage: Analysis of Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II Trial (CT.004)

Effect of Intensive Systolic Blood Pressure Lowering on Hematoma Expansion in Patients with Intracerebral Hemorrhage: Analysis of Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II Trial (CT.004)

Abstract T MP102: Hotline Use for Recruitment Support in Acute Stroke Trials: Lessons learned To Date in Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-II

Background: Use of hotline services for clinical support and safe operation of a research trial is common and important. The value of such services has not been objectively assessed within the context of a large acute stroke clinical trial. Methods: The use of three different hotline services have been tested, and cell and Email- options have also been explored for their advantages. US and Non-US sites are provided access to central hotline services, but for efficiency a local network for managing calls is established in each region. All sites may access both data management and the trial PI via hotline services when needed and this is supported by other technologies in addition. A means for supporting overall trial communications in light of these interactions has been developed and valuable insights are gained. Results: Data gathered from 211 calls logged at the Clinical Coordinating Center through the course of the ATACH-II trial have been summarized: Total Calls Reviewed: 211; Year 2 of trial: 92 calls, Year 3 of trial: 100 calls. Calls received midnight to 8 AM: 19 (9.0%), 8 AM - 5 PM 130 (61.6 %) 5 PM - 12:00 PM 65 (30.8%). Issues Resolved in &lt; 5 min 143/211 (67.8%) Taking &gt; 30 min to resolution 51/211 (24.2%). Purpose of calls: Eligibility 89 (42.2%). protocol compliance including drug management: 77 (36.5%%), randomization/emergency randomization: 16 (7.6%), protocol deviation:13 (6.2%), technological difficulties: 12 (5.7%), AE/SAE: 9 (4.3%), Subject enrollments directly associated with calls: 57 (20.8% of domestic subjects); excluded candidates directly associated with calls: 46 (% not available). Conclusions: In an international trial requiring rapid enrollment of subjects with intracerebral hemorrhage, the role of direct support via a hotline and other immediate communications means has proven to be instrumental in maintaining good protocol compliance and supporting enrollment by site team members .

Blood Pressure Lowering and Acute Perihematomal Brain Edema After Intracerebral Hemorrhage

See related article, p 1292. Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke that produces severe neurological deficits in survivors.1 There are still no proven therapeutic interventions for ICH, but there has been much interest in the potential use of acutely reducing blood pressure to limit hematoma expansion. A key factor affecting ICH outcome is hematoma size, and hematoma expansion occurs in about one third of patients with ICH.2 This has led to 3 clinical trials: Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT), Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH), and The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT).3–5 INTERACT 2 reported last year6 and suggested an improvement in outcome although this did not reach statistical significance. Understanding the importance of those results requires determination of whether acute blood pressure reductions may have detrimental and beneficial effects in patients with ICH. In this …

Increased Brain Volume Among Good Grade Patients with Intracerebral Hemorrhage. Results from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study

We ascertained the occurrence of global cerebral edema manifesting as increased brain volume in subjects with intracerebral hemorrhage (ICH) and explored the relationship between subject characteristics and three month outcomes. A post-hoc analysis of a multicenter prospective study that recruited patients with ICH, elevated SBP ≥170 mm Hg, and Glasgow Coma Scale (GCS) score ≥8, who presented within 6 h of symptom onset was performed. Computed tomographic (CT) scans at baseline and 24 h, submitted to a core image laboratory, were analyzed to measure total brain, hematoma, and perihematoma edema volumes from baseline and 24-h CT scans using image analysis software. The increased brain volume was determined by subtracting the hematoma and perihematomal edema volumes from the total brain volume. A total of 18 (44 %) of 41 subjects had increased brain volume that developed between initial CT scan and 24-h CT scan. The median increase in brain volume among the 18 subjects was 35 cc ranging from 0.12 to 296 cc. The median baseline GCS score was 15 in both groups of subjects who experienced increased brain volume and those who did not, and the median hematoma volume was 10.18 and 6.73, respectively. Three of the 18 subjects with increased brain volume underwent concurrent neurological deterioration and one subject died during hospitalization. We found preliminary evidence of increased cerebral brain volume in subjects with good grade and small ICHs, which may be suggestive of global cerebral edema.

