Evaluating the safety and efficacy of intravenous thrombolysis for acute ischemic stroke patients with a history of intracerebral hemorrhage: a systematic review and meta-analysis.

Previous intracerebral hemorrhage (ICH) is labelled as a contraindication for the use of intravenous tissue plasminogen activator (IV-tPA) in acute ischemic stroke (AIS) based on expert opinion. However, there is a paucity of data available regarding the benefits and risks of IV-tPA in this population. Recent small retrospective cohort studies reporting its off-label use suggest it may be beneficial. This study aims to investigate the safety and efficacy of IV-tPA in AIS patients with previous ICH. We performed a systematic review and meta-analysis of studies reporting on IV-tPA use in AIS patients with and without previous ICH. We searched Embase, PubMed and Cochrane Library from inception to 20 April 2021. Outcomes measured included symptomatic ICH (sICH), 3-month modified Rankin Scale (mRS) score, and 3-month mortality. We included seven retrospective cohort studies comprising 5760 AIS patients who had received IV-tPA, of which 134 had previous ICH. There was no significant difference in the odds of sICH (OR 1.57, 95% CI 0.78-3.15, p = 0.21) and 3-month mRS (mRS 0-1: OR 0.78, 95% CI 0.37-1.65, p = 0.52; mRS 0-2: OR 1.07, 95% CI 0.36-3.15, p = 0.90) between patients with and without previous ICH. There was a trend towards higher 3-month mortality in patients with previous ICH (OR 1.69, 95% CI 0.98-2.91, p = 0.06), although this did not reach statistical significance. The use of IV-tPA in AIS patients with previous ICH was not associated with an increased risk of sICH or disability at 3 months. Further larger studies are needed to establish the safety and efficacy of IV-tPA use in this population.

The use of colchicine as an anti-inflammatory agent for stroke prevention in patients with coronary artery disease: a systematic review and meta-analysis.

OBJECTIVE: The primary objective is to evaluate the use of colchicine as an anti-inflammatory agent for stroke prevention in patients with coronary artery disease. BACKGROUND: There has been a rising number of randomized controlled trials conducted in patients with coronary artery disease on the use of colchicine in reducing cardiovascular complications. Recent publications suggest colchicine reduces the risk of stroke and other cardiovascular events. METHODS: We performed a systematic review of known trials in the current literature to characterize the clinical characteristics and outcomes of colchicine treatment in patients with coronary artery disease. A literature search was performed in PubMed, Embase and SCOPUS using a suitable keyword search strategy from inception to 4 June 2021. All studies evaluating cardiovascular outcomes of colchicine treatment in patients with coronary artery disease were included. RESULTS: The systemic review included 5 randomized controlled trials assessing a total of 11,790 patients. Majority of studies used a colchicine dosing regimen of 0.5 mg once daily, with the median follow-up duration ranging from 6 to 36 months. Meta-analytic estimates for stroke incidence highlighted a statistically significant benefit for patients that were administered colchicine compared to placebo (OR 0.47, 95% CI 0.27-0.81, p = 0.006), and a non-significant benefit for myocardial infarction. There was no significant association between colchicine treatment and the adverse effects of gastrointestinal symptoms and myopathy/myalgia. CONCLUSIONS: The use of colchicine reduces the risk of stroke in patients with a history of coronary artery disease, without a significant increase in gastrointestinal and myopathy/myalgia adverse effects.

Left Atrial Volume Index Predicts New-Onset Atrial Fibrillation and Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source.

INTRODUCTION: It is unclear which surrogate of atrial cardiopathy best predicts the risk of developing a recurrent ischemic stroke in embolic stroke of undetermined source (ESUS). Left atrial diameter (LAD) and LAD index (LADi) are often used as markers of left atrial enlargement in current ESUS research, but left atrial volume index (LAVi) has been found to be a better predictor of cardiovascular outcomes in other patient populations. OBJECTIVE: We aim to compare the performance of LAVi, LAD, and LADi in predicting the development of new-onset atrial fibrillation (AF) and stroke recurrence in ESUS. METHODS: Between October 2014 and October 2017, consecutive patients diagnosed with ESUS were followed for new-onset AF, ischemic stroke recurrence, and a composite outcome of occult AF and stroke recurrence. LAVi and LADi were measured by transthoracic echocardiogram; "high" LAVi was defined as ≥35 mL/m2 in accordance with American Society of Echocardiography guidelines. RESULTS: 185 ischemic stroke patients with ESUS were recruited and followed for a median duration of 2.1 years. Increased LAVi was associated with new-onset AF detection (aOR 1.08; 95% CI 1.03-1.14; p = 0.003) and stroke recurrence (aOR 1.05; 95% CI 1.01-1.10; p = 0.026). Patients with "high" LAVi had a higher likelihood of developing a composite of AF detection and stroke recurrence (HR 3.45; 95% CI 1.55-7.67; p = 0.002). No significant association was observed between LADi and either occult AF or stroke recurrence. CONCLUSIONS: LAVi is associated with new-onset AF and stroke recurrence in ESUS patients and may be a better surrogate of atrial cardiopathy.

