ObjectiveTo estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).DesignEconomic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.SettingUK secondary care.Participants248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).InterventionsSurgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measuresIn the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.ResultsIn the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.ConclusionsIn a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).EthicsEthical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration numberISRCTN87370545.

As part of a DHSS funded study evaluating long-stay accommodation for elderly people (Bond, 1984), a survey of the services that already exist for the continuing care of elderly people has been undertaken. This survey includes a description of the dependency characteristics of elderly residents and patients in institutional care. The objectives were: To describe the dependency characteristics of elderly occupants in long term care in the catchment area of three National Health Service experimental nursing homes and in three control areas in neighbouring health authorities. To describe the residential accommodation and facilities available to residents and patients.

Abstract Background The surgical trial of lobar intracerebral haemorrhage (STICH II) was a randomised controlled trial evaluating early surgical removal of a clot. This paper investigates volume change in both arms of the trial with respect to Extended Glasgow Outcome Scale (GOSE) groups. Methods Patients randomised into STICH II had an initial diagnostic CT and a second CT 5 days after randomisation. Each scan was anonymously assessed by at least two central readers. An analysis of agreement between the two readers was conducted using kappa tests and intraclass correlation. The change in volume in both the early surgery (ES) and the initial conservative treatment (ICT) arms were analysed with respect to the six-month GOSE outcome. Results Of the 597 patients randomised in the trial there were 582 pre-randomisation scans and 566 5-day scans available for analysis of agreement. There was good agreement between the assessors for the radiological inclusion criteria including volume (ICC = 0.87) and this was better than the agreement between the assessor and local investigator (ICC = 0.73). There were 526 patients with two scans available for analysis of change in volume measurement. The median percentage change in volume for the ES group was a reduction of 92.4% (IQR 75.6%, 99.0%) while for the ICT group, in which some cases crossed over to delayed surgery, it was only 5.7% (IQR 16.4% increase, 29.5% reduction). ES patients with almost complete removal (99-100%) had the best outcome with only 30% dead or lower severely disabled. For the ICT group outcome was related to the final volume: the smaller the final volume the better the outcome. Conclusions This analysis provides evidence for central assessments of scans in exploratory analyses and further information regarding the potential advantage of early and more complete clot removal on outcome in ICH and should inform the planning of future trials. Clinical trials registration: ISRCTN22153967

Objectives: RESCUEicp studied decompressive craniectomy (DC) applied as third-tier option in severe traumatic brain injury (TBI) patients in a randomized controlled setting and demonstrated a decrease in mortality with similar rates of favorable outcome in the DC group compared to the medical management group. In many centers, DC is being used in combination with other second/third-tier therapies. The aim of the present study is to investigate outcomes from DC in a prospective non-RCT context.Methods: This is a prospective observational study of 2 patient cohorts: one from the University Hospitals Leuven (2008-2016) and one from the Brain-IT study, a European multicenter database (2003-2005). In thirty-seven patients with refractory elevated intracranial pressure who underwent DC as a second/third-tier intervention, patient, injury and management variables including physiological monitoring data and administration of thio-pental were analysed, as we l l as Extended Glasgow Outcome score (GOSE) at 6 months.Results: In the current cohorts, patients were older than in the surgical RESCUEicp cohort (mean 39.6 vs. 32.3; p < 0.001), had higher Glasgow Motor Score on admission (GMS < 3 in 24.3% vs. 53.0%; p = 0.003) and 37.8% received thiopental (vs. 9.4%; p < 0.001). Other variables were not significantly different. GOSE distribution was: death 24.3%; vegetative 2.7%; lower severe disability 10.8%; upper severe disability 13.5%; lower moderate disability 5.4%; upper moderate disability 2.7%, lower good recovery 35.1%; and upper good recover y 5.4%. The outcome was unfavorable in 51.4% and favorable in 48.6%, as opposed to 72.6% and 27.4% respectively in RESCUEicp (p = 0.02).Conclusion: Outcomes in DC patients from two prospective cohorts reflecting everyday practice were better than in RESCUEicp surgical patients. Mortality was similar, but fewer patients remained vegetative or severely disabled and more patients had a good recovery. Although patients were older and injury severity was lower, a potential partial explanation may be in the pragmatic use of DC in combination with other second/third-tier therapies in real-life cohorts. The findings underscore that DC maintains an important role in managing se-vere TBI.

BACKGROUND:Traumatic acute subdural hematomas frequently warrant surgical evacuation by means of a craniotomy (bone flap replaced) or decompressive craniectomy (bone flap not replaced). Craniectomy may prevent intracranial hypertension, but whether it is associated with better outcomes is unclear. METHODS:We conducted a trial in which patients undergoing surgery for traumatic acute subdural hematoma were randomly assigned to undergo craniotomy or decompressive craniectomy. An inclusion criterion was a bone flap with an anteroposterior diameter of 11 cm or more. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOSE) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 12 months. Secondary outcomes included the GOSE rating at 6 months and quality of life as assessed by the EuroQol Group 5-Dimension 5-Level questionnaire (EQ-5D-5L). RESULTS:A total of 228 patients were assigned to the craniotomy group and 222 to the decompressive craniectomy group. The median diameter of the bone flap was 13 cm (interquartile range, 12 to 14) in both groups. The common odds ratio for the differences across GOSE ratings at 12 months was 0.85 (95% confidence interval, 0.60 to 1.18; P = 0.32). Results were similar at 6 months. At 12 months, death had occurred in 30.2% of the patients in the craniotomy group and in 32.2% of those in the craniectomy group; a vegetative state occurred in 2.3% and 2.8%, respectively, and a lower or upper good recovery occurred in 25.6% and 19.9%. EQ-5D-5L scores were similar in the two groups at 12 months. Additional cranial surgery within 2 weeks after randomization was performed in 14.6% of the craniotomy group and in 6.9% of the craniectomy group. Wound complications occurred in 3.9% of the craniotomy group and in 12.2% of the craniectomy group. CONCLUSIONS:Among patients with traumatic acute subdural hematoma who underwent craniotomy or decompressive craniectomy, disability and quality-of-life outcomes were similar with the two approaches. Additional surgery was performed in a higher proportion of the craniotomy group, but more wound complications occurred in the craniectomy group. (Funded by the National Institute for Health and Care Research; RESCUE-ASDH ISRCTN Registry number, ISRCTN87370545.).

