Decade‐Long Nationwide Trends and Disparities in Use of Comfort Care Interventions for Patients With Ischemic Stroke

Background Stroke remains one of the leading causes of disability and death in the United States. We characterized 10‐year nationwide trends in use of comfort care interventions (CCIs) among patients with ischemic stroke, particularly pertaining to acute thrombolytic therapy with intravenous tissue‐type plasminogen activator and endovascular thrombectomy, and describe in‐hospital outcomes and costs. Methods and Results We analyzed the National Inpatient Sample from 2006 to 2015 and identified adult patients with ischemic stroke with or without thrombolytic therapy and CCIs using validated International Classification of Diseases, Ninth Revision ( ICD‐9 ) codes. We report adjusted odds ratios (ORs) and 95% CI of CCI usage across five 2‐year periods. Of 4 249 201 ischemic stroke encounters, 3.8% had CCI use. CCI use increased over time (adjusted OR, 4.80; 95% CI, 4.15–5.55) regardless of acute treatment type. Advanced age, female sex, White race, non‐Medicare insurance, higher income, disease severity, comorbidity burden, and discharge from non‐northeastern teaching hospitals were independently associated with receiving CCIs. In the fully adjusted model, thrombolytic therapy and endovascular thrombectomy, respectively, conferred a 6% and 10% greater likelihood of receiving CCIs. Among CCI users, there was a significant decline in in‐hospital mortality compared with all other dispositions over time (adjusted OR, 0.46; 95% CI, 0.38–0.56). Despite longer length of stay, CCI hospitalizations incurred 16% lower adjusted costs. Conclusions CCI use among patients with ischemic stroke has increased regardless of acute treatment type. Nonetheless, considerable disparities persist. Closing the disparities gap and optimizing access, outcomes, and costs for CCIs among patients with stroke are important avenues for further research.

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Achieving More Rapid Door-to-Needle Times and Improved Outcomes in Acute Ischemic Stroke in a Nationwide Quality Improvement Intervention

Stroke ◽

10.1161/strokeaha.121.035853 ◽

2021 ◽

Author(s):

Ying Xian ◽

Haolin Xu ◽

Eric E. Smith ◽

Jeffrey L. Saver ◽

Mathew J. Reeves ◽

...

Keyword(s):

United States ◽

Quality Improvement ◽

Ischemic Stroke ◽

Thrombolytic Therapy ◽

Phase I ◽

Acute Ischemic Stroke ◽

Symptom Onset ◽

Odds Ratio ◽

Adjusted Odds Ratio ◽

The United States

Background and Purpose: The benefits of tPA (tissue-type plasminogen activator) in acute ischemic stroke are time-dependent. However, delivery of thrombolytic therapy rapidly after hospital arrival was initially occurring infrequently in hospitals in the United States, discrepant with national guidelines. Methods: We evaluated door-to-needle (DTN) times and clinical outcomes among patients with acute ischemic stroke receiving tPA before and after initiation of 2 successive nationwide quality improvement initiatives: Target: Stroke Phase I (2010–2013) and Target: Stroke Phase II (2014–2018) from 913 Get With The Guidelines-Stroke hospitals in the United States between April 2003 and September 2018. Results: Among 154 221 patients receiving tPA within 3 hours of stroke symptom onset (median age 72 years, 50.1% female), median DTN times decreased from 78 minutes (interquartile range, 60–98) preintervention, to 66 minutes (51–87) during Phase I, and 50 minutes (37–66) during Phase II ( P <0.001). Proportions of patients with DTN ≤60 minutes increased from 26.4% to 42.7% to 68.6% ( P <0.001). Proportions of patients with DTN ≤45 minutes increased from 10.1% to 17.7% to 41.4% ( P <0.001). By the end of the second intervention, 75.4% and 51.7% patients achieved 60-minute and 45-minute DTN goals. Compared with the preintervention period, hospitals during the second intervention period (2014–2018) achieved higher rates of tPA use (11.7% versus 5.6%; adjusted odds ratio, 2.43 [95% CI, 2.31–2.56]), lower in-hospital mortality (6.0% versus 10.0%; adjusted odds ratio, 0.69 [0.64–0.73]), fewer bleeding complication (3.4% versus 5.5%; adjusted odds ratio, 0.68 [0.62–0.74]), and higher rates of discharge to home (49.6% versus 35.7%; adjusted odds ratio, 1.43 [1.38–1.50]). Similar findings were found in sensitivity analyses of 185 501 patients receiving tPA within 4.5 hours of symptom onset. Conclusions: A nationwide quality improvement program for acute ischemic stroke was associated with substantial improvement in the timeliness of thrombolytic therapy start, increased thrombolytic treatment, and improved clinical outcomes.

