Stroke Thrombolysis

OVERVIEW

  • thrombolysis for acute ischaemic stroke is a controversial intervention
  • it is supported by a number of guidelines and in general is viewed favourably by the neurological community
  • in general, the emergency medicine community views the therapy with greater skepticism (see ACEM position statement below)
  • the amount of debate far exceeds it’s relative clinical importance!

RATIONALE

  • following the onset of stroke, the neurons surrounding the ischemic core may remain viable for a period of time
  • early correction of ischaemia may rescue these neurons in the ischaemic penumbra
  • alteplase (r-tPA) acts by converting inactive plasminogen into the active form plasmin, which promotes thrombolysis by cleaving fibrin
  • thrombolysis may degrade clot and relieve ischemia

DOSE

  • 0.9mg/kg alteplase (r-TPA) (maximum 90mg) over 60 minutes (10% given as a bolus)

INDICATIONS

  • Consider for acute ischaemic CVA within 3 hours of onset after exclusion of haemorrhage
  • Most appropriately used in a stroke center or as part of a randomised controlled trial
  • Used up to 4.5 hours in some centers based on ECASS-III

See alteplase for more detail on indications and contra-indications

PUBLISHED TRIAL RESULTS

Alteplase

  • 12 controlled trials have been published on the use of thrombolysis for stroke (mostly using alteplase aka recombinant tissue plasminogen activator)
  • 2 of these RCTs found a benefit as defined by primary outcome measures (NINDS, ECASS-3)
  • 2 were stopped early because of harm (ATLANTIS)
  • 8 remaining studies had negative findings for the primary outcome (IST-3 had a positive secondary outcome)
  • supported by meta-analysis based on the above studies
  • supported by large industry funded registry data-sets

Streptokinase

  • no longer used for stroke thrombolysis
  • studied in ASK, MAST-ITALY, MAST-EUROPE
  • all negative studies
  • the Australian study (ASK) was stopped early for harm
  • NNH of 5 to cause death or disability

INTRACRANIAL HAEMORRHAGE

  • RCTs consistently show a higher risk of intracranial haemorrhage and early death compared with placebo
  • For alteplase — excess haemorrhages in the first 7 days: 58 per 1000 cases treated (95% CI 49 to 68) — deaths in the first 7 days: 25  per 1000 cases treated (11 to 39)
  • by 3-6 months death rates are similar whether treated with alteplase or not

PROPOSED BENEFITS

Alteplase for acute ischaemic stroke

  • A systematic review (Wardlow et al, 2013) found that giving alteplase within 6 hours of stroke:
    — reduces the composite outcome of death or dependency by 42/1000 people treated (95% CI 19 to 66); NNT = 24
    — has a greater effect if given within 3 hours: 90/1000 people treated (95% CI 46 to 135); NNT = 11
  • However this systematic review is based on flawed studies (see below)

POSITIVE TRIALS (AND IST-3)

NINDS trial (1995)