[Purpose] We have previously shown inversion therapy to be effective in a small prospective randomised controlled trial of patients with lumbar disc protrusions. Our purpose now was to measure symptoms and to compare the surgery rate following inversion for 85 participants with the surgery rate in 3 control groups. [Participants and Methods] Each of the 85 inverted participants acted as their own control for the "symptomatic" part of the study. In the "Need for surgery" part of the study, one control group was made up of similar patients with leg pain and sciatica who were referred to the same clinic in the same year. Two additional control groups were examined: the original control group from the pilot trial and the lumbar disc surgery waiting list patients. [Results] Inversion therapy relieved symptoms: there were improvements in the Visual Analogue Score, Roland Morris and Oswestry Disease indices and Health Utility Score compared with their pre-treatment status. Also, the 2 year surgery rate in the inversion participants in the registry (21%) was significantly lower than in the matched control group (39% at two years and 43% at four years). It was also lower than the surgery rate in the other 2 control groups. [Conclusion] Inversion therapy relieved symptoms and avoided surgery.

Background: Aneurysmal subarachnoid haemorrhage is a major cause of haemorrhagic stroke. The incidence is ≈ 80 per million population per year; it peaks in the 40–60 years age range and often has a poor prognosis with the outcome linked to severity of the initial haemorrhage. Aneurysmal subarachnoid haemorrhage accounts for 5% of strokes, but 20% of quality-adjusted life-years are lost to stroke and much of that loss is concentrated in World Federation of Neurosurgical Societies grade 4–5 (or poor-grade) aneurysmal subarachnoid haemorrhage patients. Before endovascular coiling was available, the conventional management strategy for poor-grade aneurysmal subarachnoid haemorrhage patients was to treat the ruptured aneurysm on neurological improvement. That incurs a risk of aneurysm rebleeding, which is highest soon after the first bleed; if rebleed occurs prior to aneurysm treatment, prognosis is dismal. Reducing rebleeding with early treatment might improve outcome. Therefore, an early coiling strategy in grade 4–5 patients is appealing, but not robustly evidenced. Early treatment in all grade 4–5 patients might prevent death from rebleeding but possibly at the expense of creating severely disabled survivors, with attendant societal costs. Many neuroclinicians have expressed genuine uncertainty regarding whether or not to treat all grade 4–5 aneurysmal subarachnoid haemorrhage patients emergently (as soon as possible regardless of neurological status). A pilot trial, the treatment of poor-grade subarachnoid haemorrhage trial 1 (TOPSAT1), indicated that recruitment to a randomised trial to address this uncertainty was feasible. Methods: We investigated a management policy in aneurysmal subarachnoid haemorrhage World Federation of Neurosurgical Societies grades 4 or 5 of securing the ruptured aneurysm emergently (within 24 hours of randomisation) compared with the strategy to treat the aneurysm on neurological improvement (to World Federation of Neurosurgical Societies grades 1–3), irrespective of when that improvement occurred. The treatment of poor-grade subarachnoid haemorrhage trial 2 (TOPSAT2) was a pragmatic, randomised, open-blinded, end-point design trial aiming to recruit 346 adult patients (aged 18–80 years) in 30 UK and European neuroscience centres. Randomisation was web based, with minimisation criteria relating to age, grade, presence of hydrocephalus and UK location (vs. non-UK). Fifteen sites were opened to recruitment, 12 of which were in the UK. Standard institutional procedures for securing aneurysms were followed. An exploratory magnetic resonance biomarker substudy of 100 UK participants was planned but not opened. The primary end point was functional outcome at 12 months, determined by analysis of the modified Rankin Scale score. The secondary end points relating to safety were assessed. Results: Of the 305 World Federation of Neurosurgical Societies grade 4–5 patients screened, 23 were randomised: 11 to the emergent treatment arm and 12 to the treatment on neurological improvement (control) arm. Trial recruitment was suspended when it was judged to have failed a feasibility assessment. The median time from ictus to treatment (where aneurysm was treated) was 26 hours in the emergent treatment arm and 163 hours in the treatment on neurological improvement arm. There were no statistically significant differences between arms in mortality (p = 0.4) or functional outcome at 365 days [modified Rankin Scale score 0–3 vs. 4–6 (p = 0.32)]. Sensitivity analysis was performed to examine the effect of missing data but differences remained non-significant. Limitations: A limitation was the failure to recruit to time/target. Conclusions: The randomised trial approach to investigating whether poor-grade aneurysmal subarachnoid haemorrhage patients should receive emergent treatment or be treated on neurological improvement proved unfeasible. No statistically significant differences were identified between the trial arms in mortality or functional outcome, but the small number of patients enrolled limits drawing firm conclusions. Future work: No future work is currently planned. Trial registration: Current Controlled Trials ISRCTN15960635. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 8. See the NIHR Journals Library website for further project information.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

