国循脳卒中データバンク2021編集委員会：脳卒中データバンク2021．中山書店、2021.
「脳卒中レジストリを用いた我が国の脳卒中診療実態の把握」報告書2023年（日本脳卒中データバンク）． [Internet]. Available from: https://strokedatabank.ncvc.go.jp/f12kQnRl/wp-content/uploads/日本脳卒中データバンク報告書2023年_20240129.pdf
Toyoda K, Yoshimura S, Nakai M, Koga M, Sasahara Y, Sonoda K, Kamiyama K, Yazawa Y, Kawada S, Sasaki M, Terasaki T, Miwa K, Koge J, Ishigami A, Wada S, Iwanaga Y, Miyamoto Y, Minematsu K, Kobayashi S; Japan Stroke Data Bank Investigators.
Twenty-Year Change in Severity and Outcome of Ischemic and Hemorrhagic Strokes.
JAMA Neurol. 2022 Jan 1;79(1):61-69. doi: 10.1001/jamaneurol.2021.4346.
Abstract/Text
IMPORTANCE: Whether recent changes in demographic characteristics and therapeutic technologies have altered stroke outcomes remains unknown.
OBJECTIVE: To determine secular changes in initial neurological severity and short-term functional outcomes of patients with acute stroke by sex using a large population.
DESIGN, SETTING, AND PARTICIPANTS: This nationwide, hospital-based, multicenter, prospective registry cohort study used the Japan Stroke Data Bank and included patients who developed acute stroke from January 2000 through December 2019. Patients with stroke, including ischemic and hemorrhagic strokes, who registered within 7 days after symptom onset were studied. Modified Rankin Scale scores were assessed at hospital discharge for all patients.
EXPOSURE: Time.
MAIN OUTCOMES AND MEASURES: Initial severity was assessed by the National Institutes of Health Stroke Scale for ischemic stroke and intracerebral hemorrhage and by the World Federation of Neurological Surgeons grading for subarachnoid hemorrhage. Outcomes were judged as favorable if the modified Rankin Scale score was 0 to 2 and unfavorable if 5 to 6.
RESULTS: Of 183 080 patients, 135 266 (53 800 women [39.8%]; median [IQR] age, 74 [66-82] years) developed ischemic stroke, 36 014 (15 365 women [42.7%]; median [IQR] age, 70 [59-79] years) developed intracerebral hemorrhage, and 11 800 (7924 women [67.2%]; median [IQR] age, 64 [53-75] years) developed subarachnoid hemorrhage. In all 3 stroke types, median ages at onset increased, and the National Institutes of Health Stroke Scale and World Federation of Neurological Surgeons scores decreased throughout the 20-year period on multivariable analysis. In ischemic stroke, the proportion of favorable outcomes showed an increase over time after age adjustment (odds ratio [OR], 1.020; 95% CI, 1.015-1.024 for women vs OR, 1.015; 95% CI, 1.011-1.018 for men) but then stagnated, or even decreased in men, on multivariate adjustment including reperfusion therapy (OR, 0.997; 95% CI, 0.991-1.003 for women vs OR, 0.990; 95% CI, 0.985-0.994 for men). Unfavorable outcomes and in-hospital deaths decreased in both sexes. In intracerebral hemorrhage, favorable outcomes decreased in both sexes, and unfavorable outcomes and deaths decreased only in women. In subarachnoid hemorrhage, the proportion of favorable outcomes was unchanged, and that of unfavorable outcomes and deaths decreased in both sexes.
CONCLUSIONS AND RELEVANCE: In this study, functional outcomes improved in patients with ischemic stroke during the past 20 years in both sexes presumably partly owing to the development of acute reperfusion therapy. The outcomes of patients with hemorrhagic stroke did not clearly improve in the same period.
Ramos-Pachón A, Rodríguez-Luna D, Martí-Fàbregas J, Millán M, Bustamante A, Martínez-Sánchez M, Serena J, Terceño M, Vera-Cáceres C, Camps-Renom P, Prats-Sánchez L, Rodríguez-Villatoro N, Cardona-Portela P, Urra X, Solà S, Del Mar Escudero M, Salvat-Plana M, Ribó M, Abilleira S, Pérez de la Ossa N, Silva Y; RACECAT Trial Investigators.
Effect of Bypassing the Closest Stroke Center in Patients with Intracerebral Hemorrhage: A Secondary Analysis of the RACECAT Randomized Clinical Trial.
JAMA Neurol. 2023 Oct 1;80(10):1028-1036. doi: 10.1001/jamaneurol.2023.2754.
Abstract/Text
IMPORTANCE: Prehospital transfer protocols are based on rapid access to reperfusion therapies for patients with ischemic stroke. The effect of different protocols among patients receiving a final diagnosis of intracerebral hemorrhage (ICH) is unknown.
OBJECTIVE: To determine the effect of direct transport to an endovascular treatment (EVT)-capable stroke center vs transport to the nearest local stroke center.
DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of RACECAT, a multicenter, population-based, cluster-randomized clinical trial conducted from March 2017 to June 2020 in Catalonia, Spain. Patients were evaluated by a blinded end point assessment. All consecutive patients suspected of experiencing a large vessel occlusion stroke (Rapid Arterial Occlusion Evaluation Scale [RACE] score in the field >4 on a scale of 0 to 9, with lower to higher stroke severity) with final diagnosis of ICH were included. A total of 1401 patients were enrolled in RACECAT with suspicion of large vessel occlusion stroke. The current analysis was conducted in October 2022.
INTERVENTION: Direct transport to an EVT-capable stroke center (n = 137) or to the closest local stroke center (n = 165).
MAIN OUTCOMES AND MEASURES: The primary outcome was tested using cumulative ordinal logistic regression to estimate the common odds ratio (OR) and 95% CI of the shift analysis of disability at 90 days as assessed by the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) in the intention-to-treat population. Secondary outcomes, included 90-day mortality, death or severe functional dependency, early neurological deterioration, early mortality, ICH volume and enlargement, rate of neurosurgical treatment, rate of clinical complications during initial transport, and rate of adverse events until day 5.
RESULTS: Of 1401 patients enrolled, 1099 were excluded from this analysis (32 rejected informed consent, 920 had ischemic stroke, 29 had transient ischemic attack, 12 had subarachnoid hemorrhage, and 106 had stroke mimic). Thus, 302 patients were included (204 [67.5%] men; mean [SD] age 71.7 [12.8] years; and median [IQR] RACE score, 7 [6-8]). For the primary outcome, direct transfer to an EVT-capable stroke center (mean [SD] mRS score, 4.93 [1.38]) resulted in worse functional outcome at 90 days compared with transfer to the nearest local stroke center (mean [SD] mRS score, 4.66 [1.39]; adjusted common OR, 0.63; 95% CI, 0.41-0.96). Direct transfer to an EVT-capable stroke center also suggested potentially higher 90-day mortality compared with transfer to the nearest local stroke center (67 of 137 [48.9%] vs 62 of 165 [37.6%]; adjusted hazard ratio, 1.40; 95% CI, 0.99-1.99). The rates of medical complications during the initial transfer (30 of 137 [22.6%] vs 9 of 165 patients [5.6%]; adjusted OR, 5.29; 95% CI, 2.38-11.73) and in-hospital pneumonia (49 of 137 patients [35.8%] vs 29 of 165 patients [17.6%]; OR, 2.61; 95% CI, 1.53-4.44) were higher in the EVT-capable stroke center group.
CONCLUSIONS AND RELEVANCE: In this secondary analysis of the RACECAT randomized clinical trial, bypassing the closest stroke center resulted in reduced chances of functional independence at 90 days for patients who received a final diagnosis of ICH.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02795962.
Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Blas YS, Dzialowski I, Kobayashi A, Boulanger JM, Lum C, Gubitz G, Padma V, Roy J, Kase CS, Kosior J, Bhatia R, Tymchuk S, Subramaniam S, Gladstone DJ, Hill MD, Aviv RI; PREDICT/Sunnybrook ICH CTA study group.
Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.
Lancet Neurol. 2012 Apr;11(4):307-14. doi: 10.1016/S1474-4422(12)70038-8. Epub 2012 Mar 8.
Abstract/Text
BACKGROUND: In patients with intracerebral haemorrhage (ICH), early haemorrhage expansion affects clinical outcome. Haemostatic treatment reduces haematoma expansion, but fails to improve clinical outcomes in many patients. Proper selection of patients at high risk for haematoma expansion seems crucial to improve outcomes. In this study, we aimed to prospectively validate the CT-angiography (CTA) spot sign for prediction of haematoma expansion.
METHODS: PREDICT (predicting haematoma growth and outcome in intracerebral haemorrhage using contrast bolus CT) was a multicentre prospective observational cohort study. We recruited patients aged 18 years or older, with ICH smaller than 100 mL, and presenting at less than 6 h from symptom onset. Using two independent core laboratories, one neuroradiologist determined CTA spot-sign status, whereas another neurologist masked for clinical outcomes and imaging measured haematoma volumes by computerised planimetry. The primary outcome was haematoma expansion defined as absolute growth greater than 6 mL or a relative growth of more than 33% from initial CT to follow-up CT. We reported data using standard descriptive statistics stratified by the CTA spot sign. Mortality was assessed with Kaplan-Meier survival analysis.
FINDINGS: We enrolled 268 patients. Median time from symptom onset to baseline CT was 135 min (range 22-470), and time from onset to CTA was 159 min (32-475). 81 (30%) patients were spot-sign positive. The primary analysis included 228 patients, who had a follow-up CT before surgery or death. Median baseline ICH volume was 19·9 mL (1·5-80·9) in spot-sign-positive patients versus 10·0 mL (0·1-102·7) in spot-sign negative patients (p<0·001). Median ICH expansion was 8·6 mL (-9·3 to 121·7) for spot-sign positive patients and 0·4 mL (-11·7 to 98·3) for spot-negative patients (p<0·001). In those with haematoma expansion, the positive predictive value for the spot sign was61% (95% CI 47–73) for the positive predictive value and 78% (71–84) for the negative predictive value, with 51% (39–63) sensitivity and 85% (78–90) specificity[corrected]. Median 3-month modified Rankin Scale (mRS) was 5 in CTA spot-sign-positive patients, and 3 in spot-sign-negative patients (p<0·001). Mortality at 3 months was 43·4% (23 of 53) in CTA spot-sign positive versus 19·6% (31 of 158) in CTA spot-sign-negative patients (HR 2·4, 95% CI 1·4-4·0, p=0·002).
INTERPRETATION: These findings confirm previous single-centre studies showing that the CTA spot sign is a predictor of haematoma expansion. The spot sign is recommended as an entry criterion for future trials of haemostatic therapy in patients with acute ICH.
FUNDING: Canadian Stroke Consortium and NovoNordisk Canada.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Boulouis G, Morotti A, Brouwers HB, Charidimou A, Jessel MJ, Auriel E, Pontes-Neto O, Ayres A, Vashkevich A, Schwab KM, Rosand J, Viswanathan A, Gurol ME, Greenberg SM, Goldstein JN.
Association Between Hypodensities Detected by Computed Tomography and Hematoma Expansion in Patients With Intracerebral Hemorrhage.
JAMA Neurol. 2016 Aug 1;73(8):961-8. doi: 10.1001/jamaneurol.2016.1218.
Abstract/Text
IMPORTANCE: Hematoma expansion is a potentially modifiable predictor of poor outcome following an acute intracerebral hemorrhage (ICH). The ability to identify patients with ICH who are likeliest to experience hematoma expansion and therefore likeliest to benefit from expansion-targeted treatments remains an unmet need. Hypodensities within an ICH detected by noncontrast computed tomography (NCCT) have been suggested as a predictor of hematoma expansion.
OBJECTIVE: To determine whether hypodense regions, irrespective of their specific patterns, are associated with hematoma expansion in patients with ICH.
DESIGN, SETTING, AND PARTICIPANTS: We analyzed a large cohort of 784 patients with ICH (the development cohort; 55.6% female), examined NCCT findings for any hypodensity, and replicated our findings on a different cohort of patients (the replication cohort; 52.7% female). Baseline and follow-up NCCT data from consecutive patients with ICH presenting to a tertiary care hospital between 1994 and 2015 were retrospectively analyzed. Data analyses were performed between December 2015 and January 2016.