Effect of remote ischemic preConditioning on liver injury in patients undergoing liver resection: the ERIC-LIVER trial.

OBJECTIVE: Novel hepatoprotective strategies are needed to improve clinical outcomes during liver surgery. There is mixed data on the role of remote ischemic preconditioning (RIPC). We investigated RIPC in partial hepatectomy for primary hepatocellular carcinoma (HCC). METHODS: This was a Phase II, single-center, sham-controlled, randomized controlled trial (RCT). The primary hypothesis was that RIPC would reduce acute liver injury following surgery indicated by serum alanine transferase (ALT) 24 h following hepatectomy in patients with primary HCC, compared to sham. Patients were randomized to receive either four cycles of 5 min/5 min arm cuff inflation/deflation immediately prior to surgery, or sham. Secondary endpoints included clinical, biochemical and pathological outcomes. Liver function measured by Indocyanine Green pulse densitometry was performed in a subset of patients. RESULTS: 24 and 26 patients were randomized to RIPC and control groups respectively. The groups were balanced for baseline characteristics, except the duration of operation was longer in the RIPC group. Median ALT at 24 h was similar between groups (196 IU/L IQR 113.5-419.5 versus 172.5 IU/L IQR 115-298 respectively, p = 0.61). Groups were similar in secondary endpoints. CONCLUSION: This RCT did not demonstrate beneficial effects with RIPC on serum ALT levels 24 h after partial hepatectomy.

Effect of Pretreatment Blood Pressure on Outcomes in Thrombolysed Acute Ischemic Stroke Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Blood pressure (BP) is an important determinant of functional outcome in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA). Current guidelines recommend a BP target of 185/110 mmHg before IV-tPA bolus and maintaining it at less than 180/105 mmHg for the first 24 hours. However, the effect of blood pressure on various outcome measures after systemic thrombolysis remains unclear. METHODS: Following a systematic search of Medline and EMBASE, all observational studies reporting effect of pretreatment BP on 90-day functional outcome as measured by the modified Rankin Scale (mRS) and/ or incidence of symptomatic intracranial hemorrhage (sICH) in AIS patients receiving thrombolytic therapy were included. RESULTS: Of 2181 studies screened, 26 studies, involving 38,937 subjects, met inclusion criteria. Higher prethrombolysis systolic BP was significantly-associated with poorer 90-day functional outcome (Mean difference 3.87 mmHg; 95% confidence interval [CI] 1.18-6.56) and increased incidence of sICH (Mean difference 5.31; 95% CI 2.22-8.40). When studies were stratified by different cut-offs for functional outcome (mRS 0-1 versus 0-2) and definitions of sICH used (Randomized controlled trials or SITS-MOST), there was no significant difference in mean difference between the subgroups. CONCLUSIONS: Our data showed that higher prethrombolysis SBP was associated with poorer outcomes in thrombolysed acute ischemic stroke patients. This may suggest that more aggressive lowering of BP below the current recommendations prior to thrombolysis could be beneficial. The effect of early BP trends after tPA infusion could not be evaluated due to limited available data. Ongoing randomized clinical trials, like ENCHANTED, may provide further insights into the current guidelines and optimal BP levels.

The Relationship Between Ambient Air Pollution and Acute Ischemic Stroke: A Time-Stratified Case-Crossover Study in a City-State With Seasonal Exposure to the Southeast Asian Haze Problem.

