Skip to main content Accessibility help
×
Home

Contents:

Information:

  • Access
  • Cited by 3

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Thrombolysis for acute ischemic stroke: does it work?—the con position
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Thrombolysis for acute ischemic stroke: does it work?—the con position
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Thrombolysis for acute ischemic stroke: does it work?—the con position
        Available formats
        ×
Export citation
Please note a correction has been issued for this article.

Thrombolysis for acute ischemic stroke (AIS) has become mainstream therapy, despite the scientific evidence rather than because of it. Careful scrutiny of the literature demonstrates that it has proven harm but no clear benefit, because of the sheer paucity of hard evidence supporting its use. There are only two large randomized controlled trials (RCTs) showing benefit for thrombolysis, and nine large RCTs that failed to show any significant difference to placebo (four were stopped early due to excess harm). This is in stark contrast to the clear mortality benefit for thrombolysis in six out of eight large RCT for myocardial infarction. 1 Both systematic and non-systematic reviews of thrombolysis for AIS are severely biased by the inappropriate inclusion of heterogeneous studies, to the extent that their positive conclusions can be reversed simply by eliminating those studies. The remainder of often quoted evidence in favour of thrombolysis is either uncontrolled monitoring data or hypothetical conjecture, neither of which answers the question of efficacy.

The first issue to address is defining which RCT should be included in the analysis. Wardlaw* is the lead author of six sequential literature reviews since 1992, four in the Cochrane database. The latest Cochrane systematic review in 2014 concluded that there “appears to be a net benefit of a significant reduction in the proportion who are dead or dependent at the end of follow-up,” defined as modified Rankin Scale (mRS) ≥3 (odds ratio [OR]=0.85), using data extracted from 22 of 27 studies in the review. 2 Nine of these studies, however, measured brain reperfusion as the primary outcome (not clinical improvement), used intra-arterial injections instead of intravenous, or were very small (n=16–57), and two had unacceptably poor methodological quality. The Cochrane authors acknowledged and measured the high level of heterogeneity in their choice of studies (I2=39%) but did not modify their conclusion. Therefore, there are only 11 large (n≥100) RCTs of reasonable quality and homogeneous methodology (Table 1, including the International Stroke Trial [IST-3], which was published after the Cochrane Review). If the likelihood of a good outcome (mRS≥3) is recalculated using only these 11 trials (I2=5%), thrombolysis is favoured with OR=0.87 (95% confidence interval [CI]=0.79–0.96) but with a CI close to 1.0 and a number needed to treat (NNT) of 29. Even if the statistical significance is real, the clinical significance is doubtful. There is also an excess of death or symptomatic intracranial hemorrhage (ICH) (OR=1.53) with a number needed to harm (NNH) of 11. The risk-benefit analysis now favours placebo.

Table 1 Randomized controlled trials of intravenous thrombolysis for acute ischemic stroke (n≥100)

* ASK=Australian streptokinase; ATLANTIS=alteplase thrombolysis for acute noninterventional therapy in ischemic stroke; DS=desmoteplase; DIAS=desmoteplase in acute ischemic stroke; ECASS=European Cooperative Acute Stroke Study; IST=International Stroke Trial; MAST=Multicentre Acute Stroke Trial (Italy, Europe); NINDS=National Institute of Neurological Disorders and Stroke

SK=streptokinase; tPA=tissue plasminogen activator.

If thrombolysis does not work for AIS, why are there two positive trials? This can easily be due to chance. Using the standard threshold of significance (p=0.05), if enough RCTs are performed with the same study question, 1 out of every 20 studies will demonstrate a statistically significant outcome by chance alone. In other words, the probability that 2 of 11 stroke studies will show a positive result for thrombolysis, when in reality there is no difference from placebo (type I error), is approximately 25%. This possibility is supported by the marginal results of the two positive trials: the National Institute of Neurological Disorders and Stroke (NINDS) study 3 and the European Cooperative Acute Stroke Study III (ECASS-III). 4 NINDS had the best outcome, where patients treated within 3 hours were 12% more likely to have a good functional outcome (mRS 0–1) at 3 months. In a recent Australian study, only 15% of all AIS patients who arrived within 4.5 hours were eligible for thrombolysis. 5 Therefore, for an average hospital admitting 100 stroke patients in a year, assuming ideal conditions and early presentations, 80 would have AIS, 12 would receive thrombolysis, and potentially 1 patient would have a better recovery. In addition, the trial results themselves are dependent on the definition of good outcome. For example, in ECASS-III, if it changes from mRS 0–1 to mRS 0–2 (i.e., includes mild disability) the benefit of thrombolysis disappears, referred to as wobble by Wardlaw et al. 2

