Download PDF
Semin Thromb Hemost 2017; 43(07): 750-758
DOI: 10.1055/s-0037-1604089
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Evidence for the Use of Tranexamic Acid in Subarachnoid and Subdural Hemorrhage: A Systematic Review

Thorkil Anker-Møller
1   Centre for Haemophilia and Thrombosis, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Anne Troldborg
2   Department of Rheumatology, Aarhus University Hospital and Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
,
Niels Sunde
3   Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark
,
Anne-Mette Hvas
1   Centre for Haemophilia and Thrombosis, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
› Author Affiliations
Further Information

Publication History

Publication Date:
06 September 2017 (online)

    Permissions and Reprints

Abstract

Despite neurosurgical treatment, a subarachnoid hemorrhage (SAH) can cause a debilitating stroke. The case fatality rate ranges from 27 to 44%, and many survivors are left permanently disabled; therefore, the need for improved treatment is obvious. Furthermore, subdural hemorrhages (SDHs) have a cumulative recurrence rate of 14% in the first year and are potentially fatal. The aim of this systematic review is to assess and discuss the evidence for the role of tranexamic acid (TXA) in treatment of SAH and SDH. Systematic literature searches were performed in MEDLINE, Embase, Scopus, and Web of Science (1946–2016). The inclusion criteria were TXA-treated group and control group; SAH or SDH verified by imaging, intraoperatively or at autopsy; human subjects; English; and an objective outcome. The search terms matched 443 records. Eight studies including nontraumatic SAH patients and one study including traumatic intracranial bleeding met the inclusion criteria. Comparing TXA-treated nontraumatic patients with controls, we found an overall odds ratio (OR) for rebleeding of 0.41 (95% confidence interval [CI]: 0.26–0.64), six studies reported the mortality rate with an overall OR of 0.88 (95% CI: 0.68–1.12), four studies reported no statistically significant difference on the Glasgow Outcome Scale, and one study showed a statistically significant increased risk of cerebral ischemia, whereas seven studies found no statistically significant difference. No studies including SDH patients met the inclusion criteria. TXA reduced the overall risk of rebleeding following nontraumatic SAH. A nonsignificant reduction in mortality was demonstrated in nontraumatic SAH without substantial indication of increased risk of ischemic lesions.

Keywords

systematic review - subarachnoid hemorrhage - subdural hemorrhage - tranexamic acid
 

