症例生来健康な 54 歳女性現病歴急性発症のめまいと歩行障害で救急搬送頭部 MRIで右小脳半球 PICA 領域の一部に急性期脳梗塞あり入院アスピリン開始急性期管理を行いつつ脳梗塞の原因検索を開始した

(1)

心房中隔壁異常を伴う

Cryptogenic Stroke の再発予防

東京ベイ・浦安市川医療センター

　　　　　　　　総合内科　原谷浩司

　　　　　　　　　監修　　　　江原淳

Clinical Question 2014年9月29日

J Hospitalist Network

　分野：神経

テーマ：治療

(2)

症例

生来健康な54歳女性

現病歴

•  急性発症のめまいと歩行障害で救急搬送

•  頭部MRIで右小脳半球PICA領域の一部に  

急性期脳梗塞あり入院

•  アスピリン開始、急性期管理を行いつつ  

脳梗塞の原因検索を開始した

(3)

既往歴・薬歴

生来健康　ピル内服なし　５年前に閉経

健康診断でも異常を指摘されたことはない

家族歴

血栓症の家族歴含め特になし

生活歴

喫煙歴なし　専業主婦　流産歴なし

身体所見

小脳系の神経学的所見あり

その他は正常　血圧も正常

(4)

心電図

正常洞調律

約１ヶ月間心電図モニターで不整脈なし

血液検査

耐糖能異常なし　脂質異常なし　腎機能正常

血沈正常　RPR/TPHA陰性

凝固能異常screening

PT　APTT　プロテインC/S　AT-III

ループスアンチコアグラント　ホモシステイン

抗β２GPI・カルジオリピン抗体　

経胸壁心臓超音波検査

異常なし

いずれも異常なし

(5)

MR Angio

椎骨脳底動脈解離なし

他の脳血管も目立った狭窄や口径不整なし

頸動脈超音波検査

動脈硬化所見なし　高度狭窄なし

胸腹部〜下肢造影CT

腫瘍や静脈血栓の所見含め特に異常なし

悪性腫瘍の検索

上下部消化管内視鏡　乳房単純X線写真

婦人科診察　など特に異常なし

(6)

経食道心臓超音波検査

大動脈プラークなし

PFO（卵円孔開存）なし

ASA（心房中隔瘤）なし

ASD

（心房中隔欠損）所見あり

(7)

【まとめ】

•  生来健康の54歳女性が小脳梗塞を発症

•  動脈硬化のリスクファクターは一切なし

•  入院中に不整脈は同定されず

•  血栓性素因や悪性腫瘍の存在、静脈血栓症の併存も否定的

•  ただし、経食道心臓超音波検査で

ASDが見つかった

(8)

Clinical Question

原因不明の脳梗塞患者に

（=

Cryptogenic Stroke の患者に）

ASD がみつかった場合、

再発予防はどうすればよいか？？

抗血小板薬で良いのか？

抗凝固薬が良いのか？

閉鎖術を行うべきか？

(9)

Clinical Question 

(10)

−

Cryptogenic Stroke とは？

-  Cryptogenic Stroke の診断は？

-  Cryptogenic Stroke の原因は？

-  Cryptogenic Stroke と心房中隔異常

※

の関連性は？

-  心房中隔壁異常が Cryptogenic Stroke を

起こす機序は？

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

(11)

Cryptogenic Stroke とは

十分な精査にも関わらず、

①−③のいずれも否定的な原因不明の脳梗塞

　①心原性塞栓

(

Cardiac embolism )

　②動脈硬化性

(

Large artery artherosclerosis )

　③ラクナ梗塞 (

Small artery disease )

UpToDate：Etiology, classification, and epidemiology of stroke

UpToDate：Cryptogenic stroke

(12)

−

Cryptogenic Stroke とは？

-

 

Cryptogenic Stroke の診断は？

-  Cryptogenic Stroke の原因は？

-  Cryptogenic Stroke と心房中隔異常

※

の関連性は？

-  心房中隔壁異常が Cryptogenic Stroke を

起こす機序は？

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

(13)

Cryptogenic Stroke の診断

− 明確な定義や診断基準は無い

− 診断は現場の個々の判断による

UpToDate：Etiology, classification, and epidemiology of stroke

UpToDate：Cryptogenic stroke

この患者の脳梗塞も

cryptogenic stroke と言える

臨床的には下記を満たす場合、

Cryptogenic Stroke と言ってよいか

　①心原性塞栓が否定的

　　最低２４時間〜数週間(出来れば30日間)の心電図モニターで

　　心房細動などの不整脈が認められない

　②動脈硬化性

　　大血管動脈硬化リスクファクター、動脈硬化所見、血管炎、

　　動脈解離などの所見がないor乏しい

　③ラクナ梗塞

　　ラクナ梗塞では説明できない

(14)

Cryptogenic Stroke の診断

N Engl J Med 2012;366:991-9. Supplementary Appendix（一部改変）

①塞栓源として否定出来ない所見

- 頸動脈狭窄>50％(または潰瘍形成や可動性血栓がみられる)