STUDY OBJECTIVE: Studies are divided on the short-term association of air pollution with stroke. Singapore is exposed to seasonal transboundary haze. We aim to investigate the association between air pollution and stroke incidence in Singapore. METHODS: We performed a time-stratified case-crossover analysis on all ischemic stroke cases reported to the Singapore Stroke Registry from 2010 to 2015. Exposure on days was compared with control days on which exposure did not occur. Control days were chosen on the same day of the week earlier and later in the same month in the same year. We fitted a conditional Poisson regression model to daily stroke incidence that included Pollutant Standards Index and environmental confounders. The index was categorized according to established classification (0 to 50=good, 51 to 100=moderate, and ≥101=unhealthy). We assessed the relationship between stroke incidence and Pollutant Standards Index in the entire cohort and in predetermined subgroups of individual-level characteristics. RESULTS: There were 29,384 ischemic stroke cases. Moderate and unhealthy Pollutant Standards Index levels showed association with stroke occurrence, with incidence risk ratio 1.10 (95% confidence interval 1.06 to 1.13) and 1.14 (95% confidence interval 1.03 to 1.25), respectively. Subgroup analyses showed generally significant association, except in Indians and nonhypertensive patients. The association was significant in subgroups aged 65 years or older, women, Chinese, nonsmokers and those with history of diabetes, hypertension, and hyperlipidemia. Stratified by age and smoking, the risk diminished in smokers of all ages. Risk remained elevated for 5 days after exposure. CONCLUSION: We found a short-term elevated risk of ischemic stroke after exposure to air pollution. These findings have public health implications for stroke prevention and emergency health services delivery.

Association between the extension of smoke-free legislation and incident acute myocardial infarctions in Singapore from 2010 to 2019: an interrupted time-series analysis.

BACKGROUND: We examined the association between smoke-free laws implemented in the outdoors and the common areas of residential apartment blocks and reported acute myocardial infarctions (AMI) in Singapore. METHODS: We used an interrupted time-series design and seasonal autoregressive integrated moving average models to examine the effect of the smoke-free law extensions in 2013 (common areas of residential blocks, covered pedestrian linkways, overhead bridges and within 5 m of bus stops), 2016 (parks) and 2017 (educational institutions, buses and taxis) on the monthly incidence rate of AMIs per 1 000 000 population. RESULTS: We included 133 868 AMI reports from January 2010 to December 2019. Post-2013, there was a decrease in the AMI incidence trend (ß=-0.6 per month, 95%CI -1.0 to -0.29) and 2097 (95% CI 2094 to 2100) more AMIs may have occurred without the extension. There was a significant step-decline in male AMIs and a non-significant step-increase in female AMIs post-2013. Those 65 years and older experienced a greater decline to the postlegislation 2013 trend (ß=-5.9, 95% CI -8.7 to -3.1) compared with those younger (ß=-0.4, 95% CI -0.6 to -0.2), while an estimated 19 591 (15 711 to 23472) additional AMI cases in those 65 years and above may have occurred without the extension. We found a step-increase in monthly AMI incidence post-2016 (ß=14.2, 95%CI 3.3 to 25.0). CONCLUSION: The 2013 smoke-free law extension to residential estates and other outdoor areas were associated with a decline in AMIs and those above the age of 65 years and men appeared to be major beneficiaries. Additional epidemiological evidence is required to support the expanded smoke-free legislation to parks, educational institutions, buses and taxis.

Functional and Mortality Outcomes with Medical and Surgical Therapy in Malignant Posterior Circulation Infarcts: A Systematic Review.

BACKGROUND: There remains uncertainty regarding optimal definitive management for malignant posterior circulation infarcts (MPCI). While guidelines recommend neurosurgery for malignant cerebellar infarcts that are refractory to medical therapy, concerns exist about the functional outcome and quality of life after decompressive surgery. OBJECTIVE: This study aims to evaluate the outcomes of surgical intervention compared to medical therapy in MPCI. METHODS: In this systematic review, MEDLINE, Embase and Cochrane databases were searched from inception until 2 April 2021. Studies were included if they involved posterior circulation strokes treated with neurosurgical intervention and reported mortality and functional outcome data. Data were collected according to PRISMA guidelines. RESULTS: The search yielded 6677 studies, of which 31 studies (comprising 723 patients) were included for analysis. From the included studies, we found that surgical therapy led to significant differences in mortality and functional outcomes in patients with severe disease. Neurological decline and radiological criteria were often used to decide the timing for surgical intervention, as there is currently limited evidence for preventative neurosurgery. There is also limited evidence for the superiority of one surgical modality over another. CONCLUSION: For patients with MPCI who are clinically stable at the time of presentation, in terms of mortality and functional outcome, surgical therapy appears to be equivocal to medical therapy. Reliable evidence is lacking, and further prospective studies are rendered.

Clustering of Environmental Parameters and the Risk of Acute Ischaemic Stroke.