  • References>

  • 1 Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 2009; 8 (07) 635-642
    CrossrefPubMedGoogle Scholar
  • 2 Hackett ML, Anderson CS. ; The Australian Cooperative Research on Subarachnoid Hemorrhage Study Group. Health outcomes 1 year after subarachnoid hemorrhage: an international population-based study. Neurology 2000; 55 (05) 658-662
    CrossrefPubMedGoogle Scholar
  • 3 de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007; 78 (12) 1365-1372
    CrossrefPubMedGoogle Scholar
  • 4 Naidech AM, Janjua N, Kreiter KT. , et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol 2005; 62 (03) 410-416
    CrossrefPubMedGoogle Scholar
  • 5 Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry 2000; 68 (03) 337-341
    CrossrefPubMedGoogle Scholar
  • 6 Larsen CC, Astrup J. Rebleeding after aneurysmal subarachnoid hemorrhage: a literature review. World Neurosurg 2013; 79 (02) 307-312
    CrossrefPubMedGoogle Scholar
  • 7 Ohkuma H, Tsurutani H, Suzuki S. Incidence and significance of early aneurysmal rebleeding before neurosurgical or neurological management. Stroke 2001; 32 (05) 1176-1180
    CrossrefPubMedGoogle Scholar
  • 8 Tanno Y, Homma M, Oinuma M, Kodama N, Ymamoto T. Rebleeding from ruptured intracranial aneurysms in North Eastern Province of Japan. A cooperative study. J Neurol Sci 2007; 258 (1-2): 11-16
    CrossrefPubMedGoogle Scholar
  • 9 Cha KC, Kim JH, Kang HI, Moon BG, Lee SJ, Kim JS. Aneurysmal rebleeding: factors associated with clinical outcome in the rebleeding patients. J Korean Neurosurg Soc 2010; 47 (02) 119-123
    CrossrefPubMedGoogle Scholar
  • 10 Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002; 97 (02) 250-258 , discussion 247–249
    CrossrefPubMedGoogle Scholar
  • 11 Antovic J, Bakic M, Zivkovic M, Ilic A, Blombäck M. Blood coagulation and fibrinolysis in acute ischaemic and haemorrhagic (intracerebral and subarachnoid haemorrhage) stroke: does decreased plasmin inhibitor indicate increased fibrinolysis in subarachnoid haemorrhage compared to other types of stroke?. Scand J Clin Lab Invest 2002; 62 (03) 195-199
    CrossrefPubMedGoogle Scholar
  • 12 Kasuya H, Shimizu T, Okada T, Takahashi K, Summerville T, Kitamura K. Activation of the coagulation system in the subarachnoid space after subarachnoid haemorrhage: serial measurement of fibrinopeptide A and bradykinin of cerebrospinal fluid and plasma in patients with subarachnoid haemorrhage. Acta Neurochir (Wien) 1988; 91 (3-4): 120-125
    CrossrefPubMedGoogle Scholar
  • 13 Tsementzis SA, Honan WP, Nightingale S, Hitchcock ER, Meyer CH. Fibrinolytic activity after subarachnoid haemorrhage and the effect of tranexamic acid. Acta Neurochir (Wien) 1990; 103 (3-4): 116-121
    CrossrefPubMedGoogle Scholar
  • 14 Larsen CC, Sørensen B, Nielsen JD, Astrup J. Reduced clot-stability during the first 6 hours after aneurysmal subarachnoid haemorrhage--a prospective case-control study. Thromb Res 2012; 129 (05) e229-e232
    CrossrefPubMedGoogle Scholar
  • 15 Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. ; European Stroke Organization. European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis 2013; 35 (02) 93-112
    CrossrefPubMedGoogle Scholar
  • 16 Baharoglu MI, Germans MR, Rinkel GJ. , et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2013; (08) CD001245
    PubMedGoogle Scholar
  • 17 Connolly Jr ES, Rabinstein AA, Carhuapoma JR. , et al; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012; 43 (06) 1711-1737
    CrossrefPubMedGoogle Scholar
  • 18 Bullock MR, Chesnut R, Ghajar J. , et al; Surgical Management of Traumatic Brain Injury Author Group. Surgical management of acute subdural hematomas. Neurosurgery 2006; 58 (3, Suppl) S16-S24 , discussion Si-iv
    PubMedGoogle Scholar
  • 19 Stanisic M, Lyngstadaas SP, Pripp AH. , et al. Chemokines as markers of local inflammation and angiogenesis in patients with chronic subdural hematoma: a prospective study. Acta Neurochir (Wien) 2012; 154 (01) 113-120 , discussion 120
    CrossrefPubMedGoogle Scholar
