For several years, the only therapy with proven efficacy for acute ischaemic stroke was alteplase, which is approved for use within 4·5 h after stroke onset in many countries, but only within 3 h in ...the USA. However, the recanalisation rate with alteplase is modest. Several trials have shown substantial clinical benefit of neurothrombectomy within 6 h of ischaemic stroke onset, which has initiated a new era of acute stroke therapy. As neurothrombectomy becomes part of standard practice, additional trials will be needed to determine the best way to organise delivery of this care. Continuing clinical trials with several types of advanced MRI and CT imaging to enhance patient selection are investigating alteplase, other thrombolytic drugs, and novel endovascular devices, for use in later time periods from stroke onset. Consequently, the organisation and implementation of future clinical trials will need to adapt to what has been learned from the present generation of trials. The delivery of care to patients with acute stroke will also need to incorporate newly proven therapies, and much additional work is needed to maximise outcomes in as many patients as possible.
Since large-vessel occlusion (LVO)-related acute ischemic strokes (AIS) are associated with more severe deficits, we hypothesize that the endovascular thrombectomy (ET) may disproportionately benefit ...stroke-related dependence and death.
To delineate LVO-AIS impact, systematic search identified studies measuring dependence or death modified Rankin Scale (mRS) 3-6 or mortality following ischemic stroke among consecutive patients presenting with both LVO and non-LVO events within 24 h of symptom onset.
Among 197 articles reviewed, 2 met inclusion criteria, collectively enrolling 1,467 patients. Rates of dependence or death (mRS 3-6) within 3-6 months were higher after LVO than non-LVO ischemic stroke, 64 vs. 24%, odds ratio (OR) 4.46 (CI: 3.53-5.63,
< 0.0001). Mortality within 3-6 months was higher after LVO than non-LVO ischemic stroke, 26.2 vs. 1.3%, OR 4.09 (CI: 2.5-6.68),
< 0.0001. Consequently, while LVO ischemic events accounted for 38.7% (CI: 21.8-55.7%) of all acutely presenting ischemic strokes, they accounted for 61.6% (CI: 41.8-81.3%) of poststroke dependence or death and 95.6% (CI: 89.0-98.8%) of poststroke mortality. Using literature-based projections of LVO cerebral ischemia patients treatable within 8 h of onset, ET can be used in 21.4% of acutely presenting patients with ischemic stroke, and these events account for 34% of poststroke dependence and death and 52.8% of poststroke mortality.
LVOs cause a little more than one-third of acutely presenting AIS, but are responsible for three-fifths of dependency and more than nine-tenths of mortality after AIS. At the population level, ET has a disproportionate benefit in reducing severe stroke outcomes.
The phrase "time is brain" emphasizes that human nervous tissue is rapidly lost as stroke progresses and emergent evaluation and therapy are required. Recent advances in quantitative neurostereology ...and stroke neuroimaging permit calculation of just how much brain is lost per unit time in acute ischemic stroke.
Systematic literature-review identified consensus estimates of number of neurons, synapses, and myelinated fibers in the human forebrain; volume of large vessel, supratentorial ischemic stroke; and interval from onset to completion of large vessel, supratentorial ischemic stroke.
The typical final volume of large vessel, supratentorial ischemic stroke is 54 mL (varied in sensitivity analysis from 19 to 100 mL). The average duration of nonlacunar stroke evolution is 10 hours (range 6 to 18 hours), and the average number of neurons in the human forebrain is 22 billion. In patients experiencing a typical large vessel acute ischemic stroke, 120 million neurons, 830 billion synapses, and 714 km (447 miles) of myelinated fibers are lost each hour. In each minute, 1.9 million neurons, 14 billion synapses, and 12 km (7.5 miles) of myelinated fibers are destroyed. Compared with the normal rate of neuron loss in brain aging, the ischemic brain ages 3.6 years each hour without treatment. Altering single input variables in sensitivity analyses modestly affected the estimated point values but not order of magnitude.
