Outcomes of Nonagenarians with Acute Ischemic Stroke Treated with Intravenous Thrombolytics.

BACKGROUND: Nonagenarians are under-represented in thrombolytic trials for acute ischemic stroke (AIS). The effectiveness of intravenous thrombolytics in nonagenarians in terms of safety and outcome is not well established. MATERIALS AND METHODS: We used a multinational registry to identify patients aged 90 years or older with good baseline functional status who presented with AIS. Differences in outcomes-disability level at 90 days, frequency of symptomatic intracerebral hemorrhage (sICH), and mortality-between patients who did and did not receive thrombolytics were assessed using multivariable logistic regression, adjusted for prespecified prognostic factors. Coarsened exact matching (CEM) was utilized before evaluating outcome by balancing both groups in the sensitivity analysis. RESULTS: We identified 227 previously independent nonagenarians with AIS; 122 received intravenous thrombolytics and 105 did not. In the unmatched cohort, ordinal analysis showed a significant treatment effect (adjusted common odds ratio [OR]: .61, 95% confidence interval [CI]: .39-.96). There was an absolute difference of 8.1% in the rate of excellent outcome in favor of thrombolysis (17.4% versus 9.3%; adjusted ratio: .30, 95% CI: .12-.77). Rates of sICH and in-hospital mortality were not different. Similarly, in the matched cohort, CEM analysis showed a shift in the primary outcome distribution in favor of thrombolysis (adjusted common OR: .45, 95% CI: .26-.76). CONCLUSIONS: Nonagenarians treated with thrombolytics showed lower stroke-related disability at 90 days than those not treated, without significant difference in sICH and in-hospital mortality rates. These observations cannot exclude a residual confounding effect, but provide evidence that thrombolytics should not be withheld from nonagenarians because of age alone.

Unequal access to treatment with intravenous alteplase for women with acute ischemic stroke.

BACKGROUND AND PURPOSE: A recent meta-analysis showed that women with acute ischemic stroke are less likely to receive treatment with intravenous alteplase than men. The aim of this study was to assess sex differences in treatment with intravenous alteplase and to explore the reasons for these differences. METHODS: We analyzed data from the Promoting Acute Thrombolysis for Ischaemic Stroke (PRACTISE) study. We applied a multiple logistic regression model and expressed the association between sex and treatment with an age-adjusted odds ratio with 95% confidence interval. RESULTS: In total, 5515 patients were included in PRACTISE. Women were an average of 4 years older than men. The median National Institutes of Health Stroke Scale score was 6 in women and 5 in men. Fewer women were treated with intravenous alteplase (11% versus 14%; adjusted odds ratio, 0.8; 95% confidence interval, 0.7-1.0). However, fewer women arrived within 4 hours after onset (27% versus 33%; adjusted odds ratio, 0.8; 95% confidence interval, 0.7-0.9). CONCLUSIONS: Fewer women present themselves within 4 hours from stroke onset than men and consequently less often receive thrombolytic treatment. This difference may be caused by the older age of women on average and consequently women more often living alone. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN20405426.

Promoting thrombolysis in acute ischemic stroke.

BACKGROUND AND PURPOSE: Thrombolysis with intravenous recombinant tissue plasminogen activator is an effective treatment for acute ischemic stroke, but the number of treatable patients is limited. The PRomoting ACute Thrombolysis in Ischemic StrokE (PRACTISE) trial evaluated the effectiveness of a multidimensional implementation strategy for thrombolysis with intravenous recombinant tissue plasminogen activator in acute ischemic stroke. METHODS: The PRACTISE trial was a national multicenter cluster-randomized controlled trial with randomization after pairwise matching. Twelve hospitals, both urban and community, academic and nonacademic, in the Netherlands participated. All patients admitted with stroke within 24 hours from onset of symptoms were registered. The intervention included 5 implementation meetings based on the Breakthrough Series model. The primary outcome was treatment with thrombolysis. Secondary outcomes were admission within 4 hours after onset of symptoms, death or disability at 3 months, and quality of life. RESULTS: Overall 5515 patients were included in the study' 308 patients (12.2%) in the control centers and 393 patients (13.1%) in the intervention centers were treated with thrombolysis (adjusted OR, 1.25; 95% CI, 0.93 to 1.68). Among the 1657 patients with ischemic stroke admitted within 4 hours from onset, 391 (44.5%) of 880 in the intervention centers were treated with thrombolysis and 305 (39.3%) of 777 in the control centers; the adjusted OR for treatment with thrombolysis was 1.58 (95% CI, 1.11 to 2.27). CONCLUSIONS: An intensive implementation strategy increases the proportion of patients with acute stroke treated with thrombolysis in real-life settings. An apparently pivotal factor in the improvement of the treatment rate is better application of contraindications for thrombolysis.