HomeStrokeVol. 51, No. 4Recommendations for Clinical Trials in ICH Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBRecommendations for Clinical Trials in ICHThe Second Hemorrhagic Stroke Academia Industry Roundtable The Hemorrhagic Stroke Academia Industry (HEADS) Roundtable Participants The Hemorrhagic Stroke Academia Industry (HEADS) Roundtable Participants Guest Editor for this article was Eric E. Smith, MD, MPH. Search for more papers by this author and The Second HEADS Roundtable Participants Originally published10 Feb 2020https://doi.org/10.1161/STROKEAHA.119.027882Stroke. 2020;51:1333–1338Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 10, 2020: Ahead of Print The first Hemorrhagic Stroke Academia Industry (HEADS) roundtable in 2017 established priorities for basic, translational, and clinical research in intracerebral hemorrhage (ICH) and benchmark standards for improving research in this globally serious and challenging condition.1,2 Herein, we present updated recommendations from the second HEADS roundtable meeting in 2019, which focused on the methods of clinical trials in acute ICH.The second HEADS roundtable (HEADS-2) was convened alongside the 7th World Intracranial Hemorrhage Conference in Granada, Spain in May 2019. The neutral results of several clinical trials in acute ICH published since the first HEADS meeting in 2017 have reinforced the challenges of advancing strategies for the management of this serious condition.3–5 The focus of HEADS-2 was on the execution and conduct of clinical trials in ICH, with the aim of developing recommendations to improve their design and conduct. The format was similar to the first HEADS roundtable,1,2 with Day 1 consisting of three sessions covering the following topics: (1) target selection and approaches to variables influencing outcomes including hematoma expansion, perihematomal edema (PHE), and secondary injury; (2) selecting the relevant eligible patient population for ICH trials, with an emphasis on timing, age and sex, hematoma volume and location, presence of intraventricular hemorrhage (IVH), and comorbidities; and (3) challenges in performing ICH trials from industry and academic perspectives. On Day 2, participants broke out into 3 working subgroups to address these issues. This paper consolidates the HEADS-2 recommendations with the aim of improving the rigor, efficiency, and success of future clinical trials to find effective therapies for ICH.Intracerebral Hemorrhage Is Distinct From Ischemic StrokeFor many years, ICH has been the bridesmaid, trying to follow the footsteps of its ischemic counterpart.6 However, it has become increasingly evident that clinical research in ICH has clear distinctions from acute ischemic stroke (AIS). First, the global burden of ICH is higher, particularly in low- and middle-income countries, and Asia; and the loss of productive life years from ICH is far greater than from AIS.7 The high case fatality and morbidity after ICH, complexities and variability of care, and early withdrawal-of-treatment; all significantly limit the number of potential participants available for clinical trials. Improved understanding of the patterns and process of hematoma expansion and secondary injury in ICH and differences in immediate therapeutic goals after ICH compared with AIS also impact on trial design. While the primary objective in AIS is to resuscitate the penumbral tissue to minimize disability, the primary objective in ICH is to prevent rapid deterioration and early death. Although initial interventions that target hematoma growth in ICH might be more steeply time-dependent than reperfusion therapy in AIS, the pathophysiology of secondary injury in ICH also provides opportunities for a wider therapeutic window. These distinctive differences elucidate the need for greater global collaboration to increase recruitment and improve the efficiency of ICH trials.Target Selection and Timing of Interventions in ICH TrialsBroadly, the potential therapeutic targets for ICH are prevention, limiting hematoma expansion, hematoma evacuation, or reduction, reducing ICH-induced secondary brain injury and improving repair. ICH prevention was not a focus of HEADS-2. ICH-induced brain damage involves both primary injury, including the physical disruption caused by the hemorrhage and its expansion, and secondary injury, including downstream injury cascades initiated by the initial physical injury, clot-derived neurotoxic factors such as hemoglobin and iron, and neuroinflammation8,9; all of which are intimately related.Hematoma ExpansionHematoma volume and expansion are powerful predictors of death and disability after ICH. Approximately, one-third of patients demonstrate substantial hematoma expansion (HE) in the first few hours after ICH, which worsens outcomes.10 Timing of observation influences the frequency of HE; presentation within the first few hours is associated with a higher likelihood of HE.11 Hematoma expansion is potentially modifiable, and limiting early HE has been an appealing therapeutic target for ICH. The therapeutic options to restrict HE can be medical (nonsurgical) or surgical, and the 2 approaches might be complementary. Previous trials of activated recombinant Factor VIIa12 and tranexamic acid5 have shown that these interventions can modestly arrest hematoma growth. Minimally invasive clot evacuation techniques provide an opportunity to modify and reduce ICH volume.3 However, to-date, these interventions did not result in improved functional outcomes.3,5,12 The neutral results of these ICH trials may have been influenced by time delays over patient selection and initiation of interventions, which may be most effective very soon after ICH onset.Secondary Injury After ICHUnlike HE, the secondary injury after ICH occurs over hours to weeks and is attributed to the toxic effects of blood degradation products emanating from hemolysis of red blood cells, thrombin production, and neuroinflammation.8 These processes lead to disruption of blood-brain barrier and cerebral edema. PHE, which can readily be detected using different imaging modalities, is thought to represent a radiological marker of secondary injury and is increasingly recognized as a therapeutic target or proof-of-concept surrogate marker in assessing the efficacy of interventions targeting the secondary injury in phase II ICH trials. However, whether reductions in PHE can be used as a marker of therapeutic efficacy is debated, as its assessment is complex, and formation and evolution cover several processes.13 Early PHE involves clot retraction and hydrostatic pressure change forcing serum into the perihematomal space to form vasogenic edema. Thrombin formation and activation of the coagulation cascade, erythrolysis and hemoglobin-mediated toxicity, and inflammation also contribute to the formation of vasogenic edema in the following days, while neuronal death and energy failure contribute to the formation of cytotoxic edema. These chronological pathophysiological changes must be taken into consideration, and correction algorithms should be used in the assessment of PHE. Furthermore, the relationship between PHE and long-term outcomes is uncertain. While malignant PHE may contribute to increased intracranial pressure, midline shift, and potentially herniation and death, the effects associated with small hematoma are less clear. Previous studies have been largely observational and retrospective and used different parameters, assessors, onset-to-imaging and onset-to-outcome assessment times, outcome definitions and end points, and imaging modalities.14There are pros and cons to potential therapeutic interventions that may target both primary and secondary ICH-induced brain injury. Reducing hematoma volume and expansion may limit both primary and secondary injury, but such expansion is time-dependent and only occurs in a subset of patients with ICH.10 Therefore, the effects of hemostatic agents may be maximized by very early delivery after ictus (eg, within the first 2 hours). Early arrest of hematoma growth and its stabilization may also facilitate earlier clot evacuation. There are data to suggest that minimally invasive surgical techniques, which do not use thrombolytic agents, can be safely done within few hours of ICH onset.15,16 Therefore, the timing of surgery and its relationship to ongoing hematoma expansion (benefit versus harm) are important targets for future research.Drugs targeting secondary brain injury avoid the use of surgery and can have an approximate therapeutic time window of 24 to 72 hours, dependent on agent, in preclinical studies. However, they do not affect ICH-induced primary injury. In addition, secondary brain injury after ICH involves multiple pathways which evolve spatially and temporally.9 Indeed, the same pathway (eg, neuroinflammation) may have detrimental or beneficial effects depending on time.17 The sequence of events and the human time window requires further evaluation.Imaging can provide insights into acute brain injury after ICH and the potential benefit of therapeutic strategies. One commonly assessed injury biomarker is PHE. However, there are several unanswered questions and opportunities for standardizing assessment of PHE to allow better evaluation of its role as a therapeutic target or surrogate marker. For example, the relationship between PHE and mass effect (assessed by midline shift, ventricular ablation, or intracranial pressure measurements) and outcome requires further examination. Also, the impact of age and age-related brain atrophy on these intermixed variables should be given consideration. There is a need to utilize new imaging technologies, such as magnetic resonance diffusion tensor imaging, to examine local versus global mass effect and the impact of PHE location on mass effect and outcome. Understanding the importance of PHE as a brain injury mechanism requires trials of specific anti-edema therapies. Examination of how PHE correlates with neuroinflammation, hematoma changes, and white matter injury may give further insight.RecommendationsThe targets described above are not mutually exclusive; a multimodal approach is likely required for ICH (eg, hemostatic therapy to arrest hematoma expansion followed by hematoma evacuation, and combined with an agent to limit secondary brain injury).There are limited resources and a preclinical network directly comparing different potential therapies may inform decision-making over which therapies should go forward to clinical trial.Access to data from human hematoma samples should be utilized as one of multiple bidirectional data flow to better inform preclinical studies and future trial designs.Future studies of PHE should use rigorous methodologies and systematic and standardized approaches,14 with prespecified analyses, end points, and adequate statistical power.Recovery and Timing of Outcome AssessmentsMost ICH survivors are left with some degree of disability. Therefore, rehabilitation has an important role in promoting recovery and readjustment to the illness in ICH survivors. However, there are few data on the natural long-term course and degree of recovery after ICH, frequency of the various ICH-related impairments, and their evolution over time.18 Most ICH randomized trials have conventionally assessed functional outcomes at 90 days (as in AIS), but some have pushed this out to 365 days.3–5 Emerging data from recent trials3,4 confirm that recovery takes longer after ICH compared with AIS and that a 90-day outcome assessment is too early to capture the full extent of recovery.In most large randomized controlled rehabilitation trials, patients with ICH have been included alongside patients with AIS. Injury mechanisms differ between hemorrhage and ischemia and recovery also seems to differ.19 This is a ripe area for research to help determine the duration and intensity of rehabilitation in the acute and chronic phases of ICH. In addition, such trials may be used to assess physiotherapeutic methods, robot-assisted technologies, and wearable sensors and devices to track motor recovery after ICH. There is also a great need to understand why patients vary greatly in their degree of recovery following ICH. To what extent is this dependent on the degree of initial injury, the site of injury, individual genetics, or presence of comorbidities? Advances in imaging modalities, such as diffusion tensor imaging or lesion mapping, and use of long-term and task-dependent imaging and resting-state functional MRI, could help address patient variability to predict recovery, and tailor patient-specific rehabilitation programs to maximize recovery. Our understanding of motor function deficits after ICH and ability to address them with rehabilitation are generally more advanced than with psychosocial dysfunction that also attends ICH. This is a very important area of study that merits resources. Cognitive decline occurs in many individuals after ICH with an enormous impact on the patient, family, and society; there is a need to identify rehabilitation interventions targeting cognition.RecommendationsKey outcomes for ICH—death and disability/dependency—might be best assessed at separate time points; death at 7 or 30 days, and disability at 6 to 12 months. This recommendation takes into account the pros and cons associated with increased study duration.There is a need for rehabilitation trials which specifically focus on patients with ICH.Patient Selection and Adjustment for Prognostic ConfoundersPatient selection in ICH trials influences the detection of a possible benefit and adequate evaluation of safety and has implications for the overall wider applicability of the trial results. As the characteristics of selected patients have prognostic impact on outcomes, it is important that randomization is representative of and balanced according to key baseline variables, such as age, IVH, hematoma location and volume, and important comorbidities. Adjustment for imbalances of biologically established covariates should be undertaken in final analyses.AgeMany ICH randomized trials have limited enrollment to patients aged ≤80 years. As old age alone may have little impact on the effects of an intervention, excluding patients older than 80 years from trials limits the generalizability of the results to a large proportion of patients with ICH who have the potential to benefit. However, older age is a marker of accumulating comorbidities and may be associated with increased likelihood of advanced directives and early withdrawal-of-care after ICH.RecommendationsSubstituting age with a functional threshold (eg, modified Rankin Scale score >1) or requiring an intent to provide aggressive care and postpone withdrawal-of-care orders (eg, 2–4 weeks) as criteria for enrollment in ICH trials could alleviate the preceding concerns.Epidemiological and trial data should be used to evaluate the relationship between age, hematoma volume, location, and outcome to inform trial designs, and to assess whether a specific upper age limit is justified as an eligibility criterion for ICH trials.IVHAlthough the presence and volume of IVH has important implications on prognosis in ICH,19,20 these variables are rarely included in the randomization process of ICH trials. At a minimum, adjustment for these variables should be undertaken in the analyses of final results. The presence of IVH alone should not be an exclusion criterion. Validated scales or full quantification of IVH volume should be employed.21,22RecommendationsTrial and epidemiological data should be developed to define if an upper limit for IVH volume exists to better inform exclusion and randomization processes.Hematoma LocationThe site of ICH has a clear impact on survival and functional outcome.23,24 Infratentorial location, in particular, predicts higher likelihood of death, and is a current clinical indication for surgery in case of cerebellar ICH.25 Consequently, most ICH trials exclude patients with infratentorial hemorrhage. Prognosis also varies according to deep and lobar location of supratentorial ICH23; ICH involving the posterior limb of internal capsule or thalamus tends to have poorer outcomes compared with other locations.24–26RecommendationsFuture ICH trials should consider stratifying randomization based on ICH location, for example deep thalamo-capsular versus deep non thalamo-capsular versus lobar locations. This requires a standardized process and training to minimize variability and maximize reliability of determining hemorrhage location.Hematoma VolumeLarge ICH volume is a consistent predictor of poor outcome. As a result, most clinical trials use a cutoff threshold of ICH volume or low score on the Glasgow Coma Scale as a surrogate measure of ICH severity/volume to exclude poor prognosis patients. Epidemiological and trial data suggest that patients with ICH volume <30 mL have good potential for survival and recovery.27 An argument can be made to exclude patients with ICH >30 mL from trials of medical therapies. Trials targeting hematoma growth may require even lower initial ICH volume because expansion may cause further damage. Situations unlikely to result in any clinically meaningful difference, such as a very large ICH, should be excluded from medical trials. Conversely, these patients are good candidates for inclusion in surgical trials because of the greater potential impact on outcome from hematoma evacuation in large ICH. Assessment of ICH volume should be incorporated into routine initial assessments of patients presenting with ICH.Baseline ComorbiditiesVarious clinical conditions can influence outcome after ICH.28 However, these variables are not systematically stratified at the time of randomization or later adjusted for when assessing outcomes in most ICH trials. Recent trials have employed adaptive randomization/minimization to achieve balance of 3 to 5 baseline factors.3,4 The impact of key selected or range of comorbidities, such as diabetes mellitus, renal failure, chronic small vessel disease with attendant white matter abnormality, is under-evaluated and deserves further study.The use of validated tools which combine comorbidities, such as the Charlson comorbidity index,28,29 offers another approach to assess the influence of comorbidities on the treatment effect and outcomes in ICH trials.Trial Design, Logistics, and ChallengesClinical trials in ICH pose significant challenges related to difficulty with recruitment and ability to obtain timely informed consent. While the use of selective and stringent eligibility criteria to target patients who are most likely to benefit from the study intervention could potentially increase the chances of identifying a beneficial signal, it imposes significant screening burden to identify (and not miss) the infrequent eligible patient. Despite the soundness of this strategy, a decreased pool of eligible patients with ICH places increased demands on recruitment and requires a wide recruitment network. It has been estimated that a large proportion of patients with ICH are not eligible for any trial.30 Potential solutions for improving recruitment into ICH trials are outlined below.Co-EnrollmentAllowing co-enrollment in some ICH trials could increase recruitment and allow quicker completion of the trials. However, there are potential disadvantages. There is a potential for increased burden on participants due to additional consent and multiple follow-up assessments. There are also logistical and operational challenges related to complexities of statistical analyses, harmonization of administrative tasks, assessment of interactions between the interventions, and adjudicating relatedness of adverse events to a particular intervention. These drawbacks can be remedied by preplanned discussion among the leading investigators to synchronize trials activities and design and considering factorial designs.Investigators should consider co-enrollment particularly to academic studies using a single or joint Data Safety and Monitoring Board across studies, and closely monitoring co-enrollment and its effect on recruitment, adherence to study protocols, and drop-out.Formation of an ICH International Trials ConsortiumLarge trials mitigate many of the concerns regarding differences in baseline severity and comorbidities; they also increase precision of estimation. This approach has been successful in producing successful treatments in heart disease and cancer. Collaboration between multiple countries is required to complete any such medium-to-large size phase II/III randomized, controlled, trials in ICH. Establishment of an ICH International Trials Consortium could facilitate planning, coordination, and cooperation of such trials; increase generalizability of the results; allow sharing infrastructure for co-enrollment; and would generate enthusiasm to share and optimize research ideas. However, this will require increased awareness among funders of the need for international cooperation; skillful and difficult coordination between various funding bodies from different countries; goodwill, academic credits, and trust between the oversight committee and participating investigators; and streamlining standards-of-care across participating institutions to minimize the impact of variability of care on data quality. Advanced planning, cooperation with various networks such as the Global Alliance of Independent Networks in Stroke led by the National Institute of Neurological Disorders and Stroke StrokeNet, the European Stroke Organization Trials Alliance and the Canadian Stroke Trials Consortium, as well as industrial cooperation and co-funding, would all assist in success of an ICH International Trials Consortium.Establishment of an ICH international registry or platform could also allow for assessing nonrandomized patients and data linkage for comprehensive cohorts data. Hardships related to funding and administrative oversight may be partially solved by building registries into trial designs and industrial support.Simplify Trials to Align With Existing Practice, Consent, and ProceduresThe variability in clinical practice and beliefs, complicated nature of the informed consent process and various regulatory requirements, and disabling neurological deficits in patients with ICH have long been recognized by investigators as hindrances to successful and timely recruitment. Communication, cognitive, and physical impairments among patients with ICH clearly lend to the requirement for simplification of the informed consent form and process in ICH trials to allow rapid recruitment for the testing of time-dependent treatments. Surrogate consent is not always possible in a timely manner. Community consent has been proposed for ICH trials but is rarely implemented. There is a need for a concise, easy-to-understand, stroke-specific, consent form to facilitate recruitment of patients with ICH into clinical trials while protecting their welfare and rights. Policies are needed to facilitate the use of digital technology, such as videotelephony and telemedicine to obtain consent.Simplifying trial procedures, in particular, follow-up assessments, can significantly improve recruitment and retention. Trial planning must take into consideration local variations in practice, obtain consensus from investigators on common definitions and essential assessments, and align the study protocol with usual processes and standards-of-care at various participating sites. Follow-up procedures should take into consideration the unique nature of patients with ICH, their disabling deficits, and long rehabilitation. The use of voice-over-internet technology and videotelephony is encouraged as an alternative to in-person follow-up assessments after discharge from the hospital.Selecting a translational paradigm for ICH with high potential for success is also important. One paradigm is to perform a mega-trial encompassing a wide range of patients, then identify which subgroups benefit in adequately powered statistical tests on interaction. Experience from AIS thrombolysis and endovascular trials offers an alternative paradigm; to target highly selected patient population to increase the chances of a clear signal of benefit and proof-of-concept then perform additional trials in expanded populations once an intervention is proved effective in carefully targeted population to potentially broaden its indication.Mortality as a Primary Efficacy End Point in ICH TrialsThe HEADS-2 participants considered whether early mortality should be used as the primary efficacy end point as opposed to a safety outcome for clinical trials in ICH. The question of death versus survival is the first question that most families ask caregivers. Arguments for using mortality as a primary efficacy end point are: survival is clinically meaningful and can be the primary early goal of medical intervention; it is an objective measure as opposed to the subjective nature of other measures such as health-related quality of life or functional outcome assessments; and it could increase statistical power of the study. Mortality shift if achieved in one or more trials has the potential to standardize approaches to rendering care for patients with ICH. Mortality reduction is more readily and more frequently achieved than improved functional outcomes. Although there were no significant differences in functional outcomes between treated patients and control groups in the Tranexamic acid for hyperacute primary ICH (TICH-2),5 the thrombolytic removal of intraventricular hemorrhage in treatment of severe stroke (CLEAR-III),25 and the efficacy and safety of MISTIE-III trial (minimally invasive surgery with thrombolysis in ICH evacuation,3 treated patients had lower rates of early deaths. Early mortality is readily accepted as an end point in traumatic brain injury and hemorrhagic shock trials, and an earlier primary mortality end point may be appropriate in severely affected patients with ICH where the peak functional recovery may take several months; survival being essential for recovery. Conversely, improved survival should not be at the expense of persistent and severe disability, which would increase burden on the patients, families, society, and the overall health system. Importantly, survival may not be an acceptable outcome to some patients, families, and physicians.Engagement with patient and consumer groups representative of the general population and inclusive of different cultural backgrounds is required to gain better information over the appropriateness of using reduction in early mortality as the primary measure of efficacy in future trials.ConclusionsThere are many challenges and opportunities to optimize clinical research and randomized trials in ICH. We hope these recommendations from HEADS-2 will facilitate improved rigor, efficiency, and success of future ICH trials to find effective therapies for this devastating condition (Table).Table 1. Summary of the Main HEADS-2 RecommendationsTarget Selection and Timing of Interventions Hematoma expansion: interventions targeting hematoma expansion should be initiated as soon as possible after ICH onset. Hematoma evacuation: the timing of hematoma evacuation and its relationship to ongoing hematoma expansion (benefit vs harm) are important targets for future research. Perihematomal edema: there is a need for more rigorous methodologies and standardized assessments of perihematomal edema to allow better evaluation of its relationship to clinical outcomes and its role as a potential therapeutic target or surrogate marker in ICH trials. Recovery: there is a need for rehabilitation trials which specifically focus on patients with ICH to determine the duration and intensity of rehabilitation in the acute and chronic phases and examine long-term cognitive sequelae of ICH.Patient selection and adjustment for prognostic confounders ICH location and IVH: stratification of randomization based on ICH location (lobar vs deep thalamo-capsular vs deep nonthalamo-capsular) and IVH volume or severity (using a validated scale) is recommended. Comorbidities: it is important to assess the impact of comorbidities (using a validated tool such as Charlson comorbidity index) on reported outcomes in ICH trials.Trial design, logistics, and challenges Co-enrollment: co-enrollment into academic trials on a trial-by-trial basis under close monitoring should be considered to examine the appropriateness of this strategy as a solution to maximize recruitment into ICH trials Global collaboration: formation of an ICH International Trials Consortium (ICH-ITC) and establishment of an ICH international registry or platform are needed to optimize research ideas and facilitate planning, execution, and completion of ICH trials. Trial design and consent: there is a need to simplify (1) the consent process to take into account the various impairments among patients with ICH and to allow rapid recruitment into trials investigating time-dependent therapies and (2) trial-related procedures to align with existing practice. Mortality as an end point: the use of early mortality as a primary efficacy end point in ICH trials requires further study and engagement with patient and consumer groups of different cultural backgrounds to determine its appropriateness.AppendixThe Second HEADS Roundtable ParticipantsChairs/Co-Chairs: Magdy Selim; Daniel Hanley; Thorsten Steiner; Hanne Krarup Christensen; Jesus Lafuente; David Rodriguez.Writing Group: Magdy Selim, Richard Keep, Thorsten Steiner, Craig Anderson, Daniel Hanley.Working Groups L

