今日の臨床サポート

脳出血

著者: 大槻俊輔1) 近畿大学医学部附属病院

著者: 松本昌泰2) 市立池田病院 顧問/広島大学名誉教授・大阪大学招聘教授

監修: 内山真一郎 国際医療福祉大学臨床医学研究センター

著者校正/監修レビュー済:2021/11/10
参考ガイドライン:
患者向け説明資料

概要・推奨   

  1. 脳出血急性期の血圧は、できるだけ早期に収縮期血圧140mmHg未満に降下させ、7日間維持する(推奨度1収縮期降圧の下限を110mmHg超に維持することを考慮する(推奨度2急性腎疾患を回避するためには収縮期血圧降下幅が90mmHg以上の強化降圧療法勧められない(推奨度4
  1. 脳出血急性期に用いる降圧薬としては、カルシウム拮抗薬あるいは硝酸薬の微量点滴静注が勧められる(推奨度1)。カルシウム拮抗薬のうち、ニカルジピンを適切に用いた降圧療法を考慮する推奨度2)。可能であれば、早期に経口治療へ切り替える(推奨度2
  1. 通常の高血圧性脳出血急性期で血液凝固系に異常がない場合、血液凝固因子を含めた血液製剤の投与は行うべきではない(推奨度4。高血圧性脳出血であっても血小板や血液凝固系の異常を合併し出血傾向が認められる症例では、病態に応じて血小板、プロトロンビン複合体、新鮮凍結血漿などの血液製剤の投与を考慮する(推奨度2。脳出血急性期に対して抗プラスミン薬トラネキサム酸投与を考慮してもよい(推奨度2
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には ご契約が必要となります。閲覧にはご契 約が必要となります。 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約 が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
大槻俊輔 : 特に申告事項無し[2021年]
松本昌泰 : 未申告[2021年]
監修:内山真一郎 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 脳卒中治療ガイドライン2021に基づき、治療について改訂を行った。
  1. 脳出血急性期における高血圧に対して、できるだけ早期に収縮期血圧を140mmHg未満へ降圧し、7日間維持することは妥当である。ただし、降圧の下限を110mmHg以上に維持することを考慮する。またこの過剰な降圧による急性腎疾患を回避するために収縮期血圧を90mmHg以上の降圧は回避するべき、下限の追加となた。
  1. 抗血栓薬治療中の脳出血急性期における血液製剤・中和薬の投与に関しての推奨文の推奨度とエビデンスレベル修正されている。ワルファリン内服中でPT-INR値が2.0以上の場合プロトロンビン複合体の投与およびPT-INR再上昇を避けるのビタミンK併用、トロンビン阻害薬ダビガトラン内服中のイダルシズマブ投与、抗血小板薬内服中への一律な血小板輸血は行わないこと、未分画ヘパリン療法中の硫酸プロタミンの投与、血栓溶解療法中血液凝固異常の評価血液製剤による是正について記載された。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 頭蓋内出血の中の脳実質内出血を脳出血と呼ぶ。
  1. 脳出血は冬から春先の気温が低い季節に頻度が多くなる。また、活動時、特に早朝と夕方に救急搬送頻度が多い。
  1. 週内変動として男性は月曜日、女性は金曜日に頻度が多い。
  1. 急性発症かつ重症度が高いため、発症2時間以内に脳出血、くも膜下出血の半数は搬送される頻度が高い。
  1. COVID-19パンデミック時代では、ステイホームによる運動不足、肥満、塩分摂取やアルコール多飲、また降圧薬中断により、頭蓋内血腫が季節を問わずコンスタントに搬送されている。
 
脳内出血の疫学

  1. 毎年約7万人が発症
  1. 重症度(NIHSS中央値12 vsラクナ性3アテローム性5心原性10)
  1. 死亡率:16.3%(梗塞5.5%)
  1. 予後良好(mRankin Scale値2以下):34%
a:部位別頻度
b:発症の季節別頻度 脳梗塞は年間を通じて発生するが夏に多く、脳出血は冬から春先まで多い。
c:発症日内変動 早朝と夕刻に発症頻度が増す。
d:週間変動 男性は月曜日、女性は金曜日に多い。男性は仕事に出る曜日、女性は夫が週末に帰るためとストレスがかかるためであろうか。
e:発症2時間以内来院頻度 脳内出血、くも膜下出血、心原性脳塞栓症が多い。
f:退院時mRSスコア
 
参考文献:
小林祥泰編:脳卒中データバンク2015.中山書店、2015より作成

出典

img1:  著者提供
 
 
 
  1. 急性局所神経徴候を示す頭蓋内疾患の多くを脳卒中が占める。
  1. 脳卒中データバンク2015および日本脳卒中データバンク報告書2018年によると、出血性脳卒中が脳卒中全体の24.4%を占め、その81%が脳内出血である。脳卒中全体に占める脳出血割合は東日本では高く、関東18.7%、東北21.0%であった。一方、近畿19.4%、九州12.2%と西日本では低い。発症年齢は 男性平均67.3歳、女性平均73.3歳、東日本ではやや低く、西日本ではやや高かった。男女比は約6:4であった。
 
脳卒中の病型分類

脳卒中発症7日以内の病型分類を示す。脳梗塞は3つのサブタイプに分かれている。
 
参考文献:
小林祥泰編:脳卒中データバンク2015.中山書店、2015

出典

img1:  著者提供
 
 
 
脳出血の部位と頻度(脳卒中データバンク2015、17,723例より)

a:被殻出血(29%)b:視床出血(26%)c:皮質下出血(19%)d:橋・脳幹出血(9%)e:小脳出血(8%)

出典

img1:  著者提供
 
 
 
  1. 脳出血の原因はいずれの年齢でも高血圧性脳出血が一番多いが、50歳未満では脳動静脈奇形の割合が12%と高血圧性66%に次いで多くなる。出血の病態から、下記の2つの脳出血の種類を認める。
  1. 高血圧性脳内出血:
  1. 脳出血の82%を占める。
  1. 50歳以上の84%を占める。
  1. 高血圧を有し、または搬入時、高度の血圧上昇を示す。50歳以上の高血圧症例または高血圧性臓器障害(心臓肥大、腎機能障害や眼底変化)を認めた場合、典型的な被殻、視床、小脳歯状核、脳幹・橋正中部、皮質下の穿通枝動脈破綻 からの血腫であれば高血圧性と判断してよい。
 
高血圧性脳内出血の病態生理

血圧変動を吸収できる平滑筋を有する筋性主幹動脈から鋭角的に分布する、内皮やペリサイトからなる穿通枝動脈は高血圧の影響を受けやすい。脂肪硝子変性やフィブリノイド壊死を来して小動脈瘤を形成、閾値を超えた血圧値の時点で破綻して発症するとされている。

出典

 
被殻出血

  1. 意識障害
  1. 顔面を含んだ片麻痺、痙性のことが多い。
  1. 血腫と反対側をにらむ眼球共同偏視
  1. ときに失語や半側空間無視
a: CT
b: MRI 拡散強調画像
c: MRI FLAIR画像
d: MRI T2*画像
e: MRA
f~h: CT

出典

img1:  著者提供
 
 
 
視床出血

  1. 感覚優位の片麻痺
  1. 異常感覚・疼痛
  1. 意識障害
  1. 共同偏視(鼻をにらむ)
  1. 健忘・失語
  1. 半側空間無視
a:軽症例
b、c:重症例

出典

img1:  著者提供
 
 
 
橋出血

  1. 意識障害・昏睡
  1. 四肢麻痺
  1. pinpoint pupils
  1. ocular bobbing
  1. 眼球運動制限
a:軽症例
b:中等症例
c:重症例

出典

img1:  著者提供
 
 
 
小脳出血

  1. めまい・ふらつき
  1. 嘔気・嘔吐
  1. 意識障害
  1. 眼振や眼位の異常
  1. 体幹・四肢失調
  1. 断綴言語
a~c:軽症例
d~h:水頭症合併重症例

出典

img1:  著者提供
 
 
 
皮質下出血

  1. 意識障害・せん妄
  1. 同名半盲・視覚失認
  1. 失語
  1. 左右失認、手指失認、失計算、失読、失書
  1. 失行、失認
  1. 半側空間無視、左右同時刺激における左刺激の消去現象
  1. 運動保持障害、身体失認、身体所属感の消失

出典

img1:  著者提供
 
 
 
  1. 非高血圧性脳内出血:
  1. 50歳未満の34%を占め、50歳以上では16%である。高血圧の既往や治療歴がない場合が多い。
  1. 脳動静脈奇形(50歳未満で12%、50歳以上で1%の頻度)や脳動脈瘤、海綿状血管腫等の脳血管病変からの出血である。
  1. 転移性脳腫瘍からの出血:多発性の高吸収域、血腫サイズに不釣り合いの広範囲の浮腫が認められる場合、悪性腫瘍合併例では造影CTを追加し、脳転移からの出血を確認する。
  1. 血液凝固異常、血小板減少症、DIC、特に抗血栓療法中の頻度が増加している。
  1. 高齢者で高血圧を合併していない場合、アミロイド脳血管症による皮質下出血の可能性がある。診断は組織診断となるため、MRI T2*強調画像により脳葉中心に微小出血が多発している場合、臨床的に疑い診断となることが多い。
  1. 転帰:死亡率15%。予後良好(mRS≦2)は33%しかなく、心原性脳塞栓症同様一撃で転帰不良となるノックアウト型脳卒中である。
 
  1. 脳内出血の疫学:図<図表>
 
わが国における脳内出血 手術群と保存群との予後調査

参考文献:
小林祥泰編:脳卒中データバンク2015.中山書店、2015,p137 図3より一部改変

出典

img1:  著者提供
 
 
 
Modified Rankin Scale

出典

病歴・診察のポイント  
  1. 救急車内からの連絡で呼吸循環状態、意識レベル(Japan Coma Scale)、FAST(顔面麻痺[Face]・上肢の麻痺[Arm]、発語障害[Speech]、発症時間[Time])、共同偏視の有無や瞳孔径左右差を、患者の年齢・性別・氏名とともに確認して待機する(下記の初期症候を問診している)。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

