Intensive Systolic Blood Pressure Reduction Research Articles

Systolic blood pressure reduction strategies in acute ischemic stroke patients following endovascular thrombectomy: a systematic review and meta-analysis

Background and AimsThere is no clear consensus on ideal systolic blood pressure (SBP) target post-endovascular thrombectomy (EVT) in patients with acute ischemic stroke. This study intends to investigate the relationship between reducing SBP and clinical outcomes and to determine the therapeutic efficacy of moderate and intensive SBP reduction post EVT. MethodsA comprehensive search was conducted across five electronic databases to identify studies relevant to our analysis. Data from these studies were then analyzed using pooled relative risk (RR) along with their corresponding 95 % confidence intervals (CI) for our categorical outcomes. functional independence at 90 days post-EVT was defined as a modified Rankin score (mRS) 0-2. ResultsOur meta-analysis included eight studies with 2922 patients: 1376 patients were treated with intensive SBP reduction, 306 with moderate SBP reduction, and 1243 with standard SBP reduction. There was no difference in the risk of functional independence at 90 days post-EVT with both intensive-SBP reduction (target 120-140 mmHg, relative risk (RR) =1.05, 95 % CI 0.82, 1.34, p = 0.72) and moderate-SBP reduction (>160 mm Hg) (RR= 0.95, 95 % CI 0.69, 1.31, p = 0.76) compared with standard SBP reduction (>180 mm Hg). The risk of symptomatic intracranial hemorrhage (sICH) did not significantly differ between standard-SBP reduction and intensive-SBP reduction (RR = 0.93, 95 % CI 0.66, 1.31, p = 0.36) or moderate-SBP reduction (0.72 (95 % CI [0.28, 1.87], p = 0.50) groups, respectively. Intensive-SBP reduction significantly decreased the risk of hemicraniectomy. ConclusionsWe did not identify any difference in functional independence at 90 days in acute ischemic stroke patients with either intensive-SBP reduction or moderate-SBP reduction compared with standard SBP reduction post-EVT.

Abstract MP12: Educational Attainment and the Effect of Intensive Blood Pressure Reduction: A Post-Hoc Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT)

Introduction: Hypertension is a major risk factor for cardiovascular disease (CVD). The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that systolic blood pressure (SBP) <120 mm Hg reduced CVD risk and all-cause mortality among those with elevated SBP and high CVD risk. Educational attainment (EA) is associated with CV health, but whether EA modifies the effect of intensive SBP reduction remains unclear. Hypothesis: We predicted that SPRINT participants with lower EA would have greater CVD risk reduction with intensive SBP lowering than those with higher EA. Methods: We included 9,361 individuals recruited as part of the SPRINT study and categorized them by EA (<college, some college through college graduate, and >college degree). We examined the effect of intensive SBP lowering across EA strata in relation to the composite endpoint defined by SPRINT (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or CV death) in multivariable proportional hazards models. Results: The cohort was age 67.9±9.4 years, 35.6% female, and 57.8% White race. Those with high EA were more likely to be older, male, and White race. Higher EA was associated in a dose-response manner with a larger reduction in the risk of developing the composite endpoint after intensive SBP lowering [highest to lowest EA: adjusted HR 0.48 (95% CI: 0.34, 0.70); 0.81 (0.63, 1.03); 0.90 (0.70, 1.15); P , interaction=0.01] ( Table ). The interaction between intensive SBP lowering and EA was limited to non-Black individuals; among Black participants, the association of SBP lowering with the endpoint did not differ significantly by EA. Conclusion: In the SPRINT cohort, higher EA was associated with a larger improvement in CV outcomes after intensive SBP reduction, with differences by race or ethnicity. This post-hoc SPRINT analysis suggests that the benefit of intensive SBP lowering varies by EA, and highlights a need for tailored approaches to optimize hypertension management for individuals with different social backgrounds.