- 梗塞巣と関連のある頭蓋内血管の狭窄

>50％

- 大動脈弓の高リスク所見を伴う

complex atheroma

- 大動脈解離・頸動脈解離・椎骨動脈解離

- 重症

MS/AS、M弁/A弁の疣贅や5mm以上の弁輪石灰化、人工弁

- 左室EF<30%、左心室瘤、脳梗塞発症前３ヶ月以内の前壁心筋梗塞

- 慢性/発作性心房細動、心房粗動が３０秒以上かつ２回以上

　※可逆性イベント（急性心筋梗塞、心臓手術、心筋炎etc）に関連ない

②長期抗凝固が必要となると判断された血栓性素因の存在

（

PT G20210A, protein C, protein S, AT-III欠損, factor V leiden欠損)

③長期抗凝固が必要となる判断された抗リン脂質抗体症候群

④既知の血管炎や特定の神経疾患（

SLE、GCA、多発性硬化症など)

下記は

Cryptogenic Stroke に関するある研究の Exclusion Criteria．

(15)

−

Cryptogenic Stroke とは？

-  Cryptogenic Stroke の診断は？

-

 

Cryptogenic Stroke の原因は？

-  Cryptogenic Stroke と心房中隔異常

※

の関連性は？

-  心房中隔壁異常が Cryptogenic Stroke を

起こす機序は？

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

(16)

Cryptogenic Stroke の原因

よくわかっておらず、様々な仮説が飛び交っている。

UpToDate：Etiology, classification, and epidemiology of stroke

UpToDate：Cryptogenic stroke

例）

- 動脈硬化の早期に発症した(実は)アテローム血栓性脳梗塞

- 血栓性素因が関連して起こる脳梗塞

- 単に発見し損ねている心房細動による脳梗塞

-

PFO、ASD、ASA など心房中隔壁構造に起因する脳梗塞

- 臨床的に露わにならない脳血管の(何らかの)異常による脳梗塞

- 炎症性疾患により誘発される脳梗塞(慢性炎症など)

- その他、心臓あるいは動脈由来の何らかの血栓塞栓症

(17)

−

Cryptogenic Stroke とは？

-  Cryptogenic Stroke の診断は？

-  Cryptogenic Stroke の原因は？

-

 

Cryptogenic Stroke と心房中隔異常

※

の関連性は？

-  心房中隔壁異常が Cryptogenic Stroke を

起こす機序は？

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

(18)

Cryptogenic Stroke と

心房中隔壁異常の関連性

- PFO と ASA

ある症例対照研究のメタ解析によると、

PFO や ASAの Cryptogenic Stroke との関連が示唆されている．

Cryptogenic Stroke に対するオッズ比は下記(有意差あり)．

PFO：1.83　ASA：2.35　PFO+ASA：4.96

　　　　　　

Neurology. 2000;55(8):1172.

　※その他の多くの研究で上記と同様の結果が再現されている．

-  ASD

ASD と Cryptogenic Stroke の関連性を検証した study はない．

しかし、一般的には

PFO などと同様にCryptogenic Strokeの

原因となると認識されている．

(19)

−

Cryptogenic Stroke とは？

-  Cryptogenic Stroke の診断は？

-  Cryptogenic Stroke の原因は？

-  Cryptogenic Stroke と心房中隔異常

※

の関連性は？

-

心房中隔壁異常が

Cryptogenic Stroke を

起こす機序は？

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

(20)

心房中隔壁異常が

Cryptogenic Stroke を起こす機序

①本来は肺血管床に

trap されて自然溶解するはずの、

　全身静脈系に生じた微小な血栓が、

PFO やASD における

　右左シャント

※

_{を介して動脈循環系に直接流入することで}

　動脈塞栓症を起こす

②

PFO や ASA の構造物に血栓が直接形成されて塞栓症を起こす

③深部静脈血栓が、

PFO やASD に生じた右左シャント

※

_を

　介して動脈循環系に直接流入することで動脈塞栓症を起こす

§

④

ASD、PFO、ASA があると心房細動を起こしやすくなる

UpToDate：Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults

※怒責時などの一瞬の右房圧上昇でも十分に原因となりうると考えられている

§深部静脈自体に存在した血栓は自然溶解して画像的に同定出来ないこともある

(21)

再び

(22)

Clinical Question

Cryptogenic Stroke ＋ ASD の再発予防

− 第一選択は？

- 抗血小板薬で良いのか？

-  抗凝固薬が良いのか?

(23)

心房中隔壁異常を伴う

Cryptogenic Stroke の再発予防

　

UpToDate

　

2014 AHA/ASA guideline

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

Stroke. 2014;45:2160-2236.

　

2012 ACCP guideline

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of

Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST.2012;141:2 e576S

　日本脳卒中ガイドライン２００９

Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease

on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and

Rich, DeJuran Richardson, Lee H. Schwamm and John A. Wilson

Claiborne (Clay) Johnston, Scott E. Kasner, Steven J. Kittner, Pamela H. Mitchell, Michael W.