詳しくはクリック
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: Andrew M Demchuk, Dar Dowlatshahi, David Rodriguez-Luna, Carlos A Molina, Yolanda Silva Blas, Imanuel Dzialowski, Adam Kobayashi, Jean-Martin Boulanger, Cheemun Lum, Gord Gubitz, Vasantha Padma, Jayanta Roy, Carlos S Kase, Jayme Kosior, Rohit Bhatia, Sarah Tymchuk, Suresh Subramaniam, David J Gladstone, Michael D Hill, Richard I Aviv, PREDICT/Sunnybrook ICH CTA study group
雑誌名: Lancet Neurol. 2012 Apr;11(4):307-14. doi: 10.1016/S1474-4422(12)70038-8. Epub 2012 Mar 8.
Abstract/Text BACKGROUND: In patients with intracerebral haemorrhage (ICH), early haemorrhage expansion affects clinical outcome. Haemostatic treatment reduces haematoma expansion, but fails to improve clinical outcomes in many patients. Proper selection of patients at high risk for haematoma expansion seems crucial to improve outcomes. In this study, we aimed to prospectively validate the CT-angiography (CTA) spot sign for prediction of haematoma expansion.
METHODS: PREDICT (predicting haematoma growth and outcome in intracerebral haemorrhage using contrast bolus CT) was a multicentre prospective observational cohort study. We recruited patients aged 18 years or older, with ICH smaller than 100 mL, and presenting at less than 6 h from symptom onset. Using two independent core laboratories, one neuroradiologist determined CTA spot-sign status, whereas another neurologist masked for clinical outcomes and imaging measured haematoma volumes by computerised planimetry. The primary outcome was haematoma expansion defined as absolute growth greater than 6 mL or a relative growth of more than 33% from initial CT to follow-up CT. We reported data using standard descriptive statistics stratified by the CTA spot sign. Mortality was assessed with Kaplan-Meier survival analysis.
FINDINGS: We enrolled 268 patients. Median time from symptom onset to baseline CT was 135 min (range 22-470), and time from onset to CTA was 159 min (32-475). 81 (30%) patients were spot-sign positive. The primary analysis included 228 patients, who had a follow-up CT before surgery or death. Median baseline ICH volume was 19·9 mL (1·5-80·9) in spot-sign-positive patients versus 10·0 mL (0·1-102·7) in spot-sign negative patients (p<0·001). Median ICH expansion was 8·6 mL (-9·3 to 121·7) for spot-sign positive patients and 0·4 mL (-11·7 to 98·3) for spot-negative patients (p<0·001). In those with haematoma expansion, the positive predictive value for the spot sign was61% (95% CI 47–73) for the positive predictive value and 78% (71–84) for the negative predictive value, with 51% (39–63) sensitivity and 85% (78–90) specificity[corrected]. Median 3-month modified Rankin Scale (mRS) was 5 in CTA spot-sign-positive patients, and 3 in spot-sign-negative patients (p<0·001). Mortality at 3 months was 43·4% (23 of 53) in CTA spot-sign positive versus 19·6% (31 of 158) in CTA spot-sign-negative patients (HR 2·4, 95% CI 1·4-4·0, p=0·002).
INTERPRETATION: These findings confirm previous single-centre studies showing that the CTA spot sign is a predictor of haematoma expansion. The spot sign is recommended as an entry criterion for future trials of haemostatic therapy in patients with acute ICH.
FUNDING: Canadian Stroke Consortium and NovoNordisk Canada.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22405630  Lancet Neurol. 2012 Apr;11(4):307-14. doi: 10.1016/S147・・・
著者: Gregoire Boulouis, Andrea Morotti, H Bart Brouwers, Andreas Charidimou, Michael J Jessel, Eitan Auriel, Octávio Pontes-Neto, Alison Ayres, Anastasia Vashkevich, Kristin M Schwab, Jonathan Rosand, Anand Viswanathan, Mahmut E Gurol, Steven M Greenberg, Joshua N Goldstein
雑誌名: JAMA Neurol. 2016 Aug 1;73(8):961-8. doi: 10.1001/jamaneurol.2016.1218.
Abstract/Text IMPORTANCE: Hematoma expansion is a potentially modifiable predictor of poor outcome following an acute intracerebral hemorrhage (ICH). The ability to identify patients with ICH who are likeliest to experience hematoma expansion and therefore likeliest to benefit from expansion-targeted treatments remains an unmet need. Hypodensities within an ICH detected by noncontrast computed tomography (NCCT) have been suggested as a predictor of hematoma expansion.
OBJECTIVE: To determine whether hypodense regions, irrespective of their specific patterns, are associated with hematoma expansion in patients with ICH.
DESIGN, SETTING, AND PARTICIPANTS: We analyzed a large cohort of 784 patients with ICH (the development cohort; 55.6% female), examined NCCT findings for any hypodensity, and replicated our findings on a different cohort of patients (the replication cohort; 52.7% female). Baseline and follow-up NCCT data from consecutive patients with ICH presenting to a tertiary care hospital between 1994 and 2015 were retrospectively analyzed. Data analyses were performed between December 2015 and January 2016.
MAIN OUTCOMES AND MEASURES: Hypodensities were analyzed by 2 independent blinded raters. The association between hypodensities and hematoma expansion (>6 cm3 or 33% of baseline volume) was determined by multivariable logistic regression after controlling for other variables associated with hematoma expansion in univariate analyses with P ≤ .10.
RESULTS: A total of 1029 patients were included in the analysis. In the development and replication cohorts, 222 of 784 patients (28.3%) and 99 of 245 patients (40.4%; 321 of 1029 patients [31.2%]), respectively, had NCCT scans that demonstrated hypodensities at baseline (κ = 0.87 for interrater reliability). In univariate analyses, hypodensities were associated with hematoma expansion (86 of 163 patients with hematoma expansion had hypodensities [52.8%], whereas 136 of 621 patients without hematoma expansion had hypodensities [21.9%]; P < .001). The association between hypodensities and hematoma expansion remained significant (odds ratio, 3.42 [95% CI, 2.21-5.31]; P < .001) in a multivariable model; other independent predictors of hematoma expansion were a CT angiography spot sign, a shorter time to CT, warfarin use, and older age. The independent predictive value of hypodensities was again demonstrated in the replication cohort (odds ratio, 4.37 [95% CI, 2.05-9.62]; P < .001).
CONCLUSION AND RELEVANCE: Hypodensities within an acute ICH detected on an NCCT scan may predict hematoma expansion, independent of other clinical and imaging predictors. This novel marker may help clarify the mechanism of hematoma expansion and serve as a useful addition to clinical algorithms for determining the risk of and treatment stratification for hematoma expansion.

PMID 27323314  JAMA Neurol. 2016 Aug 1;73(8):961-8. doi: 10.1001/jaman・・・
著者: Peter B Sporns, Michael Schwake, Rene Schmidt, André Kemmling, Jens Minnerup, Wolfram Schwindt, Christian Cnyrim, Tarek Zoubi, Walter Heindel, Thomas Niederstadt, Uta Hanning
雑誌名: Stroke. 2017 Jan;48(1):131-135. doi: 10.1161/STROKEAHA.116.014068. Epub 2016 Nov 22.
Abstract/Text BACKGROUND AND PURPOSE: Significant early hematoma growth in patients with intracerebral hemorrhage is an independent predictor of poor functional outcome. Recently, the novel blend sign (BS) has been introduced as a new imaging sign for predicting hematoma growth in noncontrast computed tomography. Another parameter predicting increasing hematoma size is the well-established spot sign (SS) visible in computed tomographic angiography. We, therefore, aimed to clarify the association between established SS and novel BS and their values predicting a secondary neurological deterioration.
METHODS: Retrospective study inclusion criteria were (1) spontaneous intracerebral hemorrhage confirmed on noncontrast computed tomography and (2) noncontrast computed tomography and computed tomographic angiography performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (secondary neurological deterioration versus no secondary deterioration). As secondary neurological deterioration, we defined (1) early hemicraniectomy under standardized criteria or (2) secondary decrease of Glasgow Coma Scale of >3 points, both within the first 48 hours after symptom onset.
RESULTS: Of 182 patients with spontaneous intracerebral hemorrhage, 37 (20.3%) presented with BS and 39 (21.4%) with SS. Of the 81 patients with secondary deterioration, 31 (38.3%) had BS and SS on admission. Multivariable logistic regression analysis identified hematoma volume (odds ratio, 1.07 per mL; P≤0.001), intraventricular hemorrhage (odds ratio, 3.08; P=0.008), and the presence of BS (odds ratio, 11.47; P≤0.001) as independent predictors of neurological deterioration.
CONCLUSIONS: The BS, which is obtainable in noncontrast computed tomography, shows a high correlation with the computed tomographic angiography SS and is a reliable predictor of secondary neurological deterioration after spontaneous intracerebral hemorrhage.

© 2016 American Heart Association, Inc.
PMID 27879447  Stroke. 2017 Jan;48(1):131-135. doi: 10.1161/STROKEAHA.・・・
著者: Qi Li, Gang Zhang, Xin Xiong, Xing-Chen Wang, Wen-Song Yang, Ke-Wei Li, Xiao Wei, Peng Xie
雑誌名: Stroke. 2016 Jul;47(7):1777-81. doi: 10.1161/STROKEAHA.116.013186. Epub 2016 May 12.
Abstract/Text BACKGROUND AND PURPOSE: Early hematoma growth is a devastating neurological complication after intracerebral hemorrhage. We aim to report and evaluate the usefulness of computed tomography (CT) black hole sign in predicting hematoma growth in patients with intracerebral hemorrhage.
METHODS: Patients with intracerebral hemorrhage were screened for the presence of CT black hole sign on admission head CT performed within 6 hours after onset of symptoms. The black hole sign was defined as hypoattenuatting area encapsulated within the hyperattenuating hematoma with a clearly defined border. The sensitivity, specificity, and positive and negative predictive values of CT black hole sign in predicting hematoma expansion were calculated. Logistic regression analyses were used to assess the presence of the black hole sign and early hematoma growth.
RESULTS: A total of 206 patients were enrolled. Black hole sign was found in 30 (14.6%) of 206 patients on the baseline CT scan. The black hole sign was more common in patients with hematoma growth (31.9%) than those without hematoma growth (5.8%; P<0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of back hole sign in predicting early hematoma growth were 31.9%, 94.1%, 73.3%, and 73.2%, respectively. The time-to-admission CT scan, baseline hematoma volume, and the presence of black hole sign on admission CT independently predict hematoma growth in multivariate model.
CONCLUSIONS: The CT black hole sign could be used as a simple and easy-to-use predictor for early hematoma growth in patients with intracerebral hemorrhage.

© 2016 American Heart Association, Inc.
PMID 27174523  Stroke. 2016 Jul;47(7):1777-81. doi: 10.1161/STROKEAHA.・・・
著者: Qi Li, Qing-Jun Liu, Wen-Song Yang, Xing-Chen Wang, Li-Bo Zhao, Xin Xiong, Rui Li, Du Cao, Dan Zhu, Xiao Wei, Peng Xie
雑誌名: Stroke. 2017 Nov;48(11):3019-3025. doi: 10.1161/STROKEAHA.117.017985. Epub 2017 Oct 10.
Abstract/Text BACKGROUND AND PURPOSE: The aim of the study was to investigate the usefulness of the computed tomography (CT) island sign for predicting early hematoma growth and poor functional outcome.
METHODS: We included patients with spontaneous intracerebral hemorrhage (ICH) who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016. Two readers independently assessed the presence of the island sign on the admission noncontrast CT scan. Multivariable logistic regression analysis was used to analyze the association between the presence of the island sign on noncontrast admission CT and early hematoma growth and functional outcome.
RESULTS: A total of 252 patients who met the inclusion criteria were analyzed. Among them, 41 (16.3%) patients had the island sign on baseline noncontrast CT scans. In addition, the island sign was observed in 38 of 85 patients (44.7%) with hematoma growth. Multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and the presence of the island sign on baseline CT scan independently predicted early hematoma growth. The sensitivity of the island sign for predicting hematoma expansion was 44.7%, specificity 98.2%, positive predictive value 92.7%, and negative predictive value 77.7%. After adjusting for the patients' age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, presence of subarachnoid hemorrhage, admission systolic blood pressure, baseline ICH volume, and infratentorial location, the presence of the island sign (odds ratio, 3.51; 95% confidence interval, 1.26-9.81; P=0.017) remained an independent predictor of poor outcome in patients with ICH.
CONCLUSIONS: The island sign is a reliable CT imaging marker that independently predicts hematoma expansion and poor outcome in patients with ICH. The noncontrast CT island sign may serve as a potential marker for therapeutic intervention.

© 2017 American Heart Association, Inc.
PMID 29018128  Stroke. 2017 Nov;48(11):3019-3025. doi: 10.1161/STROKEA・・・
著者: Craig S Anderson, Hisatomi Arima, Pablo Lavados, Laurent Billot, Maree L Hackett, Verónica V Olavarría, Paula Muñoz Venturelli, Alejandro Brunser, Bin Peng, Liying Cui, Lily Song, Kris Rogers, Sandy Middleton, Joyce Y Lim, Denise Forshaw, C Elizabeth Lightbody, Mark Woodward, Octavio Pontes-Neto, H Asita De Silva, Ruey-Tay Lin, Tsong-Hai Lee, Jeyaraj D Pandian, Gillian E Mead, Thompson Robinson, Caroline Watkins, HeadPoST Investigators and Coordinators
雑誌名: N Engl J Med. 2017 Jun 22;376(25):2437-2447. doi: 10.1056/NEJMoa1615715.
Abstract/Text BACKGROUND: The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion.
METHODS: In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death).
RESULTS: The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P=0.83). There were no significant between-group differences in the rates of serious adverse events, including pneumonia.
CONCLUSIONS: Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017 .).

