Cryptogenic Stroke and PFO:
The Hole Story:
Anthony J Furlan MD
Gilbert W Humphrey Professor
Chairman Department of Neurology
University Hospitals Case Medical Center
DISCLOSURES
• Principal Investigator
– CLOSURE I
• NMT Medical, Boston
PFO in Embolic Stroke
PFO in stroke:
The principle is sound. How real is the problem?
PRA
RA
PLA
LA
TEE
Patent foramen ovale In Cryptogenic Stroke Study
(PICSS)
Kaplan-Meier curves of cumulative risk of recurrent stroke or death stratified by baseline PFO status.
Homma: Circulation, Volume 105(22).June 4, 2002.2625-2631
Probability That Patients Will Remain Free from Recurrent Stroke or TIA
The log-rank test was used to calculate the P value.
Mas: N Engl J Med, Volume 345(24).December 13, 2001.1740-1746
Kaplan-Meier estimate of survival free of cerebrovascular events in 577 subjects
according to TEE presence of patent foramen ovale (PFO) SPARC Mayo
METHODS: The use of transesophageal echocardiography to identify PFO was performed by a
single echocardiographer using standardized definitions in 585 randomly sampled, Olmsted County
(Minnesota) subjects age 45 years or older participating in the Stroke Prevention: Assessment of
Risk in a Community (SPARC) study.
Meissner, I. et al. J Am Coll Cardiol 2006;47:440-445
PICSS 2-Year Stroke or Death Rate
Warfarin versus Aspirin
20%
18%
16.50%
17.40%
17.90%
16.30%
16%
14%
13.20%
13.40%
12%
9.50%
10%
8.30%
8%
ASA
Warfarin
6%
4%
2%
0%
With PFO
N=203 (P=0.49)
No PFO
N=398 (P=0.40)
With PFO (cryptogenic) No PFO (cryptogenic)
N=98 (P=0.28)
N=152 (P=0.16)
Homma S et al. Circulation. 2002;105:2625-2631.
PFO & Stroke: Metanalysis Outcomes
Transcatheter Closure vs. Medical Therapy of PFO and presumed
Paradoxical event: A systematic review. Landzberg, et al. Annals of
Internal Medicine 2003
Recurrent event
rates @ 1 Yr.
Complication rates
Key Data
Weaknesses
Medical Therapy
3.8 – 12.0%
Major: 1%/yr on
warfarin
Poor match to PFO
population.
Significant
variation in INR
targets.
Catheter Closure
0% - 4.9%
Major: 1.5%
Minor: 7.9%
Significant
selection bias.
Significant
variation in post
implant pharm.
What WAS* the HDE Indication for PFO
Device Closure?
The CardioSEAL Septal Occlusion System is indicated for closure of
PFO in:
a
Patients with recurrent cryptogenic stroke due to presumed paradoxical
embolus through the PFO who have failed medical therapy. Cryptogenic stroke
is defined as a stroke occurring in the absence of potential phanerogenic,
cardiac, pulmonary, vascular, or neurological sources. Conventional drug
therapy is defined as a therapeutic INR on oral anticoagulants. The
effectiveness of this device in this indication has not been demonstrated.
HDE did not include TIA, migraine, or first stroke and required
warfarin failure
*HDE withdrawn by CMS October 2006 with no impact on
CLOSURE recruitment rate
CLOSURE I Cumulative Enrollment (87 sites)
1000
900
N revised
Original N = 1600
Revised N = 900
910
HDE removed 10/06
800
763
700
611
600
500
Total Enrolled
424
400
300
HDE 2/00
189
200
100
21
0
2003
2004
2005
2006
2007
2008
Randomization
Randomization
1:1
N = 909
N=447
N=462
STARFlex®
Closure (within 30 Days)
6 Months Aspirin and Clopidigrel
followed by 18 Months Aspirin
Best Medical Therapy
24 Months Aspirin Or Warfarin
Or Combination
Between June 23, 2003 and October 24, 2008, 909 patients were randomized at 87
sites in the United States and Canada. Block randomization with stratification by study site and
by the presence or absence of an ASA viewed by TEE.
STARFlex®
• Double umbrella
comprised of MP35N
framework with
attached polyester
fabric
• 23mm, 28mm, 33mm
17
STARFlex Technical Success
Procedural success
Thrombus by TEE
STARFlex
n=402
95% CI
90.0%
(86.7% - 92.8%)
1.0%
(n=4; stroke in 2 at days 4, 52)
Effective closure
No recurrent stroke or TIA in
patients with residual leaks
TEE 6 mos
86.1% closed
(82.1% - 89.4%)
TEE 12 mos
86.4% closed
(82.5% - 89.8%)
86.7% closed
(82.8% - 90.0%)
TEE 24 mos
Procedural success was defined as successful delivery of one or more STARFlex devices to the site during the index procedure, deployment of the
device at the intended site, and removal of the delivery system without a major procedural complication prior to discharge. Effective closure was defined
as procedural success with either grade 0 (none) or 1 (trace) residual shunt by TEE.