Michael D. Ezekowitz, Margaret C. Fang, Marc Fisher, Karen L. Furie, Donald V. Heck, S.

Walter N. Kernan, Bruce Ovbiagele, Henry R. Black, Dawn M. Bravata, Marc I. Chimowitz,

Association/American Stroke Association

Attack: A Guideline for Healthcare Professionals From the American Heart

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic

Print ISSN: 0039-2499. Online ISSN: 1524-4628

Copyright © 2014 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231

Stroke

doi: 10.1161/STR.0000000000000024

2014;45:2160-2236; originally published online May 1, 2014;

Stroke.

http://stroke.ahajournals.org/content/45/7/2160

World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://stroke.ahajournals.org/content/45/8/e172.full.pdf

An erratum has been published regarding this article. Please see the attached page for:

http://stroke.ahajournals.org/content/suppl/2014/05/01/STR.0000000000000024.DC1.html

Data Supplement (unedited) at:

http://stroke.ahajournals.org//subscriptions/

Information about subscribing to

Stroke

is online at:

Subscriptions:

http://www.lww.com/reprints

Information about reprints can be found online at:

Reprints:

Permissions and Rights Question and Answer

document.

process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about this

Once the online version of the published article for which permission is being requested is located, click

Stroke

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.

in

Requests for permissions to reproduce figures, tables, or portions of articles originally published

Permissions:

by guest on September 18, 2014

http://stroke.ahajournals.org/

Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from http://stroke.ahajournals.org/ by guest on September 18, 2014 Downloaded from

e576S

CHEST

Supplement

Antithrombotic Therapy for Valvular Disease

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Background: Antithrombotic therapy in valvular disease is important to mitigate thromboembo-lism, but the hemorrhagic risk imposed must be considered.

Methods: The methods of this guideline follow those described in Methodology for the Develop-ment of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.

Results: In rheumatic mitral disease, we recommend vitamin K antagonist (VKA) therapy when the left atrial diameter is . 55 mm (Grade 2C) or when complicated by left atrial thrombus (Grade 1A). In candidates for percutaneous mitral valvotomy with left atrial thrombus, we recom-mend VKA therapy until thrombus resolution, and we recomrecom-mend abandoning valvotomy if the thrombus fails to resolve (Grade 1A). In patients with patent foramen ovale (PFO) and stroke or transient ischemic attack, we recommend initial aspirin therapy (Grade 1B) and suggest substitu-tion of VKA if recurrence (Grade 2C). In patients with cryptogenic stroke and DVT and a PFO, we recommend VKA therapy for 3 months (Grade 1B) and consideration of PFO closure (Grade 2C). We recommend against the use of anticoagulant (Grade 1C) and antiplatelet therapy (Grade 1B) for native valve endocarditis. We suggest holding VKA therapy until the patient is stabilized without neurologic complications for infective endocarditis of a prosthetic valve (Grade 2C). In the fi rst 3 months after bioprosthetic valve implantation, we recommend aspirin for aortic valves (Grade 2C), the addition of clopidogrel to aspirin if the aortic valve is transcatheter (Grade 2C), and VKA therapy with a target international normalized ratio (INR) of 2.5 for mitral valves (Grade 2C). After 3 months, we suggest aspirin therapy (Grade 2C). We recommend early bridging of mechanical valve patients to VKA therapy with unfractionated heparin (DVT dosing) or low-molecular-weight heparin (Grade 2C). We recommend long-term VKA therapy for all mechanical valves (Grade 1B): target INR 2.5 for aortic (Grade 1B) and 3.0 for mitral or double valve (Grade 2C). In patients with mechanical valves at low bleeding risk, we suggest the addition of low-dose aspi-rin (50-100 mg/d ) (Grade 1B). In valve repair patients, we suggest aspiaspi-rin therapy (Grade 2C). In patients with thrombosed prosthetic valve, we recommend fi brinolysis for right-sided valves and left-sided valves with thrombus area , 0.8 cm 2_{(Grade 2C). For patients with left-sided prosthetic}

valve thrombosis and thrombus area ! 0.8 cm 2_{, we recommend early surgery (Grade 2C).}

Conclusions: These antithrombotic guidelines provide recommendations based on the optimal balance of thrombotic and hemorrhagic risk. CHEST 2012; 141(2)(Suppl):e576S–e600S Abbreviations: AF 5 atrial fi brillation; APA 5 antiplatelet agent; AVR 5 aortic valve replacement; GRADE 5 Grades

of Recommendations, Assessment, Development, and Evaluation; ICH 5 intracerebral hemorrhage; IE 5 infective endocarditis; INR 5 international normalized ratio; LMWH 5 low-molecular-weight heparin; MAC 5 mitral annular calcifi cation; MVP 5 mitral valve prolapse; NBTE 5 nonbacterial thrombotic endocarditis; NYHA 5 New York Heart Association; OAC 5 oral anticoagulation; PFO 5 patent foramen ovale; PICO 5 population, intervention, comparator, and outcome; PMBV 5 percutaneous mitral balloon valvotomy; PVE 5 prosthetic valve endocarditis; PVT 5 prosthetic valve thrombosis; RCT 5 randomized controlled trial; RR 5 relative risk; TEE 5 transesophageal echocardiography; TIA 5 transient ischemic attack; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist

