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

• CCC — Alteplase (rTPA, recombinant tissue plasminogen activator)
• Schrodinger’s Fence (2013)
• The Use of Thrombolysis as a Treatment for Stroke (2013)
• Why we should be very wary of using clotbusting drugs to treat acute strokes (2013)

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

• ACEM Statement — S129 Statement on Intravenous Thrombolysis for Ischaemic Stroke (pdf) (2014)
• EMCrit — Podcast 79 Reducing Door to tPA Time in Ischemic Stroke
• EMI — Lytics in stroke
• EMLON – The Third International Stroke Trial: IST-3 (2012)
• SGEM — SGEM#70: The Secret of NINDS (Thrombolysis for Acute Stroke) (2014)
• The NNT — Thrombolytics for acute ischemic stroke (2010)