MAIN OUTCOMES AND MEASURES: Hypodensities were analyzed by 2 independent blinded raters. The association between hypodensities and hematoma expansion (>6 cm3 or 33% of baseline volume) was determined by multivariable logistic regression after controlling for other variables associated with hematoma expansion in univariate analyses with P ≤ .10.
RESULTS: A total of 1029 patients were included in the analysis. In the development and replication cohorts, 222 of 784 patients (28.3%) and 99 of 245 patients (40.4%; 321 of 1029 patients [31.2%]), respectively, had NCCT scans that demonstrated hypodensities at baseline (κ = 0.87 for interrater reliability). In univariate analyses, hypodensities were associated with hematoma expansion (86 of 163 patients with hematoma expansion had hypodensities [52.8%], whereas 136 of 621 patients without hematoma expansion had hypodensities [21.9%]; P < .001). The association between hypodensities and hematoma expansion remained significant (odds ratio, 3.42 [95% CI, 2.21-5.31]; P < .001) in a multivariable model; other independent predictors of hematoma expansion were a CT angiography spot sign, a shorter time to CT, warfarin use, and older age. The independent predictive value of hypodensities was again demonstrated in the replication cohort (odds ratio, 4.37 [95% CI, 2.05-9.62]; P < .001).
CONCLUSION AND RELEVANCE: Hypodensities within an acute ICH detected on an NCCT scan may predict hematoma expansion, independent of other clinical and imaging predictors. This novel marker may help clarify the mechanism of hematoma expansion and serve as a useful addition to clinical algorithms for determining the risk of and treatment stratification for hematoma expansion.
Sporns PB, Schwake M, Schmidt R, Kemmling A, Minnerup J, Schwindt W, Cnyrim C, Zoubi T, Heindel W, Niederstadt T, Hanning U.
Computed Tomographic Blend Sign Is Associated With Computed Tomographic Angiography Spot Sign and Predicts Secondary Neurological Deterioration After Intracerebral Hemorrhage.
Stroke. 2017 Jan;48(1):131-135. doi: 10.1161/STROKEAHA.116.014068. Epub 2016 Nov 22.
Abstract/Text
BACKGROUND AND PURPOSE: Significant early hematoma growth in patients with intracerebral hemorrhage is an independent predictor of poor functional outcome. Recently, the novel blend sign (BS) has been introduced as a new imaging sign for predicting hematoma growth in noncontrast computed tomography. Another parameter predicting increasing hematoma size is the well-established spot sign (SS) visible in computed tomographic angiography. We, therefore, aimed to clarify the association between established SS and novel BS and their values predicting a secondary neurological deterioration.
METHODS: Retrospective study inclusion criteria were (1) spontaneous intracerebral hemorrhage confirmed on noncontrast computed tomography and (2) noncontrast computed tomography and computed tomographic angiography performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (secondary neurological deterioration versus no secondary deterioration). As secondary neurological deterioration, we defined (1) early hemicraniectomy under standardized criteria or (2) secondary decrease of Glasgow Coma Scale of >3 points, both within the first 48 hours after symptom onset.
RESULTS: Of 182 patients with spontaneous intracerebral hemorrhage, 37 (20.3%) presented with BS and 39 (21.4%) with SS. Of the 81 patients with secondary deterioration, 31 (38.3%) had BS and SS on admission. Multivariable logistic regression analysis identified hematoma volume (odds ratio, 1.07 per mL; P≤0.001), intraventricular hemorrhage (odds ratio, 3.08; P=0.008), and the presence of BS (odds ratio, 11.47; P≤0.001) as independent predictors of neurological deterioration.
CONCLUSIONS: The BS, which is obtainable in noncontrast computed tomography, shows a high correlation with the computed tomographic angiography SS and is a reliable predictor of secondary neurological deterioration after spontaneous intracerebral hemorrhage.
© 2016 American Heart Association, Inc.
Li Q, Zhang G, Xiong X, Wang XC, Yang WS, Li KW, Wei X, Xie P.
Black Hole Sign: Novel Imaging Marker That Predicts Hematoma Growth in Patients With Intracerebral Hemorrhage.
Stroke. 2016 Jul;47(7):1777-81. doi: 10.1161/STROKEAHA.116.013186. Epub 2016 May 12.
Abstract/Text
BACKGROUND AND PURPOSE: Early hematoma growth is a devastating neurological complication after intracerebral hemorrhage. We aim to report and evaluate the usefulness of computed tomography (CT) black hole sign in predicting hematoma growth in patients with intracerebral hemorrhage.
METHODS: Patients with intracerebral hemorrhage were screened for the presence of CT black hole sign on admission head CT performed within 6 hours after onset of symptoms. The black hole sign was defined as hypoattenuatting area encapsulated within the hyperattenuating hematoma with a clearly defined border. The sensitivity, specificity, and positive and negative predictive values of CT black hole sign in predicting hematoma expansion were calculated. Logistic regression analyses were used to assess the presence of the black hole sign and early hematoma growth.
RESULTS: A total of 206 patients were enrolled. Black hole sign was found in 30 (14.6%) of 206 patients on the baseline CT scan. The black hole sign was more common in patients with hematoma growth (31.9%) than those without hematoma growth (5.8%; P<0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of back hole sign in predicting early hematoma growth were 31.9%, 94.1%, 73.3%, and 73.2%, respectively. The time-to-admission CT scan, baseline hematoma volume, and the presence of black hole sign on admission CT independently predict hematoma growth in multivariate model.
CONCLUSIONS: The CT black hole sign could be used as a simple and easy-to-use predictor for early hematoma growth in patients with intracerebral hemorrhage.
© 2016 American Heart Association, Inc.
Li Q, Liu QJ, Yang WS, Wang XC, Zhao LB, Xiong X, Li R, Cao D, Zhu D, Wei X, Xie P.
Island Sign: An Imaging Predictor for Early Hematoma Expansion and Poor Outcome in Patients With Intracerebral Hemorrhage.
Stroke. 2017 Nov;48(11):3019-3025. doi: 10.1161/STROKEAHA.117.017985. Epub 2017 Oct 10.
Abstract/Text
BACKGROUND AND PURPOSE: The aim of the study was to investigate the usefulness of the computed tomography (CT) island sign for predicting early hematoma growth and poor functional outcome.
METHODS: We included patients with spontaneous intracerebral hemorrhage (ICH) who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016. Two readers independently assessed the presence of the island sign on the admission noncontrast CT scan. Multivariable logistic regression analysis was used to analyze the association between the presence of the island sign on noncontrast admission CT and early hematoma growth and functional outcome.
RESULTS: A total of 252 patients who met the inclusion criteria were analyzed. Among them, 41 (16.3%) patients had the island sign on baseline noncontrast CT scans. In addition, the island sign was observed in 38 of 85 patients (44.7%) with hematoma growth. Multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and the presence of the island sign on baseline CT scan independently predicted early hematoma growth. The sensitivity of the island sign for predicting hematoma expansion was 44.7%, specificity 98.2%, positive predictive value 92.7%, and negative predictive value 77.7%. After adjusting for the patients' age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, presence of subarachnoid hemorrhage, admission systolic blood pressure, baseline ICH volume, and infratentorial location, the presence of the island sign (odds ratio, 3.51; 95% confidence interval, 1.26-9.81; P=0.017) remained an independent predictor of poor outcome in patients with ICH.
CONCLUSIONS: The island sign is a reliable CT imaging marker that independently predicts hematoma expansion and poor outcome in patients with ICH. The noncontrast CT island sign may serve as a potential marker for therapeutic intervention.
© 2017 American Heart Association, Inc.
Anderson CS, Arima H, Lavados P, Billot L, Hackett ML, Olavarría VV, Muñoz Venturelli P, Brunser A, Peng B, Cui L, Song L, Rogers K, Middleton S, Lim JY, Forshaw D, Lightbody CE, Woodward M, Pontes-Neto O, De Silva HA, Lin RT, Lee TH, Pandian JD, Mead GE, Robinson T, Watkins C; HeadPoST Investigators and Coordinators.
Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke.
N Engl J Med. 2017 Jun 22;376(25):2437-2447. doi: 10.1056/NEJMoa1615715.
Abstract/Text
BACKGROUND: The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion.
METHODS: In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death).
RESULTS: The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P=0.83). There were no significant between-group differences in the rates of serious adverse events, including pneumonia.
CONCLUSIONS: Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017 .).
Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, Lindley R, Robinson T, Lavados P, Neal B, Hata J, Arima H, Parsons M, Li Y, Wang J, Heritier S, Li Q, Woodward M, Simes RJ, Davis SM, Chalmers J; INTERACT2 Investigators.
Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage.
N Engl J Med. 2013 Jun 20;368(25):2355-65. doi: 10.1056/NEJMoa1214609. Epub 2013 May 29.
Abstract/Text
BACKGROUND: Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known.
METHODS: We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups.
RESULTS: Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.
CONCLUSIONS: In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).
Koga M, Toyoda K, Yamagami H, Okuda S, Okada Y, Kimura K, Shiokawa Y, Nakagawara J, Furui E, Hasegawa Y, Kario K, Osaki M, Miyagi T, Endo K, Nagatsuka K, Minematsu K; Stroke Acute Management with Urgent Risk-factor Assessment and Improvement Study Investigators.
Systolic blood pressure lowering to 160 mmHg or less using nicardipine in acute intracerebral hemorrhage: a prospective, multicenter, observational study (the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage study).
J Hypertens. 2012 Dec;30(12):2357-64. doi: 10.1097/HJH.0b013e328359311b.
Abstract/Text
OBJECTIVE: Optimal blood pressure (BP) control in acute intracerebral hemorrhage (ICH) remains controversial. We determined the effects of SBP lowering to 160 mmHg or more using intravenous nicardipine for acute ICH patients.
METHODS: This is a prospective, multicenter, observational study conducted in Japan, with the lack of control groups. Patients with supratentorial ICH within 3 h of onset, admission SBP 180 mmHg or more, Glasgow Coma Scale (GCS) 5 or more, and hematoma volume less than 60 ml were initially treated with intravenous nicardipine to maintain SBP between 120 and 160 mmHg with 24-h frequent BP monitoring. The primary endpoints were neurological deterioration within 72 h [GCS decrement ≥ 2 points or National Institutes of Health Stroke Scale (NIHSS) increment ≥ 4 points; estimated 90% confidence interval (CI) on the basis of previous studies: 15.2-25.9%] and serious adverse effects (SAE) to stopping intravenous nicardipine within 24 h (1.8-8.9%). The secondary endpoints included hematoma expansion more than 33% at 24 h (17.1-28.3%), modified Rankin Scale (mRS) 4 or more (54.5-67.9%) and death at 3 months (6.0-13.5%).
RESULTS: We enrolled 211 Japanese patients (81 women, 65.6 ± 12.0 years old). At baseline, BP was 201.8 ± 15.7/107.9 ± 15.0 mmHg. Median hematoma volume was 10.2 ml (interquartile range 5.6-19.2), and NIHSS score was 13 (8-17). Neurological deterioration was identified in 17 patients (8.1%), SAE in two (0.9%), hematoma expansion in 36 (17.1%), mRS 4 or more in 87 (41.2%), and death in four (1.9%). All the results were equal to or below the estimated lower 90% CI.
CONCLUSION: SBP lowering to 160 mmHg or less using nicardipine appears to be well tolerated and feasible for acute ICH.
Sakamoto Y, Koga M, Yamagami H, Okuda S, Okada Y, Kimura K, Shiokawa Y, Nakagawara J, Furui E, Hasegawa Y, Kario K, Arihiro S, Sato S, Kobayashi J, Tanaka E, Nagatsuka K, Minematsu K, Toyoda K; SAMURAI Study Investigators.
Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study.
Stroke. 2013 Jul;44(7):1846-51. doi: 10.1161/STROKEAHA.113.001212. Epub 2013 May 23.
Abstract/Text
BACKGROUND AND PURPOSE: Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known.
METHODS: Hyperacute (<3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) >180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points' decrease in Glasgow Coma Score or ≥4 points' increase in National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin Scale score 4-6 at 3 months) were assessed with multivariate logistic regression analyses.
RESULTS: Of the 211 patients (81 women, median age 65 [interquartile range, 58-74] years, and median initial National Institutes of Health Stroke Scale score 13 [8-17]) enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03-9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09-3.16), and unfavorable outcome (2.03; 1.24-3.33) after adjusting for known predictive factors.