Abstract WP296: Direct Cost Savings Associated with Intensive Systolic Blood Pressure Reduction in Patients with Intracerebral Hemorrhage

INTRODUCTION: The Antihypertensive treatment of Acute Cerebral Hemorrhage (ATACH) II is determining whether intensive systolic blood pressure (SBP) reduction (SBP ≤140mm Hg) using IV nicardipine initiated within 4.5 hours of onset of intracerebral hemorrhage (ICH) reduces the likelihood of death or disability (modified Rankin scale [mRS] score of 4-6) at 3 months by ≥10% compared with standard SBP reduction (SBP ≤180mm Hg). Objective: To determine the direct cost savings by intensive systolic blood pressure reduction if the 10% reduction in death and disability goals are met in patients with ICH. Methods: The dose and duration of IV nicardipine to achieve different SBP goals were derived from ATACH I and the probability of death or disability were obtained from placebo treated ICH patients recruited in recombinant factor VII trials. Total cost associated with acute hospitalization was derived from Nationwide Inpatient Sample files 2010 for none-mild disability (home discharge considered equivalent to mRS 0-1), moderate disability (in-patient rehabilitation=mRS 2-3), severe disability (nursing home=mRS=4-5), and death. The cost of nursing home stay, in-patient and out-patient rehabilitation services, and physician visits were derived from MetLife Market Survey of Nursing Home and Home Care and Medicare re-imbursement policy. Results: The estimated incremental costs for IV nicardipine for intensive SBP reduction was $85,600 for 100 patients treated. The direct cost of death and disability (cost of acute hospitalization, post-hospital care, and physician visits visit for 90 days) was estimated to be $4,377,142 in 100 patients treated with standard SBP reduction. The cost saving was estimated to be $147,570 if 10% of patients with mRS 4-5 changed to mRS 2-3. The cost saving was estimated to be $357,685 if 10% of patients with mRS 4-5 changed to mRS 2-3 (5%) and mRS 0-1 (5%). The net savings in the first and second scenario were $61,970 and $272,085 per 100 patients treated in the first 90 days, respectively. Conclusions: Intensive SBP reduction in patients with ICH appears to result in prominent cost savings if the ATACH II goals of reduction in death and disability are met.

Abstract WP308: Global Cerebral Edema Among Good Grade Patients with Intracerebral Hemorrhage. Results from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study

INTRODUCTION: There is some evidence that injury and blood brain barrier disruption can be seen in regions distant from the hematoma in patients with intracerebral hemorrhage (ICH). Objective: To ascertain the occurrence of global brain edema in patients with ICH and to explore the relationship between patient characteristics and three month outcomes. Design: A post-hoc analysis of a traditional Phase I dose escalation multicenter prospective study recruited patients with ICH, elevated SBP≥170 mmHg, and Glasgow Coma Scale score ≥8, who presented within 6 hours of symptom onset. Computed tomographic (CT) scans at baseline, 24 hours, and any performed at later intervals were submitted to a core image laboratory. We were able to ascertain the presence and magnitude of global brain edema in 41 of 60 subjects with adequate CT scan resolution. Settings: Emergency departments and intensive care units. Primary Outcomes: We determined the total brain, hematoma, and perihematoma edema volumes from baseline, 24 hour, and 48 hour (if available) CT scans using image analysis software. The global brain edema volume was determined by subtracting the hematoma and perihematomal edema volumes from the total brain volume. Results: A total of 18 (44%) of 41 patients had global cerebral edema that developed between initial CT scan and 24 hour CT scan. The median increase in brain volume among the 18 subjects was 35 cc ranging from 0.12 cc to 296 cc. The baseline GCS score (median 15 versus 15) and hematoma volume (mean±SD; 11.5±10.3 versus 13.9±17) were similar between subjects who experienced global cerebral edema and those who did not. The initial serum glucose was higher among subjects with global cerebral edema (150.5±74.3 mg/dl verus 119.7±34.6 mg/dl). Of the 18 patients who underwent a CT scan at 48 hours, 5 had either new or worsening global cerebral edema. Three of the 18 patients with global cerebral edema underwent neurological deterioration and 1 patient died during hospitalization. Conclusions: Global cerebral edema can occur even in subjects with mild ICH. The pathophysiological basis and prognostic significance needs to be studied in future trials.

