Intensive blood pressure lowering with nicardipine and outcomes after intracerebral hemorrhage: An individual participant data systematic review.

BACKGROUND AND AIMS: Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. METHODS: A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4-6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. SUMMARY OF REVIEW: Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00-1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02-1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00-1.05 per hour). CONCLUSIONS: Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

White Matter Hyperintensities and Blood Pressure Lowering in Acute Intracerebral Hemorrhage: A Secondary Analysis of the ATACH-2 Trial.

BACKGROUND: It is not clear whether subsets of patients with intracerebral hemorrhage (ICH) benefit from intensive blood pressure (BP) lowering. We evaluated whether white matter hyperintensities (WMH) burden influences response to this therapy. METHODS: Retrospective secondary analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. Patients were randomized to intensive (systolic BP target: 110-139 mmHg) versus standard (systolic BP target: 140-179 mmHg) BP treatment with intravenous nicardipine within 4.5 h from onset between May 2011 and September 2015. WMH were rated on magnetic resonance images (fluid-attenuated inversion recovery sequences), defining moderate-severe WMH as total Fazekas scale score ≥ 3 (range 0-6). The main outcome was death or major disability at 90 days (modified Rankin scale ≥ 3). The secondary outcome was ICH expansion, defined as hematoma growth > 33% from baseline to follow-up CT scan. Predictors of the outcomes of interest were explored with multivariable logistic regression. RESULTS: A total of 195/1000 patients had MRI images available for analysis, of whom 161 (82.6%) had moderate-severe WMH. When compared to patients with none-mild WMH, those with moderate-severe WMH did not have an increased risk of death or major disability (adjusted relative risk: 1.83, 95% CI 0.71-4.69) or ICH expansion (adjusted relative risk: 1.14, 95% CI 0.38-3.37). WMH burden did not modify the effect of intensive BP treatment on outcome (all p for interaction ≥ 0.2). CONCLUSION: The majority of acute ICH patients have moderate-severe WMH, but advanced small vessel disease burden marked by WMH does not influence ICH-related outcomes or response to intensive BP reduction.

Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion.

OBJECTIVE: To validate various noncontrast CT (NCCT) predictors of hematoma expansion in a large international cohort of ICH patients and investigate whether intensive blood pressure (BP) treatment reduces ICH growth and improves outcome in patients with these markers. METHODS: We analyzed patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized controlled trial. Participants were assigned to intensive (systolic BP <140 mm Hg) vs standard (systolic BP <180 mm Hg) treatment within 4.5 hours from onset. The following NCCT markers were identified: intrahematoma hypodensities, black hole sign, swirl sign, blend sign, heterogeneous hematoma density, and irregular shape. ICH expansion was defined as hematoma growth >33% and unfavorable outcome was defined as modified Rankin Scale score >3 at 90 days. Logistic regression was used to identify predictors of ICH expansion and explore the association between NCCT signs and clinical benefit from intensive BP treatment. RESULTS: A total of 989 patients were included (mean age 62 years, 61.9% male), of whom 186/869 experienced hematoma expansion (21.4%) and 361/952 (37.9%) had unfavorable outcome. NCCT markers independently predicted ICH expansion (all p < 0.01) with overall accuracy ranging from 61% to 78% and good interrater reliability (k > 0.6 for all markers). There was no evidence of an interaction between NCCT markers and benefit from intensive BP reduction (all p for interaction >0.10). CONCLUSIONS: NCCT signs reliably identify ICH patients at high risk of hematoma growth. However, we found no evidence that patients with these markers specifically benefit from intensive BP reduction. CLINICALTRIALSGOV IDENTIFIER: NCT01176565.

Phantom-based standardization of CT angiography images for spot sign detection.

PURPOSE: The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. METHODS: A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. RESULTS: A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p < 0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. CONCLUSION: Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.

