Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2018 Apr 17;4(4):CD005951.
doi: 10.1002/14651858.CD005951.pub4.

Haemostatic therapies for acute spontaneous intracerebral haemorrhage

Rustam Al-Shahi Salman  1 , Zhe Kang Law, Philip M Bath, Thorsten Steiner, Nikola Sprigg
Affiliations
Meta-Analysis

Haemostatic therapies for acute spontaneous intracerebral haemorrhage

Rustam Al-Shahi Salman et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume; up to one-third of ICHs enlarge within 24 hours of onset. Early haemostatic therapy might improve outcome by limiting haematoma growth. This is an update of a Cochrane Review first published in 2006, and last updated in 2009.

Objectives: To examine 1) the effectiveness and safety of individual classes of haemostatic therapies, compared against placebo or open control, in adults with acute spontaneous intracerebral haemorrhage, and 2) the effects of each class of haemostatic therapy according to the type of antithrombotic drug taken immediately before ICH onset (i.e. anticoagulant, antiplatelet, or none).

Search methods: We searched the Cochrane Stroke Trials Register, CENTRAL; 2017, Issue 11, MEDLINE Ovid, and Embase Ovid on 27 November 2017. In an effort to identify further published, ongoing, and unpublished randomised controlled trials (RCT), we scanned bibliographies of relevant articles and searched international registers of RCTs in November 2017.

Selection criteria: We sought randomised controlled trials (RCTs) of any haemostatic intervention (i.e. pro-coagulant treatments such as coagulation factors, antifibrinolytic drugs, or platelet transfusion) for acute spontaneous ICH, compared with placebo, open control, or an active comparator, reporting relevant clinical outcome measures.

Data collection and analysis: Two authors independently extracted data, assessed risk of bias, and contacted corresponding authors of eligible RCTs for specific data if they were not provided in the published report of an RCT.

Main results: We included 12 RCTs involving 1732 participants. There were seven RCTs of blood clotting factors versus placebo or open control involving 1480 participants, three RCTs of antifibrinolytic drugs versus placebo or open control involving 57 participants, one RCT of platelet transfusion versus open control involving 190 participants, and one RCT of blood clotting factors versus fresh frozen plasma involving five participants. We were unable to include two eligible RCTs because they presented aggregate data for adults with ICH and other types of intracranial haemorrhage. We identified 10 ongoing RCTs. Across all seven criteria in the 12 included RCTs, the risk of bias was unclear in 37 (44%), high in 16 (19%), and low in 31 (37%). Only one RCT was at low risk of bias in all criteria.In one RCT of platelet transfusion versus open control for acute spontaneous ICH associated with antiplatelet drug use, there was a significant increase in death or dependence (modified Rankin Scale score 4 to 6) at day 90 (70/97 versus 52/93; risk ratio (RR) 1.29, 95% confidence interval (CI) 1.04 to 1.61, one trial, 190 participants, moderate-quality evidence). All findings were non-significant for blood clotting factors versus placebo or open control for acute spontaneous ICH with or without surgery (moderate-quality evidence), for antifibrinolytic drugs versus placebo (moderate-quality evidence) or open control for acute spontaneous ICH (moderate-quality evidence), and for clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use (no evidence).

Authors' conclusions: Based on moderate-quality evidence from one trial, platelet transfusion seems hazardous in comparison to standard care for adults with antiplatelet-associated ICH.We were unable to draw firm conclusions about the efficacy and safety of blood clotting factors for acute spontaneous ICH with or without surgery, antifibrinolytic drugs for acute spontaneous ICH, and clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use.Further RCTs are warranted, and we await the results of the 10 ongoing RCTs with interest.

PubMed Disclaimer

Conflict of interest statement

RA‐SS: none known. ZKL: none known. PB: none known. 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. NS: none known.