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Abstract P338: Cardiovascular And Cerebrovascular Events Associated With Cancer Surgery In The United States

Circulation ◽

10.1161/circ.141.suppl_1.p338 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Anshul Saxena ◽

Muni Rubens ◽

Venkataraghavan Ramamoorthy ◽

Sankalp Das ◽

Chintan B Bhatt ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Perioperative Period ◽

The United States ◽

National Database ◽

Perioperative Morbidity ◽

Cerebrovascular Events ◽

Colon And Rectum ◽

National Trends ◽

Over Time

Background: Major adverse cardiovascular and cerebrovascular events (MACCE) are significant causes of perioperative morbidity and mortality but, the incidence and effects following cancer surgeries are unknown. The aims of this study were to evaluate national trends in MACCE after major cancer surgeries and to identify cancer types associated with cardiovascular events using a large national database. Methods: Patients who had major cancer surgeries from 2005 to 2014 were identified from the National Inpatient Sample database. Hospitalizations for surgeries for cancer of prostate, bladder, esophagus, pancreas, lung, liver, breast, colon and rectum were identified by ICD9 diagnosis and procedure codes. The main outcome was perioperative MACCE, defined as in-hospital, all-cause death, acute myocardial infarction (AMI), or acute ischemic stroke, and was evaluated over time. Results: Among 2,854,810 hospitalizations for major cancer surgeries, perioperative MACCE occurred in 67,316 hospitalizations (2.4%). Mean (SE) age of patients was 65.4 (0.07) years and 54.2% were male patients. MACCE occurred most frequently in patients undergoing surgeries for lung (6.8%), pancreatic (4.5%), and colorectal (3.3%) cancers. Between 2005 and 2014, the frequency of MACCE declined from 2.7% to 2.2% ( P <0.001) and was driven by a decline in the frequency of perioperative death ( P <0.001) and AMI ( P = 0.002). However, no significant changes were observed for acute ischemic stroke ( P = 0.6) during the study period. Conclusion: Perioperative MACCE occurs in 1 out of every 42 hospitalizations for major cancer surgeries. Despite reductions in the rate of death and AMI among patients undergoing major cardiac surgeries, perioperative ischemic stroke remained constant over time. The lack of improvements in perioperative ischemic stroke rate is concerning and requires additional interventions. Significant efforts should be directed towards improving cardiovascular care during the perioperative period of cancer surgeries.

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Geographic dissemination of endovascular stroke thrombectomy in Catalonia within the 2011–2015 period

European Stroke Journal ◽

10.1177/2396987317696376 ◽

2017 ◽

Vol 2 (2) ◽

pp. 163-170 ◽

Cited By ~ 2

Author(s):

Sònia Abilleira ◽

Cristian Tebé ◽

Natalia Pérez de la Ossa ◽

Marc Ribó ◽

Pere Cardona ◽

...

