卵円孔開存

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卵円孔開存

  1. 1. Patent Foramen Ovale American Journal of Therapeutics 16, 562–572 (2009) 成人のPFO  卵円孔は生後数ヶ月で75-80%が2枚の膜が癒合し閉鎖. 20-25%は癒合せず, 開存したまま. この場合, RA圧>LA圧となるとシャントが生じる.  成人におけるTEEでは10-15%でPFO(+). 大半が無症候であり, 特に問題となることは無い.  通常RA圧<LA圧であり, 右左シャントは起こらないが, Isovolumic contraction, 心室拡張早期ではRA>LAとなり, PFOは開通する. この場合普通のエコーでは検出困難.
  2. 2. Patent Foramen Ovale AJR 2005;184:234–240Figure Cryptogenic strokeの半分の原因を占める. 2 Transoesophageal echocardiography using Haemaccelâ (contrast agent), showing: (A) small-sized (lessthan 10 microbubbles), (B) small-to-moderate (more than 10 microbubbles), and (C) large right-to-left shunt. Abbre-viations: AO ¼ PFOは奇異性塞栓の原因となり, PFO ¼ patent foramen ovale and RA ¼ right atrium.  aorta, LA ¼ left atrium, MB ¼ microbubbles, PFO, ASD患者では年間1.5-14%の脳 塞発症率.patient, the largest number of microbubbles de- later).29 In the USA of the 700 000 non-hemorrhagic 大きいほど高リスクとなる.cides the size of shunt. RLSs of different sizes strokes per year 80% are ischemic and 20% areare shown in Fig. 2. cryptogenic.30 PFO and/or ASA with or without  PFOでは心房中隔瘤を Eur J Echocardiography (2007) 8, S2eS12 合併する例も多い. Table 4 Conditions associated with PFO andPatent foramen ovale inter-atrial septal abnormalities  PFO, ASDが関連する疾患 Cryptogenic strokeGeneral overview Transient ischemic attacks MigrainePersistent PFO is associated with stroke, decom- Peripheral ischemiapression sickness (DCS), and other disorders related Platypneaeorthodeoxia syndrometo paradoxical embolism (Table 4). However, it is Decompression sickness of the diversstill not clear whether this association is causal, Un-explained dementia79 Un-explained syncopedue to predisposition, or have an innocent coinci- ‘‘Economy-class’’ stroke syndrome80dence. Most evidence for a causal relation exists Obstructive sleep apnea81for young patients with cryptogenic stroke.1,28 Post-total knee arthroplasty cerebralAlso, PFO may induce hypoxemia that predispose microembolism82to the platypneaeorthodeoxia syndrome (see
  3. 3. PFOの大きさ, 他の構造異常 J Am Coll Cardiol 2001;38:613–23 1100例の剖検例の解析では,  0.2-0.5cmの小さなPFOは29%, 0.6-1.0cmは6%で認められた.  径が大きい程シャント, 脳 塞のリスクとなる. 心房中隔瘤は1.0-1.9%で認められる. (中隔が≥10mm突出している所見)  心房中隔瘤は特に脳 塞群で多く, 15%で合併する.(Controlは4%)  右左シャントにも関連性がある. Chiari network   偽中隔と静脈洞の右弁の残異物であり, 網目状の構造物.  Eustachian valveもしくはThebesian valveと, RAの前壁もしくは心房中隔に付着する.  剖検例の2-3%に認められる構造物.  Eustachian valveと同様, PFOにおける右左シャントを増悪させる. 3
  4. 4. RadioGraphics 2005; 25:441– 453 黒矢印; Eustachian弁 白矢印; Thebesian弁 *; 卵円孔Eustachian弁はIVC弁の遺残物Thebesian弁は静脈洞に隣接する構造物Eustachian弁はPFOにおける右左シャント増悪に関与する. 4
  5. 5. PFOが関連する疾患 Eur J Echocardiography (2007) 8, S2eS12Contrast Echocardiography for Shunt Detection S7 PFO患者におけるTIAの頻度 Table 5 Relationship between PFO and stroke or transient ischemic attack from prospective studies (incidence of stroke or transient ischemic attack among patients with PFO) Author Year Follow-up Echo Patients Stroke or Event rate (%) (yrs) TIA PFO PFO þ ASA No PFO Negative studies Homma26 2002 2 TEE 630 203 (34%)a 14 16 15 3 Meissner 2006 5 TEE 585 41 (7%)b 9 19 7 Positive studies Mas2 2001 4 TEE 581 24 (4%)a 2 15 4 a ¼ recurrent; b ¼ new-onset; ASA ¼ atrial septal aneurysm; PFO ¼ patent foramen ovale; TEE ¼ transesophageal echocardiogra- phy; TIA ¼ transient ischemic attack. All hazard ratios were non-significant.  PFOのみでなく, 心房中隔瘤(+)症例での発症率が高い.PFO are present in approximately half of the pa- PFO and recurrence of cerebrovasculartients with cryptogenic stroke and in approximately complicationsa quarter of healthy individuals.30 In a meta-analysisby Overell et al.31 cryptogenic stroke and tran- The annual stroke recurrence rate in patients withsient ischemic attacks were significantly associated cryptogenic stroke and PFO with or without ASAwith PFO and/or ASA. In contrast, in a recently pub- varies widely from 1.5% to 14%, depending on thelished population-based prospective study from study population. Mas et al.2 reported a cumulative 5the Mayo Clinic4 only ASA, but not PFO, was an inde-
