Real-World Effectiveness of Lipid-Lowering Medications on Outcomes after Stroke: Potential Implications of the New-User Design.

INTRODUCTION: Observational studies are increasingly being used to provide evidence on the real-world effectiveness of medications for preventing vascular diseases, such as stroke. We investigated whether the real-world effectiveness of treatment with lipid-lowering medications after ischemic stroke is affected by prevalent-user bias. METHODS: An observational cohort study of 90-day survivors of ischemic stroke using person-level data from the Australian Stroke Clinical Registry (2012-2016; 45 hospitals) linked to administrative (pharmaceutical, hospital, death) records. The use of, and adherence to (proportion of days covered <80% [poor adherence] vs. ≥80% [good adherence]), lipid-lowering medications within 90 days post-discharge was determined from pharmaceutical records. Users were further classified as prevalent (continuing) or new users, based on dispensing within 90 days prior to stroke. A propensity score-adjusted Cox regression was used to evaluate the effectiveness of lipid-lowering medications on outcomes (all-cause mortality, all-cause and cardiovascular disease readmission) within the subsequent year. Analyses were undertaken using prevalent-user (all users vs. nonusers) and new-user designs (new users vs. nonusers). RESULTS: Of 11,217 eligible patients (median age 72 years, 42% female), 9,294 (83%) used lipid-lowering medications within 90 days post-discharge, including 5,479 new users. In both prevalent-user and new-user designs, nonusers (vs. users) had significantly greater rates of mortality (hazard ratio [HR] 2.35, 95% CI: 1.89-2.92) or all-cause readmissions (HR 1.22, 95% CI: 1.05-1.40) but not cardiovascular disease readmission. In contrast, associations between having poor (vs. good) adherence on outcomes were stronger among new users than all users. Among new users, having poor adherence was associated with greater rates of mortality (HR 1.48, 95% CI: 1.12-1.96), all-cause readmission (HR 1.14, 95% CI: 1.02-1.27), and cardiovascular disease readmission (HR 1.20, 95% CI: 1.01-1.42). CONCLUSIONS: The real-world effectiveness of treatment with lipid-lowering medications after stroke is attenuated when evaluated based on prevalent-user rather than new-user design. These findings may have implications for designing studies on the real-world effectiveness of secondary prevention medications.

Hypertension Management in Stroke Prevention: Time to Consider Primary Aldosteronism.

Primary aldosteronism confers a higher risk of stroke, atrial fibrillation, and cardiovascular disease than blood pressure matched essential hypertension. It is the most common endocrine cause of secondary hypertension with prevalence estimates of up to 13% in primary care and 30% in referral centers around the world. Unlike essential hypertension, primary aldosteronism has targeted medical treatment and potentially curative surgical solutions which can ameliorate the associated cardiovascular risks. This narrative review highlights an evidence gap in the optimal diagnosis and targeted treatment of primary aldosteronism in secondary stroke prevention. Over half of the patients suffering a stroke have blood pressure in the hypertensive range and less than a third achieve optimal blood pressure control. There are no guideline recommendations to test for primary aldosteronism in these patients, although up to 30% of patients with resistant hypertension may have this disease. The accurate diagnosis of primary aldosteronism could significantly improve blood pressure, simplify the medication regimen and reduce the overall cardiovascular risk in these patients. The challenges associated with screening for primary aldosteronism following stroke may be overcome by novel blood tests which are less affected by antihypertensive medications routinely used in stroke care. Approximately one-quarter of all strokes occur in patients who have previously had a stroke. Modifying hypertension, the leading modifiable risk factor, would, therefore, have significant public health implications. As clinicians, we must increase our awareness of primary aldosteronism in patients with stroke, particularly in those with resistant hypertension, to enable targeted therapy and reduce the risk of stroke recurrence.

Mechanical thrombectomy for emergent large vessel occlusion: an Australian primary stroke centre workflow analysis.

BACKGROUND: Time to successful reperfusion is a critical prognostic factor for acute ischaemic stroke. Mechanical thrombectomy has become the gold standard treatment for emergent large vessel occlusion stroke. The timely delivery of this highly specialised procedure to patients outside of metropolitan centres presents a dilemma of inequity, with limited workflow data hindering benchmarking and service optimisation. AIMS: To analyse key stroke treatment time parameters from a primary stroke centre existing in a regional centre within a hub-and-spoke delivery model in Victoria, Australia. METHODS: Retrospective cohort study of patients transferred from a regional primary stroke centre to a metropolitan comprehensive stroke centre for mechanical thrombectomy between July 2016 and December 2018. Time workflow analysis was conducted from symptom onset to primary stroke centre departure. RESULTS: A total of 55 patients was included in this study with an average age of 70.2 years. Median National Institutes of Health Stroke Scale score on admission was 13 (interquartile range (IQR) 7-17). Median pre-hospital time was 68 min (IQR 56-137) and median door-in-door-out time was 120.5 min (IQR 98-150), constituting 36.1% and 63.9% of total median time from symptom onset to primary stroke centre departure (188.5 min) respectively. There were no significant differences across observed cohort characteristics under linear regression analysis. CONCLUSION: Protracted pre-hospital and primary stroke centre workflow times can delay effective treatment for patients with acute ischaemic stroke in regional areas. A systems-level approach to streamlining processes in these key areas is required to bridge this inequity in best practice care.

Trends over time in the risk of stroke after an incident transient ischemic attack.

BACKGROUND AND PURPOSE: Long-term population trends in the early risk of stroke after transient ischemic attack (TIA) are unknown. We hypothesized that there has been an appreciable decline in the risk of stroke after TIA for the last decade. METHODS: Population-level cohort study from Victoria, Australia (population 5.6 million), using linked data from hospitals, emergency departments, and death records (2001-2011), with a 2-year clearance period to define incident TIAs. Age-specific rates/1000, yearly incident rate ratios, and age-sex-adjusted risk of stroke after TIA were computed. RESULTS: The mean age of 46 971 patients with TIA was 71 (SD=15), 52% women. In patients ≥65 years, annual TIA rates declined between 2001 and 2011 from 5.8 to 4.8/1000 (men) and from 5.3 to 4.2/1000 (women). Yearly incident rate ratios were 0.97 (95% confidence interval, 0.96-0.98) in men and 0.97 (95% confidence interval, 0.97-0.98) in women. Overall, the 90-day stroke risk was 3.1%. Age-sex-adjusted risk of stroke at 90 days after a TIA decreased by 3% per year (odds ratio for the effect of year, 0.97; 95% confidence interval, 0.95-0.99). Male sex, direct discharge from emergency departments, public hospital care, stroke unit care, and absence of vascular risk factors were associated with a downward yearly trend of stroke within 90 days of TIA. CONCLUSIONS: Over the last 10 years, there has been a measurable decline in the 90-day risk of stroke after an incident TIA and overall decline in rates of TIA in Victoria, Australia. These trends may reflect improved primary and secondary prevention efforts for the last decade.

Door-in-door-out times for patients with large vessel occlusion ischaemic stroke being transferred for endovascular thrombectomy: a Victorian state-wide study.

Background: Time to reperfusion is an important predictor of outcome in ischaemic stroke from large vessel occlusion (LVO). For patients requiring endovascular thrombectomy (EVT), the transfer times from peripheral hospitals in metropolitan and regional Victoria, Australia to comprehensive stroke centres (CSCs) have not been studied. Aims: To determine transfer and journey times for patients with LVO stroke being transferred for consideration of EVT. Methods: All patients transferred for consideration of EVT to three Victorian CSCs from January 2017 to December 2018 were included. Travel times were obtained from records matched to Ambulance Victoria and the referring centre via Victorian Stroke Telemedicine or hospital medical records. Metrics of interest included door-in-door-out time (DIDO), inbound journey time and outbound journey time. Results: Data for 455 transferred patients were obtained, of which 395 (86.8%) underwent EVT. The median DIDO was 107 min (IQR 84-145) for metropolitan sites and 132 min (IQR 108-167) for regional sites. At metropolitan referring hospitals, faster DIDO was associated with use of the same ambulance crew to transport between hospitals (75 (63-90) vs 124 (99-156) min, p<0.001) and the administration of thrombolysis prior to transfer (101 (79-133) vs 115 (91-155) min, p<0.001). At regional centres, DIDO was consistently longer when patients were transported by air (160 (127-195) vs 116 (100-144) min, p<0.001). The overall door-to-door time by air was shorter than by road for sites located more than 250 km away from the CSC. Conclusion: Transfer times differ significantly for regional and metropolitan patients. A state-wide database to prospectively collect data on all interhospital transfers for EVT would be helpful for future study of optimal transport mode at regional sites and benchmarking of DIDO across the state.

Determining the sensitivity of emergency dispatcher and paramedic diagnosis of stroke: statewide registry linkage study.

Introduction: Correctly identifying people with suspected stroke is essential for ensuring rapid treatment. Our aims were to determine the sensitivity of emergency dispatcher and paramedic identification of patients with stroke, the factors associated with correct identification, and whether there were any implications for hospital arrival times. Methods: Observational study using patient-level data from the Australian Stroke Clinical Registry (2015-2017) linked with ambulance and emergency department records for the state of Victoria. The registry diagnosis was the reference standard to compare with the provisional diagnoses made by emergency services personnel classified as "suspected" and "not suspected" stroke/transient ischemic attack (TIA). Multivariable logistic and quintile regressions were used to determine factors associated with correct identification and timely arrival to hospital. Results: Overall, 4717 (64%) were matched to ambulance transport records (median age: 73 years, 43% female). Stroke/TIA was suspected in 56% of registrants by call-takers and 69% by paramedics. Older patients (75+ years) (adjusted odds ratio [aOR]: 0.61; 95% confidence interval [CI]: 0.49-0.75), females (aOR: 0.86; 95% CI: 0.75-0.99), those with severe stroke or intracerebral hemorrhage were less often suspected as stroke. Cases identified as stroke had a shorter arrival time to hospital (unadjusted median minutes: stroke, 54 [43, 72] vs not stroke, 66 [51, 89]). Conclusions: Emergency dispatchers and paramedics identified over half of patients with stroke in the prehospital setting. Important patient characteristics, such as being female and those having a severe stroke, were found that may enable refinement of prehospital ambulance protocols and dispatcher/paramedic education. Those correctly identified as stroke, arrived earlier to hospital optimizing their chances of receiving time-critical treatments.

Tranexamic acid for intracerebral haemorrhage within 2 hours of onset: protocol of a phase II randomised placebo-controlled double-blind multicentre trial.

RATIONALE: Haematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth. METHODS AND DESIGN: Stopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework. HYPOTHESIS: In patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo. SAMPLE SIZE ESTIMATES: A sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients. INTERVENTION: Participants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo. PRIMARY EFFICACY MEASURE: The primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan. DISCUSSION: We describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments.