Hemodynamic variability and cerebrovascular control after transient cerebral ischemia

We investigated if hemodynamic variability, cerebral blood flow (CBF) regulation, and their interrelationships differ between patients with transient ischemic attack (TIA) and controls. We recorded blood pressure (BP) and bilateral middle cerebral artery flow velocity (MCAv) in a cohort of TIA patients (n = 17), and age?matched controls (n = 15). Spontaneous fluctuations in BP and MCAv were characterized by spectral power analysis, and CBF regulation was assessed by wavelet phase synchronization analysis in the very low? (0.02–0.07 Hz), low? (0.07–0.20 Hz), and high?frequency (0.20–0.40 Hz) ranges. Furthermore, cerebrovascular CO2 reactivity was assessed as a second metric of CBF regulation by inducing hypercapnia with 8% CO2 inhalation followed by hyperventilation driven hypocapnia. We found that TIA was associated with higher BP power (group effect, P < 0.05), but not MCAv power (P = 0.11). CBF regulation (assessed by wavelet phase synchronization and CO2 reactivity) was intact in patients (all P ? 0.075) across both hemispheres (all P ? 0.51). Pooled data (controls and affected hemisphere of patients) showed that BP and MCAv power were positively correlated at all frequency ranges (R2 = 0.20–0.80, all P < 0.01). Furthermore, LF phase synchronization index was a significant determinant of MCAv power (P < 0.05), while VLF and HF phase synchronization index, and TIA were not (all P ? 0.50). These results indicate that CBF stability and control is maintained in TIA patients, but BPV is markedly elevated. BPV attenuation may be an important therapeutic strategy for enhancing secondary stroke prevention in patients who suffer a TIA

Long-Term Effect of Participation in an Early Exercise and Education Program on Clinical Outcomes and Cost Implications, in Patients with TIA and Minor, Non-Disabling Stroke

Participation in exercise and education programs following transient ischemic attack (TIA) or minor stroke may decrease cardiovascular disease risk. The purpose of this study was to assess the long-term effect (3.5 years) of an exercise and education program administered soon after TIA or minor stroke diagnosis on clinical outcome measures (stroke classification and number, patient deaths, hospital/emergency department admission) and cost implications obtained from standard hospital records. Hospital records were screened for 60 adults (male, n = 31; 71 ± 10 years), diagnosed with TIA or non-disabling stroke, who had previously been randomised and completed either an 8-week exercise and education program, or usual care control. Follow-up clinical outcomes and cost implications were obtained 3.5 ± 0.3 years post-exercise. Participants randomised to the exercise and education program had significantly fewer recurrent stroke/TIAs (n = 3 vs. n = 13, Cohen’s d = 0.79) than the control group (P ≤ 0.003). Similar finding were reported for patient deaths (n = 0 vs. n = 4, d = 0.53), and hospital admissions (n = 48 vs. n = 102, d = 0.54), although these findings were only approaching statistical significance. The relative risk (mean; 95%CI) of death, stroke/TIAs and hospital admissions were 0.11 (0.01 to 1.98), 0.23 (0.07 to 0.72) and 0.79 (0.57 to 1.09), respectively. Hospital admission costs were significantly lower for the exercise group ($9041 ± 15,080 NZD [~$6000 ± 10,000 USD]) than the control group ($21,750 ± 22,973 NZD [~$14,000 ± 15,000 USD]) during the follow-up period (P < 0.05, d = 0.69). The present study demonstrates the long-term patient benefit and economic importance of providing secondary prevention, exercise and education programs for patients with TIA and minor stroke. URL: http://www.anzctr.org.au/; Trial Registration Number: ACTRN12611000630910

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Effect of early exercise engagement on cardiovascular and cerebrovascular health in stroke and TIA patients: clinical trial protocol

Objective: This study will investigate the efficacy of implementing either an early or delayed exercise intervention on cardiovascular and cerebrovascular health for newly diagnosed stroke and high-risk Transient Ischaemic Attack (TIA) patients.Methods: The study is a randomized, parallel group clinical trial. Patients will be recruited from a local hospital based on inclusion/exclusion criteria. Participants will attend a baseline assessment within 2 to 7 days of stroke or TIA diagnosis. The assessment will consist of a series of cardiovascular and cerebrovascular primary and secondary outcome measures which will be assessed during some or all of the following; at rest, during a postural challenge, during a cerebral autoregulation and CO2 reactivity test and/or during an incremental exercise test. Primary outcome measures include vascular risk factors (resting blood pressure, blood lipid profile etc), arterial stiffness of the carotid artery and blood velocity of the carotid artery and middle cerebral artery. Secondary outcome measures include cerebral autoregulation, physical fitness, and central and peripheral blood pressure. Following the baseline assessment, participants will be randomized to either a 12-week exercise programme which will commence within 7 days (early) or 28 days (delayed) of stroke/TIA diagnosis, or to a usual care control group. The exercise programme will consist of twice weekly, 60 minute, prescribed aerobic exercise sessions, and one 30 minute home-based aerobic exercise session. An identical assessment will be implemented post-intervention. Given the practical implications of the study, the clinical significance of early or delayed exercise engagement will be assessed for each outcome variable.Conclusion: This study will advance our knowledge concerning the timing, importance and viability of exercise as a secondary prevention strategy for improving health outcomes for stroke and TIA patients. The study will provide much needed objective data for stroke and high-risk TIA patients concerning the physiological effect of regular exercise participation

Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921