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Percutaneous Closure of the Left Atrial Appendage Percutaneous Closure of the Left Atrial Appendage versus Warfarin Therapy for Prevention of Stroke versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation: A Randomized in Patients with Atrial Fibrillation: A Randomized
Non-Inferiority TrialNon-Inferiority Trial
David R. Holmes, MDDavid R. Holmes, MDVivek Y. Reddy, MDVivek Y. Reddy, MDZoltan G. Turi, MDZoltan G. Turi, MD
Shephal K. Doshi, MDShephal K. Doshi, MDHorst Sievert, MDHorst Sievert, MD
Maurice Buchbinder, MDMaurice Buchbinder, MDChristopher M. MullinChristopher M. Mullin
Peter Sick, MDPeter Sick, MDFor the PROTECT AF InvestigatorsFor the PROTECT AF Investigators
Non-Valvular Atrial FibrillationNon-Valvular Atrial FibrillationAn EPIDEMICAn EPIDEMIC
• Affects 1-1.5% of population in Affects 1-1.5% of population in developed worlddeveloped world
• Lifetime risk in men & women >40 is 1 in 4Lifetime risk in men & women >40 is 1 in 4
• PrevalencePrevalence0.5% age 0-590.5% age 0-599.0% age >809.0% age >80
• Currently 2.5 million adults in U.S.Currently 2.5 million adults in U.S.
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Savelieva: J Intern Med 250, 2001Savelieva: J Intern Med 250, 2001Go: JAMA 285, 2001Go: JAMA 285, 2001Miyasaka: Circ 114, 2006Miyasaka: Circ 114, 2006
Non-Valvular Atrial FibrillationNon-Valvular Atrial FibrillationAn EPIDEMICAn EPIDEMIC
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0
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4
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8
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1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
Mayo Clinic data (assuming a Mayo Clinic data (assuming a continued increase in AF continued increase in AF incidence)incidence)Mayo Clinic data (assuming further Mayo Clinic data (assuming further increase in AF incidence)increase in AF incidence)ATRIA study data (50% >80 yo)ATRIA study data (50% >80 yo)
Patients Patients with atrial with atrial fibrillation fibrillation (millions)(millions)
YearYear
2.08 2.26 2.44 2.66 2.943.33
3.8 4.344.78
5.16 5.42 5.615.1 5.6
6.16.8
7.58.4
9.410.3
11.111.7 12.1
5.15.9
6.7
7.7
8.9
10.2
11.7
13.1
14.3
15.215.9
0
5
10
15
20
25
30
35
50-59 60-69 70-79 80-89
Non-Valvular Atrial FibrillationNon-Valvular Atrial Fibrillation
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%%
Percent of Total StrokesPercent of Total StrokesAttributable to Atrial FibrillationAttributable to Atrial Fibrillation
Stroke 22(18), 1991Stroke 22(18), 1991
• 500,000 strokes/year in U.S.500,000 strokes/year in U.S.
• Up to 20% of ischemic strokes occur in Up to 20% of ischemic strokes occur in patients with atrial fibrillationpatients with atrial fibrillation
Non-Valvular Atrial Fibrillation Stroke PreventionNon-Valvular Atrial Fibrillation Stroke PreventionMedical RxMedical Rx
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Cooper: Arch Int Med 166, 2006Cooper: Arch Int Med 166, 2006Lip: Thromb Res 118, 2006Lip: Thromb Res 118, 2006
• Warfarin cornerstone of therapyWarfarin cornerstone of therapy
• Assuming 51 ischemic strokes/1000 pt-yrAssuming 51 ischemic strokes/1000 pt-yr• Adjusted standard dose warfarin prevents Adjusted standard dose warfarin prevents
28 strokes at expense of 11 fatal bleeds28 strokes at expense of 11 fatal bleeds• Aspirin prevents 16 strokes at expense Aspirin prevents 16 strokes at expense
of 6 fatal bleedsof 6 fatal bleeds
• WarfarinWarfarin• 60-70% risk reduction vs no treatment60-70% risk reduction vs no treatment• 30-40% risk reduction vs aspirin30-40% risk reduction vs aspirin
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Non-Valvular Atrial Fibrillation Stroke PreventionNon-Valvular Atrial Fibrillation Stroke PreventionMedical RxMedical Rx
Warfarin ProblematicWarfarin Problematic
• Narrow therapeutic windowNarrow therapeutic window• Multiple drug-drug/drug-food interactionsMultiple drug-drug/drug-food interactions• Genetic variabilityGenetic variability
• Long half-life Long half-life
• PCI issues – triple therapyPCI issues – triple therapy
• ComplianceCompliance