  6. 6. Table 6 Observational and cross-sectional studies (prevalence of PFO among patients with stroke) Author Year Echo Patients Cryptogenic stroke Non-cryptogenic stroke Control PFO/stroke (n) % PFO/stroke (n) % PFO/controls (n) % Negative studies Hausmann83 1992 TEE 238 16/74 22 10/48 21 25/116 22 Jones84 1994 TEE 422 14/71 20 21/149 14 31/202 15 85 Fisher 1995 TEE 1000 39/391 10 NA NA 391/609 9 Positive studies Lechat1 1988 TTE 160 14/26 54 4/19 21 10/100 10 Webster86 1988 TTE 80 20/40 50 NA NA 6/40 15 De Belder5 1992 TEE 198 9/35 26 10/69 14 3/94 3 De Tullio87 1992 TEE 146 22/45 48 4/101 4 NA NA Cabanes6 1993 TEE 150 56/100 56 NA NA 9/50 18 Job71 1994 TCD 137 27/41 66 11/33 33 27/63 43 Van Camp88 1994 TEE 57 6/29 21 NA NA 0/28 0 Abbreviations as in Table 2. NA ¼ Not applicable. PFOと脳 塞 Eur J Echocardiography (2007) 8, S2eS12  Cryptogenic strokeの約半数を占める原因. 特に<55yrの脳 塞では40-60%にPFO(+). Control群でのPFOの頻度は20%前後のみ. 6
  7. 7. Table 8 Improvement of migraine after PFO closure Migraine Migraine with aura Migraine without aura Patients % Patients % Patients %Wilmshurst41 2000 18/21 86 15/16 94 3/5 60Morandi40 2003 15/17 88 NA NA NA NASchwerzmann91 2004 35/43 81 26/33 79 9/10 90Azarbal42 2005 24/30 80 16/20 80 8/10 80Reisman92 2005 35/50 70 NA NA NA NAComposite 127/161 79 57/69 83 20/25 80  PFOと片頭痛 Eur J Echocardiography (2007) 8, S2eS12  特に前兆を伴う片頭痛との関連性が認められている. 微小塞栓, 遺伝性の因子など様々な原因が言われているが, 不明のまま.  PFOの閉鎖により片頭痛頻度は改善することが分かっている. 7
  8. 8. PFOとplatypnea-orthodeoxia syndrome PFOと低酸素血症  PFOにおいて右左シャントが増大することで低酸素を生じる.  PFOの大きさ, 右心肥大, 右心室の拡張障害がシャントに関与. 右心圧が正常例でも生じることが分かっている. 18例の報告では平均年齢は71±6yr[59-79]と高齢. Chest 2001;119;1624-1625  また, 体位性にシャント量が変化し, 酸素化が変化することから, Platypnea-orthodeoxia syndromeとも呼ばれる.  起立 → RA圧上昇, IVC血流低下し, PFOの右左シャントが増大.  治療はPFOの閉鎖のみだが, 肺高血圧合併例では閉鎖により 心拍出量の低下を来すため, 注意が必要. American Journal of Therapeutics 16, 562–572 (2009)
  9. 9. Eustachian valve Figure 1. Anatomic and diagrammatic representation of the right atrium viewed on a frontal or coronal 構造上, SVCからの血流はTVへ流れるが, plane, showing the preferential streamline maps of the flow paths from the superior and inferior caval veins. CS ϭ coronary sinus; CT ϭ crista terminalis; FO ϭ fossa ovalis; IVC ϭ inferior vena cava; SVC ϭ superior vena cava. IVCからの血流は卵円孔に流れやすい. inferior vena cava relative to the atrial septum) anatomically fused flap valve. The other physiologic 特にEustachian valveが残存している患者では inspires a strong opinion that each of these hypoth- eses might be itself responsible for right-to-left and anatomic causes (ie, physiologic transient spon- taneous reversal gradient, changes of right chambers shunting and linked diseases such as paradoxical compliance, and anatomic disarray) may also inter- より卵円孔への血流量が増加し, シャント量も増える. embolism, platypnea-orthodeoxia syndrome,19 mi- graine with aura,20 –22 transient global amnesia,23 and fere with the venous inflow in the adult human heart, but they only play a concomitant role. This basic but decompression sickness in sport divers.24 fundamental knowledge of embryology, anatomy, また, 圧負荷により心房中隔瘤も形成しやすい. However, the major issue regarding the right-to- left shunting despite normal intracardiac pressures is and physiology is capable of leading us to the unanswered question of “what causes water to flow how the definitive right atrium repositions and re- uphill?” and to understanding the mystery of right- models itself, after the right horn of the sinus to-left atrial shunting despite normal intracardiac venosus is incorporated into the right posterior wall pressures. of the developing atrium, giving rise to the sinus Chest 2005;128;998-1002
  10. 10. 他にPlatypnea-orthodeoxiaを来す疾患 Cardiol Clin 2005;23:85-89 心疾患 肺疾患 消化器疾患 PFO, ASD, 心房中隔瘤, 肺気腫, AVM, 肺葉切除後, 肝肺症候群 心嚢水貯留, 大動脈拡張 肺塞栓症 Eustachian valve遺残 収縮性心膜炎 筋骨格系 神経疾患 Deficient abdominal musculature 自律神経障害 Kyphoscoliosis 主に, 換気血流不均衡, 肺, 心内シャント, 低換気状態, 心臓拡張障害が原因となる.  心臓の拡張障害では, 前負荷が低下する(立位)と, COが低下する機序.  自律神経障害では, 立位時の血管収縮障害により, 換気血流不均衡を誘発する機序. 10
  11. 11. PFOの検査 Current Pharmaceutical Design, 2010, 16, 3497-3502 PFOの診断はContrast-enhanced TEEが有用 感度90%, 特異度95%で診断可能.  造影無しのカラードップラーエコーのみでは感度は低下.  エコー中にValsalva法を行うことでシャント量が増加し, より感度が上昇する. 11
