Date:  24 March 2013

“Now everybody, Have you heard, If you’re in the game (of emergency medicine), Then the stroke’s the word, Don’t take no rhythm, Don’t take no style,  Gotta thirst for killin’, Grab your vial (of tPA) and stroke me, stroke me…”  Billy Squier The Stroke

Case Scenario: A 83-year-old woman arrives from home with right-sided weakness beginning four hours prior.  You diagnose acute ischemic CVA with no contra-indications to thrombolysis.

Question: Does thrombolysis given to acute ischemic CVA in <6hrs increase the proportion of people who are alive and independent at six months?

Background: Acute ischemic strokes represent the leading cause of disability in our society and the third most common cause of death. There have been many studies performed looking at thrombolysis for acute CVA. For a summary of the major tials check out Dr. David Newman’s Number Needed to Treat site. Another good review of the topic is a paper done by Dr. Chris Carpenter published in the Journal of Emergency Medicine.

When tPA was approved in the European Union it was restricted to 3 hrs and age less than 80 years old. A Cochrane review suggested that tPA might be beneficial up to 6hrs. Older people (>80) have been under represented in the previous tPA stroke trials. This set the basis for the study we will be talking about today. The IST-3 study was to establish the balance of benefits and harms of tPA in patients not meeting licence criteria (mainly older patients and up to 6 hrs).

Reference:  IST-3 Collaborative Group. 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

  • Population: Multi-centre, open-label, randomized control trial (n=3035)
  • Intervention: tPA 0.9mg/kg
  • Control: Placebo
  • Outcome: Alive/independent on OHS at 6 months

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Results: Total of 3035 patients (1515 treatment and 1520 control). 95% did not meet the European Union licence approved criteria. Over half (53% were >80 years old. Mean time to treatment was 4.2hrs.

No difference in alive/independent of activities of daily living (OHS 0-2)

  • Primary Outcome:
    • 37% tPA vs 35% control with adjusted OR 1.13 (95% CI; 0.95-1.35)
  • Harm:
    • Died at 7 days: 11% tPA vs 7% control with adjusted OR 1.6 (95% CI; 1.22-2.08)
    • Fatal or non-fatal ICH: 7% tPA vs 1% control with adjusted OR 6.94 (95%CI; 4.07-11.8)
    • Death 6 months: no difference 27% tPA vs 27% control
  • Secondary Outcome: significant difference in ordinal shift
    • common OR 1.27 (95%CI; 1.10-1.47)

Authors’ Conclusions: “For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.”

BEEM Comments: This was a pragmatic, multi-centre, randomized controlled, open-label trial. It sought to determine if older patients and patients treated <6hrs of CVA onset would benefit from tPA. The trial did not meet its target of 6,000 . The outcomes of patients >80yo were no different than those of younger patients. Also, patients treated with tPA >3hrs showed no significant benefit over those treated with placebo.

  • The quotation “The lady doth protest too much, methinks.” comes from Shakespeare‘s Hamlet, Act III, scene II, where it is spoken by Queen Gertrude, Hamlet’s mother. The phrase has come to mean that one can “insist so passionately about something not being true that people suspect the opposite of what one is saying.” Wikipedia

Limitations and EBM Issues: There were many limitations to the IST-3 study. It represents an excellent opportunity to discuss a number of evidence based medicine issues.

  1. Pragmatic trial

  2. Open Label/Allocation Concealment
  3. Only patients thought to benefit were included
  4. Missed their target of 6,000 patients by 50%
  5. After seven years they seemed to move the goal posts
  6. Another statistician was brought in to “persuade” them
  7. Big harm (death and bleeding)
  8. Came up with a secondary outcome which was significant
  9. Primary outcome showed NO DIFFERENCE
  10. Was reported as a positive study????

BEEM Bottom Line: Treatment with tPA in this study harmed (death) 1 in 25 early, the fatal and non-fatal bleed rate went up significantly and there was no benefit seen at six months in the primary outcome.

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Comments on IST-3 by other Experts:

Case Resolution: You discuss the options with the patient and their family. Given her age and the time now being over 4.5hrs you reach a shared decision not to use tPA.

Keener ContestLast weeks winner was Sam Brewer a PGY-4. He correctly identified that metoclopramide (Maxeran/Reglan) can cause extrapyramidal side effects like dystonia/tardive dyskinesia. The treatment for this feared reaction is diphenhydramine (Benadryl) or benztropine (Cogentin).

Be sure to listen to the podcast to hear this weeks Keener Kontest question. Email your answer to  TheSGEM@gmail.com. Use “Keener Kontest” in the subject line. First one to email me the correct answer wins.

Remember to be skeptical of anything you learn, even if you heard it on The Skeptics’ Guide to Emergency Medicine.