Keyword(s):

Primary Care ◽

Ischemic Stroke ◽

Confidence Interval ◽

Acute Ischemic Stroke ◽

Care Service ◽

Primary Care Service ◽

Large Artery ◽

Endovascular Thrombectomy ◽

Service Areas ◽

Over Time

Introduction Endovascular thrombectomy was recently established as a new standard of care in acute ischemic stroke patients with large artery occlusions. Using small area health statistics, we sought to assess dissemination of endovascular thrombectomy in Catalonia throughout the period 2011–2015. Patients and methods We used registry data to identify all endovascular thrombectomies for acute ischemic stroke performed in Catalonia within the study period. The SONIIA registry is a government-mandated, population-based and externally audited data base that includes all reperfusion therapies for acute ischemic stroke. We linked endovascular thrombectomy cases identified in the registry with the Central Registry of the Catalan Public Health Insurance to obtain the primary care service area of residence for each treated patient, age and sex. We calculated age-sex standardized endovascular thrombectomy rates over time according to different territorial segmentation patterns (metropolitan/provincial rings and primary care service areas). Results Region-wide age-sex standardized endovascular thrombectomy rates increased significantly from 3.9 × 100,000 (95% confidence interval: 3.4–4.4) in 2011 to 6.8 × 100,000 (95% confidence interval: 6.2–7.6) in 2015. Such increase occurred in inner and outer metropolitan rings as well as provinces although highest endovascular thrombectomy rates were persistently seen in the inner metropolitan area. Changes in endovascular thrombectomy access across primary care service areas over time were more subtle, but there was a rather generalized increase of standardized endovascular thrombectomy rates. Discussion This study demonstrates temporal and territorial dissemination of access to endovascular thrombectomy in Catalonia over a 5-year period although variation remains at the completion of the study. Conclusion Mapping of endovascular thrombectomy is essential to assess equity and propose actions for access dissemination.

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Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome

Cerebrovascular Diseases ◽

10.1159/000447722 ◽

2016 ◽

Vol 42 (5-6) ◽

pp. 404-414 ◽

Cited By ~ 9

Author(s):

Marie-Christine Alessi ◽

Christophe Gaudin ◽

Philippe Grosjean ◽

Valérie Martin ◽

Serge Timsit ◽

...

Keyword(s):

Ischemic Stroke ◽

Thrombolytic Therapy ◽

Clinical Severity ◽

Tissue Type ◽

Stroke Severity ◽

Thrombin Activatable Fibrinolysis Inhibitor ◽

Nihss Score ◽

Multicenter Observational Study ◽

Fibrinolysis Inhibitor ◽

Prospective Longitudinal

Background and Purpose: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). Methods: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. Results: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). Conclusion: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

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Endovascular Thrombectomy after Large-Vessel Ischemic Stroke: Utilization, Outcomes, and Readmissions across the United States

Radiology ◽

10.1148/radiol.2021203082 ◽

2021 ◽

Vol 299 (1) ◽

pp. 179-189

Author(s):

Pedram Golnari ◽

Pouya Nazari ◽

Sameer A. Ansari ◽

Michael C. Hurley ◽

Ali Shaibani ◽

...

Keyword(s):

United States ◽

Ischemic Stroke ◽

The United States ◽

Large Vessel ◽

Endovascular Thrombectomy

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Abstract WP41: Age-Specific Differences in the Use of Endovascular Treatment and Hospital Outcomes in Patients With Acute Ischemic Stroke: A Community-Wide Perspective

Stroke ◽

10.1161/str.51.suppl_1.wp41 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Saqib A Chaudhry ◽

Iqra N Akhtar ◽

Ameer E Hassan ◽

Mohammad Rauf A Chaudhry ◽

Mohsain Gill ◽

...

Keyword(s):

