Risk of bleeding

One of the reasons for the underuse of intravenous rt-PA 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 rt-PA 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 24 h 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 22–36 h 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 age 11
  • 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 ≥100ml)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 rt-PA is made. However, the benefits of thrombolysis usually outweigh the risks and therefore the decision to administer rt-PA 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

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

References 
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  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.
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