Transcript Recurrent Stroke with Patent Foramen Ovale

©2016 American Academy of Neurology
Practice Advisory (Update of Practice Parameter)
Recurrent Stroke with Patent Foramen Ovale
Report by:
Guideline Development, Dissemination, and Implementation Subcommittee
of the American Academy of Neurology
©2016 American Academy of Neurology
Practice Advisory Funding
This practice advisory was developed with financial support
from the American Academy of Neurology (AAN). Authors who
serve as AAN subcommittee members or methodologists
(S.R.M., G.G.) were reimbursed by the AAN for expenses
related to travel to subcommittee meetings where drafts of
manuscripts were reviewed.
©2016 American Academy of Neurology
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©2016 American Academy of Neurology
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Presentation Objectives
• To present the evidence systematically reviewed in
the update to the 2004 AAN guideline for patients
with stroke and patent foramen ovale (PFO)
 Whether percutaneous closure of PFO is superior to medical
therapy alone
 Whether anticoagulation is superior to antiplatelet therapy
for the prevention of recurrent stroke
• To present practice recommendations
©2016 American Academy of Neurology
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Overview
 Introduction
 Clinical questions
 AAN practice advisory process
 Methods
 Conclusions
 Practice recommendations
©2016 American Academy of Neurology
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Introduction
• In 2004, the AAN published a practice guideline addressing secondary stroke in
patients with PFO.
• The guideline concluded that the optimal therapy for secondary stroke prevention
in this population was unknown.1
• Since that time, additional studies necessitated that we update our prior guideline,
addressing the following therapeutic questions:
1.
2.
In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does percutaneous
PFO closure reduce the risk of stroke recurrence compared with medical therapy alone?
In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does
anticoagulation reduce the risk of stroke recurrence compared with antiplatelet medication?
• This practice advisory is not intended to be a comprehensive guideline for the
management of other stroke risk factors or causes. The primary audiences are
neurologists, cardiologists, and other clinicians caring for patients with cryptogenic
ischemic stroke and PFO.
©2016 American Academy of Neurology
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Clinical Questions
Clinical Question 1
• In patients with a PFO who have had a cryptogenic ischemic
stroke or TIA, does percutaneous PFO closure reduce the risk of
stroke recurrence compared with medical therapy alone?
Clinical Question 2
• In patients with a PFO who have had a cryptogenic ischemic
stroke or TIA, does anticoagulation reduce the risk of stroke
recurrence compared with antiplatelet medication?
©2016 American Academy of Neurology
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AAN Practice Advisory Process*
• Clinical Question
• Evidence
• Conclusions
• Modified Delphi Consensus
• Recommendations
*Practice advisory developed using the 2011 AAN Clinical Practice Guideline Process Manual, as amended.
©2016 American Academy of Neurology
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Literature Search/Review
Rigorous, Comprehensive, Transparent
809 abstracts
Searched: EMBASE, MEDLINE (via PubMED), and Cochrane
databases from 20022014
Inclusion criteria:
Exclusion criteria:
• Randomized studies pertinent to
the questions
• Primary outcomes of interest:
recurrent ischemic stroke or the
combination of stroke and death
(or both)
• Studies in animals or languages
other than English
• TIAs from assessed outcomes when
feasible because TIA is subjective3
5 rated
articles
©2016 American Academy of Neurology
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AAN Classification of Evidence
Therapeutic Scheme (2011 amended in 2015)
Class I
 Randomized controlled clinical trial (RCT) in a representative population
 Masked or objective outcome assessment*
 Relevant baseline characteristics are presented and substantially equivalent between treatment groups, or there is
appropriate statistical adjustment for differences
 Also required:
a. Concealed allocation
b. No more than 2 primary outcomes specified
c. Exclusion/inclusion criteria clearly defined
d. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers
with numbers sufficiently low to have minimal potential for bias
e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also
required*:
· 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority
· 2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard
treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to those previously shown to be effective)
· 3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to
those of previous studies establishing efficacy of the standard treatment
· 4. The interpretation of the study results is based on a per-protocol analysis that accounts for dropouts or crossovers
f. For crossover trials, both period and carryover effects examined and statistical adjustments performed, if
appropriate
Note: Numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III
*Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias
(e.g., blood tests, administrative outcome data).