Introduction: Completion of the MISTIE procedure requires a period of hematoma stability before and during hematoma removal and, if necessary, dosing of rtPA which can take days to complete. Early surgery was intended in the STICH I and II trials, yet was performed after varying delays. No previous analysis has evaluated the timing for hematoma removal on outcomes in these trials. Objective: Determine if time from ictus to completion of hematoma removal may have affected patient outcome in three large surgical clinical trials of ICH evacuation. Methods: Patients randomized to surgery in the MISTIE III (n=242), STICH I (n=464) and STICH II (n=266) trials who received the procedure were analyzed, excluding cases crossing over to surgery. Time from ictus to end of treatment, defined as 24 hours after last dose in (MISTIE III) or time to craniotomy (STICH I and II), was analyzed in relation to likelihood of survival and functional outcome at 180 days. Cubic spline models with dichotomized outcomes were used. Results: The probability of achieving an mRS 0-3 increased significantly with longer time until completion of the procedure, up to 83 hours post-ictus, and worsened with longer delays thereafter (p=0.05). Better mRS was also achieved in STICH I patients with longer time until surgical removal, up to 60 hours post-ictus (p=0.0002), but not with longer delays (p=0.49). In STICH II (lobar cases), there was greater likelihood of mRS 0-3 with longer delay after 22 hours post-ictus (p=0.004), but not with earlier surgery (p=0.19). There was no significant benefit in survival, with earlier intervention across modalities and trials. Adjustment by initial hematoma volume further validated that early procedures do not favor survival or achieving a mRS 0-3. Conclusion: Early hematoma evacuation up to 60-80 hours post-ictus does not increase the probability of survival nor a good functional outcome in non-herniating ICH patients included in clinical trials, likely in view of bleeding instability. This was true in minimally invasive intervention as well as open surgeries.