Antithrombotic and Thrombolytic Therapy

for Valvular Disease

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

Richard P. Whitlock , MD ; Jack C. Sun , MD ; Stephen E. Fremes , MD , FCCP ; Fraser D. Rubens , MD ; and Kevin H. Teoh , MD

Downloaded From: http://journal.publications.chestnet.org/ on 09/18/2014

(24)

Cryptogenic Stroke＋ASDの再発予防

UpToDate

●Cryptogenic Stroke + ASD の再発予防は確立していない

● 奇異性塞栓による

Cryptogenic Stroke + ASDでは、

　

ASD 閉鎖術を推奨する（Class IIa; LOE C）

※

　

※ACC/AHA 2008 Guidelines for Adults With CHD

2014 AHA/ASA guidelines

　

Cryptogenic Stroke + ASDに関する推奨なし

Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease

on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and

Rich, DeJuran Richardson, Lee H. Schwamm and John A. Wilson

Claiborne (Clay) Johnston, Scott E. Kasner, Steven J. Kittner, Pamela H. Mitchell, Michael W.

Michael D. Ezekowitz, Margaret C. Fang, Marc Fisher, Karen L. Furie, Donald V. Heck, S.

Walter N. Kernan, Bruce Ovbiagele, Henry R. Black, Dawn M. Bravata, Marc I. Chimowitz,

Association/American Stroke Association

Attack: A Guideline for Healthcare Professionals From the American Heart

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic

Print ISSN: 0039-2499. Online ISSN: 1524-4628

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231

Stroke

doi: 10.1161/STR.0000000000000024

2014;45:2160-2236; originally published online May 1, 2014;

Stroke.

http://stroke.ahajournals.org/content/45/7/2160

World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://stroke.ahajournals.org/content/45/8/e172.full.pdf

An erratum has been published regarding this article. Please see the attached page for:

http://stroke.ahajournals.org/content/suppl/2014/05/01/STR.0000000000000024.DC1.html

Data Supplement (unedited) at:

http://stroke.ahajournals.org//subscriptions/

is online at:

Stroke

Information about subscribing to

Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at:

Reprints:

Permissions and Rights Question and Answer document. process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about this Once the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.

Stroke

in Requests for permissions to reproduce figures, tables, or portions of articles originally published

Permissions:

2012 ACCP guidelines

　

Cryptogenic Stroke + ASDに関する推奨なし

e576S

CHEST

Supplement

Conclusions: These antithrombotic guidelines provide recommendations based on the optimal balance of thrombotic and hemorrhagic risk. CHEST 2012; 141(2)(Suppl):e576S–e600S

Abbreviations: AF 5 atrial fi brillation; APA 5 antiplatelet agent; AVR 5 aortic valve replacement; GRADE 5 Grades

Antithrombotic and Thrombolytic Therapy

for Valvular Disease

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

日本脳卒中ガイドライン２００９

　

Cryptogenic Stroke + ASDに関する推奨なし

本症例のような

Cryptogenic Stroke ＋ ASDに関しては、ほぼ推奨なし

推奨根拠となる文献なし

（expert opinion）

(25)

Cryptogenic Stroke ＋ ASDについては、

ガイドラインでは、ほぼ全く言及されていない．

唯一みられた

ACC/AHA 2008 Guidelines for Adults

With CHDの推奨は、expert opinion．

記載内容も非常に曖昧（奇異性塞栓の定義など）

ということで、

Cryptogenic Stroke ＋ ASDについて

何か有用な情報がないか検索してみた．

(26)

Cryptogenic Stroke ＋ ASD の再発予防について

下記の検索ワードを用いて

PubMedで検索したが、

Cryptogenic Stroke ＋ ASD の再発予防に関する研究は

全く存在しなかった．

Cryptogenic Stroke ＋ ASDの再発予防

>Search ("Heart Septal Defects, Atrial"[Mesh]) AND Cryptogenic stroke

　

Filters: Clinical Trial

>Search Cryptogenic stroke ASD

Cryptogenic Stroke ＋ ASD の再発予防については

参考に出来る

evidenceがほぼ皆無！！

(27)

困った・・・　代わりとして

Cryptogenic Stroke ＋ PFO (卵円孔開存)  

について考察してみた．

(28)

Clinical Question

Cryptogenic Stroke + PFO の再発予防

− 第一選択は？

- 抗血小板薬で良いのか？

-

抗凝固薬が良いのか?