Ischemic Stroke ◽

Endovascular Treatment ◽

Acute Ischemic Stroke ◽

International Classification Of Diseases ◽

The United States ◽

Primary Diagnosis ◽

Limited Information ◽

Hospital Outcomes ◽

The Impact ◽

Over Time

Background: Relatively limited information is available about trends over time in the use of endovascular treatment in patients of different ages hospitalized with acute ischemic stroke and the association between use of thrombectomy treatment and hospital outcomes in age strata. We performed this analysis to evaluate trends in the utilization of endovascular treatment in acute ischemic stroke by age strata in real-world practice. Methods: We conducted this study by identifying patients admitted with a primary diagnosis of ischemic stroke in the United States from 2007 to 2016 using the Nationwide Inpatient Sample. International Classification of Diseases, ninth revision, and tenth, Clinical Modification (ICD-9-CM, ICD-10-CM) codes were used to identify patients admitted for ischemic stroke and undergoing endovascular treatment. Results: Of the 4,590,533 patients admitted with ischemic stroke, 269,922 (5.88%) received intravenous thrombolytic treatment, and 51,375 (1.12%) underwent endovascular treatment. There is almost 12-fold significant increase in the use of endovascular treatment patients admitted with acute ischemic stroke between 2007 to 2016. Patients who were 75 years and older experienced a marked increase in the receipt of endovascular treatment over time (0.12% 2007; 1.91% 2016; trend p<0.0001). We observed statistically significant improvement in outcomes including minimal disability (6.3% to 18.8%; trend p<0.0001) and in hospital mortality (25.0% to 16.5%; trend p<0.0001) in patients 75 years and older treated with endovascular treatment in study period. We observed similar trend of outcomes in each of the other age-specific groups under study (<55, 55-64 and 65-74 years). Conclusions: Our findings indicate a recent increase in the use of endovascular in middle-aged and elderly patients with acute ischemic strokes. The impact of endovascular treatment on hospital outcomes was observed in each of our age strata understudy though the magnitude of absolute and relative benefit varied according to age.

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Abstract WMP94: Temporal Trends in Racial, Age, and Sex-Specific Utilization of Decompressive Hemicraniectomy Among Acute Ischemic Stroke Patients in the United States

Stroke ◽

10.1161/str.51.suppl_1.wmp94 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Sai P Polineni ◽

Fadar O Otite ◽

Seemant Chaturvedi

Keyword(s):

United States ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Temporal Trends ◽

Age Groups ◽

The United States ◽

Decompressive Hemicraniectomy ◽

Study Results ◽

Over Time ◽

Age And Sex

Background: The aim of this study is to evaluate current trends in racial, age, and sex-specific utilization of decompressive hemicraniectomy (HC) in acute ischemic stroke (AIS) patients in the United States over the last decade. Methods: All adult patients with a diagnosis of AIS were identified from the 2004-2015 Nationwide Inpatient Sample (weighted N=4,792,428) using International Classification of Diseases Ninth revision (ICD-9) codes. Proportion of patients undergoing HC in various age, race, and sex groups were ascertained using ICD-9 procedural codes. Temporal trends were mapped by year in order to track changes in utilization over time. Analysis of utilization disparities and trends within age, sex, and race subgroups was conducted via multivariate logistic regression. Results: Of all eligible AIS patients from 2004-2015, 0.25% underwent HC (.08 in 2004 to .46 in 2015). Increased utilization over time was seen in both men (.13 to .57) and women (.08 to .54), with women showing comparable odds of utilization to men [OR: 0.95 (95% CI: .87-1.04, p=0.27)]. Similarly, increased utilization trends were seen in all age groups (Figure 1) with the highest rates in the 18-39 subgroup (1.41%). Compared to trends in this younger subgroup (.43 to 2.12), patients aged 60-79 experienced a similar overall increase but at lower utilization rates (.06 to .37). Compared to white patients in multivariate models, blacks did not show significant differences in odds of HC [1.09 (.96-1.24, p=0.20)], while patients from Hispanic [1.25 (1.03-1.51, p=0.02)] and other [1.26 (1.04-1.52, p=0.02)] race-ethnic groups showed increased odds. Conclusions: From 2004-2015, hemicraniectomy rates have seen substantial increases in all age, sex, and race groups. The increasing rates of hemicraniectomies among those over age 60 suggest that there has been at least partial acceptance of DESTINY 2 study results.

