2. Patent Foramen Ovale
AJR 2005;184:234–240
Figure Cryptogenic strokeの半分の原因を占める.
2 Transoesophageal echocardiography using Haemaccelâ (contrast agent), showing: (A) small-sized (less
than 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% are
are 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 and
Patent foramen ovale inter-atrial septal abnormalities
PFO, ASDが関連する疾患 Cryptogenic stroke
General overview Transient ischemic attacks
Migraine
Persistent PFO is associated with stroke, decom- Peripheral ischemia
pression sickness (DCS), and other disorders related Platypneaeorthodeoxia syndrome
to paradoxical embolism (Table 4). However, it is Decompression sickness of the divers
still not clear whether this association is causal, Un-explained dementia79
Un-explained syncope
due to predisposition, or have an innocent coinci-
‘‘Economy-class’’ stroke syndrome80
dence. Most evidence for a causal relation exists Obstructive sleep apnea81
for young patients with cryptogenic stroke.1,28 Post-total knee arthroplasty cerebral
Also, PFO may induce hypoxemia that predispose microembolism82
to the platypneaeorthodeoxia syndrome (see
5. PFOが関連する疾患
Eur J Echocardiography (2007) 8, S2eS12
Contrast 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 cerebrovascular
tients with cryptogenic stroke and in approximately complications
a quarter of healthy individuals.30 In a meta-analysis
by Overell et al.31 cryptogenic stroke and tran- The annual stroke recurrence rate in patients with
sient ischemic attacks were significantly associated cryptogenic stroke and PFO with or without ASA
with PFO and/or ASA. In contrast, in a recently pub- varies widely from 1.5% to 14%, depending on the
lished population-based prospective study from study population. Mas et al.2 reported a cumulative
5
the Mayo Clinic4 only ASA, but not PFO, was an inde-
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. 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 60
Morandi40 2003 15/17 88 NA NA NA NA
Schwerzmann91 2004 35/43 81 26/33 79 9/10 90
Azarbal42 2005 24/30 80 16/20 80 8/10 80
Reisman92 2005 35/50 70 NA NA NA NA
Composite 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
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
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. 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
16. PFOのMRI画像
AJR 2005;184:234–240
A
B C D
E F 16 G
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
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 article
Closure 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 RCT
Background
The 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 Medical
higher than that in the general population. Closure with a percutaneous device is Center, Cleveland (A.J.F.); Swedish Medical
Center, Seattle (M.R.); Harvard Clinical
often 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. Table 1. Baseline Characteristics of the Patients.*
Closure Medical Therapy
Baseline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. 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. 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. 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 t
Background
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 percutaneous
closure 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 Clinical
Methods
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.); University
and Australia in which the assessors of end points were unaware of the study-group Hospital, Jagiellonian University Medical
College, Krakow, Poland (D.D.); Aarhus
assignments. Patients with a patent foramen ovale and ischemic stroke, transient University Hospital, Aarhus, Denmark
ischemic 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, Montreal
signed 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 1-6mo
death, 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.
Results
The 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 Patent
the 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 Treatment
therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence in Patients with Cryptogenic Embolism
interval [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. 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. 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 recurrent
ischemic 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 in
preventing 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 of
25 primary end-point events had been observed and adjudicated.
Results
We enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapy
group received one or more antiplatelet medications (74.8%) or warfarin (25.2%).
Treatment exposure between the two groups was unequal (1375 patient-years in the
closure group vs. 1184 patient-years in the medical-therapy group, P = 0.009) owing to
a 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. 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. 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 Event
B 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 Event
Figure 1. Primary End-Point Events in the Intention-to-Treat and As-Treated
Cohorts.
In the intention-to-treat cohort (Panel A), there were 25 primary end-point
events, all of which were recurrent nonfatal ischemic strokes; 9 occurred in
patients who were assigned to the closure group and 16 in patients assigned
to the medical-therapy group. Three patients with recurrent ischemic stroke
N Engl J Med 2013;368:1092-100. 27
who had been randomly assigned to the closure group did not have a device