PMID 28636854  N Engl J Med. 2017 Jun 22;376(25):2437-2447. doi: 10.10・・・
著者: Craig S Anderson, Emma Heeley, Yining Huang, Jiguang Wang, Christian Stapf, Candice Delcourt, Richard Lindley, Thompson Robinson, Pablo Lavados, Bruce Neal, Jun Hata, Hisatomi Arima, Mark Parsons, Yuechun Li, Jinchao Wang, Stephane Heritier, Qiang Li, Mark Woodward, R John Simes, Stephen M Davis, John Chalmers, INTERACT2 Investigators
雑誌名: N Engl J Med. 2013 Jun 20;368(25):2355-65. doi: 10.1056/NEJMoa1214609. Epub 2013 May 29.
Abstract/Text BACKGROUND: Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known.
METHODS: We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups.
RESULTS: Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.
CONCLUSIONS: In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

PMID 23713578  N Engl J Med. 2013 Jun 20;368(25):2355-65. doi: 10.1056・・・
著者: Masatoshi Koga, Kazunori Toyoda, Hiroshi Yamagami, Satoshi Okuda, Yasushi Okada, Kazumi Kimura, Yoshiaki Shiokawa, Jyoji Nakagawara, Eisuke Furui, Yasuhiro Hasegawa, Kazuomi Kario, Masato Osaki, Tetsuya Miyagi, Kaoru Endo, Kazuyuki Nagatsuka, Kazuo Minematsu, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement Study Investigators
雑誌名: J Hypertens. 2012 Dec;30(12):2357-64. doi: 10.1097/HJH.0b013e328359311b.
Abstract/Text OBJECTIVE: Optimal blood pressure (BP) control in acute intracerebral hemorrhage (ICH) remains controversial. We determined the effects of SBP lowering to 160 mmHg or more using intravenous nicardipine for acute ICH patients.
METHODS: This is a prospective, multicenter, observational study conducted in Japan, with the lack of control groups. Patients with supratentorial ICH within 3 h of onset, admission SBP 180 mmHg or more, Glasgow Coma Scale (GCS) 5 or more, and hematoma volume less than 60 ml were initially treated with intravenous nicardipine to maintain SBP between 120 and 160 mmHg with 24-h frequent BP monitoring. The primary endpoints were neurological deterioration within 72 h [GCS decrement ≥ 2 points or National Institutes of Health Stroke Scale (NIHSS) increment ≥ 4 points; estimated 90% confidence interval (CI) on the basis of previous studies: 15.2-25.9%] and serious adverse effects (SAE) to stopping intravenous nicardipine within 24 h (1.8-8.9%). The secondary endpoints included hematoma expansion more than 33% at 24 h (17.1-28.3%), modified Rankin Scale (mRS) 4 or more (54.5-67.9%) and death at 3 months (6.0-13.5%).
RESULTS: We enrolled 211 Japanese patients (81 women, 65.6 ± 12.0 years old). At baseline, BP was 201.8 ± 15.7/107.9 ± 15.0 mmHg. Median hematoma volume was 10.2 ml (interquartile range 5.6-19.2), and NIHSS score was 13 (8-17). Neurological deterioration was identified in 17 patients (8.1%), SAE in two (0.9%), hematoma expansion in 36 (17.1%), mRS 4 or more in 87 (41.2%), and death in four (1.9%). All the results were equal to or below the estimated lower 90% CI.
CONCLUSION: SBP lowering to 160 mmHg or less using nicardipine appears to be well tolerated and feasible for acute ICH.

PMID 22990355  J Hypertens. 2012 Dec;30(12):2357-64. doi: 10.1097/HJH.・・・
著者: Yuki Sakamoto, Masatoshi Koga, Hiroshi Yamagami, Satoshi Okuda, Yasushi Okada, Kazumi Kimura, Yoshiaki Shiokawa, Jyoji Nakagawara, Eisuke Furui, Yasuhiro Hasegawa, Kazuomi Kario, Shoji Arihiro, Shoichiro Sato, Junpei Kobayashi, Eijirou Tanaka, Kazuyuki Nagatsuka, Kazuo Minematsu, Kazunori Toyoda, SAMURAI Study Investigators
雑誌名: Stroke. 2013 Jul;44(7):1846-51. doi: 10.1161/STROKEAHA.113.001212. Epub 2013 May 23.
Abstract/Text BACKGROUND AND PURPOSE: Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known.
METHODS: Hyperacute (<3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) >180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points' decrease in Glasgow Coma Score or ≥4 points' increase in National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin Scale score 4-6 at 3 months) were assessed with multivariate logistic regression analyses.
RESULTS: Of the 211 patients (81 women, median age 65 [interquartile range, 58-74] years, and median initial National Institutes of Health Stroke Scale score 13 [8-17]) enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03-9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09-3.16), and unfavorable outcome (2.03; 1.24-3.33) after adjusting for known predictive factors.
CONCLUSIONS: High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.

PMID 23704107  Stroke. 2013 Jul;44(7):1846-51. doi: 10.1161/STROKEAHA.・・・
著者: Adnan I Qureshi, Yuko Y Palesch, William G Barsan, Daniel F Hanley, Chung Y Hsu, Renee L Martin, Claudia S Moy, Robert Silbergleit, Thorsten Steiner, Jose I Suarez, Kazunori Toyoda, Yongjun Wang, Haruko Yamamoto, Byung-Woo Yoon, ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network
雑誌名: N Engl J Med. 2016 Sep 15;375(11):1033-43. doi: 10.1056/NEJMoa1603460. Epub 2016 Jun 8.
Abstract/Text BACKGROUND: Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage.
METHODS: We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments.
RESULTS: Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002).
CONCLUSIONS: The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).

PMID 27276234  N Engl J Med. 2016 Sep 15;375(11):1033-43. doi: 10.1056・・・
著者: Tom J Moullaali, Xia Wang, Reneé H Martin, Virginia B Shipes, Thompson G Robinson, John Chalmers, Jose I Suarez, Adnan I Qureshi, Yuko Y Palesch, Craig S Anderson
雑誌名: Lancet Neurol. 2019 Sep;18(9):857-864. doi: 10.1016/S1474-4422(19)30196-6.
Abstract/Text BACKGROUND: Uncertainty persists over the effects of blood pressure lowering in acute intracerebral haemorrhage. We aimed to combine individual patient-level data from the two largest randomised controlled trials of blood pressure lowering strategies in patients with acute intracerebral haemorrhage to determine the strength of associations between key measures of systolic blood pressure control and safety and efficacy outcomes.
METHODS: We did a preplanned pooled analysis of individual patient-level data acquired from the main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) and the second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. These trials included adult patients aged 19-99 years with spontaneous (non-traumatic) intracerebral haemorrhage and elevated systolic blood pressure, without a clear indication or contraindication to treatment. Patients were excluded if they had a structural cerebral cause for the intracerebral haemorrhage, had a low score (3-5) on the Glasgow Coma Scale, or required immediate neurosurgery. Our primary analysis assessed the independent associations between three post-randomisation systolic blood pressure summary measures-magnitude of reduction in 1 h, mean achieved systolic blood pressure, and variability in systolic blood pressure between 1 h and 24 h-and the primary outcome of functional status, as defined by the distribution of scores on the modified Rankin Scale at 90 days post-randomisation. We analysed the systolic blood pressure measures as continuous variables using generalised linear mixed models, adjusted for baseline covariables and trial. The primary and safety analyses were done in a modified intention-to-treat population, which only included patients with sufficient data on systolic blood pressure.
FINDINGS: 3829 patients (mean age 63·1 years [SD 12·9], 1429 [37%] women, and 2490 [65%] Asian ethnicity) were randomly assigned in INTERACT2 and ATACH-II, with a median neurological impairment defined by scores on the National Institutes of Health Stroke Scale of 11 (IQR 6-16) and median time from the onset of symptoms of intracerebral haemorrhage to randomisation of 3·6 h (2·7-4·4). We excluded 20 patients with insufficient or no systolic blood pressure data, and we imputed missing systolic blood pressure data in 23 (1%) of the remaining 3809 patients. Overall, the mean magnitude of early systolic blood pressure reduction was 29 mm Hg (SD 22), and subsequent mean systolic blood pressure achieved was 147 mm Hg (15) and variability in systolic blood pressure was 14 mm Hg (8). Achieved systolic blood pressure was continuously associated with functional status (improvement per 10 mm Hg increase adjusted odds ratio [OR] 0·90 [95% CI 0·87-0·94], p<0·0001). Symptomatic hypotension occurred in 28 (1%) patients, renal serious adverse events occurred in 26 (1%) patients, and cardiac serious adverse events occurred in 99 (3%) patients.
INTERPRETATION: Our pooled analyses indicate that achieving early and stable systolic blood pressure seems to be safe and associated with favourable outcomes in patients with acute intracerebral haemorrhage of predominantly mild-to-moderate severity.
FUNDING: None.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31397290  Lancet Neurol. 2019 Sep;18(9):857-864. doi: 10.1016/S14・・・
著者: Simona Lattanzi, Claudia Cagnetti, Leandro Provinciali, Mauro Silvestrini
雑誌名: Cerebrovasc Dis. 2017;43(5-6):207-213. doi: 10.1159/000462986. Epub 2017 Feb 28.
Abstract/Text BACKGROUND: The optimal treatment of high blood pressure (BP) after acute intra-cerebral hemorrhage (ICH) is controversial.
SUMMARY: The aim of the study was to evaluate the safety and efficacy of early intensive vs. conservative BP lowering treatment in patients with ICH. Randomized controlled trials with active and control groups receiving intensive and conservative BP lowering treatments were identified. The following outcomes were assessed: 3-month mortality and combined death or major disability, 24-h hematoma growth, early neurological deterioration, occurrence of hypotension, severe hypotension, and serious treatment-emergent adverse events. Five trials were included involving 4,350 participants, 2,162 and 2,188 for intensive and conservative treatment groups, respectively. The pooled risk ratio of 3-month death or major disability was 0.96 (0.91-1.01) and the weighted mean difference in absolute hematoma growth was -1.53 (95% CI -2.94 to -0.12) mL in the intensive compared to conservative BP-lowering. There were no differences across the treatments in the incidence rates of 3-month mortality, early neurological deterioration, hypotension, and treatment-related adverse effects other than renal events. Key Messages: The early intensive anti-hypertensive treatment was overall safe and reduced the hematoma expansion in patients presenting with acute-onset spontaneous ICH and high BP levels.

© 2017 S. Karger AG, Basel.
PMID 28241129  Cerebrovasc Dis. 2017;43(5-6):207-213. doi: 10.1159/000・・・
著者: Gregoire Boulouis, Andrea Morotti, Joshua N Goldstein, Andreas Charidimou
雑誌名: J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):339-345. doi: 10.1136/jnnp-2016-315346. Epub 2017 Feb 18.
Abstract/Text INTRODUCTION: It is unclear whether intensive lowering of blood pressure (BP) at the acute phase of intracerebral haemorrhage (ICH) is beneficial. We performed a meta-analysis of randomised controlled trials (RCTs) to assess whether intensive BP lowering in patients with acute ICH is safe and effective in improving clinical outcomes.
METHODS: We searched PubMed, EMBASE and the Cochrane databases for relevant RCTs and calculated pooled OR for 3-month mortality (safety outcome) and 3-month death or dependency (modified Rankin Scale (mRs) ≥3;efficacy outcome), in patients with acute ICH randomised to either intensive BP-lowering or standard BP-lowering treatment protocols. We also investigated the association between treatment arm and ICH expansion at 24 hours. Random effects models with DerSimonian-Laird weights were used.
RESULTS: Five eligible studies including 4360 patients with acute ICH were pooled in meta-analysis. The risk of 3-month mortality was similar between patients randomised to intensive BP-lowering treatment and standard BP-lowering treatment (OR: 0.99; 95% CI: 0.82 to 1.20, p=0.909). Intensive BP-lowering treatment showed a (non-significant) trend for an association with lower 3-month death or dependency risk compared with standard treatment (OR: 0.91; 95% CI: 0.80 to 1.02), p=0.106). Intensive BP reduction was associated with a trend for lower risk of significant ICH expansion compared with standard treatment (OR: 0.82; 95% CI: 0.68 to 1.00, p=0.056), especially in larger RCTs.
CONCLUSIONS: For patients with acute ICH similar to those included in RCTs and without contraindication to acute BP treatment, intensive acute BP lowering is safe, but does not seem to provide an incremental clinical benefit in terms of functional outcomes. The effect of intensive BP lowering on significant haematoma expansion at 24 hours warrants further investigation.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) [year]. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28214798  J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):339-345. ・・・
著者: Magdy Selim, Lydia D Foster, Claudia S Moy, Guohua Xi, Michael D Hill, Lewis B Morgenstern, Steven M Greenberg, Michael L James, Vineeta Singh, Wayne M Clark, Casey Norton, Yuko Y Palesch, Sharon D Yeatts, i-DEF Investigators
雑誌名: Lancet Neurol. 2019 May;18(5):428-438. doi: 10.1016/S1474-4422(19)30069-9. Epub 2019 Mar 18.
Abstract/Text BACKGROUND: Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.
METHODS: We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.
FINDINGS: We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.
INTERPRETATION: Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile.
FUNDING: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30898550  Lancet Neurol. 2019 May;18(5):428-438. doi: 10.1016/S14・・・
著者: Lewis B Morgenstern, J Claude Hemphill, Craig Anderson, Kyra Becker, Joseph P Broderick, E Sander Connolly, Steven M Greenberg, James N Huang, R Loch MacDonald, Steven R Messé, Pamela H Mitchell, Magdy Selim, Rafael J Tamargo, American Heart Association Stroke Council and Council on Cardiovascular Nursing
雑誌名: Stroke. 2010 Sep;41(9):2108-29. doi: 10.1161/STR.0b013e3181ec611b. Epub 2010 Jul 22.
Abstract/Text PURPOSE: The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.
METHODS: A formal literature search of MEDLINE was performed. Data were synthesized with the use of evidence tables. Writing committee members met by teleconference to discuss data-derived recommendations. The American Heart Association Stroke Council's Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statements Oversight Committee and Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years' time.
RESULTS: Evidence-based guidelines are presented for the care of patients presenting with intracerebral hemorrhage. The focus was subdivided into diagnosis, hemostasis, blood pressure management, inpatient and nursing management, preventing medical comorbidities, surgical treatment, outcome prediction, rehabilitation, prevention of recurrence, and future considerations.
CONCLUSIONS: Intracerebral hemorrhage is a serious medical condition for which outcome can be impacted by early, aggressive care. The guidelines offer a framework for goal-directed treatment of the patient with intracerebral hemorrhage.

