Journal Jam 10 Thrombolysis & Endovascular Therapy for Stroke Part 1

 

In this 2 part EM Cases Journal Jam podcast Justin Morgenstern, Rory 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 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.”

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

 

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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About the Author:

Dr. Anton Helman is an Emergency Physician at North York General in Toronto. He is an Assistant Professor at the University of Toronto, Division of Emergency Medicine, the Education Innovation Lead at the Schwartz-Reisman Emergency Medicine Instititute and is on the advisory board of The Teaching Institute. He is the founder and host of Emergency Medicine Cases.

2 Comments

  1. Jim Siegler July 9, 2017 at 12:42 pm - Reply

    Hi,

    My attention was brought to your blog by a listener to both of our podcasts. I’d like to start by saying I am certainly glad that groups like the EM Cases podcast are approaching the literature with a skeptical, critical eye. That being said, I am appalled by what you are trying to promote here.

    The first comment by the author was that 2 out of 12 studies suggested a benefit. This is aggravating for 2 reasons. First, to say that 2 trials “suggest a benefit” is inaccurate, this should be re-worded to “demonstrate a benefit.” “Suggest” is the word statisticians use to describe p values > 0.05 when they are still convinced that the signal they are observing is correct. Second, the author is comparing apples and oranges. The 12 studies referenced here included investigations using a variety of therapeutics (urokinase, streptokinase, desmotleplase, alteplase…). Over time, we in the stroke community have learned that only alteplase has proven benefit and this has been corroborated by far more than 12 studies–and the author even references a great Cochrane review on the subject (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000213.pub2/full). I would compare this author’s comment to one like “2 out of 12 trials suggested a benefit of antibiotics for meningitis in young adults.” If 10 out of those trials randomized patients to cephalexin, and the other 2 combined ceftriaxone and vancomycin, you can imagine their results would be much different.

    The next comment deals with the primary outcome that has become standard for clinical trials in stroke patients: the modified Rankin Scale, a 0-6 ordinal scale of neurologic function. The author calls it “subjective,” “variable” and “unreliable.” Agreed, it is a subjective score of neurologic function. There is no way we can quantitate whether a patient is able to return to work, drive a car effectively, open a jar of pickles, pay their bills, bathe themselves, or even turn over in bed without support. It’s not like measuring body temperature in a patient with endocarditis, or pCO2 in a patient with obstructive airway disease. But, we ARE able to confirm whether a patient requires support with ambulation. And we are able to determine if a patient needs help with daily tasks. Those are simple binary outcomes of neurologic function which are captured using the mRS. If you need help with daily activities, then your mRS is at least >2. If you need support with ambulation, your mRS is at least 4 or more. And it just so happens that the primary outcome for most stroke trials rests on the thresholds of 2 or 4. In this way, I would not consider these thresholds subject to “variable” interpretation between clinicians trained in the mRS. And it is certainly not unreliable when you are assigning these clearer thresholds.

    One other thing to recognize is that tPA is not a benign intervention. It carries a ~5% risk of symptomatic intracranial hemorrhage. (The author is correct here, there is an inconsistency among the clinical trialists regarding this definition. But they all state their definitions in the methods.) When I’m saying symptomatic ICH, I mean the patient sustains a hemorrhage that worsens a patient’s neurologic symptoms. IN SPITE OF THIS DECLINE, which kills some patients, there is still a statistically significant reduction in morbidity among tPA treated patients, mortality, and many other outcome measures (http://jamanetwork.com/journals/jama/fullarticle/1697967?tab=cme). So there remains a strong, positive signal favoring the use of tPA in spite of its risks. There is so much data supporting this in fact, The American Heart Association has assigned intravenous alteplase a Class I, Level of Evidence A recommendation for the treatment of acute stroke within 3 hours (Level of Evidence B for 3-4.5 hours).