CONCLUSIONS: High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.
Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL, Moy CS, Silbergleit R, Steiner T, Suarez JI, Toyoda K, Wang Y, Yamamoto H, Yoon BW; ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network.
Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.
N Engl J Med. 2016 Sep 15;375(11):1033-43. doi: 10.1056/NEJMoa1603460. Epub 2016 Jun 8.
Abstract/Text
BACKGROUND: Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage.
METHODS: We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments.
RESULTS: Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002).
CONCLUSIONS: The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).
Moullaali TJ, Wang X, Martin RH, Shipes VB, Robinson TG, Chalmers J, Suarez JI, Qureshi AI, Palesch YY, Anderson CS.
Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: a preplanned pooled analysis of individual participant data.
Lancet Neurol. 2019 Sep;18(9):857-864. doi: 10.1016/S1474-4422(19)30196-6.
Abstract/Text
BACKGROUND: Uncertainty persists over the effects of blood pressure lowering in acute intracerebral haemorrhage. We aimed to combine individual patient-level data from the two largest randomised controlled trials of blood pressure lowering strategies in patients with acute intracerebral haemorrhage to determine the strength of associations between key measures of systolic blood pressure control and safety and efficacy outcomes.
METHODS: We did a preplanned pooled analysis of individual patient-level data acquired from the main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) and the second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. These trials included adult patients aged 19-99 years with spontaneous (non-traumatic) intracerebral haemorrhage and elevated systolic blood pressure, without a clear indication or contraindication to treatment. Patients were excluded if they had a structural cerebral cause for the intracerebral haemorrhage, had a low score (3-5) on the Glasgow Coma Scale, or required immediate neurosurgery. Our primary analysis assessed the independent associations between three post-randomisation systolic blood pressure summary measures-magnitude of reduction in 1 h, mean achieved systolic blood pressure, and variability in systolic blood pressure between 1 h and 24 h-and the primary outcome of functional status, as defined by the distribution of scores on the modified Rankin Scale at 90 days post-randomisation. We analysed the systolic blood pressure measures as continuous variables using generalised linear mixed models, adjusted for baseline covariables and trial. The primary and safety analyses were done in a modified intention-to-treat population, which only included patients with sufficient data on systolic blood pressure.
FINDINGS: 3829 patients (mean age 63·1 years [SD 12·9], 1429 [37%] women, and 2490 [65%] Asian ethnicity) were randomly assigned in INTERACT2 and ATACH-II, with a median neurological impairment defined by scores on the National Institutes of Health Stroke Scale of 11 (IQR 6-16) and median time from the onset of symptoms of intracerebral haemorrhage to randomisation of 3·6 h (2·7-4·4). We excluded 20 patients with insufficient or no systolic blood pressure data, and we imputed missing systolic blood pressure data in 23 (1%) of the remaining 3809 patients. Overall, the mean magnitude of early systolic blood pressure reduction was 29 mm Hg (SD 22), and subsequent mean systolic blood pressure achieved was 147 mm Hg (15) and variability in systolic blood pressure was 14 mm Hg (8). Achieved systolic blood pressure was continuously associated with functional status (improvement per 10 mm Hg increase adjusted odds ratio [OR] 0·90 [95% CI 0·87-0·94], p<0·0001). Symptomatic hypotension occurred in 28 (1%) patients, renal serious adverse events occurred in 26 (1%) patients, and cardiac serious adverse events occurred in 99 (3%) patients.
INTERPRETATION: Our pooled analyses indicate that achieving early and stable systolic blood pressure seems to be safe and associated with favourable outcomes in patients with acute intracerebral haemorrhage of predominantly mild-to-moderate severity.
FUNDING: None.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M.
How Should We Lower Blood Pressure after Cerebral Hemorrhage? A Systematic Review and Meta-Analysis.
Cerebrovasc Dis. 2017;43(5-6):207-213. doi: 10.1159/000462986. Epub 2017 Feb 28.
Abstract/Text
BACKGROUND: The optimal treatment of high blood pressure (BP) after acute intra-cerebral hemorrhage (ICH) is controversial.
SUMMARY: The aim of the study was to evaluate the safety and efficacy of early intensive vs. conservative BP lowering treatment in patients with ICH. Randomized controlled trials with active and control groups receiving intensive and conservative BP lowering treatments were identified. The following outcomes were assessed: 3-month mortality and combined death or major disability, 24-h hematoma growth, early neurological deterioration, occurrence of hypotension, severe hypotension, and serious treatment-emergent adverse events. Five trials were included involving 4,350 participants, 2,162 and 2,188 for intensive and conservative treatment groups, respectively. The pooled risk ratio of 3-month death or major disability was 0.96 (0.91-1.01) and the weighted mean difference in absolute hematoma growth was -1.53 (95% CI -2.94 to -0.12) mL in the intensive compared to conservative BP-lowering. There were no differences across the treatments in the incidence rates of 3-month mortality, early neurological deterioration, hypotension, and treatment-related adverse effects other than renal events. Key Messages: The early intensive anti-hypertensive treatment was overall safe and reduced the hematoma expansion in patients presenting with acute-onset spontaneous ICH and high BP levels.
© 2017 S. Karger AG, Basel.
Boulouis G, Morotti A, Goldstein JN, Charidimou A.
Intensive blood pressure lowering in patients with acute intracerebral haemorrhage: clinical outcomes and haemorrhage expansion. Systematic review and meta-analysis of randomised trials.
J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):339-345. doi: 10.1136/jnnp-2016-315346. Epub 2017 Feb 18.
Abstract/Text
INTRODUCTION: It is unclear whether intensive lowering of blood pressure (BP) at the acute phase of intracerebral haemorrhage (ICH) is beneficial. We performed a meta-analysis of randomised controlled trials (RCTs) to assess whether intensive BP lowering in patients with acute ICH is safe and effective in improving clinical outcomes.
METHODS: We searched PubMed, EMBASE and the Cochrane databases for relevant RCTs and calculated pooled OR for 3-month mortality (safety outcome) and 3-month death or dependency (modified Rankin Scale (mRs) ≥3;efficacy outcome), in patients with acute ICH randomised to either intensive BP-lowering or standard BP-lowering treatment protocols. We also investigated the association between treatment arm and ICH expansion at 24 hours. Random effects models with DerSimonian-Laird weights were used.
RESULTS: Five eligible studies including 4360 patients with acute ICH were pooled in meta-analysis. The risk of 3-month mortality was similar between patients randomised to intensive BP-lowering treatment and standard BP-lowering treatment (OR: 0.99; 95% CI: 0.82 to 1.20, p=0.909). Intensive BP-lowering treatment showed a (non-significant) trend for an association with lower 3-month death or dependency risk compared with standard treatment (OR: 0.91; 95% CI: 0.80 to 1.02), p=0.106). Intensive BP reduction was associated with a trend for lower risk of significant ICH expansion compared with standard treatment (OR: 0.82; 95% CI: 0.68 to 1.00, p=0.056), especially in larger RCTs.
CONCLUSIONS: For patients with acute ICH similar to those included in RCTs and without contraindication to acute BP treatment, intensive acute BP lowering is safe, but does not seem to provide an incremental clinical benefit in terms of functional outcomes. The effect of intensive BP lowering on significant haematoma expansion at 24 hours warrants further investigation.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) [year]. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Toyoda K, Yoshimura S, Fukuda-Doi M, Qureshi AI, Inoue M, Miwa K, Koga M; ATACH Trial Investigators; SAMURAI Investigators.
Intravenous nicardipine for Japanese patients with acute intracerebral hemorrhage: an individual participant data analysis.
Hypertens Res. 2023 Jan;46(1):75-83. doi: 10.1038/s41440-022-01046-4. Epub 2022 Oct 13.
Abstract/Text
The effects of acute systolic blood pressure levels achieved with continuous intravenous administration of nicardipine for Japanese patients with acute intracerebral hemorrhage on clinical outcomes were determined. A systematic review and individual participant data analysis of articles were performed based on prospective studies involving adults developing hyperacute intracerebral hemorrhage who were treated with intravenous nicardipine. 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 or more from baseline to 24 h computed tomography. Of the total 499 Japanese patients (age 64.9 ± 11.8 years, 183 women, initial BP 203.5 ± 18.3/109.1 ± 17.2 mmHg) studied, death or disability occurred in 35.6%, and hematoma expansion occurred in 15.6%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio 1.25, 95% confidence interval 1.03-1.52 per 10 mmHg) and hematoma expansion (1.49, 1.18-1.87). These odds ratios were relatively high as compared to the reported ones for overall global patients of this individual participant data analysis [1.12 (95% confidence interval 1.00-1.26) and 1.16 (1.02-1.32), respectively]. In conclusion, lower levels of systolic blood pressure by continuous intravenous nicardipine were associated with lower risks of hematoma expansion and 90-day death or disability in Japanese patients with hyperacute intracerebral hemorrhage. The impact of systolic blood pressure lowering on better outcome seemed to be stronger in Japanese patients than the global ones.
© 2022. The Author(s).
Selim M, Foster LD, Moy CS, Xi G, Hill MD, Morgenstern LB, Greenberg SM, James ML, Singh V, Clark WM, Norton C, Palesch YY, Yeatts SD; i-DEF Investigators.
Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial.
Lancet Neurol. 2019 May;18(5):428-438. doi: 10.1016/S1474-4422(19)30069-9. Epub 2019 Mar 18.
Abstract/Text
BACKGROUND: Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.
METHODS: We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.
FINDINGS: We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.
INTERPRETATION: Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile.
FUNDING: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.
Copyright © 2019 Elsevier Ltd. All rights reserved.
日本脳卒中学会・脳卒中合同ガイドライン委員会編：脳卒中治療ガイドライン2015、高血圧性脳内出血の非手術的治療 止血剤の投与、p142、高血圧以外の原因による脳出血の治療 抗血栓療法に伴う脳出血（急性期）、p173-176、妊娠分娩に伴う脳出血、p179-180、協和企画、2015.
Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messé SR, Mitchell PH, Selim M, Tamargo RJ; American Heart Association Stroke Council and Council on Cardiovascular Nursing.
Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
Stroke. 2010 Sep;41(9):2108-29. doi: 10.1161/STR.0b013e3181ec611b. Epub 2010 Jul 22.
Abstract/Text
PURPOSE: The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.
METHODS: A formal literature search of MEDLINE was performed. Data were synthesized with the use of evidence tables. Writing committee members met by teleconference to discuss data-derived recommendations. The American Heart Association Stroke Council's Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statements Oversight Committee and Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years' time.
RESULTS: Evidence-based guidelines are presented for the care of patients presenting with intracerebral hemorrhage. The focus was subdivided into diagnosis, hemostasis, blood pressure management, inpatient and nursing management, preventing medical comorbidities, surgical treatment, outcome prediction, rehabilitation, prevention of recurrence, and future considerations.
CONCLUSIONS: Intracerebral hemorrhage is a serious medical condition for which outcome can be impacted by early, aggressive care. The guidelines offer a framework for goal-directed treatment of the patient with intracerebral hemorrhage.
Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, Christensen H, Ciccone A, Collins R, Czlonkowska A, Dineen RA, Duley L, Egea-Guerrero JJ, England TJ, Krishnan K, Laska AC, Law ZK, Ozturk S, Pocock SJ, Roberts I, Robinson TG, Roffe C, Seiffge D, Scutt P, Thanabalan J, Werring D, Whynes D, Bath PM; TICH-2 Investigators.
Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.
Lancet. 2018 May 26;391(10135):2107-2115. doi: 10.1016/S0140-6736(18)31033-X. Epub 2018 May 16.
Abstract/Text
BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.
METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.
FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).
INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.
FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.
Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Meretoja A, Yassi N, Wu TY, Churilov L, Sibolt G, Jeng JS, Kleinig T, Spratt NJ, Thijs V, Wijeratne T, Cho DY, Shah D, Cloud GC, Phan T, Bladin C, Moey A, Aviv RI, Barras CD, Sharma G, Hsu CY, Ma H, Campbell BCV, Mitchell P, Yan B, Parsons MW, Tiainen M, Curtze S, Strbian D, Tang SC, Harvey J, Levi C, Donnan GA, Davis SM.
Tranexamic acid in patients with intracerebral haemorrhage (STOP-AUST): a multicentre, randomised, placebo-controlled, phase 2 trial.