Intensive Blood Pressure Reduction and Spot Sign in Intracerebral Hemorrhage: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The computed tomographic angiography (CTA) spot sign is associated with intracerebral hemorrhage (ICH) expansion and may mark those patients most likely to benefit from intensive blood pressure (BP) reduction. Objective: To investigate whether the spot sign is associated with ICH expansion across a wide range of centers and whether intensive BP reduction decreases hematoma expansion and improves outcome in patients with ICH and a spot sign. Design, Setting, and Participants: SCORE-IT (Spot Sign Score in Restricting ICH Growth) is a preplanned prospective observational study nested in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized clinical trial. Participants included consecutive patients with primary ICH who underwent a CTA within 8 hours from onset at 59 sites from May 15, 2011, through December 19, 2015. Data were analyzed for the present study from July 1 to August 31, 2016. Main Outcomes and Measures: Patients in ATACH-II were randomized to intensive (systolic BP target, <140 mm Hg) vs standard (systolic BP target, <180 mm Hg) BP reduction within 4.5 hours from onset. Expansion of ICH was defined as hematoma growth of greater than 33%, and an unfavorable outcome was defined as a 90-day modified Rankin Scale score of 4 or greater (range, 0-6). The association among BP reduction, ICH expansion, and outcome was investigated with multivariable logistic regression. Results: A total of 133 patients (83 men [62.4%] and 50 women [37.6%]; mean [SD] age, 61.9 [13.1] years) were included. Of these, 53 (39.8%) had a spot sign, and 24 of 123 without missing data (19.5%) experienced ICH expansion. The spot sign was associated with expansion with sensitivity of 0.54 (95% CI, 0.34-0.74) and specificity of 0.63 (95% CI, 0.53-0.72). After adjustment for potential confounders, intensive BP treatment was not associated with a significant reduction of ICH expansion (relative risk, 0.83; 95% CI, 0.27-2.51; P = .74) or improved outcome (relative risk of 90-day modified Rankin Scale score ≥4, 1.24; 95% CI, 0.53-2.91; P = .62) in spot sign-positive patients. Conclusions and Relevance: The predictive performance of the spot sign for ICH expansion was lower than in prior reports from single-center studies. No evidence suggested that patients with ICH and a spot sign specifically benefit from intensive BP reduction. Trial Registration: clinicaltrials.gov Identifier: NCT01176565.

Differences in ischemic and hemorrhagic recurrence rates among race-ethnic groups in the PRoFESS secondary stroke prevention trial.

BACKGROUND AND AIMS: Epidemiological studies show that vascular risk factors are the same across the world but their effect vary between different race-ethnic groups. However, few studies have evaluated differences in recurrent stroke rates in various race-ethnicities. In >20 000 patients spanning 35 countries encompassing most race-ethnicities, we evaluated the incidence of ischemic and hemorrhagic strokes and myocardial infarction in patients within the context of the largest secondary stroke prevention trial (Prevention Regimen for Effectively Avoiding Secondary Strokes) to identify any significant differences. METHODS: There were 20 332 patients with a recent ischemic stroke randomized in a factorial design to receive the antiplatelet agent clopidogrel vs. aspirin plus extended-release dipyridamole, and 80 mg of the anthypertensive telmisartan vs. placebo. The primary outcome for the trial was the time to any recurrent stroke. Statistical analysis was used to detect race-ethnic differences in recurrent vascular events. RESULTS: Mean patient age was 66 (±8·6) years and 36% were women. The study included 58% European/Caucasian, 33% Asians, 5% Latin/Hispanic, and 4% Black African. There were 74% of patients that were hypertensive, and average systolic and diastolic blood pressure was 144·1/83·8 mmHg. There was at least one significant difference in the overall test of all race-ethnic groups in myocardial infarction and symptomatic intracerebral hemorrhage occurrence. In the Kaplan-Meier hemorrhage and stroke-free survival curves, Asians showed a significantly higher recurrence of ischemic stroke risk in the 135-150 mmHg and greater than 150 mm Hg blood pressure groups, and a greater risk of hemorrhage recurrence in the greater than 150 mmHg blood pressure group. CONCLUSIONS: We found a significant difference in myocardial infarction and symptomatic intracerebral hemorrhage recurrence among different race-ethnic groups. The risk of recurrent ischemic and hemorrhagic stroke was greater in Asians with high blood pressure.

Is intra-arterial thrombolysis beneficial for M2 occlusions? Subgroup analysis of the PROACT-II trial.

BACKGROUND AND PURPOSE: The role of endovascular therapy for acute M2 trunk occlusions is debatable. Through a subgroup analysis of Prolyse in Acute Cerebral Thromboembolism-II, we compared outcomes of M2 occlusions in treatment and control arms. METHODS: Solitary M2 occlusions were identified from the Prolyse in Acute Cerebral Thromboembolism-II database. Primary endpoints were successful angiographic reperfusion (TICI 2-3) at 120 minutes and functional independence (mRS 0-2) at 90 days. RESULTS: Forty-four patients with solitary M2 occlusions, 30 in the treatment arm and 14 in the control arm, were identified. Successful reperfusion (TICI 2-3) was achieved in 53.6% and 16.7% of patients in the treatment and control arms, respectively (P=0.04). A favorable clinical outcome (mRS 0-2) was observed in 53.3% and 28.6%, respectively (P=0.19). Baseline characteristics were similar between the 2 groups. CONCLUSIONS: Intra-arterial thrombolysis may lead to a 3-fold increase in the rate of early reperfusion of solitary M2 occlusions and could potentially double the chance of a favorable functional outcome at 90 days. Clinical Trial Registration- This trial was not registered because enrollment began before July 1, 2005.

Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: interim results of a prospective cohort study.