Lifetime health effects and medical costs of integrated stroke services - a non-randomized controlled cluster-trial based life table approach.

BACKGROUND: Economic evaluation of stroke services indicates that such services may lead to improved quality of life at affordable cost. The present study assesses lifetime health impact and cost consequences of stroke in an integrated service setting. METHODS: The EDISSE study is a prospective non-randomized controlled cluster trial that compared stroke services (n = 151 patients) to usual care (n = 187 patients). Health status and cost trial-data were entered in multi-dimensional stroke life-tables. The tables distinguish four levels of disability which are defined by the modified Rankin scale. Quality-of-life scores (EuroQoL-5D), transition and survival probabilities are based on concurrent Dutch follow-up studies. Outcomes are quality-adjusted life years lived and lifetime medical cost by disability category. An economic analysis compares outcomes from a successful stroke service to usual care, by bootstrapping individual costs and effects data from patients in each arm. RESULTS: Lifetime costs and QALYs after stroke depend on age-of-onset of first-ever stroke. Lifetime QALYs after stroke are 2.42 (90% CI - 0.49 - 2.75) for male patients in usual care and 2.75 (-0.61; 6.26) for females. Lifetime costs for men in the usual care setting are €39,335 (15,951; 79,837) and €42,944 (14,081; 95,944) for women. A comparison with the stroke service results in an ICER of €11,685 saved per QALY gained (€14,211 and €7,745 for men and women respectively). This stroke service is with 90% certainty cost-effective. CONCLUSIONS: Our analysis shows the potential of large health benefits and cost savings of stroke services, taking a lifetime perspective, also in other European settings.

Hospital rates of thrombolysis for acute ischemic stroke: the influence of organizational culture.

BACKGROUND AND PURPOSE: The purpose of this study was to determine if organizational culture explains differences in rates of intravenous thrombolysis for acute ischemic stroke between different hospitals. METHODS: A cohort study was done in 12 centers admitting 5515 consecutive patients with acute stroke in The Netherlands. A multilevel logistic regression model was used to relate the likelihood of treatment with thrombolysis to characteristics of the organizational culture of the centers. Organizational culture was defined by 10 characteristics and scored by a panel. A sum score was created by adding all scores and dividing by 10. RESULTS: Thrombolysis rates varied from 5.7% to 21.7%. We observed an association between thrombolysis and the availability of informal and formal feedback (OR, 1.18; 95% CI, 1.09 to 1.28); a learning culture (OR, 1.12; 95% CI, 1.02 to 1.23); uncompromising, individual clinical leadership (OR, 1.12; 95% CI, 1.03 to 1.23); explicit goals (OR, 1.08; 95% CI, 1.01 to 1.17); and with the sum score (OR, 1.12; 95% CI, 1.02 to 1.23). CONCLUSIONS: Several cultural characteristics of the hospital organization are related to thrombolysis rate. Organizational culture may be an important target for interventions aimed at increasing rates of thrombolysis for acute ischemic stroke in hospitals.

Development and validation of the Dutch Stroke Score for predicting disability and functional outcome after ischemic stroke: A tool to support efficient discharge planning.