Lancet Neurol. 2020 Dec;19(12):980-987. doi: 10.1016/S1474-4422(20)30369-0. Epub 2020 Oct 28.
Abstract/Text
BACKGROUND: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage.
METHODS: We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636).
FINDINGS: Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication.
INTERPRETATION: Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified.
FUNDING: National Health and Medical Research Council, Royal Melbourne Hospital Foundation.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators.
Recombinant activated factor VII for acute intracerebral hemorrhage.
N Engl J Med. 2005 Feb 24;352(8):777-85. doi: 10.1056/NEJMoa042991.
Abstract/Text
BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke and is associated with high mortality. Among patients who undergo computed tomography (CT) within three hours after the onset of intracerebral hemorrhage, one third have an increase in the volume of the hematoma related to subsequent bleeding. We sought to determine whether recombinant activated factor VII (rFVIIa) can reduce hematoma growth after intracerebral hemorrhage.
METHODS: We randomly assigned 399 patients with intracerebral hemorrhage diagnosed by CT within three hours after onset to receive placebo (96 patients) or 40 microg of rFVIIa per kilogram of body weight (108 patients), 80 microg per kilogram (92 patients), or 160 microg per kilogram (103 patients) within one hour after the baseline scan. The primary outcome measure was the percent change in the volume of the intracerebral hemorrhage at 24 hours. Clinical outcomes were assessed at 90 days.
RESULTS: Hematoma volume increased more in the placebo group than in the rFVIIa groups. The mean increase was 29 percent in the placebo group, as compared with 16 percent, 14 percent, and 11 percent in the groups given 40 microg, 80 microg, and 160 microg of rFVIIa per kilogram, respectively (P=0.01 for the comparison of the three rFVIIa groups with the placebo group). Growth in the volume of intracerebral hemorrhage was reduced by 3.3 ml, 4.5 ml, and 5.8 ml in the three treatment groups, as compared with that in the placebo group (P=0.01). Sixty-nine percent of placebo-treated patients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), as compared with 55 percent, 49 percent, and 54 percent of the patients who were given 40, 80, and 160 microg of rFVIIa, respectively (P=0.004 for the comparison of the three rFVIIa groups with the placebo group). Mortality at 90 days was 29 percent for patients who received placebo, as compared with 18 percent in the three rFVIIa groups combined (P=0.02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7 percent of rFVIIa-treated patients, as compared with 2 percent of those given placebo (P=0.12).
CONCLUSIONS: Treatment with rFVIIa within four hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days, despite a small increase in the frequency of thromboembolic adverse events.
Copyright 2005 Massachusetts Medical Society.
Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T; FAST Trial Investigators.
Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage.
N Engl J Med. 2008 May 15;358(20):2127-37. doi: 10.1056/NEJMoa0707534.
Abstract/Text
BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes.
METHODS: We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke.
RESULTS: Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 microg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04).
CONCLUSIONS: Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov].).
Copyright 2008 Massachusetts Medical Society.
Gladstone DJ, Aviv RI, Demchuk AM, Hill MD, Thorpe KE, Khoury JC, Sucharew HJ, Al-Ajlan F, Butcher K, Dowlatshahi D, Gubitz G, De Masi S, Hall J, Gregg D, Mamdani M, Shamy M, Swartz RH, Del Campo CM, Cucchiara B, Panagos P, Goldstein JN, Carrozzella J, Jauch EC, Broderick JP, Flaherty ML; SPOTLIGHT and STOP-IT Investigators and Coordinators.
Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials.
JAMA Neurol. 2019 Dec 1;76(12):1493-1501. doi: 10.1001/jamaneurol.2019.2636.
Abstract/Text
IMPORTANCE: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy.
OBJECTIVE: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH.
DESIGN, SETTING, AND PARTICIPANTS: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017.
INTERVENTIONS: Eligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset.
MAIN OUTCOMES AND MEASURES: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial.
RESULTS: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60).
CONCLUSIONS AND RELEVANCE: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.
Al-Shahi Salman R, Frantzias J, Lee RJ, Lyden PD, Battey TWK, Ayres AM, Goldstein JN, Mayer SA, Steiner T, Wang X, Arima H, Hasegawa H, Oishi M, Godoy DA, Masotti L, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Jang DK, Davalos A, Castillo J, Yao X, Claassen J, Volbers B, Kazui S, Okada Y, Fujimoto S, Toyoda K, Li Q, Khoury J, Delgado P, Sabín JÁ, Hernández-Guillamon M, Prats-Sánchez L, Cai C, Kate MP, McCourt R, Venkatasubramanian C, Diringer MN, Ikeda Y, Worthmann H, Ziai WC, d'Esterre CD, Aviv RI, Raab P, Murai Y, Zazulia AR, Butcher KS, Seyedsaadat SM, Grotta JC, Martí-Fàbregas J, Montaner J, Broderick J, Yamamoto H, Staykov D, Connolly ES, Selim M, Leira R, Moon BH, Demchuk AM, Di Napoli M, Fujii Y, Anderson CS, Rosand J; VISTA-ICH Collaboration; ICH Growth Individual Patient Data Meta-analysis Collaborators.
Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.
Lancet Neurol. 2018 Oct;17(10):885-894. doi: 10.1016/S1474-4422(18)30253-9. Epub 2018 Aug 14.
Abstract/Text
BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07).
INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
FUNDING: UK Medical Research Council and British Heart Foundation.
Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, Bendszus M, Bösel J, Christensen H, Dohmen C, Hennerici M, Kollmer J, Stetefeld H, Wartenberg KE, Weimar C, Hacke W, Veltkamp R.
Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial.
Lancet Neurol. 2016 May;15(6):566-73. doi: 10.1016/S1474-4422(16)00110-1. Epub 2016 Apr 11.
Abstract/Text
BACKGROUND: Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH.
METHODS: We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915.
FINDINGS: Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7-197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism).
INTERPRETATION: In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA.
FUNDING: Octapharma.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Christensen H, Cordonnier C, Kõrv J, Lal A, Ovesen C, Purrucker JC, Toni D, Steiner T.
European Stroke Organisation Guideline on Reversal of Oral Anticoagulants in Acute Intracerebral Haemorrhage.
Eur Stroke J. 2019 Dec;4(4):294-306. doi: 10.1177/2396987319849763. Epub 2019 May 14.
Abstract/Text
The aim of the present European Stroke Organisation guideline document is to provide clinically useful evidence-based recommendation on reversal of anticoagulant activity VKA (warfarin, phenprocoumon and acenocoumarol), direct factor II (thrombin) inhibitors (dabigatran etexilat) and factor-Xa-inhibitors (apixaban, edoxaban and rivaroxaban) in patients with acute intracerebral haemorrhage. The guideline was prepared following the Standard Operational Procedure for a European Stroke Organisation guideline document and according to GRADE methodology. As a basic principle, we defined use of oral anticoagulation pragmatically: oral anticoagulation use is assumed by positive medical history unless relevant anticoagulant activity is regarded unlikely by medical history or has been ruled out by laboratory testing. Overall, we strongly recommend using prothrombin complex over no treatment and fresh-frozen plasma in patients on VKA plus vitamin K. We further strongly recommend using idarucizumab in patients on dabigatran and make a recommendation for andexanet alfa in patients on rivaroxaban and apixaban over no treatment. We make a weak recommendation on using high-dose prothrombin complex concentrate (50 IU/kg) for all patients taking edoxaban and for patients on rivaroxaban or apixaban in case andexanet alfa is not available. We recommend against using tranexamic acid and rFVIIa, outside of trials. The presented treatment recommendations aim to normalise coagulation, there is no or only indirect data on effects on functional outcome or mortality, and only little data from randomised controlled trials.
© European Stroke Organisation 2019.
Demchuk AM, Yue P, Zotova E, Nakamya J, Xu L, Milling TJ Jr, Ohara T, Goldstein JN, Middeldorp S, Verhamme P, Lopez-Sendon JL, Conley PB, Curnutte JT, Eikelboom JW, Crowther M, Connolly SJ; ANNEXA-4 Investigators.
Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy.
Stroke. 2021 Jun;52(6):2096-2105. doi: 10.1161/STROKEAHA.120.030565. Epub 2021 May 10.
Abstract/Text
BACKGROUND AND PURPOSE: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH).
METHODS: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days.
RESULTS: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population).
CONCLUSIONS: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.
Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr; ANNEXA-4 Investigators.
Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors.
N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051. Epub 2019 Feb 7.
Abstract/Text
BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).
RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.
CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).
Copyright © 2019 Massachusetts Medical Society.
Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Jüttler E, Grau A, Palm F, Röther J, Michels P, Hamann GF, Hüwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bäzner H, Roth A, Wöhrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Müllges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Günther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dörfler A, Köhrmann M, Schwab S, Huttner HB.
Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage.
JAMA. 2015 Feb 24;313(8):824-36. doi: 10.1001/jama.2015.0846.
Abstract/Text
IMPORTANCE: Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).
OBJECTIVE: To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.
EXPOSURES: Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.
MAIN OUTCOMES AND MEASURES: Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.
RESULTS: Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).
CONCLUSIONS AND RELEVANCE: Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01829581.
Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, Majoie CB, Beenen LF, Marquering HA, Vermeulen M, Nederkoorn PJ, de Haan RJ, Roos YB; PATCH Investigators.
Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.
Lancet. 2016 Jun 25;387(10038):2605-2613. doi: 10.1016/S0140-6736(16)30392-0. Epub 2016 May 10.
Abstract/Text
BACKGROUND: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use.
METHODS: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed.
FINDINGS: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay.
INTERPRETATION: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice.
FUNDING: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Desborough MJR, Al-Shahi Salman R, Stanworth SJ, Havard D, Woodhouse LJ, Craig J, Krishnan K, Brennan PM, Dineen RA, Coats TJ, Hepburn T, Bath PM, Sprigg N; DASH trial investigators.
Desmopressin for patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs (DASH): a UK-based, phase 2, randomised, placebo-controlled, multicentre feasibility trial.
Lancet Neurol. 2023 Jul;22(7):557-567. doi: 10.1016/S1474-4422(23)00157-6.
Abstract/Text
BACKGROUND: The risk of death from spontaneous intracerebral haemorrhage is increased for people taking antiplatelet drugs. We aimed to assess the feasibility of randomising patients on antiplatelet drug therapy with spontaneous intracerebral haemorrhage to desmopressin or placebo to reduce the antiplatelet drug effect.
METHODS: DASH was a phase 2, randomised, placebo-controlled, multicentre feasibility trial. Patients were recruited from ten acute stroke centres in the UK and were eligible if they had an intracerebral haemorrhage with stroke symptom onset within 24 h of randomisation, were aged 18 years or older, and were taking an antiplatelet drug. Participants were randomly assigned (1:1) to a single dose of intravenous desmopressin 20 μg or matching placebo. Treatment allocation was concealed from all staff and patients involved in the trial. The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. The trial was prospectively registered with ISRCTN (reference ISRCTN67038373), and it is closed to recruitment.
FINDINGS: Between April 1, 2019, and March 31, 2022, 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned to receive desmopressin (n=27) or placebo (n=27). The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). The recruitment rate increased after the enrolment period was extended from 12 h to 24 h, but it was then impaired due to the COVID-19 pandemic. Of the 54 participants included in the analysis (mean age 76·4 years [SD 11·3]), most were male (36 [67%]) and White (50 [93%]). 53 (98%) of 54 participants received all of their allocated treatment (one participant assigned desmopressin only received part of the infusion). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 (modified Rankin Scale score >4) occurred in six (22%) of 27 participants in the desmopressin group and ten (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group. The most common adverse events were expansion of the haemorrhagic stroke (four [15%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group) and pneumonia (one [4%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group).
INTERPRETATION: Our results show it is feasible to randomise patients with spontaneous intracerebral haemorrhage who are taking antiplatelet drugs to desmopressin or placebo. Our findings support the need for a definitive trial to determine if desmopressin improves outcomes in patients with intracerebral haemorrhage on antiplatelet drug therapy.
FUNDING: National Institute for Health Research.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Yoshida K, Takahashi JC, Takenobu Y, Suzuki N, Ogawa A, Miyamoto S.
Strokes Associated With Pregnancy and Puerperium: A Nationwide Study by the Japan Stroke Society.
Stroke. 2017 Feb;48(2):276-282. doi: 10.1161/STROKEAHA.116.014406. Epub 2016 Dec 27.
