Antithrombotic treatment after stroke due to intracerebral haemorrhage

BACKGROUND: This is an update of the Cochrane Review last published in 2017. Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of major adverse cardiovascular events (MACE). Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of ischaemic MACE after ICH, but they may increase the risk of bleeding. OBJECTIVES: To determine the overall effectiveness and safety of antithrombotic drugs on MACE and its components for people with ICH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (5 October 2021). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2021, Issue 10), MEDLINE Ovid (from 1948 to October 2021) and Embase Ovid (from 1980 to October 2021). The online registries of clinical trials searched were the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (5 October 2021). We screened the reference lists of included randomised controlled trials (RCTs) for additional, potentially relevant RCTs. SELECTION CRITERIA: We selected RCTs in which participants with ICH of any age were allocated to a class of antithrombotic treatment as intervention or comparator. DATA COLLECTION AND ANALYSIS: In accordance with standard methodological procedures recommended by Cochrane, two review authors assessed each selected RCT for its risk of bias and extracted data independently. The primary outcome was a composite of MACE, and secondary outcomes included death, individual components of the MACE composite, ICH growth, functional status and cognitive status. We estimated effects using the frequency of outcomes that occurred during the entire duration of follow‐up and calculated a risk ratio (RR) for each RCT. We grouped RCTs separately for analysis according to 1) the class(es) of antithrombotic treatment used for the intervention and comparator, and 2) the duration of antithrombotic treatment use (short term versus long term). We pooled the intention‐to‐treat populations of RCTs using a fixed‐effect model for meta‐analysis, but used a random‐effects model if RCTs differed substantially in their design or there was considerable heterogeneity (I(2) ≥ 75%) in their results. We applied GRADE to assess the certainty of the evidence. MAIN RESULTS: We identified seven new completed RCTs for this update, resulting in the inclusion of a total of nine RCTs based in secondary care, comprising 1491 participants (average age ranged from 61 to 79 years and the proportion of men ranged from 44% to 67%). The proportion of included RCTs at low risk of bias, by category was: random sequence generation (67%), allocation concealment (67%), performance (22%), detection (78%), attrition (89%), and reporting (78%). For starting versus avoiding short‐term prophylactic dose anticoagulation after ICH, no RCT reported MACE. The evidence is very uncertain about the effect of starting short‐term prophylactic dose anticoagulation on death (RR 1.00, 95% CI 0.59 to 1.70, P = 1.00; 3 RCTs; very low‐certainty evidence), venous thromboembolism (RR 0.84, 95% CI 0.51 to 1.37, P = 0.49; 4 RCTs; very low‐certainty evidence), ICH (RR 0.24, 95% CI 0.04 to 1.38, P = 0.11; 2 RCTs; very low‐certainty evidence), and independent functional status (RR 2.03, 95% CI 0.78 to 5.25, P = 0.15; 1 RCT; very low‐certainty evidence) over 90 days. For starting versus avoiding long‐term therapeutic dose oral anticoagulation for atrial fibrillation after ICH, starting long‐term therapeutic dose oral anticoagulation probably reduces MACE (RR 0.61, 95% CI 0.40 to 0.94, P = 0.02; 3 RCTs; moderate‐certainty evidence) and probably reduces all major occlusive vascular events (RR 0.27, 95% CI 0.14 to 0.53, P = 0.0002; 3 RCTs; moderate‐certainty evidence), but probably results in little to no difference in death (RR 1.05, 95% CI 0.62 to 1.78, P = 0.86; 3 RCTs; moderate‐certainty evidence), probably increases intracranial haemorrhage (RR 2.43, 95% CI 0.88 to 6.73, P = 0.09; 3 RCTs; moderate‐certainty evidence), and may result in little to no difference in independent functional status (RR 0.98, 95% CI 0.78 to 1.24, P = 0.87; 2 RCTs; low‐certainty evidence) over one to three years. For starting versus avoiding long‐term antiplatelet therapy after ICH, the evidence is uncertain about the effects of starting long‐term antiplatelet therapy on MACE (RR 0.89, 95% CI 0.64 to 1.22, P = 0.46; 1 RCT; moderate‐certainty evidence), death (RR 1.08, 95% CI 0.76 to 1.53, P = 0.66; 1 RCT; moderate‐certainty evidence), all major occlusive vascular events (RR 1.03, 95% CI 0.68 to 1.55, P = 0.90; 1 RCT; moderate‐certainty evidence), ICH (RR 0.52, 95% CI 0.27 to 1.03, P = 0.06; 1 RCT; moderate‐certainty evidence) and independent functional status (RR 0.95, 95% CI 0.77 to 1.18, P = 0.67; 1 RCT; moderate‐certainty evidence) over a median follow‐up of two years. For adults within 180 days of non‐cardioembolic ischaemic stroke or transient ischaemic attack and a clinical history of prior ICH, there was no evidence of an effect of long‐term cilostazol compared to aspirin on MACE (RR 1.33, 95% CI 0.74 to 2.40, P = 0.34; subgroup of 1 RCT; low‐certainty evidence), death (RR 1.65, 95% CI 0.55 to 4.91, P = 0.37; subgroup of 1 RCT; low‐certainty evidence), or ICH (RR 1.29, 95% CI 0.35 to 4.69, P = 0.70; subgroup of 1 RCT; low‐certainty evidence) over a median follow‐up of 1.8 years; all major occlusive vascular events and functional status were not reported. AUTHORS' CONCLUSIONS: We did not identify beneficial or hazardous effects of short‐term prophylactic dose parenteral anticoagulation and long‐term oral antiplatelet therapy after ICH on important outcomes. Although there was a significant reduction in MACE and all major occlusive vascular events after long‐term treatment with therapeutic dose oral anticoagulation for atrial fibrillation after ICH, the pooled estimates were imprecise, the certainty of evidence was only moderate, and effects on other important outcomes were uncertain. Large RCTs with a low risk of bias are required to resolve the ongoing dilemmas about antithrombotic treatment after ICH