(29)

Cryptogenic Stroke + PFO の再発予防

UpToDate

● Cryptogenic Stroke + PFO の再発予防は確立していない

● Cryptogenic Stroke + PFO の再発予防目的の全ての患者は、

　可能な限り、薬物療法と閉鎖術の比較試験に登録されるべき

2014 AHA/ASA guidelines

● Cryptogenic Stroke + PFO の再発予防で

　抗凝固が抗血小板薬よりよいかどうかについては現時点で

　データが不十分（

Class IIB; LOE B）

Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease

on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and

Rich, DeJuran Richardson, Lee H. Schwamm and John A. Wilson

Claiborne (Clay) Johnston, Scott E. Kasner, Steven J. Kittner, Pamela H. Mitchell, Michael W.

Michael D. Ezekowitz, Margaret C. Fang, Marc Fisher, Karen L. Furie, Donald V. Heck, S.

Walter N. Kernan, Bruce Ovbiagele, Henry R. Black, Dawn M. Bravata, Marc I. Chimowitz,

Association/American Stroke Association

Attack: A Guideline for Healthcare Professionals From the American Heart

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic

Stroke

doi: 10.1161/STR.0000000000000024

2014;45:2160-2236; originally published online May 1, 2014;

Stroke.

World Wide Web at:

The online version of this article, along with updated information and services, is located on the

An erratum has been published regarding this article. Please see the attached page for:

Data Supplement (unedited) at:

http://stroke.ahajournals.org//subscriptions/ Information about subscribing to Stroke is online at:

Subscriptions:

Reprints:

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Request Permissions in the middle column of the Web page under Services. Further information about this Once the online version of the published article for which permission is being requested is located, click Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. in Requests for permissions to reproduce figures, tables, or portions of articles originally published

Permissions:

Cryptogenic Stroke + PFO の再発予防についても

十分な

evidenceが無いという大前提がある．

(30)

Cryptogenic Stroke + PFO の再発予防

UpToDate

● Cryptogenic Stroke + PFO の再発予防において、

ASAの有無に関わらず、抗血小板薬を第一選択に推奨する

　

(可能なら閉鎖術との比較臨床試験に登録する)

2014 AHA/ASA guidelines

● Cryptogenic Stroke + PFO の再発予防において、

　抗血小板薬を推奨する（

Class I; LOE B）

Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease

on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and

Rich, DeJuran Richardson, Lee H. Schwamm and John A. Wilson

Claiborne (Clay) Johnston, Scott E. Kasner, Steven J. Kittner, Pamela H. Mitchell, Michael W.

Michael D. Ezekowitz, Margaret C. Fang, Marc Fisher, Karen L. Furie, Donald V. Heck, S.

Walter N. Kernan, Bruce Ovbiagele, Henry R. Black, Dawn M. Bravata, Marc I. Chimowitz,

Association/American Stroke Association

Attack: A Guideline for Healthcare Professionals From the American Heart

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic

Stroke

doi: 10.1161/STR.0000000000000024

2014;45:2160-2236; originally published online May 1, 2014;

Stroke.

World Wide Web at:

The online version of this article, along with updated information and services, is located on the

An erratum has been published regarding this article. Please see the attached page for:

Data Supplement (unedited) at:

Subscriptions:

Reprints:

document.

Permissions and Rights Question and Answer

process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about this Once the online version of the published article for which permission is being requested is located, click Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. in

Requests for permissions to reproduce figures, tables, or portions of articles originally published

Permissions:

2012 ACCP guidelines

● Cryptogenic Stroke + PFO の再発予防において、

　抗血小板薬を推奨する（

Grade１A）

e576S

CHEST

Supplement

Antithrombotic and Thrombolytic Therapy

for Valvular Disease

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

日本脳卒中ガイドライン２００９

(31)

いずれの推奨をみても、

Cryptogenic Stroke + PFO に対する再発予防の

第一選択として、抗血小板薬が推奨されている．

※

ASAの有無は治療の選択には影響しないようである．

ただし・・・

これらの推奨の根拠となった論文は下記の一つのみ．

Cryptogenic Stroke + PFO の再発予防

PICSS（PFO in Cryptogenic Stroke Study）

Circulation. 2002;105:2625-2631

※下記の用語で、

PubMed search したが、抗血小板薬と抗凝固薬の比較試験は他には無かった．

Search

"Foramen Ovale, Patent"[Mesh] Filters: Clinical Trial

(32)

ence in the time to primary end points. Among the

crypto-genic subgroup, in patients with and without PFO, there was

a trend toward primary event reduction in warfarin-treated

patients, as was seen in WARSS.

27

_{With and without}

inclu-sion of TIA as an end point, however, no significant

differ-ence was observed between warfarin- and aspirin-treated

cryptogenic stroke patients with PFO. Thus, in stroke patients

with PFO, therapy with warfarin or aspirin results in similar

rates of adverse events. Whether the patients with PFO will

experience further reduction in adverse events with closure of

PFO remains to be seen. The mean INR achieved was 2.04 in

our patients assigned to warfarin. WARSS has demonstrated

that event rates decrease when INR is !1.5, and this effect

remained similar for higher INRs.

27

_{Thus, we feel that}

appropriate anticoagulation was achieved in our patients.