Abstract/Text
BACKGROUND AND PURPOSE: The incidence and cause of strokes associated with pregnancy and the puerperium are still not fully understood. The aim of this study was to characterize pregnancy-related strokes in Japan using a large-scale survey with current imaging techniques.
METHODS: A retrospective analysis was conducted based on clinical chart reviews in 736 stroke teaching hospitals certified by the Japan Stroke Society between 2012 and 2013, using a web-based questionnaire requesting the detailed clinical course without any personally identifying information. The collection rate of this questionnaire was 70.5%, with 151 pregnancy-associated strokes extracted.
RESULTS: Hemorrhagic strokes were observed in 111 cases (73.5%), ischemic strokes in 37 (24.5%), and mixed type in 3 cases (2.0%). The estimated incidence of pregnancy-associated stroke was 10.2 per 100 000 deliveries. Major causes of hemorrhage were aneurysm (19.8%), arteriovenous malformation (17.1%), pregnancy-induced hypertension (11.7%), and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) (8.1%). Preexisting cerebrovascular diseases responsible for hemorrhage were detected in 59 cases (53.1%). Among the ischemic strokes, 28 (75.7%) were arterial and 9 (24.3%) were venous infarctions. The most frequent cause of arterial infarctions was reversible cerebral vasoconstriction syndrome. Hemorrhagic stroke showed much poorer prognosis than ischemic stroke.
CONCLUSIONS: The incidence of pregnancy-associated stroke in Japan did not seem higher than that in other Asian and Western countries. The proportion of hemorrhagic stroke among Japanese women was much higher than that in white women. Preexisting cerebrovascular diseases and reversible cerebral vasoconstriction syndrome play a key role in hemorrhagic and ischemic stroke, respectively.
© 2016 American Heart Association, Inc.
Takahashi JC, Iihara K, Ishii A, Watanabe E, Ikeda T, Miyamoto S.
Pregnancy-associated intracranial hemorrhage: results of a survey of neurosurgical institutes across Japan.
J Stroke Cerebrovasc Dis. 2014 Feb;23(2):e65-71. doi: 10.1016/j.jstrokecerebrovasdis.2013.08.017. Epub 2013 Nov 13.
Abstract/Text
BACKGROUND: Pregnancy-associated hemorrhagic stroke is considered a serious complication. Although coagulopathy, pregnancy-induced hypertension, eclampsia, and other systemic complications have been emphasized, pre-existing cerebrovascular diseases (CVDs) have not been fully analyzed. To clarify the role of these vascular lesions more in detail, the Japan Neurosurgical Society conducted a nationwide survey on all the neurosurgical institutes across Japan.
METHODS: This 2-year survey focused on hemorrhagic stroke occurring in pregnancy, delivery, and puerperium. Clinical data based on retrospective chart review were obtained through a questionnaire and analyzed according to the time of onset, underlying CVDs, obstetric systemic complications, therapeutic approaches, and maternal and neonatal prognoses.
RESULTS: The survey identified 97 hemorrhagic strokes that were associated with pregnancy. Baseline CVDs responsible for hemorrhage were detected in 54 cases (55.7%), among which 47 lesions (87.0%) had been undiagnosed before stroke onset. The detection rate of baseline CVDs before the 32nd week of gestation was significantly higher than that after the 32nd week (90.0% versus 53.3%, P = .0017). Arteriovenous malformations (AVMs) were the most frequent CVDs causing intracranial hemorrhage, occurring at 1.8 times the frequency of ruptured aneurysms during pregnancy. Poor outcomes, including 10 deaths, were seen in 36.1% of the cases despite aggressive treatment.
CONCLUSION: Pregnancy-associated hemorrhagic strokes frequently concealed baseline CVDs, especially when they occurred before the 32nd week of gestation. AVMs were the predominant bleeding source. For appropriate treatment, therefore, close examination for cerebral vascular lesions is essential when a pregnancy-associated hemorrhagic stroke is encountered.
Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Haapaniemi E, Strbian D, Rossi C, Putaala J, Sipi T, Mustanoja S, Sairanen T, Curtze S, Satopää J, Roivainen R, Kaste M, Cordonnier C, Tatlisumak T, Meretoja A.
The CAVE score for predicting late seizures after intracerebral hemorrhage.
Stroke. 2014 Jul;45(7):1971-6. doi: 10.1161/STROKEAHA.114.004686. Epub 2014 May 29.
Abstract/Text
BACKGROUND AND PURPOSE: Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients.
METHODS: Retrospective analysis of the observational Helsinki ICH Study (n=993; median follow-up, 2.7 years) and the Lille Prognosis of InTra-Cerebral Hemorrhage (n=325; 2.2 years) cohorts of consecutive ICH patients admitted between 2004 and 2010. Helsinki ICH Study patients' province-wide electronic records were evaluated for early seizures occurring within 7 days of ICH and among 7-day survivors (n=764) for late seizures (LSs) occurring >7 days from ICH. A Cox regression model estimating risk of LSs was used to derive a prognostic score, validated in the Prognosis of InTra-Cerebral Hemorrhage cohort.
RESULTS: Of the Helsinki ICH Study patients, 109 (11.0%) had early seizures within 7 days of ICH. Among the 7-day survivors, 70 (9.2%) patients developed LSs. The cumulative risk of LSs was 7.1%, 10.0%, 10.2%, 11.0%, and 11.8% at 1 to 5 years after ICH, respectively. We created the CAVE score (0-4 points) to estimate the risk of LSs, with 1 point for each of cortical involvement, age<65 years, volume>10 mL, and early seizures within 7 days of ICH. The risk of LSs was 0.6%, 3.6%, 9.8%, 34.8%, and 46.2% for CAVE scores 0 to 4, respectively. The c-statistic was 0.81 (0.76-0.86) and 0.69 (0.59-0.78) in the validation cohort.
CONCLUSIONS: One in 10 patients will develop seizures after ICH. The risk of this adverse outcome can be estimated by a simple score based on baseline variables.
© 2014 American Heart Association, Inc.
Peter-Derex L, Philippeau F, Garnier P, André-Obadia N, Boulogne S, Catenoix H, Convers P, Mazzola L, Gouttard M, Esteban M, Fontaine J, Mechtouff L, Ong E, Cho TH, Nighoghossian N, Perreton N, Termoz A, Haesebaert J, Schott AM, Rabilloud M, Pivot C, Dhelens C, Filip A, Berthezène Y, Rheims S, Boutitie F, Derex L.
Safety and efficacy of prophylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Neurol. 2022 Sep;21(9):781-791. doi: 10.1016/S1474-4422(22)00235-6.
Abstract/Text
BACKGROUND: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage.
METHODS: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding.
FINDINGS: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group.
INTERPRETATION: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage.
FUNDING: French Ministry of Health.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Fukuhara M, Arima H, Ninomiya T, Hata J, Yonemoto K, Doi Y, Hirakawa Y, Matsumura K, Kitazono T, Kiyohara Y.
Impact of lower range of prehypertension on cardiovascular events in a general population: the Hisayama Study.
J Hypertens. 2012 May;30(5):893-900. doi: 10.1097/HJH.0b013e328351d380.
Abstract/Text
OBJECTIVES: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) defined blood pressure (BP) levels of 120-139/80-89 mmHg as prehypertension. The objective of the present analysis was to examine the impact of prehypertension and its population-attributable fraction for development of cardiovascular events in a general Japanese population.
METHODS: Two thousand, six hundred and thirty-four residents of the town of Hisayama aged at least 40 years without cardiovascular disease were followed up for 19 years. BP categories were defined using JNC7, and prehypertension was divided into the lower (120-129/80-84 mmHg) and higher ranges (130-139/85-89 mmHg). During the follow-up period, 449 participants developed cardiovascular disease (305 strokes and 187 coronary heart diseases).
RESULTS: The frequencies of normal BP, prehypertension, and stages 1 and 2 hypertension were 24.9, 37.7, 23.8, and 13.6%, respectively. The age and sex-adjusted incidence of cardiovascular disease rose progressively with elevation of BP levels (P < 0.001 for trend). The risks of cardiovascular disease in lower and higher ranges of prehypertension were 58% [95% confidence interval (CI) 11-126%] and 70% (95% CI 18-144%) higher than normal BP even after controlling for other cardiovascular risk factors. The population-attributable fraction of prehypertension was 13.2%, which was similar to those of stages 1 and 2 hypertension.
CONCLUSIONS: The risks of cardiovascular disease increased significantly from the lower range of prehypertension in a general Japanese population. Approximately one-third of excess cardiovascular events attributable to elevated BP levels were estimated to occur among individuals with prehypertension.
Takashima N, Ohkubo T, Miura K, Okamura T, Murakami Y, Fujiyoshi A, Nagasawa SY, Kadota A, Kita Y, Miyagawa N, Hisamatsu T, Hayakawa T, Okayama A, Ueshima H; NIPPON DATA80 Research Group.
Long-term risk of BP values above normal for cardiovascular mortality: a 24-year observation of Japanese aged 30 to 92 years.
J Hypertens. 2012 Dec;30(12):2299-306. doi: 10.1097/HJH.0b013e328359a9f7.
Abstract/Text
OBJECTIVE: In Western populations, blood pressure (BP) measured at baseline has been reported to predict long-term (over 20 years) risk of mortality from cardiovascular diseases (CVDs). However, corresponding evidence is scarce in Asia where stroke is dominant. We investigated the association between baseline BP and 24-year mortality risk due to CVD, in a representative Japanese general population.
METHODS: We followed up a nationwide sample of 8592 Japanese, aged 30 years or above without a history of CVD and antihypertensive medication at baseline, for 24 years. Hazard ratios for CVD mortality in BP categories defined according to JCN7 criteria were estimated using Cox model adjusted for potential confounding factors with normal BP treated as the reference category.
RESULTS: We observed 689 CVD deaths. Hazard ratios for CVD mortality were progressively and significantly increased from the category of prehypertension. Population-attributable fraction (PAF) demonstrated that 43 and 48% of CVD and stroke deaths were explained by non-normal BP at baseline. Hazard ratios and PAF were remarkably higher in younger participants (aged 30-59 years) than those in the elderly (aged 60 years or above). Particularly, in younger men, 81% of CVD deaths were explained by non-normal BP. In sensitivity analysis, participants with antihypertensive medication showed the highest hazard ratio for CVD morality compared with the other categories.
CONCLUSIONS: BP levels above normal at baseline retained significant relative and absolute risks of CVD and stroke mortality during 24 years. Long-lasting burden of non-normal BP particularly in younger individuals suggests the importance of primary prevention of high BP from younger generation.
Arima H, Tanizaki Y, Yonemoto K, Doi Y, Ninomiya T, Hata J, Fukuhara M, Matsumura K, Iida M, Kiyohara Y.
Impact of blood pressure levels on different types of stroke: the Hisayama study.
J Hypertens. 2009 Dec;27(12):2437-43. doi: 10.1097/HJH.0b013e328330e882.
Abstract/Text
OBJECTIVE: Clinical uncertainty remains whether the blood pressure classification and risk stratifications recommended by the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009) are useful in predicting the risks of stroke and its subtypes in the general Japanese population.
METHODS: A total of 1621 stroke-free residents of a Japanese community aged at least 40 years were followed up for 32 years. Outcomes were total and cause-specific stroke (lacunar infarction, atherothrombotic infarction, cardioembolic infarction, cerebral haemorrhage and subarachnoid haemorrhage). Incidence was calculated by the pooling of repeated observations method.
RESULTS: The age-adjusted incidence of total stroke rose progressively with higher blood pressure levels in both sexes (both P for trend <0.0001). A similar pattern was observed for lacunar infarction in both sexes and for cerebral haemorrhage in men: the differences were significant between optimal blood pressure and grades 1-3 hypertension (all P < 0.05). The age-adjusted incidence of atherothrombotic infarction in either sex and that of cardioembolic infarction and subarachnoid haemorrhage in women significantly increased in grade 3 hypertension (all P < 0.05). These associations remained substantially unchanged even after adjustment for other risk factors. In regard to risk stratification, the age-adjusted incidence of stroke significantly increased with the level of risk in both sexes.
CONCLUSION: Our findings suggest that the blood pressure classification and risk stratifications recommended by the JSH 2009 guidelines are useful in predicting the risk of stroke in a general Japanese population, but the magnitude and patterns of the impact of blood pressure categories are different among stroke subtypes.