Background Study was a PROBE design phase II randomized controlled trial (RCT). We assessed trial feasibility and technical efficacy and safety of two novel thrombectomy devices – ERIC (a retriever device) and SOFIA (a distal access catheter) – used alone or in combination depending on operator preference. Methods Four UK neuroscience centers enrolled adults with proximal large artery occlusion (LAO) stroke on imaging where arterial puncture was achievable within 5.5 hours (8.5 hours for posterior circulation) of symptom onset; National Institutes of Health Stroke Scale (NIHSS) ≥6 with limited ischemic change on CT imaging. Randomization was 2:1 into intervention arm (ERIC and/or SOFIA). Patients and core lab were blinded to allocation. Primary outcome was independent core lab adjudication of reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) scale). Secondary outcomes were modified Rankin score (mRS) at 90 and 365 days (independence and shift analysis), 30-day mortality, symptomatic intracranial hemorrhage (sICH), procedural complications and NIHSS change. Results Sixty-six patients were enrolled. TICI 2B/3 reperfusion was achieved in 72% in intervention compared with 90% in control arm on intention to treat (ITT) analysis (P=0.2) and 78% compared with 86% on per protocol analysis (P=0.7). Functional independence at 90 days was 40% (intervention) compared with 43% (control) on ITT analysis (P=1.0). sICH rates were low at 0% and 5%, respectively (P=0.3). The 30-day mortality was 9% intervention compared with 14% control (P=0.7). Conclusions Study indicated feasibility of a phase II RCT trial approach for assessing new thrombectomy devices. In a broad LAO stroke population ERIC and SOFIA were not statistically different from control devices. Larger trials are needed.