Figures

1
1
Study flow diagram
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias criteria for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias criteria presented as percentages across all included studies
4
4
Funnel plot of comparison: 1 Blood clotting factors vs placebo or open control, outcome: 1.1 Death or dependence (mRS 4 to 6) at day 90
1.1
1.1. Analysis
Comparison 1 Blood clotting factors vs placebo or open control, Outcome 1 Death or dependence (mRS 4 to 6) at day 90.
1.2
1.2. Analysis
Comparison 1 Blood clotting factors vs placebo or open control, Outcome 2 Death or dependence (GOS‐E 1 to 4) at day 90.
1.3
1.3. Analysis
Comparison 1 Blood clotting factors vs placebo or open control, Outcome 3 Death by day 90.
1.4
1.4. Analysis
Comparison 1 Blood clotting factors vs placebo or open control, Outcome 4 All serious adverse events.
1.5
1.5. Analysis
Comparison 1 Blood clotting factors vs placebo or open control, Outcome 5 Thromboembolic serious adverse events.
1.6
1.6. Analysis
Comparison 1 Blood clotting factors vs placebo or open control, Outcome 6 Intracerebral haemorrhage growth by 24 hours.
2.1
2.1. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 1 Death or dependence (mRS 4 to 6) at day 90.
2.2
2.2. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 2 Death by day 90.
2.3
2.3. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 3 All serious adverse events.
2.4
2.4. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 4 Thromboembolic serious adverse events.
2.5
2.5. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 5 Barthel Index.
2.6
2.6. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 6 EuroQoL health utility score.
2.7
2.7. Analysis
Comparison 2 Antifibrinolytic drugs vs placebo or open control, Outcome 7 Intracerebral haemorrhage growth by 24 hours.
3.1
3.1. Analysis
Comparison 3 Platelet transfusion vs open control, Outcome 1 Death or dependence (mRS 4 to 6) at day 90.
3.2
3.2. Analysis
Comparison 3 Platelet transfusion vs open control, Outcome 2 Death by day 90.
3.3
3.3. Analysis
Comparison 3 Platelet transfusion vs open control, Outcome 3 All serious adverse events.
3.4
3.4. Analysis
Comparison 3 Platelet transfusion vs open control, Outcome 4 Thromboembolic serious adverse events.
3.5
3.5. Analysis
Comparison 3 Platelet transfusion vs open control, Outcome 5 Intracerebral haemorrhage growth by 24 hours.
4.1
4.1. Analysis
Comparison 4 Blood clotting factors vs fresh frozen plasma, Outcome 1 Death by day 90.
4.2
4.2. Analysis
Comparison 4 Blood clotting factors vs fresh frozen plasma, Outcome 2 All serious adverse events.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Arumugam 2015 {published data only}
    1. Arumugam A, Rahman NAA, Theophilus SC, Shariffudin A, Abdullah JM. Tranexamic acid as antifibrinolytic agent in non traumatic intracerebral hemorrhages. Malaysian Journal of Medical Sciences 2015;December(Special issue):62‐71. - PMC - PubMed
Baharoglu 2016 (PATCH) {published data only}
    1. Baharoglu MI, Cordonnier C, Al‐Shahi Salman R, Gans K, Koopman MM, Brand A, the PATCH Investigators. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open‐label, phase 3 trial. Lancet 2016;387(10038):2605‐13. - PubMed
    1. Gans K, Haan RJ, Majoie CB, Koopman MK, Brand A, Dijkgraaf MG: the PATCH Investigators. PATCH: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial. BMC Neurology 2010;10:19. [Netherlands National Trial Register NTR1303] - PMC - PubMed
Boulis 1999 {published data only}
    1. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin‐related intracranial hemorrhage. Neurosurgery 1999;45(5):1113‐8. - PubMed
F7ICH‐1602 2007 {unpublished data only}
    1. Novo Nordisk. Randomised, double‐blind, multicentre, placebo controlled dose‐escalation study to evaluate the safety and preliminary efficacy of activated recombinant factor VII (NN‐007) in acute intracerebral haemorrhage. Unpublished 2007. [Novo Nordisk Trial ID F7ICH‐1602]
Imbert 2012 (PRE‐SICH) {published data only}
    1. Imberti R, Pietrobono L, Klersy C, Gamba G, Iotti GA, Cornara G. Intraoperative intravenous administration of rFVIIa and hematoma volume after early surgery for spontaneous intracerebral hemorrhage: a randomized prospective phase II study. Minerva Anestesiologica 2012;78(2):168‐75. - PubMed
Li 2012 {published data only}
    1. Li X, Wang YQ, Li W. Intervention study on recombinant activated factor VIIa in depressing early hematoma extensions of cerebral hemorrhage. Chinese Journal of New Drugs 2012;21(2):161‐3.
Mayer 2005a {published data only}
    1. Mayer SA, Brun NC, Broderick J, Davis S, Diringer MN, Skolnick BE, et al. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 2005;36(1):74‐9. - PubMed
Mayer 2005b {published data only}
    1. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. New England Journal of Medicine 2005;352(8):777‐85. - PubMed
Mayer 2006 {published and unpublished data}
    1. Mayer SA, Brun NC, Broderick J, Davis SM, Diringer MN, Skolnick BE, et al. Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. Neurocritical Care 2006;4(3):206‐14. [Novo Nordisk Trial ID F7ICH‐2073] - PubMed
Mayer 2008 (FAST) {published data only (unpublished sought but not used)}
    1. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. New England Journal of Medicine 2008; Vol. 358, issue 20:2127‐37. - PubMed
Sprigg 2014 (TICH‐1) {published data only}
    1. Sprigg N, Renton C, Kwong Y, Dineen R, Bath PM. Tranexamic acid for acute intracerebral haemorrhage (TICH): results of the first randomised controlled trial. International Journal of Stroke 2012;7:7.
    1. Sprigg N, Renton CJ, Dineen RA, Kwong Y, Bath PMW. Tranexamic acid for spontaneous intracerebral hemorrhage: a randomized controlled pilot trial. Journal of Stroke and Cerebrovascular Diseases 2014;23(6):1312‐8. [ISRCTN50867461] - PubMed
Zazulia 2001 (ATICH) {unpublished data only}
    1. Zazulia AR. Antifibrinolytic therapy in acute intracerebral hemorrhage ‐ ATICH. www.strokecenter.org (accessed 27 November 2017).