Law MR, Morris JK, Wald NJ.
Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies.
BMJ. 2009 May 19;338:b1665. doi: 10.1136/bmj.b1665. Epub 2009 May 19.
Abstract/Text
OBJECTIVES: To determine the quantitative efficacy of different classes of blood pressure lowering drugs in preventing coronary heart disease (CHD) and stroke, and who should receive treatment.
DESIGN: Meta-analysis. Data source Medline (1966-2007).
STUDY SELECTION: Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) ("blood pressure difference trials"), and 46 trials compared drugs ("drug comparison trials"). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people.
PARTICIPANTS: 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke.
RESULTS: In the blood pressure difference trials beta blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs. The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of beta blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the meta-analyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective beta blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%).
CONCLUSIONS: With the exception of the extra protective effect of beta blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.
Biffi A, Anderson CD, Battey TW, Ayres AM, Greenberg SM, Viswanathan A, Rosand J.
Association Between Blood Pressure Control and Risk of Recurrent Intracerebral Hemorrhage.
JAMA. 2015 Sep 1;314(9):904-12. doi: 10.1001/jama.2015.10082.
Abstract/Text
IMPORTANCE: Intracerebral hemorrhage (ICH) is the most severe form of stroke. Survivors are at high risk of recurrence, death, and worsening functional disability.
OBJECTIVE: To investigate the association between blood pressure (BP) after index ICH and risk of recurrent ICH.
DESIGN, SETTING, AND PARTICIPANTS: Single-site, tertiary care referral center observational study of 1145 of 2197 consecutive patients with ICH presenting from July 1994 to December 2013. A total of 1145 patients with ICH survived at least 90 days and were followed up through December 2013 (median follow-up of 36.8 months [minimum, 9.8 months]).
EXPOSURES: Blood pressure measurements at 3, 6, 9, and 12 months, and every 6 months thereafter, obtained from medical personnel (inpatient hospital or outpatient clinic medical or nursing staff) or via patient self-report. Exposure was characterized in 3 ways: (1) recorded systolic and diastolic measurements; (2) classification as adequate or inadequate BP control based on American Heart Association/American Stroke Association recommendations; and (3) stage of hypertension based on Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 criteria.
MAIN OUTCOMES AND MEASURES: Recurrent ICH and its location within the brain (lobar vs nonlobar).
RESULTS: There were 102 recurrent ICH events among 505 survivors of lobar ICH and 44 recurrent ICH events among 640 survivors of nonlobar ICH. During follow-up adequate BP control was achieved on at least 1 measurement by 625 patients (54.6% of total [range, 49.2%-58.7%]) and consistently (ie, at all available time points) by 495 patients (43.2% of total [range, 34.5%-51.0%]). The event rate for lobar ICH was 84 per 1000 person-years among patients with inadequate BP control compared with 49 per 1000 person-years among patients with adequate BP control. For nonlobar ICH the event rate was 52 per 1000 person-years with inadequate BP control compared with 27 per 1000 person-years for patients with adequate BP control. In analyses modeling BP control as a time-varying variable, inadequate BP control was associated with higher risk of recurrence of both lobar ICH (hazard ratio [HR], 3.53 [95% CI, 1.65-7.54]) and nonlobar ICH (HR, 4.23 [95% CI, 1.02-17.52]). Systolic BP during follow-up was associated with increased risk of both lobar ICH recurrence (HR, 1.33 per 10-mm Hg increase [95% CI, 1.02-1.76]) and nonlobar ICH recurrence (HR, 1.54 [95% CI, 1.03-2.30]). Diastolic BP was associated with increased risk of nonlobar ICH recurrence (HR, 1.21 per 10-mm Hg increase [95% CI, 1.01-1.47]) but not with lobar ICH recurrence (HR, 1.36 [95% CI, 0.90-2.10]).
CONCLUSIONS AND RELEVANCE: In this observational single-center cohort study of ICH survivors, reported BP measurements suggesting inadequate BP control during follow-up were associated with higher risk of both lobar and nonlobar ICH recurrence. These data suggest that randomized clinical trials are needed to address the benefits and risks of stricter BP control in ICH survivors.
McKinney JS, Kostis WJ.
Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials.
Stroke. 2012 Aug;43(8):2149-56. doi: 10.1161/STROKEAHA.112.655894. Epub 2012 May 15.
Abstract/Text
BACKGROUND AND PURPOSE: Statin therapy decreases the risk of ischemic stroke. An increased risk of intracerebral hemorrhage (ICH) has been observed in some studies. To investigate this issue, we performed a meta-analysis of randomized controlled trials using statins that reported ICH.
METHODS: We performed a literature search of Medline, Web of Science, and The Cochrane Library through January 25, 2012, and identified additional randomized controlled trials by reviewing reference lists of retrieved studies and prior meta-analyses. All randomized controlled trials of statin therapy that reported ICH or hemorrhagic stroke were included. The primary outcome variable was ICH. Thirty-one randomized controlled trials were included. All analyses used random effects models and heterogeneity was not observed in any of the analyses.
RESULTS: A total of 91,588 subjects were included in the active group and 91,215 in the control group. There was no significant difference in incidence of ICH observed in the active treatment group versus control (OR, 1.08; 95% CI, 0.88-1.32; P=0.47). ICH risk was not related to the degree of low-density lipoprotein reduction or achieved low-density lipoprotein cholesterol. Total stroke (OR, 0.84; 95% CI, 0.78-0.91; P<0.0001) and all-cause mortality (OR, 0.92; CI, 0.87-0.96; P=0.0007) were significantly reduced in the active therapy group. There was no evidence of publication bias.
CONCLUSIONS: Active statin therapy was not associated with significant increase in ICH in this meta-analysis of 31 randomized controlled trials of statin therapy. A significant reduction in all stroke and all-cause mortality was observed with statin therapy.
Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE, Donner A, Mamdani M, Douketis JD, Arima H, Chalmers J, MacMahon S, Tirschwell DL, Psaty BM, Bushnell CD, Aguilar MI, Capampangan DJ, Werring DJ, De Rango P, Viswanathan A, Danchin N, Cheng CL, Yang YH, Verdel BM, Lai MS, Kennedy J, Uchiyama S, Yamaguchi T, Ikeda Y, Mrkobrada M.
Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis.
Circulation. 2011 Nov 15;124(20):2233-42. doi: 10.1161/CIRCULATIONAHA.111.055269. Epub 2011 Oct 17.
Abstract/Text
BACKGROUND: A recent large, randomized trial suggested that statins may increase the risk of intracerebral hemorrhage. Accordingly, we systematically reviewed the association of statins with intracerebral hemorrhage in randomized and observational data.
METHODS AND RESULTS: We screened 17 electronic bibliographic databases to identify eligible studies and consulted with experts in the field. We used DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. Randomized trials, cohort studies, and case-control studies were analyzed separately. Only adjusted risk estimates were used for pooling observational data. We included published and unpublished data from 23 randomized trials and 19 observational studies. The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10; 95% confidence interval, 0.86-1.41), cohort studies (risk ratio, 0.94; 95% confidence interval, 0.81-1.10), or case-control studies (risk ratio, 0.60; 95% confidence interval, 0.41-0.88). Substantial statistical heterogeneity was evident for the case-control studies (I(2)=66%, P=0.01), but not for the cohort studies (I(2)=0%, P=0.48) or randomized trials (I(2)=30%, P=0.09). Sensitivity analyses by study design features, patient characteristics, or magnitude of cholesterol lowering did not materially alter the results.
CONCLUSIONS: We found no evidence that statins were associated with intracerebral hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.
Wang X, Dong Y, Qi X, Huang C, Hou L.
Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis.
Stroke. 2013 Jul;44(7):1833-9. doi: 10.1161/STROKEAHA.113.001326. Epub 2013 May 23.
Abstract/Text
BACKGROUND AND PURPOSE: Cholesterol levels are inconsistently associated with the risk of hemorrhagic stroke. The purpose of this study is to assess their relationships using a meta-analytic approach.
METHODS: We searched PubMed and Embase for pertinent articles published in English. Only prospective studies that reported effect estimates with 95% confidential intervals (CIs) of hemorrhagic stroke for ≥3 categories of cholesterol levels, for high and low comparison, or for per 1 mmol/L increment of cholesterol concentrations were included. We used the random-effects model to pool the study-specific results.
RESULTS: Twenty-three prospective studies were included, totaling 1 430 141 participants with 7960 (5.6%) hemorrhagic strokes. In high versus low analysis, the summary relative risk of hemorrhagic stroke was 0.69 (95% CI, 0.59-0.81) for total cholesterol, 0.98 (95% CI, 0.80-1.19) for high-density lipoprotein cholesterol, and 0.62 (95% CI, 0.41-0.92) for low-density lipoprotein cholesterol. In dose-response analysis, the summary relative risk of hemorrhagic stroke for 1 mmol/L increment of total cholesterol was 0.85 (95% CI, 0.80-0.91), for high-density lipoprotein cholesterol was 1.11 (95% CI, 0.99-1.25), and for low-density lipoprotein cholesterol was 0.90 (95% CI, 0.77-1.05). The pooled relative risk for intracerebral hemorrhage was 1.17 (95% CI, 1.02-1.35) for high-density lipoprotein cholesterol.
CONCLUSIONS: Total cholesterol level is inversely associated with risk of hemorrhagic stroke. Higher level of low-density lipoprotein cholesterol seems to be associated with lower risk of hemorrhagic stroke. High-density lipoprotein cholesterol level seems to be positively associated with risk of intracerebral hemorrhage.
Emerging Risk Factors Collaboration; Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J.
Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
Lancet. 2010 Jun 26;375(9733):2215-22. doi: 10.1016/S0140-6736(10)60484-9.
Abstract/Text
BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances.
METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease.
FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors.
INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease.
FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.
Copyright 2010 Elsevier Ltd. All rights reserved.
Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N.
Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
Lancet. 2009 May 23;373(9677):1765-72. doi: 10.1016/S0140-6736(09)60697-8.
Abstract/Text
BACKGROUND: Whether intensive control of glucose reduces macrovascular events and all-cause mortality in individuals with type 2 diabetes mellitus is unclear. We undertook a meta-analysis of randomised controlled trials to determine whether intensive treatment is beneficial.
METHODS: We selected five prospective randomised controlled trials of 33 040 participants to assess the effect of an intensive glucose-lowering regimen on death and cardiovascular outcomes compared with a standard regimen. We gathered information about events of non-fatal myocardial infarction, coronary heart disease (fatal and non-fatal myocardial infarction), stroke, and all-cause mortality, and did a random-effects meta-analysis to obtain summary effect estimates for the clinical outcomes with use of odds ratios calculated from the raw data of every trial. Statistical heterogeneity across trials was assessed with the chi(2) and I(2) statistics.
FINDINGS: The five trials provided information on 1497 events of non-fatal myocardial infarction, 2318 of coronary heart disease, 1127 of stroke, and 2892 of all-cause mortality during about 163 000 person-years of follow-up. The mean haemoglobin A(1c) concentration (HbA(1c)) was 0.9% lower for participants given intensive treatment than for those given standard treatment. Intensive glycaemic control resulted in a 17% reduction in events of non-fatal myocardial infarction (odds ratio 0.83, 95% CI 0.75-0.93), and a 15% reduction in events of coronary heart disease (0.85, 0.77-0.93). Intensive glycaemic control had no significant effect on events of stroke (0.93, 0.81-1.06) or all-cause mortality (1.02, 0.87-1.19).
INTERPRETATION: Overall, intensive compared with standard glycaemic control significantly reduces coronary events without an increased risk of death. However, the optimum mechanism, speed, and extent of HbA(1c) reduction might be different in differing populations.
FUNDING: None.
Yatsuya H, Toyoshima H, Yamagishi K, Tamakoshi K, Taguri M, Harada A, Ohashi Y, Kita Y, Naito Y, Yamada M, Tanabe N, Iso H, Ueshima H; Japan Arteriosclerosis Longitudinal Study (JALS) group.
Body mass index and risk of stroke and myocardial infarction in a relatively lean population: meta-analysis of 16 Japanese cohorts using individual data.
Circ Cardiovasc Qual Outcomes. 2010 Sep;3(5):498-505. doi: 10.1161/CIRCOUTCOMES.109.908517. Epub 2010 Aug 10.