Individualising intensive systolic blood pressure reduction in hypertension using computational trial phenomaps and machine learning: a post-hoc analysis of randomised clinical trials

The cardiovascular benefits of intensive systolic blood pressure control vary across clinical populations tested in large randomised clinical trials. We aimed to evaluate the application of machine learning to clinical trials of patients without and with type 2 diabetes to define the personalised cardiovascular benefit of intensive control of systolic blood pressure. In SPRINT, a trial of intensive (systolic blood pressure <120 mm Hg) versus standard (systolic blood pressure <140 mm Hg) systolic blood pressure control in patients without type 2 diabetes, we defined a phenotypic representation of the study population using 59 baseline variables. We extracted personalised treatment effect estimates for the primary outcome, time-to-first major adverse cardiovascular event (MACE; cardiovascular death, myocardial infarction or acute coronary syndrome, stroke, and acute decompensated heart failure), through iterative Cox regression analyses providing average hazard ratio (HR) estimates weighted for the phenotypic distance of each participant from the index patient of each iteration. Next, we trained an extreme gradient boosting algorithm (known as XGBoost) to predict the personalised effect of intensive systolic blood pressure control using features most consistently linked to increased personalised benefit, before evaluating its performance in the ACCORD BP trial of patients with type 2 diabetes randomly assigned to receive intensive versus standard systolic blood pressure control. We stratified patients based on their predicted treatment effect, and key demographic groups (age, sex, cardiovascular disease, and smoking). We assessed the presence of heterogeneity with an interaction test, and assessed the performance of the algorithm in a simulation analysis of SPRINT in the presence or absence of an artificially introduced heterogeneous treatment effect. From SPRINT, we included all 9361 study participants (mean age 67·9 years [SD 9·4], 3332 [35·6%] female) who underwent randomisation to either intensive (n=4678) or standard (n=4683) treatment. The median individualised HR for MACE was 0·63 (IQR 0·53-0·78). An eight-feature tool built for this analysis to predict personalised benefit in SPRINT was externally tested in ACCORD BP (4733 participants (mean age 62·7 years [SD 6·7], 2258 [47·7%] female), wherein it successfully identified individuals with differential benefit from intensive versus standard systolic blood pressure control (adjusted HR for MACE of 0·70 [95% CI 0·55-0·90] in individuals with above-median MACE benefit versus 1·05 [95% CI 0·84-1·32] for below-median predicted benefit; pinteraction=0·0184). Subgroup analysis based on age (<65 years: HR 0·89 [95% CI 0·71-1·12]; ≥65 years: 0·85 [0·67-1·09]), sex (male: 0·89 [0·72-1·10]; female: 0·85 [0·65-1·10]), established cardiovascular disease (no: 0·89 [0·70-1·14]; yes: 0·84 [0·67-1·06]), or active smoking (no: 0·85 [0·71-1·02]; yes: 1·01 [0·64-1·60]) did not identify groups with heterogeneity of treatment effect. In a simulation analysis of SPRINT, the proposed algorithm detected groups with heterogeneous treatment effects in the presence, but not absence, of simulated subgroup differences. By use of machine learning to define an individual's personalised benefit through phenotypic representations of clinical trials, we created a practical tool for individualising the selection of intensive versus standard systolic blood pressure control in patients without and with type 2 diabetes. National Heart, Lung, and Blood Institute of the US National Institutes of Health.

Influence of Baseline Diastolic Blood Pressure on the Effects of Systolic Blood Pressure Lowering on Cognitive Function in Type 2 Diabetes Mellitus.

Lowering of systolic blood pressure (SBP) in patients with low diastolic blood pressure (DBP), can further lower DBP. This can potentially decrease cerebral perfusion and cognition. We examined the influence of baseline DBP on the effect of lowering SBP on cognition. This is a post hoc analysis of the Memory in Diabetes (MIND) substudy (N = 1,430) of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (NCT00000620). Standard neuropsychological tests (Digit Symbol Substitution Test [DSST], Mini-Mental State Examination [MMSE], Rey Auditory Verbal Learning Test [RAVLT], and Stroop test) were performed at baseline and months 20 and 40. We compared the effects of intensive (goal SBP <120 mm Hg) vs. standard (goal SBP <140 mm Hg) SBP control on the changes in the 4 test scores from baseline to the averages of months 20 and 40 across the range of baseline DBP using cubic spline terms. Mean age was 63 ± 6 years, 55% were women and 66% White. Participates with lower baseline DBP were older, had more cardiovascular events and a longer duration of diabetes. There was no difference in the change in DSST (-0.22; 95% CI -0.97, 0.52), MMSE (-0.14; 95% CI -0.34, 0.06), RAVLT (-0.12; 95% CI -0.29, 0.06), and Stroop interference (-0.47; 95% CI -1.76, 0.82) in the intensive vs. standard SBP intervention. There was no interaction between baseline DBP and change in scores with the SBP intervention. Intensive SBP reduction does not adversely affect cognition, even in those with low baseline DBP.