BACKGROUND: We sought to examine the detection rate of cancer cells in peripheral blood (PBL) and in bone marrow (BM) using an established 7-gene marker panel and evaluated whether there were any definable associations of any individual gene with traditional predictors of prognosis. METHODS: Patients with T1-T3 primary breast cancer were enrolled into a prospective, multi-institutional cohort study. In this interim analysis 215 PBL and 177 BM samples were analyzed by multimarker, real-time RT-PCR analysis designed to detect circulating and disseminated breast cancer cells. RESULTS: At a threshold of three standard deviations from the mean expression level of normal controls, 63% (136/215) of PBL and 11% (19/177) of BM samples were positive for at least one cancer-associated marker. Marker positivity in PBL demonstrated a statistically significant association with grade II-III (vs. grade I; p = 0.0083). Overexpression of the mammaglobin (mam) gene alone had a statistically significant association with high tumor grade (p = 0.0315), and showed a trend towards ER-negative tumors and a high risk category. There was no association between marker positivity in PBL and the pathologic (H&E) and/or molecular (RT-PCR) status of the axillary lymph nodes (ALN). CONCLUSION: This study suggests that molecular detection of circulating cancer cells in PBL detected by RT-PCR is associated with high tumor grade and specifically that overexpression of the mam gene in PBL may be a poor prognostic indicator. There was no statistically significant association between overexpression of cancer-associated genes in PBL and ALN status, supporting the concept of two potentially separate metastatic pathways.

Molecular analysis improves sensitivity of breast sentinel lymph node biopsy: results of a multi-institutional prospective cohort study.

BACKGROUND: Pathologic evaluation may lack the sensitivity required for accurate staging of the axilla in breast cancer patients. We have completed enrollment of a multi-institutional prospective cohort study designed to determine if molecular analyses can improve axillary staging. In subset analyses, we have attempted to address the following questions: (1) Does molecular analysis improve the sensitivity of sentinel lymph node biopsy (SLNB) and (2) is the sentinel lymph node (SLN) hypothesis valid at the molecular level? METHODS: Four hundred eighty-nine subjects with T1, T2, or T3 breast cancer and no evidence of axillary lymph node (ALN) involvement were enrolled. ALNs were analyzed by routine pathology (hematoxylin-eosin staining), and by multimarker real-time reverse transcriptase-polymerase chain reaction analysis CRT-PCR to detect breast cancer metastases. Pathology and molecular data for both SLNs and nonsentinel ALNs were available for a subset of 207 subjects. RESULTS: The sensitivity of pathologic analysis of the SLN to predict the pathologic status of ALNs was 84.1%. The sensitivity of combining pathologic with molecular analysis of the SLN to predict the pathologic status of ALNs was 92.8%, a statistically significant increase in sensitivity (P = .031 by the McNemar test for correlated proportions). Finally, the sensitivity of combining pathologic with molecular analysis of the SLN to predict the pathologic or molecular status of ALNs was 85.4%. CONCLUSIONS: The combination of pathologic and molecular analysis of SLNs resulted in the highest sensitivity for prediction of the pathologic status of ALNs. The data also provide evidence that the SLN hypothesis remains valid at the molecular level.

Prevalence of posttraumatic stress disorder in Veterans Affairs primary care clinics.

Although posttraumatic stress disorder (PTSD) is relatively common in community epidemiologic surveys (5-6% for men, 10-12% for women), and psychiatric patients with PTSD are known to have poor functioning and high levels of psychiatric comorbidity, there are no studies that address PTSD prevalence, functioning, and burden in primary care settings. This article reports on (1) the prevalence of PTSD using Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition diagnostic criteria in Veterans Affairs (VA) primary care settings, (2) associated sociodemographic characteristics and comorbidities, (3) functional status related to PTSD, (4) the extent to which PTSD was recognized by providers and (5) health services use patterns (including specialty mental health) of PTSD patients. Patients were randomly selected from those who had an outpatient visit in FY 1999 at one of four VA hospitals; 888 patients consented (74.1% of 1198 contacted); 746 patients (84.0% of consenting patients; 62.3% of contacted patients) were reached for telephone diagnostic interviews. Diagnostic interviews with the Clinician Administered PTSD Scale yielded estimates of current PTSD prevalence of 11.5%. At statistically significant levels, PTSD was positively associated with a variety of comorbid psychiatric disorders, war zone service, age <65 years, not working, less formal education and decreased functioning. Of patients diagnosed with PTSD by study procedures, 12-month medical record review indicated that providers identified only 46.5% and only 47.7% had used mental health specialty services. PTSD-positive [PTSD(+)] patients who used mental health care in the past 12 months were more apt to be identified as having PTSD than nonmental health service users (78.0% vs. 17.8%). Although PTSD(+) patients had more medical record diagnoses than PTSD-negative [PTSD(-)] patients (6.28 vs. 4.95), their use of primary care, urgent care and inpatient care was not different from PTSD(-) patients.