To the Editor:
We read with great interest the article published in the October 2010 issue of Neurosurgery titled “Short-term Antifibrinolytic Therapy Before Early Aneurysm Treatment in Subarachnoid Hemorrhage: Effects on Rehemorrhage, Cerebral Ischemia, and Hydrocephalus.”1 In that article, the authors reported their experience with the use of an antifibrinolytic (AF), ϵ-aminocaproic acid, in the management of aneurysmal subarachnoid hemorrhage (SAH). As in 3 previous published articles, the particularity of this study was to use the AF treatment during a short period of time (always < 3 days) and along with nimodipine administration to prevent cerebral ischemia.2-4 The authors showed that use of the short-term AF treatment resulted in impressive findings, with a risk of rebleeding of 1.4% and a really low risk of ischemic brain injury of 3.1% proven with computed tomography scan.
It would have been interesting to know the functional outcome in this cohort of patients according to the modified Rankin Scale or Glasgow Outcome Scale. To assess the efficiency of AF therapy in SAH, we performed a systematic review (using only Pubmed) to identify previous studies that compared AF treatment with a control treatment and that evaluated the functional outcome at follow-up. We also compared their results with the results of studies that permitted Roos et al in a meta-analysis of randomized controlled trials to show that AF therapy used for a long period of time (often > 7 days) did not result in better functional outcome.5
We identified 5 studies, 2 that used AF therapy for a short time period3,4 and 3 that used AF therapy for a long-time period,6-8 and pooled their results using the Peto-fixed effect model and RevMan5.9 We compared the number of patients who presented with poor functional outcome at the end of follow-up (Glasgow Outcome Scale = 1, 2, or 3; modified Rankin Scale = 4, 5, or 6) in an AF therapy group (ϵ-aminocaproic acid or tranexamic acid) and in a control group with or without placebo.
Our results strongly suggest that AF therapy results in better functional outcome only when used for a short period (Figure). In the short-term AF treatment group, we noticed a nearly significantly benefit of AF therapy, with a decrease of the rate of poor outcome from 37.8% in the control group to 29% in the AF group (pooled odds ratio, 0.79; 95% confidence interval, 0.57-1.08). In the long-term AF therapy group, the effects appeared to be the opposite, which is consistent with Roos' results. Such findings were explained by a significant increase in cerebral ischemia in the AF group.
FIGURE. Forrest plot...Image Tools
Our results confirm the interest in the use of short-term AF therapy in the management of aneurysmal SAH as strongly suggested by Dr Harrigan and colleagues. Their findings clearly explained the results in terms of functional outcome: Short-term AF therapy avoids the occurrence of the disastrous early rebleeding without increasing the risk of cerebral ischemia as observed when used for a long-term period.
We agree with Dr Harrigan and colleagues that a new randomized controlled trial with an adapted power is strongly indicated. Until then, and in part thanks to this interesting article, we have decided to put in place a short-term AF therapy protocol for our patients suffering from aneurysmal SAH.
1. Harrigan MR, Rajneesh KF, Ardelt AA, Fisher WS III. Short-term antifibrinolytic therapy before early aneurysm treatment in subarachnoid hemorrhage: effects on rehemorrhage, cerebral ischemia, and hydrocephalus. Neurosurgery
2. Leipzig TJ, Redelman K, Horner TG. Reducing the risk of rebleeding before early aneurysm surgery: a possible role for antifibrinolytic therapy. J Neurosurg
3. Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg
4. Starke RM, Kim GH, Fernandez A. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke
5. Roos YB, Rinkel GJ, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage. Cochrane Database Syst Rev
6. Roos Y. Antifibrinolytic treatment in aneurysmal subarachnoid haemorrhage: a randomized placebo controlled trial for the STAR-study group. Neurology
7. Tsementzis SA, Hitchcock ER, Meyer CH. Benefits and risks of antifibrinolytic therapy in the management of ruptured intracranial aneurysms: a double-blind placebo-controlled study. Acta Neurochir (Wien)
8. Vermeulen M, Lindsay KW, Murray GD, et al. Antifibrinolytic treatment in subarachnoid hemorrhage. N Engl J Med
9. Review Manager (RevMan) [computer program]. Version 5.0. Copenhagen, Denmark: Nordic Cochrane Centre, Cochrane Collaboration; 2008.