Abstract/Text
BACKGROUND: The association of overweight/obesity with the incidence of cardiovascular diseases, especially stroke, has not been comprehensively examined in relatively lean populations in which stroke is more prevalent than coronary heart disease.
METHODS AND RESULTS: Pooled individual data from 16 Japanese cohorts comprising 45 235 participants ages 40 to 89 years without previous history of cardiovascular disease were studied. During follow-up, 1113 incident strokes and 190 myocardial infarctions were identified. At baseline, mean ages of men and women were 55.4 and 56.5 years and mean body mass indices (BMI) were 23.0 and 23.4 kg/m(2), respectively. Compared with those with BMI <21.0, incidence rates of cerebral infarction in subjects with BMI ≥ 27.5 were significantly elevated in both men (hazard ratio, 1.81; 95% confidence interval [CI], 1.28 to 2.56) and women (hazard ratio, 1.65; 95% CI, 1.23 to 2.21), adjusted for age, smoking, and drinking habit. Incidence of cerebral hemorrhage was also associated positively with BMI in both men (hazard ratio, 2.51; 95% CI, 1.21 to 5.20) and women (hazard ratio, 1.98; 95% CI, 1.12 to 3.52). Adjustment for systolic blood pressure, a mediating factor, significantly attenuated most BMI association with stroke in both sexes. For myocardial infarction, the hazard ratio was 3.16 (95% CI, 1.66 to 6.01) for BMI 27.5 or greater versus less than 21.0 only in men, which appeared partly mediated by total cholesterol and SBP.
CONCLUSIONS: Overweight/obesity was associated with an increased risk of cerebral infarction and hemorrhage in men and women and myocardial infarction in men. Weight control may have the potential to prevent both stroke and myocardial infarction in Japan.
Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J.
Alcohol consumption and risk of stroke: a meta-analysis.
JAMA. 2003 Feb 5;289(5):579-88. doi: 10.1001/jama.289.5.579.
Abstract/Text
CONTEXT: Observational studies suggest that heavy alcohol consumption may increase the risk of stroke while moderate consumption may decrease the risk.
OBJECTIVE: To examine the association between alcohol consumption and relative risk of stroke.
DATA SOURCES: Studies published in English-language journals were retrieved by searching MEDLINE (1966-April 2002) using Medical Subject Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke; Dissertation Abstracts Online using the keywords stroke and alcohol; and bibliographies of retrieved articles.
STUDY SELECTION: From 122 relevant retrieved reports, 35 observational studies (cohort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; the relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and abstainers served as the reference group.
DATA EXTRACTION: Information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, and risk estimates was abstracted independently by 3 investigators using a standardized protocol.
DATA SYNTHESIS: A random-effects model and meta-regression analysis were used to pool data from individual studies. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval [CI], 1.39-1.93); ischemic stroke, 1.69 (95% CI, 1.34-2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48-3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke.
CONCLUSIONS: These results indicate that heavy alcohol consumption increases the relative risk of stroke while light or moderate alcohol consumption may be protective against total and ischemic stroke.
Iso H, Date C, Yamamoto A, Toyoshima H, Watanabe Y, Kikuchi S, Koizumi A, Wada Y, Kondo T, Inaba Y, Tamakoshi A; JACC Study Group.
Smoking cessation and mortality from cardiovascular disease among Japanese men and women: the JACC Study.
Am J Epidemiol. 2005 Jan 15;161(2):170-9. doi: 10.1093/aje/kwi027.
Abstract/Text
To examine the effect of smoking cessation on cardiovascular disease mortality in Asians, the authors conducted a 10-year prospective cohort study of 94,683 Japanese (41,782 men and 52,901 women) aged 40-79 years who were part of the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). During 941,043 person-years of follow-up between 1989-1990 and 1999, 698 deaths from stroke, 348 from coronary heart disease, and 1,555 from total cardiovascular disease occurred in men and 550, 199, and 1,155, respectively, in women. For men, the multivariate relative risks for current smokers compared with never smokers were 1.39 (95% confidence interval (CI): 1.13, 1.70) for stroke, 2.51 (95% CI: 1.79, 3.51) for coronary heart disease, and 1.60 (95% CI: 1.39, 1.84) for total cardiovascular disease. The respective relative risks for women were 1.65 (95% CI: 1.21, 2.25), 3.35 (95% CI: 2.23, 5.02), and 2.06 (95% CI: 1.69, 2.51), with larger excess risks for persons aged 40-64 years than for older persons. The risk decline after smoking cessation occurred for coronary heart disease and total cardiovascular disease within 2 years and for total stroke after 2-4 years. For each endpoint and in both age subgroups of 40-64 and 65-79 years, most of the benefit of cessation occurred after 10-14 years following cessation. Findings imply the importance of smoking cessation at any age to prevent cardiovascular disease in Japanese.
Gouya G, Arrich J, Wolzt M, Huber K, Verheugt FW, Gurbel PA, Pirker-Kees A, Siller-Matula JM.
Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis.
Stroke. 2014 Feb;45(2):492-503. doi: 10.1161/STROKEAHA.113.002590. Epub 2013 Dec 24.
Abstract/Text
BACKGROUND AND PURPOSE: The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis.
METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science. Twenty-two studies comprising 173 371 patients were included.
RESULTS: In the overall population, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in comparison to aspirin monotherapy reduced the relative risk of total stroke by 20% (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.73-0.88; P<0.0001; I(2)=28%) and of ischemic stroke or transient ischemic attack by 23% (RR, 0.77; 95% CI, 0.69-0.85; P<0.0001; I(2)=18%) without increasing the risk of intracranial hemorrhage. In the secondary prevention cohort, DAPT with aspirin and clopidogrel also reduced the relative risk of total stroke by 24% as compared with aspirin alone (RR, 0.76; 95% CI, 0.68-0.86; P<0.0001; I(2)=0%). DAPT with prasugrel or ticagrelor and aspirin versus DAPT with clopidogrel and aspirin was not associated with a risk reduction of stroke.
CONCLUSIONS: DAPT with clopidogrel and aspirin compared with aspirin effectively reduces the risk of total and ischemic stroke in the overall cohort consisting of patients with cardiovascular disease without increase in intracranial hemorrhage, as well as decreases the risk of a recurrent total stroke in patients with a previous stroke/transient ischemic attack. Our meta-analysis suggests that DAPT including low-dose aspirin (75-100 mg) and clopidogrel (75 mg) should be further investigated as a strategy to reduce recurrent strokes.
CLINICAL TRIAL REGISTRATION URL: http://www.crd.york.ac.uk/prospero. Unique identifier: CRD42011001596.
SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM.
Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial.
Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S0140-6736(13)60852-1. Epub 2013 May 29.
Abstract/Text
BACKGROUND: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke.
METHODS: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306.
FINDINGS: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent.
INTERPRETATION: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial.
FUNDING: National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).
Copyright © 2013 Elsevier Ltd. All rights reserved.
Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M.
Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis.
Circulation. 2015 Jul 21;132(3):194-204. doi: 10.1161/CIRCULATIONAHA.114.013267. Epub 2015 May 20.
Abstract/Text
BACKGROUND: Evidence regarding the use of direct oral anticoagulants (DOACs) in the elderly, particularly bleeding risks, is unclear despite the presence of greater comorbidities, polypharmacy, and altered pharmacokinetics in this age group.
METHODS AND RESULTS: We performed a systematic review and meta-analysis of randomized trials of DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban) for efficacy and bleeding outcomes in comparison with vitamin K antagonists (VKA) in elderly participants (aged ≥75 years) treated for acute venous thromboembolism or stroke prevention in atrial fibrillation. Nineteen studies were eligible for inclusion, but only 11 reported data specifically for elderly participants. The efficacy in managing thrombotic risks for each DOAC was similar or superior to VKA in elderly patients. A nonsignificantly higher risk of major bleeding than with VKA was observed with dabigatran 150 mg (odds ratio, 1.18; 95% confidence interval, 0.97-1.44) but not with the 110-mg dose. Significantly higher gastrointestinal bleeding risks with dabigatran 150 mg (1.78, 1.35-2.35) and dabigatran 110 mg (1.40, 1.04-1.90) and lower intracranial bleeding risks than VKA for dabigatran 150 mg (0.43, 0.26-0.72) and dabigatran 110 mg (0.36, 0.22-0.61) were also observed. A significantly lower major bleeding risk in comparison with VKA was observed for apixaban (0.63, 0.51-0.77), edoxaban 60 mg (0.81, 0.67-0.98), and 30 mg (0.46, 0.38-0.57), whereas rivaroxaban showed similar risks.
CONCLUSIONS: DOACs demonstrated at least equal efficacy to VKA in managing thrombotic risks in the elderly, but bleeding patterns were distinct. In particular, dabigatran was associated with a higher risk of gastrointestinal bleeding than VKA. Insufficient published data for apixaban, edoxaban, and rivaroxaban indicate that further work is needed to clarify the bleeding risks of these DOACs in the elderly.
SYSTEMATIC REVIEW REGISTRATION: http://www.crd.york.ac.uk/PROSPERO. Unique identifier: PROSPERO CRD42014007171/.
© 2015 American Heart Association, Inc.
Caldeira D, Barra M, Pinto FJ, Ferreira JJ, Costa J.
Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis.
J Neurol. 2015 Mar;262(3):516-22. doi: 10.1007/s00415-014-7462-0. Epub 2014 Aug 14.
Abstract/Text
The new oral anticoagulants/non-vitamin K antagonists oral anticoagulants (NOACs) have recently reached the market and less is known about their safety in comparison to their efficacy. Therefore, we aimed to evaluate intracranial hemorrhage (ICH) risk with NOACs, the most feared adverse event of anticoagulation treatment. This is a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) comparing NOACs versus any control and reporting ICH events. Studies were searched through Medline and Cochrane Library (April 2014). Reviews and reference lists were also screened. Random effects' meta-analysis was performed to derive pooled estimates expressed as relative risk (RR) and 95 % CI. Number needed to treat/harm (NNT/NNH) taking into account the baseline risk was also calculated. Heterogeneity was evaluated with I (2) test. 18 RCTs evaluating 148,149 patients were included. NOAC significantly reduced ICH risk compared to vitamin K antagonists (VKA) (RR 0.44; 95 % CI 0.36-0.54; I (2) = 37 %; NNT: 137 during 2 years) and to sequential treatment with low molecular weight heparin and VKA (RR 0.28; 95 % CI 0.12-0.65; I (2) = 0 %; NNT: 463 patients during 7 months). Compared to placebo, NOACs were associated with an increased ICH risk (RR 3.31; 95 % CI 1.59-6.90; I (2) = 0 %; NNH: 433 during 1 year). Results were similar for the different NOAC drugs and across the different clinical conditions. In patients requiring anticoagulation treatment, the risk of ICH is about half with the NOACs in comparison to standard antithrombotic treatment. This safer profile found in RCTs should be confirmed in real-world database studies.
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S0140-6736(13)62343-0. Epub 2013 Dec 4.
Abstract/Text
BACKGROUND: Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.
METHODS: We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.
FINDINGS: 42,411 participants received a new oral anticoagulant and 29,272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73-0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38-0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85-0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39-0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01-1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59-0·81 vs 0·93, 0·76-1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84-1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43-1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02-1·60; p=0·045).
INTERPRETATION: This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk-benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.
FUNDING: None.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Murthy SB, Zhang C, Diaz I, Levitan EB, Koton S, Bartz TM, DeRosa JT, Strobino K, Colantonio LD, Iadecola C, Safford MM, Howard VJ, Longstreth WT Jr, Gottesman RF, Sacco RL, Elkind MSV, Howard G, Kamel H.
Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies.
JAMA Neurol. 2021 Jul 1;78(7):809-816. doi: 10.1001/jamaneurol.2021.0925.
Abstract/Text
IMPORTANCE: Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown.
OBJECTIVE: To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction.
DESIGN, SETTING, AND PARTICIPANTS: An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020.
EXPOSURE: Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria.
MAIN OUTCOMES AND MEASURES: The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications.
RESULTS: Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1).
CONCLUSIONS AND RELEVANCE: This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.
Pennlert J, Overholser R, Asplund K, Carlberg B, Van Rompaye B, Wiklund PG, Eriksson M.
Optimal Timing of Anticoagulant Treatment After Intracerebral Hemorrhage in Patients With Atrial Fibrillation.