INTRODUCTION: We aimed to develop and validate a prognostic score for disability at discharge and functional outcome at three months in patients with acute ischemic stroke based on clinical information available on admission. PATIENTS AND METHODS: The Dutch Stroke Score (DSS) was developed in 1227 patients with ischemic stroke included in the Paracetamol (Acetaminophen) In Stroke study. Predictors for Barthel Index (BI) at discharge ('DSS-discharge') and modified Rankin Scale (mRS) at three months ('DSS-3 months') were identified in multivariable ordinal regression. The models were internally validated with bootstrapping techniques. The DSS-3 months was externally validated in the PRomoting ACute Thrombolysis in Ischemic StrokE study (1589 patients) and the Preventive Antibiotics in Stroke Study (2107 patients). Model performance was assessed in terms of discrimination, expressed by the area under the receiver operating characteristic curve (AUC), and calibration. RESULTS: At model development, the strongest predictors of Barthel Index at discharge were age per decade over 60 (odds ratio = 1.55, 95% confidence interval (CI) 1.41-1.68), National Institutes of Health Stroke Scale (odds ratio = 1.24 per point, 95% CI 1.22-1.26) and diabetes (odds ratio = 1.62, 95% CI 1.32-1.91). The internally validated AUC was 0.76 (95% CI 0.75-0.79). The DSS-3 months, additionally consisting of previous stroke and atrial fibrillation, performed similarly at internal (AUC 0.75, 95% CI 0.74-0.77) and external validation (AUC 0.74 in PRomoting ACute Thrombolysis in Ischemic StrokE (95% CI 0.72-0.76) and 0.69 in Preventive Antibiotics in Stroke Study (95% CI 0.69-0.72)). Observed outcome was slightly better than predicted.Discussion: The DSS had satisfactory performance in predicting BI at discharge and mRS at three months in ischemic stroke patients. CONCLUSION: If further validated, the DSS may contribute to efficient stroke unit discharge planning alongside patients' contextual factors and therapeutic needs.

Intravenous thrombolysis in acute ischaemic stroke: from trial exclusion criteria to clinical contraindications. An international Delphi study.

OBJECTIVE: Several studies indicate that only a small proportion of patients with acute ischaemic stroke are treated with intravenous thrombolysis. Indications and contraindications for this treatment are usually based on the inclusion and exclusion criteria of randomised clinical trials. The trial context of these criteria hampers implementation in real life settings. We therefore aimed to obtain specialist opinion in a Delphi consensus on these contraindications. METHODS: We used the Delphi approach on an international group of specialists in the field of thrombolysis. Inclusion and exclusion criteria were reworded into 18 quantitatively phrased propositions. Feedback consisted of the median score, interquartile range and the panellist's own score in the previous round. For each item, we defined consensus as the achievement of an interdecile range within two prespecified clinically relevant units. RESULTS: Thirty-one specialists participated in the first round and 30 completed all three rounds. Consensus was reached on 12 of the 18 propositions: previous ischaemic stroke, head trauma and gastrointestinal tract bleeding should not have taken place earlier than 1.5 months, 2 months and 14 days, respectively; the severity of the neurological deficit is defined as a National Institutes of Health Stroke Scale (NIHSS) score of 2-3 or more, and blood pressure level should not be >185/110 mmHg; platelet count should be >90x10(12)/l, glucose levels 2.7-22 mmol/l, international normalised ratio <1.5 and activated partial thromboplastin time <50 s. No consensus was reached on propositions concerning the stroke onset to treatment time, patient's age, recent medical procedures, spontaneous improvement rate and blood pressure treatment. CONCLUSIONS: We present specialists' opinion on contraindications for intravenous thrombolysis in ischaemic stroke. The results of this study may be relevant for routine clinical practice as they may help to increase the number of treated patients.

Elevated pretreatment blood pressure and IV thrombolysis in stroke.

OBJECTIVES: We investigated whether an active blood pressure-lowering strategy is associated with more patients receiving thrombolytics compared with a conservative "watch and measure" strategy, and assessed safety and functional outcome of these 2 treatment strategies. METHODS: This is a post hoc analysis in 2 randomized controlled stroke trials, the PRACTISE (Promoting Acute Thrombolysis in Ischemic Stroke) and the PASS (Preventive Antibiotics in Stroke Study). We included all patients with elevated pretreatment blood pressure above 185/110 mm Hg at presentation but otherwise eligible for IV thrombolysis (IVT). The decision to use an active or conservative strategy was in accordance with local hospital treatment guidelines. The primary outcome was the proportion of patients treated with IVT. Secondary outcomes were (1) symptomatic intracranial hemorrhage (increased neurologic deficit with a concomitant hemorrhage on neuroimaging), (2) functional outcome at 3 months, and (3) the door-to-needle time. RESULTS: We included 224 patients, 66 (29%) received the active and 158 (71%) the conservative strategy. In the active group, 55 patients (83%) received thrombolytics vs 87 (55%) in the conservative group, an increase of 28% (95% confidence interval: 16%-40%). If only patients actually treated with IVT were considered, the rate of symptomatic intracranial hemorrhage was 7% in both groups. There was no difference in door-to-needle time. CONCLUSIONS: Active blood pressure lowering was associated with an increased proportion of patients treated with IVT compared with a conservative strategy, without a difference in symptomatic hemorrhage rate.