PMID 20651276  Stroke. 2010 Sep;41(9):2108-29. doi: 10.1161/STR.0b013e・・・
著者: Nikola Sprigg, Katie Flaherty, Jason P Appleton, Rustam Al-Shahi Salman, Daniel Bereczki, Maia Beridze, Hanne Christensen, Alfonso Ciccone, Ronan Collins, Anna Czlonkowska, Robert A Dineen, Lelia Duley, Juan Jose Egea-Guerrero, Timothy J England, Kailash Krishnan, Ann Charlotte Laska, Zhe Kang Law, Serefnur Ozturk, Stuart J Pocock, Ian Roberts, Thompson G Robinson, Christine Roffe, David Seiffge, Polly Scutt, Jegan Thanabalan, David Werring, David Whynes, Philip M Bath, TICH-2 Investigators
雑誌名: Lancet. 2018 May 26;391(10135):2107-2115. doi: 10.1016/S0140-6736(18)31033-X. Epub 2018 May 16.
Abstract/Text BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.
METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.
FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).
INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.
FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 29778325  Lancet. 2018 May 26;391(10135):2107-2115. doi: 10.1016/・・・
著者: Stephan A Mayer, Nikolai C Brun, Kamilla Begtrup, Joseph Broderick, Stephen Davis, Michael N Diringer, Brett E Skolnick, Thorsten Steiner, Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators
雑誌名: N Engl J Med. 2005 Feb 24;352(8):777-85. doi: 10.1056/NEJMoa042991.
Abstract/Text BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke and is associated with high mortality. Among patients who undergo computed tomography (CT) within three hours after the onset of intracerebral hemorrhage, one third have an increase in the volume of the hematoma related to subsequent bleeding. We sought to determine whether recombinant activated factor VII (rFVIIa) can reduce hematoma growth after intracerebral hemorrhage.
METHODS: We randomly assigned 399 patients with intracerebral hemorrhage diagnosed by CT within three hours after onset to receive placebo (96 patients) or 40 microg of rFVIIa per kilogram of body weight (108 patients), 80 microg per kilogram (92 patients), or 160 microg per kilogram (103 patients) within one hour after the baseline scan. The primary outcome measure was the percent change in the volume of the intracerebral hemorrhage at 24 hours. Clinical outcomes were assessed at 90 days.
RESULTS: Hematoma volume increased more in the placebo group than in the rFVIIa groups. The mean increase was 29 percent in the placebo group, as compared with 16 percent, 14 percent, and 11 percent in the groups given 40 microg, 80 microg, and 160 microg of rFVIIa per kilogram, respectively (P=0.01 for the comparison of the three rFVIIa groups with the placebo group). Growth in the volume of intracerebral hemorrhage was reduced by 3.3 ml, 4.5 ml, and 5.8 ml in the three treatment groups, as compared with that in the placebo group (P=0.01). Sixty-nine percent of placebo-treated patients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), as compared with 55 percent, 49 percent, and 54 percent of the patients who were given 40, 80, and 160 microg of rFVIIa, respectively (P=0.004 for the comparison of the three rFVIIa groups with the placebo group). Mortality at 90 days was 29 percent for patients who received placebo, as compared with 18 percent in the three rFVIIa groups combined (P=0.02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7 percent of rFVIIa-treated patients, as compared with 2 percent of those given placebo (P=0.12).
CONCLUSIONS: Treatment with rFVIIa within four hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days, despite a small increase in the frequency of thromboembolic adverse events.

Copyright 2005 Massachusetts Medical Society.
PMID 15728810  N Engl J Med. 2005 Feb 24;352(8):777-85. doi: 10.1056/N・・・
著者: Stephan A Mayer, Nikolai C Brun, Kamilla Begtrup, Joseph Broderick, Stephen Davis, Michael N Diringer, Brett E Skolnick, Thorsten Steiner, FAST Trial Investigators
雑誌名: N Engl J Med. 2008 May 15;358(20):2127-37. doi: 10.1056/NEJMoa0707534.
Abstract/Text BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes.
METHODS: We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke.
RESULTS: Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 microg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04).
CONCLUSIONS: Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov].).

Copyright 2008 Massachusetts Medical Society.
PMID 18480205  N Engl J Med. 2008 May 15;358(20):2127-37. doi: 10.1056・・・
著者: David J Gladstone, Richard I Aviv, Andrew M Demchuk, Michael D Hill, Kevin E Thorpe, Jane C Khoury, Heidi J Sucharew, Fahad Al-Ajlan, Ken Butcher, Dar Dowlatshahi, Gord Gubitz, Stephanie De Masi, Judith Hall, David Gregg, Muhammad Mamdani, Michel Shamy, Richard H Swartz, C Martin Del Campo, Brett Cucchiara, Peter Panagos, Joshua N Goldstein, Janice Carrozzella, Edward C Jauch, Joseph P Broderick, Matthew L Flaherty, SPOTLIGHT and STOP-IT Investigators and Coordinators
雑誌名: JAMA Neurol. 2019 Aug 19;. doi: 10.1001/jamaneurol.2019.2636. Epub 2019 Aug 19.
Abstract/Text Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy.
Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH.
Design, Setting, and Participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017.
Interventions: Eligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset.
Main Outcomes and Measures: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial.
Results: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60).
Conclusions and Relevance: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes.
Trial Registration: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.

PMID 31424491  JAMA Neurol. 2019 Aug 19;. doi: 10.1001/jamaneurol.2019・・・
著者: Kazumichi Yoshida, Jun C Takahashi, Yohei Takenobu, Norihiro Suzuki, Akira Ogawa, Susumu Miyamoto
雑誌名: Stroke. 2017 Feb;48(2):276-282. doi: 10.1161/STROKEAHA.116.014406. Epub 2016 Dec 27.
Abstract/Text BACKGROUND AND PURPOSE: The incidence and cause of strokes associated with pregnancy and the puerperium are still not fully understood. The aim of this study was to characterize pregnancy-related strokes in Japan using a large-scale survey with current imaging techniques.
METHODS: A retrospective analysis was conducted based on clinical chart reviews in 736 stroke teaching hospitals certified by the Japan Stroke Society between 2012 and 2013, using a web-based questionnaire requesting the detailed clinical course without any personally identifying information. The collection rate of this questionnaire was 70.5%, with 151 pregnancy-associated strokes extracted.
RESULTS: Hemorrhagic strokes were observed in 111 cases (73.5%), ischemic strokes in 37 (24.5%), and mixed type in 3 cases (2.0%). The estimated incidence of pregnancy-associated stroke was 10.2 per 100 000 deliveries. Major causes of hemorrhage were aneurysm (19.8%), arteriovenous malformation (17.1%), pregnancy-induced hypertension (11.7%), and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) (8.1%). Preexisting cerebrovascular diseases responsible for hemorrhage were detected in 59 cases (53.1%). Among the ischemic strokes, 28 (75.7%) were arterial and 9 (24.3%) were venous infarctions. The most frequent cause of arterial infarctions was reversible cerebral vasoconstriction syndrome. Hemorrhagic stroke showed much poorer prognosis than ischemic stroke.
CONCLUSIONS: The incidence of pregnancy-associated stroke in Japan did not seem higher than that in other Asian and Western countries. The proportion of hemorrhagic stroke among Japanese women was much higher than that in white women. Preexisting cerebrovascular diseases and reversible cerebral vasoconstriction syndrome play a key role in hemorrhagic and ischemic stroke, respectively.

© 2016 American Heart Association, Inc.
PMID 28028148  Stroke. 2017 Feb;48(2):276-282. doi: 10.1161/STROKEAHA.・・・
著者: Jun C Takahashi, Koji Iihara, Akira Ishii, Eiju Watanabe, Tomoaki Ikeda, Susumu Miyamoto
雑誌名: J Stroke Cerebrovasc Dis. 2014 Feb;23(2):e65-71. doi: 10.1016/j.jstrokecerebrovasdis.2013.08.017. Epub 2013 Nov 13.
Abstract/Text BACKGROUND: Pregnancy-associated hemorrhagic stroke is considered a serious complication. Although coagulopathy, pregnancy-induced hypertension, eclampsia, and other systemic complications have been emphasized, pre-existing cerebrovascular diseases (CVDs) have not been fully analyzed. To clarify the role of these vascular lesions more in detail, the Japan Neurosurgical Society conducted a nationwide survey on all the neurosurgical institutes across Japan.
METHODS: This 2-year survey focused on hemorrhagic stroke occurring in pregnancy, delivery, and puerperium. Clinical data based on retrospective chart review were obtained through a questionnaire and analyzed according to the time of onset, underlying CVDs, obstetric systemic complications, therapeutic approaches, and maternal and neonatal prognoses.
RESULTS: The survey identified 97 hemorrhagic strokes that were associated with pregnancy. Baseline CVDs responsible for hemorrhage were detected in 54 cases (55.7%), among which 47 lesions (87.0%) had been undiagnosed before stroke onset. The detection rate of baseline CVDs before the 32nd week of gestation was significantly higher than that after the 32nd week (90.0% versus 53.3%, P = .0017). Arteriovenous malformations (AVMs) were the most frequent CVDs causing intracranial hemorrhage, occurring at 1.8 times the frequency of ruptured aneurysms during pregnancy. Poor outcomes, including 10 deaths, were seen in 36.1% of the cases despite aggressive treatment.
CONCLUSION: Pregnancy-associated hemorrhagic strokes frequently concealed baseline CVDs, especially when they occurred before the 32nd week of gestation. AVMs were the predominant bleeding source. For appropriate treatment, therefore, close examination for cerebral vascular lesions is essential when a pregnancy-associated hemorrhagic stroke is encountered.

Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.
PMID 24239197  J Stroke Cerebrovasc Dis. 2014 Feb;23(2):e65-71. doi: 1・・・
著者: Rustam Al-Shahi Salman, Joseph Frantzias, Robert J Lee, Patrick D Lyden, Thomas W K Battey, Alison M Ayres, Joshua N Goldstein, Stephan A Mayer, Thorsten Steiner, Xia Wang, Hisatomi Arima, Hitoshi Hasegawa, Makoto Oishi, Daniel A Godoy, Luca Masotti, Dar Dowlatshahi, David Rodriguez-Luna, Carlos A Molina, Dong-Kyu Jang, Antonio Davalos, José Castillo, Xiaoying Yao, Jan Claassen, Bastian Volbers, Seiji Kazui, Yasushi Okada, Shigeru Fujimoto, Kazunori Toyoda, Qi Li, Jane Khoury, Pilar Delgado, José Álvarez Sabín, Mar Hernández-Guillamon, Luis Prats-Sánchez, Chunyan Cai, Mahesh P Kate, Rebecca McCourt, Chitra Venkatasubramanian, Michael N Diringer, Yukio Ikeda, Hans Worthmann, Wendy C Ziai, Christopher D d'Esterre, Richard I Aviv, Peter Raab, Yasuo Murai, Allyson R Zazulia, Kenneth S Butcher, Seyed Mohammad Seyedsaadat, James C Grotta, Joan Martí-Fàbregas, Joan Montaner, Joseph Broderick, Haruko Yamamoto, Dimitre Staykov, E Sander Connolly, Magdy Selim, Rogelio Leira, Byung Hoo Moon, Andrew M Demchuk, Mario Di Napoli, Yukihiko Fujii, Craig S Anderson, Jonathan Rosand, VISTA-ICH Collaboration, ICH Growth Individual Patient Data Meta-analysis Collaborators
雑誌名: Lancet Neurol. 2018 Oct;17(10):885-894. doi: 10.1016/S1474-4422(18)30253-9. Epub 2018 Aug 14.
Abstract/Text BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07).
INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
FUNDING: UK Medical Research Council and British Heart Foundation.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 30120039  Lancet Neurol. 2018 Oct;17(10):885-894. doi: 10.1016/S1・・・
著者: Thorsten Steiner, Sven Poli, Martin Griebe, Johannes Hüsing, Jacek Hajda, Anja Freiberger, Martin Bendszus, Julian Bösel, Hanne Christensen, Christian Dohmen, Michael Hennerici, Jennifer Kollmer, Henning Stetefeld, Katja E Wartenberg, Christian Weimar, Werner Hacke, Roland Veltkamp
雑誌名: Lancet Neurol. 2016 May;15(6):566-73. doi: 10.1016/S1474-4422(16)00110-1. Epub 2016 Apr 11.
Abstract/Text BACKGROUND: Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH.
METHODS: We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915.
FINDINGS: Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7-197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism).
INTERPRETATION: In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA.
FUNDING: Octapharma.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27302126  Lancet Neurol. 2016 May;15(6):566-73. doi: 10.1016/S147・・・
著者: Charles V Pollack, Paul A Reilly, John Eikelboom, Stephan Glund, Peter Verhamme, Richard A Bernstein, Robert Dubiel, Menno V Huisman, Elaine M Hylek, Pieter W Kamphuisen, Jörg Kreuzer, Jerrold H Levy, Frank W Sellke, Joachim Stangier, Thorsten Steiner, Bushi Wang, Chak-Wah Kam, Jeffrey I Weitz
雑誌名: N Engl J Med. 2015 Aug 6;373(6):511-20. doi: 10.1056/NEJMoa1502000. Epub 2015 Jun 22.
Abstract/Text BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran.
METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis.
RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.
CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).

PMID 26095746  N Engl J Med. 2015 Aug 6;373(6):511-20. doi: 10.1056/NE・・・
著者: Stuart J Connolly, Mark Crowther, John W Eikelboom, C Michael Gibson, John T Curnutte, John H Lawrence, Patrick Yue, Michele D Bronson, Genmin Lu, Pamela B Conley, Peter Verhamme, Jeannot Schmidt, Saskia Middeldorp, Alexander T Cohen, Jan Beyer-Westendorf, Pierre Albaladejo, Jose Lopez-Sendon, Andrew M Demchuk, Daniel J Pallin, Mauricio Concha, Shelly Goodman, Janet Leeds, Sonia Souza, Deborah M Siegal, Elena Zotova, Brandi Meeks, Sadia Ahmad, Juliet Nakamya, Truman J Milling, ANNEXA-4 Investigators
雑誌名: N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051. Epub 2019 Feb 7.
Abstract/Text BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).
RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.
CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Copyright © 2019 Massachusetts Medical Society.
PMID 30730782  N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.105・・・
著者: Hanne Christensen, Charlotte Cordonnier, Janika Kõrv, Avtar Lal, Christian Ovesen, Jan C Purrucker, Danilo Toni, Thorsten Steiner
雑誌名: Eur Stroke J. 2019 Dec;4(4):294-306. doi: 10.1177/2396987319849763. Epub 2019 May 14.
Abstract/Text The aim of the present European Stroke Organisation guideline document is to provide clinically useful evidence-based recommendation on reversal of anticoagulant activity VKA (warfarin, phenprocoumon and acenocoumarol), direct factor II (thrombin) inhibitors (dabigatran etexilat) and factor-Xa-inhibitors (apixaban, edoxaban and rivaroxaban) in patients with acute intracerebral haemorrhage. The guideline was prepared following the Standard Operational Procedure for a European Stroke Organisation guideline document and according to GRADE methodology. As a basic principle, we defined use of oral anticoagulation pragmatically: oral anticoagulation use is assumed by positive medical history unless relevant anticoagulant activity is regarded unlikely by medical history or has been ruled out by laboratory testing. Overall, we strongly recommend using prothrombin complex over no treatment and fresh-frozen plasma in patients on VKA plus vitamin K. We further strongly recommend using idarucizumab in patients on dabigatran and make a recommendation for andexanet alfa in patients on rivaroxaban and apixaban over no treatment. We make a weak recommendation on using high-dose prothrombin complex concentrate (50 IU/kg) for all patients taking edoxaban and for patients on rivaroxaban or apixaban in case andexanet alfa is not available. We recommend against using tranexamic acid and rFVIIa, outside of trials. The presented treatment recommendations aim to normalise coagulation, there is no or only indirect data on effects on functional outcome or mortality, and only little data from randomised controlled trials.

© European Stroke Organisation 2019.
PMID 31903428  Eur Stroke J. 2019 Dec;4(4):294-306. doi: 10.1177/23969・・・
著者: Joji B Kuramatsu, Stefan T Gerner, Peter D Schellinger, Jörg Glahn, Matthias Endres, Jan Sobesky, Julia Flechsenhar, Hermann Neugebauer, Eric Jüttler, Armin Grau, Frederick Palm, Joachim Röther, Peter Michels, Gerhard F Hamann, Joachim Hüwel, Georg Hagemann, Beatrice Barber, Christoph Terborg, Frank Trostdorf, Hansjörg Bäzner, Aletta Roth, Johannes Wöhrle, Moritz Keller, Michael Schwarz, Gernot Reimann, Jens Volkmann, Wolfgang Müllges, Peter Kraft, Joseph Classen, Carsten Hobohm, Markus Horn, Angelika Milewski, Heinz Reichmann, Hauke Schneider, Eik Schimmel, Gereon R Fink, Christian Dohmen, Henning Stetefeld, Otto Witte, Albrecht Günther, Tobias Neumann-Haefelin, Andras E Racs, Martin Nueckel, Frank Erbguth, Stephan P Kloska, Arnd Dörfler, Martin Köhrmann, Stefan Schwab, Hagen B Huttner
雑誌名: JAMA. 2015 Feb 24;313(8):824-36. doi: 10.1001/jama.2015.0846.
Abstract/Text IMPORTANCE: Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).
OBJECTIVE: To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.
EXPOSURES: Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.
MAIN OUTCOMES AND MEASURES: Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.
RESULTS: Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).
CONCLUSIONS AND RELEVANCE: Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01829581.

PMID 25710659  JAMA. 2015 Feb 24;313(8):824-36. doi: 10.1001/jama.2015・・・
著者: M Irem Baharoglu, Charlotte Cordonnier, Rustam Al-Shahi Salman, Koen de Gans, Maria M Koopman, Anneke Brand, Charles B Majoie, Ludo F Beenen, Henk A Marquering, Marinus Vermeulen, Paul J Nederkoorn, Rob J de Haan, Yvo B Roos, PATCH Investigators
雑誌名: Lancet. 2016 Jun 25;387(10038):2605-13. doi: 10.1016/S0140-6736(16)30392-0. Epub 2016 May 10.
Abstract/Text BACKGROUND: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use.
METHODS: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed.
FINDINGS: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay.
INTERPRETATION: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice.
FUNDING: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27178479  Lancet. 2016 Jun 25;387(10038):2605-13. doi: 10.1016/S0・・・
著者: Elena Haapaniemi, Daniel Strbian, Costanza Rossi, Jukka Putaala, Tuulia Sipi, Satu Mustanoja, Tiina Sairanen, Sami Curtze, Jarno Satopää, Reina Roivainen, Markku Kaste, Charlotte Cordonnier, Turgut Tatlisumak, Atte Meretoja
雑誌名: Stroke. 2014 Jul;45(7):1971-6. doi: 10.1161/STROKEAHA.114.004686. Epub 2014 May 29.
Abstract/Text BACKGROUND AND PURPOSE: Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients.
METHODS: Retrospective analysis of the observational Helsinki ICH Study (n=993; median follow-up, 2.7 years) and the Lille Prognosis of InTra-Cerebral Hemorrhage (n=325; 2.2 years) cohorts of consecutive ICH patients admitted between 2004 and 2010. Helsinki ICH Study patients' province-wide electronic records were evaluated for early seizures occurring within 7 days of ICH and among 7-day survivors (n=764) for late seizures (LSs) occurring >7 days from ICH. A Cox regression model estimating risk of LSs was used to derive a prognostic score, validated in the Prognosis of InTra-Cerebral Hemorrhage cohort.
RESULTS: Of the Helsinki ICH Study patients, 109 (11.0%) had early seizures within 7 days of ICH. Among the 7-day survivors, 70 (9.2%) patients developed LSs. The cumulative risk of LSs was 7.1%, 10.0%, 10.2%, 11.0%, and 11.8% at 1 to 5 years after ICH, respectively. We created the CAVE score (0-4 points) to estimate the risk of LSs, with 1 point for each of cortical involvement, age<65 years, volume>10 mL, and early seizures within 7 days of ICH. The risk of LSs was 0.6%, 3.6%, 9.8%, 34.8%, and 46.2% for CAVE scores 0 to 4, respectively. The c-statistic was 0.81 (0.76-0.86) and 0.69 (0.59-0.78) in the validation cohort.
CONCLUSIONS: One in 10 patients will develop seizures after ICH. The risk of this adverse outcome can be estimated by a simple score based on baseline variables.

© 2014 American Heart Association, Inc.
PMID 24876089  Stroke. 2014 Jul;45(7):1971-6. doi: 10.1161/STROKEAHA.1・・・
著者: Masayo Fukuhara, Hisatomi Arima, Toshiharu Ninomiya, Jun Hata, Koji Yonemoto, Yasufumi Doi, Yoichiro Hirakawa, Kiyoshi Matsumura, Takanari Kitazono, Yutaka Kiyohara
雑誌名: J Hypertens. 2012 May;30(5):893-900. doi: 10.1097/HJH.0b013e328351d380.
Abstract/Text OBJECTIVES: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) defined blood pressure (BP) levels of 120-139/80-89  mmHg as prehypertension. The objective of the present analysis was to examine the impact of prehypertension and its population-attributable fraction for development of cardiovascular events in a general Japanese population.
METHODS: Two thousand, six hundred and thirty-four residents of the town of Hisayama aged at least 40 years without cardiovascular disease were followed up for 19 years. BP categories were defined using JNC7, and prehypertension was divided into the lower (120-129/80-84  mmHg) and higher ranges (130-139/85-89  mmHg). During the follow-up period, 449 participants developed cardiovascular disease (305 strokes and 187 coronary heart diseases).
RESULTS: The frequencies of normal BP, prehypertension, and stages 1 and 2 hypertension were 24.9, 37.7, 23.8, and 13.6%, respectively. The age and sex-adjusted incidence of cardiovascular disease rose progressively with elevation of BP levels (P < 0.001 for trend). The risks of cardiovascular disease in lower and higher ranges of prehypertension were 58% [95% confidence interval (CI) 11-126%] and 70% (95% CI 18-144%) higher than normal BP even after controlling for other cardiovascular risk factors. The population-attributable fraction of prehypertension was 13.2%, which was similar to those of stages 1 and 2 hypertension.
CONCLUSIONS: The risks of cardiovascular disease increased significantly from the lower range of prehypertension in a general Japanese population. Approximately one-third of excess cardiovascular events attributable to elevated BP levels were estimated to occur among individuals with prehypertension.