References to studies excluded from this review

Ciccone 2007 {unpublished data only}
    1. Ciccone A, Brambilla G, Pozzi M, Roccatagliata D, Botto E, Gruccione A. Antifibrinolytic treatment of acute spontaneous intracerebral haemorrhage: rationale of the ANTITHESIS protocol. Proceedings of the Italian Stroke Forum. Florence, Italy, 2007:Abst. EMORR_03.
Kerebel 2013 {published data only}
    1. Kerebel D, Joly L‐M, Honnart D, Schmidt J, Galanaud D, Negrier C, Lex206 Investigator Group. A French multicenter randomised trial comparing two dose‐regimens of prothrombin complex concentrates in urgent anticoagulation reversal. Critical Care 2013;17:R4. - PMC - PubMed
Li 2016 {published data only}
    1. Li J‐Y, Yuan L‐X, Zhang G‐M, Zhou L, Gao Y, Li Q‐B, et al. Activating blood circulation to remove stasis treatment of hypertensive intracerebral hemorrhage: a multi‐center prospective randomized open‐label blinded‐endpoint trial. Chinese Journal of Integrative Medicine 2016;22(5):328‐33. - PubMed
Madjdinasab 2008 {published data only}
    1. Madjdinasab NN, Sharafaddinzadeh N, Mohamadianinejad E, Bavarsad R, Khakzadeh A. Effect of Novoseven on hospitalization duration of Iranian ICH patients. Cerebrovascular Diseases 2008;25(Suppl 2):158.
Meng 2003 {published data only}
    1. Meng L, Wu J, Zhou C. Auxiliary treatment of aprotinin on cerebral hemorrhage: clinical observation. Journal of Apoplexy and Nervous Diseases 2003;20(3):233‐4.
NCT00222625 {unpublished data only}
    1. NCT00222625. rFVIIa in ICH in patients treated with anticoagulants or anti‐platelets. clinicaltrials.gov/ct2/show/NCT00222625 (first received 22 September 2005).
NCT02429453 {unpublished data only}
    1. NCT02429453. FFP versus PCC in intracranial hemorrhage. clinicaltrials.gov/ct2/show/NCT02429453 (first received 29 April 2015).
Steiner 2016 (INCH) {published data only}
    1. Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurology 2016;15(6):566‐73. - PubMed
Zhou 2005 {published data only}
    1. Zhou C, Wu J, Meng L. Mechanism of aprotinin in auxiliary treatment of cerebral hemorrhage. Chinese Journal of Neurology 2005;38(1):22‐4.

