PREVAIL: 5-Year Outcomes From a Randomized Trial of …€¢ Both protocols specified 5 years of...

PREVAIL: 5-Year Outcomes From a Randomized Trial of Left Atrial Appendage Closure vs Medical

Therapy in Patients With NonvalvularAtrial Fibrillation

Dr. Saibal Kar, MD

TCT 2017 Late Breaking Clinical Trial

Denver, CO USA

Authors: V Reddy, S Doshi; S Kar, D Gibson, M Price, K Huber, R

Horton, M Buchbinder, P Neuzil, N Gordon, DR Holmes Jr on behalf of

the PREVAIL and PROTECT-AF Investigators

Disclosures

• Dr. Kar

Has received research grants from and

served as a consultant for Abbott Vascular

and Boston Scientific;

Has served as a member of the advisory

board for left atrial appendage closure;

Is the national principal investigator of the

Continuous Access Registries (CAP & CAP2);

Has served as a proctor for Boston Scientific.

Background

• PROTECT AF and PREVAIL were RCTs comparing left atrial

appendage closure (LAAC) with WATCHMAN to warfarin

• PROTECT-AF demonstrated similar stroke reduction to

warfarin (at a mean of 3.8 years follow up)

JAMA 312:1988-98 (2014)

• PREVAIL produced inconclusive findings due to a warfarin

cohort with an implausibly low ischemic stroke rate, relatively

few patients and relatively short follow up (~10 months)

JACC 64:1-12 (2014)

• Both protocols specified 5 years of follow-up for all patients

5 year follow up completed in 2013 (final)

5 year follow up completed in 2017 (final)

Objectives

• To report the final, 5 year results of

PREVAIL, both alone and as part of a

patient-level meta-analysis with

PROTECT-AF final 5 year data

Methods

PREVAIL

PREVAIL efficacy endpoints were never designed to be analyzed

without the informative prior from PROTECT AF.

• 1st Primary efficacy: Comparison of rate ratios of 18-month event

rates for composite of stroke, SE, and CV/Unexplained death; Upper

CrI 1.75 for NI

• 2nd primary efficacy: 1-tailed test, either the ratio or the difference

between rates of ischemic stroke or SE >7 days post implant in the

two arms satisfied the non-inferiority criteria, using 95% upper

credible intervals (CrI) <2.0 and <0.0275, respectively, and posterior

probability for non-inferiority ≥ 97.5%.

• All analyses ITT; rates are events per 100 patient-years (indicated for

simplicity by %).

All PREVAIL analysis were pre-specified to use an informative

prior that included a portion of PROTECT AF

Methods

Patient-Level Meta-Analysis

• ITT: censoring data from patients without events at the time of the

last known status

• Disabling Strokes: increase in the Modified Rankin Score (MRS)

by at least 2 points

• Comparison of Event Rates: Cox proportional hazards model

with confidence intervals (CIs)

Stratified by study to account for differences in risk profiles

Kaplan-Meier curves used for graphical assessment of time-

dependent events

Frequentist statistics and 2-sided p-values nominally significant at p <

0.05, without adjustment for multiple comparisons

Follow-up

TrialNumber of Patients

TotalMean Follow-

up (months)

Total

Patient

YearsDevice Control

PROTECT AF 463 244 707 47.6 ± 21.3 2,717

PREVAIL-only* 269 138 407 47.9 ± 19.4 1,626

Total 732 382 1114 4,343* Does not include PROTECT AF informative prior from Bayesian model

Demographics: Combined Cohort Endpoint

for Patient-Level Meta Analysis Characteristic

Device

N=732

Control

N=382p-value

Age, years 72.6±8.4 73.5±8.6 0.09

Sex, male 69.4 71.7 0.42

CHADS2 Score 2.3±1.1 2.4±1.2 0.06

CHA2DS2-Vasc Score 3.6 ± 1.4 3.9 ± 1.5 0.02

Risk Factors

CHF 25.5 25.7 0.97

Hypertension 89.2 92.7 0.06

Age ≥ 75 years 40.4 43.2 0.38

Diabetes 27.9 29.6 0.55

Prior Stroke/TIA 22.1 23.6 0.59

AF Pattern

Paroxysmal 45.2 44.5 0.82

Persistent 24.9 23.3 0.56

Permanent 27.6 30.1 0.38

Unknown 1.4 0.8 0.56

Paced 1.0 1.3 0.56

RESULTS

Results

PREVAIL Efficacy

Dataset

Device

18-Month

Rate

Control

18-Month

Rate

18-Month Rate

Ratio

(95% CrI)

Criteria Met?