Introduction Recent data suggest that statin use after intracerebral haemorrhage might be beneficial. However, data on the effects of early in-hospital statin exposure are lacking. Therefore, we sought to assess whether (1) early statin exposure during the acute phase after intracerebral haemorrhage and (2) early continuation of prevalent statin use are associated with favourable functional outcome. Patients and methods Data were obtained from the Virtual International Stroke Trials Archive. Patients were categorised according to use patterns of statins during this early in-hospital phase (continuation, discontinuation or new initiation of statins). Univariate and multivariable analyses were conducted to explore the association between early statin exposure and functional outcome. Results A total of 919 patients were included in the analysis. Early in-hospital statin exposure (n = 89, 9.7%) was associated with better functional outcome (modified Rankin Scale <= 3) compared with 790 patients without statin exposure before or early after the event (66% versus 47%, adjusted OR 2.1, 95% confidence interval 1.3-3.6). Compared with patients without exposure to statins before and early after the event, early continuation of statin therapy (n = 57) was associated with favourable functional outcome (adjusted odds ratio 2.6, 95% confidence interval 1.3-5.2). The association between early continuation of statins and outcome remained robust in sensitivity analyses restricted to patients able to take oral medication within 72 h and one-week survivors. Discussion It is possible that part of the observed associations are not due to a protective effect of statins but are confounded by indication bias. Conclusion Statin exposure and continuation of prevalent statin therapy early after intracerebral haemorrhage are associated with favourable functional outcome after 90 days.

