Atte Meretoja

Reducing in-hospital delay to 20 minutes in stroke thrombolysis

Objectives: Efficacy of thrombolytic therapy for ischemic stroke decreases with time elapsed from symptom onset. We analyzed the effect of interventions aimed to reduce treatment delays in our single-center observational series. Methods: All consecutive ischemic stroke patients treated with IV alteplase (tissue plasminogen activator [tPA]) were prospectively registered in the Helsinki Stroke Thrombolysis Registry. A series of interventions to reduce treatment delays were implemented over the years 1998 to 2011. In-hospital delays were analyzed as annual median door-to-needle time (DNT) in minutes, with interquartile range. Results: A total of 1,860 patients were treated between June 1995 and June 2011, which included 174 patients with basilar artery occlusion (BAO) treated mostly beyond 4.5 hours from symptom onset. In the non-BAO patients, the DNT was reduced annually, from median 105 minutes (65–120) in 1998, to 60 minutes (48–80) in 2003, further on to 20 minutes (14–32) in 2011. In 2011, we treated with tPA 31% of ischemic stroke patients admitted to our hospital. Of these, 94% were treated within 60 minutes from arrival. Performing angiography or perfusion imaging doubled the in-hospital delays. Patients with in-hospital stroke or arriving very soon from symptom onset had longer delays because there was no time to prepare for their arrival. Conclusions: With multiple concurrent strategies it is possible to cut the median in-hospital delay to 20 minutes. The key is to do as little as possible after the patient has arrived at the emergency room and as much as possible before that, while the patient is being transported.

Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study

Background: Global stroke epidemiology is changing rapidly. Although age-standardized rates of stroke mortality have decreased worldwide in the past 2 decades, the absolute numbers of people who have a stroke every year, and live with the consequences of stroke or die from their stroke, are increasing. Regular updates on the current level of stroke burden are important for advancing our knowledge on stroke epidemiology and facilitate organization and planning of evidence-based stroke care. Objectives: This study aims to estimate incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke (IS) and hemorrhagic stroke (HS) for 188 countries from 1990 to 2013. Methodology: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated using all available data on mortality and stroke incidence, prevalence and excess mortality. Statistical models and country-level covariate data were employed, and all rates were age-standardized to a global population. All estimates were produced with 95% uncertainty intervals (UIs). Results: In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS) and 10.3 million new strokes (67% IS). Over the 1990-2013 period, there was a significant increase in the absolute number of DALYs due to IS, and of deaths from IS and HS, survivors and incident events for both IS and HS. The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-related DALYs. Globally, the proportional contribution of stroke-related DALYs and deaths due to stroke compared to all diseases increased from 1990 (3.54% (95% UI 3.11-4.00) and 9.66% (95% UI 8.47-10.70), respectively) to 2013 (4.62% (95% UI 4.01-5.30) and 11.75% (95% UI 10.45-13.31), respectively), but there was a diverging trend in developed and developing countries with a significant increase in DALYs and deaths in developing countries, and no measurable change in the proportional contribution of DALYs and deaths from stroke in developed countries. Conclusion: Global stroke burden continues to increase globally. More efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority.

Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016

The last 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs may reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems.Summary Background Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends. Methods We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016. Findings The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72·3% (95% uncertainty interval [UI] 71·2–73·2) of deaths in 2016 with 19·3% (18·5–20·4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8·43% (8·00–8·67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006–16—age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1·80 million deaths (95% UI 1·59 million to 1·89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176–181) increase in deaths in ages 90–94 years and a 210% (208–212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2·89%); the median annualised rate of change for all other causes was lower (a decrease of 1·59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe. Interpretation The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems. Funding Bill & Melinda Gates Foundation.

Off-Label Thrombolysis Is Not Associated With Poor Outcome in Patients With Stroke

Background and Purpose— Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use. Methods— All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables. Results— One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage. Conclusions— Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.

Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months

Objective: To test the transferability of the Helsinki stroke thrombolysis model that achieved a median 20-minute door-to-needle time (DNT) to an Australian health care setting. Methods: The existing “code stroke” model at the Royal Melbourne Hospital was evaluated and restructured to include key components of the Helsinki model: 1) ambulance prenotification with patient details alerting the stroke team to meet the patient on arrival; 2) patients transferred directly from triage onto the CT table on the ambulance stretcher; and 3) tissue plasminogen activator (tPA) delivered in CT immediately after imaging. We analyzed our prospective, consecutive tPA registry for effects of these protocol changes on our DNT after implementation during business hours (8 am to 5 pm Monday–Friday) from May 2012. Results: There were 48 patients treated with tPA in the 8 months after the protocol change. Compared with 85 patients treated in 2011, the median (interquartile range) DNT was reduced from 61 (43–75) minutes to 46 (24–79) minutes (p = 0.040). All of the effect came from the change in the in-hours DNT, down from 43 (33–59) to 25 (19–48) minutes (p = 0.009), whereas the out-of-hours delays remain unchanged, from 67 (55–82) to 62 (44–95) minutes (p = 0.835). Conclusion: We demonstrated rapid transferability of an optimized tPA protocol to a different health care setting. With the cooperation of ambulance, emergency, and stroke teams, we succeeded in the absence of a dedicated neurologic emergency department or electronic patient records, which are features of the Finnish system. The next challenge is providing the same service out-of-hours.

Predicting outcome of IV thrombolysis–treated ischemic stroke patients The DRAGON score

Objective: To develop a functional outcome prediction score, based on immediate pretreatment parameters, in ischemic stroke patients receiving IV alteplase. Methods: The derivation cohort consists of 1,319 ischemic stroke patients treated with IV alteplase at the Helsinki University Central Hospital, Helsinki, Finland. We evaluated the predictive value of parameters associated with the 3-month outcome and developed the score according to the magnitude of logistic regression coefficients. We assessed accuracy of the model with bootstrapping. External validation was performed in a cohort of 330 patients treated at the University Hospital Basel, Basel, Switzerland. We assessed the score performance with area under the receiver operating characteristic curve (AUC-ROC). Results: The DRAGON score (0–10 points) consists of (hyper)Dense cerebral artery sign/early infarct signs on admission CT scan (both = 2, either = 1, none = 0), prestroke modified Rankin Scale (mRS) score >1 (yes = 1), Age (≥80 years = 2, 65–79 years = 1, <65 years = 0), Glucose level at baseline (>8 mmol/L [>144 mg/dL] = 1), Onset-to-treatment time (>90 minutes = 1), and baseline National Institutes of Health Stroke Scale score (>15 = 3, 10–15 = 2, 5–9 = 1, 0–4 = 0). AUC-ROC was 0.84 (0.80–0.87) in the derivation cohort and 0.80 (0.74–0.86) in the validation cohort. Proportions of patients with good outcome (mRS score 0–2) were 96%, 88%, 74%, and 0% for 0–1, 2, 3, and 8–10 points, respectively. Proportions of patients with miserable outcome (mRS score 5–6) were 0%, 2%, 5%, 70%, and 100% for 0–1, 2, 3, 8, and 9–10 points, respectively. External validation showed similar results. Conclusions: The DRAGON score is valid at our site and was reliable externally. It can support clinical decision-making, especially when invasive add-on strategies are considered. The score was not studied in patients with basilar artery occlusion. Further external validation is warranted.

Symptomatic intracranial hemorrhage after stroke thrombolysis: The SEDAN Score

A study was undertaken to develop a score for assessing risk for symptomatic intracranial hemorrhage (sICH) in ischemic stroke patients treated with intravenous (IV) thrombolysis.

Stroke Thrombolysis Save a Minute, Save a Day

Background and Purpose— Stroke thrombolysis is highly time-critical, but data on long-term effects of small reductions in treatment delays have not been available. Our objective was to quantify patient lifetime benefits gained from faster treatment. Methods— Observational prospective data of consecutive stroke patients treated with intravenous thrombolysis in Australian and Finnish centers (1998–2011; n=2258) provided distributions of age, sex, stroke severity, onset-to-treatment times, and 3-month modified Rankin Scale in daily clinical practice. Treatment effects derived from a pooled analysis of thrombolysis trials were used to model the shift in 3-month modified Rankin Scale distributions with reducing treatment delays, from which we derived the expected lifetime and level of long-term disability with faster treatment. Results— Each minute of onset-to-treatment time saved granted on average 1.8 days of extra healthy life (95% prediction interval, 0.9–2.7). Benefit was observed in all groups: each minute provided 0.6 day in old severe (age, 80 years; National Institutes of Health Stroke Scale [NIHSS] score, 20) patients, 0.9 day in old mild (age, 80 years; NIHSS score, 4) patients, 2.7 days in young mild (age, 50 years; NIHSS score, 4) patients, and 3.5 days in young severe (age, 50 years; NIHSS score, 20) patients. Women gained slightly more than men over their longer lifetimes. In the whole cohort, each 15 minute decrease in treatment delay provided an average equivalent of 1 month of additional disability-free life. Conclusions— Realistically achievable small reductions in stroke thrombolysis delays would result in significant and robust average health benefits over patients’ lifetimes. The awareness of concrete importance of speed could promote practice change.

