Bottom Line
Reanalysis of the original ECASS-III data does not support a patient-oriented benefit of tPA given 3–4.5 hours after onset of stroke symptoms and confirms the known potential harm.
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ACEP Now: Vol 39 – No 09 – September 2020Summary of Thrombolytics for AIS
There are 13 RCTs of thrombolytics for AIS (see Table 1). Four were stopped early for harm (bleeding) or futility, and all 13 failed to show a statistical benefit after the reanalysis of NINDS-2 and ECASS-III.
Table 1: Trials Involving Thrombolytics for Acute Ischemic Stroke
| Trial | Number of Patients | Reference | Time to Treatment | ThrombolyticS | Results |
|---|---|---|---|---|---|
| MAST-Italy | 622 | Lancet. 1995;3461509-1514. | <6 hours | Streptokinase | No difference in primary benefit, increased chance of early death. |
| ECASS-I | 620 | JAMA 1995;274:1017-1025. | <6 hours | tPA | No difference on disability scores and 7% increase in mortality. |
| NINDS-I | 291 | N Engl J Med. 1995;333:1581-1588. | <3 hours | tPA | No difference in neurologic improvement at 24 hours |
| NINDS-II* | 333 | Ann Emerg Med. 2009;54:329-336 | <3 hours | tPA | No difference in favorable mRS at 90 days, 6% absolute increase in brain bleeds, and no mortality difference. |
| MAST- Europe | 310 | N Engl J Med. 1996;335:145-150. | <6 hours | Streptokinase | No difference in death or disability at 3–6 months, 18% increase in brain bleed, and stopped early due to harm. |
| ASK | 340 | JAMA. 1996; 276:961-966. | <4 hours | Streptokinase | No difference in death or disability at 3 months, 10% increase in brain bleeds, and stopped early due to harm. |
| ECASS-II | 800 | Lancet. 1998;352:1245-1251. | <6 hours | tPA | No difference in outcomes on the mRS or mortality, and 7% increase in brain bleeds. |
| ATLANTIS-B | 613 | JAMA. 1999; 282:2019-2026. | 3–5 hours | tPA | No difference in neurologic recovery and stopped early because “unlikely to prove beneficial.” |
| ATLANTIS-A | 142 | Stroke. 2000; 31:811-816. | <6 hours | tPA | No benefit in NIH stroke scale at 30 days, 18% greater risk of mortality, and stopped early due to harm. |
| ECASS-III ** | 821 | BMJ Evid Based Med. 2020. doi: 10.1136/bmjebm-2020-111386. | 3–4.5 hours | tPA | No difference in favorable mRS score after 90 days, and 9% increased rate of brain bleed. |
| DIAS-2 | 193 | Lancet Neuro. 2009;8:141-150. | 3–9 hours | Desmoteplase | No difference in clinical response, and increased rate of brain bleed. |
| IST-3 | 3035 | Lancet. 2012; 379:2352-2363. | <6 hours | tPA | No difference in mortality or independence after 6 months, 4% increase in death at 1 week, and 6% increase in fatal or non-fatal brain bleeding. |
| DIAS-3 | 492 | Lancet Neuro. 2015;14:575-584. | 3–9 hours | Desmoteplase | No difference in favorable mRS at 90 days, and no difference in major adverse events. |
* Reanalysis of NINDS-2, ** Reanalysis of ECASS-III , Red indicates trials that were stopped before completion.
The table does not include two newer RCTs looking at extending the therapeutic window to 4.5–9 hours. These newer trials were done with more advanced brain imaging, selecting patients with a perfusion mismatch. Both RCTs were stopped early, which can introduce bias toward efficacy. In addition, the majority of patients included in these trials would now qualify for endovascular therapy (EVT) clot retrieval. EVT has more evidence for efficacy than systemic thrombolysis and a recent RCT has shown that EVT alone is noninferior to EVT plus tPA.
Case Resolution
You provide the patient with the latest information on thrombolytics for stroke. Her mental status is intact and she clearly understands the information as presented. She elects not to move forward with systemic tPA administration.
Thank you to Prof. Daniel Fatovich, an emergency physician at Royal Perth Hospital in western Australia and the head of the Centre for Clinical Research in EM, for his help with this review.
Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.
References
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.
- Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med. 2009;54(3):329-336.
- 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.
- Brown MD, Burton JH, Nazarian DJ, et al. Clinical policy: use of intravenous tissue plasminogen activator for the management of acute ischemic stroke in the emergency department. Ann Emerg Med. 2015;66:322-333.
- Quinn TJ, Dawson J, Walters MR, et al. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40(10): 3393-3395.
- Wilson JT, Hareendran A, Hendry A, et al. Reliability of the modified Rankin Scale across multiple raters: Benefits of a structured interview. Stroke 2005;36(4):777-781.
- Farkas J. What is the fragility index of the NINDS trial? PulmCrit (EMCrit) website. Accessed Aug. 24, 2020.
- Wasserestin RL, Lazar NA. The ASA’s statement on p-values: Context, process, and purpose. Am Stat. 2016;70(2):129-133.
- IST-3 collaborative group, Sandercock P, Wardlaw JM, 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.
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3 Responses to “After Re-Analysis, No Trials Show Efficacy of tPA in Acute Ischemic Stroke”
October 3, 2020
Brian TenneyMeta-analyses (x3) are cited in the 2018 AHA guidelines as supporting TPA in the 3-4.5 hour window. Incredibly, by my reading, none of the meta-analyses supports benefit:The Cochrane review plainly states no benefit out to 4.5 hours as the confidence interval crosses 1: Odd Ratio of 0.93 [CI 0.66 to 1.32])showed a symptomatic ICH rate of 5%does not include IST-3The first Lancet article only studys 0-3 and 3-6 hours, no mention of 3-4.5 hour window analysisThe second Lancet meta-analysis did show OR of 1.4 (CI 1.1–1.9) but this study does not include IST-3 in its analysis!!
October 12, 2020
Ken MilneThanks for posting this information. SRMA are only as good as the studies included. These types of analysis have their own thread to validity. One is that biases in the original studies can be compounded by the SRMA process. It can result in a misleading point estimate with a significant p-value. This can give an illusion of certainty when certainly does not exist.
January 13, 2021
M Bruce ParkerI have elicited criticism for sharing this article in EM department meetings. There is considerable inertia toward continuing to continue what “we” have been doing.
As Jerry Hoffman put it: “I wish I knew.”