Global Stroke Corner

01 Mar 2019 Global Stroke Corner

Anderson CS, Huang Y, Lindley RI, et al. ENCHANTED Investigators and Coordinators. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. Lancet. 2019 Feb 6. pii: S0140-6736(19)30038-8. doi: 10.1016/S0140-6736(19)30038-8. [Epub ahead of print] PMID: 30739745

The ENCHANTED trial reported that in the setting of intravenous thrombolysis for acute ischaemic stroke, intensive blood pressure management reduced the risk of intracranial haemorrhage but did not improve functional outcome.

ENCHANTED was a PROBE trial in which 2227 alteplase-eligible patients with acute ischaemic stroke of mild-to-moderate severity (NIHSS 7]) were randomly allocated within 6 hours of stroke onset to receive intensive (target systolic BP 130–140 mm Hg within 1 h) or guideline-recommended (target <180 mm Hg) blood pressure-lowering therapy over 72 h.

Mean systolic BP over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001), not reaching the planned 15 mm Hg difference.

The primary efficacy endpoint was functional status at 90 days, measured by a shift of modified Rankin Scale (mRS) scores. There was no significant shift in mRS scores between groups was observed (odds ratio [OR] 1·01, 95% CI 0·87–1·17), despite there being fewer intracranial haemorrhages in the intensive group than in the guideline group (14.8% vs 18·7%; OR 0·75, 0·60–0·94, p=0·0137).

Connolly SJ, Crowther M, Eikelboom JW, et al ; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med., 2019 Feb 7.. doi: 10.1056/NEJMoa1814051. [Epub ahead of print] PMID: 30730782

In May, 2018, andexanet alfa was approved by the US FDA for urgent reversal of the anticoagulant effect of the direct factor Xa inhibitors apixaban (Eliquis) and rivaroxaban (Xarelto) in patients with life-threatening or uncontrolled bleeding

This paper reports the results of the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) single-group cohort study of 352 patients with acute major bleeding (64% intracranial, 26% gastrointestinal) who had received a factor Xa inhibitor (apixaban, rivaroxaban or edoxaban) within the previous 18 hours, and were administered a bolus of andexanet over 15-30 minutes (400-800 mg), followed by a 2-hour infusion, (480-960 mg). The results showed that andexanet alfa markedly reduced anti–factor Xa activity from baseline, and 82% of patients had excellent or good hemostatic efficacy at 12 hours after the andexanet infusion, with consistent effects across all subgroups. At 30 days, 14% of patients died and 10% experienced thrombotic events, most in patients in whom resumption of oral anticoagulation was delayed or not started.

Dennis M. et al. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. The Lancet 2019; Volume 393, Issue 10168, Pages 265-274

Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. Functional status was assessed at 6 months and 12 months after randomisation. Findings: Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.

Feigin VL. Et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. NEJM 2018;379 (25); 20 Dec 2018; pages 2429-2437.

The lifetime risk of stroke has been calculated in a limited number of selected populations. The authors estimated the lifetime risk of stroke at the regional, country, and global level using GBD data from a comprehensive study of the prevalence of major diseases. RESULTS The estimated global lifetime risk of stroke from the age of 25 years onward was 24.9% (95% uncertainty interval, 23.5 to 26.2); the risk among men was 24.7% (95% uncertainty interval, 23.3 to 26.0), and the risk among women was 25.1% (95% uncertainty interval, 23.7 to 26.5). The highest estimated lifetime risks of stroke according to GBD region were in East Asia (38.8%), Central Europe (31.7%), and Eastern Europe (31.6%), and the lowest risk was in eastern sub-Saharan Africa (11.8%). The mean global lifetime risk of stroke increased from 22.8% in 1990 to 24.9% in 2016, a relative increase of 8.9% (95% uncertainty interval, 6.2 to 11.5). CONCLUSIONS In 2016, the global lifetime risk of stroke from the age of 25 years onward was approximately 25% among both men and women. There was geographic variation in the lifetime risk of stroke, with the highest risks in East Asia, Central Europe, and Eastern Europe.

Hanley DF, Thompson RE, Rosenblum M, et al. MISTIE III Investigators. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019 Feb 6. doi: 10.1016/S0140-6736(19)30195-3. [Epub ahead of print] PMID: 30739747

MISTIE III was a PROBE trial in which 506 adults with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more were randomly assigned to image-guided MISTIE (minimally invasive catheter evacuation followed by thrombolysis [1·0 mg alteplase every 8 h for up to nine doses])) or standard medical care.

MISTIE did not improve functional outcome at 1 year as measured by a modified Rankin Scale score of 0-3 (45% MISTIE group vs 41% standard medical care group; adjusted risk difference 4% [95% CI -4 to 12]; p=0·33).

RIGHT-2 Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. Lancet. 2019 Feb 5. doi: 10.1016/S0140-6736(19)30194-1. [Epub ahead of print] PMID: 30738649

The RIGHT-2 study was a multicentre, ambulance-based, randomised, sham-controlled, phase 3 trial of the safety and efficacy of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, in 1149 patients with hyperacute (< 4 hours) stroke. 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had TIA, and 297 (26%) had a non-stroke mimic. The median time to randomisation was 71 min (IQR 45-116).

In the GTN group, participants' systolic BP was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic BP was lowered by 2·6 mm Hg (p=0·0026) at hospital admission.

There was no difference in primary the outcome (modified Rankin Scale) at 90 days in the GTN group compared with the sham group in cohort 1 (patients with stroke or TIA; adjusted common odds ratio [acOR] 1·25 [95% CI 0·97–1·60]; p=0·083) or in cohort 2 (all patients—ie, intention to treat [ITT]; 1·04 [0·84–1·29]; p=0·69).

Nor was there any difference between treatment groups in deaths at day 4 in either cohort (cohort 1: acOR 1·17 [0·57–2·39]; p=0·68; cohort 1: 1·19 [0·60–2·35]; p=0·63).

Additional analyses suggested potential harm, with worse outcomes in GTN-treated patients with intracerebral haemorrhage (p=0·057), the earliest enrolled (<1 h) patients (p=0·014), and the most severe strokes (NIHSS >12; 0·044).

This is another study, and the first in a hyperacute, ambulance-based, setting suggesting that blood pressure-lowering in the acute stroke does not improve functional outcome

It is another study however showing the feasibility of paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting.

Ziff O et al. Statins and the risk of intracerebral haemorrhage in patients with stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2019;90(1):75-83

This meta-analysis examined the risk of intracerebral haemorrhage (ICH) in statin recipients with a history of stroke. A search of various electronic databases identified 43 studies (317,291 patient-years of follow-up) that compared statin therapy with controls (placebo or no treatment) in patients with previous ICH or ischaemic stroke. Meta-analysis of the data showed that statins had no significant impact on the pooled risk ratio (RR) for recurrent ICH In patients with previous ICH, but were associated with significant reductions in mortality (RR, 0.49) and poor functional outcome (RR, 0.71). In patients with previous ischaemic stroke, statins were associated with a non-significant increase in ICH, but significantly lower risks of recurrent ischaemic stroke (RR, 0.74), any stroke (RR, 0.82), mortality (RR, 0.68) and poor functional outcome (RR, 0.83).

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