thrombolysis in stroke

see also:

• thrombolytics;
• stroke (CVA)
• ED Mx of stroke
• The NNT blog: commentary on the International Stroke Trial 3 (‘IST-3’) published in 2012
• Emedicine article on thrombolysis in stroke
• LITFL: Why we should be very wary of using clotbusting drugs to treat acute strokes
• BML Mar 2015: researchers call for re-think on use of Alteplase in stroke - evidence suggests harm outweighs benefit at greater than 3 hrs
• 2026 AHA consensus guidelines on Mx of ischaemic stroke

• number needed to treat for 1 independent discharge = 9
• will recanalise 30% pts & a 1/3rd of these will have excellent recovery; risk of ICH = 6%.
• NB. if oedema present on CT then thrombolysis unlikely to help as infarct area is irreversible - ? role of MRI to show area that could be saved
• NB. younger patients tend to develop irreversible infarct faster as they have less collaterals.
• ECASS III (Sept 08 N Eng J Med) showed the NNT for a favourable outcome to be 14 and a 10-fold increase in symptomatic ICH
  • suggesting the safety of TPA use within 4.5 hours but the patients were younger, the stroke scores lower and the diabetes rates lower, all possible explanations for the lower haemorrhage rate
• the ATLANTIS trial in 1999 looking at the 3-5 hours group showed no improvement but significantly higher ICH, fatal ICH and mortality rates and did not recommended the use of TPA beyond 3 hours.
• ECASS I & II showed no benefit and their conclusions were to not recommend it.
• the NINDS trial in 1995 is the only positive randomized trial to date.
• a metaanalysis of alteplase trials published in 2014 ¹⁾:
  • intracranial haemorrhage in alteplase group:
    • fatal cases within 7 days: 2·7% vs 0·4% OR 7·14 with even higher absolute risk among patients who had more severe strokes
    • type 2 parenchymal haemorrhage within 7 days: 6·8% vs 1·3% OR 5·55
  • overall 90 day mortality: 17·9% in the alteplase group versus 16·5% in the control group (hazard ratio 1·11, 95% CI 0·99—1·25, p=0·07)
  • “good stroke outcome” defined as no significant disability at 3—6 months, defined by a modified Rankin Score of 0 or 1:
    • alteplase within 3hrs onset: 32·9% versus 23·1% of controls (OR 1·75, 95% CI 1·35—2·27)
    • alteplase 3hrs to 4.5 hrs from onset: 35·3% versus 30·1% (OR 1·26, 95% CI 1·05—1·51)
    • alteplase delay > 4.5 hrs from onset: 32·6% versus 30·6% (OR 1·15, 95% CI 0·95—1·40)
    • hmmm… seems if you delay giving placebo, you improve outcomes from 23% to 30% - something very fishy going on here!!!
    • in fact, this study then seems to suggest perhaps the best thing you can do for your patient is delay giving a placebo as this will improve stroke outcome to nearly the same as with giving alteplase but without the 7-fold risk of fatal intracranial haemorrhage - the authors do not give this same conclusion though!
• NB. giving a DOAC as well as a thrombolytic did NOT improve stroke outcomes ²⁾

• single bolus tenectaplase (TNK) at dose of 0.25mg/kg appears to be non-inferior to alteplase, easier to administer, longer half-life (3x as longer and even longer terminal half life), more fibrin specific (14x), less drop in systemic fibrinogen levels (10x), more resistant to PAI-1 (80x), more potent, less MMPp9 activation, possibly safer and less expensive
• non-inferior studies:
  • 2016 metanalysis ³⁾
  • 2017 Nor-Test study ⁴⁾
  • 2018 EXTEND-1A TNK ⁵⁾
  • 2019 metanalysis ⁶⁾
  • 2019 Drip-and-ship Model - thrombolysis prior to transfer for endovascular clot retrieval ⁷⁾
  • 2020 EXTEND-1A TNK part 2 ⁸⁾
  • 2021: TRACE 2
  • 2022 Nor-TEST 2 ⁹⁾ - TNK at 0.4mg/kg gave higher bleed outcomes hence dose of 0.25mg/kg is prime recommendation from the studies
  • 2022 AcT Trial ¹⁰⁾
  • 2023: Florida ¹¹⁾

• see ED Mx of stroke with possible thrombolytic Rx

• within 4.5 hours in younger adults of onset of ischaemic stroke (possibly longer in those with cerebral perfusion mismatches)
• more than just minimal neurologic deficit (greater than minimal weakness, isolated ataxia, isolated sensory deficits, or isolated dysarthria)
  • ie. clinical diagnosis of ischaemic stroke causing measurable neurological deficits (impaired language, motor function, cognition and/or gaze, vision, or neglect)
• no obvious infarct on CT (and no haemorrhage)
• age > 18yrs
• no C/I to thrombolytics (see below)
• preferably neurologist decision made to thrombolyse

• possibility that symptoms are not an ischaemic stroke:
  • hypotensive shock suggests watershed ischaemia hence Rx the shock do NOT thrombolyse!
  • Rapidly improving neurological signs - maybe it's just a transient ischaemic attack (TIA)
  • Seizure at stroke onset - might be just a Todd's paresis
  • Symptoms suggestive of subarachnoid hemorrhage, even if CT brain is normal
  • intracranial haemorrhage on CT brain
  • Glucose <2.8 mM or > 22mM
  • possible migraine
• unacceptable risk of bleeding:
  • Stroke or serious head trauma within 3 months
  • Major surgery or serious bodily trauma within 2 weeks
  • History of a prior ICH
  • Intracranial neoplasm
  • Arteriovenous malformation or aneurysm
  • GI or urinary tract hemorrhage within 21 days
  • Arterial puncture at a noncompressible site or lumbar puncture within 1 week
  • Concomitant oral anticoagulant (INR>1.3)
  • Systolic blood pressure (SBP) greater than 185 mm Hg or diastolic blood pressure (DBP) greater than 110 mm Hg or aggressive (continuous intravenous) treatment required to lower BP to this range
  • Suspected acute pericarditis
  • Platelet count <100 x 109/L
  • Prothrombin time (PT) >15 (INR >1.3)
  • Activated partial thromboplastin time (aPTT) elevated beyond reference range
  • Positive pregnancy test or parturition within 30 days

• Early signs of major infarction on initial CT scan (eg, mass effect, edema, hypodensity involving more than one third of the middle cerebral artery territory) are a reason for caution in the use of thrombolytic therapy, because the risk of hemorrhage is increased.

• see thrombolytics