Antithrombotic treatment after intracerebral hemorrhage: Surveys among stroke physicians in Scandinavia and the United Kingdom

BACKGROUND AND AIMS: It is unclear whether patients with previous intracerebral hemorrhage (ICH) should receive antithrombotic treatment to prevent ischemic events. We assessed stroke physicians' opinions about this, and their views on randomizing patients in trials assessing this question. METHODS: We conducted three web‐based surveys among stroke physicians in Scandinavia and the United Kingdom. RESULTS: Eighty‐nine of 205 stroke physicians (43%) responded to the Scandinavian survey, 161 of 180 (89%) to the UK antiplatelet survey, and 153 of 289 (53%) to the UK anticoagulant survey. In Scandinavia, 19 (21%) stroke physicians were uncertain about antiplatelet treatment after ICH for ischemic stroke or transient ischemic attack (TIA) and 21 (24%) for prior myocardial infarction. In the United Kingdom, 116 (77%) were uncertain for ischemic stroke or TIA and 115 (717%) for ischemic heart disease. In Scandinavia, 32 (36%) were uncertain about anticoagulant treatment after ICH for atrial fibrillation, and 26 (29%) for recurrent deep vein thrombosis or pulmonary embolism. In the United Kingdom, 145 (95%) were uncertain about anticoagulants after ICH in at least some cases. In both regions combined, 191 of 250 (76%) would consider randomizing ICH survivors in a trial of starting versus avoiding antiplatelets, and 176 of 242 (73%) in a trial of starting versus avoiding anticoagulants. CONCLUSION: Considerable proportions of stroke physicians in Scandinavia and the United Kingdom were uncertain about antithrombotic treatment after ICH. A clear majority would consider randomizing patients in trials assessing this question. These findings support the need for such trials

Plasma linoleic acid levels and cardiovascular risk factors:results from the Norwegian ACE 1950 Study

Background A high intake of linoleic acid (LA), the major dietary polyunsaturated fatty acid (PUFA), has previously been associated with reduced cardiovascular (CV) morbidity and mortality in observational studies. However, recent secondary analyses from clinical trials of LA-rich diet suggest harmful effects of LA on CV health. Methods A total of 3706 participants, all born in 1950, were included in this cross-sectional study. We investigated associations between plasma phospholipid levels of LA and CV risk factors in a Norwegian general population, characterized by a relative low LA and high marine n-3 PUFA intake. The main statistical approach was multivariable linear regression. Results Plasma phospholipid LA levels ranged from 11.4 to 32.0 wt%, with a median level of 20.8 wt% (interquartile range 16.8–24.8 wt%). High plasma LA levels were associated with lower serum low-density lipoprotein cholesterol levels (standardized regression coefficient [Std. β-coeff.] −0.04, p = 0.02), serum triglycerides (Std. β-coeff. −0.10, p < 0.001), fasting plasma glucose (Std. β-coeff. −0.10, p < 0.001), body mass index (Std. β-coeff. −0.13, p < 0.001), systolic and diastolic blood pressure (Std. β-coeff. −0.04, p = 0.03 and Std. β-coeff. −0.02, p = 0.02, respectively) and estimated glomerular filtration rate (Std. β-coeff. −0.09, p < 0.001). We found no association between plasma LA levels and high-density lipoprotein cholesterol levels, glycated hemoglobin, carotid intima-media thickness, or C-reactive protein. Conclusion High plasma LA levels were favorably associated with several CV risk factors in this study of a Norwegian general population

