WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation

• Sponsor: Boston Scientific Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00129545
• Collaborator: (none)
• Enrollment: 800
• Locations: 62
• Arms: 3
• Duration (Months): 110.9
• Patients Per Site: 12.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a multi-center, prospective, randomized study, stratified by center, comparing the WATCHMAN device to long term warfarin therapy, demonstrating that the treatment arm is non-inferior to the control arm. This study was amended to allow for a non-randomized arm and increased enrollment.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation; Stroke	Device: WATCHMAN Left Atrial Appendage Closure Technology; Drug: Warfarin	Phase 2/Phase 3

Detailed Description

The WATCHMAN device is designed to be permanently implanted distal to the ostium of the left atrial appendage (LAA) to trap potential emboli before they exit the LAA.

Study Design

• Study Type: Interventional
• Actual Enrollment: 800 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation (PROTECT AF)
• Study Start Date: Feb 1, 2005
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: WATCHMAN Implant of WATCHMAN Left Atrial Appendage Closure Technology	Device: WATCHMAN Left Atrial Appendage Closure Technology; Implant of WATCHMAN Left Atrial Appendage Closure Technology; Other Names: WATCHMAN
Active Comparator: Warfarin control Subjects are treated with current standard of care Oral Anticoagulation Therapy with Warfarin	Drug: Warfarin; Subjects receive warfarin; Other Names: Coumadin
Other: Roll-in Implant of WATCHMAN Left Atrial Appendage Closure Technology. Up to 3 non-randomized subjects per site, these subjects were not included in the primary analysis.	Device: WATCHMAN Left Atrial Appendage Closure Technology; Implant of WATCHMAN Left Atrial Appendage Closure Technology; Other Names: WATCHMAN

Outcome Measures

Primary Outcome Measures

1. Composite of Stroke, Systemic Embolism and Cardiovascular or Unexplained Death [5 years]

   A Bayesian model allowed for sequential evaluation of the primary endpoints, event rates reported per 100 patient-years (calculated as 100*N events/Total patient-years)

2. The Occurrence of Life-threatening Events, Including Device Embolization or Serious Bleeding Events [5 years]

   Serious bleeding events evaluated by the Clinical Events Committee included pericardial effusion requiring drainage, cranial bleeding events due to any source, gastrointestinal bleeds requiring transfusion, and any bleeding related to the device or procedure that necessitates an operation.

Secondary Outcome Measures

1. Procedure Success [Initial implant procedure]

   Implant procedure success is defined as the delivery and release of a WATCHMAN Device into the LAA.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient has paroxysmal, persistent or permanent non-valvular atrial fibrillation (AF)

• Eligible for long term warfarin

• CHADS score >= 1 [congestive heart failure (CHF), history of high blood pressure, 75 years of age or older, diabetes, prior stroke or transient ischemic attack (TIA)]

Exclusion Criteria:

• Contraindicated for warfarin

• Contraindicated for aspirin or clopidogrel (Plavix)