  • 2-part MC RCT
  • led to FDA approval for alteplase in stroke in 1995
  • n = 291+ 333 patients
  • randomisation stratified by clinical center and by time from the onset of stroke to treatment (0 to 90 minutes and 91 to 180 minutes)
  • blinding?
  • inclusion: acute ischemic stroke patients presenting <3 hours of symptom onset
  • comparison: placebo versus IV treatment with 0.9 mg/kg of the human recombinant tPA alteplase, with 10% of the total dose administered as a bolus and the remaining 90% infused over 60 minutes (maximum dose 90 mg)
  • primary outcomes:
    — NINDS I: complete resolution of the stroke symptoms or an improvement in NIHSS score by 4 or more points at 24 h
    ———> no difference
    — NINDS II: favorable outcome at 3 months using a global endpoint derived from 4 assessment scales: the Barthel Index, modified Rankin Scale, Glasgow Outcome Scale and NIHSS
    ———> odds ratio (OR) for a favorable outcome in the tPA group, defined as minimal or no disability at 90 days, was 1.7 (95% CI 1.2 to 2.6; P<.008)
    ———> for modified Rankin Scale score outcome of 0 or 1: 12% absolute increase in the number of patients with minimal or no disability in the tPA group, NNT = 8.3
  • secondary analyses:
    — no difference for age, sex, stroke severity, and stroke type
    — subsequent reanalysis of the trial data suggested that the NNT to produce a 1-point shift in the Rankin Scale, including from states of severe disability to more moderate disability, may be as low as 3.6
    — another reanalysis fount that benefits persisted to 90-days, without a difference in mortality rates
  • baseline imbalance is a serious flaw in this study:
    — placebo group had more severe strokes at baseline
    — graphical analysis by Hoffman and Schriger of the original data showed that the improved final outcome for alteplase patients paralleled the greater number of alteplase patients who had had a very mild stroke (criticised for not accounting for non-linearity of NIH stroke scale)
  • Mortality was similar in both groups (17% for tPA versus 21% for placebo; P<0.30)
    — an increase in symptomatic intracerebral hemorrhage in the tPA-treated group during the first 36 hours (6% versus 0.6% in the placebo group; P<.001)
    — many of these tPA-related hemorrhages were fatal (45%) — the improved 90-day outcomes in the tPA group (without an increased overall mortality) occurred despite the excess mortality in patients who had symptomatic intracerebral hemorrhage
  • no control over post-thrombolytic therapy (e.g. rehabilitation, other therapies such as aspirin or heparin)
  • issues with the 3 hour window:
    — benefit for up to 3 hours biased by 50% of the patients having thrombolysis <90 minutes
    — <90 min OR 1.71 (1.06-2.7)
    — 91-180 min OR 1.12 (0.71-1.76) (not significant)
  • these ordinal scales are not linear
    — e.g. a change in NIHSS from 6 to 10 is not the same degree of benefit as from 16-20
  • Industry influence

ECASS-III (2008)

  • MC RCT
  • n = 821 stroke patients at 3 to 4.5h after onset
  • stratified randomisation
  • same dosing regimen and inclusion/exclusion criteria as the NINDS protocol with additional exclusions: age > 80 years, baseline NIHSS score >25, any oral anticoagulant use (regardless of the INR), and the combination of a previous stroke and diabetes mellitus
  • comparison: thrombolysis with alteplase vs placebo
  • primary outcome: disability at 90 days, dichotomized as a favorable outcome (mRS score of 0 or 1) or an unfavorable outcome (mRS of 2 to 6)
    — favoured alteplase (52.4% vs. 45.2%; OR 1.34; 95% CI 1.02 to 1.76; P=0.04)
  • adverse effects:
    — intracranial hemorrhage was higher with alteplase (for any ICH: 27.0% vs. 17.6%; P=0.001; for symptomatic ICH: 2.4% vs. 0.2%; P=0.008)
    — mortality did not differ significantly (7.7% and 8.4%, respectively; P=0.68).
  • baseline imbalance is a serious flaw in this study:
    — placebo had more previous strokes (14% vs 8%, p=0.03) and more severe strokes (NIHSS 11.6 vs 10.7, p=0.03)
  • used an unusual primary outcome with mild disability (a modified Rankin scale score of 2) being grouped with dead (score of 6)
    — If those with a score of 0-2 are compared with those with a score of 3-6, there is no significant difference between alteplase and placebo
  • industry influence

IST3 (2012)