  12. 12. for detection of shunts (including TTE, TEE and used aircontained contrast agents such as agitated TCD), because of superior resolution TEE is the saline were not able to pass the pulmonary circula- most commonly used technique for detection of tion; in the normal circulation no contrast agent 右→左シャント評価の造影エコー shunts especially in the current era if PFO closure would appear in the left side of the heart, which is considered.10,11 However, a good Valsalva ma- implied that it was useless for the analysis of noeuvre (see later) is often more difficult to obtain left-sided cardiac morphology. This property, how- from a patient during TEE study, especially S2eS12 Eur J Echocardiography (2007) 8, if he/or ever, forms the basis for visualization of right- she is heavily sedated than can do a patient during to-left shunts (RLSs): if contrast appears in the TTE study. The most relevant contrast studies that 肺毛細血管を通過しない大きさのMicrobubbleを使用した, left side of the heart, there must be a shunt. Cur- compared two or more of the echocardiographic rently, a variety of echocardiographic techniques techniques for the detection of shunts are summa- 経食道エコー, Transcranial echoがシャント評価に有用. are available for visualization of cardiac shunts, rized in Table 2. such as transthoracic (TTE) and transesophageal (TEE) echocardiography and transcranial Doppler 主に使用されるのは撹拌された生理食塩水だが, ultrasonography (TCD). In this article, the value of 他に以下の造影剤が使用される. contrast echocardiography for detection of Table 1 Echo-contrast agents commonly used for shunts and its clinical implications are discussed. shunt detection Emphasis will be on the four most common shunt  20Gの留置針を使用し, Agents Recommended types: PFO, atrial septal defect (ASD), ventricular dose (ml) 三方活栓, 2つの10ccシリンジを使用. septal defect (VSD) and pulmonary arterio-venous malformations (PAVMs). Saline/blood/air 9 ml 0.9% saline/1 ml NS, NS+血液 5-20cc, blood þ 0.1 ml air Dextrose 5% water 10 Echovist® contrast Principles of5-10ccを使用する. D-galactose microparticle 5e10 echocardiography solution (Echovistâ)  通常9µmを超える粒子は肺でTrapされる Urea-linked gelatin 10 (Haemaccelâ)a Microbubble generation Oxypolygelatine 10  検査中はValsalva法, (Gelifundolâ)22 The established theory is that the contrast effect 咳嗽により感度が上昇. is based on microbubbles that are already present a Main agent in our echo-lab used for shunt detection. (無症候のPFO患者では, Valsalva法によりPFO検出率が5%→18%) 12
  13. 13.  TEE, TCDは双方とも感度良好だが, TCDは特異性が低い.  ただしTCDはTEEと比較し, 低侵襲. また外来でも施行可能. American Journal of Therapeutics 16, 562–572 (2009) 13
  14. 14. 造影エコーのS4 右→左シャントへの感度, 特異度 O.I.I. Soliman et al. Eur J Echocardiography (2007) 8, S2eS12 Table 2 Contrast echocardiography for detection of right-to-left shunts (transesophageal echocardiography used as gold standard) Authors Year Patients Echocardiographic Contrast Patients with Sensitivity Specificity technique agent RLS at TEE Di Tullio70 1993 49 TCD Saline 19 68 100 Job71 1994 137 TCD Gelifundolâ 64 89 92 Klotzsch72 ¨ 1994 111 TCD Echovistâ 50 91 94 Devuyst73 1997 37 TCD Saline 24 100 100 Hamann17 1998 44 TCD Echovistâ 22 75 100 Stendel11 2000 92 TCD Echovistâ 24 92 97 Droste74 2000 64 TCD Echovistâ 20 100 65 Di Tullio70 1993 49 TTE-FI Saline 19 47 100 Kuhl75 1999 111 TTE-FI Gelifundolâ 51 62 100 TTE-HI Gelifundolâ 51 92 100 Stendel11 2000 92 TTE-FI Echovistâ 24 42 83 Ha16 2000 136 TTE-FI Saline 40 22 100 TTE-HI Saline 40 63 100 Van Camp76 2000 109 TTE-FI Saline 24 46 100 TTE-HI Saline 24 100 100 Daniels77 2004 256 TTE-HI Saline 53 91 97 FI ¼ fundamental imaging, HI ¼ harmonic imaging, TCD ¼ transcranial Doppler ultrasonography, TTE ¼ transthoracic echocardiography. 14
  15. 15. PFOのMRI所見 AJR 2005;184:234–240 15名のPFO, 5名のControlでTEE, 心臓MRIを施行.  平均年齢49±14名.  TEEの評価; Valsalva法を行いながら施行. Grade 0; RA→LAへの造影剤通過無し. Grade 1; 3-9 microbubblesがRA→LAに通過 Grade 2; 10-30 microbubblesが通過 Grade 3; >30 microbubblesが通過. 心房中隔瘤→ 心房壁が10mm以上右 or 左に貫入している像.  MRIの評価; 造影MRIにてCine MRIを撮影. Grade 0; 造影剤が肺動脈に到達する前にLAが染まらない. Grade 1; 肺動脈が染まる前に, LAが染まるが, 中隔付近の一部のみ Grade 2; 肺動脈が染まる前に, LAが染まるが, 一部のみ Grade 3; 肺動脈が染まる前に, LAが著明に染まる. 15
  16. 16. PFOのMRI画像 AJR 2005;184:234–240 A B C D E F 16 G
