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Date: November 6th , 2018

Reference: Sprigg et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018

Guest Skeptic: Dr. Robert Edmonds is an emergency physician in the US Air Force in Virginia. This is Bob’s eighth visit to the SGEM.

DISCLAIMER: The views and opinions of this podcast do not represent the United States Government or the US Air Force.

Case: Your next patient is a stroke alert for a 67-year-old male living at a nursing home presents with severe right sided upper and lower extremity weakness noticed one hour ago while eating a meal.  He obtains a stat head CT which shows an intracerebral hemorrhage.  In addition to controlling his elevated blood pressure, you wonder if there is more you can offer this patient to improve his outcome and odds of survival.  A resident points out that tranexamic acid (TXA) has been shown to decrease mortality for other hemorrhagic conditions, and questions if that could be helpful.

Background: Stroke due to intracerebral hemorrhage (ICH) comprises approximately 20% of all strokes, but about half of all stroke deaths worldwide.  Currently the only intervention known to adjust mortality in these cases is blood pressure management.

Lowering BP in ICH cases of was covered on SGEM#73: How Low Can You Go. The AHA Guidelines were updated since those episodes and recommend the following (Hemphill et al Stroke 2015):

  • For ICH patients presenting with SBP between 150 and 220 mmHg and without contraindication to acute BP treatment, acute lowering of SBP to 140 mmHg is safe (Class I; Level of Evidence A) and can be effective for improving functional outcome (Class IIa; Level of Evidence B). (Revised from the previous guideline)
  • For ICH patients presenting with SBP >220 mmHg, it may be reasonable to consider aggressive reduction of BP with a continuous intravenous infusion and frequent BP monitoring (Class IIb; Level of Evidence C). (New recommendation)

SGEM#172: Don’t Bring My Blood Pressure Down (Intensively) – The ATACH2 Trial did not support intensely lowing blood pressure. There was no statistical difference in death or disability between intensive blood pressure reduction (SBP 110-139 mm Hg) vs. standard blood pressure reduction (SBP 140-179 mm Hg) in patients with acute intracerebral hemorrhage.

TXA is a cheap drug that has been shown to improve mortality in trauma (CRASH-2), presumably due to its antifibrinolytic effect.

TXA has been discussed on the SGEM a number of times for epistaxis, trauma and post-partum hemorrhage:

  • SGEM#53: Sunday, Bloody Sunday (Epistaxis and Tranexamic Acid)
  • SGEM#80: CRASH-2 (Classic Paper)
  • SGEM#210: (Don’t) Let it Bleed – TXA for Epistaxis in Patients on Anti-Platelet Drugs
  • SGEM#214: Woman – The TXA Trial for Post-Partum Hemorrhage

Before this trial was started there were apparently only two small randomized control trials using TXA with a total of 54 patients. They provided no clear evidence for benefit or harm.

Clinical Question: Does administration of tranexamic acid reduce hematoma expansion and improve outcomes in adults with stroke due to intracerebral hemorrhage?

Reference: Sprigg et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018

  • Population: Adults with acute intracerebral hemorrhage admitted within eight hours of symptom onset.
    • Exclusion: Intracerebral haemorrhage secondary to anticoagulation, thrombolysis, trauma, or a known underlying structural abnormality; patients for whom TXA was thought to be contra-indicated; pre-stroke dependence (mRS score >4); life expectancy less than three months; and GCS score less than five. A complete list of exclusion criteria is available in previous publication.
  • Intervention: Administration of TXA, as a 1-gram loading dose in 100 ml normal saline (NS) over ten minutes, followed by another 1-gram in 250 ml NS over eight hours.
  • Comparison: Placebo-normal saline administered with an identical regimen.
  • Outcome:
    • Primary Outcome: Functional status at day 90 as assessed with the modified Rankin Scale (mRS).
    • Secondary Outcomes:
      • Neurological impairment at day seven or discharge (whichever came first)
      • Radiological efficacy (change in hematoma volume from baseline to 24 hours and hematoma location)
      • Health-related quality of life
      • Activities of daily living
      • Cognition and verbal fluency
      • Mood
      • Costs (length of hospital stay and discharge destination)

Authors’ Conclusions: “Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.

 Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Unsure
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They enrolled 2,325 patients into the trial. The mean age was 69 years old with 56% being male. The median time from stroke onset to randomization was 3.6 hours.