95% CrI Upper

Bound < 1.75

Posterior

Probability

Non-

inferiority

(PNI ≥97.5%)

First Primary Endpoint (ITT) - stroke, SE, and CV/Unexplained Death

Primary analysis

(Jan 2013)0.064 0.063

1.07

(0.57, 1.89)No 93%

1st Post Hoc Analysis

(Jun 2014)0.065 0.057

1.21

(0.69, 2.05)No 93%

Final 5-Year Analysis

(Sep 2017)0.066 0.051

1.33

(0.78, 2.13)No 88.4%

Dataset

Device

18-Month

Rate

Control

18-Month

Rate

18-Month Rate

Ratio

(95% CrI)

Criteria Met?

95% CI Upper

Bound < 2.0

18-Month Rate

Difference

(95% CrI)

Criteria Met?

95% CrI

Upper Bound

< 0.0275

Posterior

Probability

Non-

inferiority

(PNI ≥97.5%)

Second Primary Endpoint (ITT) – ischemic stroke or SE >7 days Must meet at least one criteria

Primary analysis

(Jan 2013)0.0253 0.0200

1.6

(0.5, 4.2)No

0.0053

(-0.0190, 0.0273)Yes 97.6


(Jun 2014)0.0294 0.0131

2.8

(0.9, 7.3)No

0.0163

(-0.0023, 0.0342)No 89.2


(Sep 2017)0.0255 0.0135

2.2

(0.8, 4.9)No

0.0120

(-0.0036, 0.0275)Yes 97.5%

* Upper CrI is displayed as 0.0275, but if all significant digits were displayed, it is less than upper bound of 0.0275

Results

PREVAIL 2nd Endpoint Met

Dataset

Device

18-Month

Rate

Control

18-Month

Rate

18-Month Rate

Ratio

(95% CrI)

Criteria Met?

95% CrI Upper

Bound < 1.75

Posterior

Probability

Non-

inferiority

(PNI ≥97.5%)

First Primary Endpoint (ITT) - stroke, SE, and CV/Unexplained Death

Primary analysis

(Jan 2013)0.064 0.063

1.07

(0.57, 1.89)No 93%


(Jun 2014)0.065 0.057

1.21

(0.69, 2.05)No 93%


(Sep 2017)0.066 0.051

1.33

(0.78, 2.13)No 88.4%

Dataset

Device

18-Month

Rate

Control

18-Month

Rate

18-Month Rate

Ratio

(95% CrI)

Criteria Met?

95% CI Upper

Bound < 2.0

18-Month Rate

Difference

(95% CrI)

Criteria Met?

95% CrI

Upper Bound

< 0.0275

Posterior

Probability

Non-

inferiority

(PNI ≥97.5%)

Second Primary Endpoint (ITT) – ischemic stroke or SE >7 days Must meet at least one criteria

Primary analysis

(Jan 2013)0.0253 0.0200

1.6

(0.5, 4.2)No

0.0053

(-0.0190, 0.0273)Yes 97.6


(Jun 2014)0.0294 0.0131

2.8

(0.9, 7.3)No

0.0163

(-0.0023, 0.0342)No 89.2


(Sep 2017)0.0255 0.0135

2.2

(0.8, 4.9)No

0.0120

(-0.0036, 0.0275)Yes 97.5%

* Upper CrI is displayed as 0.0275, but if all significant digits were displayed, it is less than upper bound of 0.0275

Results

PROTECT AF and PREVAIL Event Rates

PROTECT-AF Subjects PREVAIL Subjects

Device

(n=463)

Control

(n=244)

Device

(n=269)

