STROKE: Clot Busters … Busted?

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Original EM Cases Post Here! 

Additional (extensive!) Detail on each of RCT’s can be found here:

Justin Morgenstern’s First10EM post on Thrombolytics for Stroke: The Evidence

 

In this 2 part EM Cases Journal Jam podcast Justin MorgensternRory Spiegel and Anton Helman do a deep dive into the world’s literature on systemic thrombolysis for ischemic stroke followed by an analysis of endovascular therapy for stroke. We elucidate the important issues related to p-values, ordinal analysis, fragility index, heterogeneity of studies, stopping trials early and conflicts of interest related to this body of evidence. While “calling a code stroke” is now considered standard for most stroke patients and tPA for stroke is considered a class 1A drug, a close look at the literature tells us that the evidence is not as strong as our stroke protocols suggest…

 Podcast: Play in new window | Download (Duration: 1:29:10 — 122.5MB)

Podcast produced by Anton Helman, Justin Morgenstern and Rory Spiegel; sound design and editing by Anton Helman; EBM bomb by Anton Nikoline.

Written Summary and blog post by Anton Helman July, 2016

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.”

Go on to PART 2 on Endovascular Therapy Trials 

 

References

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

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