Factors Associated with Individual Variations in Systolic Blood Pressure Responsive to Intravenous Antihypertensive Medication. Results from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study (P04.079)

Factors Associated with Individual Variations in Systolic Blood Pressure Responsive to Intravenous Antihypertensive Medication. Results from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study (P04.079)

Blood pressure control for acute ischemic and hemorrhagic stroke

Acute stroke, including the subtypes of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), typically involves significant fluctuations in blood pressure (BP). Treatment of BP after all stroke types is controversial. In each case, there are theoretical dangers to leaving BP alone as well as altering it artificially. In this article, we review the role of BP in each stroke subtype and the existing evidence for BP optimization. Except in patients receiving thrombolytic therapy, there is insufficient evidence to recommend active BP management in ischemic stroke. In ICH, the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) trial and Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) have demonstrated that systolic BP reduction to 140 mmHg is well tolerated and associated with attenuation of hematoma expansion. The impact of BP reduction on outcomes is being evaluated in the ongoing phase III ATACH II and INTERACT 2 trials. No evidence exists to recommend definitive BP management strategies in acute SAH, although hypertension should likely be avoided before an aneurysm is secured, and hypotension should be avoided altogether. Evidence for BP management in acute stroke is limited, although large randomized trials are currently in progress for both ischemic stroke and ICH. BP management in SAH remains woefully understudied.

Abstract 3688: Factors Associated with Individual Variations in Systolic Blood Pressure Responsive to Intravenous Antihypertensive Medication. Results from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) Study

Introduction: There is considerable variation in blood pressure response to intravenous antihypertensive medication within patients with intracerebral hemorrhage (ICH). Objective: To study the variation in systolic blood pressure (SBP) responsiveness to IV nicardipine infusion and effect of various baseline factors on such responsiveness. We also studied the effect of SBP responsiveness on hematoma expansion, perihematomal edema, and three month outcome among subjects with ICH. Material and Methods: A post-hoc analysis of a multicenter prospective study recruiting subjects with ICH and elevated systolic blood pressure (SBP)≥170 mm Hg who presented within 6 hours of symptom onset was performed. Baseline SBP was calculated using the average of maximum and minimum SBP recorded prior to initiation of treatment. The SBP responsiveness was defined by the ratio between maximum change in SBP (difference between initial SBP and minimum SBP within the first hour) and maximum dose of nicardipine used in the first hour. This value was dichotomized at the median of 8.0, and we defined those with higher values to be responders and lower to be non-responders. We evaluated the effect of SBP reduction (relative to initial SBP) on: (1) hematoma expansion, defined as an increase in the volume of intraparenchymal hemorrhage of &gt;33% measured on the 24-hour computed tomographic (CT) scan compared with the baseline CT scan; (2) relative edema expansion, defined as increase of &gt;40% in edema volume to hematoma volume ratio between baseline and 24-hour CT scan; and (3) poor outcome defined by modified Rankin scale (mRS) of 4-6 at 3 months following treatment. Results: A total of 56 subjects were treated with IV nicardipine (aged 62 ±15 years; 57% men). The initial mean serum glucose was higher, although not statistically significant, among the 29 responders compared with 27 poor responders (148±72 versus 125±41). There were no clinically meaningful differences in the patient’s age, initial hematoma volume, initial Glasgow Coma Scale score, serum creatinine, or previous use of antihypertensive medication between responders and poor responders. The mean maximum dose of IV nicardipine used was 6.9 (±4.2) mg/hr and mean maximum reduction of SBP of 55.4 (±32.0) mm Hg within the first hour. The risk of poor outcome (mRS 4-6) in the responder was 10% less relative to the non-responders (relative risk [RR]=0.90, 95% confidence interval [CI]: 0.48, 1.69; n=50). The RRs were 0.81 (95% CI: 0.34, 1.93; n=54) for hematoma expansion &gt;33%; and 0.89 (95% CI: 0.52, 1.53; n=51) for relative edema expansion &gt;40%. Conclusions: There is considerable variation in blood pressure responsiveness to intravenous antihypertensive medication with potential prognostic implications. The variation in responsiveness does not appear to be influenced by other patient related factors that are known to influence functional outcome from ICH.