• Congestive heart failure (CHF) Class 4

• Implanted mechanical valve

• Atrial septal or Patent Foramen Ovale (PFO) device

• Platelets < 100,000 or hemoglobin < 10

• Left ventricular ejection fraction (LVEF) < 30%

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Advanced Cardiac Specialists	Gilbert	Arizona	United States	85233
2	Arizona Arrhythmia	Scottsdale	Arizona	United States	85251
3	Foundation for Cardiovascular Medicine	La Jolla	California	United States	92037
4	Los Angeles Cardiology Associates	Los Angeles	California	United States	90017
5	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
6	El Camino Hospital	Mountain View	California	United States	94040
7	Orange County Heart	Orange County	California	United States	92868
8	UC Davis Medical Center	Sacramento	California	United States	95817
9	St. John's Hospital / Pacific Heart	Santa Monica	California	United States	90404
10	Washington Hospital Center	Washington	District of Columbia	United States	20010
11	University of Miami	Miami	Florida	United States	33136
12	Baptist Cardiac and Vascular Institute	Miami	Florida	United States	33176
13	Bay Heart Group	Tampa	Florida	United States	33607
14	Emory University Midtown Hospital	Atlanta	Georgia	United States	30308
15	Piedmont Hospital	Atlanta	Georgia	United States	30309
16	Emory University Hospital	Atlanta	Georgia	United States	30322
17	University of Chicago	Chicago	Illinois	United States	60637
18	North Shore University	Evanston	Illinois	United States	60201
19	Loyola University Medical Center	Maywood	Illinois	United States	60153
20	Prairie Education Research Cooperative	Springfield	Illinois	United States	60637
21	Baptist Hospital West	Lexington	Kentucky	United States	40503
22	University of Kentucky	Lexington	Kentucky	United States	40536-0294
23	Terrebonne General Medical Center	Houma	Louisiana	United States	70360
24	Ochsner Clinic	New Orleans	Louisiana	United States	70121
25	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
26	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
27	William Beaumont	Royal Oak	Michigan	United States	48073
28	Abbott Northwestern Hospital	Minneapolis	Minnesota	United States	55407
29	Mayo Clinic	Rochester	Minnesota	United States	55902
30	St. Paul Heart Clinic	St. Paul	Minnesota	United States	55102
31	University of Mississippi Healthcare Center	Jackson	Mississippi	United States	39216
32	St. Luke's Hospital	Kansas City	Missouri	United States	64111
33	Nebraska Heart Institute	Lincoln	Nebraska	United States	68526
34	Cooper University Hospital	Camden	New Jersey	United States	08103
35	New Mexico Heart Institute	Albuquerque	New Mexico	United States	87102
36	New York University Medical Center	New York	New York	United States	10016
37	Columbia University Medical Center	New York	New York	United States	10032
38	Mt. Sinai Medical Center	New York	New York	United States
39	Summa Health System	Akron	Ohio	United States	44304
40	Lindner Clinical Trial Center	Cincinnati	Ohio	United States	45219
41	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
42	Ohio State University	Columbus	Ohio	United States	43210
43	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
44	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
45	Harrisburg Hospital / Associated Cardiology	Harrisburg	Pennsylvania	United States	17110
46	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
47	Presbyterian University Hospital	Pittsburgh	Pennsylvania	United States	15213
48	Moffitt Heart & Vascular	Wormleysburg	Pennsylvania	United States	17043
49	Mercy Medical Center West	Knoxville	Tennessee	United States	37934
50	St. Thomas Research Institute	Nashville	Tennessee	United States
51	Texas Cardiac Arrhythmia	Austin	Texas	United States	78705
52	St. Lukes Episcopal Hospital	Houston	Texas	United States	77030
53	Intermountain Medical Center	Salt Lake City	Utah	United States	84107
54	University of Virginia	Charlottesville	Virginia	United States	22908
55	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
56	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
57	Swedish Medical Center	Seattle	Washington	United States	98104
58	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
59	Na Homolce	Prague		Czech Republic	15030
60	Krankenhaus der Barmherzige Bruder	Regensburg	Bayern	Germany	93049
61	Cardiovasculares Centrum Frankfurt - Sankt Katharinen	Frankfurt am Main	Hessen	Germany	60389
62	Herzzentrum	Leipzig		Germany

Sponsors and Collaborators

• Boston Scientific Corporation

Investigators

• Principal Investigator: David Holmes, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Sponsor website

Publications

None provided.

• Responsible Party: Boston Scientific Corporation
• ClinicalTrials.gov Identifier: NCT00129545
• Other Study ID Numbers: ST1021 and ST1055
• First Posted: Aug 12, 2005
• Last Update Posted: May 15, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by Boston Scientific Corporation: Atrial Fibrillation; AF; A Fib; Stroke; Coumadin; Warfarin; Blood thinning medication; transient ischemic attack (TIA); WATCHMAN; Left atrial appendage; LAA isolation; LAA occlusion
• Additional relevant MeSH terms: Atrial Fibrillation; Warfarin

Study Results

Participant Flow

Arm/Group Title	Roll-in	WATCHMAN	WARFARIN
Arm/Group Description	Investigational centers were allowed up to 3 roll in subjects before initiating the randomization phase	Randomized to receive implantation of the WATCHMAN left atrial appendage (LAA) closure Technology	Randomized to receive Warfarin control
Period Title: Overall Study
STARTED	93	463	244
COMPLETED	67	299	133
NOT COMPLETED	26	164	111

Baseline Characteristics

Arm/Group Title	WATCHMAN	Warfarin Control	Roll-in	Total
Arm/Group Description	WATCHMAN Left Atrial Appendage Closure Technology:	Subjects were treated with current standard of care Oral Anticoagulation Therapy with Warfarin	Subjects received WATCHMAN Left Atrial Appendage Closure Technology but were not included in the outcome analysis	Total of all reporting groups
Overall Participants	463	244	93	800
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.7 (8.8)	72.7 (9.2)	72.2 (8.9)	72.0 (8.9)
Sex: Female, Male (Count of Participants)
Female	137 29.6%	73 29.9%	28 30.1%	238 29.8%
Male	326 70.4%	171 70.1%	65 69.9%	562 70.3%
Race/Ethnicity, Customized (participants) [Number]
Asian	4 0.9%	1 0.4%	0 0%	5 0.6%
Black/African American	6 1.3%	5 2%	3 3.2%	14 1.8%
Caucasian	425 91.8%	222 91%	87 93.5%	734 91.8%
Hispanic/Latino	25 5.4%	15 6.1%	3 3.2%	43 5.4%
Hawaiian/Pacific Islander	1 0.2%	1 0.4%	0 0%	2 0.3%
other	2 0.4%	0 0%	0 0%	2 0.3%
Region of Enrollment (participants) [Number]
United States	382 82.5%	201 82.4%	87 93.5%	670 83.8%
Czech Republic	19 4.1%	10 4.1%	3 3.2%	32 4%
Germany	62 13.4%	33 13.5%	3 3.2%	98 12.3%