  17. 17. Currently, contrast-enhanced MRI cannot A B replace TEE to exclude other potential embo- ■ LAの輝度,with atrial septal aneurysm (arrow) on MRI. Fig. 2.—32-year-old man ○ PAの輝度. lic sources such as thrombus in left atrial ap- pendage. The feasibility of contrast-enhanced A and B, Typical bulging of atrial septum is shown toward left atrium (LA) in horizontal long axis (A) and toward right MRI to exclude this embolic source was not 左がPFO(+), 右がPFO(-) atrium (RA) in short axis (B). addressed in our study and warrants further investigation. Compared with TEE, contrast- cies might reflect the intraindividual variability Another cause for the limited correlation in enhanced MRI examinations currently are  PFO(-)では, 肺動脈とLAはほぼ同時に染まる. of performing the Valsalva maneuver, which is grading scores for both techniques in PFO pa- more expensive and need a longer examina- the most effective way to induce a right-to-left tients can be sought in the limited number of tion time. atrial shunting [20]. If the patient does not per- imaging planes despite the much-improved This pilot study was designed to show the 一方, PFO(+)群では, LAの輝度は2峰性をとるのがPoint. form a Valsalva maneuver correctly, a PFO can temporal and spatial resolution. We used two potential of this new application to evaluate be missed [21]. Therefore, deep sedation might different imaging planes in the present study. and grade PFO and to detect atrial septal an- alter the cooperation required to perform this For a more reliable quantification, a 3D vol- eurysms. A larger prospective study is needed maneuver and thus bias the degree of shunt ob- ume would be needed. This is currently avail- to confirm our findings and to show the pre- served. This might pose a problem in patients able for neither TEE nor contrast-enhanced dictive value of PFO grading for clinical out- who cannot tolerate the transesophageal probe MRI. Because of the opposite anatomic posi- come. Our initial contrast-enhanced MRI or the contrast-enhanced MRI investigation tion of the ostium of the inferior vena cava in experience, however, encourages the design without IV sedation. relation to the fossa ovalis, a contrast injec- of studies to show the feasibility of contrast- AJR 2005;184:234–240 500 600 450 500 400 350 Baseline Signal (%) 400 Baseline Signal (%) 300 250 300 200 200 150 100 100 50 0 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 Time (sec) Time (sec) 17
  18. 18. PFOの治療 Eur J Echocardiography (2007) 8, S2eS12 PFO + TIA or Stroke患者の治療  TIA, StrokeでPFOを認める全患者でPFOの閉鎖治療が推奨される. 困難な場合は予防目的のアスピリン, ワーファリンが推奨される.  また, <55yrの脳 塞, TIA症例ではPFOの精査が推奨. >> PFO, 右→左シャントのみの場合は,   内科治療, 外科治療の選択肢を提示し, 患者と相談. >> PFOと心房中隔瘤がある場合はHigh riskであり,   PFOの閉鎖が強く推奨される. 18
  19. 19. 脳 塞+PFO患者のRCT The n e w e ng l a n d j o u r na l of m e dic i n e original articleClosure or Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale Anthony J. Furlan, M.D., Mark Reisman, M.D., Joseph Massaro, Ph.D., Laura Mauri, M.D., Harold Adams, M.D., Gregory W. Albers, M.D., Robert Felberg, M.D., Howard Herrmann, M.D., Saibal Kar, M.D., Michael Landzberg, M.D., Albert Raizner, M.D., and Lawrence Wechsler, M.D., for the CLOSURE I Investigators* N Engl J Med 2012;366:991-9.  CLOSURE I trial;   A BS T R AC T  18-60歳のcryptogenic strokeで, PFO(+)であった909例のopen-label RCTBackgroundThe prevalence of patent foramen ovale among patients with cryptogenic stroke isTherapyに割り付け, 2年フォロー.  カテーテルによるPFO閉鎖術 vs Medical From University Hospitals Case Medicalhigher than that in the general population. Closure with a percutaneous device is Center, Cleveland (A.J.F.); Swedish Medical Center, Seattle (M.R.); Harvard Clinicaloften recommended in such patients, but it + not known whether this intervention Research Institute (J.M., L.M.) and PFOは造影TEE is バルサルバ法で心房レベルでの右左シャントで評価.reduces the risk of recurrent stroke. Brigham and Women’s Hospital (M.L.) — both in Boston; University of Iowa,Methods  カテーテル治療群; 閉鎖後にClopidogrel 75mg/d 6mo Stanford University Iowa City (H.A.); + ASA 81-325mg 2yr. Medical Center, Palo Alto, CA (G.W.A.);We conducted a multicenter, randomized, open-label trial of closure with a percu- Geisinger Medical Center, Danville, PA  Medical Therapy; ワーファリン, ASA or 併用療法.taneous device, as compared with medical therapy alone, in patients between 18 and (R.F.); University of Pennsylvania, Philadel- phia (H.H.); Cedars–Sinai Medical Center,60 years of age who presented with a cryptogenic stroke or transient ischemic attack Los Angeles (S.K.); Methodist Hospital,