  • open-label (non-randomised) trial
  • n = 3,035
  • inclusion criteria: patients with ischemic stroke up to 6 hours from symptom onset in whom benefit was deemed to be uncertain (the majority of whom had contraindications to tPA defined by NINDS criteria in the 0- to 3-hour window or ECASS-3 criteria in the 3- to 4.5-hour window)
  • comparison: r-tPA <6h versus placebo
  • primary outcome: no difference proportion of patients functionally independent at six months (Oxford Handicap Score 0-2, similar to mRS) (95% CI of 0.95 to 1.35)
  • Secondary ordinal analysis found a non-significant shift in Oxford handicap scale (OHS) score in favour of alteplase — the authors claimed that the study had a positive outcome based on this, despite the negative primary outcome!
  • Good baseline balance but marked difference in co-interventions
  • in patients aged >80, there is a trend towards benefit with TPA, CI 0.97-1.88
    — suggests a trend towards harm in patients <80y as a result!
    — this is inconsistent with assumptions from previous studies such as NINDS where elderly were excluded
  • no correlation between benefit/ harm and time from 0 to 6 hours (an odd finding based on the rationale for thrombolysis in stroke)
  • more pronounced benefits in more severe strokes (NIHSS >14) — neutral or trends to harm for less severe strokes
  • This study is strongly biased towards alteplase:
    — open label study
    — scores were collected by postal survey and telephone rather than objective face to face assessment
  • a subsequent 18 month outcome analysis showing no net difference in mortality but improved self reported function is susceptible to the same biases
  • industry influence

SUMMARY OF PROBLEMS WITH THROMBOLYSIS TRIALS

  • numerous methodologic flaws
  • missing patient data from studies stopped early for harm
  • heterogeneity calculations strongly suggesting pooling of data to be inappropriate
    — different inclusion/ exclusion criteria
    — different thrombolysis regimens and time windows
  • imbalances in baseline stroke severity (NINDS, ECASS-3)
    — placebo group had significantly worse strokes, and/or pre-existing strokes, at baseline
  • the use of subjective outcome measures with weak inter-rater reliability (e.g. modified Rankin Score, Oxford Handicap Scale)
  • influence of manufacturer involvement in the only two blinded studies suggesting benefit (NINDS, ECASS-3)
  • IST-3 was an open-label study subject to bias with follow up based on telephone calls (subject to recall bias and measurement bias)
  •  the meta-analysis is flawed, because it is based on the above flawed studies
  • controversy over the time window — poor time correlation in IST-3; apparent time window may reflect that more severe strokes are more likely to present early

COMPARISON WITH THROMBOLYSIS FOR STEMI

STEMI thrombolysis

  • large number of patients studied (>60,000 patients in RCTs)
  • every study across all populations positive benefit found
  • clear mortality benefit (2%) and small functional benefit
  • simple workup with well defined patient selection criteria (i.e. meets STEMI criteria)
  • consistent pathological process (acute plaque rupture causing vascular occlusion)
  • 6 hour time frame for benefit
  • many patients suitable for treatment (unless at a center where PCI is preferred)
  • greater benefit for large infarcts
  • rapid response/ benefit
  • high risk (1% risk of death)

Stroke thrombolysis

  • small number of patients studied (<10,000 patients in RCTs)
  • most studies negative, positive studies not replicated with the same outcomes and methodology
  • 3-4.5h time frame for benefit (better if earlier)
  • few patients suitable for treatment
  • complex workup with uncertain patient selection criteria
  • inconsistent pathological process (a large number are embolic or unknown)
  • rapid response/ benefit not present (based on NINDS I in first 24 hours)
  • very high risk (3% risk of death) — clear early harm

This comparison highlights the much stronger evidence for thrombolysis in STEMI, simpler workup, clearer risk-benefit analysis and greater biological plausibility

POSITION STATEMENTS AND CLINICAL POLICIES

Current ACEM position, March 2014 (Statement S129)

  • ACEM recognises intravenous thrombolysis as a potentially beneficial intervention for acute ischaemic stroke. There is however, conflicting evidence such that the administration of stroke thrombolysis by ED staff is a controversial area and cannot currently be considered a ‘standard of care’

Stroke thrombolysis is endorsed by:

  • FDA
  • American Academy of Neurology
  • American Heart Association
  • Australian Stoke foundation
  • BAEM (thrombolysis may be considered)
  • ACEP (clinical policy here)

CICM does not have a published position statement on this therapy

PROS AND CONS SUMMARY

Advantages

  • NNT ~ 8 with persisting benefits in terms of neurological outcomes (at least 3 months)
  • no increase in mortality overall (early deaths from ICH offset by those that avoid ICH and improve over time?)
  • given the burden of stroke any benefit may be significant
  • registry data suggests that safety is similar in the ‘real world’ to clinical trials
  • supported by many professional societies and independent reviewers
  • little disruption to ED practice if additional resources provided by stroke team