• ContraindicationsContraindications
• Bleeding risksBleeding risks
010203040506070
<55 55-64 65-74 75-84 85
Non-Valvular Atrial Fibrillation Warfarin Non-Valvular Atrial Fibrillation Warfarin Use in AF Patients by AgeUse in AF Patients by Age
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Ann Int Med 131(12), 1999Ann Int Med 131(12), 1999
• Only 55% of AF patients with no contraindications have Only 55% of AF patients with no contraindications have
evidence of warfarin use in previous 3 monthsevidence of warfarin use in previous 3 months
• Other studies cite warfarin use in AF patients from 17-50%Other studies cite warfarin use in AF patients from 17-50%
• Elderly patients with increased absolute risk least likely to Elderly patients with increased absolute risk least likely to be taking warfarinbe taking warfarin
• Contraindications 30-40%Contraindications 30-40%
0 20 40 60 80 100
Non-Valvular Atrial Fibrillation Non-Valvular Atrial Fibrillation Adequacy of Anticoagulation in ClinicAdequacy of Anticoagulation in Clinic
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Bungard: Pharmacotherapy 20:1060, 2001Bungard: Pharmacotherapy 20:1060, 2001
Low INR <1.6Low INR <1.6
TherapeuticTherapeuticINR 2-3INR 2-3
High INR >3.2High INR >3.2
Efficacy Efficacy 4-fold 4-fold
Non-Valvular Atrial FibrillationNon-Valvular Atrial FibrillationStroke PathologyStroke Pathology
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Brass. Stroke 28(12), 1997Brass. Stroke 28(12), 1997VanWalraven: JAMA 288, 2002VanWalraven: JAMA 288, 2002
• Major fatal bleed with age >75 = 3%/year Major fatal bleed with age >75 = 3%/year (30% over 10 years)(30% over 10 years)
• Intracranial hemorrhageIntracranial hemorrhage• 0.3-0.5%/100 patient-years0.3-0.5%/100 patient-years• 3% in INR >4.03% in INR >4.0• 10% if INR >4.510% if INR >4.5
Non-Valvular Atrial FibrillationNon-Valvular Atrial FibrillationStroke PathologyStroke Pathology
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Blackshear: Ann Thoracic Surg 61, 1996Blackshear: Ann Thoracic Surg 61, 1996Johnson: Eur J Cardiothoracic Surg 17, 2000Johnson: Eur J Cardiothoracic Surg 17, 2000Fagan: Echocardiography 17, 2000Fagan: Echocardiography 17, 2000
• Insufficient contraction of LAA leads to Insufficient contraction of LAA leads to stagnant blood flowstagnant blood flow
• Most likely culprit: embolization of LAA clotMost likely culprit: embolization of LAA clot
• 90% of thrombus found in LAA90% of thrombus found in LAA
• TEE-based risk factorsTEE-based risk factors• Enlarged LAAEnlarged LAA• Reduced inflow and outflow velocitiesReduced inflow and outflow velocities• Spontaneous Echo contrastSpontaneous Echo contrast
WATCHMAN® LAA Closure TechnologyWATCHMAN® LAA Closure Technology
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PROTECT AF Clinical Trial DesignPROTECT AF Clinical Trial Design
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• Prospective, randomized study of WATCHMAN LAA Device vs Prospective, randomized study of WATCHMAN LAA Device vs long-term warfarin therapylong-term warfarin therapy
• 2:1 allocation ratio device to control2:1 allocation ratio device to control
• 800 patients enrolled from Feb 2005 to Jun 2008800 patients enrolled from Feb 2005 to Jun 2008• Device group (463)Device group (463)• Control group (244)Control group (244)• Roll-in group (93)Roll-in group (93)
• 59 enrolling centers (U.S. & Europe)59 enrolling centers (U.S. & Europe)
• Follow-up requirementsFollow-up requirements• TEE follow-up at 45 days, 6 months and 1 yearTEE follow-up at 45 days, 6 months and 1 year• Clinical follow-up biannually up to 5 yearsClinical follow-up biannually up to 5 years• Regular INR monitoring while taking warfarinRegular INR monitoring while taking warfarin
• Enrollment continues in Continued Access Protocol (CAP Study)Enrollment continues in Continued Access Protocol (CAP Study)
Key Participation CriteriaKey Participation Criteria
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Key inclusion criteriaKey inclusion criteria
• Age 18 years or olderAge 18 years or older
• Documented non-valvular AFDocumented non-valvular AF
