Stroke-Thrombolytic Predictive Instrument Research Articles

WHEN ONE PROBLEM ISN'T ENOUGH: PULMONARY EMBOLISM COMPLICATED BY MULTIPLE HEMORRHAGIC PHENOMENA

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: The use of systemic intravenous thrombolytic therapy has been associated with improved outcomes in select patients with pulmonary embolism (PE). Life-threatening adverse events have been reported with its use. We present a patient who developed numerous hemorrhagic complications after administration of alteplase, an analogue of tissue-plasminogen activator (tPA), in the setting of pulmonary embolism complicated by obstructive shock. CASE PRESENTATION: Our patient is a 63-year-old male with a history of untreated hypertension and alcohol use disorder. He presented to the emergency department with altered sensorium and bilateral leg pain. He was tachycardic and his electrocardiogram showed ST-segment depression in lateral and inferior leads in addition to troponin elevation of 8.56 ng/ml (< 0.015). Computed tomography (CT) of his head did not reveal hemorrhage or infarction. He was admitted to the intensive care unit (ICU) for management of alcohol withdrawal with concomitant non-ST elevation myocardial infarction (NSTEMI). Transthoracic echocardiogram (TTE) revealed a dilated right ventricle in addition to a mobile structure in his left atrium suspicious for a thrombus-in-transit. His ICU course was complicated by the development of respiratory failure and obstructive shock requiring endotracheal intubation and vasopressor therapy. Further work-up revealed bilateral deep vein thromboses of his lower extremities and pulmonary emboli involving the right main pulmonary artery in addition to several lobar and segmental branches. Alteplase was administered while the patient remained on heparin for MI-related anticoagulation. He subsequently developed epistaxis and endobronchial bleeding in addition to multiple hematomas involving his abdominal musculature, pelvis, and chest for which he required several transfusions of packed red blood cells. Repeat CT head obtained for persistently altered sensorium revealed a right posterior front lobe infarct with associated petechial hemorrhage attributed to a later-diagnosed patent foramen ovale (PFO). He required intermittent discontinuation and resumption of his anticoagulation and was later discharged to a skilled nursing facility in stable condition for intensive physical therapy. DISCUSSION: Intravenous systemic thrombolytic therapy has been associated with major hemorrhagic complications. Risk factors for developing complications have been better studied in patients receiving tPA for ischemic stroke where age, gender, and weight have been shown to increase the risk of complications. A multi-disciplinary approach with early catheter-directed thrombectomy can be live-saving. CONCLUSIONS: The lack of risk stratification tools makes the decision of mechanical versus chemical thrombus removal challenging. Further research is required to establish evidence-based management algorithms for patients with complicated pulmonary emboli. Reference #1: 1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ. Executive Summary. Chest. 2012;141(2):7S-47S. https://doi.org/10.1378/chest.1412S3 Reference #2: 2. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: A meta-analysis of the randomized controlled trials. Circulation. 2004;110(6):744-749. https://doi.org/10.1161/01.CIR.0000137826.09715.9C Reference #3: 3. Kent DM, Ruthazer R, Decker C, et al. Development and validation of a simplified Stroke-Thrombolytic Predictive Instrument. Neurology. 2015;85(11):942-949. https://doi.org/10.1212/WNL.0000000000001925 DISCLOSURES: No relevant relationships by Daniel Kotok, source=Web Response No relevant relationships by Haris Zia, source=Web Response

Validation of the Simplified Stroke-Thrombolytic Predictive Instrument to Predict Functional Outcomes in Chinese Patients.