Both trials have been criticized for their methodology, especially because the patients in the placebo groups of both trials had more severe strokes at enrolment, and, in ECASS-III, more placebo patients had prior strokes. 6 Two groups re-analysed the NINDS data adjusting for baseline differences, with different conclusions. 7 , 8 Furthermore, care in a multidisciplinary stroke unit is the only proven therapy to date, with a reduction in death and disability equivalent to that claimed by thrombolysis. 9 IST-3 was the only trial to control for this variable, and it is plausible that some of the benefits seen in NINDS and ECASS-III were due to variability in level of care.

Can the nine negative trials be explained away? Proponents of thrombolysis have decided that tissue plasminogen activator (tPA) is effective, but other fibrinolytic agents are not, ignoring trials that used streptokinase and desmoteplase. 10 Apart from biological implausibility, this view is inconsistent with the literature for strokes and other diseases. Two of three small pilot studies using desmoteplase in AIS showed benefit for thrombolysis and were included in the 2014 Cochrane Review. 11 13 Food and Drug Administration (FDA)-approved agents for thrombolysis in pulmonary embolus include streptokinase, urokinase, and tPA. 14 In eight large (n>1000) placebo-controlled RCTs of thrombolysis in ST-elevation myocardial infarction, both streptokinase and tPA were effective. 1

It has also been argued that many studies failed because they included patients after 4.5 hours. In 2004, Hacke* et al. published a pooled analysis of six tPA trials (ECASS, alteplase thrombolysis for acute noninterventional therapy in ischemic stroke [ATLANTIS], NINDS) attempting to show that earlier treatment had better outcomes. 15 The study selection is arbitrary and biased in favour of NINDs patients. This work is speculation, not evidence. Furthermore, there is no pattern in the literature that supports a relationship between time of treatment and outcome: the Australian streptokinase (ASK) study had a 4-hour enrolment limit and ATLANTIS-B a 3–5 hour window, both similar to the 4.5-hour limit in ECASS-III, but with negative results. Subgroup analysis of the 0–3 hour period in ASK, ECASS-I, and ECASS-II showed no benefit in that period (in contrast to the 3-hour limit in NINDS) and neither did the ATLANTIS-B review of the 3- to 4-hour subgroup. IST-3 demonstrated a worse outcome in the 3- to 4.5-hour period than in the later (4.5- to 6-hour) period. Similarly, NINDS reported combined parts I and II results at 3 months, and patients treated after 90 minutes had better outcomes than those treated earlier.

IST-3 deserves special mention here as the largest trial with 3,035 patients. 16 The primary outcome was the proportion of people who were alive and independent at 6 months. It was powered to detect a 4.7% difference, yet the final difference was only 1.5% and not significant. The author’s astonishing statement that secondary ordinal analysis “provided evidence of a favourable shift in the distribution of Oxford Handicap Scores at 6 months with treatment” is completely irrelevant to the negative outcome of the trial. Post-hoc analyses and secondary outcomes are of value only in generating hypotheses for future study and should not be used to contradict the primary outcome—thrombolysis did not work!

Stroke registries and community studies are often touted as supportive evidence for thrombolysis, because outcomes are similar to RCTs, but the purpose of post-marketing monitoring is to measure the “real-world” safety of treatment. Without control groups, they cannot determine efficacy. The Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) is a large multinational voluntary database, but up to half of treated patients are not reported, and up to one third of registered patients have protocol violations. 17 Authors of three well-known safety studies suggested that excellent outcomes in treated patients were comparable to NINDS. SITS-MOST (Monitoring Study) by Wahlgren* et al., the American Standard Treatment with Alteplase to Reverse Stroke (STARS) project by Albers* et al., and the Canadian Alteplase for Stroke Effectiveness Study (CASES) report by Hill* et al. are all industry-sponsored studies mandated by licensing authorities. 18 20 Excellent outcomes (mRS 0–1) in treated patients in these studies were 39%, 35%, and 32%, respectively. By contrast, the placebo groups in RCTs using the same methodology as NINDS (ECASS-II/III, ATLANTIS-B) have better outcomes at 90 days (37%, 45%, 41%, respectively). Data from the safety studies could therefore just as easily support an argument that treatment is worse than placebo.

That thrombolysis is dangerous is not in dispute. Excess mortality in the treatment group is reported in the Cochrane Review to be 1.4%. 2 Symptomatic ICH occurs in about 2% of controls but 7% of treated patients (up to 22% in less strictly controlled community studies). 17 , 21 , 22 The case for thrombolysis is a “house of cards” resting on two weak RCTs. Let’s be honest; the overwhelming majority of hard evidence shows no benefit, yet the risk of harm is clear.

Competing Interests: Author did declare financial benefit from Boehringer Ingelheim (manufacturer of alteplase outside of the United States, Canada, and Japan).

References

1. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Lancet 1994;343(8893):311-322.
2. Wardlaw, JM, Murray, V, Berge, E, Del Zoppo, GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014;29(7):CD000213. doi:10.1002/14651858.
3. 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(24):1581-1587.
4. Hacke, W, Kaste, M, Bluhmki, E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317-1329.
5. Eissa, A KI, Levi, C, Sturm, J, et al. Understanding the reasons behind the low utilisation of thrombolysis in stroke. Australas Med J 2013;6(3):152-167.
6. Fatovich, DM. Believing is seeing: stroke thrombolysis remains unproven after the third international stroke trial (IST-3). Emerg Med Australas 2012;24(5):477-479.
7. Hoffman, JR, Schriger, DL. A graphic reanalysis of the NINDS trial. Ann Emerg Med 2009;54(3):329-336.e35.
8. Ingall, TJ, O’Fallon, WM, Asplund, K, et al. Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial. Stroke 2004;35(10):2418-2424.
9. Middleton, S, Levi, C, Ward, J, et al. Death, dependency and health status 90 days following hospital admission for acute stroke in NSW. Int Med J 2011;41(10):736-743.
10. Wardlaw, JM, Murray, V, Berge, E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012;379(9834):2364-2372.
11. Hacke, W, Furlan, AJ, Al-Rawi, Y, et al. 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 Neurol 2009;8(2):141-150.
12. Furlan, AJ, Eyding, D, Albers, GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37(5):1227-1231.
13. Hacke, W, Albers, G, Al-Rawi, Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36(1):66-73.
14. Konstantinides, S, Goldhaber, SZ. Pulmonary embolism: risk assessment and management. Eur Heart J 2012;33(24):3014-3022.
15. Hacke, W, Donnan, G, Fieschi, C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363(9411):768-774.
16. Group, ISTc, Sandercock, P, Wardlaw, JM, Lindley, RI, et al. 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;379(9834):2352-2363.
17. Leyden, JM, Chong, WK, Kleinig, T, et al. A population-based study of thrombolysis for acute stroke in South Australia. Med J Aust 2011;194(3):111-115.
18. Wahlgren, N, Ahmed, N, Davalos, A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. [Erratum appears in Lancet 2007;369(9564):826]. Lancet 2007;369(9558):275-282.
19. Albers, GW, Bates, VE, Clark, WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 2000;283(9):1145-1150.
20. Hill, MD, Buchan, AM. Canadian Alteplase for Stroke Effectiveness Study I. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ 2005;172(10):1307-1312.
21. Katzan, IL, Furlan, AJ, Lloyd, LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000;283(9):1151-1158.
22. Katzan, IL, Hammer, MD, Furlan, AJ, et al. Cleveland Clinic Health System Stroke Quality Improvement T. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003;34(3):799-800.
23. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet 1995;346(8989):1509-1514.
24. Hacke, W, Kaste, M, Fieschi, C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274(13):1017-1025.
25. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicentre Acute Stroke Trial--Europe Study Group. N Engl J Med 1996;335(3):145-150.
26. Donnan, GA, Davis, SM, Chambers, BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996;276(12):961-966.
27. 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(9136):1245-1251.
28. Clark, WM, Wissman, S, Albers, GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999;282(21):2019-2026.
29. Clark, WM, Albers, GW, Madden, KP, Hamilton, S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thrombolytic therapy in acute ischemic stroke study investigators. Stroke 2000;31(4):811-816.