• Eligible for long-term warfarin therapy, and has no other Eligible for long-term warfarin therapy, and has no other conditions that would require long-term warfarin therapyconditions that would require long-term warfarin therapy
• Calculated CHADS2 score Calculated CHADS2 score 11
Key exclusion criteriaKey exclusion criteria
• NYHA class IV congestive heart failureNYHA class IV congestive heart failure
• ASD and/or atrial septal repair or closure deviceASD and/or atrial septal repair or closure device
• Planned ablation procedure within 30 days of potential Planned ablation procedure within 30 days of potential WATCHMAN Device implantWATCHMAN Device implant
• Symptomatic carotid diseaseSymptomatic carotid disease
• LVEF <30% LVEF <30%
• TEE criteria: suspected or known intracardiac thrombus TEE criteria: suspected or known intracardiac thrombus (dense spontaneous Echo contract(dense spontaneous Echo contract
PROTECT AF Trial EndpointsPROTECT AF Trial Endpoints
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• Primary efficacy endpointPrimary efficacy endpoint
• All stroke: ischemic or hemorrhagic All stroke: ischemic or hemorrhagic • Deficit with symptoms persisting more than 24 hours or Deficit with symptoms persisting more than 24 hours or • Symptoms less than 24 hours confirmed by CT or MRISymptoms less than 24 hours confirmed by CT or MRI
• Cardiovascular and unexplained death: includes sudden Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure death, MI, CVA, cardiac arrhythmia and heart failure
• Systemic embolizationSystemic embolization
• Primary safety endpoint Primary safety endpoint
• Device embolization requiring retrievalDevice embolization requiring retrieval
• Pericardial effusion requiring interventionPericardial effusion requiring intervention
• Cranial bleeds and gastrointestinal bleedsCranial bleeds and gastrointestinal bleeds
• Any bleed that requires Any bleed that requires 2uPRBC2uPRBC
Some events will be counted as Some events will be counted as both safety and efficacy endpointsboth safety and efficacy endpoints
0.7
0.8
0.9
1.0
0 365 730 1095
Intent-to-TreatIntent-to-TreatPrimary Safety ResultsPrimary Safety Results
ITT cohort: patients ITT cohort: patients analyzed based on their analyzed based on their randomly assigned group randomly assigned group (regardless of treatment (regardless of treatment received)received)
Ev
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Ev
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DaysDays244244 143143 5151 1111463463 261261 8787 1919
DeviceDevice
ControlControl
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EventsEvents TotalTotal RateRate EventsEvents TotalTotal RateRate RRRRCohortCohort (no.)(no.) pt-yrpt-yr (95% CI)(95% CI) (no.)(no.) pt-yrpt-yr (95% CI)(95% CI) (95% CI)(95% CI)
600 pt-yr600 pt-yr 4545 386.4386.4 11.611.6 99 220.4220.4 4.14.1 2.852.85(8.5, 15.3)(8.5, 15.3) (1.9, 7.2)(1.9, 7.2) (1.48, 6.43)(1.48, 6.43)
900 pt-yr900 pt-yr 4848 554.2554.2 8.78.7 1313 312.0312.0 4.24.2 2.082.08(6.4, 11.3)(6.4, 11.3) (2.2, 6.7)(2.2, 6.7) (1.18, 4.13)(1.18, 4.13)
DeviceDevice ControlControl
900 patient-year analysis900 patient-year analysis
Randomization Randomization allocation (2 device:1 allocation (2 device:1 control)control)
Specific Safety Endpoint EventsSpecific Safety Endpoint Events
• Pericardial effusions – largest fraction Pericardial effusions – largest fraction of safety events in device groupof safety events in device group
• Stroke events – most serious fraction Stroke events – most serious fraction of safety events in control groupof safety events in control group
• Bleeding events were also frequent Bleeding events were also frequent
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Safety EventsSafety EventsPericardial EffusionPericardial Effusion
Pericardial effusions – 47% of total device eventsPericardial effusions – 47% of total device events
• 22 classified as “serious” (4.8% of patients)22 classified as “serious” (4.8% of patients)• 7 required surgical intervention: extended 7 required surgical intervention: extended
hospitalization by 6 dayshospitalization by 6 days• 15 treated percutaneously: extended 15 treated percutaneously: extended