Acute ischaemic stroke (AIS) risk on days with similar environmental profiles remains unknown. We investigated the association between clusters of days with similar environmental parameters and AIS incidence in Singapore. We grouped calendar days from 2010 to 2015 with similar rainfall, temperature, wind speed, and Pollutant Standards Index (PSI) using k-means clustering. Three distinct clusters were formed 'Cluster 1' containing high wind speed, 'Cluster 2' having high rainfall, and 'Cluster 3' having high temperatures and PSI. We aggregated the number of AIS episodes over the same period with the clusters and analysed their association using a conditional Poisson regression in a time-stratified case-crossover design. Comparing the three clusters, Cluster 3 had the highest AIS occurrence (IRR 1.09; 95% confidence interval (CI) 1.05-1.13), with no significant difference between Clusters 1 and 2. Subgroup analyses in Cluster 3 showed that AIS risk was amplified in the elderly (≥65 years old), non-smokers, and those without a history of ischaemic heart disease/atrial fibrillation/vascular heart disease/peripheral vascular disease. In conclusion, we found that AIS incidence may be higher on days with higher temperatures and PSI. These findings have important public health implications for AIS prevention and health services delivery during at-risk days, such as during the seasonal transboundary haze.

Impact of time-to-compression on out-of-hospital cardiac arrest survival outcomes: A national registry study.

OBJECTIVE: We aimed to quantify the association of no-flow interval in out-of-hospital cardiac arrests (OHCA) with the odds of neurologically favorable survival and survival to hospital discharge/ 30th day. Our secondary aim was to explore futility thresholds to guide clinical decisions, such as prehospital termination of resuscitation. METHODS: All OHCAs from 2012 to 2017 in Singapore were extracted. We examined the association between no-flow interval (continuous variable) and survival outcomes using univariate and multivariable logistic regressions. The primary outcome was survival with favorable cerebral performance (Glasgow-Pittsburgh Cerebral Performance Categories 1/2), the secondary outcome was survival to hospital discharge/ 30th day if not discharged. To determine futility thresholds, we plotted the adjusted probability of good neurological outcomes to no-flow interval. RESULTS: 12,771 OHCAs were analyzed. The per-minute adjusted OR when no-flow interval was incorporated as a continuous variable in the multivariable model was: good neurological function- aOR 0.98 (95%CI: 0.97-0.98); survival to discharge- aOR 0.98 (95%CI: 0.98-0.99). Taking the 1% futility of survival line gave a no-flow interval cutoff of 12 mins (NPV 99%, sensitivity 85% and specificity 42%) overall and 7.5 mins for witnessed arrests. CONCLUSION: We demonstrated that prolonged no-flow interval had a significant effect on lower odds of favorable neurological outcomes, with medical futility occurring when no-flow interval was >12 mins (>7.5 mins for witnessed arrest). Our study adds to the literature of the importance of early CPR and EMS response and provided a threshold beyond traditional 'down-times', which could aid clinical decisions in TOR or OHCA management.

Clustering of Environmental Parameters and the Risk of Acute Myocardial Infarction.

The association between days with similar environmental parameters and cardiovascular events is unknown. We investigate the association between clusters of environmental parameters and acute myocardial infarction (AMI) risk in Singapore. Using k-means clustering and conditional Poisson models, we grouped calendar days from 2010 to 2015 based on rainfall, temperature, wind speed and the Pollutant Standards Index (PSI) and compared the incidence rate ratios (IRR) of AMI across the clusters using a time-stratified case-crossover design. Three distinct clusters were formed with Cluster 1 having high wind speed, Cluster 2 high rainfall, and Cluster 3 high temperature and PSI. Compared to Cluster 1, Cluster 3 had a higher AMI incidence with IRR 1.04 (95% confidence interval 1.01-1.07), but no significant difference was found between Cluster 1 and Cluster 2. Subgroup analyses showed that increased AMI incidence was significant only among those with age ≥65, male, non-smokers, non-ST elevation AMI (NSTEMI), history of hyperlipidemia and no history of ischemic heart disease, diabetes or hypertension. In conclusion, we found that AMI incidence, especially NSTEMI, is likely to be higher on days with high temperature and PSI. These findings have public health implications for AMI prevention and emergency health services delivery during the seasonal Southeast Asian transboundary haze.

Impact of Traditional and Non-Traditional Lipid Parameters on Outcomes after Intravenous Thrombolysis in Acute Ischemic Stroke.