The best treatment modality to prevent recurrent stroke in

patients with PFO has not been defined. There are 4 major

choices: surgical closure, percutaneous device closure,

med-ical therapy with anticoagulant, and medmed-ical therapy with

antiplatelet agents. In terms of surgical closure, we reported

our experience in 28 cryptogenic stroke patients. With a mean

follow-up time of 19 months, we saw 4 neurological events,

all in patients !45 years old.

12

_{Devuyst et al}

13

_{followed up 30}

patients with stroke and surgical PFO closure without any

recurrent ischemic events. Dearani et al

14

_{reported 8 TIAs in}

91 patients with a mean follow-up of 2 years. For

percutane-ous closure, Bridges et al

9

_{reported PFO closure in 36 patients}

with presumed paradoxical embolism and saw 4 TIAs in 8.4

months. Windecker et al

10

_{reported 8 recurrent embolic}

events in 80 patients with a 1.6-year follow-up. Hung et al

11

reported on 63 patients followed up for 2.6 years with 4

recurrent neurological events. Reasons for recurrent ischemic

events after either surgical or percutaneous PFO closure

remain unclear. The cause for initial or subsequent stroke

may not be paradoxical embolization, and thrombus

forma-tion at the site of surgical or device closure has been reported,

which could serve as a potential source of embolism.

29,30

Furthermore, incomplete closure of a PFO may lead to

subsequent paradoxical embolization.

In terms of medical therapy, Bogousslavsky et al

7

_reported

5 deaths and 16 neurological events in 140 patients "60 years

old treated with aspirin, warfarin, or surgery at 36 months of

follow-up. Recently, Cujec et al

8

_{reported on 52 cryptogenic}

stroke patients "60 years old with PFO followed up for 46

months compared with 38 without PFO; 14 with PFO

experienced recurrent neurological events, compared with 6

without PFO. Most recently, Mas et al

20

_{reported a 4.5%}

recurrent stroke rate in 267 cryptogenic stroke patients "55

years old with PFO with 4 years of follow-up.

In interpreting the results of previously published studies,

in addition to the small number of patients in most studies,

most problematically, none of the studies randomized the

therapy. As such, our data are unique in that the patients were

randomly assigned to warfarin or aspirin in a double-blind

manner. Furthermore, in our study, all TE studies were

analyzed at a central location, and the patients were then

rigorously followed up. Paradoxical embolization is one of

the mechanisms for stroke in patients with PFO. This is

consistent with the finding of an association of large PFO

with cryptogenic stroke and a higher prevalence of deep

venous thrombus in stroke patients with PFO as well as with

the reports of trapped thrombus in PFO.

31–33

_{Nevertheless, it}

is likely that ischemic stroke in patients with PFO has

multiple causative mechanisms, including potential atrial

vulnerability to arrhythmia.

34

_{Our results indicate that when}

receiving medical therapy, ischemic stroke patients with and

without PFO have similar adverse event rates. Although the

closure of PFO may further reduce the event rates, this

remains to be demonstrated. Currently, we do not believe that

it is necessary to close a PFO unless the patient has a

contraindication to medical therapy or has a recurrent event

on medical therapy.

Limitations

The association of PFO with cryptogenic stroke has not been

shown consistently in all age groups. Thus, our findings may

not apply to all age groups or to those who meet unambiguous

criteria for paradoxical embolism. Because the mean INR in

our warfarin-treated patients was 2.04, a higher INR might

have given different results. Finally, the role of other

anti-platelet agents remains untested.

Appendix

Study Participants

National Institute of Neurological Disorders and Stroke (NINDS): J.R. Marler, Program Director.

Data Management Center members: R.M. Lazar, D.E. Gohs, M. Clavijo, K. Slane, D. Balbuena, D. Martino, C. Inguanzo, J. Pittman, R.R. Sciacca, K. Evans, K. Lord, B. Jaffe, J. Kim, L. Lynn, J. Ruzicka, P. Chugh, A. Zidel, B. Fields, M. Coleman, R. King, J.G. Mohr, I. Carretero, O. Mendoza, A. Barlow.

TABLE 3.

**Two-Year Rates of Recurrent Stroke or Death* in Patients With and**

Without PFO Assigned to Warfarin or Aspirin

Warfarin Aspirin

Hazard Ratio

(95% CI) P

Entire PICSS cohort

With PFO (n!203) 16.5% (n!97) 13.2% (n!106) 1.29 (0.63–2.64) 0.49 No PFO (n!398) 13.4% (n!195) 17.4% (n!203) 0.80 (0.49–1.33) 0.40 Cryptogenic cohort

With PFO (n!98) 9.5% (n!42) 17.9% (n!56) 0.52 (0.16–1.67) 0.28

No PFO (n!152) 8.3% (n!72) 16.3% (n!80) 0.50 (0.19–1.31) 0.16

*From Kaplan-Meier curves.

