Source: Long B, Gottlieb M. Tranexamic acid for aneurysmal subarachnoid hemorrhage. Academic Emergency Medicine. Published online April 5, 2022:acem.14482.
Study Population: 13 trials comprising 2888 patients diagnosed acutely with aneurysmal SAH and awaiting surgical management
Efficacy Endpoints: All-cause mortality, poor functional recovery, risk of rebleeding
Harm Endpoints: Adverse events
Narrative: Subarachnoid hemorrhage (SAH) is a deadly cerebrovascular emergency that accounts for approximately 5% of strokes.1 It most commonly is the result of a ruptured intracranial aneurysm, which releases blood into the subarachnoid space.2, 3 Rebleeding can occur in up to 20% of SAH cases, with the highest risk in the first 24 h following the initial hemorrhage,4, 5, 6, 7 suggesting interventions that reduce the risk of rebleeding may improve outcomes. Securing the culprit aneurysm is the most effective means, but immediate control may not be possible in all patients.8 Tranexamic acid (TXA) is an antifibrinolytic agent that inhibits the conversion of plasminogen to plasmin and has been studied for a variety of uses.9 While current evidence supports the early repair of aneurysmal SAH,8 there is no clear consensus on administration of TXA if rapid repair is not possible.10, 11, 12 The American Heart Association 2012 guidelines state that if there is an unavoidable delay in surgical treatment, risk of rebleeding, and no contraindications, short-term therapy with TXA or aminocaproic acid is reasonable to reduce risk of early rebleeding.13 Despite this recommendation use of TXA remains controversial in those with aneurysmal SAH.10, 11, 12
The systematic review summarized here included randomized controlled trials (RCTs) of patients diagnosed with SAH with suspected or confirmed ruptured aneurysm randomized to TXA or placebo.14 The primary outcome used to evaluate the efficacy of TXA included all-cause mortality at the end of follow-up. Causes of mortality included rebleeding, hydrocephalus, cerebral ischemia, extracranial causes, and any complication from an operation or anesthesia. Secondary outcomes included poor functional outcome and rebleeding risk. Poor functional outcomes were evaluated using the modified Rankin Scale (mRS ≥4) or Glasgow Outcome Scale (GOS ≤3). Rebleeding was defined as definite (e.g., imaging) or possible (e.g., sudden deterioration). Safety endpoints included serious adverse events defined as hydrocephalus, cerebral ischemia, or venous thromboembolism (VTE).
The systematic review included 13 RCTs (n = 2888 patients). Of the included patients, 1451 received TXA. Sample size ranged from 39 to 954. Twelve of the trials were conducted in Europe. Five were multicenter RCTs. Three trials were published after 2000, and the remainder were published prior to 2000. Initial dosing was 1 g intravenously in nine trials, followed by maintenance dosing. One study administered TXA orally.15 The duration of therapy for TXA ranged from <72 h to 6 weeks.
TXA had no significant effect on mortality compared with control treatment (risk ratio [RR]: 1.0; 95% confidence interval [CI]: 0.8–1.1; 12 trials, 2426 patients). Analysis based on treatment duration (≤3 days versus >3 days), follow up period, and long-term mortality (>90 days) also demonstrated no subgroup benefit with TXA. TXA had no significant effect on poor functional outcome (RR: 1.0; 95% CI: 0.9–1.2; 5 RCTs, 2491 patients). TXA reduced risk of rebleeding compared with control (RR: 0.6; 95% CI: 0.4–0.8; absolute risk reduction 8.7%; NNT 12; 12 RCTs, 2851 patients). Adverse events did not differ between those receiving TXA versus control, specifically cerebral ischemia (RR: 1.2; 95% CI: 1.0–1.5; 8 RCTs, 2646 patients), hydrocephalus (RR: 1.1; 95% CI: 1.0–1.2; 7 RCTs, 2180 patients), or deep venous thrombosis (RR: 1.2; 95% CI: 0.8–1.8; 7 RCTs, 2151 patients). Cerebral ischemia was the most common side effect and second most common cause of death.
Caveats: This systematic review has several limitations. Importantly, there was clinical heterogeneity among studies, including SAH severity and patient comorbidities. Some studies lacked blinding and allocation concealment, which may introduce bias, and the means of detecting SAH may have varied over time due to differences in sensitivity and availability of different imaging modalities, as 10 studies predated the year 2000. Current management including critical care interventions, intracranial pressure monitoring, and surgical care for patients with SAH has evolved over time and may not reflect the management performed at the time of these studies. Importantly, the meta-analysis was not restricted to only studies in which aneurysm repair was delayed. While several studies included patients in whom surgical treatment was delayed, several did not involve delayed surgery. In the largest and most recent study, treatment was not specifically delayed and occurred on average 14 h after diagnosis.12 The authors also did not separate out aneurysmal versus non-aneurysmal SAH when studies included mixed populations. Of note, it is unclear whether the meta-analysis authors evaluated subgroup data from the included trials. Additionally, there were differences in the administration of TXA by dose, route, and maintenance therapy. The duration of TXA treatment also varied significantly from <72 h to 6 weeks. Although adverse outcomes were not statistically significant between patients receiving TXA compared to placebo, it is possible there was not sufficient power to detect a difference. Given the potential impact of the major adverse events (e.g., cerebral ischemia, hydrocephalus, deep venous thrombosis), TXA should not be considered as having “no risk”. Finally, follow up period varied from 3 weeks to 43 months.
Based on the available evidence, while there was a clear reduction in the secondary outcome of rebleeding with TXA, there was no measurable clinical benefit, suggesting TXA does not benefit patients with SAH awaiting surgery. This seems even clearer in the three largest, most methodologically rigorous trials, which all demonstrated a clear lack of benefit in reducing all-cause mortality and poor functional outcome. Due to the heterogeneity of this evidence and absence of improved patient-oriented outcomes we have assigned a color recommendation of Red (No benefit) for use of TXA in patients with aneurysmal SAH.
The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.
Author: Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD
Published/Updated: May 3, 2022
The title bar is color-coded with our overall recommendation.