Stroke. 2017 Feb;48(2):314-320. doi: 10.1161/STROKEAHA.116.014643. Epub 2016 Dec 20.
Abstract/Text
BACKGROUND AND PURPOSE: This study aims to provide observational data on the relationship between the timing of antithrombotic treatment and the competing risks of severe thrombotic and hemorrhagic events in a cohort of Swedish patients with atrial fibrillation and intracerebral hemorrhage (ICH).
METHODS: Patients with atrial fibrillation and a first-ever ICH were identified in the Swedish Stroke Register, Riksstroke, 2005 to 2012. Riksstroke was linked with other national registers to find information on treatment, comorbidity, and outcome. The optimal timing of treatment in patients with low and high thromboembolic risk was described through cumulative incidence functions separately for thrombotic and hemorrhagic events and for the combined end point vascular death or nonfatal stroke.
RESULTS: The study included 2619 ICH survivors with atrial fibrillation with 5759 person-years of follow-up. Anticoagulant treatment was associated with a reduced risk of vascular death and nonfatal stroke in high-risk patients with no significantly increased risk of severe hemorrhage. The benefit seemed to be greatest when treatment was started 7 to 8 weeks after ICH. For high-risk women, the total risk of vascular death or stroke recurrence within 3 years was 17.0% when anticoagulant treatment was initiated 8 weeks after ICH and 28.6% without any antithrombotic treatment (95% confidence interval for difference, 1.4%-21.8%). For high-risk men, the corresponding risks were 14.3% versus 23.6% (95% confidence interval for difference, 0.4%-18.2%).
CONCLUSIONS: This nationwide observational study suggests that anticoagulant treatment may be initiated 7 to 8 weeks after ICH in patients with atrial fibrillation to optimize the benefit from treatment and minimize risk.
© 2016 American Heart Association, Inc.
Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, Vermeer SE, Kerkhoff H, Zock E, Luijckx GJ, Messchendorp GP, van Tuijl J, Bienfait HP, Booij SJ, van den Wijngaard IR, Remmers MJM, Schreuder AHCML, Dippel DW, Staals J, Brouwers PJAM, Wermer MJH, Coutinho JM, Kwa VIH, van Gelder IC, Schutgens REG, Zweedijk B, Algra A, van Dalen JW, Jaap Kappelle L, Rinkel GJE, van der Worp HB, Klijn CJM; APACHE-AF Trial Investigators.
Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial.
Lancet Neurol. 2021 Nov;20(11):907-916. doi: 10.1016/S1474-4422(21)00298-2.
Abstract/Text
BACKGROUND: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial.
METHODS: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites.
FINDINGS: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0-3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7-21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2-20·8]; adjusted hazard ratio 1·05 [95% CI 0·48-2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation.
INTERPRETATION: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous.
FUNDING: Dutch Heart Foundation (grant 2012T077).
Copyright © 2021 Elsevier Ltd. All rights reserved.
SoSTART Collaboration.
Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial.
Lancet Neurol. 2021 Oct;20(10):842-853. doi: 10.1016/S1474-4422(21)00264-7. Epub 2021 Sep 3.
Abstract/Text
BACKGROUND: Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation.
METHODS: SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete.
FINDINGS: Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49-265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97-1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72-8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study.
INTERPRETATION: Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials.
FUNDING: British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Al-Shahi Salman R, Stephen J, Tierney JF, Lewis SC, Newby DE, Parry-Jones AR, White PM, Connolly SJ, Benavente OR, Dowlatshahi D, Cordonnier C, Viscoli CM, Sheth KN, Kamel H, Veltkamp R, Larsen KT, Hofmeijer J, Kerkhoff H, Schreuder FHBM, Shoamanesh A, Klijn CJM, van der Worp HB; Collaboration of Controlled Randomised Trials of Long-Term Oral Antithrombotic Agents After Spontaneous Intracranial Haemorrhage (COCROACH).
Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.
Lancet Neurol. 2023 Dec;22(12):1140-1149. doi: 10.1016/S1474-4422(23)00315-0. Epub 2023 Oct 12.
Abstract/Text
BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation.
METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133.
FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%).
INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials.
FUNDING: British Heart Foundation.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Aggarwal R, Ruff CT, Virdone S, Perreault S, Kakkar AK, Palazzolo MG, Dorais M, Kayani G, Singer DE, Secemsky E, Piccini J, Tahir UA, Shen C, Yeh RW.
Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.
Circulation. 2023 Sep 19;148(12):936-946. doi: 10.1161/CIRCULATIONAHA.123.064556. Epub 2023 Aug 25.
Abstract/Text
BACKGROUND: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs).
METHODS: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score.
RESULTS: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001).
CONCLUSIONS: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.
RESTART Collaboration.
Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial.
Lancet. 2019 Jun 29;393(10191):2613-2623. doi: 10.1016/S0140-6736(19)30840-2. Epub 2019 May 22.
Abstract/Text
BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92).
INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.
FUNDING: British Heart Foundation.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators.
Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease.
N Engl J Med. 2019 Sep 19;381(12):1103-1113. doi: 10.1056/NEJMoa1904143. Epub 2019 Sep 2.
Abstract/Text
BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease.
METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority.
RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority).
CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).
Copyright © 2019 Massachusetts Medical Society.
Al-Shahi Salman R, Dennis MS, Sandercock PAG, Sudlow CLM, Wardlaw JM, Whiteley WN, Murray GD, Stephen J, Rodriguez A, Lewis S, Werring DJ, White PM; RESTART Collaboration.
Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial.
JAMA Neurol. 2021 Oct 1;78(10):1179-1186. doi: 10.1001/jamaneurol.2021.2956.
Abstract/Text
IMPORTANCE: The Restart or Stop Antithrombotics Randomized Trial (RESTART) found that antiplatelet therapy appeared to be safe up to 5 years after intracerebral hemorrhage (ICH) that had occurred during antithrombotic (antiplatelet or anticoagulant) therapy.
OBJECTIVES: To monitor adherence, increase duration of follow-up, and improve precision of estimates of the effects of antiplatelet therapy on recurrent ICH and major vascular events.
DESIGN, SETTING AND PARTICIPANTS: From May 22, 2013, through May 31, 2018, this prospective, open, blinded end point, parallel-group randomized clinical trial studied 537 participants at 122 hospitals in the UK. Participants were individuals 18 years or older who had taken antithrombotic therapy for the prevention of occlusive vascular disease when they developed ICH, discontinued antithrombotic therapy, and survived for 24 hours. After initial follow-up ended on November 30, 2018, annual follow-up was extended until November 30, 2020, for a median of 3.0 years (interquartile range [IQR], 2.0-5.0 years) for the trial cohort.
INTERVENTIONS: Computerized randomization that incorporated minimization allocated participants (1:1) to start or avoid antiplatelet therapy.
MAIN OUTCOMES AND MEASURES: Participants were followed up for the primary outcome (recurrent symptomatic ICH) and secondary outcomes (all major vascular events) for up to 7 years. Data from all randomized participants were analyzed using Cox proportional hazards regression, adjusted for minimization covariates.
RESULTS: A total of 537 patients (median age, 76.0 years; IQR, 69.0-82.0 years; 360 [67.0%] male; median time after ICH onset, 76.0 days; IQR, 29.0-146.0 days) were randomly allocated to start (n = 268) or avoid (n = 269 [1 withdrew]) antiplatelet therapy. The primary outcome of recurrent ICH affected 22 of 268 participants (8.2%) allocated to antiplatelet therapy compared with 25 of 268 participants (9.3%) allocated to avoid antiplatelet therapy (adjusted hazard ratio, 0.87; 95% CI, 0.49-1.55; P = .64). A major vascular event affected 72 participants (26.8%) allocated to antiplatelet therapy compared with 87 participants (32.5%) allocated to avoid antiplatelet therapy (hazard ratio, 0.79; 95% CI, 0.58-1.08; P = .14).
CONCLUSIONS AND RELEVANCE: Among patients with ICH who had previously taken antithrombotic therapy, this study found no statistically significant effect of antiplatelet therapy on recurrent ICH or all major vascular events. These findings provide physicians with some reassurance about the use of antiplatelet therapy after ICH if indicated for secondary prevention of major vascular events.
TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN71907627.
Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM; STICH II Investigators.
Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial.
Lancet. 2013 Aug 3;382(9890):397-408. doi: 10.1016/S0140-6736(13)60986-1. Epub 2013 May 29.
Abstract/Text
BACKGROUND: The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients.
METHODS: In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967.
FINDINGS: 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367).
INTERPRETATION: The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage.
FUNDING: UK Medical Research Council.
Copyright © 2013 Mendelow et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd. All rights reserved.
Hanley DF, Thompson RE, Muschelli J, Rosenblum M, McBee N, Lane K, Bistran-Hall AJ, Mayo SW, Keyl P, Gandhi D, Morgan TC, Ullman N, Mould WA, Carhuapoma JR, Kase C, Ziai W, Thompson CB, Yenokyan G, Huang E, Broaddus WC, Graham RS, Aldrich EF, Dodd R, Wijman C, Caron JL, Huang J, Camarata P, Mendelow AD, Gregson B, Janis S, Vespa P, Martin N, Awad I, Zuccarello M; MISTIE Investigators.
Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial.
Lancet Neurol. 2016 Nov;15(12):1228-1237. doi: 10.1016/S1474-4422(16)30234-4. Epub 2016 Oct 11.
Abstract/Text
BACKGROUND: Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage.
METHODS: MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770.
FINDINGS: Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051).
INTERPRETATION: MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage.
FUNDING: National Institute of Neurological Disorders and Stroke, Genentech, and Codman.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Vespa P, Hanley D, Betz J, Hoffer A, Engh J, Carter R, Nakaji P, Ogilvy C, Jallo J, Selman W, Bistran-Hall A, Lane K, McBee N, Saver J, Thompson RE, Martin N; ICES Investigators.
ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial.
Stroke. 2016 Nov;47(11):2749-2755. doi: 10.1161/STROKEAHA.116.013837. Epub 2016 Oct 6.
Abstract/Text
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome.
METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year.
RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19).
CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.
© 2016 American Heart Association, Inc.
Kuramatsu JB, Biffi A, Gerner ST, Sembill JA, Sprügel MI, Leasure A, Sansing L, Matouk C, Falcone GJ, Endres M, Haeusler KG, Sobesky J, Schurig J, Zweynert S, Bauer M, Vajkoczy P, Ringleb PA, Purrucker J, Rizos T, Volkmann J, Müllges W, Kraft P, Schubert AL, Erbguth F, Nueckel M, Schellinger PD, Glahn J, Knappe UJ, Fink GR, Dohmen C, Stetefeld H, Fisse AL, Minnerup J, Hagemann G, Rakers F, Reichmann H, Schneider H, Rahmig J, Ludolph AC, Stösser S, Neugebauer H, Röther J, Michels P, Schwarz M, Reimann G, Bäzner H, Schwert H, Claßen J, Michalski D, Grau A, Palm F, Urbanek C, Wöhrle JC, Alshammari F, Horn M, Bahner D, Witte OW, Günther A, Hamann GF, Hagen M, Roeder SS, Lücking H, Dörfler A, Testai FD, Woo D, Schwab S, Sheth KN, Huttner HB.
Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.
JAMA. 2019 Oct 8;322(14):1392-1403. doi: 10.1001/jama.2019.13014.
Abstract/Text
IMPORTANCE: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established.
OBJECTIVE: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH.
DESIGN, SETTING, AND PARTICIPANTS: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015).
EXPOSURE: Surgical hematoma evacuation vs conservative treatment.
MAIN OUTCOMES AND MEASURES: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH.
RESULTS: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02).
CONCLUSIONS AND RELEVANCE: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.
Shah VA, Thompson RE, Yenokyan G, Acosta JN, Avadhani R, Dlugash R, McBee N, Li Y, Hansen BM, Ullman N, Falcone G, Awad IA, Hanley DF, Ziai WC.
One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability.
JAMA Neurol. 2022 Sep 1;79(9):856-868. doi: 10.1001/jamaneurol.2022.1991.
Abstract/Text
IMPORTANCE: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited.
OBJECTIVE: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery.
DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022.
EXPOSURES: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care.
MAIN OUTCOMES AND MEASURES: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort.
RESULTS: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001).
CONCLUSIONS AND RELEVANCE: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.
