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Risk of bleeding

One of the reasons for the underuse of intravenous thrombolytic therapy for the treatment of an acute ischaemic stroke is the physician's inappropriate evaluation of the benefit/risk ratio of thrombolysis.1


Although the efficacy of thrombolytic therapy has been clearly confirmed, there is some confusion about the associated risk of symptomatic intracranial haemorrhage (sICH). This is mainly due to the different definitions of sICH that have been used in various studies.

Definitions of sICH


NINDS

  • A haemorrhage was considered symptomatic if it was not seen on a previous CT scan and there had subsequently been either a suspicion of haemorrhage or any decline in neurologic status.2
  • To detect intracranial haemorrhage, CT scans were required at 24h and 7–10 days after the onset of stroke and when clinical findings suggested haemorrhage.2
     

ECASS 2

  • Any intracranial bleed and ≥4 points worsening on the NIHSS (same as ECASS 3 definition, except that causal relationship between haemorrhage and clinical deterioration not required).3
     

ECASS 3

  • An intracranial bleed, associated with a clinical deterioration, defined as ≥4 points worsening on the NIHSS, or leading to death and identified as the predominant cause of the deterioration.4
     

SITS

Local or remote parenchymal haematoma type II on the 22–36h post-treatment imaging scan, combined with a neurologic deterioration of ≥4 points on the NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 or leading to death.5

Incidence of sICH following thrombolysis

Symptomatic intracranial haemorrhage occurs at a relatively consistent rate throughout the stroke studies (odds ratio, OR 3.40; 95% CI 2.81-4.33).6,7 The incidence of sICH in the SITS-MOST study (7.3%) was similar to that found in the NINDS study (10.9%) for patients treated with thrombolysis within 3 hours of the onset of stroke symptoms.2,5

  • The incidence of sICH in SITS-MOST did not differ significantly between experienced and inexperienced centres.5
  • In ECASS 3, using thrombolysis up to 4.5 hours after the onset of acute ischaemic stroke, the incidence of sICH was increased in comparison to placebo, but this did not affect mortality.4
  • In the SITRS-ISTR registry, the incidence of sICH for patient treated at 0-3 hours and at 3-4.5 hours after stroke onset was similar.8  
       

Predictors of risk of haemorrhage


Many factors are thought to contribute to an increased risk of sICH following thrombolysis for an acute ischaemic stroke. These include:

  • Hypertension9
  • Chronic atrial fibrillation10
  • Increasing age11
  • Increased blood glucose12
  • High NIHSS score2
  • Overweight13
  • Early ischaemic change on CT scan14,15
  • Profound cerebral blood volume reduction16
  • Large perfusion/diffusion abnormalities (diffusion volume ≥100 ml)17-19
  • Early blood-brain barrier disruption on FLAIR imaging sequences20
  • Leukoaraiosis of the deep white matter21

Contrary to popular belief, transient ischaemic attack prior to an ischaemic stroke is not a risk factor for sICH following thrombolysis (OR 2.04 (0.45-9.32), p=0.36).22


Ideally, the risk of bleeding and the likelihood of a good outcome with thrombolysis should be assessed for each patient before the decision to administer thrombolytic therapy is made. However, the benefits of thrombolysis usually outweigh the risks and therefore the decision to administer thrombolytic therapy should not be made on the basis of risk factors alone.


The Alberta Stroke Program Early CT Score (ASPECTS) may help to predict the risk of haemorrhage in stroke patients who are eligible for thrombolysis.23

  • In a retrospective analysis of 217 patients treated with intravenous or intra-arterial rt-PA, the risk of sICH (n=23, 10.6% of all patients) was seen to be significantly higher for patients with a DWI-ASPECTS score of 0-7 (n=21, 15.1%) compared with patients with a score of 8-10 (n=2, 2.6%, p=0.004).
  • The authors conclude that performing a DWI-ASPECTS assessment may help to predict the risk of sICH prior to thrombolysis.24  
      

Management of sICH


The management of thrombolysis-associated sICH has not yet been clearly defined.


A study looking at the management of sICH, showed that bleeding often continues after the diagnosis has been made, and that this is associated with poor outcomes if not treated. In the patients that were treated for sICH, a variety of potential strategies have been suggested, including25:

  • Anti-fibrinolytic therapy
  • Fibrinogen replacement (fresh frozen plasma, cryoprecipitate)
  • Platelet infusion
  • Procoagulant therapy
       

sICH and mortality following thrombolysis

The SITS registry and the Canadian stroke registry both demonstrated that mortality increases with increasing delay to initiation of thrombolysis, so that patients treated between 3-4.5 hours after onset of symptoms have a slightly higher mortality and also higher risk of sICH than those patients treated within 0-3 hours of stroke onset.8,26