Outcome Measures

1. Primary Outcome

Title	Composite of Stroke, Systemic Embolism and Cardiovascular or Unexplained Death
Description	A Bayesian model allowed for sequential evaluation of the primary endpoints, event rates reported per 100 patient-years (calculated as 100*N events/Total patient-years)
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

event rates reported per 100 patient-years (calculated as 100*N events/Total patient-years) total patient years 2717, 95% Credible Intervals per predefined Bayesian Statistics Roll-in subjects were not included in the primary outcome analysis per study design.

Arm/Group Title	Implantable Device	Warfarin Control
Arm/Group Description	Implantable WATCHMAN Left ATrial Appendage Occlusion Device WATCHMAN Left Atrial Appendage Closure Technology: Implant of WATCHMAN Left Atrial Appendage Closure Technology	Subjects are treated with current standard of care Oral Anticoagulation Therapy with Warfarin Warfarin: Subjects receive warfarin
Measure Participants	463	244
Number (95% Confidence Interval) [events per 100 pt yrs]	2.2	3.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Implantable Device, Warfarin Control
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The posterior probability of non-inferiority is defined as the probability that the event rate for the Device group is less than twice that for the Control group. This probability was required to be greater than 0.975 for a finding of non-inferiority. The criterion for non-inferiority was consistently met at each analysis time point demonstrating the Device group is non-inferior to the Control group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.42 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relative Risk calculated as Device Rate over Control rate, with 95% Credible Intervals

2. Primary Outcome

Title	The Occurrence of Life-threatening Events, Including Device Embolization or Serious Bleeding Events
Description	Serious bleeding events evaluated by the Clinical Events Committee included pericardial effusion requiring drainage, cranial bleeding events due to any source, gastrointestinal bleeds requiring transfusion, and any bleeding related to the device or procedure that necessitates an operation.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Event rates reported per 100 patient-years (calculated as 100*N events/Total patient-years) total patient years 2717, 95% Credible Intervals per predefined Bayesian Statistics Roll-in subjects were not included in the primary outcome analysis per study design.

Arm/Group Title	Implantable Device	Warfarin Control
Arm/Group Description	Implantable WATCHMAN Left ATrial Appendage Occlusion Device WATCHMAN Left Atrial Appendage Closure Technology: Implant of WATCHMAN Left Atrial Appendage Closure Technology	Subjects are treated with current standard of care Oral Anticoagulation Therapy with Warfarin Warfarin: Subjects receive warfarin
Measure Participants	463	244
Number (95% Confidence Interval) [Events per 100 pt-yrs]	3.5	3.2

3. Secondary Outcome

Title	Procedure Success
Description	Implant procedure success is defined as the delivery and release of a WATCHMAN Device into the LAA.
Time Frame	Initial implant procedure

Outcome Measure Data

Analysis Population Description

14 subjects did not have an implant procedure attempted

Arm/Group Title	WATCHMAN
Arm/Group Description	Implantable WATCHMAN Left ATrial Appendage Occlusion Device Implant of WATCHMAN Left Atrial Appendage Closure Technology
Measure Participants	449
Number [percentage of implant attempts]	90.9