Disadvantages

  • definite risk of early intracranial haemorrhage and death
  • the 2 positive trials are methodologically flawed and suffer from baseline imbalance
  • the 2 positive trials suffer from industry influence and author conflicts of interest
  • few patients studies (despite mutliple meta-analyses (“meta-inflation”) and post-hoc analyses)
  • majority of studies show no overall benefit or harm (though these include patients up to 6 hours and different thrombolytics)
  • registry data is unreliable
  • systematic reviews based on flawed studies
  • only about 5% of stroke patients attending ED are eligible for stroke thrombolysis
  • potential disruption of ED service (e.g. CT priority, high triage priority)
  • NNT likely inflated by patients treated <90 minutes in studies (less likely to occur outside of trials)
  • difficulty distinguishing stroke mimics (10-30% of cases) may lead to inappropriate r-tPA administration (e.g. Todds palsy, migraine)
  • consent is problematic (e.g. cognitive impairment, complex evidence base)
  • investment in stroke prevention and rehabilitation may be more cost-effective (or to other ED patients)
  • protocol violations are common
  • improvement in patients often inccorectly attributed to thrombolysis — studies indicate that r-TPA does not confer any benefit in the first 24 hours and that 7% of patients who present with stroke improve with placebo
  • unlikely to benefit: LACIs, large vessel occulsons (e.g. ICA, Basilar, M1, >1/3 MCA territory),patients without occlusion at time of imaging

CONCLUSION

My view

  • Despite incorporation into clinical guidelines and widespread adoption by the neurological community, the evidence for stroke thrombolysis is weak
  • there is a preponderance of negative studies and the few positive studies have methodological laws, are subject to bias and in turn make subsequent meta-analysis unreliable
  • continued use of stroke thrombolysis outside the setting of RCTs is a cause for concern and should be considered an experimental therapy, but future studies seem unlikely now
  • other strategies involving clot retrieval or imaging to identify patients those suitable for treatment may hold more promise that crude time-based clinical approaches as it is likely that some patients do benefit from thrombolysis

References and Links

LITFL

Journal articles and systematic reviews

  • Brown SGA, Macdonald SPJ, and Hankey GJ. Do risks outweigh benefits in thrombolysis for stroke? BMJ 2013;347:f5215 [Full Text]
  • Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med. 2009 Sep;54(3):329-36, 336.e1-35. PMID: 19464756.
  • Radecki RP. Pharmaceutical sponsorship bias influences thrombolytic literature in acute ischemic stroke. West J Emerg Med. 2011 Nov;12(4):435-41. PMC3236136.
  • Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012 Jun 23;379(9834):2364-72. PMC3386494.

Stroke trials (chronological order)

  • Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. The Lancet 1995 Dec.;346(8989):1509 -1514. PMID: 7491044
  • Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct.;274(13):1017–1025.1. PMID: 7563451
  • Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (NINDS). N Engl J Med 1995 Dec.;333(24):1581–1587. PMID: 7477192 [Free Full Text]
  • Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial–Europe Study Group (MAST-E). N Engl J Med 1996 Jul.;335(3):145–150. PMID: 8657211
  • Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996 Sep.;276(12):961–966. PMID: 8805730
  • 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. The Lancet 1998 Oct.;352(9136):1245–1251. PMID: 9788453
  • Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS (B) Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999 Dec.;282(21):2019–2026. PMID: 10591384 
  • The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators.(ATLANTIS A) Stroke 2000 Apr.;31(4):811–816. PMID: 10753980
  • Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurology 2008 Apr.;7(4):299–309.PMID: 18296121
  • Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke (ECASS III). N Engl J Med 2008 Sep.;359(13):1317–1329. PMID: 18815396 [Free full text]
  • Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurology 2009 Feb.;8(2):141–150. PMCID: 2730486
  • The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012 May 23.PMID: 22632908

FOAM and web resources

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

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