©2016 American Academy of Neurology
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AAN Classification of Evidence
Therapeutic Scheme (2011 amended in 2015)
Class II
• An RCT that lacks 1 or 2 criteria
ae (see Class I) or a prospective
matched cohort study meeting
criteria be (see Class I)
• Randomized crossover trial
missing 1 of the following 2
characteristics:
a. Period and carryover effects
described
b. Baseline characteristics of
treatment order groups
presented
• All relevant baseline
characteristics are presented and
substantially equivalent among
treatment groups, or there is
appropriate statistical
adjustment for differences
• Masked or objective outcome
assessment
Class III
• Controlled studies (including
external controls)
• Crossover trial missing both of
the following 2 criteria:
a. Period and carryover effects
described
b. Baseline characteristics
presented
• A description of major
confounding differences
between treatment groups that
could affect outcome*
• Outcome assessment masked,
objective, or performed by
someone who is not a member
of the treatment team
Class IV
• Did not include patients with the
disease
• Did not include patients receiving
different interventions
• Had undefined or unaccepted
interventions or outcome
measures
• Had no measures of
effectiveness or statistical
precision presented or calculable
*Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).
©2016 American Academy of Neurology
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AAN Conclusions and Recommendation
• Confidence in evidence anchored to the studies’ risk of bias




Highly likely or highly probable* = high confidence level
Likely or probable = moderate confidence level
Possibly = low confidence level
Insufficient evidence = very low confidence level




Evidence systematically reviewed
Strong evidence derived from related conditions
Axiomatic principles of care
Inferences made from one or more statements in the recommendation rationale





Must (or must not) = Level A (strong)
Should (or should not) = Level B (moderate)
May (or may not) = Level C (weak)
Should not = Level R (restricted to research setting only)
No recommendation made = Level U (insufficient evidence)
• Recommendations informed by premises
• Clinician level of obligation assigned (modified Delphi)
*Italics denotes language that would appear in the conclusions or recommendations
©2016 American Academy of Neurology
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Clinical Question 1
In patients with a PFO who have had a cryptogenic
ischemic stroke or TIA, does percutaneous PFO closure
reduce the risk of stroke recurrence compared with
medical therapy alone?
©2016 American Academy of Neurology
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From Evidence to Conclusion
[The advisory authors] judged that the differences
between the STARFlex and AMPLATZER PFO Occluder
were sufficient to warrant separate evidence
syntheses and conclusions.
©2016 American Academy of Neurology
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STARFlex
• For patients with cryptogenic stroke and PFO,
percutaneous PFO closure with the STARFlex device
 possibly does not provide a large benefit in preventing
stroke in place of medical therapy alone—RD 0.13%, 95%
CI -2.2% to 2.0%; possibly increases the risk of newonset atrial fibrillation (AF)—RD 5%, 95% CI 2%–8% (1
Class I study, confidence downgraded to low for risk of
bias relative to magnitude of effect);
 probably is associated with a serious periprocedural
complication risk of 3.2%, 95% CI 1.9–5.2% (1 Class I
study).
©2016 American Academy of Neurology
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AMPLATZER PFO Occluder
• For patients with cryptogenic stroke and PFO,
percutaneous PFO closure with the AMPLATZER PFO
Occluder
 possibly decreases the risk of recurrent stroke—RD -1.68%,
95% CI -3.18% to -0.19%;
 possibly increases the risk of new-onset AF—RD 1.64%, 95% CI
0.07%–3.2% (2 Class I studies; confidence downgraded to low
for risk of bias relative to magnitude of effect and
imprecision);
 is highly likely to be associated with a procedural
complication risk of 3.4%, 95% CI 2.3%–5% (2 Class I studies).
©2016 American Academy of Neurology
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Recommendations: Clinical Question 1
Level A
©2016 American Academy of Neurology
• Clinicians must counsel patients considering percutaneous
PFO closure that having a PFO is common; it occurs in about
1 in 4 people; it is impossible to determine with certainty
whether their PFOs caused their strokes or TIAs; the
effectiveness of the procedure for reducing stroke risk
remains uncertain; and the procedure is associated with
relatively uncommon, yet potentially serious,
complications.
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Recommendations: Clinical Question 1
Level R
• Clinicians should not routinely offer percutaneous PFO
closure to patients with cryptogenic ischemic stroke outside
of a research setting.
Level C
• In rare circumstances, such as recurrent strokes despite
adequate medical therapy with no other mechanism
identified, clinicians may offer the AMPLATZER PFO Occluder
if it is available.
©2016 American Academy of Neurology
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Random-effects Meta-Analyses of Risk
Differences
AMPLATZER PFO Occluder closure vs medical therapy
alone. Outcome stroke. Risk difference in percent.