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	electronic case report form (e-CRF) completion by sites, followed by independent Clinical Events Committee (CEC) adjudication
Arm/Group Title	Roll-in		WATCHMAN		WARFARIN
Arm/Group Description	Investigational centers were allowed up to 3 roll in subjects before initiating the randomization phase		Randomized to receive implantation of the WATCHMAN LAA closure Device		Randomized to receive Warfarin control
All Cause Mortality
	Roll-in		WATCHMAN		WARFARIN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Roll-in		WATCHMAN		WARFARIN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/93 (31.2%)		143/463 (30.9%)		70/244 (28.7%)
Blood and lymphatic system disorders
Anemia Requiring Transfusion	0/93 (0%)	0	2/463 (0.4%)	2	1/244 (0.4%)	4
Device Thrombus	0/93 (0%)	0	2/463 (0.4%)	2	0/244 (0%)	0
Systemic Embolization	0/93 (0%)	0	3/463 (0.6%)	3	0/244 (0%)	0
Cardiac disorders
Arrhythmias	0/93 (0%)	0	2/463 (0.4%)	2	0/244 (0%)	0
Cardiac Perforation	1/93 (1.1%)	1	7/463 (1.5%)	7	0/244 (0%)	0
Pericardial Effusion with Cardiac Tamponade	4/93 (4.3%)	4	13/463 (2.8%)	13	0/244 (0%)	0
Pericardial Effusion-Serious	0/93 (0%)	0	4/463 (0.9%)	4	0/244 (0%)	0
Gastrointestinal disorders
Gastrointestinal Bleeding	9/93 (9.7%)	12	26/463 (5.6%)	32	22/244 (9%)	27
Oral Bleeding	0/93 (0%)	0	0/463 (0%)	0	1/244 (0.4%)	1
Rectal Bleeding	1/93 (1.1%)	1	1/463 (0.2%)	1	1/244 (0.4%)	1
General disorders
Death	5/93 (5.4%)	5	59/463 (12.7%)	59	44/244 (18%)	44
Infections and infestations
Infection	1/93 (1.1%)	1	2/463 (0.4%)	2	0/244 (0%)	0
Investigations
Device Embolization	0/93 (0%)	0	3/463 (0.6%)	4	0/244 (0%)	0
Other Study Related	4/93 (4.3%)	4	17/463 (3.7%)	18	2/244 (0.8%)	2
Nervous system disorders
Stroke - Hemorrhagic	0/93 (0%)	0	3/463 (0.6%)	3	10/244 (4.1%)	10
Stroke - Ischemic	5/93 (5.4%)	5	24/463 (5.2%)	26	10/244 (4.1%)	11
Transient Ischemic Attack (TIA)	1/93 (1.1%)	1	5/463 (1.1%)	5	0/244 (0%)	0
Renal and urinary disorders
Hematuria	0/93 (0%)	0	4/463 (0.9%)	4	0/244 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Pulmonary Edema	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Vascular disorders
AV Fistula	1/93 (1.1%)	1	1/463 (0.2%)	1	0/244 (0%)	0
Bleeding from Varicose Veins	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Bruising - Hematoma	2/93 (2.2%)	2	5/463 (1.1%)	5	0/244 (0%)	0
Cranial Bleed	1/93 (1.1%)	1	4/463 (0.9%)	4	1/244 (0.4%)	1
Epistaxis	2/93 (2.2%)	2	4/463 (0.9%)	4	0/244 (0%)	0
Major Bleed Requiring Transfusion	1/93 (1.1%)	1	2/463 (0.4%)	2	1/244 (0.4%)	1
Pseudoaneurysm	0/93 (0%)	0	3/463 (0.6%)	3	0/244 (0%)	0
Thrombosis	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Other (Not Including Serious) Adverse Events
	Roll-in		WATCHMAN		WARFARIN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/93 (20.4%)		71/463 (15.3%)		17/244 (7%)
Blood and lymphatic system disorders
Anemia Requiring Transfusion	0/93 (0%)	0	2/463 (0.4%)	2	1/244 (0.4%)	1
Cardiac disorders
Pericardial Effusion	3/93 (3.2%)	3	10/463 (2.2%)	10	0/244 (0%)	0
Gastrointestinal disorders
Gastrointestinal Bleeding	1/93 (1.1%)	1	3/463 (0.6%)	3	2/244 (0.8%)	2
Oral Bleeding	0/93 (0%)	0	2/463 (0.4%)	2	1/244 (0.4%)	1
Rectal Bleeding	1/93 (1.1%)	1	3/463 (0.6%)	5	5/244 (2%)	5
General disorders
Other Non-Study Related	0/93 (0%)	0	2/463 (0.4%)	2	0/244 (0%)	0
Immune system disorders
Allergic Reaction to Contrast Media	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Infections and infestations
Infection	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Injury, poisoning and procedural complications
Air Embolism	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Inability to Move or Retrieve Device	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Investigations
Device Thrombus	2/93 (2.2%)	2	14/463 (3%)	15	0/244 (0%)	0
Other Study Related	9/93 (9.7%)	9	19/463 (4.1%)	20	2/244 (0.8%)	2
Nervous system disorders
Stroke - Ischemic	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Transient Ischemic Attack (TIA)	1/93 (1.1%)	1	2/463 (0.4%)	2	0/244 (0%)	0
Vasovagal Reactions	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Renal and urinary disorders
Hematuria	0/93 (0%)	0	2/463 (0.4%)	2	2/244 (0.8%)	2
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Vascular disorders
AV Fistula	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Bleeding from Varicose Veins	0/93 (0%)	0	1/463 (0.2%)	1	0/244 (0%)	0
Bruising - Hematoma	0/93 (0%)	0	3/463 (0.6%)	3	2/244 (0.8%)	2
Epistaxis	4/93 (4.3%)	4	11/463 (2.4%)	13	5/244 (2%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.