PMID 22388232  J Hypertens. 2012 May;30(5):893-900. doi: 10.1097/HJH.0・・・
著者: Naoyuki Takashima, Takayoshi Ohkubo, Katsuyuki Miura, Tomonori Okamura, Yoshitaka Murakami, Akira Fujiyoshi, Shin-Ya Nagasawa, Aya Kadota, Yoshikuni Kita, Naoko Miyagawa, Takashi Hisamatsu, Takehito Hayakawa, Akira Okayama, Hirotsugu Ueshima, NIPPON DATA80 Research Group
雑誌名: J Hypertens. 2012 Dec;30(12):2299-306. doi: 10.1097/HJH.0b013e328359a9f7.
Abstract/Text OBJECTIVE: In Western populations, blood pressure (BP) measured at baseline has been reported to predict long-term (over 20 years) risk of mortality from cardiovascular diseases (CVDs). However, corresponding evidence is scarce in Asia where stroke is dominant. We investigated the association between baseline BP and 24-year mortality risk due to CVD, in a representative Japanese general population.
METHODS: We followed up a nationwide sample of 8592 Japanese, aged 30 years or above without a history of CVD and antihypertensive medication at baseline, for 24 years. Hazard ratios for CVD mortality in BP categories defined according to JCN7 criteria were estimated using Cox model adjusted for potential confounding factors with normal BP treated as the reference category.
RESULTS: We observed 689 CVD deaths. Hazard ratios for CVD mortality were progressively and significantly increased from the category of prehypertension. Population-attributable fraction (PAF) demonstrated that 43 and 48% of CVD and stroke deaths were explained by non-normal BP at baseline. Hazard ratios and PAF were remarkably higher in younger participants (aged 30-59 years) than those in the elderly (aged 60 years or above). Particularly, in younger men, 81% of CVD deaths were explained by non-normal BP. In sensitivity analysis, participants with antihypertensive medication showed the highest hazard ratio for CVD morality compared with the other categories.
CONCLUSIONS: BP levels above normal at baseline retained significant relative and absolute risks of CVD and stroke mortality during 24 years. Long-lasting burden of non-normal BP particularly in younger individuals suggests the importance of primary prevention of high BP from younger generation.

PMID 23079682  J Hypertens. 2012 Dec;30(12):2299-306. doi: 10.1097/HJH・・・
著者: Hisatomi Arima, Yumihiro Tanizaki, Koji Yonemoto, Yasufumi Doi, Toshiharu Ninomiya, Jun Hata, Masayo Fukuhara, Kiyoshi Matsumura, Mitsuo Iida, Yutaka Kiyohara
雑誌名: J Hypertens. 2009 Dec;27(12):2437-43. doi: 10.1097/HJH.0b013e328330e882.
Abstract/Text OBJECTIVE: Clinical uncertainty remains whether the blood pressure classification and risk stratifications recommended by the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009) are useful in predicting the risks of stroke and its subtypes in the general Japanese population.
METHODS: A total of 1621 stroke-free residents of a Japanese community aged at least 40 years were followed up for 32 years. Outcomes were total and cause-specific stroke (lacunar infarction, atherothrombotic infarction, cardioembolic infarction, cerebral haemorrhage and subarachnoid haemorrhage). Incidence was calculated by the pooling of repeated observations method.
RESULTS: The age-adjusted incidence of total stroke rose progressively with higher blood pressure levels in both sexes (both P for trend <0.0001). A similar pattern was observed for lacunar infarction in both sexes and for cerebral haemorrhage in men: the differences were significant between optimal blood pressure and grades 1-3 hypertension (all P < 0.05). The age-adjusted incidence of atherothrombotic infarction in either sex and that of cardioembolic infarction and subarachnoid haemorrhage in women significantly increased in grade 3 hypertension (all P < 0.05). These associations remained substantially unchanged even after adjustment for other risk factors. In regard to risk stratification, the age-adjusted incidence of stroke significantly increased with the level of risk in both sexes.
CONCLUSION: Our findings suggest that the blood pressure classification and risk stratifications recommended by the JSH 2009 guidelines are useful in predicting the risk of stroke in a general Japanese population, but the magnitude and patterns of the impact of blood pressure categories are different among stroke subtypes.

PMID 19657282  J Hypertens. 2009 Dec;27(12):2437-43. doi: 10.1097/HJH.・・・
著者: M R Law, J K Morris, N J Wald
雑誌名: BMJ. 2009 May 19;338:b1665. Epub 2009 May 19.
Abstract/Text OBJECTIVES: To determine the quantitative efficacy of different classes of blood pressure lowering drugs in preventing coronary heart disease (CHD) and stroke, and who should receive treatment.
DESIGN: Meta-analysis. Data source Medline (1966-2007).
STUDY SELECTION: Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) ("blood pressure difference trials"), and 46 trials compared drugs ("drug comparison trials"). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people.
PARTICIPANTS: 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke.
RESULTS: In the blood pressure difference trials beta blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs. The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of beta blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the meta-analyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective beta blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%).
CONCLUSIONS: With the exception of the extra protective effect of beta blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.

PMID 19454737  BMJ. 2009 May 19;338:b1665. Epub 2009 May 19.
著者: Alessandro Biffi, Christopher D Anderson, Thomas W K Battey, Alison M Ayres, Steven M Greenberg, Anand Viswanathan, Jonathan Rosand
雑誌名: JAMA. 2015 Sep 1;314(9):904-12. doi: 10.1001/jama.2015.10082.
Abstract/Text IMPORTANCE: Intracerebral hemorrhage (ICH) is the most severe form of stroke. Survivors are at high risk of recurrence, death, and worsening functional disability.
OBJECTIVE: To investigate the association between blood pressure (BP) after index ICH and risk of recurrent ICH.
DESIGN, SETTING, AND PARTICIPANTS: Single-site, tertiary care referral center observational study of 1145 of 2197 consecutive patients with ICH presenting from July 1994 to December 2013. A total of 1145 patients with ICH survived at least 90 days and were followed up through December 2013 (median follow-up of 36.8 months [minimum, 9.8 months]).
EXPOSURES: Blood pressure measurements at 3, 6, 9, and 12 months, and every 6 months thereafter, obtained from medical personnel (inpatient hospital or outpatient clinic medical or nursing staff) or via patient self-report. Exposure was characterized in 3 ways: (1) recorded systolic and diastolic measurements; (2) classification as adequate or inadequate BP control based on American Heart Association/American Stroke Association recommendations; and (3) stage of hypertension based on Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 criteria.
MAIN OUTCOMES AND MEASURES: Recurrent ICH and its location within the brain (lobar vs nonlobar).
RESULTS: There were 102 recurrent ICH events among 505 survivors of lobar ICH and 44 recurrent ICH events among 640 survivors of nonlobar ICH. During follow-up adequate BP control was achieved on at least 1 measurement by 625 patients (54.6% of total [range, 49.2%-58.7%]) and consistently (ie, at all available time points) by 495 patients (43.2% of total [range, 34.5%-51.0%]). The event rate for lobar ICH was 84 per 1000 person-years among patients with inadequate BP control compared with 49 per 1000 person-years among patients with adequate BP control. For nonlobar ICH the event rate was 52 per 1000 person-years with inadequate BP control compared with 27 per 1000 person-years for patients with adequate BP control. In analyses modeling BP control as a time-varying variable, inadequate BP control was associated with higher risk of recurrence of both lobar ICH (hazard ratio [HR], 3.53 [95% CI, 1.65-7.54]) and nonlobar ICH (HR, 4.23 [95% CI, 1.02-17.52]). Systolic BP during follow-up was associated with increased risk of both lobar ICH recurrence (HR, 1.33 per 10-mm Hg increase [95% CI, 1.02-1.76]) and nonlobar ICH recurrence (HR, 1.54 [95% CI, 1.03-2.30]). Diastolic BP was associated with increased risk of nonlobar ICH recurrence (HR, 1.21 per 10-mm Hg increase [95% CI, 1.01-1.47]) but not with lobar ICH recurrence (HR, 1.36 [95% CI, 0.90-2.10]).
CONCLUSIONS AND RELEVANCE: In this observational single-center cohort study of ICH survivors, reported BP measurements suggesting inadequate BP control during follow-up were associated with higher risk of both lobar and nonlobar ICH recurrence. These data suggest that randomized clinical trials are needed to address the benefits and risks of stricter BP control in ICH survivors.

PMID 26325559  JAMA. 2015 Sep 1;314(9):904-12. doi: 10.1001/jama.2015.・・・
著者: James S McKinney, William J Kostis
雑誌名: Stroke. 2012 Aug;43(8):2149-56. doi: 10.1161/STROKEAHA.112.655894. Epub 2012 May 15.
Abstract/Text BACKGROUND AND PURPOSE: Statin therapy decreases the risk of ischemic stroke. An increased risk of intracerebral hemorrhage (ICH) has been observed in some studies. To investigate this issue, we performed a meta-analysis of randomized controlled trials using statins that reported ICH.
METHODS: We performed a literature search of Medline, Web of Science, and The Cochrane Library through January 25, 2012, and identified additional randomized controlled trials by reviewing reference lists of retrieved studies and prior meta-analyses. All randomized controlled trials of statin therapy that reported ICH or hemorrhagic stroke were included. The primary outcome variable was ICH. Thirty-one randomized controlled trials were included. All analyses used random effects models and heterogeneity was not observed in any of the analyses.
RESULTS: A total of 91,588 subjects were included in the active group and 91,215 in the control group. There was no significant difference in incidence of ICH observed in the active treatment group versus control (OR, 1.08; 95% CI, 0.88-1.32; P=0.47). ICH risk was not related to the degree of low-density lipoprotein reduction or achieved low-density lipoprotein cholesterol. Total stroke (OR, 0.84; 95% CI, 0.78-0.91; P<0.0001) and all-cause mortality (OR, 0.92; CI, 0.87-0.96; P=0.0007) were significantly reduced in the active therapy group. There was no evidence of publication bias.
CONCLUSIONS: Active statin therapy was not associated with significant increase in ICH in this meta-analysis of 31 randomized controlled trials of statin therapy. A significant reduction in all stroke and all-cause mortality was observed with statin therapy.

PMID 22588266  Stroke. 2012 Aug;43(8):2149-56. doi: 10.1161/STROKEAHA.・・・
著者: Daniel G Hackam, Mark Woodward, L Kristin Newby, Deepak L Bhatt, Mingyuan Shao, Eric E Smith, Allan Donner, Muhammad Mamdani, James D Douketis, Hisatomi Arima, John Chalmers, Stephen MacMahon, David L Tirschwell, Bruce M Psaty, Cheryl D Bushnell, Maria I Aguilar, Dan J Capampangan, David J Werring, Paola De Rango, Anand Viswanathan, Nicolas Danchin, Ching-Lan Cheng, Yea-Huei Kao Yang, B Marianne Verdel, Mei-Shu Lai, James Kennedy, Shinichiro Uchiyama, Takenori Yamaguchi, Yasuo Ikeda, Marko Mrkobrada
雑誌名: Circulation. 2011 Nov 15;124(20):2233-42. doi: 10.1161/CIRCULATIONAHA.111.055269. Epub 2011 Oct 17.
Abstract/Text BACKGROUND: A recent large, randomized trial suggested that statins may increase the risk of intracerebral hemorrhage. Accordingly, we systematically reviewed the association of statins with intracerebral hemorrhage in randomized and observational data.
METHODS AND RESULTS: We screened 17 electronic bibliographic databases to identify eligible studies and consulted with experts in the field. We used DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. Randomized trials, cohort studies, and case-control studies were analyzed separately. Only adjusted risk estimates were used for pooling observational data. We included published and unpublished data from 23 randomized trials and 19 observational studies. The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10; 95% confidence interval, 0.86-1.41), cohort studies (risk ratio, 0.94; 95% confidence interval, 0.81-1.10), or case-control studies (risk ratio, 0.60; 95% confidence interval, 0.41-0.88). Substantial statistical heterogeneity was evident for the case-control studies (I(2)=66%, P=0.01), but not for the cohort studies (I(2)=0%, P=0.48) or randomized trials (I(2)=30%, P=0.09). Sensitivity analyses by study design features, patient characteristics, or magnitude of cholesterol lowering did not materially alter the results.
CONCLUSIONS: We found no evidence that statins were associated with intracerebral hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.

