Rebleeding after aSAH – TXA a way to go

Rebleeding after aSAH is a serious problem. Mortality increases in such a case up to 80% (1). Especially ultra-early rebleeding is underestimated (2). So it is reasonable to treat the bleeding. There are basically two methods to perform a definitive bleeding protection. One way to go is the endovascular approach by coiling the aneurysm. The open way done by neurosurgery is clipping the aneurysm.
The decision what way to go should by made in a dialogue between the treating specialities.
In an ideal scenario there would be no delay between diagnosing and treating the aneurysm. But that is not the path we are taking most of the time in a world of limited resources.
An answer is the very detailed guideline of the AHA/ASA for the management of aneursymal subarachnoid haemorrhage (3). They give three conservative recommendations to prevent rebleeding.

1. Between the time of aSAH symptom onset and aneurysm obliteration, blood pressure should be controlled with a titratable agent to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure (Class I; Level of Evidence B). (New recommendation)

2. The magnitude of blood pressure control to reduce the risk of rebleeding has not been established, but a decrease in systolic blood pressure to <160 mm Hg is reasonable (Class IIa; Level of Evidence C). (New recommendation) 

3. For patients with an unavoidable delay in obliteration of aneurysm, a significant risk of rebleeding, and no compelling medical contraindications, short-term (<72 hours) therapy with tranexamic acid or aminocaproic acid is reasonable to reduce the risk of early aneurysm rebleeding (Class IIa; Level of Evidence B). (Revised recommendation from previous guidelines)

Let us have a look at recommendation three. Antifibrinolytic therapies were tested during the last decades. After all they showed no benefit with the main complication of thromboembolic events. These studies had a maximum of 14d to include a patient to the first dose of TXA (tranexamic acid 4-9g/d) or EACA (epsilon aminocaproic acid 24g/d) and treated the patients up to 6 weeks. For a reduction of rebleeding events of about 50% they suffered for an increase of ischemic events by about 50%. So with no benefit at hand that kind of therapy was dimissed (9).
In 2002 Hillmann et. all. published a prospective randomised trial in which they administered TXA directly after diagnosing an aSAH. They gave 1g immediately and 1g each 6h until aneurysma occlusion or 72h. Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot (4). 254 patients received TXA and 251 placebo. The incidence of rebleeding was reduced from 10,8% to 2,4%. This result were repeated by Harrigan (5) and Starke (6). In the retrospective study ogf Harrigan is of note, three of the five rebleeds never received the drug before they bled.

For the future there is a randomized controlled trial (ULTRA) (7) in the Netherlands. They are looking for potential benefit in preventing rebleeding as well as preventing DINDs. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome. I await a positive result. Take a look at existing data and you know, it is just a problem of underpowered trials.

Baharoglu et. all. (8) published in September 2013 a chochrane report on TXA in which they not recommended the use in case of SAH. In the end they stated in contrast to the older cochrane report (9) that the ultra early giving of antifibrinolytics shows promise. In their point of view the current level of evidence is not sufficient to use it outside of clinical trials. this is what they actually do (7).

My personal opinion  goes alongside with the AHA/ASA guideline. Especially if you bled under PAH therapy TXA should be administered.

1. Ameen A, Illingworth R. Anti-fibrinolytic treatment in the pre-operative management of subarachnoid haemorrhage caused by ruptured intracranial aneurysm. Journal of Neurology, Neurosurgery & Psychiatry 1981;44:220-6.
2. Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R. Ultra-early rebleeding in spontaneous subarachnoid hemorrhage. J Neurosurg 1996;84:35-42.
3. Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke; a journal of cerebral circulation 2012;43:1711-37.
4. McCormack PL. Tranexamic Acid. Drugs 2012;72:585-617.
5. Harrigan MR, Rajneesh KF, Ardelt AA, Fisher III WS. Short-term antifibrinolytic therapy before early aneurysm treatment in subarachnoid hemorrhage: effects on rehemorrhage, cerebral ischemia, and hydrocephalus. Neurosurgery 2010;67:935-40.
6. Starke RM, Kim GH, Fernandez A, et al. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke; a journal of cerebral circulation 2008;39:2617-21.
7. Germans MR, Post R, Coert BA, Rinkel GJ, Vandertop WP, Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials 2013;14:143.
8. Baharoglu, M. I., Germans, M. R., Rinkel, G. J. E., Algra, A., Vermeulen, M., van Gijn, J., & YBWEM, R. (2013). Drugs for preventing blood clot dissolution (antifibrinolytic therapy) to reduce the occurrence of rebleeding in aneurysmal subarachnoid haemorrhage. Health.
9. Roos, Y. B., Rinkel, G. J., Vermeulen, M., Algra, A., & Van Gijn, J. (2003). Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev, 2.


Another failed neuroprotective agent – ALIAS part 2

Today i give a little review about ALBUMIN 25% as a neuroprotective agent in case of ischemic stroke. Ginsberg et. all. published in the LANCET NEUROLOGY a placebo controlled double blinded phase 3 trial  where they looked for a favourable outcome for the use of ALBUMIN in the early treatment of stroke. ALIAS part 1 showed a trend to a favourable outcome. So about 800 patients were enrolled. Patients in the verum group received 25% ALBUMIN (2g per kg/KG). Favourable outcome was defined as NIH-SS of 0 and 1 or/and mRS of 0 and 1 at 90 days. About 85% in both groups received thrombolysis. The investigation was stopped due to futility in september 2012. There was no outcome differ after 841 patients enrolled. During the early phase of the trial there was promissing data in favour of ALB treatment.
Pulmonary oedema was more common as well as intracerebral hemorrhage in the ALB group.
I personally exspected a different result. In the light of SAFE-TBI there could have been even a different result showing harm if using ALB.
So standard fluid for resus a patient with ischemic insult remains cristalloid. But i think that you have an option for ALB in selected cases.

SAFE-TBI, Cooper et all., J Neurotrauma. 2013 Apr 1;30(7):512-8. doi: 10.1089/neu.2012.2573. Epub 2013 Mar 21.
ALIAS part 1, Hill et all., Stroke. 2011 Jun;42(6):1621-5. doi: 10.1161/STROKEAHA.110.610980. Epub 2011 May 5.
ALIAS part 2, Ginsberg et all., Lancet Neurol. 2013 Sep 26. pii: S1474-4422(13)70223-0. doi: 10.1016/S1474-4422(13)70223-0. [Epub ahead of print]