DM/CABG/valve/CVA day 627
indexACA
Age 60 multiple TIA spells/30 sec focal with DW+/TEE neg
Index punctate MCA
Etiology unclear
Afib/Laclot on day16/stroke day 52
Multiple punctate
Afibflutter/CVA day 22
PAF/valve disease/day 238
StarFlex Arm
Recurrent DWMR+ infarcts
(n= 7/12; wnl 2; not done 3)
heart cath with 3 stents on day 232
LA clot on TEE day 4
Multiple punctate
Afib 3/ LA clot 1/ heart cath 1/ ASO 1
5/7 different area from index
4/7 single territory
2/7 multiple same territory
1/7 multiple territories
Medical Arm - Recurrent DW+ Infarcts
Age 43/day 32/
multiple subcortical/
? MS ? Vasculitis
Clinical TIA
Age 35/d1y 122/migraine/
clinical TIA NIH 0/
Angio neg/ multiple
DW+ BG,IC,cerebellum
?paradoxical
Age 42/day 146/migraine/clinical
TIA/NIH 0/warfarin/?paradoxical
Age 60/migraine with aura/
Day 143sudden left fingers only
NIH 0/old lacunes
Age 59/day 143/htn;smoker;hpl
NIH 3
Age 31/migraine/day 367
Index cerebellar/ ? coincidental
/
Age 42/index R parietal
/recur L parietal day150
Switch to warfarin/
?paradoxical
Day 15/htn/hpl/mitral regurg/
possible extension/age 50
Age 53/Day 635/ASO/LCEA
(n= 9/13; WNL 4: retinal 1/IV tpa 1/minor sxs >24hr ?? migraine 2
6/9 different territory than index ; 5/9 multiple infarcts same territory; 1/9 multiple territories
Exploratory Paradoxical Embolism Analyses
2 Year Composite Primary Endpoint
Set
ITT
ITT
ITT
Characteristic
≤ 50
≤ 50 minus all subsets
<40
P value
0.14*
0.61*
0.10*
ITT
ITT
ITT
<40 minus all subsets
0.40*
No HTN history
0.71
Index crypto stroke minus subcortical 0.54*
ITT
No reported afib
0.10
PP
PP
PP
PP
PP
PP
≤ 50
≤ 40
< 50 minus all subsets
< 40 minus all subsets
No HTN history
Index crypto stroke minus subcortical
0.11*
0.06*
0.62*
0.40*
0.60
0.62*
PP
No reported afib
0.09
*Adjusting performed using Cox Proportional Hazard Regression and adjusting for related
patient characteristics including: age, atrial septal aneurysm, prior TIA/CVA, smoking, hypertension,
hypercholesterolemia , subcortical infarcts. ITT = Intent to Treat. PP = Per Protocol
CONCLUSIONS
• CLOSURE I is the first completed, prospective, randomized,
independently adjudicated PFO device closure study
• Superiority of PFO closure with STARFlex® plus medical
therapy over medical therapy alone was not demonstrated
–
–
–
–
no significant benefit related to degree of initial shunt
no significant benefit with atrial septal aneurysm
insignificant trend (1.8%) favoring device driven by TIA
2 year stroke rate essentially identical in both arms (3%)
• Major vascular (procedural) complications in 3% of device arm
• Significantly higher rate of atrial fibrillation in device arm (5.7%)
– 60% periprocedural
CONCLUSIONS
•
Alternative explanation unrelated to paradoxical embolism present in
80% of patients with recurrent stroke or TIA
– cryptogenic stroke and TIA include multiple etiologies
– in many patients with cryptogenic stroke or TIA a PFO may be coincidental
– diagnostic criteria for paradoxical embolism are imprecise
•
Percutaneous closure with STARFlex® plus medical therapy does not offer any
significant benefit over medical therapy alone for the prevention of recurrent
stroke or TIA in patients < age 60 presenting with cryptogenic stroke or TIA and a
PFO
– initial medical therapy appropriate in most patients
– device specific complications need further study but not likely to explain CLOSURE I
results by themselves
– potential efficacy of PFO device closure in better defined patient subgroups requires
further study
NMT Medical, Inc. Assigns All of Its Assets for the Benefit of Creditors
Company Release - 04/19/2011 16:05
BOSTON, MA -- (MARKET WIRE) -- 04/19/11 -- NMT Medical, Inc. (OTCQB: NMTI) (PINKSHEETS: NMTI) today announced that, despite
the Company's efforts to obtain additional financing and identify potential strategic transactions, it has failed to raise additional funds or enter
into such strategic transaction and, therefore, it has entered into an Assignment for the Benefit of Creditors, effective immediately, in
accordance with Massachusetts law (the "Assignment"). The purpose of the Assignment is to conclude the Company's operations and
provide for an orderly liquidation of its assets. The Company previously disclosed that it did not have resources to sufficiently fund its
continuing business operation and additional capital was required to remain a going concern, and the Company had been seeking strategic
alternatives, including financings, recapitalization, sale or disposition of one or more corporate assets, a potential merger and/or a strategic
business combination, with various third parties over the course of the past year.