hospitalization by 4 dayshospitalization by 4 days
• None resulted in deathNone resulted in death
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Pericardial Effusions by ExperiencePericardial Effusions by Experience
• Throughout PROTECT AF Trial, procedural modifications Throughout PROTECT AF Trial, procedural modifications and training enhancements were implemented and training enhancements were implemented
• Procedural events would be expected to decrease over Procedural events would be expected to decrease over timetime
• Pericardial effusions within 7 days of the procedure are Pericardial effusions within 7 days of the procedure are most relevant to the device performancemost relevant to the device performance
No.No. %% No.No. %% No.No. %%
Early patients (1-3)Early patients (1-3) 13/15413/154 8.48.4 12/15412/154 7.87.8 10/15410/154 6.56.5
Late patients (Late patients (4)4) 27/38827/388 7.07.0 24/38824/388 6.26.2 17/38817/388 4.44.4
TotalTotal 40/54240/542 7.27.2 36/54236/542 6.66.6 27/54227/542 5.05.0
Site implant group Site implant group (includes roll-in (includes roll-in
subjects)subjects) AnyAny
Any Any procedure/ procedure/
device relateddevice relatedAny Any
seriousserious
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Effusions in Recent Implant ExperienceEffusions in Recent Implant Experience
• Rates obtained in the CONTINUED ACCESS Rates obtained in the CONTINUED ACCESS Study confirm that the lower rates are sustainedStudy confirm that the lower rates are sustained
No.No. %% No.No. %% No.No. %%
1/881/88 1.11.1 1/881/88 1.11.1 1/881/88 1.11.1
AnyAny
Any Any procedure/ procedure/
device relateddevice relatedAny Any
seriousserious
0.7
0.8
0.9
1.0
0 365 730 1095
Intent-to-TreatIntent-to-TreatPrimary Efficacy ResultsPrimary Efficacy Results
ITT cohort: patients ITT cohort: patients analyzed based on their analyzed based on their randomly assigned randomly assigned group (regardless of group (regardless of treatment received)treatment received)
Ev
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Ev
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DaysDays244244 147147 5252 1212463463 270270 9292 2222
WATCHMANWATCHMAN
ControlControl
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900 patient-year analysis900 patient-year analysis
EventsEvents TotalTotal RateRate EventsEvents TotalTotal RateRate RRRR Non-Non- SuperioritySuperiorityCohortCohort (no.)(no.) pt-yrpt-yr (95% CI)(95% CI) (no.)(no.) pt-yrpt-yr (95% CI)(95% CI) (95% CI)(95% CI) inferiorityinferiority
600600 1818 409.3409.3 4.44.4 1313 223.6223.6 5.85.8 0.760.76 0.9920.992 0.7340.734pt-yrpt-yr (2.6, 6.7)(2.6, 6.7) (3.0, 9.1)(3.0, 9.1) (0.39, 1.67)(0.39, 1.67)
900900 2020 582.3582.3 3.43.4 1616 318.0318.0 5.05.0 0.680.68 0.9980.998 0.8370.837pt-yrpt-yr (2.1, 5.2)(2.1, 5.2) (2.8, 7.6)(2.8, 7.6) (0.37, 1.41)(0.37, 1.41)
DeviceDevice ControlControl Posterior probabilitiesPosterior probabilities
Randomization Randomization allocation (2 device:1 allocation (2 device:1 control)control)
0.7
0.8
0.9
1.0
0 365 730 1095
Intent-to-TreatIntent-to-TreatHemorrhagic StrokeHemorrhagic Stroke
ITT cohort: patients ITT cohort: patients analyzed based on their analyzed based on their randomly assigned randomly assigned group (regardless of group (regardless of treatment received)treatment received)
Ev
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Ev
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DaysDays244244 147147 5353 1212463463 275275 9595 2323
DeviceDevice
ControlControl
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900 patient-year analysis900 patient-year analysis
EventsEvents TotalTotal RateRate EventsEvents TotalTotal RateRate RRRR Non-Non- SuperioritySuperiorityCohortCohort (no.)(no.) pt-yrpt-yr (95% CI)(95% CI) (no.)(no.) pt-yrpt-yr (95% CI)(95% CI) (95% CI)(95% CI) inferiorityinferiority
600600 11 416.7416.7 0.20.2 44 224.7224.7 1.81.8 0.130.13 0.9980.998 0.9860.986pt-yrpt-yr (0.0, 0.9)(0.0, 0.9) (0.5, 3.9)(0.5, 3.9) (0.00, 0.80)(0.00, 0.80)
900900 11 593.6593.6 0.20.2 66 319.4319.4 1.91.9 0.090.09 >0.999>0.999 0.9980.998pt-yrpt-yr (0.0, 0.6)(0.0, 0.6) (0.7, 3.7)(0.7, 3.7) (0.00, 0.45)(0.00, 0.45)