References to ongoing studies

Liu 2017 (TRAIGE) {unpublished data only}
    1. Liu L, Wang Y, Meng X, Li N, Tan Y, Nie X, et al. the TRAIGE investigators. Tranexamic acid for acute intracerebral hemorrhage growth predicted by spot sign trial: rationale and design. International Journal of Stroke 2017;12(3):326–31. - PubMed
Meretoja 2014 (STOP‐AUST) {unpublished data only}
    1. Meretoja A, Churilov L, Campbell BCV, Aviv RI, Yassi N, Barras C, et al. The Spot sign and Tranexamic acid On Preventing ICH growth – AUStralasia Trial (STOP‐AUST): protocol of a phase II randomized, placebo‐controlled, double‐blind,multicenter trial. International Journal of Stroke 2014;9(4):519–24. - PubMed
NCT00699621 {unpublished data only}
    1. NCT00699621. Platelet transfusion in acute intracerebral hemorrhage. clinicaltrials.gov/ct2/show/NCT00699621 (first received 18 June 2008).
NCT00810888 {unpublished data only}
    1. NCT00810888. The Spot Sign for predicting and treating ICH growth study (STOP‐IT). clinicaltrials.gov/ct2/show/NCT00810888 (first received 18 December 2008).
NCT01359202 {unpublished data only}
    1. NCT01359202. 'Spot Sign' selection of intracerebral hemorrhage to guide hemostatic therapy (SPOTLIGHT). clinicaltrials.gov/ct2/show/NCT01359202 (first received 24 May 2011).
NCT02777424 {published data only}
    1. NCT02777424. Prothrombin complex concentrate versus fresh frozen plasma to correct coagulation disorders in adult neurosurgical patients (CLOT‐CRANE). clinicaltrials.gov/ct2/show/NCT02777424 (first received 19 May 2016).
NCT02866838 {published data only}
    1. NCT02866838. Treatment of Intracerebral Hemorrhage in Patients on Non‐vitamin K Antagonist (TICH‐NOAC). clinicaltrials.gov/ct2/show/NCT02866838 (first received 15 August 2016).
NCT03044184 {unpublished data only}
    1. NCT03044184. Tranexamic acid for spontaneous acute cerebral hemorrhage trial (TRANSACT). clinicaltrials.gov/ct2/show/NCT03044184 (first received 6 February 2017).
NOR‐ICH {published data only}
    1. The Norwegian Intracerebral Hemorrhage Trial (NOR‐ICH). helseforskning.etikkom.no/prosjekterirek/prosjektregister/prosjekt?p_doc... (first received 1 March 2013).
Sprigg 2016 (TICH‐2) {unpublished data only}
    1. Sprigg N, Robson K, Bath P, Dineen R, Roberts I, Robinson T, for the TICH‐2 Investigators. Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: protocol for a randomized, placebo‐controlled trial. International Journal of Stroke 2016;11(6):717–23. - PubMed