Background and Purpose- The simplified stroke-thrombolytic predictive instrument (s-Stroke-TPI) is useful for predicting the outcomes in thrombolysis-treated patients in Western populations. We aimed to validate its predictive value in Chinese patients. Methods- Data from thrombolysis implementation and monitor of acute ischemic stroke in China were analyzed. Patients with acute ischemic stroke and treated with thrombolysis within 4.5 hours of symptom onset were included. The 3-month functional outcomes were assessed with the modified Rankin Scale (mRS). Model discrimination was quantified by calculating the area under receiver operating characteristic curve. s-Stroke-TPI was compared with dense artery sign, mRS score, age, glucose, onset to treatment time, and National Institutes of Health Stroke Scale or stroke prognostication using age and National Institutes of Health Stroke Scale. Results- A total of 1102 patients who received thrombolysis were enrolled. The area under receiver operating characteristic curve of s-Stroke-TPI for predicting a catastrophic outcome (mRS score, 5-6), a normal/near-normal outcome (mRS score, 0-1), and independent outcome (mRS score, 0-2) at 3 months were 0.80, 0.73, and 0.75, respectively, which were significantly higher than or similar to those of dense artery sign, mRS score, age, glucose, onset to treatment time, and National Institutes of Health Stroke Scale or stroke prognostication using age and National Institutes of Health Stroke Scale. The calibration analysis of the s-Stroke-TPI showed a high correlation between the predicted and observed probabilities of the functional outcomes at 3 months. Conclusions- The s-Stroke-TPI reliably predicted the 3-month functional outcomes, especially catastrophic outcomes, in Chinese stroke patients with thrombolysis. Further validation is needed to confirm outcome predictions in patients both with and without thrombolysis.

The proposed ‘concordance-statistic for benefit’ provided a useful metric when modeling heterogeneous treatment effects

ObjectivesClinical prediction models that support treatment decisions are usually evaluated for their ability to predict the risk of an outcome rather than treatment benefit–the difference between outcome risk with vs. without therapy. We aimed to define performance metrics for a model's ability to predict treatment benefit. Study Design and SettingWe analyzed data of the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial and of three recombinant tissue plasminogen activator trials. We assessed alternative prediction models with a conventional risk concordance-statistic (c-statistic) and a novel c-statistic for benefit. We defined observed treatment benefit by the outcomes in pairs of patients matched on predicted benefit but discordant for treatment assignment. The ‘c-for-benefit’ represents the probability that from two randomly chosen matched patient pairs with unequal observed benefit, the pair with greater observed benefit also has a higher predicted benefit. ResultsCompared to a model without treatment interactions, the SYNTAX score II had improved ability to discriminate treatment benefit (c-for-benefit 0.590 vs. 0.552), despite having similar risk discrimination (c-statistic 0.725 vs. 0.719). However, for the simplified stroke–thrombolytic predictive instrument (TPI) vs. the original stroke-TPI, the c-for-benefit (0.584 vs. 0.578) was similar. ConclusionThe proposed methodology has the potential to measure a model's ability to predict treatment benefit not captured with conventional performance metrics.

Are the results of intravenous thrombolysis trials reproduced in clinical practice? Comparison of observed and expected outcomes with the stroke-thrombolytic predictive instrument (STPI)

AimIn patients with cerebral ischemia, intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) increases survival without handicap or dependency despite an increased risk of bleeding. This study evaluated whether the results of randomized controlled trials are reproduced in clinical practice. MethodData from a registry of consecutive patients treated by rt-PA at Lille University Hospital were retrospectively analyzed for outcomes, using modified Rankin Scale (mRS) scores, at 3 months. The observed outcomes were then compared with the probability of good (mRS 0–1) and of catastrophic (mRS 5–6) outcomes, as predicted by the stroke-thrombolytic predictive instrument (STPI). ResultsOf the 1000 consecutive patients (469 male, median age 74 years, median baseline National Institutes of Health Stroke Scale 11, median onset-to-needle time 143min), 438 (43.8%) had a good outcome, 565 (56.5%) had an mRS score 0–2 or similar to their pre-stroke mRS, 155 (15.5%) died within 3 months and 74 (7.4%) developed symptomatic intracerebral hemorrhage according to ECASS-II (Second European–Australasian Acute Stroke Study) criteria. Of the 613 patients (61.3%) eligible for evaluation by the s-TPI, the observed rate of good outcomes was 41.3% (95% CI: 37.5–45.3%), while expected rates with and without rt-PA were 48.8% (95% CI: 44.8–52.7%) and 32.5% (95% CI: 28.8–36.2%), respectively; the observed rate of catastrophic outcomes was 17.0% (95% CI: 14.0–19.9%), while the expected rate was 19.2% (95% CI: 16.1–22.4%) with or without rt-PA. ConclusionIn clinical practice, the rate of good outcomes is slightly lower than expected, according to the s-TPI, except for the most severe cases, whereas the rate of catastrophic outcomes is roughly similar. However, the rate of good outcomes is higher than predicted without treatment. This finding suggests that rt-PA is effective for improving outcomes in clinical practice.

