SGEM#322: TXA for SAH – Won’t Stop Me Now

Date: March 11th, 2021 Guest Skeptic: Dr. Robert Edmonds is an emergency physician in the US Air Force in Ohio. DISCLAIMER: THE VIEWS AND OPINIONS OF THIS PODCAST DO NOT REPRESENT THE UNITED STATES GOVERNMENT OR THE US AIR FORCE. Reference: Post et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet 2021 Case: You’re working a busy evening shift in your community emergency department (ED) when a 58 year old female presents with a rapid onset terrible intensity headache.  She has no significant headache history and you are concerned for subarachnoid hemorrhage so you order a head CT which confirms your suspicions.  You page neurosurgery at the bigger ED in town, and while you wait for the page back, you wonder if giving tranexamic acid (TXA) could help improve the patient’s chances for a good outcome given its effects in other bleeding processes. Background: In the case presented, the woman would qualify using the Ottawa SAH Rule because of the rapid onset of an intense headache and her age. We have discussed the incredible work done by Dr. Jeff Perry and his group in the development of the Ottawa SAH Rule. Jeff was actually on the SGEM as the guest skeptic discussing this clinical decision instrument way back in 2013 (SGEM#48). The Ottawa SAH Rule is to be applied to alert patients older than 15 years of age with new severe non-traumatic headache reaching maximum intensity within one hour. It is not meant for patients with new neurologic deficits, previous aneurysms, SAH, brain tumor, or who have a history of recurrent headaches. This is defined as at least three or more episodes over the course of at least six months. Our SGEM Bottom Line eight years ago was that the Ottawa SAH “Tool” was not ready for prime time to rule out low risk patients from investigations. Fast forward to 2018 and the validation of the Ottawa SAH Rule by Dr. Perry and his group. The results of this prospective observational study were that the clinical decision instrument was 100% sensitive (missed no SAH patients) and 13.6% specific. Dr. Chris Carpenter The guest skeptic for SGEM#201 was Dr. Chris Carpenter, who literally wrote the book on diagnostic accuracy of clinical decision instruments in the ED with Dr. Jesse Pines. The SGEM bottom line from the episode was that the Ottawa SAH Rule needs external validation, a meaningful impact analysis performed, and patient acceptability of incorporating this rule into a shared decision-making instrument before being widely adopted. Dr. Perry did publish a prospective implementation of the Ottawa SAH Rule (Stroke 2019). This article was covered on the SGEM with EM Nerd Dr. Rory Spiegel. The results demonstrated that the Ottawa SAH Rule is highly sensitive (100%) but has very poor specificity (13%). It is unclear how it performs against unstructured clinical judgement or in non-urban tertiary care teaching hospitals (SGEM#283). Another issue the case brings up is whether a CT scan is good enough to rule out a SAH. The debate has historically been about whether or not you need to also get a lumbar puncture on these patients after a non-contrast CT head. Dr. Jeff Perry This brings us back to more work done by Jeff Perry. His team published a prospective cohort study that suggested if you got the CT scan done within six hours of headache onset, it was a third generation CT scanner, and it was read by a neuroradiologist, then you did not need to get an LP to rule out a SAH (BMJ 2011). There were some limitations to this observational study. Another study was done in the UK that tried to address this issue of LP post normal CT. This was covered on SGEM#134. It found that the NNTap (number needed to Tap) to diagnose one aneurysm not identified by CT scan was 250. The final issue the case identified was the use of TXA in treating patients with a SAH. We are skeptical given the previous review we did on the topic (SGEM#236). This was a structured critical review of the 2018 TICH trial published in the Lancet. The primary outcome showed no superiority of TXA compared to placebo for the mRS at 90 days. The SGEM bottom line was that TXA does not currently have evidence of improving outcomes in hemorrhagic stroke and routine administration cannot be recommended at this time. However, as good healthy skeptics our positions are tentative and will change when presented with convincing evidence. Just because TXA was not demonstrated to “work” in one RCT does not mean we can claim TXA does not work. The burden of proof is on those making the claim of efficacy. Patients deserve the best care, based on the best evidence. TXA has been discussed on the SGEM numerous times for treating a variety of conditions including: Trauma, isolated traumatic brain injury, gastrointestinal bleeding, post-partum hemorrhage and epistaxis.  Although some EM docs would like to believe TXA is one of the universal duct tapes of the ED, it has mixed results. Patients suffering an aneurysmal SAH are at risk of rebleeding, which could worsens their long term clinical outcome and chance of death.  A hypothesis raised in the previous Sprigg et al RCT was that perhaps by treating these people earlier with TXA they would have a patient-oriented benefit. Clinical Question: Does rapid administration of tranexamic acid in patients with CT confirmed SAH improve clinical outcome? Reference:  Post et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet 2021 Population: Adults 18 years and older with signs and symptoms for less than 24 hours indicating subarachnoid hemorrhage (SAH) AND who have a non-contrast CT confirming SAH. Exclusions: Perimesencephalic bleed in combination with a GSC score of 13–15, and without loss of consciousness directly after ictus or focal neurological deficit on admission; traumatic SAH; ongoing treatment for VTE (DVT/PE); a history of a hypercoagulability disorder; pregnancy; severe renal failure, or imminent death within 24 h. Intervention: TXA 1g IV bolus as soon as possible after a non-contrast CT proven diagnosis of SAH. This was followed by 1g infusion every 8 hours up to 24 hours (4g total) or until endovascular or surgical treatment, whichever came first. Comparison: Usual care Outcome: Primary Outcome: Neurologic outcome dichotomized to good (mRS of 0-3) or poor (mRS 4-6) at six months Secondary Outcomes: Excellent clinical outcome (mRS 0-2), ordinal shift of the mRS score, all-cause mortality (30 days and 6 months) and serious adverse events. Authors’ Conclusions: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Unsure The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Results: The cohort consisted of 955 patients with a mean age of 58 years and two-thirds were female. The median time from ictus to CT scan was 93 minutes and the median time from signs and symptoms suggestive of SAH and TXA was 185 minutes.  Key Result: No superiority of TXA compared to usual care for patients with a subarachnoid hemorrhage. Primary Outcome: Good clinical outcome (mRS 0-3) 60% TXA vs 64% control Adjusted Odds Ratio (aOR) 0.86 ( 95% CI; 0.66 to 1.12) Secondary Outcomes:  Excellent clinical outcome (mRS 0-2): 48% TXA vs 56% control, aOR 73 (95% CI; 0.57 to 0.95) Ordinal shift of the mRS: No statistical difference All-cause mortality at 30 days (22%) and 6 months (26%): No statistical difference Adverse events: No statistical difference 1. Open label: The patient, investigators, and clinicians treating the patient were ALL aware of the patient’s inclusion in the treatment arm of the trial. This opens the study to significant biases. It’s unknown why the authors elected to pursue an open label study instead of providing the control group with a placebo, as this would have reduced the chances for bias significantly. 2. Patient Selection: It was not stated in the methods section that these were ED patients but it is likely that they were from the ED. They also did not explicitly say the patients were recruited consecutively 24/7/365. Twenty patients allocated to the TXA group did not receive treatment with nine of the twenty for “unknown” reasons. Patients were also excluded on the subjective assessment that death was imminent within 24 hours. These factors could have introduced some selection bias into the cohort of included patients. 3. Subgroup Analysis: The authors state that their findings show that routine use of TXA in spontaneous SAH cannot be recommended. However, the fact that their secondary outcome of excellent clinical outcome (mRS 0-2) was worse in the TXA group by a statistically significant amount is concerning. We need to be careful not to over-interpret subgroup analyses.