  20. 20. Table 1. Baseline Characteristics of the Patients.* Closure Medical TherapyBaselineのデータ. Characteristic Age — yr (N = 447) (N = 462) P Value Mean† 46.3±9.6 45.7±9.1 0.39 Range 18–60 18–60 Male sex — no. of patients (%) 233 (52.1) 238 (51.5) 0.89 Race or ethnic group — no. of patients (%)‡ 0.53 Asian 7 (1.6) 8 (1.7) Black 19 (4.2) 26 (5.6) White 398 (89.0) 414 (89.6) Hispanic or Latino 30 (6.7) 22 (4.8) Cigarette smoking during the previous year — 96/447 (21.5) 104/460 (22.6) 0.69 no. of patients/total no. (%) Blood pressure — mm Hg Mean§ 91.7±10.6 92.3±10.7 0.37 Range 59–127 63–137 Medical history — no. of patients (%) Hypertension 151 (33.8) 131 (28.4) 0.08 Hypercholesterolemia 212 (47.4) 189 (40.9) 0.05 Family history of cardiovascular disease 247 (55.3) 257 (55.6) 0.95 Congestive heart disease 2 (0.4) 0 0.24 Ischemic heart disease 6 (1.3) 4 (0.9) 0.54 Myocardial infarction 7 (1.6) 5 (1.1) 0.57 Valvular dysfunction 49 (11.0) 45 (9.7) 0.59 Arrhythmia 26 (5.8) 19 (4.1) 0.28 Catheterization 23 (5.1) 17 (3.7) 0.33 PTCA 6 (1.3) 2 (0.4) 0.17 Peripheral vascular disease 5 (1.1) 7 (1.5) 0.77 Stokes–Adams syndrome 4 (0.9) 3 (0.6) 0.72 Pulmonary embolus 0 4 (0.9) 0.12 Pericarditis 2 (0.4) 3 (0.6) 1.00 Cardiomyopathy 1 (0.2) 0 0.49 Index neurologic event for study entry — 0.71 no. of patients/total no. (%) Cryptogenic stroke 324/446 (72.6) 329/461 (71.4) TIA 122/446 (27.4) 132/461 (28.6) Result on TEE — no. of patients (%) N Engl J Med 2012;366:991-9. Moderate or substantial shunt 250 (55.9) 231 (50.0) 0.07 Atrial septal aneurysm ≥10 mm 168 (37.6) 165 (35.7) 0.56
  21. 21. Table 2. Kaplan–Meier Event Rates for Primary End Point at 2 Years.* Closure Medical Therapy Hazard Ratio End Point (N = 447) (N = 462) (95% CI)†‡ P Value† Intention-to-treat population Composite end point — no. (%) 23 (5.5) 29 (6.8) 0.78 (0.45–1.35) 0.37 Stroke — no. (%) 12 (2.9) 13 (3.1) 0.90 (0.41–1.98) 0.79 TIA — no. (%) 13 (3.1) 17 (4.1) 0.75 (0.36–1.55) 0.44 Modified intention-to-treat population Composite end point — no./total no. (%) 22/400 (5.6) 29/451 (6.9) 0.78 (0.44–1.35) 0.37 Stroke — no./total no. (%) 12/400 (3.1) 13/451 (3.1) 0.94 (0.43–2.07) 0.88 TIA — no./total no. (%) 12/400 (3.0) 17/451 (4.2) 0.72 (0.34–1.51) 0.38 Per-protocol population Composite end point — no./total no. (%) 22/378 (5.8) 29/375 (7.7) 0.74 (0.42–1.29) 0.28 Stroke — no./total no. (%) 12/378 (3.2) 13/375 (3.5) 0.91 (0.41–1.99) 0.80 TIA — no./total no. (%) 12/378 (3.2) 17/375 (4.6) 0.68 (0.33–1.43) 0.31* Percentages in parentheses are Kaplan–Meier estimates of the event rates. Totals for the composite-end-point categories Outcome; 2年以内の脳 塞リスク, TIAリスクは両者で変わらない. may be higher than the sum of the individual events in that category, since some patients may have had both types of events (i.e., stroke and transient ischemic attack [TIA]).† Values were adjusted with the use of Cox proportional-hazards regression for age, presence or absence of atrial septal aneurysm, presence or absence of a history of TIA or cerebrovascular accident, and status with respect to smoking, hy- pertension, and hypercholesterolemia.‡ The hazard ratio was calculated for the closure group as compared with the medical-therapy group.shunt (see the Supplementary Appendix). Throm- ment effect in subgroups, including2012;366:991-9. N Engl J Med those defined
  22. 22. Medical P Value for Subgroup Closure Therapy Hazard Ratio (95% CI) P Value Interaction no. of patients/total no. (%) Overall modified intention-to-treat 22/400 (5.6) 29/451 (6.9) 0.78 (0.44–1.35) 0.37 population Sex 0.16 Male 7/208 (3.4) 15/232 (6.8) 0.50 (0.20–1.22) 0.13 Female 15/192 (7.9) 14/219 (7.0) 1.13 (0.55–2.34) 0.74 Atrial septal aneurysm 0.95 No 15/249 (6.2) 20/291 (7.4) 0.81 (0.42–1.59) 0.55 Yes 7/151 (4.6) 9/160 (6.0) 0.78 (0.30–2.13) 0.64 Shunt size 0.78 None or trace 8/118 (6.9) 10/155 (6.8) 0.99 (0.39–2.52) 0.99 Moderate 7/144 (5.0) 12/163 (7.9) 0.61 (0.24–1.55) 0.30 Substantial 3/87 (3.5) 3/65 (4.9) 0.72 (0.15–3.57) 0.69 Entry event 0.33 Stroke 15/300 (5.1) 15/324 (5.1) 1.01 (0.49–2.07) 0.98 Transient ischemic attack 7/100 (7.1) 14/126 (11.6) 0.60 (0.24–1.49) 0.27 Baseline medication None 0/13 (0) 2/38 (5.9) — — 0.65 Aspirin alone 15/286 (5.3) 16/252 (6.7) 0.79 (0.39–1.59) 0.50 Warfarin alone 1/25 (4.2) 8/111 (7.9) 0.52 (0.06–4.12) 0.53 Aspirin plus warfarin 6/72 (8.5) 2/40 (5.4) 1.59 (0.32–7.89) 0.57 0.1 1.0 10.0 Closure Medical Therapy Better Better Figure 2. Results of Primary-End-Point Analysis at 2 Years, According to Subgroup, in the Modified Intention-to-Treat Population. Percentages in parentheses are Kaplan–Meier estimates of the event rates.