Development of a decision analytic model to support decision making and risk communication about thrombolytic treatment.

BackgroundIndividualised prediction of outcomes can support clinical and shared decision making. This paper describes the building of such a model to predict outcomes with and without intravenous thrombolysis treatment following ischaemic stroke.MethodsA decision analytic model (DAM) was constructed to establish the likely balance of benefits and risks of treating acute ischaemic stroke with thrombolysis. Probability of independence, (modified Rankin score mRS ≤ 2), dependence (mRS 3 to 5) and death at three months post-stroke was based on a calibrated version of the Stroke-Thrombolytic Predictive Instrument using data from routinely treated stroke patients in the Safe Implementation of Treatments in Stroke (SITS-UK) registry. Predictions in untreated patients were validated using data from the Virtual International Stroke Trials Archive (VISTA). The probability of symptomatic intracerebral haemorrhage in treated patients was incorporated using a scoring model from Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) data.ResultsThe model predicts probabilities of haemorrhage, death, independence and dependence at 3-months, with and without thrombolysis, as a function of 13 patient characteristics. Calibration (and inclusion of additional predictors) of the Stroke-Thrombolytic Predictive Instrument (S-TPI) addressed issues of under and over prediction. Validation with VISTA data confirmed that assumptions about treatment effect were just. The C-statistics for independence and death in treated patients in the DAM were 0.793 and 0.771 respectively, and 0.776 for independence in untreated patients from VISTA.ConclusionsWe have produced a DAM that provides an estimation of the likely benefits and risks of thrombolysis for individual patients, which has subsequently been embedded in a computerised decision aid to support better decision-making and informed consent.

Spotlight on the September 15 Issue

#### Notable in Neurology This issue features an article investigating cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk and another on the development and validation of a simplified Stroke–Thrombolytic Predictive Instrument. Another featured article focuses on the clinical relevance of voltage-gated potassium channel–complex antibodies in children. ### Recurrent vascular events in lacunar stroke patients with metabolic syndrome and/or diabetes This study enrolled 3,020 patients with lacunar strokes. Metabolic syndrome and diabetes mellitus were comorbid conditions in lacunar stroke patients and were associated …

Development and validation of a simplified Stroke-Thrombolytic Predictive Instrument.

The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) predicts the probability of good and bad outcomes with and without recombinant tissue plasminogen activator (rtPA). We sought to rebuild and externally validate a simpler Stroke-TPI to support implementation in routine clinical care. Using the original derivation cohort of 1,983 patients from a combined database of randomized clinical trials (NINDS [National Institute of Neurological Disorders and Stroke] 1 and 2; ATLANTIS [Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke] A and B; and ECASS [European Cooperative Acute Stroke Study] II), we simplified the Stroke-TPI by reducing variables and interaction terms and by exploring simpler (3- and 8-item) stroke severity scores. External validation was performed in the ECASS III trial (n = 821). The following 6 variables were most predictive of good outcomes: age, systolic blood pressure, diabetes, stroke severity, symptom onset to treatment time, and rtPA therapy. Treatment effect modifiers included onset to treatment time and systolic blood pressure. For the models predicting a bad outcome (modified Rankin Scale [mRS] score ≥5), significant variables included age, stroke severity, and serum glucose. rtPA therapy did not change the risk of a poor outcome. Compared with models using the full NIH Stroke Scale, models using the 3-item severity score showed similar discrimination and excellent calibration. External validation on ECASS III showed similar performance (C statistics 0.75 [mRS score ≤1] and 0.80 [mRS score ≤2]). A simpler model using a 3-item stroke severity score, instead of the 15-item NIH Stroke Scale, has similar prognostic value and may be easier to use in routine care. Future studies are needed to test whether it can improve process and clinical outcomes.