©2016 American Academy of Neurology
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Meta-Analysis of AMPLATZER PFO Occluder
Studies Using Hazard Ratios
Forest plot with 95% Confidence Intervals
Author Year
Effect Variance
RESPECT
0.490
0.170
PC Trial
0.200
1.291
Summary (FE)
0.441
0.151
I squared:
©2016 American Academy of Neurology
0%
0.01
0.10
1.00
10.00
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Clinical Question 2
In patients with a PFO who have had a cryptogenic
ischemic stroke or TIA, does anticoagulation reduce the
risk of stroke recurrence compared with antiplatelet
medication?
©2016 American Academy of Neurology
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From Evidence to Conclusion
• Using a random-effects meta-analysis (appendix e9 of the published practice advisory), there was no
significant difference between treatments, and the
summary estimate of effect was an RD of 2%
favoring antiplatelet treatment (95% CI -21% to
25%). The CI of the pooled effect included
potentially substantial benefits or harms of
anticoagulation compared with antiplatelets.
©2016 American Academy of Neurology
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From Evidence to Conclusion
• For the start of the modified Grading of
Recommendations Assessment, Development and
Evaluation process, the confidence in evidence was
anchored at moderate (appendix e-8 of the
published practice advisory) and then downgraded
to very low because of severe imprecision and
heterogeneity (I2 = 65%).
©2016 American Academy of Neurology
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Anticoagulation vs. Antiplatelet
Medication
• For patients with cryptogenic stroke and PFO,
there is insufficient evidence to determine the
efficacy of anticoagulation compared with
antiplatelet therapy in preventing recurrent stroke
(RD 2%, 95% CI -21% to 25% [2 Class II studies,
confidence downgraded for severe imprecision and
inconsistency]).
©2016 American Academy of Neurology
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Recommendations: Clinical Question 2
Level C
©2016 American Academy of Neurology
• In the absence of another indication for anticoagulation,
clinicians may routinely offer antiplatelet medications
instead of anticoagulation to patients with cryptogenic
stroke and PFO.
• In rare circumstances, such as stroke that recurs while a
patient is undergoing antiplatelet therapy, clinicians may
offer anticoagulation to patients with cryptogenic stroke
and PFO.
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Random-effects Meta-Analyses of Risk
Differences
Anticoagulation vs antiplatelet medication. Outcome
stroke (Shariat 201314 includes 2 TIAs). Risk
difference in percent.
Study
Risk diff (95% CI)
PICCS
-8.4 (-24 to 7)
Shariat 2013
15 (-7 to 37)
Summary (RE)
2 (-21 to 25)
I2
65%
-40
-20
Favors Warfarin
©2016 American Academy of Neurology
0
20
40
60
Favors Antiplatelet
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Recommendations for Future Research
At least 3 large RCTs comparing PFO closure with medications are ongoing…it is possible that these ongoing trials may fail to
provide definitive evidence for efficacy, and the aggregate data may not define a patient population with a clear reduction in
stroke risk and acceptable procedural risk profile.
If so, additional RCTs may be required, and these future studies should make great efforts to carefully select patients who have
limited vascular risk factors and have undergone a thorough evaluation to exclude other stroke etiologies. 22
[T]hese studies should use blinded endpoint ascertainment and adjudication (as opposed to open ascertainment with blinded
endpoint adjudication), assess subsequent stroke risk and safety, and follow patients over a reasonably long period to compare
the near- and long-term safety fairly with any subsequent stroke risk reduction.
If a PFO closure device is approved in the United States, a postmarketing prospective, observational, long-term registry should be
established to further inform our understanding of long-term benefits and risks.
Finally, there are ongoing studies comparing novel anticoagulants, factor Xa inhibitors, and direct thrombin inhibitors with
antiplatelet medications for the prevention of recurrent embolic stroke of uncertain source. Because the novel anticoagulant
medications have less bleeding risk, effective venous thrombosis prevention, and greater convenience than warfarin, these
medications may be viable alternatives for patients with stroke and a PFO, and it would be reasonable to consider studies in this
patient population.
©2016 American Academy of Neurology
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References
References cited here can be found in the published
practice advisory, available at AAN.com/guidelines.
©2016 American Academy of Neurology
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Access Practice Advisory and
Summary Tools
• To access the practice advisory and related summary
tools, visit AAN.com/guidelines.
• Practice advisory article
• Summary for clinicians and summary for patients/families
©2016 American Academy of Neurology
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Questions?
©2016 American Academy of Neurology