Control

(n=138)

No. of

Events Rate *

No. of

Events Rate * p-value

No. of

Events Rate *

No. of


2:1 Randomization

Primary Efficacy:

Stroke/SE/CV Death40 / 1787.7 2.24 34 / 929.4 3.66 0.04 37 / 1038.3 3.65 15 / 530.4 2.94 0.47

All Stroke 26 / 1781.7 1.46 20 / 929.4 2.15 0.23 19 / 1042.4 1.97 7 / 530.4 1.29 0.32

Ischemic Stroke 24 / 1781.7 1.35 10 / 932.8 1.07 0.49 17 / 1043.1 1.68 4 / 533.3 0.73 0.13

Hemorrhagic Stroke 3 / 1837.7 0.16 10 / 945.6 1.06 0.005 2 / 1084.6 0.18 3 / 538.0 0.54 0.23

Systemic Embolism 3 / 1837.1 0.16 0 n/a n/a 1 / 1080.6 0.09 0 / 540.9 n/a n/a

CV/Unexplained Death 19 / 1843.2 1.03 22 / 948.9 2.32 0.009 18 / 1084.7 1.79 10 / 540.9 1.98 0.76

* Events are per 100 patient-years

PROTECT AF ResultsWATCHMAN Superior Efficacy, Hemorrhagic

Stroke, CV Death


Device

(n=463)

Control

(n=244)

Device

(n=269)

Control

(n=138)

No. of

Events Rate *

No. of


No. of

Events Rate *

No. of


2:1 Randomization

Primary Efficacy:


All Stroke 26 / 1781.7 1.46 20 / 929.4 2.15 0.23 19 / 1042.4 1.97 7 / 530.4 1.29 0.32

Ischemic Stroke 24 / 1781.7 1.35 10 / 932.8 1.07 0.49 17 / 1043.1 1.68 4 / 533.3 0.73 0.13





PREVAIL ResultsWATCHMAN Comparable For Efficacy

Control Group Continued To Overperform


Device

(n=463)

Control

(n=244)

Device

(n=269)

Control

(n=138)

No. of

Events Rate *

No. of


No. of

Events Rate *

No. of


2:1 Randomization

Primary Efficacy:


All Stroke 26 / 1781.7 1.46 20 / 929.4 2.15 0.23 19 / 1042.4 1.97 7 / 530.4 1.29 0.32

Ischemic Stroke 24 / 1781.7 1.35 10 / 932.8 1.07 0.49 17 / 1043.1 1.68 4 / 533.3 0.73 0.13





2:1 randomization

Control Group continues to overperform

Rate = 0.7%

Ischemic

Stroke Risk

(events per

100 pt-yrs)

PREVAIL

PROTECT AF

Untreated AFTreated with WarfarinWATCHMAN Arm

CAP2

CAP

Baseline CHA2DS2-VASc Score

EWOLUTION

WASP

ResultsWATCHMAN Comparable to Warfarin for

Ischemic Stroke

EWOLUTION: Boersma Lva et al Heart Rhythm 2017;doi-10.1016/j.hrthm.2017.05.038; WASP: Philips K, et al.Journal of Arrhythmia (in press).

1.3

1.2

1.7

2.3

1.1

1.5

0

2

4

6

8

10

1 2 3 4 5

HR

p-

value

Efficacy 0.82 0.3

All stroke or SE 0.96 0.9

Ischemic stroke or SE 1.7 0.08

Hemorrhagic stroke 0.2 0.0022

Ischemic stroke or SE >7 days 1.4 0.3

CV/unexplained death 0.59 0.03

All-cause death 0.73 0.04

Major bleed, all 0.91 0.6

Major bleeding, non procedure-related 0.48 0.0003

0.01 0.1 1 10

Favors WATCHMAN Favors warfarin

Hazard Ratio (95% CI)