Outcomes of Intensive Systolic Blood Pressure Reduction in Patients with Intracerebral Hemorrhage and Excessively High Initial Systolic Blood Pressure: Post Hoc Analysis of a Randomized Clinical Trial

Current guidelines from the American Heart Association and American Stroke Association call for intensive and aggressive blood pressure control in patients presenting with spontaneous intracerebral hemorrhage (ICH). In patients with systolic blood pressure (SBP) between 150 and 220 mmHg, lowering SBP to 140 mmHg is considered safe and is associated with improved functional outcomes. For patient with systolic blood pressures greater than 220mmHg, it is recommended to use continuous intravenous medications and frequent blood pressure monitoring to aggressively lower blood pressures, though there are no specific goal parameters recommended and inadequate data to evaluate the safety of such intensive blood pressure control.

Outcomes of Intensive Systolic Blood Pressure Reduction in Patients With Intracerebral Hemorrhage and Excessively High Initial Systolic Blood Pressure

The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown. To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg. This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included. Intravenous nicardipine infusion titrated to goals. Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge. A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events. The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.

Pharmacological treatment of high-normal blood pressure (prehypertension) in high-risk patients for primary prevention of cardiovascular events.

Currently, the best treatment strategy for patients with a high-normal blood pressure (prehypertension) is not known. The authors aimed to determine whether pharmacological reduction of systolic blood pressure (SBP) to a normal level (<120mmHg) would prevent cardiac morbidity and mortality in prehypertensive patients. In this secondary analysis, the authors obtained the data from SPRINT from the National Heart, Lung, and Blood Institute data repository center. Among 9361 patients enrolled in SPRINT, 289 high-risk (ASCVD risk=24.8%±13.0 [10-65]) prehypertensive patients without previous cardiovascular disease and not receiving any antihypertensive medications were enrolled. One hundred and forty-eight of them were assigned to standard treatment which consisted of clinical follow-up till SBP goes above 140mmHg and then staring medications to keep SBP <140mmHg. One hundred and forty-one were assigned to the intensive treatment receiving pharmacological SBP reduction to <120mmHg upon enrollment. The primary composite outcome was myocardial infarction, and other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Throughout the 3.06years of follow-up, a primary outcome event was confirmed in three participants (0.74% per year) in the intensive-treatment group and 8 (1.61% per year) in the standard-treatment group (hazard ratio [HR], 0.19; P=.045). Rates of serious adverse events were not increased by intensive-treatment (HR, 0.83; P=.506). Based on this secondary post hoc analysis, intensive SBP reduction may probably be beneficial for primary prevention of cardiovascular morbidity and mortality in high-risk prehypertensive patients. This finding needs to be evaluated in a larger trial designed specifically to answer this question.

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.

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.

Low on-treatment diastolic blood pressure and cardiovascular outcome: A post-hoc analysis using NHLBI SPRINT Research Materials

Recent studies including the SPRINT trial have shown beneficial effects of intensive systolic blood pressure reduction over the standard approach. The awareness of the J-curve for diastolic blood pressure (DBP) causes some uncertainty regarding the net clinical effects of blood pressure reduction. The current analysis was performed to investigate effects of low on-treatment DBP on cardiovascular risk in the SPRINT population. The primary composite outcome was the occurrence of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure or death from cardiovascular causes. The prevalence of primary outcomes was significantly higher in subjects within low DBP in both standard (44–67 mmHg [10.8%] vs 67–73 mmHg [6.7%] vs 73–78 mmHg [5.1%] vs 78–83 mmHg [4.4%] vs 83–113 mmHg [4.3%], p < 0.001) and intensive treatment (38–61 mmHg [6.7%] vs 61–66 mmHg [4.1%] vs 66–70 mmHg [4.5%] vs 70–74 mmHg [2.7%] vs 74–113 mmHg [3.4%], p < 0.001) arms. After adjusting for covariates, low DBP showed no significant effects on cardiovascular risk. Therefore, while reaching blood pressure targets, low DBP should not be a matter of concern.

