The frequency of thrombotic events among adults given antifibrinolytic drugs for spontaneous bleeding: systematic review and meta-analysis of observational studies and randomized trials.
OBJECTIVE
The antifibrinolytic drug tranexamic acid (TXA) improves survival after trauma. Antifibrinolytic drugs may also improve outcome after spontaneous bleeding, so we conducted a systematic review of the frequency of thrombotic events associated with their use after spontaneous bleeding, to help design future randomized controlled trials.


METHODS
We sought trials or observational studies of ≥20 adults involving any antifibrinolytic drug (TXA, epsilonaminocaproic acid (EACA) or aprotinin) for spontaneous (non-traumatic, non-surgical/iatrogenic), non-heamophiliac bleeding. We searched the Cochrane Central Register of Controlled Trials, OVID Medline from 1966, EMBASE from 1980, and the bibliographies of relevant articles in October 2009. We meta-analysed proportions of patients with thrombotic events, using a random effects model.


RESULTS
We found 57 studies involving 5,049 patients, 3,616 (72%) of whom had spontaneous subarachnoid haemorrhage. 3,414 (68%) patients received TXA-based treatment and 1,635 (32%) received EACA. The frequencies of limb ischaemia and myocardial infarction were <1% for TXA and EACA. The frequency of deep vein thrombosis or pulmonary embolism was 1.9% (95% confidence interval (CI) 1.1 to 2.9) for TXA and 3.0% (95% CI 1.8 to 4.6) for EACA. The occurrence of cerebral infarction was restricted to studies of subarachnoid haemorrhage when compared to other indications, both for TXA (9.7% [95% CI 5.5 to 14.8] versus 0% [95% CI 0 to 0.5]) and for EACA (7.7% [95% CI 1.8 to 17.4] versus 0% [95% CI 0 to 2.1]).


CONCLUSIONS
Thrombotic events have occurred infrequently with antifibrinolytic drugs after spontaneous bleeding apart from subarachnoid haemorrhage, so further exploration of their safety and efficacy after spontaneous bleeding is justified in randomized trials.
Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, UK.
Jenny
J
Ross
Rustam
R
Al-Shahi Salman
D000328:Adult; D000368:Aged; D015119:Aminocaproic Acid / Q000009:adverse effects / Q000627:therapeutic use; D000933:Antifibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007611:Aprotinin / Q000009:adverse effects / Q000627:therapeutic use; D006470:Hemorrhage / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy; D013927:Thrombosis / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D014148:Tranexamic Acid / Q000009:adverse effects / Q000627:therapeutic use
D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid; D007611:Aprotinin; D015119:Aminocaproic Acid