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Review
. 2023 Oct 23;10(10):CD005951.
doi: 10.1002/14651858.CD005951.pub5.

Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage

Helle Eilertsen  1   2 , Chaamanti S Menon  3 , Zhe Kang Law  4 , Chen Chen  5   6   7 , Philip M Bath  3 , Thorsten Steiner  8   9 , Michael Jr Desborough  10 , Else C Sandset  11   12 , Nikola Sprigg  3 , Rustam Al-Shahi Salman  13
Affiliations
Review

Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage

Helle Eilertsen et al. Cochrane Database Syst Rev. .

Abstract

Background: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018.

Objectives: To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset.

Search methods: We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022.

Selection criteria: We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator.

Data collection and analysis: We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90.

Main results: We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence).

Authors' conclusions: In this updated Cochrane Review including 20 RCTs involving 4652 participants, rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH. Thirteen RCTs are ongoing and are likely to increase the certainty of the estimates of treatment effect.

Trial registration: ClinicalTrials.gov NCT00266006 NCT00128050 NCT02625948 NCT01566786 NCT00426803 NCT01563445 NCT00127283 NCT01702636 NCT02866838 NCT00928915 NCT00222625 NCT02429453 NCT03388970 NCT03696121 NCT03496883 NCT00699621 NCT02777424 NCT03044184 NCT04742205 NCT03385928.

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Conflict of interest statement

HE: has received lecture honoraria from Bristol Myers Squibb. She undertook the eligibility decisions about, extracted data from, carried out the risk of bias assessment for, and performed GRADE assessments of all studies. She is not affiliated to any of the included studies.

CSM: none known. CSM undertook the eligibility decisions about, extracted data from, carried out the risk of bias assessment for, and performed GRADE assessments of all studies. She is not affiliated to any of the included studies.

ZKL: was involved with Sprigg 2018 – TICH‐2. ZKL played a role in arbitration of risk of bias, but Sprigg 2018 – TICH‐2 did not require any decision to be arbitrated.

CC: none known. CC carried out the risk of bias assessment and performed the GRADE assessments of one study. She is not affiliated to any of the included studies.

PMB: has received lecture honoraria and consulting fees from Phagenesis, F Hoffmann‐La Roche AG, and DiaMedica. He holds stock options with CoMind. PMB was involved in Sprigg 2014 – TICH‐1, Sprigg 2018 – TICH‐2, and Sprigg 2022 – TICH‐3. PMB had no role in study selection, assessment, and data extraction with regard to these studies. PMB currently holds NIHR and British Heart Foundation grants that are paid to the University of Nottingham, UK.

TS: has received lecture honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi Sankyo, and AstraZeneca, and a travel grant from AstraZeneca. TS has received payment for participation in an adjudication committee from IQVIA. TS has been chair of the European Stroke Organisation guideline board. TS declared intellectual competing interests due to his involvement with some included RCTs (Mayer 2005a; Mayer 2005b; Mayer 2006; Mayer 2008 – FAST; Steiner 2016 – INCH). TS had no role in study selection, assessment, and data extraction with regard to these studies.

MJRD: has received lecture honoraria from Sanofi, Amgen, Portola Pharmaceuticals, Takeda California, and Pfizer. He has received a travel grant from Janssen Biotech. MJRD is involved with the ongoing Desborough 2020 – DASH trial.

ECS: has received honoraria from Boston Scientific, Portola Pharmaceuticals, and Daiichi‐Sankyo. ECS is on the Trial Steering Committees for the 2018‐002620‐17 – Annexa‐I trial (funded by AstraZeneca), the Sprigg 2022 – TICH‐3 trial (unpaid), AXIOMATIC‐SSP trial (funded by Bristol‐Myers Squibb), and OCEANIC trial (funded by Bayer). ECS is a member of the working group on ESO ICH guidelines.

NS: has received research funding grants for clinical trials (Sprigg 2018 – TICH‐2, Desborough 2020 – DASH, and Sprigg 2022 – TICH‐3). NS was involved with Sprigg 2014 – TICH‐1 and Sprigg 2018 – TICH‐2, and the ongoing Desborough 2020 – DASH and Sprigg 2022 – TICH‐3. NS had no role in study selection, assessment, and data extraction with regard to these studies.

RA‐SS: was involved with Baharoglu 2016 – PATCH and Sprigg 2018 – TICH‐2, and the ongoing Sprigg 2022 – TICH‐3. RA‐SS was involved in the grant applications for the TICH trials. RA‐SS currently holds two NIHR grants paid to the University of Edinburgh. He is the past‐president of the British and Irish Association of Stroke Physicians. RA‐SS had no role in study selection, assessment, and data extraction with regard to these studies. RA‐SS was a member of the Cochrane Stroke Editorial Team, but he was not involved in the editorial process.

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References

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