Abstract W P16: Comparing Outcome Prediction Scoring Systems in the Interventional Management of Stroke (IMS) III Trial: No Clear Winner

Introduction: Several prognostic scores have been developed to predict patient outcome after ischemic stroke. We aimed to compare eight scores in the IMS -III dataset. Hypothesis: Prediction of good and poor outcome using different scores is possible in IMS-III. Methods: We retrospectively calculated area under the curve (AUC), sensitivity, and specificity for poor (mRS 4-6) and good (mRS 0-2) 90-day outcome in all IMS-III participants with complete data. The scoring systems analyzed were: Houston Intra-arterial Therapy 2 (HIAT2), Ischemic Stroke Predictive Risk Score (iScore), Totaled Health Risks in Vascular Events (THRIVE), DRAGON, Hemorrhage after Thrombolysis (HAT), Alberta Stroke Programme Early CT Score (ASPECTS), Stroke-Thrombolytic Predictive Instrument (TPI), and Simple Variables Model (SVM). Those receiving IV rtPA followed by endovascular therapy (treatment) and those receiving IV rtPA only (control) were analyzed separately. Results: Among 656 IMS III subjects, 651 had complete data, including 429 treatment and 222 control subjects. Overall, all scoring systems showed good prediction abilities (AUC range 0.60 to 0.78). AUC comparisons did not clearly favor a single scoring system. Treatment group: For predicting poor outcome, the TPI score outperformed ASPECTS (AUC 0.73 vs 0.61; P &lt;0.05). For predicting good outcome, the HAT score was significantly better than ASPECTS (0.73 vs. 0.64; P &lt;0.05). Control group: For poor outcome, the TPI score was significantly better than ASPECTS and THRIVE (0.78 vs. 0.62 and 0.71, respectively; P &lt;0.05). For good outcome, TPI performed better than ASPECTS and THRIVE (0.73 vs. 0.61 and 0.67, respectively; P &lt;0.05). Conclusions: Outcome prediction using different scores in IMS III is possible. HIAT2, iSCORE, DRAGON, HAT, TPI, and SVM all performed comparably. Prognostic performances were comparable in both treatment arms.

Targeting Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Based on Risk of Intracranial Hemorrhage or Poor Functional Outcome

Background and Purpose— Intravenous recombinant tissue-type plasminogen activator (r-tPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit. Methods— We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg r-tPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with r-tPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome. Results— Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risks in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH ( P for difference &gt;0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58–0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77–0.82) similarly to complex models. There was no evidence that the effect of r-tPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk. Conclusions— There is a clinically relevant net positive effect of r-tPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN25765518.

Validating the Stroke-Thrombolytic Predictive Instrument in a Population in the United Kingdom

This study aimed to test the explanatory qualities of the Stroke-Thrombolytic Predictive Instrument (S-TPI) when applied to patients treated in routine practice. S-TPI predictions were compared with observed outcomes in terms of normal/near-normal (modified Rankin Scale score, ≤1) and catastrophic outcome (modified Rankin Scale score, ≥5) at 3 months. Logistic regression was used to calibrate and expand the S-TPI. The S-TPI overestimated probability of catastrophic outcomes and overestimated the probability of a normal/near normal outcome above 0.4 and underestimated those below. Calibrating the S-TPI minimized discrepancies between predicted and observed outcomes, in the case of normal/near-normal outcomes, where including additional predictors (serum glucose and signs of current infarction on pretreatment brain scan) further reduced discrepancies between predicted and observed outcomes. The explanatory power of the S-TPI in thrombolytic-treated patients can be improved to reflect outcomes seen in routine practice.

Utility of the stroke-thrombolytic predictive instrument

Objective: The goal of this study was to evaluate the utility of the stroke thrombolytic predictive instrument (s-TPI) in predicting clinical outcome in patients with acute ischaemic stroke treated with...

Can Multivariable Risk-Benefit Profiling Be Used to Select Treatment-Favorable Patients for Thrombolysis in Stroke in the 3- to 6-Hour Time Window?

The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) uses multivariate equations to predict outcomes with and without thrombolysis. We sought to examine whether such a multivariate predictive instrument might be useful in selecting patients with a favorable risk-benefit treatment profile for therapy after 3 hours. We explored outcomes in patients from 5 major randomized clinical trials testing intravenous recombinant tissue plasminogen activator (rt-PA) classified by the Stroke-TPI as "treatment-favorable" or "treatment-unfavorable." We used iterative bootstrap re-sampling to estimate how such a model would perform on independent test data. Among patients treated within the 3- to 6-hour window, 67% of patients were classified by Stroke-TPI predicted outcomes as "treatment-favorable" and 33% were classified as "treatment-unfavorable." Outcomes in the treatment-favorable group demonstrated benefit for thrombolysis (modified Rankin Scale score < or =1: 44.0% with rt-PA versus 34.2 with placebo, P=0.005), whereas harm was demonstrated in the treatment-unfavorable group (modified Rankin Scale score < or =1: 31.3% with rt-PA versus 38.3% with placebo; P=0.004). Bootstrap resampling with complete cross-validation showed that the absolute margin of benefit in the treatment-favorable group diminished on average by 36% between derivation and independent validation sets, but still represented a significant tripling of improvement in benefit compared with conventional inclusion criteria (5.2% [interquartile range, 1.7% to 8.6%] versus 1.8% [interquartile range, -0.5 to 4.1], P<0.0001). Such multivariable risk-benefit profiling may be useful in the selection of acute stroke patients for rt-PA therapy even more than 3 hours after symptom onset. Prospective testing is indicated.