PROTECT AF and PREVAIL 5 years

HR

p-

value

Efficacy 0.82 0.3









0.01 0.1 1 10



Patient-Level Meta-AnalysisWATCHMAN Comparable To Warfarin For Ischemic Stroke

HR

p-

value

Efficacy 0.82 0.3









0.01 0.1 1 10



Patient-Level Meta-AnalysisWATCHMAN Superior for Hemorrhagic Stroke, CV Death,

All-Cause Death, Post-procedure Bleeding


WATCHMAN Superior Reduction in Disabling

Strokes

0.00%

0.50%

1.00%

1.50%

2.00%

WATCHMAN warfarin

Disabling/Fatal Strokes Non-Disabling Strokes

Disabling Stroke defined as MRS ≥2

Two strokes in PREVAIL are excluded because the baseline MRS score was unavailable


WATCHMAN Superior Reduction in Disabling

Strokes

0.00%

0.50%

1.00%

1.50%

2.00%

WATCHMAN warfarin

Disabling/Fatal Strokes Non-Disabling Strokes

Disabling Stroke defined as MRS ≥2

Two strokes in PREVAIL are excluded because the baseline MRS score was unavailable

HR 0.45 (0.21 – 0.94)

P=0.03

55%

Reduction

Subgroup

Interaction

p-value

Age< 75

0.98> 75

SexFemale

0.94Male

CHADS2

Score

≤ 30.47

>3

CHA2DS2-

VASc Score

≤ 40.13

>4

HAS-BLED≤ 2

0.054>2

History of TIA

Stroke

No0.35

Yes

Hazard Ratio



No Significant Difference In Outcomes By Patient Subset

0.1 1.0 10.0

Summary

PREVAIL 5 year follow-up demonstrates:

• 2nd primary endpoint meets non-inferiority while the 1st

endpoint remains unchanged

• No significant differences between WATCHMAN and warfarin

for primary efficacy measures despite an implausibly low rate

of ischemic stroke (0.73%) in the control arm

Meta-Analysis of PROTECT AF and PREVAIL with 5 year

follow-up demonstrates:

• Comparable efficacy and stroke rates, with no significant

differnce across subgroups

• No significant differences in ischemic stroke rates versus

warfarin

• Significant, superior reductions in disabling strokes, non-

procedural bleeding, and mortality

*Kaplan Meier Rate

Conclusion

Long term 5-year outcomes of 2 RCTs demonstrate

• LAAC with the Watchman device provides stroke

prevention in NVAF patients to a similar degree

as oral anticoagulation

• By minimizing major bleeding, particularly

hemorrhagic stroke, LAAC results in less

disability or death than warfarin

For patients who are poor candidates for long-term oral

anticoagulation, left atrial appendage closure is a reasonable

strategy for stroke prophylaxis

Conclusion

Long term 5-year outcomes of 2 RCTs demonstrate

• LAAC with the Watchman device provides stroke

prevention in NVAF patients to a similar degree

as oral anticoagulation

• By minimizing major bleeding, particularly

hemorrhagic stroke, LAAC results in less

disability or death than warfarin

For patients who are poor candidates for long-term oral

anticoagulation, left atrial appendage closure is a reasonable

strategy for stroke prophylaxis

WE HAVE PREVAILED!

ABBREVIATED STATEMENT (US)

WATCHMANTM Left Atrial Appendage Closure Device

with Delivery System and WATCHMAN Access System

INDICATIONS FOR USE

The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation who:

• Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy;

• Are deemed by their physicians to be suitable for warfarin; and

• Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin.

The WATCHMAN Access System is intended to provide vascular and transseptal access for all WATCHMAN Left Atrial Appendage Closure Devices with Delivery Systems.

CONTRAINDICATIONS

Do not use the WATCHMAN Device if:

• Intracardiac thrombus is visualized by echocardiographic imaging.

• An atrial septal defect repair or closure device or a patent foramen ovale repair or closure device is present.

• The LAA anatomy will not accommodate a device. See Table 46 in the DFU.

• Any of the customary contraindications for other percutaneous catheterization procedures (e.g., patient size too small to accommodate TEE probe or required catheters) or conditions (e.g., active infection,

bleeding disorder) are present.

• There are contraindications to the use of warfarin, aspirin, or clopidogrel.

• The patient has a known hypersensitivity to any portion of the device material or the individual components (see Device Description section) such that the use of the WATCHMAN Device is contraindicated.