Homma et al

PFO in Cryptogenic Stroke Study

2629

by guest on September 18, 2014

http://circ.ahajournals.org/

Downloaded from

-  98人のPFOを伴うCryptogenic Stroke 群を対象

-  Warfarin 割付群とAspirin 割付群

-  脳梗塞再発または死亡というprimary endpoint に有意差はみられなかった．

※考察

この研究は、元々は非心原性脳梗塞の再発予防に対するwarfarinとaspirinの差を

検証した

RCT(WARSS study. NEJM 2001; 345:1444.)の、prespecification が不明な

Subgroup 解析であり、もとは上記のoutcome を検証するために計画されたstudyではない．

よって、このoutcome に関してはサンプル数検定すらされていない．

上図をみると、有意差こそないが、傾向としてはwarfarin 群で再発が少ない傾向が見られる．

サンプル数をしっかり確保したprespecified RCT を行えば、Aspirin と Warfarin に有意差が

出るかもしれないという仮説は立てられる．

現時点で、

PFOを伴う

Cryptogenic Strokeの再

発予防に対する抗凝固と

抗血小板薬の効果を

検証した唯一の介入研究

Circulation. 2002;105:2625-2631

(33)

Cryptogenic Stroke + PFO の再発予防

UpToDate

● Cryptogenic Stroke + PFO の再発予防において、

ASAの有無に関わらず、抗血小板薬を第一選択に推奨する

　

(可能なら閉鎖術との比較臨床試験に登録する)

2014 AHA/ASA guidelines

● Cryptogenic Stroke + PFO の再発予防において、

　抗血小板薬を推奨する（

Class I; LOE B）

Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease

on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and

Rich, DeJuran Richardson, Lee H. Schwamm and John A. Wilson

Claiborne (Clay) Johnston, Scott E. Kasner, Steven J. Kittner, Pamela H. Mitchell, Michael W.

Michael D. Ezekowitz, Margaret C. Fang, Marc Fisher, Karen L. Furie, Donald V. Heck, S.

Walter N. Kernan, Bruce Ovbiagele, Henry R. Black, Dawn M. Bravata, Marc I. Chimowitz,

Association/American Stroke Association

Attack: A Guideline for Healthcare Professionals From the American Heart

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic

Stroke

doi: 10.1161/STR.0000000000000024

2014;45:2160-2236; originally published online May 1, 2014;

Stroke.

World Wide Web at:

The online version of this article, along with updated information and services, is located on the

An erratum has been published regarding this article. Please see the attached page for:

Data Supplement (unedited) at:

Subscriptions:

Reprints:

document.

Permissions and Rights Question and Answer

process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about this Once the online version of the published article for which permission is being requested is located, click Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. in

Requests for permissions to reproduce figures, tables, or portions of articles originally published

Permissions:

2012 ACCP guidelines

● Cryptogenic Stroke + PFO の再発予防において、

　抗血小板薬を推奨する（

Grade１A）

e576S

CHEST

Supplement

Antithrombotic and Thrombolytic Therapy

for Valvular Disease

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

日本脳卒中ガイドライン２００９

●抗血小板薬と抗凝固薬は同等と期待される（グレードB）

(34)

Cryptogenic Stroke+PFO の再発予防に関する

抗血小板薬と抗凝固薬の比較の根拠となる研究は、

お世辞にも質が良いとは言えないPICSSのみである．

にも関わらず、

AHA/ASA、ACCPガイドラインが共に推奨度Class1とは腑に

落ちない・・・

まして

ACCPの推奨根拠のLOEがAとは全く意味不明・・・

Cryptogenic Stroke+PFO で抗血小板薬が

第一選択として推奨されているが、

その根拠となった論文の

Evidence level は低い！！

明確な結論や推奨があるとは言いがたい！！

(35)

Clinical Question

Cryptogenic Stroke ＋ PFO の再発予防

− 第一選択は？

- 抗血小板薬で良いのか？

-  抗凝固薬が良いのか?

(36)

PFO閉鎖術をしたほうがよいか？

下記の用語で、

PubMed searchした．

Search

"Foramen Ovale, Patent"[Mesh] Filters: Clinical Trial

Search

(“Secondary Prevention”[Mesh]) AND "Foramen Ovale, Patent"[Mesh]

Cryptogenic Stroke の再発予防効果に対する

PFO 閉鎖術と薬物療法の RCT が３つヒットした．

①

RESPECT trial. N Engl J Med 2013;368:1092-1100.

②

CLOSURE trial. N Engl J Med 2012;366:991-999.

③

PC trial：N Engl J Med 2013;368:1083-1091. 

また、上記RCTのメタ解析もいくつかヒットした．

④

BMJ Open. 2014;4:e004282.

⑤

Int J Cardiol. 2013;169:101.

⑥

JACC Cardiovas Interven. 2013;6:1316.