Quantitative estimates of the pace of neural circuitry loss in human ischemic stroke emphasize the time urgency of stroke care. The typical patient loses 1.9 million neurons each minute in which stroke is untreated.
Whether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown.
In a multicenter, randomized, open-label ...trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory.
We enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval CI, 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group.
Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270 .).
Background and Purpose- TNK (tenecteplase), a newer fibrinolytic agent, has practical delivery advantages over ALT (alteplase) that would make it a useful agent if noninferior in acute ischemic ...stroke treatment outcome. Accordingly, the most recent US American Heart Association/American Stroke Association acute ischemic stroke guideline recognized TNK as an alternative to ALT, but only based on informal consideration, rather than formal meta-analysis, of completed randomized control trials. Methods- Systematic literature search and formal meta-analysis were conducted per PRISMA guidelines (Preferred Reporting Items for Systemic Reviews and Meta-Analyses), adapted to noninferiority analysis. The primary outcome of freedom from disability (modified Rankin Scale score, 0-1) outcome at 3 m, and additional efficacy and safety outcomes, were analyzed. Results- Systematic search identified 5 trials enrolling 1585 patients (828 TNK, 757 ALT). Across all trials, mean age was 70.8, 58.5% male, baseline National Institutes of Health Stroke Scale mean 7.0, and time from last known well to treatment start mean 148 minutes. All ALT patients received standard 0.9 mg/kg dosing, while TNK dosing was 0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%. For the primary end point, crude cumulative rates of disability-free (modified Rankin Scale score, 0-1) 3 m outcome were TNK 57.9% versus ALT 55.4%. Informal, random-effects meta-analysis, the risk difference was 4% (95% CI, -1% to 8%). The lower 95% CI bound fell well within the prespecified noninferiority margin. Similar results were seen for the additional efficacy end points: functional independence (modified Rankin Scale score, 0-2): crude TNK 71.9% versus ALT 70.5%, risk difference 2% (95% CI, -3% to 6%); and modified Rankin Scale shift analysis, common odds ratio 1.21 (95% CI, 0.93-1.57). For safety end points, lower event rates reduced power, but point estimates were also consistent with noninferiority Conclusions- Accumulated clinical trial data provides strong evidence that TNK is noninferior to ALT in the treatment of acute ischemic stroke. These findings provide formal support for the recent guideline recommendation to consider TNK an alternative to ALT.
Stroke recently declined from the third to the fourth leading cause of death in the United States, its first rank transition among sources of American mortality in nearly 75 years.
This is a ...narrative review supplemented by new analyses of Centers for Disease Control and Prevention National Vital Statistics Reports from 1931 to 2008.
Historically, stroke transitioned from the second to the third leading cause of death in the United States in 1937, but stroke death rates were essentially stable from 1930 to 1960. Then a long, great decline began, moderate in the 1960s, precipitous in the 1970s and 1980s, and moderate again in the 1990s and 2000s. By 2008, age-adjusted annual death rates from stroke were three fourths less than the historic 1931 to 1960 norm (40.6 versus 175.0 per 100,000). Total actual stroke deaths in the United States declined from a high of 214,000 in 1973 to 134,000 in 2008. Improved stroke prevention, through control of hypertension, hyperlipidemia, and tobacco, contributed most greatly to the mortality decline with a lesser but still substantial contribution of improved acute stroke care. Persisting challenges include race-ethnicity, sex, and geographic disparities in stroke mortality; the burden of stroke disability; the expanding obesity epidemic and aging of the US population; and the epidemic of cerebrovascular disease in low- and middle-income countries worldwide.
The recent rank decline of stroke among leading causes of American death is testament to a half century of societal progress in cerebrovascular disease prevention and acute care. Renewed commitments are needed to preserve and broaden this historic achievement.