The Unsolved Conundrum of Optimal Blood Pressure Target During Acute Haemorrhagic Stroke: A Comprehensive Analysis.

Intracerebral haemorrhage (ICH) is a devastating cerebrovascular disease, which accounts to 15% of all strokes. Among modifiable risk factors for ICH, hypertension is the most frequent. High blood pressure (BP) is detected in more than 75-80% of patients with ICH. Extremely elevated BP has been associated with early hematoma growth, a relatively frequent occurrence and powerful predictor of poor outcome in patients with spontaneous ICH. On the other hand, excessively low BP might cause cerebral hypoperfusion and ultimately lead to poor outcome. This review will analyse the most important trials that have tried to establish how far should BP be lowered during acute ICH. These trials have demonstrated either a small non-significant benefit (INTERACT-2, INTEnsive blood pressure Reduction in Acute Cerebral haemorrhage Trial) or no benefit (ATACH-2, Antihypertensive treatment of acute cerebral haemorrhage II study) when intensive systolic BP reduction was compared with modest or standard BP reduction. The more recent meta-analyses including studies investigating this issue yielded similar conclusions: aggressive BP control in the acute phase of ICH is not beneficial. For these reasons the 2018 European Society of Cardiology/ European Society of Hypertension Guidelines for the management of arterial hypertension, do not recommend treatment to immediately lowerBPin patients with acute ICH and systolic BP < 220mmHg. Careful lowering of SBP to less than 180mmHg via i.v. Infusion may be considered only in patients with SBP ≥ 220mmHg.

Effect of intensive blood pressure lowering on cardiovascular outcomes based on cardiovascular risk: A secondary analysis of the SPRINT trial.

It is not clear whether risk stratification can help choose the most favourable systolic blood pressure target for primary prevention of cardiovascular events. A secondary analysis of Systolic Blood Pressure Intervention Trial (SPRINT). To perform a secondary analysis, we obtained the data from SPRINT from the National Heart, Lung, and Blood Institute data repository centre. In SPRINT, an open-label trial, participants without diabetes with systolic blood pressure of ≥130 mmHg were randomly assigned to intensive and standard treatment groups with systolic blood pressure targets of <120 and <140 mmHg, respectively. The primary composite outcome was myocardial infarction and other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Here, we have analysed data from participants without cardiovascular disease and chronic kidney disease aged under 75 years categorised based on the baseline 10-year Framingham risk score (<10% (low risk); ≥10% and <15% (intermediate risk); ≥15% (high risk)). A total of 4298 patients were included in the analysis. With intensive treatment, there was a significant reduction in the primary outcome events in patients at high risk (0.86% per year vs. 1.81% per year; hazard ratio (HR) 0.51; 95% confidence interval (CI) 0.31 to 0.85; P = 0.010), and at intermediate risk (0.60% per year vs. 1.46% per year; HR 0.37; 95% CI 0.17 to 0.82; P = 0.014) but not for those at low risk (0.75% per year vs. 0.57% per year; HR 1.14; 95% CI 0.55 to 2.38; P = 0.714). Intensive systolic blood pressure reduction is beneficial for primary prevention of cardiovascular morbidity and mortality in patients without diabetes with more than low cardiac risk (above 10%).

Evaluation of Acute Kidney Injury and Mortality After Intensive Blood Pressure Control in Patients With Intracerebral Hemorrhage