Measuring Quality Improvement in Acute Ischemic Stroke Care: Interrupted Time Series Analysis of Door-to-Needle Time.

BACKGROUND: In patients with acute ischemic stroke, early treatment with recombinant tissue plasminogen activator (rtPA) improves functional outcome by effectively reducing disability and dependency. Timely thrombolysis, within 1 h, is a vital aspect of acute stroke treatment, and is reflected in the widely used performance indicator 'door-to-needle time' (DNT). DNT measures the time from the moment the patient enters the emergency department until he/she receives intravenous rtPA. The purpose of the study was to measure quality improvement from the first implementation of thrombolysis in stroke patients in a university hospital in the Netherlands. We further aimed to identify specific interventions that affect DNT. METHODS: We included all patients with acute ischemic stroke consecutively admitted to a large university hospital in the Netherlands between January 2006 and December 2012, and focused on those treated with thrombolytic therapy on admission. Data were collected routinely for research purposes and internal quality measurement (the Erasmus Stroke Study). We used a retrospective interrupted time series design to study the trend in DNT, analyzed by means of segmented regression. RESULTS: Between January 2006 and December 2012, 1,703 patients with ischemic stroke were admitted and 262 (17%) were treated with rtPA. Patients treated with thrombolysis were on average 63 years old at the time of the stroke and 52% were male. Mean age (p = 0.58) and sex distribution (p = 0.98) did not change over the years. The proportion treated with thrombolysis increased from 5% in 2006 to 22% in 2012. In 2006, none of the patients were treated within 1 h. In 2012, this had increased to 81%. In a logistic regression analysis, this trend was significant (OR 1.6 per year, CI 1.4-1.8). The median DNT was reduced from 75 min in 2006 to 45 min in 2012 (p < 0.001 in a linear regression model). In this period, a 12% annual decrease in DNT was achieved (CI from 16 to 8%). We could not find a significant association between any specific intervention and the trend in DNT. CONCLUSION AND IMPLICATIONS: The DNT steadily improved from the first implementation of thrombolysis. Specific explanations for this improvement require further study, and may relate to the combined impact of a series of structural and logistic interventions. Our results support the use of performance measures for internal communication. Median DNT should be used on a monthly or quarterly basis to inform all professionals treating stroke patient of their achievements.

The effectiveness of thrombolysis with intravenous alteplase for acute ischemic stroke in daily practice.

BACKGROUND: Thrombolysis with intravenous alteplase has been proven an effective treatment for patients with acute ischemic stroke in randomized clinical trials. In daily practice, the effect of thrombolysis may be less, and complications may occur more often. AIMS: The aim of this study was to assess effectiveness and safety of thrombolysis in an unselected observational cohort of patients. METHODS: During a two-year period, all patients over 18 years with acute stroke who were admitted within four-hours from onset of symptoms in 12 centers were registered. We compared outcomes in patients who were treated with alteplase with patients who were not treated with alteplase. The primary outcome was good functional outcome at three-months measured with the modified Rankin Scale ≤2). The safety end point was symptomatic intracranial hemorrhage and mortality. We used a multivariable logistic regression model to adjust for baseline imbalances and multilevel analysis to take into account within center correlations. RESULTS: Overall, 1657 patients with ischemic stroke were admitted within four-hours from onset of symptoms and 696 (42%) were treated with alteplase. Treatment with alteplase was associated with a favorable outcome (adjusted odds ratio 1·3; 95% confidence interval 1·0 to 1·7). After further adjustment for potential clustering effects, the adjusted odds ratio for good outcome was 1·4 (95% confidence interval 1·0 to 1·8). Thirty-six (5%) of the 696 patients treated with alteplase had a symptomatic intracranial bleeding complication. CONCLUSIONS: Thrombolysis for ischemic stroke with intravenous alteplase is an effective treatment also in an unselected observational cohort of patients.