Comparative assessment of acute ischemic stroke care quality provided by hospitals in the United States has been hampered by the unavailability of the National Institutes of Health Stroke Scale ...(NIHSS) in administrative data sets, preventing adequate adjustment for variations in patient case-mix risk. In response to stakeholder concerns, the US Centers for Medicare & Medicaid Services in 2016 implemented optional reporting of NIHSS scores.
To analyze the distributional, convergent, and predictive validity of nationally submitted NIHSS values in the National Inpatient Sample.
This population-based retrospective cross-sectional study took place from October 1 to December 31, 2016. The nationally representative sample included US adults who had ischemic stroke hospitalizations during the first calendar quarter in which optional NIHSS reporting was implemented. Analysis began September 2019.
Distribution of NIHSS scores, functional independence at discharge, inpatient mortality, and administrative reporting of NIHSS.
Among 154 165 ischemic stroke hospitalizations during the first 3 months of the reporting policy, NIHSS scores were reported in 21 685 patients (14%) (10 925 women 50.4%; median interquartile range age, 72 61-82 years). Median (interquartile range) NIHSS score was 4 (2-11), and frequency of severity categories included absent (NIHSS score, 0) in 2080 patients (9.6%), minor (NIHSS score, 1-4) in 8760 patients (40.4%), and severe (NIHSS score, 21-42) in 1930 patients (8.9%). National Institutes of Health Stroke Scale score of 10 or more, an indicator of possible large vessel occlusions, was present in 6290 patients (29%). Presenting NIHSS score was higher in very elderly patients (age ≥80 y) and women and also in patients receiving endovascular thrombectomy vs intravenous thrombolysis alone vs no reperfusion therapy (median interquartile range, 17 12-22 vs 6 4-12 vs 4 2-9, respectively) (P < .001). National Institutes of Health Stroke Scale scores were similarly higher for discharge outcomes of mortality vs discharge to skilled nursing facility vs discharge home (median interquartile range, 19 12-25 vs 7 3-15 vs 2 1-5, respectively) (P < .001). Likelihood of NIHSS scores being reported independently increased with interfacility transfer, receipt of acute reperfusion therapies, larger hospital size, academic centers, and region other than the West.
In the initial national optional reporting period in the United States, NIHSS scores were reported in nearly 1 in 7 ischemic stroke hospitalizations. The distribution of NIHSS scores was similar to that from narrow population-based studies and registries, and NIHSS scores were powerfully associated with discharge outcome, supporting the validity and potential to aid care quality assessment.
Stroke treatments are generally not curative, but rather alter patient outcome over the entire range of functional measures. Dichotomizing outcome scales reduces computational complexity, but ...discards substantial outcome information, artificially privileges only a single health state transition as clinically meaningful, and often reduces study power. Newer approaches to endpoint analysis have several advantageous properties. Summary of Review- The global statistic assesses treatment effects on multiple outcome measures simultaneously. However, translating the global statistic multidimensional vector effect at the population level into benefit or harm expected in the individual patient is problematic. Responder analysis adjusts outcome thresholds to patient stroke severity at study entry, identifying achievable goals for each patient. However, responder analysis still discards substantial outcome information. Shift analysis gauges change in outcome distributions over the full range of ascertained outcomes, incorporating benefit and harm at all health state transitions valued by patients and clinicians, and often increasing study power. Translation of findings of shift analyses into clinically accessible terms may be accomplished using the recently developed joint outcome table specification technique, which yields the following values for the number needed to treat for 1 patient to improve in a clinically important manner: nimodipine in subarachnoid hemorrhage, 6.8; coiling over clipping, 5.9; intra-arterial pro-urokinase in acute cerebral ischemia, 4.8; intravenous tissue plasminogen activator, 3.3.
Dichotomized, global statistic, responder, and shift analyses each offer distinctive benefits and drawbacks. Choice of primary end point analytic technique should be tailored to the study population, expected treatment response, and study purpose. Shift analysis generally provides the most comprehensive index of a treatment's clinical impact.
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