Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial Lancet 2019 Nov 9;394(10210):1713-1723.
P：29ヵ国175施設の、GCSが12以下または頭蓋内出血のある受傷後3時間以内の外傷性脳損傷(TBI)患者（n=12,737）
E：初回負荷量1gのトラネキサム酸を10分間で投与後、更に1gを8時間かけて持続点滴
C：プラセボ（0.9％生理食塩水、同様の方法で投与）
O：頭部外傷24時間以内の頭部外傷関連死、後遺症、合併症
こちらは2019年にLancetに掲載された、頭部外傷患者におけるトラネキサム酸の有用性の示した有名な論文です。CRASH-2に続いてまたもやトラネキサム酸投与の有用性が示されたことになります。外傷患者にはトラネキサム酸で間違いありませんね。（受傷から時間が経過している場合は除く）こちらも一読しておくべき論文です、特に救急外来最前線で戦ってくれている研修医の先生方にとっては。
CRASH-2 重症出血を伴う外傷患者に早期のトラネキサム酸投与は有用である
背景：トラネキサム酸は、外傷性頭蓋外出血の患者の外科的出血を減らし、死亡率を減らす。頭蓋内出血は、外傷性脳損傷(TBI)の後によく見られ、脳ヘルニアや死を引き起こす可能性がある。TBIにおけるトラネキサム酸の効果を評価することを目的とした。
方法：29ヶ国175施設での多施設２重盲検ランダム化比較試験である。Inclusion criteriaは受傷後3時間以内の頭部外傷患者でGCSは12以下の患者またはCTで頭蓋内出血を認めた患者で、Exclusion criteriaはGCS3または、両側対光反射消失重症非頭蓋内出血がある患者である。Primary outcomeは受傷後3時間以内の頭部外傷患者で28日以内の病院内での頭部関連外傷死とした。Secondary outcomeは受傷後24時間以内の頭部外傷関連死、後遺症、合併症とした。サンプル数は、α=0.01でPower90%で15%相対的死亡率減少を検出するために10000人を推定したが、Inclution criteriaを受傷後8時間以内から3時間以内に途中変更したことにより13000人に変更された。
結果：期間は2012年7月20日から2019年1月31日で12737人の頭部外傷患者が登録され、トラネキサム酸の投与群に6404人(50.3%)とプラセボ投与群に6331人(49.7)が割り付けられた。このうち受傷後3時間以内の患者は9202人(72.2%)だった。 Primary outcomeである受傷後3時間以内の頭部外傷患者の頭部外傷関連死の相対リスクは、それぞれ18.5%,19.8%(0.94［0.86-1.02］)であり有意差はなかった。GCS3または両側対光反射消失、重症非頭蓋内出血の患者を除外した場合の相対リスクは12.5%,14.0%(0.89［0.80-1.00］)で有意差なし。GCS9-15で中等度の頭部外傷患者に対するそれぞれの相対的リスクは0.78［0.64-0.95］)で有意差あり、重症では0.99［0.91-1.07］で有意差が示されなかった。中等度の頭部外傷患者では3時間以内の早期の治療が晩期での治療と比較すると早期治療が死亡率を改善させた（p＝0.005）のに対し、重症患者ではその差が見られなかった(p=0.73)。血管閉塞症の合併症はRR(0.98［0.74-1.28］)、痙攣は(1.09［0.90-1.33］)でどれも有意差はなかった。
Interpretation：トラネキサム酸がTBIの患者に安全であり、損傷から3時間以内の治療が頭部損傷に関連する死亡を減らすことを示した。 患者は受傷後早急にトラネキサム酸が投与されるべきである。
Background: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI.
Methods: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277).
Results: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]).
Interpretation: Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury.
Funding: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme).
コメント