PMID 22007076  Circulation. 2011 Nov 15;124(20):2233-42. doi: 10.1161/・・・
著者: Xiang Wang, Yan Dong, Xiangqian Qi, Chengguang Huang, Lijun Hou
雑誌名: Stroke. 2013 Jul;44(7):1833-9. doi: 10.1161/STROKEAHA.113.001326. Epub 2013 May 23.
Abstract/Text BACKGROUND AND PURPOSE: Cholesterol levels are inconsistently associated with the risk of hemorrhagic stroke. The purpose of this study is to assess their relationships using a meta-analytic approach.
METHODS: We searched PubMed and Embase for pertinent articles published in English. Only prospective studies that reported effect estimates with 95% confidential intervals (CIs) of hemorrhagic stroke for ≥3 categories of cholesterol levels, for high and low comparison, or for per 1 mmol/L increment of cholesterol concentrations were included. We used the random-effects model to pool the study-specific results.
RESULTS: Twenty-three prospective studies were included, totaling 1 430 141 participants with 7960 (5.6%) hemorrhagic strokes. In high versus low analysis, the summary relative risk of hemorrhagic stroke was 0.69 (95% CI, 0.59-0.81) for total cholesterol, 0.98 (95% CI, 0.80-1.19) for high-density lipoprotein cholesterol, and 0.62 (95% CI, 0.41-0.92) for low-density lipoprotein cholesterol. In dose-response analysis, the summary relative risk of hemorrhagic stroke for 1 mmol/L increment of total cholesterol was 0.85 (95% CI, 0.80-0.91), for high-density lipoprotein cholesterol was 1.11 (95% CI, 0.99-1.25), and for low-density lipoprotein cholesterol was 0.90 (95% CI, 0.77-1.05). The pooled relative risk for intracerebral hemorrhage was 1.17 (95% CI, 1.02-1.35) for high-density lipoprotein cholesterol.
CONCLUSIONS: Total cholesterol level is inversely associated with risk of hemorrhagic stroke. Higher level of low-density lipoprotein cholesterol seems to be associated with lower risk of hemorrhagic stroke. High-density lipoprotein cholesterol level seems to be positively associated with risk of intracerebral hemorrhage.

PMID 23704101  Stroke. 2013 Jul;44(7):1833-9. doi: 10.1161/STROKEAHA.1・・・
著者: Emerging Risk Factors Collaboration, N Sarwar, P Gao, S R Kondapally Seshasai, R Gobin, S Kaptoge, E Di Angelantonio, E Ingelsson, D A Lawlor, E Selvin, M Stampfer, C D A Stehouwer, S Lewington, L Pennells, A Thompson, N Sattar, I R White, K K Ray, J Danesh
雑誌名: Lancet. 2010 Jun 26;375(9733):2215-22. doi: 10.1016/S0140-6736(10)60484-9.
Abstract/Text BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances.
METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease.
FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors.
INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease.
FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20609967  Lancet. 2010 Jun 26;375(9733):2215-22. doi: 10.1016/S01・・・
著者: Kausik K Ray, Sreenivasa Rao Kondapally Seshasai, Shanelle Wijesuriya, Rupa Sivakumaran, Sarah Nethercott, David Preiss, Sebhat Erqou, Naveed Sattar
雑誌名: Lancet. 2009 May 23;373(9677):1765-72. doi: 10.1016/S0140-6736(09)60697-8.
Abstract/Text BACKGROUND: Whether intensive control of glucose reduces macrovascular events and all-cause mortality in individuals with type 2 diabetes mellitus is unclear. We undertook a meta-analysis of randomised controlled trials to determine whether intensive treatment is beneficial.
METHODS: We selected five prospective randomised controlled trials of 33 040 participants to assess the effect of an intensive glucose-lowering regimen on death and cardiovascular outcomes compared with a standard regimen. We gathered information about events of non-fatal myocardial infarction, coronary heart disease (fatal and non-fatal myocardial infarction), stroke, and all-cause mortality, and did a random-effects meta-analysis to obtain summary effect estimates for the clinical outcomes with use of odds ratios calculated from the raw data of every trial. Statistical heterogeneity across trials was assessed with the chi(2) and I(2) statistics.
FINDINGS: The five trials provided information on 1497 events of non-fatal myocardial infarction, 2318 of coronary heart disease, 1127 of stroke, and 2892 of all-cause mortality during about 163 000 person-years of follow-up. The mean haemoglobin A(1c) concentration (HbA(1c)) was 0.9% lower for participants given intensive treatment than for those given standard treatment. Intensive glycaemic control resulted in a 17% reduction in events of non-fatal myocardial infarction (odds ratio 0.83, 95% CI 0.75-0.93), and a 15% reduction in events of coronary heart disease (0.85, 0.77-0.93). Intensive glycaemic control had no significant effect on events of stroke (0.93, 0.81-1.06) or all-cause mortality (1.02, 0.87-1.19).
INTERPRETATION: Overall, intensive compared with standard glycaemic control significantly reduces coronary events without an increased risk of death. However, the optimum mechanism, speed, and extent of HbA(1c) reduction might be different in differing populations.
FUNDING: None.

PMID 19465231  Lancet. 2009 May 23;373(9677):1765-72. doi: 10.1016/S01・・・
著者: Hiroshi Yatsuya, Hideaki Toyoshima, Kazumasa Yamagishi, Koji Tamakoshi, Masataka Taguri, Akiko Harada, Yasuo Ohashi, Yoshikuni Kita, Yoshihiko Naito, Michiko Yamada, Naohito Tanabe, Hiroyasu Iso, Hirotsugu Ueshima, Japan Arteriosclerosis Longitudinal Study (JALS) group
雑誌名: Circ Cardiovasc Qual Outcomes. 2010 Sep;3(5):498-505. doi: 10.1161/CIRCOUTCOMES.109.908517. Epub 2010 Aug 10.
Abstract/Text BACKGROUND: The association of overweight/obesity with the incidence of cardiovascular diseases, especially stroke, has not been comprehensively examined in relatively lean populations in which stroke is more prevalent than coronary heart disease.
METHODS AND RESULTS: Pooled individual data from 16 Japanese cohorts comprising 45 235 participants ages 40 to 89 years without previous history of cardiovascular disease were studied. During follow-up, 1113 incident strokes and 190 myocardial infarctions were identified. At baseline, mean ages of men and women were 55.4 and 56.5 years and mean body mass indices (BMI) were 23.0 and 23.4 kg/m(2), respectively. Compared with those with BMI <21.0, incidence rates of cerebral infarction in subjects with BMI ≥ 27.5 were significantly elevated in both men (hazard ratio, 1.81; 95% confidence interval [CI], 1.28 to 2.56) and women (hazard ratio, 1.65; 95% CI, 1.23 to 2.21), adjusted for age, smoking, and drinking habit. Incidence of cerebral hemorrhage was also associated positively with BMI in both men (hazard ratio, 2.51; 95% CI, 1.21 to 5.20) and women (hazard ratio, 1.98; 95% CI, 1.12 to 3.52). Adjustment for systolic blood pressure, a mediating factor, significantly attenuated most BMI association with stroke in both sexes. For myocardial infarction, the hazard ratio was 3.16 (95% CI, 1.66 to 6.01) for BMI 27.5 or greater versus less than 21.0 only in men, which appeared partly mediated by total cholesterol and SBP.
CONCLUSIONS: Overweight/obesity was associated with an increased risk of cerebral infarction and hemorrhage in men and women and myocardial infarction in men. Weight control may have the potential to prevent both stroke and myocardial infarction in Japan.

PMID 20699444  Circ Cardiovasc Qual Outcomes. 2010 Sep;3(5):498-505. d・・・
著者: Kristi Reynolds, Brian Lewis, John David L Nolen, Gregory L Kinney, Bhavani Sathya, Jiang He, Brian L Lewis
雑誌名: JAMA. 2003 Feb 5;289(5):579-88.
Abstract/Text CONTEXT: Observational studies suggest that heavy alcohol consumption may increase the risk of stroke while moderate consumption may decrease the risk.
OBJECTIVE: To examine the association between alcohol consumption and relative risk of stroke.
DATA SOURCES: Studies published in English-language journals were retrieved by searching MEDLINE (1966-April 2002) using Medical Subject Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke; Dissertation Abstracts Online using the keywords stroke and alcohol; and bibliographies of retrieved articles.
STUDY SELECTION: From 122 relevant retrieved reports, 35 observational studies (cohort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; the relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and abstainers served as the reference group.
DATA EXTRACTION: Information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, and risk estimates was abstracted independently by 3 investigators using a standardized protocol.
DATA SYNTHESIS: A random-effects model and meta-regression analysis were used to pool data from individual studies. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval [CI], 1.39-1.93); ischemic stroke, 1.69 (95% CI, 1.34-2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48-3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke.
CONCLUSIONS: These results indicate that heavy alcohol consumption increases the relative risk of stroke while light or moderate alcohol consumption may be protective against total and ischemic stroke.

PMID 12578491  JAMA. 2003 Feb 5;289(5):579-88.
著者: Hiroyasu Iso, Chigusa Date, Akio Yamamoto, Hideaki Toyoshima, Yoshiyuki Watanabe, Shogo Kikuchi, Akio Koizumi, Yasuhiko Wada, Takaaki Kondo, Yutaka Inaba, Akiko Tamakoshi, JACC Study Group
雑誌名: Am J Epidemiol. 2005 Jan 15;161(2):170-9. doi: 10.1093/aje/kwi027.
Abstract/Text To examine the effect of smoking cessation on cardiovascular disease mortality in Asians, the authors conducted a 10-year prospective cohort study of 94,683 Japanese (41,782 men and 52,901 women) aged 40-79 years who were part of the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). During 941,043 person-years of follow-up between 1989-1990 and 1999, 698 deaths from stroke, 348 from coronary heart disease, and 1,555 from total cardiovascular disease occurred in men and 550, 199, and 1,155, respectively, in women. For men, the multivariate relative risks for current smokers compared with never smokers were 1.39 (95% confidence interval (CI): 1.13, 1.70) for stroke, 2.51 (95% CI: 1.79, 3.51) for coronary heart disease, and 1.60 (95% CI: 1.39, 1.84) for total cardiovascular disease. The respective relative risks for women were 1.65 (95% CI: 1.21, 2.25), 3.35 (95% CI: 2.23, 5.02), and 2.06 (95% CI: 1.69, 2.51), with larger excess risks for persons aged 40-64 years than for older persons. The risk decline after smoking cessation occurred for coronary heart disease and total cardiovascular disease within 2 years and for total stroke after 2-4 years. For each endpoint and in both age subgroups of 40-64 and 65-79 years, most of the benefit of cessation occurred after 10-14 years following cessation. Findings imply the importance of smoking cessation at any age to prevent cardiovascular disease in Japanese.

PMID 15632267  Am J Epidemiol. 2005 Jan 15;161(2):170-9. doi: 10.1093/・・・
著者: Ghazaleh Gouya, Jasmin Arrich, Michael Wolzt, Kurt Huber, Freek W A Verheugt, Paul A Gurbel, Agnes Pirker-Kees, Jolanta M Siller-Matula
雑誌名: Stroke. 2014 Feb;45(2):492-503. doi: 10.1161/STROKEAHA.113.002590. Epub 2013 Dec 24.
Abstract/Text BACKGROUND AND PURPOSE: The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis.
METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science. Twenty-two studies comprising 173 371 patients were included.
RESULTS: In the overall population, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in comparison to aspirin monotherapy reduced the relative risk of total stroke by 20% (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.73-0.88; P<0.0001; I(2)=28%) and of ischemic stroke or transient ischemic attack by 23% (RR, 0.77; 95% CI, 0.69-0.85; P<0.0001; I(2)=18%) without increasing the risk of intracranial hemorrhage. In the secondary prevention cohort, DAPT with aspirin and clopidogrel also reduced the relative risk of total stroke by 24% as compared with aspirin alone (RR, 0.76; 95% CI, 0.68-0.86; P<0.0001; I(2)=0%). DAPT with prasugrel or ticagrelor and aspirin versus DAPT with clopidogrel and aspirin was not associated with a risk reduction of stroke.
CONCLUSIONS: DAPT with clopidogrel and aspirin compared with aspirin effectively reduces the risk of total and ischemic stroke in the overall cohort consisting of patients with cardiovascular disease without increase in intracranial hemorrhage, as well as decreases the risk of a recurrent total stroke in patients with a previous stroke/transient ischemic attack. Our meta-analysis suggests that DAPT including low-dose aspirin (75-100 mg) and clopidogrel (75 mg) should be further investigated as a strategy to reduce recurrent strokes.
CLINICAL TRIAL REGISTRATION URL: http://www.crd.york.ac.uk/prospero. Unique identifier: CRD42011001596.