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Contemporary utilization patterns and outcomes of thrombolytic administration for ischemic stroke among patients with cancer

International Journal of Stroke ◽

10.1177/1747493019895709 ◽

2019 ◽

pp. 174749301989570 ◽

Cited By ~ 2

Author(s):

Jocelyn Owusu-Guha ◽

Avirup Guha ◽

P Elliott Miller ◽

Sumeet Pawar ◽

Amit K Dey ◽

...

Keyword(s):

Ischemic Stroke ◽

Thrombolytic Therapy ◽

Hospital Mortality ◽

Acute Ischemic Stroke ◽

Intracranial Bleeding ◽

National Database ◽

Readmission Rates ◽

Patients With Cancer ◽

Comorbidity Burden ◽

Utilization Patterns

Background Thrombolytic therapy significantly improves outcomes among patients with acute ischemic stroke. While cancer outcomes have dramatically improved, the utilization, safety, and mortality outcomes of patients with cancer who receive thrombolytic therapy for acute ischemic stroke are unknown. Methods Using a national database, we identified all hospitalizations for acute ischemic stroke requiring thrombolytic therapy between 2003 and 2015. Patients with contraindications to thrombolytic therapy were excluded. Following propensity score matching for comorbidity burden, trends in thrombolytic therapy use and its effect on in-hospital mortality, intracranial or all-cause bleeding, and the combined endpoint of mortality and all-cause bleeding, by presence/absence of cancer were evaluated. We also evaluated 30- and 90-day readmission rates post-thrombolytic therapy administration. Results We identified 237,687 acute ischemic stroke hospitalizations requiring thrombolytic therapy, of which 26,328 (11%) had an underlying cancer. Over the study period, thrombolytic therapy use increased across all acute ischemic stroke admissions, irrespective of cancer presence (12.4/1000 in 2003 to 81.1/1000 in 2015, P < 0.0001). However, thrombolytic therapy utilization differed by cancer presence (4.8% cancer vs.·5.1% non-cancer, P = 0.001). There was no difference in intracranial bleeding (9.6% vs. 9.7%), all-cause bleeding (13.2% vs. 13.2%), or in-hospital mortality (7.6% vs. 7.2%). While there was no difference in 30-day readmission rates by cancer presence (24% vs. 29%, P = 0.40), at 90-days, cancer patients saw higher readmission rates (17.2% vs. 13.3%, P = 0.02). Conclusions Contemporary thrombolytic therapy use for acute ischemic stroke has risen, irrespective of presence of cancer. Yet, patients with comorbid cancer appear to see lower rates of thrombolytic therapy use for acute ischemic stroke, despite no difference in the rate of intracranial bleeding or mortality after adjustment for comorbidities.

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Changes in the associations of race and rurality with SARS-CoV-2 infection, mortality, and case fatality in the United States from February 2020 to March 2021: A population-based cohort study

PLoS Medicine ◽

10.1371/journal.pmed.1003807 ◽

2021 ◽

Vol 18 (10) ◽

pp. e1003807

Author(s):

George N. Ioannou ◽

Jacqueline M. Ferguson ◽

Ann M. O’Hare ◽

Amy S. B. Bohnert ◽

Lisa I. Backus ◽

...

Keyword(s):