Real-life costs and effects of an implementation program to increase thrombolysis in stroke.

OBJECTIVES: We have shown that a Breakthrough Series-based implementation program increases the number of patients with acute ischemic stroke treated with alteplase 4.5% in real-life settings. It is unclear whether such an implementation program is cost-effective. METHODS: The practice study includes 12 randomized hospitals and 5,515 patients. Its present cost-effectiveness analysis involves 1,657 patients with ischemic stroke admitted within 4 hours from onset. Defined primary outcomes are thrombolysis rate and actual health care costs up to 3 months, including additional implementation efforts. Secondary outcomes are lifetime quality-adjusted years (QALYs) and lifetime costs of individual trial patients, using a validated probabilistic, disability-stratified stroke life table. Differences in outcome include 95% confidence intervals (CI), adjusted for intracluster correlation. RESULTS: The thrombolysis rate in the intervention group was 44.3% vs 39.8% in the control group (difference 4.5%; 95% CI 3.1% to 5.9%. Mean costs per patient at 3 months (euros were converted to 2010 USD) were $9,192 USD in the intervention group and $9,647 USD in the control group (difference -$455 USD; 95% CI -$232 to -$679 USD). Lifetime QALYs in the intervention group were 3.89 and in the control group 3.84 (difference 0.05; 95% CI -0.04 to 0.14). The mean lifetime costs in the intervention group were $22,994 USD against $24,315 USD in the control group (difference -$1,321 USD; 95% CI -$1,722 to -$921 USD). CONCLUSIONS: A Breakthrough Series implementation program of thrombolysis increases thrombolysis. It saves short- and long-term health care costs due to lower hospital admission and residential costs, increasing stroke care efficiency.

Promoting Acute Thrombolysis for Ischaemic Stroke (PRACTISE).

RATIONALE: Thrombolysis with intravenous rtPA is an effective treatment for patients with ischaemic stroke if given within 3 h from onset. Generally, more than 20% of stroke patients arrive in time to be treated with thrombolysis. Nevertheless, in most hospitals, only 1-8% of all stroke patients are actually treated. Interorganisational, intraorganisational, medical and psychological barriers are hampering broad implementation of thrombolysis for acute ischaemic stroke. AIMS: To evaluate the effect of a high-intensity implementation strategy for intravenous thrombolysis in acute ischaemic stroke, compared with regular implementation; to identify success factors and obstacles for implementation and to assess its cost-effectiveness, taking into account the costs of implementation. DESIGN: The PRACTISE study is a national cluster-randomised-controlled trial. Twelve hospitals have been assigned to the regular or high-intensity intervention by random allocation after pair-wise matching. The high-intensity implementation consists of training sessions in conformity with the Breakthrough model, and a tool kit. All patients who are admitted with acute stroke and onset of symptoms not longer than 24 h are registered. STUDY OUTCOMES: The primary outcome measure is treatment with thrombolysis. Secondary outcomes are admission within 4 h after onset of symptoms, death or disability at 3 months, the rate of haemorrhagic complications in patients treated with thrombolysis, and costs of implementation and stroke care in the acute setting. Tertiary outcomes are derived from detailed criteria for the organisational characteristics, such as door-to-needle time and protocol violations. These can be used to monitor the implementation process and study the effectiveness of specific interventions. DISCUSSION: This study will provide important information on the effectiveness and cost-effectiveness of actively implementing an established treatment for acute ischaemic stroke. The multifaceted aspect of the intervention will make it difficult to attribute a difference in the primary outcome measure to a specific aspect of the intervention. However, careful monitoring of intermediate parameters as well as monitoring of accomplished SMART tasks can be expected to provide useful insights into the nature and role of factors associated with implementation of thrombolysis for acute ischaemic stroke, and of effective acute interventions in general.