心室中隔瘤の有無, シャント率の大きさ required sample size would have been prohibi- Of particular note was the increased rate of tively large if stroke had been used as the only end atrial fibrillation in the closure group. Atrial fibril-Medical therapy群の治療選択(ASA単独,been reported in 5 to 20% of patients in point.26,27 The 2-year rate of stroke (approxi- lation has ワーファリン単独, 併用)別の mately 3%) was low and virtually identical in the whom a patent foramen ovale was closed with the評価でも特に両者で有意差は認められない. closure and medical-therapy groups, suggesting use of various devices.25,28,29 OccultN Engl J Med 2012;366:991-9. atrial fibrilla-
  23. 23. new england The N Engl J Med 2013;368:1083-91. journal of medicine established in 1812 march 21, 2013 vol. 368 no. 12 Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism Bernhard Meier, M.D., Bindu Kalesan, Ph.D., Heinrich P. Mattle, M.D., Ahmed A. Khattab, M.D., David Hildick-Smith, M.D., Dariusz Dudek, M.D., Grethe Andersen, M.D., Reda Ibrahim, M.D., Gerhard Schuler, M.D., Antony S. Walton, M.D., Andreas Wahl, M.D., Stephan Windecker, M.D., and Peter Jüni, M.D., for the PC Trial Investigators* A bs t r ac tBackground  PC trial; PFO(+)で脳 塞, TIA, 血栓症を来した414名のRCT.The options for secondary prevention of cryptogenic embolism in patients with pat- From the Departments of Cardiology  患者は≤60y, TEEでPFOを認め, 他に血栓症の原因が認めない患者群.ent foramen ovale are administration of antithrombotic medications or percutaneousclosure of the patent foramen ovale. We investigated whether closure is superior to (B.M., B.K., A.A.K., A.W., S.W.) and Neu- rology (H.P.M.), Bern University Hospi- tal, and the Institute of Social and Pre-medical therapy. ventive Medicine (B.K., P.J.) and ClinicalMethods  Amplatzerを用いたPFO閉鎖療法群 vs 薬剤治療群に割り付け, Trials Unit (B.K., P.J.), University of Bern — both in Bern, Switzerland; Brighton and Sussex University Hospitals, Brighton,We performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil,  塞栓症, 脳 塞, TIAの再発リスクを比較. United Kingdom (D.H.-S.); Universityand Australia in which the assessors of end points were unaware of the study-group Hospital, Jagiellonian University Medical College, Krakow, Poland (D.D.); Aarhusassignments. Patients with a patent foramen ovale and ischemic stroke, transient University Hospital, Aarhus, Denmarkischemic attack (TIA), or a peripheral thromboembolic event were randomly as-  薬剤療法; ASA 100-325mg/d 5-6m以上 + 以下のどちらか. (G.A.); University of Montreal, Montrealsigned to undergo closure of the patent foramen ovale with the Amplatzer PFO (R.I.); Herzzentrum Leipzig, Leipzig, Germany (G.S.); and Alfred Hospital,Occluder or to receive medical therapy. The primary end point was a composite of Melbourne, VIC, Australia (A.S.W.). Ad- Ticlopidine 250-500mg/d or Clopidogrel 75-150mg/d 1-6modeath, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data dress reprint requests to Dr. Meier at the Department of Cardiology, Bern Univer-for the intention-to-treat population. sity Hospital, 3010 Bern, Switzerland, or at bernhard.meier@insel.ch.ResultsThe mean duration of follow-up was 4.1 years in the closure group and 4.0 years in * Investigators in the Clinical Trial Com- paring Percutaneous Closure of Patentthe medical-therapy group. The primary end point occurred in 7 of the 204 patients Foramen Ovale Using the Amplatzer(3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical- PFO Occluder with Medical Treatmenttherapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence in Patients with Cryptogenic Embolisminterval [CI], 0.24 to 1.62; P = 0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the (PC Trial) are listed in the Supplemen- 23 tary Appendix, available at NEJM.org.