A meta-analysis of studies using rt-PA for thrombolysis of acute ischaemic stroke 0-6 hours after stroke onset showed that beyond 4.5 hours, mortality increases further, but the incidence of large parenchymal haemorrhage did not change significantly. The incidence of sICH, however, was not reported in this meta-analysis.7


It is not clear what causes the increase in mortality, as haemorrhage is only responsible for approximately 20% of all deaths. Further investigations are currently underway.7,26

sICH with rt-PA versus TNK-tPA

In a retrospective observational study of 9,238 patients using data from the large multicentre international Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischaemic Stroke (CERTAIN), 0.25-mg/kg tenecteplase (TNK-tPA) was associated with lower odds of sICH than treatment with alteplase.27


In summary, the benefits of thrombolytic therapy in acute ischaemic stroke very often outweigh the risks of bleeding following thrombolysis, but each patient needs to be assessed individually.

References

  1. Brown DL, Barsan WG, Lisabeth LD et al. Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischaemic stroke. Ann Emerg Med 2005;46(1):56-60.

  2. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.

  3. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-1251.

  4. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329.

  5. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute ischemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282.

  6. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009; Issue 4. Art. No: CD000213. doi:10.1002/14651858.CD000213.pub2.

  7. Lees KR, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-1703.

  8. Ahmed N, Wahlgren N, Grond M, et al; for the SITS Investigators: Implementation and outcome of thrombolysis with alteplase 3–4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol 2010;9:866-874.

  9. Ribo M, Montaner J, Molina CA, et al. Admission fibrinolytic profile is associated with symptomatic hemorrhagic transformation in stroke patients treated with tissue plasminogen activator. Stroke 2004;35:2123-2127.

  10. Seet RC, Zhang Y, Wijdicks EF, Rabinstein AA. Relationship between chronic atrial fibrillation and worse outcomes in stroke patients after intravenous thrombolysis. Arch Neurol 2011;68:1454-1458.

  11. Tanne D, Kasner SE, Demchuk AM, et al. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator for acute ischemic stroke in clinical practice: the Multicenter rt-PA Acute Stroke Survey. Circulation 2002;105:1679-1685.

  12. Wardlaw JM, Dorman PJ, Caldelise L, Signorini DF. The influence of baseline prognostic variables on outcome after thrombolysis. MAST- Italy Collaborative group. J Neurol 1999;246:1059-1062.

  13. Wahlgren N, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke 2008;39:3316-3322.

  14. Hamann GF, del Zoppo GJ, von Kummer R. Hemorrhagic transformation of cerebral infarction: possible mechanisms. Thromb Haemost 1999;82:92-94.

  15. von Kummer R. Early major ischemic changes on computed tomography should preclude use of tissue plasminogen activator. Stroke 2003;34:820-821.

  16. Campbell BC, et al. Regional very low cerebral blood volume predicts hemorrhagic transformation better than diffusion-weighted imaging volume and thresholded apparent diffusion coefficient in acute ischaemic stroke. Stroke 2010;41:82-88.

  17. Derex L, et al. Clinical and imaging predictors of intracerebral haemorrhage in stroke patients treated with intravenous tissue plasminogen activator. J Neurol Neurosurg Psychiatry 2005;76:70-75.

  18. Albers GW, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-517.

  19. Singer OC, et al. Risk for symptomatic intracerebral hemorrhage after thrombolysis assessed by diffusion-weighted magnetic resonance imaging. Ann Neurol 2008;63:52-60.

  20. Latour LL, Kang DW, Ezzeddine MA, Chalela JA, Warach S. Early blood–brain barrier disruption in human focal brain ischemia. Ann Neurol 2004 56:468-477.

  21. Neumann-Haefelin T, et al. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke 2006;37:2463-2466.

  22. De Lecinana MA, Fuentes B, Masjuan J, et al. Thrombolytic therapy for acute ischemic stroke after recent transient ischemic attack. Int J Stroke 2011;ePub ahead of print.

  23. Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000;355:1670-1674.

  24. Singer Q, Kurre W, Humpich M, et al. Risk assessment of symptomatic intracranial intracerebral haemorrhage after thrombolysis using DWI-ASPECTS. Stroke 2009;40:2743-2748.

  25. Goldstein JN, Marrero M, Masrur S, et al. Management of thrombolysis-associated symptomatic intracranial haemorrhage. Arch Neurol 2010;67(8):965-969.

  26. Shobha N, Buchan AM, Hill MD; on behalf of Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators: Thrombolysis at 3–4.5 hours after acute ischemic stroke onset – evidence from the Canadian Alteplase for Stroke Effectiveness Study (CASES) registry. Cerebrovasc Dis 2011;31:223-228.

  27. Warach SJ, Ranta A, Kim J, et al. Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) Collaboration. JAMA Neurol 2023 ;80(7):732-738. doi: 10.1001/jamaneurol.2023.1449.

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