症例 生来健康な 54 歳女性 現病歴 急性発症のめまいと歩行障害で救急搬送 頭部 MRIで右小脳半球 PICA 領域の一部に 急性期脳梗塞あり入院 アスピリン開始 急性期管理を行いつつ 脳梗塞の原因検索を開始した

心房中隔壁異常を伴う

Cryptogenic Stroke の再発予防

東京ベイ・浦安市川医療センター

総合内科 原谷浩司

監修 江原淳

Clinical Question 2014年9月29日

J Hospitalist Network

分野：神経

テーマ：治療

症例

生来健康な54歳女性

現病歴

• 急性発症のめまいと歩行障害で救急搬送

• 頭部MRIで右小脳半球PICA領域の一部に

急性期脳梗塞あり入院

• アスピリン開始、急性期管理を行いつつ

脳梗塞の原因検索を開始した

既往歴・薬歴

生来健康 ピル内服なし ５年前に閉経

健康診断でも異常を指摘されたことはない

家族歴

血栓症の家族歴含め特になし

生活歴

喫煙歴なし 専業主婦 流産歴なし

身体所見

小脳系の神経学的所見あり

その他は正常 血圧も正常

心電図

正常洞調律

約１ヶ月間心電図モニターで不整脈なし

血液検査

耐糖能異常なし 脂質異常なし 腎機能正常

血沈正常 RPR/TPHA陰性

凝固能異常screening

PT APTT プロテインC/S AT-III

ループスアンチコアグラント ホモシステイン

抗β２GPI・カルジオリピン抗体

経胸壁心臓超音波検査

異常なし

いずれも異常なし

MR Angio

椎骨脳底動脈解離なし

他の脳血管も目立った狭窄や口径不整なし

頸動脈超音波検査

動脈硬化所見なし 高度狭窄なし

胸腹部〜下肢造影CT

腫瘍や静脈血栓の所見含め特に異常なし

悪性腫瘍の検索

上下部消化管内視鏡 乳房単純X線写真

婦人科診察 など特に異常なし

経食道心臓超音波検査

大動脈プラークなし

PFO（卵円孔開存）なし

ASA（心房中隔瘤）なし

ASD

（心房中隔欠損）所見あり

【まとめ】

• 生来健康の54歳女性が小脳梗塞を発症

• 動脈硬化のリスクファクターは一切なし

• 入院中に不整脈は同定されず

• 血栓性素因や悪性腫瘍の存在、静脈血栓症の併存も否定的

• ただし、経食道心臓超音波検査で

ASDが見つかった

Clinical Question

原因不明の脳梗塞患者に

（=

Cryptogenic Stroke の患者に）

ASD がみつかった場合、

再発予防はどうすればよいか？？

抗血小板薬で良いのか？

抗凝固薬が良いのか？

閉鎖術を行うべきか？

Clinical Question

−

Cryptogenic Stroke とは？

- Cryptogenic Stroke の診断は？

- Cryptogenic Stroke の原因は？

- Cryptogenic Stroke と心房中隔異常

※

症例生来健康な 54 歳女性現病歴急性発症のめまいと歩行障害で救急搬送頭部 MRIで右小脳半球 PICA 領域の一部に急性期脳梗塞あり入院アスピリン開始急性期管理を行いつつ脳梗塞の原因検索を開始した

　　　　　　　　総合内科　原谷浩司

　　　　　　　　　監修　　　　江原淳

　分野：神経

•  急性発症のめまいと歩行障害で救急搬送

•  頭部MRIで右小脳半球PICA領域の一部に  

•  アスピリン開始、急性期管理を行いつつ  

生来健康　ピル内服なし　５年前に閉経

喫煙歴なし　専業主婦　流産歴なし

その他は正常　血圧も正常

耐糖能異常なし　脂質異常なし　腎機能正常

血沈正常　RPR/TPHA陰性

PT　APTT　プロテインC/S　AT-III

ループスアンチコアグラント　ホモシステイン

抗β２GPI・カルジオリピン抗体　

動脈硬化所見なし　高度狭窄なし

上下部消化管内視鏡　乳房単純X線写真

婦人科診察　など特に異常なし

•  生来健康の54歳女性が小脳梗塞を発症

•  動脈硬化のリスクファクターは一切なし

•  入院中に不整脈は同定されず

•  血栓性素因や悪性腫瘍の存在、静脈血栓症の併存も否定的

•  ただし、経食道心臓超音波検査で

Clinical Question 

-  Cryptogenic Stroke の診断は？

-  Cryptogenic Stroke の原因は？

-  Cryptogenic Stroke と心房中隔異常

-  心房中隔壁異常が Cryptogenic Stroke を

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

　①心原性塞栓

　②動脈硬化性

　③ラクナ梗塞 (

-  Cryptogenic Stroke の原因は？

-  Cryptogenic Stroke と心房中隔異常

-  心房中隔壁異常が Cryptogenic Stroke を

- ※心房中隔異常とは下記の３つ

　ASD（Atrial Septal Defect：心房中隔欠損）

　ASA（Atrial Septal Aneurysm：心房中隔瘤）

　PFO（Patent Foramen Ovale：卵円孔開存）

　①心原性塞栓が否定的

　　最低２４時間〜数週間(出来れば30日間)の心電図モニターで

　　心房細動などの不整脈が認められない

　②動脈硬化性

　　大血管動脈硬化リスクファクター、動脈硬化所見、血管炎、

　　動脈解離などの所見がないor乏しい

　③ラクナ梗塞

　　ラクナ梗塞では説明できない