BackgroundWe sought to assess the risk of acute kidney injury (AKI) and mortality associated with intensive systolic blood pressure reduction in acute intracerebral hemorrhage.Methods and ResultsPatients with acute intracerebral hemorrhage had spontaneous cause and symptom onset within 24 hours. We excluded patients with structural causes, coagulopathy, thrombocytopenia, and preexisting end‐stage renal disease. We defined AKI using the Acute Kidney Injury Network criteria. Chronic kidney disease status was included in risk stratification and was defined by Kidney Disease Outcomes Quality Initiative staging. Maximum systolic blood pressure reduction was defined over a 12‐hour period and dichotomized using receiver operating characteristic curve analysis. Descriptive statistics were done using independent sample t tests, χ2 tests, and Mann‐Whitney U tests, whereas multivariable logistic regression analysis was used to evaluate for predictors for AKI and mortality. A total of 448 patients with intracerebral hemorrhage met inclusion criteria. Maximum systolic blood pressure reduction was dichotomized to 90 mm Hg and found to increase the risk of AKI in patients with normal renal function (odds ratio, 2.1; 95% confidence interval, 1.19–3.62; P=0.010) and chronic kidney disease (odds ratio, 3.91; 95% confidence interval, 1.26–12.15; P=0.019). The risk of AKI was not significantly different in normal renal function versus chronic kidney disease groups when adjusted for demographics, presentation characteristics, and medications associated with AKI. AKI positively predicted mortality for patients with normal renal function (odds ratio, 2.41; 95% confidence interval, 1.11–5.22; P=0.026) but not for patients with chronic kidney disease (odds ratio, 3.13; 95% confidence interval, 0.65–15.01; P=0.154).ConclusionsThese results indicate that intensive systolic blood pressure reduction with a threshold >90 mm Hg in patients with acute intracerebral hemorrhage may be an independent predictor for AKI.

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.

Management of Acute Hypertensive Response in Intracerebral Hemorrhage Patients After ATACH-2 Trial.

Acute hypertensive response is elevation of systolic blood pressure (SBP) in the first 24h after symptom onset which is highly prevalent in patients with intracerebral hemorrhage (ICH). Observational studies suggested association between acute hypertensive response and hematoma expansion, peri-hematoma edema and death and disability, and possible reduction in these adverse outcomes with treatment of acute hypertensive response. Recent clinical trials have focused on determining the clinical efficacy of early intensive SBP reduction in ICH patients. The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-2) trial was the latest phase 3 randomized controlled multicenter clinical trial aimed to study the efficacy of early intensive reduction of SBP in ICH patients. In this review article, we summarize the results of recent clinical trials, treatment principles based on the latest guidelines, and the anticipated interpretation and incorporation of ATACH-2 trial results in clinical practice.

Direct Cost Savings Associated with Intensive Systolic Blood Pressure Reduction in Patients with Intracerebral Hemorrhage (P05.224)

Direct Cost Savings Associated with Intensive Systolic Blood Pressure Reduction in Patients with Intracerebral Hemorrhage (P05.224)

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.

わが国におけるAntihypertensive Treatment of Acute Cerebral Hemorrhage（ATACH）-II試験の開始：デザインと国内研究体制の構築

The Antihypertensive Treatment for Acute Cerebral Hemorrhage (ATACH)-II Trial (ClinicalTrials.gov no. NCT01176565; (UMIN 000006526) is an international, multicenter, randomized, concurrently-controlled, parallel arm, Phase III trial to determine the therapeutic benefit of early intensive systolic blood pressure (SBP) lowering compared with standard SBP lowering for acute hypertension in patients with spontaneous intracerebral hemorrhage (ICH). The Trial is funded by the National Institutes of Health in the United States and led by Dr. Adnan Qureshi at the University of Minnesota. Seventeen Japanese institutions will participate in this Trial. This article describes the latest version of the study design and our endeavors to develop the Japanese research network for stroke clinical research. The ATACH-II Trial plans to randomize a maximum of 1,280 (approximately 400 from Japan) subjects who have supratentorial ICH (hematoma volume <60cc) with Glasgow Coma Scale ≥5 and SBP of >180mmHg. Subjects undergo a follow-up assessment for functional and quality of life assessment at 90 days post-randomization. The primary research hypothesis of the trial is that intensive SBP reduction (to ≤140mmHg) using intravenous nicardipine infusion for 24 hours post-randomization reduces the proportion of death and disability at 90 days by ≥10% (absolute) compared to the standard SBP reduction (to 140-180mmHg range) among subjects with ICH whose treatment is initiated within 4.5 hours of symptom onset. The ATACH-II Trial could be the seminal research project for stroke researchers in Japan to demonstrate themselves as effective contributing members of investigator-initiated international clinical trials.

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.