Contradicting evidence exists regarding the role of lipids in outcomes following intravenous (IV) thrombolysis with tissue plasminogen activator (tPA). Restricted cubic spline curves and adjusted logistic regression were used to evaluate associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratio with poor functional outcome, symptomatic intracranial hemorrhage (SICH) and 90-day mortality, among 1004 acute ischemic stroke (AIS) patients who received IV tPA in a comprehensive stroke center. Quartile (Q) 1, Q2 and Q3 of HDL-C were associated with increased odds of poor functional outcome (adjusted odds ratio (adjOR) 1.66, 95% CI 1.06-2.60, p = 0.028, adjOR 1.63, 95% CI 1.05-2.53, p = 0.027, adjOR 1.56, 95% CI 1.01-2.44, p = 0.048) compared to Q4. Q2 and Q4 of non-HDL-C were associated with increased odds of SICH (adjOR 4.28, 95% CI 1.36-18.90, p = 0.025, adjOR 5.17, 95% CI 1.64-22.81, p = 0.011) compared to Q3. Q1 and Q2 of LDL-C was associated with increased odds of mortality (adjOR 2.57, 95% CI 1.27-5.57, p = 0.011 and adjOR 2.28, 95% CI 1.10-5.02, p = 0.032) compared to Q3. In AIS patients who received IV tPA, low LDL-C was associated with increased odds of mortality while HDL-C may be protective against poor functional outcome.

Containing COVID-19 in the Emergency Department: The Role of Improved Case Detection and Segregation of Suspect Cases.

OBJECTIVES: Patients with COVID-19 may present with respiratory syndromes indistinguishable from common viruses. This poses a challenge for early detection during triage in the emergency department (ED). Over a 3-month period, our ED aimed to minimize nosocomial transmission by using broader suspect case criteria for better detection and using appropriate personal protective equipment (PPE) for health care workers (HCWs). METHODS: All ED admissions with respiratory syndromes over a 3-month period were tested for COVID-19. The sensitivity and specificity of screening criteria in detecting COVID-19 were assessed. A risk-stratified approach was adopted for PPE usage in the ED, based on high-risk "fever areas" and lower-risk zones. When a case of COVID-19 was confirmed, surveillance was conducted for potentially exposed patients and HCWs. RESULTS: A total of 1,841 cases presenting with respiratory syndromes required admission over the study period. Among these, 70 cases of COVID-19 were subsequently confirmed. The majority (84.2%, 59/70) were detected at ED triage because they fulfilled suspect case criteria. Of these, 34 met the official screening criteria; an additional 25 were detected by the broader internal screening criteria. Over the 12-week period, the cumulative sensitivity of internal screening criteria was 84.3% (95% confidence interval [CI] = 73.6% to 91.9%), whereas the sensitivity of the official screening criteria was 48.6% (95% CI = 36.4% to 60.8%). Given the broadened internal criteria, the preexisting ED "fever area" was insufficient and had to be expanded. However, there were no cases of nosocomial transmission from intra-ED exposure, despite extensive surveillance. CONCLUSION: Frontline physicians need to be given leeway to decide on the disposition of cases based on clinical suspicion during an ongoing outbreak of COVID-19. If a broader criterion is used at ED triage, ED facilities and isolation facilities need to be readied to accommodate a surge of suspect cases. Usage of appropriate PPE is essential in minimizing nosocomial transmission.

Effect of vertical location on survival outcomes for out-of-hospital cardiac arrest in Singapore.

BACKGROUND: A large proportion of out-of-hospital cardiac arrest (OHCA) cases occur in high-rise residential buildings. This study aims to investigate the effect of vertical location on survival outcomes and response times. METHODS: This is a retrospective study based on data obtained from the Singapore cohort of the Pan-Asian Resuscitation Outcomes Study (PAROS) from January 2011 to December 2014. Study subjects were OHCA cases, unwitnessed and transported by EMS personnel, with known vertical location (floor) data. Traumatic arrests with no resuscitation attempted and missing vertical locations were excluded. The primary outcome was survival to hospital discharge or 30 days post-cardiac arrest. RESULTS: A total of 5678 OHCA cases were included in the study. The effect of floors on survival was manifested as a U-shaped response. Survival rates of 4.5% for the 4 pooled basement floors and 6.2% for the ground floor (floor 1) were contrasted by a substantial drop to 2.7% at floor 2 and continuing decline to 0.7% at floor 6. In a multivariable model using stepwise logistic regression, both linear (p = 0.0285) and quadratic (p = 0.0018) floor effects remained significant after adjustment for other significant risk factors, age, bystander witnessed arrest, first arrest rhythm, ROSC on scene/enroute, and EMS response times. Harrell's C-statistic for a predictive model incorporating these variables was 0.933. CONCLUSIONS: Vertical location is associated with OHCA survival probability with a U-shaped response, and this significance remained after adjustment for other significant OHCA variables. This relationship is likely multifactorial and more research is needed to elucidate the various factors.

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 µg/kg) followed by a 120-minute infusion (4 µg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.