DeviceDevice ControlControl Posterior probabilitiesPosterior probabilities
Randomization Randomization allocation (2 device:1 allocation (2 device:1 control)control)
Risk/Benefit AnalysisRisk/Benefit Analysis
• Intent-to-treat analysisIntent-to-treat analysis
• Primary endpoint (intent to treat) achievedPrimary endpoint (intent to treat) achieved
• Other statistically significant endpoint findingsOther statistically significant endpoint findings• Noninferiority for the primary efficacy event rate – 32% lower Noninferiority for the primary efficacy event rate – 32% lower
in device groupin device group• Noninferiority for stroke rate – 26% lower in device groupNoninferiority for stroke rate – 26% lower in device group• Superiority for hemorrhagic stroke – 91% lower in device Superiority for hemorrhagic stroke – 91% lower in device
groupgroup• Noninferiority for mortality rate – 39% lower rate in device Noninferiority for mortality rate – 39% lower rate in device
groupgroup
• Increased rate of primary safety events for the device group Increased rate of primary safety events for the device group relative to the control group relative to the control group • Most events in the device group were procedural effusions Most events in the device group were procedural effusions
that decreased over the course of the studythat decreased over the course of the study• 87% of patients discontinued warfarin at 45 days87% of patients discontinued warfarin at 45 days• Death/disability conclusionDeath/disability conclusion
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Risk / Benefit AnalysisRisk / Benefit Analysis
Per-protocol analysisPer-protocol analysis
• Superiority for the primary efficacy event rateSuperiority for the primary efficacy event rate
• Approximately 86% of patients in the device Approximately 86% of patients in the device group were able to be successfully implanted group were able to be successfully implanted and discontinue warfarin therapyand discontinue warfarin therapy
• Study demonstrates the role of the left atrial Study demonstrates the role of the left atrial appendage in the pathogenesis of stroke due appendage in the pathogenesis of stroke due to AFto AF
• Based on average age, patients will Based on average age, patients will experience a 56% reduction in safety eventsexperience a 56% reduction in safety events
Risk/Benefit AnalysisRisk/Benefit Analysis
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SummarySummary
• Long-term warfarin treatment of patients with AF has been Long-term warfarin treatment of patients with AF has been found effective, but presents difficulties and riskfound effective, but presents difficulties and risk
• PROTECT AF trial was a randomized, controlled, PROTECT AF trial was a randomized, controlled, statistically valid study to evaluate the WATCHMAN device statistically valid study to evaluate the WATCHMAN device compared to warfarincompared to warfarin
• In PROTECT AF, hemorrhagic stroke risk is significantly In PROTECT AF, hemorrhagic stroke risk is significantly lower with the device.lower with the device.• When hemorrhage occurred, risk of death was When hemorrhage occurred, risk of death was
markedly increasedmarkedly increased
• In PROTECT AF, all cause stroke and all cause mortality In PROTECT AF, all cause stroke and all cause mortality risk are equivalent to that with warfarinrisk are equivalent to that with warfarin
• In PROTECT AF, there are early safety events, specifically In PROTECT AF, there are early safety events, specifically pericardial effusion; hese events have decreased over timepericardial effusion; hese events have decreased over time
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ConclusionConclusion
The WATCHMAN LAA Technology offers a The WATCHMAN LAA Technology offers a safe and effective alternative to warfarin in safe and effective alternative to warfarin in patients with non-valvular atrial fibrillation at patients with non-valvular atrial fibrillation at risk for stroke and who are eligible for risk for stroke and who are eligible for warfarin therapywarfarin therapy
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