WARNINGS

• Device selection should be based on accurate LAA measurements obtained using fluoro and ultrasound guidance (TEE recommended) in multiple angles (e.g., 0º, 45º, 90º, 135º).

• Do not release the WATCHMAN Device from the core wire if the device does not meet all release criteria.

• If thrombus is observed on the device, warfarin therapy is recommended until resolution of thrombus is demonstrated by TEE.

• The potential for device embolization exists with cardioversion <30 days following device implantation. Verify device position post-cardioversion during this period.

• Administer appropriate endocarditis prophylaxis for 6 months following device implantation. The decision to continue endocarditis prophylaxis beyond 6 months is at physician discretion.

• For single use only. Do not reuse, reprocess, or resterilize.

PRECAUTIONS

• The safety and effectiveness (and benefit-risk profile) of the WATCHMAN Device has not been established in patients for whom long-term anticoagulation is determined to be contraindicated.

• The LAA is a thin-walled structure. Use caution when accessing the LAA and deploying the device.

• Use caution when introducing the WATCHMAN Access System to prevent damage to cardiac structures.

• Use caution when introducing the Delivery System to prevent damage to cardiac structures.

• To prevent damage to the Delivery Catheter or device, do not allow the WATCHMAN Device to protrude beyond the distal tip of the Delivery Catheter when inserting the Delivery System into the Access Sheath.

• If using a power injector, the maximum pressure should not exceed 100 psi.

• In view of the concerns that were raised by the RE-ALIGN1 study of dabigatran in the presence of prosthetic mechanical heart valves, caution should be used when prescribing oral anticoagulants other than

warfarin in patients treated with the WATCHMAN Device. The WATCHMAN Device has only been evaluated with the use of warfarin post-device implantation.

ADVERSE EVENTS

Potential adverse events (in alphabetical order) which may be associated with the use of a left atrial appendage closure device or implantation procedure include but are not limited to:

Air embolism, Airway trauma, Allergic reaction to contrast media/medications or device materials, Altered mental status, Anemia requiring transfusion, Anesthesia risks, Angina, Anoxic encephalopathy, Arrhythmias,

Atrial septal defect , AV fistula , Bruising, hematoma or seroma, Cardiac perforation , Chest pain/discomfort, Confusion post procedure, Congestive heart failure, Contrast related nephropathy, Cranial bleed,

Decreased hemoglobin, Deep vein thrombosis, Death, Device embolism, Device fracture, Device thrombosis, Edema, Excessive bleeding, Fever, Groin pain, Groin puncture bleed, Hematuria, Hemoptysis,

Hypotension, Hypoxia, Improper wound healing, Inability to reposition, recapture, or retrieve the device, Infection / pneumonia, Interatrial septum thrombus, Intratracheal bleeding, Major bleeding requiring transfusion,

Misplacement of the device / improper seal of the appendage / movement of device from appendage wall, Myocardia erosion, Nausea, Oral bleeding, Pericardial effusion / tamponade, Pleural effusion, Prolonged

bleeding from a laceration, Pseudoaneurysm, Pulmonary edema, Renal failure, Respiratory insufficiency / failure, Surgical removal of the device, Stroke – Ischemic , Stroke – Hemorrhagic, Systemic embolism, TEE

complications (throat pain, bleeding, esophageal trauma), Thrombocytopenia, Thrombosis, Transient ischemic attack (TIA), Valvular damage, Vasovagal reactions

There may be other potential adverse events that are unforeseen at this time.

CAUTION: Federal law (USA) restricts this device to sale by or on the order of a physician. Rx only. Prior to use, please see the complete “Directions for Use” for more information on Indications, Contraindications,

Warnings, Precautions, Adverse Events, and Operator’s Instructions.

© 2015 Boston Scientific Corporation or its affiliates. All rights reserved.1Eikelboom JW, Connolly SJ, Brueckmann M, et al. N Engl J Med 2013;369:1206-14.

PREVAIL: 5-Year Outcomes From a Randomized Trial of …€¢ Both protocols specified 5 years of...

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