The Stroke–Thrombolytic Predictive Instrument

Many patients with ischemic stroke eligible for recombinant tissue plasminogen activator (rt-PA) are not treated in part because of the risks and benefits perceived by treating physicians. Therefore, we aimed to develop a Stroke-Thrombolytic Predictive Instrument (TPI) to aid physicians considering thrombolysis for stroke. Using data from 5 major randomized clinical trials (n=2184) testing rt-PA in the 0- to 6-hour window, we developed logistic regression equations using clinical variables as potential predictors of a good outcome (modified Rankin Scale score < or =1) and of a catastrophic outcome (modified Rankin Scale score > or =5), with and without rt-PA. The models were internally validated using bootstrap re-sampling. To predict good outcome, in addition to rt-PA treatment, 7 variables significantly affected prognosis and/or the treatment-effect of rt-PA: age, diabetes, stroke severity, sex, previous stroke, systolic blood pressure, and time from symptom onset. To predict catastrophic outcome, only age, stroke severity, and serum glucose were significant; rt-PA treatment was not. For patients treated within 3 hours, the median predicted probability of a good outcome with rt-PA was 42.9% (interquartile range [IQR]=18.6% to 64.7%) versus 25.3% (IQR=9.8% to 46.2%) without rt-PA; the median predicted absolute benefit was 12.5% (IQR=5.1% to 21.0%). The median probability for a catastrophic outcome, with or without, rt-PA was 15.2% (IQR=8.0% to 31.2%). The area under the receiver-operator characteristic curve was 0.788 for the model predicting good outcome and 0.775 for the model predicting bad outcome. The Stroke-TPI predicts good and bad functional outcomes with and without thrombolysis. Incorporated into a usable tool, it may assist in decision-making.

The Stroke-Thrombolytic Predictive Instrument Provides Valid Quantitative Estimates of Outcome Probabilities and Aids Clinical Decision-Making

Computerized clinical decision support systems are increasingly popular in health sciences and have been demonstrated to improve practitioner performance.1 For an emergency closely related to ischemic stroke, acute myocardial infarction, a thrombolytic predictive instrument was developed for real-time use in emergency medical-service settings to identify patients likely to benefit from thrombolysis and to facilitate the earliest possible use of this therapy.2,3 A similar instrument, designed for ischemic stroke, could also prove to be useful. Thrombolysis for ischemic stroke remains underused even under ideal circumstances. Approximately 40% of emergency physicians in a national survey report that they would not use recombinant tissue plasminogen activator (rt-PA) for stroke, citing the risk of symptomatic intracranial hemorrhage and relative lack of benefit.4 Similar results were reported by Bobrow et al in a survey of the Arizona chapter of the American College of Emergency Physicians. Only 52% of the emergency physicians who responded to the survey indicated that they would endorse rt-PA use for stroke under ideal conditions.5 Physicians’ perceptions of risks and benefits of rt-PA for stroke are not uniformly accurate.6 Merino et al reported that only 11% (95% CI, 0 to 22) of surveyed emergency medicine physicians and neurologists could correctly convey the expected magnitude of beneficial effect of rt-PA, and that only 39% (95% CI, 21 to 57) could accurately report the expected rate of symptomatic and fatal intracranial hemorrhage of rt-PA.6 This misperception may interfere with their willingness to endorse this treatment. It would be helpful to draw a distinction between true and perceived efficacy and between true and perceived harm associated with rt-PA for stroke. In this issue of Stroke, Kent et al7 developed a Stroke-Thrombolytic Predictive Instrument (TPI) to aid physicians considering thrombolysis for a patient with acute ischemic stroke. The authors …