PMID 24368560  Stroke. 2014 Feb;45(2):492-503. doi: 10.1161/STROKEAHA.・・・
著者: SPS3 Study Group, O R Benavente, C S Coffey, R Conwit, R G Hart, L A McClure, L A Pearce, P E Pergola, J M Szychowski
雑誌名: Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S0140-6736(13)60852-1. Epub 2013 May 29.
Abstract/Text BACKGROUND: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke.
METHODS: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306.
FINDINGS: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent.
INTERPRETATION: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial.
FUNDING: National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23726159  Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S014・・・
著者: Manuj Sharma, Victoria R Cornelius, Jignesh P Patel, J Graham Davies, Mariam Molokhia
雑誌名: Circulation. 2015 Jul 21;132(3):194-204. doi: 10.1161/CIRCULATIONAHA.114.013267. Epub 2015 May 20.
Abstract/Text BACKGROUND: Evidence regarding the use of direct oral anticoagulants (DOACs) in the elderly, particularly bleeding risks, is unclear despite the presence of greater comorbidities, polypharmacy, and altered pharmacokinetics in this age group.
METHODS AND RESULTS: We performed a systematic review and meta-analysis of randomized trials of DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban) for efficacy and bleeding outcomes in comparison with vitamin K antagonists (VKA) in elderly participants (aged ≥75 years) treated for acute venous thromboembolism or stroke prevention in atrial fibrillation. Nineteen studies were eligible for inclusion, but only 11 reported data specifically for elderly participants. The efficacy in managing thrombotic risks for each DOAC was similar or superior to VKA in elderly patients. A nonsignificantly higher risk of major bleeding than with VKA was observed with dabigatran 150 mg (odds ratio, 1.18; 95% confidence interval, 0.97-1.44) but not with the 110-mg dose. Significantly higher gastrointestinal bleeding risks with dabigatran 150 mg (1.78, 1.35-2.35) and dabigatran 110 mg (1.40, 1.04-1.90) and lower intracranial bleeding risks than VKA for dabigatran 150 mg (0.43, 0.26-0.72) and dabigatran 110 mg (0.36, 0.22-0.61) were also observed. A significantly lower major bleeding risk in comparison with VKA was observed for apixaban (0.63, 0.51-0.77), edoxaban 60 mg (0.81, 0.67-0.98), and 30 mg (0.46, 0.38-0.57), whereas rivaroxaban showed similar risks.
CONCLUSIONS: DOACs demonstrated at least equal efficacy to VKA in managing thrombotic risks in the elderly, but bleeding patterns were distinct. In particular, dabigatran was associated with a higher risk of gastrointestinal bleeding than VKA. Insufficient published data for apixaban, edoxaban, and rivaroxaban indicate that further work is needed to clarify the bleeding risks of these DOACs in the elderly.
SYSTEMATIC REVIEW REGISTRATION: http://www.crd.york.ac.uk/PROSPERO. Unique identifier: PROSPERO CRD42014007171/.

© 2015 American Heart Association, Inc.
PMID 25995317  Circulation. 2015 Jul 21;132(3):194-204. doi: 10.1161/C・・・
著者: Daniel Caldeira, Márcio Barra, Fausto J Pinto, Joaquim J Ferreira, João Costa
雑誌名: J Neurol. 2015 Mar;262(3):516-22. doi: 10.1007/s00415-014-7462-0. Epub 2014 Aug 14.
Abstract/Text The new oral anticoagulants/non-vitamin K antagonists oral anticoagulants (NOACs) have recently reached the market and less is known about their safety in comparison to their efficacy. Therefore, we aimed to evaluate intracranial hemorrhage (ICH) risk with NOACs, the most feared adverse event of anticoagulation treatment. This is a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) comparing NOACs versus any control and reporting ICH events. Studies were searched through Medline and Cochrane Library (April 2014). Reviews and reference lists were also screened. Random effects' meta-analysis was performed to derive pooled estimates expressed as relative risk (RR) and 95 % CI. Number needed to treat/harm (NNT/NNH) taking into account the baseline risk was also calculated. Heterogeneity was evaluated with I (2) test. 18 RCTs evaluating 148,149 patients were included. NOAC significantly reduced ICH risk compared to vitamin K antagonists (VKA) (RR 0.44; 95 % CI 0.36-0.54; I (2) = 37 %; NNT: 137 during 2 years) and to sequential treatment with low molecular weight heparin and VKA (RR 0.28; 95 % CI 0.12-0.65; I (2) = 0 %; NNT: 463 patients during 7 months). Compared to placebo, NOACs were associated with an increased ICH risk (RR 3.31; 95 % CI 1.59-6.90; I (2) = 0 %; NNH: 433 during 1 year). Results were similar for the different NOAC drugs and across the different clinical conditions. In patients requiring anticoagulation treatment, the risk of ICH is about half with the NOACs in comparison to standard antithrombotic treatment. This safer profile found in RCTs should be confirmed in real-world database studies.

PMID 25119841  J Neurol. 2015 Mar;262(3):516-22. doi: 10.1007/s00415-0・・・
著者: Christian T Ruff, Robert P Giugliano, Eugene Braunwald, Elaine B Hoffman, Naveen Deenadayalu, Michael D Ezekowitz, A John Camm, Jeffrey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, Elliott M Antman
雑誌名: Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S0140-6736(13)62343-0. Epub 2013 Dec 4.
Abstract/Text BACKGROUND: Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.
METHODS: We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.
FINDINGS: 42,411 participants received a new oral anticoagulant and 29,272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73-0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38-0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85-0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39-0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01-1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59-0·81 vs 0·93, 0·76-1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84-1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43-1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02-1·60; p=0·045).
INTERPRETATION: This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk-benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.
FUNDING: None.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24315724  Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S014・・・
著者: Johanna Pennlert, Rosanna Overholser, Kjell Asplund, Bo Carlberg, Bart Van Rompaye, Per-Gunnar Wiklund, Marie Eriksson
雑誌名: Stroke. 2017 Feb;48(2):314-320. doi: 10.1161/STROKEAHA.116.014643. Epub 2016 Dec 20.
Abstract/Text BACKGROUND AND PURPOSE: This study aims to provide observational data on the relationship between the timing of antithrombotic treatment and the competing risks of severe thrombotic and hemorrhagic events in a cohort of Swedish patients with atrial fibrillation and intracerebral hemorrhage (ICH).
METHODS: Patients with atrial fibrillation and a first-ever ICH were identified in the Swedish Stroke Register, Riksstroke, 2005 to 2012. Riksstroke was linked with other national registers to find information on treatment, comorbidity, and outcome. The optimal timing of treatment in patients with low and high thromboembolic risk was described through cumulative incidence functions separately for thrombotic and hemorrhagic events and for the combined end point vascular death or nonfatal stroke.
RESULTS: The study included 2619 ICH survivors with atrial fibrillation with 5759 person-years of follow-up. Anticoagulant treatment was associated with a reduced risk of vascular death and nonfatal stroke in high-risk patients with no significantly increased risk of severe hemorrhage. The benefit seemed to be greatest when treatment was started 7 to 8 weeks after ICH. For high-risk women, the total risk of vascular death or stroke recurrence within 3 years was 17.0% when anticoagulant treatment was initiated 8 weeks after ICH and 28.6% without any antithrombotic treatment (95% confidence interval for difference, 1.4%-21.8%). For high-risk men, the corresponding risks were 14.3% versus 23.6% (95% confidence interval for difference, 0.4%-18.2%).
CONCLUSIONS: This nationwide observational study suggests that anticoagulant treatment may be initiated 7 to 8 weeks after ICH in patients with atrial fibrillation to optimize the benefit from treatment and minimize risk.

© 2016 American Heart Association, Inc.
PMID 27999135  Stroke. 2017 Feb;48(2):314-320. doi: 10.1161/STROKEAHA.・・・
著者: RESTART Collaboration
雑誌名: Lancet. 2019 Jun 29;393(10191):2613-2623. doi: 10.1016/S0140-6736(19)30840-2. Epub 2019 May 22.
Abstract/Text BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92).
INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.
FUNDING: British Heart Foundation.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 31128924  Lancet. 2019 Jun 29;393(10191):2613-2623. doi: 10.1016/・・・
著者: Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, AFIRE Investigators
雑誌名: N Engl J Med. 2019 Sep 19;381(12):1103-1113. doi: 10.1056/NEJMoa1904143. Epub 2019 Sep 2.
Abstract/Text BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease.
METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority.
RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority).
CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31475793  N Engl J Med. 2019 Sep 19;381(12):1103-1113. doi: 10.10・・・
著者: A David Mendelow, Barbara A Gregson, Elise N Rowan, Gordon D Murray, Anil Gholkar, Patrick M Mitchell, STICH II Investigators
雑誌名: Lancet. 2013 Aug 3;382(9890):397-408. doi: 10.1016/S0140-6736(13)60986-1. Epub 2013 May 29.
Abstract/Text BACKGROUND: The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients.
METHODS: In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967.
FINDINGS: 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367).
INTERPRETATION: The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage.
FUNDING: UK Medical Research Council.

Copyright © 2013 Mendelow et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd. All rights reserved.
PMID 23726393  Lancet. 2013 Aug 3;382(9890):397-408. doi: 10.1016/S014・・・
著者: Daniel F Hanley, Richard E Thompson, John Muschelli, Michael Rosenblum, Nichol McBee, Karen Lane, Amanda J Bistran-Hall, Steven W Mayo, Penelope Keyl, Dheeraj Gandhi, Tim C Morgan, Natalie Ullman, W Andrew Mould, J Ricardo Carhuapoma, Carlos Kase, Wendy Ziai, Carol B Thompson, Gayane Yenokyan, Emily Huang, William C Broaddus, R Scott Graham, E Francois Aldrich, Robert Dodd, Cristanne Wijman, Jean-Louis Caron, Judy Huang, Paul Camarata, A David Mendelow, Barbara Gregson, Scott Janis, Paul Vespa, Neil Martin, Issam Awad, Mario Zuccarello, MISTIE Investigators
雑誌名: Lancet Neurol. 2016 Nov;15(12):1228-1237. doi: 10.1016/S1474-4422(16)30234-4. Epub 2016 Oct 11.
Abstract/Text BACKGROUND: Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage.
METHODS: MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770.
FINDINGS: Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051).
INTERPRETATION: MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage.
FUNDING: National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27751554  Lancet Neurol. 2016 Nov;15(12):1228-1237. doi: 10.1016/・・・
著者: Paul Vespa, Daniel Hanley, Joshua Betz, Alan Hoffer, Johnathan Engh, Robert Carter, Peter Nakaji, Chris Ogilvy, Jack Jallo, Warren Selman, Amanda Bistran-Hall, Karen Lane, Nichol McBee, Jeffery Saver, Richard E Thompson, Neil Martin, ICES Investigators
雑誌名: Stroke. 2016 Nov;47(11):2749-2755. doi: 10.1161/STROKEAHA.116.013837. Epub 2016 Oct 6.
Abstract/Text BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome.
METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year.
RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19).
CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.

© 2016 American Heart Association, Inc.
PMID 27758940  Stroke. 2016 Nov;47(11):2749-2755. doi: 10.1161/STROKEA・・・
著者: Joji B Kuramatsu, Alessandro Biffi, Stefan T Gerner, Jochen A Sembill, Maximilian I Sprügel, Audrey Leasure, Lauren Sansing, Charles Matouk, Guido J Falcone, Matthias Endres, Karl Georg Haeusler, Jan Sobesky, Johannes Schurig, Sarah Zweynert, Miriam Bauer, Peter Vajkoczy, Peter A Ringleb, Jan Purrucker, Timolaos Rizos, Jens Volkmann, Wolfgang Müllges, Peter Kraft, Anna-Lena Schubert, Frank Erbguth, Martin Nueckel, Peter D Schellinger, Jörg Glahn, Ulrich J Knappe, Gereon R Fink, Christian Dohmen, Henning Stetefeld, Anna Lena Fisse, Jens Minnerup, Georg Hagemann, Florian Rakers, Heinz Reichmann, Hauke Schneider, Jan Rahmig, Albert Christian Ludolph, Sebastian Stösser, Hermann Neugebauer, Joachim Röther, Peter Michels, Michael Schwarz, Gernot Reimann, Hansjörg Bäzner, Henning Schwert, Joseph Claßen, Dominik Michalski, Armin Grau, Frederick Palm, Christian Urbanek, Johannes C Wöhrle, Fahid Alshammari, Markus Horn, Dirk Bahner, Otto W Witte, Albrecht Günther, Gerhard F Hamann, Manuel Hagen, Sebastian S Roeder, Hannes Lücking, Arnd Dörfler, Fernando D Testai, Daniel Woo, Stefan Schwab, Kevin N Sheth, Hagen B Huttner
雑誌名: JAMA. 2019 Oct 8;322(14):1392-1403. doi: 10.1001/jama.2019.13014.
Abstract/Text Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established.
Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH.
Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015).
Exposure: Surgical hematoma evacuation vs conservative treatment.
Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH.
Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02).
Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

PMID 31593272  JAMA. 2019 Oct 8;322(14):1392-1403. doi: 10.1001/jama.2・・・

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから