Transcript Test

PROACT: Prospective Randomized On-X
Anticoagulation Clinical Trial –
Reduced Anticoagulation for a Mechanical
Heart Valve
John D. Puskas MD, FACS, FACC
Emory University
International Principal Investigator
On Behalf of the PROACT Investigators
Disclosure Slide
 Data tables and analyses were provided by Clinipace Inc,
CRO/DCC for the PROACT trial.
 Dr Puskas and Emory University have only a research
agreement for the PROACT trial with On-X Life
Technologies, Inc, manufacturers of the On-X valve.
 Dr Puskas has received only travel expenses to
Investigator’s meetings from On-X Life Technologies
 Dr Puskas and Emory University have no other financial
relationship with On-X Life Technologies or Clinipace.
PROACT Objective
 To determine whether it is safe and
effective to manage patients with less
aggressive anticoagulation therapy than
is currently recommend by ACC/AHA
guidelines after implantation of the On-X
bileaflet mechanical heart valve.
 FDA Investigational Device Exemption
trial.
 After AVR with bileaflet mechanical or Medtronic Hall
prostheses, in patients with no risk factors, warfarin is
indicated to achieve an INR of 2.0 to 3.0. If the patient
has risk factors, warfarin is indicated to achieve an
INR of 2.5 to 3.5 (Level of Evidence: B)
 The addition of aspirin 75 to 100 mg once daily to
therpeutic warfarin is recommended for all patients
with mechanical heart valve and those patients with
biological valves who have risk factors. (Level of
Evidence: B)
4/8/2016 – slide 5
PROACT Study Design
 Multicenter RCT; FDA IDE trial
 All patients receive standard anticoagulation therapy
for 90 postoperative days
 Randomized to low dose anticoagulation (“test”) vs
standard therapy (“control”) groups at 3 months
 Non-inferiority hypothesis
 Endpoint: sum of TE, thrombosis and bleeding events,
defined per AATS/STS guidelines
 Also tested against FDA objective performance criteria
(OPC) – (%/ptyr: 3.0 TE, 0.8 thrombosis, 3.5 bleeding)
 Kaplan-Meier and linearized rates
 Secondary endpoints – Echo results, NYHA class and
other valve-related adverse events
Sample Size
 For non-inferiority trials sample requirements
generally fall between 700 and 1000 patient years
 For OPC the requirement is generally 800 patient
years but can be less if rates are lower than the criteria
by at least 2/3
 Initial design: 200 patients per group at 5 years
 Alternatively, 150 patients followed for an average of
6.7 years as now allowed in AVR low risk and MVR
 6 groups (3 test and 3 control) for a total of 1000
patients
3 Low-Dose Test Groups
 Early postop period (three months), standard therapy
per AHA/ACC: warfarin plus ASA 81 mg/day.
 Low risk AVR
 Clopidogrel 75 mg/day, plus aspirin 325 mg/day
 High risk AVR
 INR 1.5 to 2.0, plus 81 mg/day aspirin
 All MVR
 INR 2.0 to 2.5, plus 81 mg/day aspirin
 Three randomized control groups, all on standard
warfarin therapy plus 81 mg/day aspirin
 All patients on warfarin receive home monitoring after
three months
Inclusion
 Isolated AVR and MVR or with other
concomitant cardiac surgery
 Adults; informed consent and agreement to
follow-up
 Risk groups for AVR defined by
 Clinical and Laboratory Criteria
 Platelet Responsiveness
Exclusion
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Multiple valve replacement (MV repair allowed)
Active endocarditis
Terminal illness
Emergency cases
Inability to return for follow-up
Persons unable to give adequate consent
AVR High Risk Criteria
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Chronic atrial fibrillation
Left ventricular ejection fraction < 30 %
Enlarged left atrium >50mm diameter
Spontaneous echo contrasts in the left atrium
Neurological events (any Hx prior stroke, TIA, or RIND)
Left or right ventricular aneurysm
Women receiving estrogen replacement therapy
Hypercoagulability
Inadequate platelet response to aspirin or clopidogrel
Hypercoagulability
 APC resistance (Factor V-Leiden mutation; heterozygous
or homozygous)
 Prothrombin mutation—heterozygous or homozygous
 AT III activity below normal
 Protein C activity below normal
 Protein S activity below normal
 Factor VIII activity elevated above 250% normal
 Tested at Hemostasis Reference Laboratory, Hamilton,
Ontario, directed by Dr. H. Hoogendoorn
Drug Response Tests
 Urine 11 dehydro-thromboxane B2—must be reduced after
aspirin treatment (≤ 298 pg/mg)
 P2Y12 must be reduced after clopidogrel treatment (≥35 %
inhibition)
 Resistance to aspirin or clopidogrel in AVR patients defined
by clinical core laboratory test results done after pateints have
been taking aspirin and clopidogrel for at least 5 days
 Patients must be given these drugs one week prior to testing
and the drugs will be removed after testing. This testing may
be done either prior to surgery or postoperatively.
 Both ASA and clopidogrel tests done simultaneously.
Active Centers
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Tacoma General – D. Nichols
Univ AZ/VA – B. Rhenman, G. Sethi
Maine Medical – R. Quinn
Emory - J. Puskas
St. Francis, Indianapolis – M. Gerdisch
Sentara – M. McGrath
Duke - C. Hughes
Univ OK/VA – T. Trotter, M. Peyton
UT Southwestern – M. Wait
St. Joseph Mercy, Ann Arbor - B. Kong
Shands (Univ FL)
Florida Hospital
Wake Medical
New Mexico Heart
Providence, Portland, OR
Loma Linda
St. Paul’s, Vancouver
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Baylor Dallas
Texas Cardiac, Lubbock
Beth Israel
St. Luke’s, NY
Mary Washington
Cotton O’Neil
Forsyth, Winston Salem
Ohio State University
Cleveland Clinic
CSA, Florida
Barnes Jewish, WUSTL
Texas Heart
Univ of Alberta, Edmonton
London, Ontario
Johns Hopkins
SE Texas Cardiovascular
St. Luke’s, Milwaukee
PROACT Study Centers
PROACT Enrollment by Group
Overall Patients
Enrolled
Test
Control
Pending
Removed
Low Risk AVR
Enrolled
Test
Control
Pending
Removed
238
41
41
81
75
High Risk AVR
Enrolled
Test
Control
Pending
Removed
861
289
297
97
178
435
185
190
0
60
Mitral
Enrolled
Test
Control
Pending
Removed
188
53
66
16
43
Data as of 2/28/2011
Enrollment Process AVR High Risk
- Closed AVR HIGH RISK Enrollment
preop or up to 60 days postop
Surgery
Discharge/30 day
Complete and submit home monitor
paperwork
Test
90 day: Randomize
Provide, train, test home monitor.
Control
Removal Before Randomization
Reason
AVR High
Risk
Adverse event exclusion
10
Early death
8
Repair
0
Different valve used/double
10
Patient/physician withdrawn
10
Labs problem
0
No surgery
4
Lost to follow-up
2
Blood test failure
11
Unknown
5
Age and Gender AVR High Risk Group
Group
Age (years)
% Male
55.2 ± 12.4 (20-85)
79.0
Control
55.8 ± 12.0 (22-85)
81.0
Test
54.2 ± 12.9 (20-83)
81.0
AVR High Risk
No differences between high risk control and test.
Etiology Of Native Valve Pathology
AVR High (N=435)
N (%)
Rheumatic
7(2)
Calcific
291(67)
Congenital
151(35)
Degenerative
72(17)
Endocarditis
13(3)
Prosthetic
Dysfunction
18(4)
Other
34(8)
Native Valve Lesions
Stenosis
AVR High N=435
N (%)
227(52)
Regurgitation
92(21)
Mixed
101(23)
Other
12(3)
Preoperative NYHA Class
NYHA Class
I
AVR High (N=435)
N (%)
89(20)
II
167(38)
III
120(28)
IV
26(6)
Unknown/Missing
34(8)
Clinical Conditions Causing
“High Risk” Status in AVR Patients
Condition
Number
% AVR High Risk
Atrial Fibrillation
19
4.4
Ejection Fraction < 30%
17
3.9
LA Diameter > 50mm
44
10.1
Echo Contrasts
3
0.7
Ventricular Aneurysm
4
0.9
Neurologic Events
21
4.8
Estrogen Therapy
6
1.4
Clinical Factors Only
137
31.3
Laboratory Errors
3
0.7
Enrollment Errors
8
1.8
Abnormal Laboratory Test Results
Test
Number
Percent of
AVR High
Risk
Factor V Leiden
10
2.3
Prothrombin Mutation
7
1.6
AT III Activity
59
13.6
Protein C
21
4.8
Protein S
6
1.4
Factor VIII
4
0.9
Aspirin Response
169
38.8
Clopidogrel Response
107
24.6
Multiple Causes
98
22.4
Lab Test Only
289
66.0
Patients with only laboratory high risk criteria.
Comparisons of AVR High Risk
Groups – Native Pathology
Etiology
AVR High Risk
p-value
Control - N (%)
Test - N (%)
Rheumatic
3 (2)
3 (2)
0.712
Calcific
130 (68)
122 (66)
0.763
Congenital
72 (38)
68 (37)
0.926
Endocarditis
5 (3)
8 (4)
0.806
Degenerative
32 (17)
31 (17)
0.891
Prosthetic Valve
Dysfunction
8 (4)
7 (4)
0.792
Other
12 (6)
12 (6)
0.828
Comparisons of AVR High Risk
Groups – Valve Lesion
Lesion
AVR High Risk
p-value
Control - N (%)
Test - N (%)
Stenosis
97 (51)
94 (51)
0.918
Regurgitation
34 (18)
46 (25)
0.127
Mixed
53 (28)
40 (22)
0.222
Other
5 (3)
4 (2)
0.773
Comparisons of AVR High Risk
Groups – NYHA Classification
NYHA Class
AVR High Risk
Control - N (%)
Test - N (%)
I
36 (19)
40 (22)
II
73 (38)
72 (39)
III
51 (27)
49 (26)
IV
16 (8)
7 (4)
Unknown
14 (7)
17 (9)
p-value by Chi Square test = 0.406.