Risk Factors ◽

Case Fatality ◽

The United States ◽

Population Based ◽

Rural Residence ◽

White Race ◽

Comorbidity Burden ◽

High Comorbidity ◽

Urban Versus ◽

Over Time

Background We examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study. Methods and findings In a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2–related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value <0.001), mortality (AOR 3.85 [95% CI 3.30 to 4.50], p-value < 0.001), and case fatality (AOR 2.56, 95% CI 2.23 to 2.93, p-value < 0.001) in February to March 2020, but these associations were attenuated and not statistically significant by November 2020 for infection (AOR 1.03 [95% CI 1.00 to 1.07] p-value = 0.05) and mortality (AOR 1.08 [95% CI 0.96 to 1.20], p-value = 0.21) and were reversed for case fatality (AOR 0.86, 95% CI 0.78 to 0.95, p-value = 0.005). American Indian/Alaska Native (AI/AN versus White) race was associated with higher risk of SARS-CoV-2 infection in April and May 2020; this association declined over time and reversed by March 2021 (AOR 0.66 [95% CI 0.51 to 0.85] p-value = 0.004). Hispanic (versus non-Hispanic) ethnicity was associated with higher risk of SARS-CoV-2 infection and mortality during almost every time period, with no evidence of attenuation over time. Urban (versus rural) residence was associated with higher risk of infection (AOR 2.02, [95% CI 1.83 to 2.22], p-value < 0.001), mortality (AOR 2.48 [95% CI 2.08 to 2.96], p-value < 0.001), and case fatality (AOR 2.24, 95% CI 1.93 to 2.60, p-value < 0.001) in February to April 2020, but these associations attenuated over time and reversed by September 2020 (AOR 0.85, 95% CI 0.81 to 0.89, p-value < 0.001 for infection, AOR 0.72, 95% CI 0.62 to 0.83, p-value < 0.001 for mortality and AOR 0.81, 95% CI 0.71 to 0.93, p-value = 0.006 for case fatality). Throughout the observation period, high comorbidity burden, younger age, and obesity were consistently associated with infection, while high comorbidity burden, older age, and male sex were consistently associated with mortality. Limitations of the study include that changes over time in the associations of some risk factors may be affected by changes in the likelihood of testing for SARS-CoV-2 according to those risk factors; also, study results apply directly to VA enrollees who are predominantly male and have comprehensive healthcare and need to be confirmed in other populations. Conclusions In this study, we found that strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality observed early in the pandemic were ameliorated or reversed by March 2021.

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Abstract 16: IV TPA in the 0-3 Hour Window: Quantitative Fragility-Robustness Assessment of the Strength of the RCT Evidence

Stroke ◽

10.1161/str.52.suppl_1.16 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Katherine T Mun ◽

Jordan B Bonomo ◽

David S Liebeskind ◽

Jeffrey L Saver

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Individual Patient Data ◽

Endovascular Thrombectomy ◽

Strength Of Evidence ◽

Evidence Strength ◽

Meta Analyses ◽

Robustness Assessment ◽

Over Time ◽

Iv Tpa

Background: After 3 decades, the era of RCTs of IV tPA as a standalone therapy in acute ischemic stroke has now likely closed, with the completion of TESPI, PRISMS, and late, imaging-selection RCTs, and the advent of endovascular thrombectomy. Some non-expert contrarians questioned the accumulating evidence regarding tPA; the recently formulated fragility-robustness index (FRI) enables quantification of the actual rigor of evidence throughout the era of IV tPA investigation. Methods: The FRI summarizing the strength of the statistical evidence for clinical trial findings is the minimum nonevent to event changes needed to turn a statistically significant to non-significant result. The FRI was applied to disability-free (mRS 0-1) and independence (mRS 0-2) outcomes; cumulative meta-analyses delineated evidence strength after each successive RCT. FRI scores were classified: Not Robust (FRI 0-4), Somewhat Robust (5-12), Robust (13-33), and Highly Robust (>33). Results: Systematic search identified 8 RCTs (1960 patients) of IV tPA in the 0-3h window from 1995 - 2018. Study-level meta-analyses showed FRIs of 42 for mRS 0-1 and 40 for mRS 0-2; individual patient data meta-analyses showed FRIs of 40 for both mRS 0-1 and mRS 0-2, placing IV tPA in the highest quintile of FRIs among meta-analyses for all conditions. Evolution of RCT evidence over time is shown in Table 1. Strength of evidence for IV tPA superiority was already robust with publication of the initial 2 NINDS-tPA in 1995, remained robust through 2011 after 4 additional RCTs, increased to highly robust with the IST-3 mega-trial in 2012, and remains highly robust today after 1 additional trial. Conclusions: Intravenous tPA for acute ischemic stroke in 0-3h patients is one of the most robustly proven therapies in medicine. This therapy was already robustly supported with publication of the initial trials 25 years ago and advanced 9 years ago after additional trials to highly robust/non-fragile.

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