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials

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

Middle Cerebral Artery Pulsatility Index is Associated with Cognitive Impairment in Lacunar Stroke

BACKGROUND AND PURPOSE Pulsatility index (PI) of the middle cerebral artery is postulated to reflect the vascular resistance in the artery distal of the probe, and has been reported to increase in small vessel disease, diabetes mellitus, ageing, and dementia. Lacunar infarcts are considered to be related to cognitive impairment. We therefore conducted a study to assess the association between cognitive impairment and PI in patients with a lacunar infarct. METHODS Consecutive patients presenting with an acute lacunar syndrome who were admitted to the stroke unit were enrolled. The patients were examined with Doppler ultrasonography of the intracranial arteries, and the PI of the middle cerebral artery was recorded. Cognitive function was evaluated by mini-mental state examination (MMSE), clock drawing test, and trail making test (TMT) A and B. RESULTS Among the 113 patients included, 85 patients had an acute lacunar infarct and 28 had one or more nonlacunar infarcts. The mean PI was 1.46 (SD = .33). PI was significantly (P < .05) associated with MMSE, TMT A and TMT B in patients with lacunar infarct, even after adjustment for multiple patient characteristics (age, sex, prestroke hypertension, smoking, previous stroke, and diabetes). CONCLUSIONS PI was associated with the cognitive performance in patients with lacunar infarcts and a lacunar syndrome. An elevated PI may be related to impairment in several cognitive domains. These findings suggest that transcranial Doppler ultrasonography could be an adjunct tool for early diagnosis of cognitive impairment after stroke

A pragmatic approach to sonothrombolysis in acute ischaemic stroke: The Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS)

Background: Ultrasound accelerates thrombolysis with tPA (sonothrombolysis). Ultrasound in the absence of tPA also accelerates clot break-up (sonolysis). Adding intravenous gaseous microbubbles may potentiate the effect of ultrasound in both sonothrombolysis and sonolysis. The Norwegian Sonothrombolysis in Acute Stroke Study aims in a pragmatic approach to assess the effect and safety of contrast enhanced ultrasound treatment in unselected acute ischaemic stroke patients. Methods/Design: Acute ischaemic stroke patients ≥18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4½ hours after symptom onset, are included in NOR-SASS. NOR-SASS is superimposed on a separate trial randomising patients with acute ischemic stroke to either tenecteplase or alteplase (The Norwegian Tenecteplase Stroke Trial NOR-TEST). The NOR-SASS trial has two arms: 1) the thrombolysis-arms (NOR-SASS A and B) includes patients given intravenous thrombolysis (tenecteplase or alteplase), and 2) the no-thrombolysis-arm (NOR-SASS C) includes patients with contraindications to thrombolysis. First step randomisation of NOR-SASS A is embedded in NOR-TEST as a 1:1 randomisation to either tenecteplase or alteplase. Second step NOR-SASS randomisation is 1:1 to either contrast enhanced sonothrombolysis (CEST) or sham CEST. Randomisation in NOR-SASS B (routine alteplase group) is 1:1 to either CEST or sham CEST. Randomisation of NOR-SASS C is 1:1 to either contrast enhanced sonolysis (CES) or sham CES. Ultrasound is given for one hour using a 2-MHz pulsed-wave diagnostic ultrasound probe. Microbubble contrast (SonoVue®) is given as a continuous infusion for ~30 min. Recanalisation is assessed at 60 min after start of CEST/CES. Magnetic resonance imaging and angiography is performed after 24 h of stroke onset. Primary study endpoints are 1) major neurological improvement measured with NIHSS score at 24 h and 2) favourable functional outcome defined as mRS 0–1 at 90 days. Discussion: NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤4½ hours after stroke onset in an unselected acute ischaemic stroke population eligible or not eligible for intravenous thrombolysis, with or without a defined arterial occlusion on CTA. If a positive effect and safety can be proven, contrast enhanced ultrasound treatment will be an option for all acute ischaemic stroke patients. EudraCT No 201200032341; www.​clinicaltrials.​gov NCT01949961