The systemic thrombolysis for stroke RCTs
Two out of 12 systemic thrombolysis studies suggest a benefit: NINDS-2 and ECASS-3.
NINDS-1 tested neurologic improvement at 24 hours and found no benefit.
NINDS-2 subjects in the thrombolytic arm experienced milder strokes than those in the placebo arm.
Outcome measure = “chance of a good outcome” 12% better (even though goal was to show 20%)
Overall: Benefit = NNT of 8 for post-hoc “favorable outcome” measure
MAST-I 1995 – <6hrs, increased death (OR 2.7), slight decrease disability (OR 0.5)
ECASS 1 1995 – <6hrs, no difference in disability or death (included big bad strokes)
ECASS-3 Three to 4.5hrs window; more favorable outcomes with tPA, no mortality difference
NNT=15 for “favorable outcome” – again, milder strokes in lytic arm
MAST-Europe 1996 – <6hrs increased mortality and ICH stopped early
ASK 1996 <4-5hrs window, slight decrease disability but increased mortality at 3 months; stopped early
ECASS-ll 1998 – <6hrs (20% <3hrs) no difference in favorable outcome (modified Rankin) at 3 months
ATLANTIS-B 1999 3-5hrs window, favourable outcome at 3 months, increased ICH, slight increase mortality, stopped early
ATLANTIS A 2000 <6hrs improved NIHSS at 24hrs but 1 month favored placebo, increased ICH and increased mortality at 3 months stopped early
DIAS-2 2008 – 3-9hrs window, notable inclusion is reversible ischemic penumbra on MR or CT; no difference in favorable outcome
IST-3 2012 0-6hrs window, short term 1wk increased mortality, no difference in primary outcome (% alive and independent at 6 months)
Secondary ordinal analysis showing a “shift” in outcomes favoring thrombolytics
Overall harm (symptomatic ICH) NNH: 1 in 20
Issues with the thrombolysis for stroke literature
The modified Rankin Scale used to measure outcomes in most stroke trials is subjective. Even among trained neurologists there is variability in categorizing patients into the scale. The modified Rankin Scale has been shown in a systematic review to be unreliable.
There is no consistency in the definition of intracranial hemorrhage between trials.
Ordinal analysis used in many stroke trials makes the outcomes difficult to interpret.
P-values in the studies have been misinterpreted. P-values don’t convey the truth, they simply alter the post-test probability. A decent p-value only tells us that a trial should be replicated. However NINDS-2 never was replicated, so we don’t know the truth.
The Fragility index of the two positive trials (NINDS and ECASS-3) are only 3 and 1 respectively. The Fragility index indicates how easily random chance could have changed the results of a trial. This means that in the ECASS-3 trial, if a single patient had a different outcome, the trial would have been reported as negative instead of positive.
Fragility index for NINDS is discussed in Pulmcrit by Josh Farkas
Suggested shared decision making script for thrombolysis in stroke management
Care of Justin Morgenstern @First10EM
“There is a treatment we sometimes use for stroke that is supposed to break down the clot causing the stroke. The treatment is controversial, and you will probably hear different things from different doctors. The issue is that out of 12 major trials, only 2 have shown benefit, and both of those trials have some problems, and they were both paid for by the people who make the drug. There are some risks that we’re certain about: about 1 in 12 patients will have severe bleeding resulting in worse neurologic outcome. Despite that risk, in the best case scenario, about 1 in 10 people given this drug early will have a noticeable improvement in their function after 3 months. Unfortunately, it isn’t clear how reliable the science has been, and we don’t know which patients have the greatest chance at benefit or harm. The choice to receive this medication remains up to each individual patient.”
Justin Morgenstern’s First10EM post on Thrombolytics for Stroke: The Evidence
Go on to PART 2 on Endovascular Therapy Trials
Drs. Helman, Morgenstern and Spiegel have no conflicts of interest to declare
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):1581-7.
Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40(10):3393-5.
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):1151-8.
QUALITY IMPROVEMENT AND TISSUE-TYPE PLASMINOGEN ACTIVATOR FOR ACUTE ISCHEMIC STROKE: A CLEVELAND UPDATE Katzan, I.L., et al, Stroke 34:799, March 2003
FREQUENCY OF THROMBOLYTIC THERAPY IN PATIENTS WITH ACUTE ISCHEMIC STROKE AND THE RISK OF IN-HOSPITAL MORTALITY: THE GERMAN STROKE REGISTERS STUDY GROUP Heuschmann, P.U., et al, Stroke 34:1106, May 2003
THROMBOLYSIS IN STROKE PATIENTS AGED 80 YEARS AND OLDER: SWISS SURVEY OF IV THROMBOLYSIS Engelter, S.T., et al, Neurology 65:1795, December 2005
MORTALITY OF STROKE PATIENTS TREATED WITH THROMBOLYSIS: ANALYSIS OF NATIONWIDE INPATIENT SAMPLE Dubinsky, R., et al, Neurology 66:1742, June 2006
THROMBOLYSIS WITH ALTEPLASE FOR ACUTE ISCHAEMIC STROKE IN THE SAFE IMPLEMENTATION OF THROMBOLYSIS IN STROKE-MONITORING STUDY (SITS- MOST): AN OBSERVATIONAL STUDY Wahlgren, N., et al, Lancet 369:275, January 27, 2007
THROMBOLYSIS WITH ALTEPLASE 3-4.5 H AFTER ACUTE ISCHAEMIC STROKE (SITS-ISTR): AN OBSERVATIONAL STUDY Wahlgren, N., et al, Lancet 372:1303, October 11, 2008
TIME TO TREATMENT WITH INTRAVENOUS TISSUE PLASMINOGEN ACTIVATOR AND OUTCOME FROM ACUTE ISCHEMIC STROKE Saver, J.L., et al, JAMA 309(23):2480, June 19, 2013
Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol. 2006 Jun-Jul;27(6):1177-82.
Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008 Apr;39(4):1205-12.
Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):904-13.
Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):914-23
Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903.
Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke (MR CLEAN). N Engl J Med. 2015;372:(1)11-20.
Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection (EXTEND-IA). N Engl J Med. 2015;372:1009-18.
Goyal M, Demchuk AM, Menon BK, et al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke (ESCAPE). N Engl J Med. 372:1019-30
Saver JL, Goyal M, Bonafe A, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. (SWIFT PRIME) N Engl J Med. 2015
Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. (REVASCAT) N Engl J Med. 2015;
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):1509-14.
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):1017-25.
Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial–Europe Study Group. N Engl J Med. 1996;335(3):145-50.
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):961-6.
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):1245-51.
Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. 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):2019-26.
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: 811–816.
Hoffman JR, Schriger DL. A graphic re-analysis of the NINDS trial. Ann Emerg Med. 2009; 54(3): 329-36
Thompson SG. Systematic Review: Why sources of heterogeneity in meta-analysis should be investigated. BMJ. 1994; 309(6965): 1351-1355
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;379(9834):2364-72. PubMed PMID: 22632907; PubMed Central PMCID: PMC3386494.
Shy BD. Implications of ECASS III Error on Emergency Department Treatment of Ischemic Stroke. J Emerg Med. 2012 Nov 7. doi:pii: S0736-4679(12)00655-5. 10.1016/j.jemermed.2012.05.014.
Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000213. DOI: 10.1002/14651858.CD000213.pub2.
FOAMed Resources on thrombolytics for stroke
NNT for thrombolytics in stroke
St. Emlyn’s JC: Kicking against the prick: Systematic Review of stroke thrombolysis
The SGEM on Thrombolysis for Acute Stroke
Justin Morgenstern’s First10EM post on Thrombolytics for Stroke: The Evidence