No difference in mRS at 90 days between those who received tranexamic acid and placebo.

  • Primary Outcome: Adjusted odds ratio 0.88 (95% CI 0.76-1.03, p=0.11)
  • Secondary Outcomes: There were no significant differences in any of the day 90 functional outcomes between treatment groups, including length of hospital stay and discharge disposition.
    • By day seven, fewer patients had died in the TXA group (9%) than placebo (11%, p=0.04)
    • Survival did not differ between groups over 90 days (adjusted hazard ratio 0.92, 95% CI 0.77-1.10, p=0.37)

1) Safety: Although the trial failed to show a benefit for patients, it did show a decrease in serious adverse events (day two 33% vs. 36%, p=0.0272; day seven 39% vs. 43%, p=0.0200; day 90 45% vs. 48% p=0.0393), which notably included no increase in VTE (3% both groups, p=0.98).  The authors point out how this study group was significantly older with more comorbidities than previous studies of TXA.  This suggests that if there is another condition this patient with a hemorrhagic stroke has, such as a trauma resulting from an MVC, it does not appear less safe merely because of the presence of the hemorrhagic CVA.

2) Modified Rankin Scale (mRS) Score: Previous study by Wilson et al 2005 has demonstrated substantial inter-rater reliability. In addition, these assessments were done by telephone interview and if could not be contacted were mailed a survey. This brings into question the accuracy of this primary outcome assessment.

3) Early Deaths: The study did show a reduction in early deaths by day seven. However, the difference disappeared by day 90.  There was no difference in length of hospital stay or discharge disposition, so its hard to say what these patient’s clinical course looked like.  The participants’ seven day NIHSS scores were the same between groups (10.13 vs. 10.29) so it suggests that administration of TXA did not result in a temporary improvement in functional status in the group of treatment patients that showed a delay in death, between day seven and 90.

4) Ordinal Analysis: Stroke outcomes using the mRS had traditionally used a dichotomous outcome. It was usually divided into a good neurologic outcome (0-1 or 0-2) or a poor neurologic outcome (2-6 or 3-6). Proponents of using an ordinal analysis argue more granularity can be found using an ordinal shift approach rather than using a dichotomous approach.  A problem with this is it assumes a uniformity of the treatment effect across the entirety of the scale. We have already mentioned the problem with inter-rater reliability. Expecting precision from the clinical uncertainty in stroke outcome measure is a problem. We can all agree on no disability (mRS 0) and death (mRS 6) but it becomes much more difficult to agree on the other ordinals. The way ordinal analysis can be used to manipulate conclusions can be seen in the IST-3 trial that was a negative trial for the primary outcome but was spun into a positive trial using a secondary ordinal analysis. We discussed this on SGEM#29. If you are interested in learning more about the issues with ordinal analysis check out Rory Spiegel’s post on EMNerd.

5) Hypothesis Generating: They discuss some of their subgroup analyses in the discussion. While these are interesting, they should not be overinterpreted. They also discuss that they may not have given TXA soon enough to show benefit. These should be viewed as hypothesis generating. If they want to answer these specific questions about certain subgroups and timing, they need to design a properly powered trial. Until that point all they can do is speculate.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion, especially with their assertion that additional studies are needed to confirm or refute a clinically significant treatment effect.  They did find a statistically significant reduction in early deaths by day seven, and larger trials could show this to be a true finding.

SGEM Bottom Line: TXA does not currently have evidence of improving outcomes in hemorrhagic stroke and routine administration cannot be recommended at this time.

Case Resolution: You manage the patient’s blood pressure and contact the appropriate specialists for admission to the intensive care unit.  You commend the resident for their thought process but inform them of this trial and that TXA did not show benefit, so you will not give it.

Dr. Robert Edmonds

Clinical Application: No change to my current management of a hemorrhagic stroke. However, if the stroke results in a significant trauma or other condition requiring TXA, this study may be used to justify giving TXA for the other condition, as there were no increased serious adverse events in this trial.

What Do I Tell My Patient?  We are going to do everything we can to control your blood pressure to help increase your chances of doing well. We’ll be talking with some other doctors that will be helping you while you stay in our hospital.

Keener Kontest: There was no winner last week. The correct answer the first factor Xa inhibitor was isolated from the salivary glands of the Mexican Leech Haementeria officinalis. 

Listen to the SGEM podcast on iTunes to hear this the new keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

 

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