Additional references

Al‐Shahi Salman 2009a
    1. Al‐Shahi Salman R, Labovitz DL, Stapf C. Spontaneous intracerebral haemorrhage. BMJ 2009;339:b2586. - PubMed
Brott 1997
    1. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28(1):1‐5. - PubMed
Dastur 2017
    1. Dastur YK, Wengui Y. Current management of spontaneous intracerebral haemorrhage. Stroke and Vascular Neurology 2017;2(1):21‐9. - PMC - PubMed
Davis 2006
    1. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66(8):1175‐81. - PubMed
Feigin 2009
    1. Feigin VL, Lawes CM, Bennett DA, Barker‐Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population‐based studies: a systematic review. Lancet Neurology 2009;8(4):355‐69. - PubMed
Feigin 2015
    1. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, et al. Update on the global burden of ischemic and hemorrhagic stroke in 1990‐2013: the GBD 2013 Study. Neuroepidemiology 2015;45(3):161‐76. - PMC - PubMed
Hemphill 2015 (AHA ICH)
    1. Hemphill JC, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46(7):2032‐60. - PubMed
Higgins 2011
    1. Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Iorio 2012
    1. Iorio. Personal communication (email) 9th April 2012.
Johansen 2015
    1. Johansen M, Wikkelsø A, Lunde J, Wetterslev J, Afshari A. Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non‐bleeding patients. Cochrane Database of Systematic Reviews 2015, Issue 7. [DOI: 10.1002/14651858.CD010555.pub2] - DOI - PMC - PubMed
Ker 2015
    1. Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database of Systematic Reviews 2015, Issue 5. [DOI: 10.1002/14651858.CD004896.pub4] - DOI - PMC - PubMed
Lovelock 2007
    1. Lovelock CE, Molyneux AJ, Rothwell PM, Oxford Vascular Study. Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population‐based study. Lancet Neurology 2007;6(6):487‐93. - PubMed
Mayer 2007
    1. Mayer SA. Personal communication (discussion at the European Stroke Conference, Glasgow, UK 2007.
Poon 2014
    1. Poon MT, Fonville AF, Al‐Shahi Salman R. Long‐term prognosis after intracerebral haemorrhage: systematic review and meta‐analysis. Journal of Neurology, Neurosurgery and Psychiatry 2014;85(6):660‐7. - PubMed
Prasad 2008
    1. Prasad K, Mendelow AD, Gregson B. Surgery for primary supratentorial intracerebral haemorrhage. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD000200.pub2] - DOI - PubMed
RCP 2016
    1. Intercollegiate Stroke Working Party. National Clinical Guideline for Stroke. Fifth. London: Royal College of Physicians, 2016.
Samarasekera 2015
    1. Samarasekera N, Fonville A, Lerpiniere C, Farrall AJ, Wardlaw JM, White PM, the Lothian Audit of the Treatment of Cerebral Haemorrhage Collaborators. Influence of intracerebral hemorrhage location on incidence, characteristics, and outcome: population‐based study. Stroke 2015;46(3):361‐8. - PubMed
Stanworth 2012
    1. Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database of Systematic Reviews 2012, Issue 2. [DOI: 10.1002/14651858.CD005011.pub4] - DOI - PMC - PubMed
Steiner 2014 (ESO ICH)
    1. Steiner T, Al‐Shahi Salman R, Beer R, Christensen H, Cordonnier C, Csiba L, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. International Journal of Stroke 2014;9(7):840‐55. - PubMed
Wikkelsø 2013
    1. Wikkelsø A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Møller AM, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database of Systematic Reviews 2013, Issue 8. [DOI: 10.1002/14651858.CD008864.pub2] - DOI - PMC - PubMed
Zazulia 2005
    1. Zazulia. Personal communication email 1, 15, 30 Nov 2005 2005.

References to other published versions of this review

Al‐Shahi 2007
    1. Al‐Shahi R, You H. Hemostatic drug therapies for acute, nontraumatic intracerebral hemorrhage. Stroke 2007;38:204‐5.
Al‐Shahi Salman 2009b
    1. Al‐Shahi Salman R. Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD005951.pub3] - DOI - PubMed
You 2006
    1. You H, Al‐Shahi Salman R. Haemostatic drug therapies for acute primary intracerebral haemorrhage. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD005951.pub2] - DOI - PubMed

MeSH terms

LinkOut - more resources