    These are just my thoughts and I worry that critical–inaccurate?–reviews of the literature like this may actually threaten the lives of many stroke patients by discouraging EM physicians from utilizing this proven, life-saving therapy. It is easy for EM physicians to say they are concerned that tPA will risk symptomatic hemorrhage or won’t improve outcome because they don’t have to continue seeing these patients in follow up. But when I have to see patients time and time again in my clinic, patients who could have received IV tPA and didn’t, it breaks my heart.

    -jim

    • Justin Morgenstern July 11, 2017 at 12:33 am - Reply

      Thanks for taking the time to comment. There is definitely a lot to discuss here.

      You raise an interesting point about the use of language in evidence based medicine. It is true that the authors of negative trials frequently use the word “suggest” to try to indicate a potential trend. Although this is a common use of the word, I find it inappropriate because it tends to imply benefit from negative trials. It is true that NINDS2 and ECASS3 are positive trials, however they are positive trials that only suggest a benefit. There are a number of reasons for this distinction, which are all discussed at some length in the podcast, such as bias, conflict of interest, and the baseline imbalances between the groups. However, the real reason that I think the word “suggest” is appropriate here is simply science. A single trial does not prove benefit. We cover this when we discuss the meaning on the p values in the podcast. Science is based on replication. A single trial can only ever suggest the truth. Replication and attempts at disconfirmation are what build certainty.

      You raise the common point that these studies used different agents and different time frames. First of all, you can’t simply look retrospectively at trials that are positive and decide that they had they right methods. When the trials were started, the researchers thought that in each case their protocol would work. Cherry picking only certain trials after the fact introduces a systematic bias to the data. With regard to the agent being used, there is no difference between these agents in MI, and the most recent Cochrane review concludes that there is no evidence that tPa is superior to any of the other thrombolytics in stroke either. Similarly, as is discussed in the podcast, there is no convincing reason to think that the 0-3 hour time frame is what made NINDS2 positive.

      With regards to the subjectivity of the modified Rankin score, I can only point you to the literature on the topic. In the range of scores we care about most in these trials, it is highly subjective. Even trained neurologists disagree on the score of any given patient. (See Quinn 2009) This subjectivity is increased when the scoring is done over the phone or by mail, as is frequently the case in these trials.

      I agree with you that we should not be comparing the risk of intracranial hemorrhage against the potential benefits. The bad outcomes of hemorrhage are included in the global outcome score. However, there is no clear consistent benefit demonstrated in this literature. There are two positive trials, both with significant problems and risk of bias. There is a reasonable chance, based on this literature, that thrombolytics provide no benefit at all, in which case considering the significant harms demonstrated in these studies would be important.

      The AHA does list tPa as having level A evidence, but that is highly unusual. Level A usually means that there are consistent results across multiple high level studies. As this review highlights, that is clearly not the case when it comes to thrombolytics for stroke. The results are highly inconsistent and the quality of the studies is questionable. The AHA also has a well documented financial conflict of interest when it comes to this recommendation. Here is a reference for bias in guidelines that supports these points http://www.bmj.com/content/346/bmj.f3830.

      Finally, I think it is important to be careful with language. You refer to tPa as “life saving”. I hear it described this way to patients all the time. However, even if there is a real functional benefit, these trials clearly demonstrate no benefit in mortality. Using language like “life saving” confuses patients who are already in a stressful, high-stakes situation.

      I think the review in this podcast is reasonable. It is possible that thrombolytics provide a functional benefit for some patients, but the studies are inconsistent, biased, and conflicted. It is also possible that there is no net benefit, or even that there is harm. Perhaps there is a subgroup we have not yet identified who truly benefit. The point is, we simply don’t know. To call this treatment “level A” and “life saving” ignores those issues and prevents important research from being done that would benefit out patients. The conclusion is not that we shouldn’t be giving tPa, but simply that the science is questionable. It might help, but we can’t ignore the fact that there is also a possibility that we are harming patients. The most appropriate road forward is a replication of NINDS, which would be the usual scientific process when faced with questions like this.

      A lot of these points are discussed in a little more detail in my accompanying blog post: https://first10em.com/2017/05/26/thrombolytics-for-stoke/

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