Key messages
Treatments that help blood to clot (known as 'haemostatic therapies') might help people who have a stroke due to bleeding in the brain (known as 'intracerebral haemorrhage').
– Platelet transfusion probably harms people who had intracerebral haemorrhage whilst taking a drug like aspirin.
– All other therapies showed neither harm nor benefit.
– 13 ongoing studies are investigating haemostatic therapies after intracerebral haemorrhage and their results might change our conclusions.
What is an intracerebral haemorrhage?
More than one-tenth of all strokes are caused by intracerebral haemorrhage. The bigger the haemorrhage, the more likely it is to be fatal. Roughly one-fifth of intracerebral haemorrhages enlarge significantly, most during the first three hours after the bleed started.
How could haemostatic therapies improve outcome after intracerebral haemorrhage?
Haemostatic therapies might slow down bleeding and reduce brain damage, leading to better recovery, especially if given soon after the bleeding starts.
However, haemostatic therapies might cause unwanted side effects due to clotting, such as heart attacks, strokes, and clots in lungs.
What did we want to find out?
We wanted to find out if haemostatic therapies such as platelet transfusions, antifibrinolytic medicines (mostly tranexamic acid), clotting factor 7, or prothrombin complex concentrate improve the recovery of people with stroke due to intracerebral haemorrhage.
We also wanted to find out if haemostatic therapies caused any unwanted effects.
What did we do?
We searched for clinical trials involving people with intracerebral haemorrhage that compared haemostatic therapies with standard care, placebo (pretend treatment), or an alternative blood clotting treatment.
We separated the treatments into four groups: clotting factor 7 versus placebo, antifibrinolytic medicines versus placebo, platelet transfusion versus standard care for people already taking an antiplatelet medicine (medications that prevent blood clots from forming such as aspirin), and fresh frozen plasma (a blood product made from the liquid portion of whole blood used to treat people with low blood clotting factors) versus prothrombin complex concentrate (which causes blood clotting) for people already taking warfarin (a medicine commonly used to treat and prevent blood clots).
We compared and summarised the results of the studies and rated our certainty about the evidence, based on factors such as study numbers, methods, and sizes.
What did we find?
We found 20 clinical trials including 4652 people with intracerebral haemorrhage.
Clotting factor 7 likely results in little to no difference in improving recovery, reducing further bleeding, death, or unwanted effects.
Antifibrinolytic medicines result in little to no difference in improving recovery; a slight reduction in further bleeding within 24 hours; and little to no difference in death, unwanted effects, mood, memory, and quality of life.
Platelet transfusion likely worsens recovery for people already taking an antiplatelet medicine, but has little to no effect on further bleeding, death, or unwanted effects.
The evidence is very uncertain about the effect of different clotting factors for people already taking warfarin, and there is little to no difference between them on recovery, further bleeding, death, and unwanted effects.
What are the limitations of the evidence?
Although we found 20 studies including 4652 people, they were spread across four different comparisons of haemostatic therapies. This meant that many of the studies were not precise enough and they could have missed small but important benefits. Two of the comparisons included only one study each. Eight studies used placebo but in the others it is possible that people were aware of which treatment they were getting, which might have biased the results. Some of the studies did not provide data about all the outcomes that we intended to assess. More information will become available from 13 studies that were ongoing at the time of this review.
How up to date is this evidence?
This review updates our previous review in 2018. The evidence is up to date to September 2022.
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.
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.
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.
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.
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.
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.
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).