Introduction: The Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation Phase III trial (MISTIE III) concluded that the extent of hematoma reduction confers a mortality and functional benefit. It is unclear if a minimum extent of evacuation is needed for mortality and functional outcome benefit in lobar cases with MISTIE and with open surgical interventions. Objective: We analyzed the effect of extent of lobar ICH evacuation on clinical outcome at 180 days after undergoing the MISTIE procedure and open craniotomy, in the context of the MISTIE III and STICH II clinical trials, respectively. Methods: Patients randomized to the surgical arm with lobar ICH, who underwent the procedure in the MISTIE III trial (n=84) and the STICH II trial (n=266) were analyzed, excluding cases crossing over to surgery. We assessed end of treatment ICH volume on post procedure CT scans and % hematoma evacuation, in relation to survival and likelihood of mRS 0-3. Cubic spline modeling with dichotomized outcome was used to compare the extent of hematoma evacuation on clinical outcome. Results: End of treatment volume of < 28 mL in lobar ICH MISTIE III patients and < 30 mL in STICH II trial patients showed a significantly increased probability of achieving an mRS of 0-3 at 180 days (p<0.03, p<0.006, respectively). This threshold was achieved in 83.1% of lobar cases undergoing MISTIE and in 92.1% of surgical cases in STICH II. Achieving survival benefit at 180 days trended towards improved probability with further hematoma volume reduction without a threshold value in MISTIE III, and was significant per mL reduction in STICH II (p<0.001). Analysis by percent of hematoma evacuation trended toward better probabilities of survival and improved functional outcome but were not significant. Conclusion: This analysis confirms that extent of hematoma evacuation is important in attaining the benefits of both minimally invasive and open surgical interventions in non-herniating lobar ICH patients randomized in clinical trials. Extent of ICH evacuation must be considered in the analysis of comparative effectiveness of various techniques and in the design of future trials.