  24. 24. Table 2. Clinical Outcomes.* PFO Closure Medical Therapy Hazard Ratio or Relative Outcome (N = 204) (N = 210) Risk (95% CI)† P Value no. of patients (%) Primary composite outcome of death, stroke, 7 (3.4) 11 (5.2) 0.63 (0.24–1.62) 0.34 TIA, or peripheral embolism Death‡ 2 (1.0) 0 5.20 (0.25–107.61) 0.24 Cardiovascular 0 0 NA Noncardiovascular 2 (1.0) 0 5.20 (0.25–107.61) 0.24 Thromboembolic event Stroke§ 1 (0.5) 5 (2.4) 0.20 (0.02–1.72) 0.14 TIA 5 (2.5) 7 (3.3) 0.71 (0.23–2.24) 0.56 Peripheral embolism 0 0 NA Secondary composite outcome of stroke, TIA, 5 (2.5) 11 (5.2) 0.45 (0.16–1.29) 0.14 or peripheral embolism * NA denotes not applicable, PFO patent foramen ovale, and TIA transient ischemic attack. † アウトカム; 4年間のフォローにて, Hazard ratios were calculated by means of the Cox proportional-hazards model. For the comparison of deaths (for which one group had no events), the relative risk was calculated instead of the hazard ratio with the use of continuity correction, and the corresponding P value was obtained by means of a two-sided Fisher’s exact test. ‡ One  塞栓症は両群で有意差無し. 死亡リスクも変わらない. other died from a glioma. patient died of respiratory failure because of chronic obstructive pulmonary disease; the § All listed strokes were major strokes.  Sub-analysisでも有意差は認められなかった. ing studies (Table 2, and Fig. S4, S5, and S6 in Adverse Events  合併症, 副作用も両者同等. the Supplementary Appendix). TIAs occurred in A total of 113 adverse events were reported in five patients (2.5%) and seven patients (3.3%), 71 patients (34.8%) in the closure group and respectively (hazard ratio, 0.71; 95% CI, 0.23 to 120 events in 62 patients (29.5%) in the medical-N Engl J Med 2013;368:1083-91. 24 2.24; P = 0.56). There were no peripheral embolic therapy group (Table 3). Of these, 60 events in
  25. 25. original article N Engl J Med 2013;368:1092-100. Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke John D. Carroll, M.D., Jeffrey L. Saver, M.D., David E. Thaler, M.D., Ph.D., Richard W. Smalling, M.D., Ph.D., Scott Berry, Ph.D., Lee A. MacDonald, M.D., David S. Marks, M.D., and David L. Tirschwell, M.D., for the RESPECT Investigators*  RESPECT A bs t r ac t trial; 18-60yのCryptogenic strokeでBackground  PFOを認める980名を対象としたRCT.Whether closure of a patent foramen ovale is effective in the prevention of recurrentischemic stroke in patients who have had a cryptogenic stroke is unknown. We con-ducted a trial to evaluate whether closure is superior to medical therapy alone inpreventing recurrent ischemic stroke vs 薬物療法群に割り付け, 脳  PFO閉鎖術 or early death in patients 18 to 60 years of age. 塞再発率を比較.Methods 薬物療法; ASA, clopidogrel, warfarin, dipyridamole.In this prospective, multicenter, randomized, event-driven trial, we randomly as-signed patients, in a 1:1 ratio, to medical therapy alone or closure of the patent 閉鎖術; カテーテルにて閉鎖. 閉鎖後ASA+clopidogrel 1m, ASA 5m継続.foramen ovale. The primary results of the trial were analyzed when the target of25 primary end-point events had been observed and adjudicated.ResultsWe enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapygroup received one or more antiplatelet medications (74.8%) or warfarin (25.2%).Treatment exposure between the two groups was unequal (1375 patient-years in theclosure group vs. 1184 patient-years in the medical-therapy group, P = 0.009) owing toa higher dropout rate in the medical-therapy group. In the intention-to-treat cohort,9 patients in the closure group and 16 in the medical-therapy group had a recur- 25