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: Design, Methods, and Rationale

The December 2003 report from the National Institute of Neurological Disorders and Stroke (NINDS) Workshop on priorities for clinical research in intracerebral hemorrhage (ICH) recommended clinical trials for evaluation of blood pressure management in acute ICH as a leading priority. The Special Writing Group of the Stroke Council of the American Heart Association in 1999 and 2007 emphasized the need for clinical trials to ensure evidence-based treatment of acute hypertensive response in ICH. To address important gaps in knowledge, we conducted a pilot study funded by the NINDS, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) I Trial, during 2004-2008 to determine the appropriate level of systolic blood pressure (SBP) reduction. We now have initiated a multi-center, randomized Phase III trial, the ATACH II Trial, to definitively determine the efficacy of early, intensive, antihypertensive treatment using intravenous (IV) nicardipine initiated within 3h of onset of ICH and continued for the next 24h in subjects with spontaneous supratentorial ICH. The primary hypothesis of this large (N=1,280), streamlined, and focused trial is that SBP reduction to ≤140mm Hg reduces the likelihood of death or disability at 3months after ICH, defined by modified Rankin scale score of 4-6, by at least 10% absolute compared to standard SBP reduction to ≤180mm Hg. The ATACH II trial is a natural extension of numerous case series, the subsequent ATACH I pilot trial, and a preliminary, randomized, and controlled trial in this patient population funded by the Australian National Health and Medical Research Council. Both trials recently confirmed the safety and tolerability of both the regimen and goals of antihypertensive treatment in acutely hypertensive patients with ICH, as proposed in the present trial. The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately 73% of the patients with acute ICH. The Australian trial provided preliminary evidence of attenuation of hematoma expansion with intensive SBP reduction. The ATACH II trial will have important public health implications by providing evidence of, or lack thereof, regarding the efficacy and safety of acute antihypertensive treatment in subjects with ICH. This treatment represents a strategy that can be made widely available without the need for specialized equipment and personnel, and therefore, can make a major impact upon clinical practice for treating patients with ICH.

FP26-TU-03 Antihypertensive treatment of acute cerebral hemorrhage (ATACH): final results

FP26-TU-03 Antihypertensive treatment of acute cerebral hemorrhage (ATACH): final results

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): Rationale and Design

This trial is a multicenter open-labeled pilot trial to determine the tolerability and safety of three escalating levels of antihypertensive treatment goals for acute hypertension in 60 subjects with supratentorial intracerebral hemorrhage (ICH). The pilot trial is the natural development of numerous case series evaluating the effect of antihypertensive treatment of acute hypertension in subjects with ICH. The proposed trial will have important public health implications by providing necessary information for a definitive phase III study regarding the efficacy of antihypertensive treatment of acute hypertension in subjects with ICH. The specific aims of the present pilot study are to: (1) Determine the tolerability of the treatment as assessed by achieving and maintaining three different systolic blood pressure goals with intravenous nicardipine infusion for 18 to 24 hours postictus in subjects with ICH who present within 6 hours of symptom onset; (2) Define the safety, assessed by the rate of neurological deterioration during treatment and serious adverse events, of three escalating systolic blood pressure treatment goals using intravenous nicardipine infusion; and (3) Obtain preliminary estimates of the treatment effect using the rate of hematoma expansion (within 24 hours) and modified Rankin scale and Barthel index at 3 months following symptom onset.