The Assignment is a common law business liquidation mechanism under Massachusetts law that is an alternative to a formal bankruptcy
proceeding. Under the terms of the Assignment, the Company transferred all of its assets to an assignee for orderly liquidation and
distribution of the proceeds to the Company's creditors. The designated assignee for the Company is Joseph F. Finn, Jr. For creditors and
other affected parties of NMT Medical, Inc. all inquiries related to this action should be addressed to Joseph F. Finn, Jr. at Finn, Warnke and
Gayton, 167 Worcester Street, Suite 201, Wellesley Hills, MA 02481 (781-237-8840). Following the liquidation of the Company's assets and
distribution of proceeds by the assignee, the Company does not expect that there will be any proceeds for distribution to the Company's
stockholders. As part of the Assignment, the Company has terminated the employment of all of its employees.
This news release contains express or implied forward-looking statements within the meaning of the Private Securities Litigation Reform Act
of 1995 that are based on current expectations of management. These statements relate to, among other things, expectations concerning the
transfer of all of the Company's Assets to an assignee under and Assignment for the Benefit of Creditors and matters relating to the payment
of creditors. These statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are
beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements.
Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the
date hereof. We undertake no obligation to update or revise the information contained in this press release, whether as a result of new
information, future events or circumstances or otherwise. For additional information regarding these and other risks that we face, see the
disclosure contained in our filings with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K and
subsequent Quarterly Reports on Form 10-Q.
Source: NMT Medical
RESPECT
Amplatzer® Occluder
REDUCE Clinical Study
HELEXR occluder
RESPECT
PC TRIAL
CLOSURE v RESPECT v PC
CLOSURE
n=909
RESPECT
n=980
PC
N=414
Inclusion
TIA, stroke
(MR+”TIA”)
stroke (MR+”TIA”)
“TIA” (MR+)
stroke, peripheral
Device
Starflex
clamshell
Amplatzer
plug
Amplatzer
plug
Medical
aspirin
warfarin
aspirin, clopidogrel,
aggrenox
warfarin
aspirin,
ticlopidine,
clopidogrel,warfarin
Outcome
2 years
TIA/stroke
8 years
Event driven
4 years
“TIA”/stroke/
peripheral
Intent to Treat
Primary result
negative
negative
negative
PFO Trials: What Went Wrong
• The question implies we knew the answer
– preconceived biases were not confirmed
• Off label bias caused major recruitment
problems
– need to link device IND with RCT (eg stents)
• Industry disappointed
– NMT went bankrupt
– St Jude FDA pending
– market smaller than industry (and interventionalists)
had hoped
PFO Trials: What Went Wrong
• Any benefit of device likely small
– device specific (thrombus, erosion, afib, residual
shunt)
– subgroup specific
– long followup required
– difficult (? impossible) to power a single trial
• Best medical therapy is unknown
– may be subgroup specific like device
– antiplatelet versus antithrombotic
• role of new antithrombotics unknown
PFO Trials: What Went Wrong
• What endpoint?
– only CLOSURE included classic TIA endpoint
• well defined TIA versus ill defined spell
– but all 3 trials included imaging positive “TIA”
• early MR not routine for TIA
• Evaluation of cryptogenic stroke not
standardized
– cortical v subcortical infarcts
– “hypercoagulopathy”
– atrial fibrillation
PFO Trials: What Went Right
• PFO coincidental in many patients with TIA
or stroke
– indiscriminate device closure halted
– annual stroke risk is low
– patient selection criteria being refined
• PFO is more likely related in some patients compared to
others
• ROPE
– evaluation of cryptogenic stroke being reassessed
“The margin
of potential
benefit for
PFO closure is
narrow.”
6
single subcortical lacune
Risk of Paradoxical Embolism (RoPE) Score
Kent D etal Stroke. 2012;43:A84
Variables negatively associated with the presence of a PFO included: age (odds ratio [OR] = 0.97 per 1 year increase, p <0.0001); diabetes
(OR= 0.65, p < 0.001); hypertension (OR =0.68, p < 0.0001); smoking (OR = 0.70, p<0.60); prior stroke or TIA (OR = 0.78, p=0.04).
Cortical stroke on neuroimaging (OR = 1.46, p < 0.001) was also associated with PFO. Based on this, a simple index was created in which
the absence of each stroke risk factor was assigned a point, with age dichotomized at 50 years. PFO prevalence in each stratum is
shown in the table for patients < age 60, i.e. the subset of patients likely to be considered for PFO closure trials.