Effectiveness of Primary and Comprehensive Stroke Centers PERFECT Stroke: A Nationwide Observational Study From Finland

Background and Purpose— Previous studies show better outcomes for patients with stroke receiving care in stroke units, but many different stroke unit criteria have been published. In this study, we explored whether stroke centers fulfilling standardized Brain Attack Coalition criteria produce better patient outcomes than hospitals without stroke centers. Methods— We did an observational register–linkage study of all patients with ischemic stroke treated in Finland between 1999 and 2006. After exclusion of recurrent strokes and nonanalyzable patients, we included 61 685 consecutive patients treated in 333 hospitals classified in national audits either as Comprehensive Stroke Centers, Primary Stroke Centers, or General Hospitals according to Brain Attack Coalition criteria. Primary outcome measures were case-fatality and being in institutional care 1 year after stroke. Results— Care in stroke centers was associated with lower 1-year case-fatality and reduced institutional care compared with General Hospitals. The number-needed-to-treat to prevent 1 death or institutional care at 1 year was 29 for Comprehensive Stroke Centers and 40 for Primary Stroke Centers versus General Hospitals. Patients treated in stroke centers had lower mortality during the entire follow-up of up to 9 years and their median survival was increased by 1 year. Conclusions— This study shows a clear association between the level of acute stroke care and patient outcome and supports use of published criteria for primary and comprehensive stroke centers.

Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis

Objectives: To assess the impact of symptomatic intracerebral hemorrhage (sICH) on outcome of thrombolysis-treated ischemic stroke patients, as additional to recognized prognosticators. Methods: The study cohort included 985 ischemic stroke patients treated with IV thrombolysis at the Helsinki University Central Hospital (1995–2008). In a multivariable model adjusted for baseline stroke severity, age, onset-to-treatment time, baseline glucose, hyperdense cerebral artery sign, and early infarct signs on baseline imaging, and prior modified Rankin Scale (mRS), we calculated risk ratios (RRs) of patients with sICH (separately per Safe Implementation of Thrombolysis in Stroke[SITS]–Monitoring Study, European Cooperative Acute Stroke Study II [ECASS-II], and National Institute of Neurological Disorders and Stroke [NINDS] definitions) for poor 3-month outcome (mRS 3–6) and mortality. Receiver operating characteristic (ROC) curve and integrated discrimination improvement (IDI) evaluated impact of sICH on outcome. Internal cross-validation of the model was done with bootstrap statistics. Results: The frequency of sICH was 2.1% (SITS), 7.0% (ECASS-II), and 9.4% (NINDS). RRs for poor and fatal outcome, respectively, were 1.7 and 4.8 (SITS), 1.6 and 3.8 (ECASS-II), and 1.6 and 3.4 (NINDS). In IDI analyses, sICH improved prediction model for 3-month mRS of 3–6 and 4–6, respectively, by 1.4% and 3.0% (SITS), 4.0% and 5.9% (ECASS-II), and 4.7% and 6.1% (NINDS). In case of 3-month mRS 5–6 and mortality, it was 6.1% and 5.3% (SITS), 11.3% and 9.3% (ECASS-II), and 10.3% and 8.0% (NINDS). ROC analysis revealed similar results. Conclusions: Patients with sICH have increased risk of poor and fatal outcome. Compared with recognized stroke prognosticators, contribution of sICH is smaller. Definition-wise, ECASS-II- and NINDS-based sICH contribute relatively more; ECASS-II has the largest contribution to worst outcomes.