  26. 26. Closure Medical-Therapy P Value by P Value for Subgroup Group Group Hazard Ratio (95% CI) Log-Rank Test Interaction no. of patients/total no. (%) Overall 9/499 (1.8) 16/481 (3.3) 0.49 (0.22–1.11) 0.08 Age 0.52 18–45 yr 4/230 (1.7) 5/210 (2.4) 0.70 (0.19–2.60) 0.59 46–60 yr 5/262 (1.9) 11/266 (4.1) 0.41 (0.14–1.17) 0.08 Sex 0.73 Male 5/268 (1.9) 10/268 (3.7) 0.45 (0.15–1.31) 0.13 Female 4/231 (1.7) 6/213 (2.8) 0.57 (0.16–2.02) 0.38 Shunt size 0.07 None, trace, or moderate 7/247 (2.8) 6/244 (2.5) 1.03 (0.35–3.08) 0.95 Substantial 2/247 (0.8) 10/231 (4.3) 0.18 (0.04–0.81) 0.01 Atrial septal aneurysm 0.10 Present 2/180 (1.1) 9/169 (5.3) 0.19 (0.04–0.87) 0.02 Absent 7/319 (2.2) 7/312 (2.2) 0.89 (0.31–2.54) 0.83 Index infarct topography 0.39 Superficial 5/280 (1.8) 12/269 (4.5) 0.37 (0.13–1.04) 0.05 Small deep 2/57 (3.5) 1/70 (1.4) 1.76 (0.16–19.93) 0.64 Other 2/157 (1.3) 3/139 (2.2) 0.56 (0.09–3.34) 0.52 Planned medical regimen 0.20 Anticoagulant 4/132 (3.0) 3/121 (2.5) 1.14 (0.26–5.10) 0.86 Antiplatelet 5/367 (1.4) 13/359 (3.6) 0.34 (0.12–0.94) 0.03 0.01 0.10 1.00 10.00 Closure Better Medical Therapy Better Figure 2. Analysis of the Primary End-Point According to Subgroup, in the Intention-to-Treat Cohort. Potential heterogeneity of the treatment effect was noted with respect to two baseline characteristics, with a suggestion of greater risk アウトカム N Engl J Med 2013;368:1092-100. reductions with closure than with medical therapy alone in patients with an atrial septal aneurysm or a substantial shunt size. The per- centages are Kaplan–Meier estimates of the event rates.  イベント率は両者で有意差無し. Sub-analysisではAtrial septal aneurysm(+)でのみ有意差あり. The strengths of RESPECT include the ran- Point estimates for the relative reduction in domized design; the frequency of monitoring at recurrent ischemic strokes with closure versus また, 抗血小板療法のみよりは抗凝固療法のほうが予防率は良好 all sites; the adjudication of end-point events by medical therapy alone were large, but the abso-
  27. 27. A Intention-to-Treat Cohort 1.0 0.9 0.8 1.00 0.99 Closure group  Study毎では有意差ないが, Event-free Probability 0.98 (N=9) 0.7 0.97 0.6 0.96 0.5 0.95 0.94  PFO閉鎖療法の方が若干の 0.93 Medical-therapy group 0.4 0.92 0.3 0.91 0.90 (N=16) 優位性が見込める可能性がある. 0 1 2 3 4 5 6 7 0.2 0.1 Hazard ratio, 0.49 (95% CI, 0.22–1.11) P=0.08 by log-rank test  大規模StudyやMetaでは 0.0 0 1 2 3 4 5 6 7 有意差がでるかもしれない. Years to EventB As-Treated Cohort 1.0 0.9 1.00 0.8 0.99 Event-free Probability 0.98 0.7 0.97 Closure group 0.96 (N=5) 0.6 0.95 0.5 0.94 0.93 0.4 0.92 Medical-therapy group 0.91 (N=16) 0.3 0.90 0 1 2 3 4 5 6 7 0.2 Hazard ratio, 0.27 (95% CI, 0.10–0.75) 0.1 P=0.007 by log-rank test 0.0 0 1 2 3 4 5 6 7 Years to EventFigure 1. Primary End-Point Events in the Intention-to-Treat and As-TreatedCohorts.In the intention-to-treat cohort (Panel A), there were 25 primary end-pointevents, all of which were recurrent nonfatal ischemic strokes; 9 occurred inpatients who were assigned to the closure group and 16 in patients assignedto the medical-therapy group. Three patients with recurrent ischemic stroke N Engl J Med 2013;368:1092-100. 27who had been randomly assigned to the closure group did not have a device
  28. 28. PFO閉鎖治療 AACN Clinical Issues 2005;16:252–266 外科的治療は98-100%の閉鎖成功率だが, 開胸であり侵襲高. カテーテル治療  人工心肺, 開胸の必要がなく, 低侵襲と言えるが, 合併症はそこそこある.  術後1, 3, 6, 12moフォローが必要であり, 挿入時に何かしらの合併症を認めた場合は, 術後5年間は毎年検査が必要.  カテーテル治療の合併症は, 血栓症(<2%), シャント残存(<4%), 不整脈(<5%), ASD/septal size mismatch(<5%)   血栓症のリスクは高く, 術後3-6moはワーファリン or アスピリン投与を推奨している.  また, 感染性心膜炎のリスクも上昇. 28

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