External ventricular drainage (EVD) may be used for therapeutic cerebrospinal fluid (CSF) drainage to control intracranial pressure (ICP) after traumatic brain injury (TBI). However, there is currently uncertainty regarding the optimal timing for EVD insertion. This study aims to compare patient outcomes for patients with early and late EVD insertion. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, MEDLINE/EMBASE/Scopus/Web of Science/Cochrane Central Register of Controlled Trials were searched for published literature involving at least 10 severe TBI (sTBI) patients from their inception date to December 2019. Outcomes assessed were mortality, functional outcome, ICP control, length of stay, therapy intensity level, and complications. Twenty-one studies comprising 4542 sTBI patients with an EVD were included; 19 of the studies included patients with an early EVD, and two studies had late EVD placements. The limited number of studies, small sample sizes, imbalance in baseline characteristics between the groups and poor methodological quality have limited the scope of our analysis. We present the descriptive statistics highlighting the current conflicting data and the overall lack of reliable research into the optimal timing of EVD. There is a clear need for high quality comparisons of early vs. late EVD insertion on patient outcomes in sTBI.

Background Despite promising epidemiological data, it remains unclear if increased blood pressure variability is associated with death after acute ischemic stroke. Our objective was to examine this association in a large cohort of acute ischemic stroke patients. Methods We conducted a retrospective analysis of anonymized, pooled, participant data from the Virtual International Stroke Trial Archive. We included patients with a 90-day modified Rankin Scale and blood pressure readings in the 24 h after study enrollment. The exposure was blood pressure variability during the day after study enrollment, calculated for the systolic and diastolic blood pressure using six statistical methodologies. The primary outcome was death within 90 days of stroke onset. Results Our cohort comprised 1891 patients of whom 277 (14.7%) died within 90 days. All indices of blood pressure variability were higher in patients who died, but the difference was more pronounced for systolic than diastolic blood pressure variability (systolic standard deviation for alive versus dead patients = 13.4 versus 15.9 mmHg, p < 0.001). Similar results were found in logistic regression models fit to the outcome of death, but only systolic blood pressure variability remained significant in adjusted models (Odds Ratio for death when comparing highest to lowest tercile of systolic blood pressure variability = 1.41–1.89, p < 0.03 for all). Conclusions and relevance: These results reinforce prior studies that found increased blood pressure variability is associated with worse neurologic outcome after stroke. These data should help guide research on blood pressure variability after stroke and advocate for the inclusion of death as a clinical outcome in future studies that therapeutically reduce blood pressure variability.

Introduction: Antibiotics used to treat post-stroke infections have differing antimicrobial and anti-inflammatory effects. Our aim was to investigate whether antibiotic class was associated with outcome after post-stroke infection. Methods: We analyzed pooled individual participant data from the Virtual International Stroke Trials Archive (VISTA)-Acute. Patients with ischemic stroke and with an infection treated with systemic antibiotic therapy during the first 2 weeks after stroke onset were eligible. Antibiotics were grouped into eight classes, according to antimicrobial mechanism and prevalence. The primary analysis investigated whether antibiotic class for any infection, or for pneumonia, was independently associated with a shift in 90 day modified Rankin Scale (mRS) using ordinal logistic regression. Results: 2,708 patients were eligible (median age [IQR] = 74 [65 to 80] y; 51% female; median [IQR] NIHSS score = 15 [11 to 19]). Pneumonia occurred in 35%. Treatment with macrolides (5% of any infections; 9% of pneumonias) was independently associated with more favorable mRS distribution for any infection [OR (95% CI) = 0.59 (0.42 to 0.83), p = 0.004] and for pneumonia [OR (95% CI) = 0.46 (0.29 to 0.73), p = 0.001]. Unfavorable mRS distribution was independently associated with treatment of any infection either with carbapenems, cephalosporins or monobactams [OR (95% CI) = 1.62 (1.33 to 1.97), p < 0.001], penicillin plus β-lactamase inhibitors [OR (95% CI) = 1.26 (1.03 to 1.54), p = 0.025] or with aminoglycosides [OR (95% CI) = 1.73 (1.22 to 2.46), p = 0.002]. Conclusion: This retrospective study has several limitations including effect modification and confounding by indication. Macrolides may have favorable immune-modulatory effects in stroke-associated infections. Prospective evaluation of the impact of antibiotic class on treatment of post-stroke infections is warranted.

Background and Purpose- Observational data suggest that antiplatelet therapy after intracerebral hemorrhage (ICH) alleviates thromboembolic risk without increasing the risk of recurrent ICH. Given the paucity of data on the relationship between antiplatelet therapy after ICH and functional outcomes, we aimed to study this association in a multicenter cohort. Methods- We meta-analyzed data from (1) the Massachusetts General Hospital ICH registry (n=1854), (2) the Virtual International Stroke Trials Archive database (n=762), and (3) the Yale stroke registry (n=185). Our exposure was antiplatelet therapy after ICH, which was modeled as a time-varying covariate. Our primary outcomes were all-cause mortality and a composite of major disability or death (modified Rankin Scale score 4-6). We used Cox proportional regression analyses to estimate the hazard ratio of death or poor functional outcome as a function of antiplatelet therapy and random-effects meta-analysis to pool the estimated HRs across studies. Additional analyses stratified by hematoma location (lobar and deep ICH) were performed. Results- We included a total of 2801 ICH patients, of whom 288 (10.3%) were started on antiplatelet medications after ICH. Median times to antiplatelet therapy ranged from 7 to 39 days. Antiplatelet therapy after ICH was not associated with mortality (hazard ratio, 0.85; 95% CI, 0.66-1.09), or death or major disability (hazard ratio, 0.83; 95% CI, 0.59-1.16) compared with patients not started on antiplatelet therapy. Similar results were obtained in additional analyses stratified by hematoma location. Conclusions- Antiplatelet therapy after ICH appeared safe and was not associated with all-cause mortality or functional outcome, regardless of hematoma location. Randomized clinical trials are needed to determine the effects and harms of antiplatelet therapy after ICH.