  • 20 Ito H, Saito K, Yamamoto S, Hasegawa T. Tissue-type plasminogen activator in the chronic subdural hematoma. Surg Neurol 1988; 30 (03) 175-179
    CrossrefPubMedGoogle Scholar
  • 21 Lim DJ, Chung YG, Park YK. , et al. Relationship between tissue plasminogen activator, plasminogen activator inhibitor and CT image in chronic subdural hematoma. J Korean Med Sci 1995; 10 (05) 373-378
    CrossrefPubMedGoogle Scholar
  • 22 Schmidt L, Gørtz S, Wohlfahrt J, Melbye M, Munch TN. Recurrence of subdural haematoma in a population-based cohort - risks and predictive factors. PLoS One 2015; 10 (10) e0140450
    CrossrefPubMedGoogle Scholar
  • 23 Tanweer O, Frisoli FA, Bravate C. , et al. Tranexamic acid for treatment of residual subdural hematoma after bedside twist-drill evacuation. World Neurosurg 2016; 91: 29-33
    CrossrefPubMedGoogle Scholar
  • 24 Kageyama H, Toyooka T, Tsuzuki N, Oka K. Nonsurgical treatment of chronic subdural hematoma with tranexamic acid. J Neurosurg 2013; 119 (02) 332-337
    CrossrefPubMedGoogle Scholar
  • 25 Iorio-Morin C, Blanchard J, Richer M, Mathieu D. Tranexamic acid in chronic subdural hematomas (TRACS): study protocol for a randomized controlled trial. Trials 2016; 17 (01) 235
    CrossrefPubMedGoogle Scholar
  • 26 StataCorp. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP; 2013
    Google Scholar
  • 27 Fodstad H, Liliequist B, Schannong M, Thulin CA. Tranexamic acid in the preoperative management of ruptured intracranial aneurysms. Surg Neurol 1978; 10 (01) 9-15
    PubMedGoogle Scholar
  • 28 Chandra B. Treatment of subarachnoid hemorrhage from ruptured intracranial aneurysm with tranexamic acid: a double-blind clinical trial. Ann Neurol 1978; 3 (06) 502-504
    CrossrefPubMedGoogle Scholar
  • 29 Fodstad H, Forssell A, Liliequist B, Schannong M. Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical trial. Neurosurgery 1981; 8 (02) 158-165
    CrossrefPubMedGoogle Scholar
  • 30 Fodstad H, Nilsson IM. Coagulation and fibrinolysis in blood and cerebrospinal fluid after aneurysmal subarachnoid haemorrhage: effect of tranexamic acid (AMCA). Acta Neurochir (Wien) 1981; 56 (1-2): 25-38
    CrossrefPubMedGoogle Scholar
  • 31 Vermeulen M, Lindsay KW, Murray GD. , et al. Antifibrinolytic treatment in subarachnoid hemorrhage. N Engl J Med 1984; 311 (07) 432-437
    CrossrefPubMedGoogle Scholar
  • 32 Roos Y. ; STAR Study Group. Antifibrinolytic treatment in subarachnoid hemorrhage: a randomized placebo-controlled trial. Neurology 2000; 54 (01) 77-82
    CrossrefPubMedGoogle Scholar
  • 33 Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002; 97 (04) 771-778
    CrossrefPubMedGoogle Scholar
  • 34 CRASH-2 Collaborators, Intracranial Bleeding Study. Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study). BMJ 2011; 343: d3795
    CrossrefPubMedGoogle Scholar
  • 35 Wijdicks EF, Hasan D, Lindsay KW. , et al. Short-term tranexamic acid treatment in aneurysmal subarachnoid hemorrhage. Stroke 1989; 20 (12) 1674-1679
    CrossrefPubMedGoogle Scholar
  • 36 Stary JM, Hutchins L, Vega RA. Tranexamic acid for recurring subdural hematomas following surgical evacuation: a clinical case series. J Neurol Surg A Cent Eur Neurosurg 2016; 77 (05) 422-426
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Miyazaki S, Katayama Y, Tsubokawa T, Yoshino A, Koyama S. Antifibrinolytic Therapy of Chronic Subdural Hematomas. Tokyo, Japan: Springer-Verlag; 1993: 140
    Google Scholar
  • 38 Harvey V, Perrone J, Kim P. Does the use of tranexamic acid improve trauma mortality?. Ann Emerg Med 2014; 63 (04) 460-462
    CrossrefPubMedGoogle Scholar
  • 39 Vujkovac B, Sabovic M. Treatment of subdural and intracerebral haematomas in a haemodialysis patient with tranexamic acid. Nephrol Dial Transplant 2000; 15 (01) 107-109
    CrossrefPubMedGoogle Scholar
  • 40 Perel P, Al-Shahi Salman R, Kawahara T. , et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury–a nested randomised, placebo-controlled trial. Health Technol Assess 2012; 16 (13) iii-xii , 1–54
    PubMedGoogle Scholar
  • 41 Greene KA, Marciano FF, Johnson BA, Jacobowitz R, Spetzler RF, Harrington TR. Impact of traumatic subarachnoid hemorrhage on outcome in nonpenetrating head injury. Part I: a proposed computerized tomography grading scale. J Neurosurg 1995; 83 (03) 445-452
    CrossrefPubMedGoogle Scholar
  • 42 Adams Jr HP, Kassell NF, Torner JC, Haley Jr EC. Predicting cerebral ischemia after aneurysmal subarachnoid hemorrhage: influences of clinical condition, CT results, and antifibrinolytic therapy. A report of the Cooperative Aneurysm Study. Neurology 1987; 37 (10) 1586-1591
    CrossrefPubMedGoogle Scholar
  • 43 Hijdra A, van Gijn J, Nagelkerke NJ, Vermeulen M, van Crevel H. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 1988; 19 (10) 1250-1256
    CrossrefPubMedGoogle Scholar
  • 44 Pinna G, Pasqualin A, Vivenza C, Da Pian R. Rebleeding, ischaemia and hydrocephalus following anti-fibrinolytic treatment for ruptured cerebral aneurysms: a retrospective clinical study. Acta Neurochir (Wien) 1988; 93 (3-4): 77-87
    CrossrefPubMedGoogle Scholar
  • 45 Tsementzis SA, Meyer CH, Hitchcock ER. Cerebral blood flow in patients with a subarachnoid haemorrhage during treatment with tranexamic acid. Neurochirurgia (Stuttg) 1992; 35 (03) 74-78
    PubMedGoogle Scholar
  • 46 Vergouwen MD, Vermeulen M, van Gijn J. , et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010; 41 (10) 2391-2395
    CrossrefPubMedGoogle Scholar
  • 47 Cremers CH, Vos PC, van der Schaaf IC. , et al. CT perfusion during delayed cerebral ischemia after subarachnoid hemorrhage: distinction between reversible ischemia and ischemia progressing to infarction. Neuroradiology 2015; 57 (09) 897-902
    CrossrefPubMedGoogle Scholar
  • 48 Mir DI, Gupta A, Dunning A. , et al. CT perfusion for detection of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. AJNR Am J Neuroradiol 2014; 35 (05) 866-871
    CrossrefPubMedGoogle Scholar
  • 49 Wong GK, Poon WS. Clinical, transcranial Doppler ultrasound, radiological features and, prognostic significance of delayed cerebral ischemia. Acta Neurochir Suppl (Wien) 2013; 115: 9-11
    PubMedGoogle Scholar
  • 50 Germans MR, Post R, Coert BA, Rinkel GJ, Vandertop WP, Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials 2013; 14: 143
    CrossrefPubMedGoogle Scholar
  • 51 Girvin J. Protection from rebleeding. J Neurosurg 2002; 97 (04) 751 , discussion 751–752
    CrossrefPubMedGoogle Scholar
  • 52 Kaste M, Ramsay M. Tranexamic acid in subarachnoid hemorrhage. A double-blind study. Stroke 1979; 10 (05) 519-522
    CrossrefPubMedGoogle Scholar
  • 53 Maurice-Williams RS. Prolonged antifibrinolysis: an effective non-surgical treatment for ruptured intracranial aneurysms?. BMJ 1978; 1 (6118): 945-947
    CrossrefPubMedGoogle Scholar
  • 54 Tsementzis SA, Hitchcock ER, Meyer CH. Benefits and risks of antifibrinolytic therapy in the management of ruptured intracranial aneurysms. A double-blind placebo-controlled study. Acta Neurochir (Wien) 1990; 102 (1-2): 1-10
    CrossrefPubMedGoogle Scholar
  • 55 van Rossum J, Wintzen AR, Endtz LJ, Schoen JH, de Jonge H. Effect of tranexamic acid on rebleeding after subarachnoid hemorrhage: a double-blind controlled clinical trial. Ann Neurol 1977; 2 (03) 238-242
    CrossrefPubMedGoogle Scholar
  • 56 Mikkelsen R, Anker-Møller T, Hvas A, Sunde N. Tranexamic acid as an adjunct in recurrent subdural hematoma. Am J Case Rep 2017; DOI: 10.12659/AJCR.904117.
    CrossrefPubMedGoogle Scholar
  • 57 University of Washington. Prehospital tranexamic acid use for traumatic brain injury (TXA) [NCT01990768]. Available at https://ClinicalTrials.gov/show/NCT01990768 . Accessed April 22, 2017
    PubMedGoogle Scholar
  • 58 London School of Hygiene and Tropical Medicine. Clinical randomisation of an antifibrinolytic in significant head injury (CRASH-3) [NCT01402882]. Available at https://ClinicalTrials.gov/show/NCT01402882 . Accessed April 22, 2017
    PubMedGoogle Scholar
  • 59 RenJi Hospital. Pre-hospital administration of tranexamic acid for moderate and severe traumatic brain injury [NCT02645552]. Available at https://ClinicalTrials.gov/show/NCT02645552 . Accessed April 22, 2017
    PubMedGoogle Scholar