Comparisons of AVR High Risk
Groups – Clinical Risk Factors
Risk Factor
AVR High Risk
p-value
Control - N (%)
Test - N (%)
Atrial Fibrillation
11 (6)
3 (2)
0.088
Ejection Fraction < 30%
7 (4)
9 (5)
0.827
Estrogen Therapy
2 (1)
4 (2)
0.710
Left Atrial Diameter > 50mm
22 (12)
19 (10)
0.436
Neurological Events
9 (6)
6 (3)
0.469
Spontaneous Echo Contrasts
2 (1)
0 (0)
0.525
Ventricular Aneurysm
1 (0.5)
1 (0.5)
0.464
Comparisons of AVR High Risk
Groups – Laboratory Tests
Laboratory Test
AVR High Risk
p-value
Control - N (%)
Test - N (%)
AT-III Activity
24 (13)
29 (16)
0.497
Factor VIII Activity
1 (0.5)
2 (1)
0.604
Factor V Leiden Mutation
3 (2)
6 (3)
0.772
Protein C Activity
9 (5)
10 (5)
0.813
Prothrombin Mutation
3 (2)
4 (2)
0.712
Protein S Activity
3 (2)
3 (2)
0.712
P2Y12 Inhibition
52 (27)
42 (23)
0.438
Urine Thromboxane
69 (36)
85 (46)
0.062
Home INR Compliance
Patients testing and reporting by group
Initial Reporting
 AVR High
 Control – 91.6%
 Test – 91.9%
Current Reporting
 AVR High
 Control – 88.3%
 Test – 87.6%
Home INR Results
High Risk AVR Groups
(p<0.0001)
Target INR
Control N=174
2.0-3.0
Test N=171
1.5-2.0
Mean INR
2.49
1.89
Stdev
0.63
0.50
15.5%
(2.5% <1.5)
11.9%
In Range
70.0%
68.4%
High (> 3.0)
14.5%
25.7%
(3.1% >3.0)
Total Readings
13482
12901
Low (< 2.0)
Total INR readings 26,383
INR Distribution High Risk AVR
70.0
60.0
Percent
50.0
40.0
AVR High Control
30.0
AVR High Test
20.0
10.0
0.0
<1.5 1.5-2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 >4.5
International Normalized Ratio (INR)
Randomized Patients and Years
Type
Group
Patients
Mean Yrs
Follow-up
Patient
Years
AVR High
All
375
1.60
598.4
Test
185
1.56
288.8
Control
190
1.63
310.6
Pre-Randomization Events
Peri-operative Bleed
Major Bleed
Minor Bleed
Total Bleed
Intra-operative TE
Stroke
TIA
Neurologic Event
Peripheral TE
Thrombosis
Major Event
(Major bleed, stroke, thrombosis)
All Above Events (except operation related)
All Events
Sudden Death
Valve-related death (incl. sudden)
Total Mortality
AVR High Risk (435)
N
Rate (%)
35
10
7
52
1
3
1
5
0
0
13
8.05
2.30
1.61
11.95
0.23
0.69
0.23
1.15
0.00
0.00
2.99
21
4.83
57
2
3
8
13.10
0.46
0.69
1.84
Patients Withdrawn After Randomization
Reason
AVR High Risk
Test
Control
Adverse event exclusion
1
0
Death
6
4
Patient withdrawal
5
3
Physician withdrawal
5
0
Lost to follow-up
5
2
Unknown
1
0
AVR High Risk Events
After Randomization (Intent to Treat)
Event
Major Bleed
Minor Bleed
Total Bleed
Stroke
TIA
Neurologic Event
Peripheral TE
Thrombosis
Major Event
(Major bleed, stroke,
thrombosis)
All Above Events
Sudden Death
Valve-related death
(incl. sudden)
Total Mortality
Control
(ptyr = 310.6)
N Rate (%/ptyr)
13
4.19
15
4.83
28
9.01
1
0.32
2
0.64
3
0.97
1
0.32
0
0.00
14
4.51
Test
Rate Ratio
95% CI
(ptyr = 288.8)
N Rate (%/ptyr) (control/test)
8
2.77
1.51
0.58-4.21
9
3.12
1.55
0.64-4.02
17
5.89
1.53
0.81-2.98
4
1.39
0.23
0.005-2.35
5
1.73
0.37
0.04-2.27
9
3.12
0.31
0.05-1.24
2
0.69
0.46
0.01-8.93
0
0.00
12
4.16
1.08
0.47-2.57
Pvalue
32
1
1
10.30
0.32
0.32
29
1
4
10.04
0.35
1.39
1.03
0.93
0.15
0.60-1.76 0.920
0.01-72.99 0.959
0.005-2.35 0.155
4
1.29
6
2.08
0.62
0.13-2.61
0.355
0.295
0.162
0.155
0.218
0.063
0.522
0.836
0.454
AVR High Risk Bleeding and TE Comparisons
Intent to Treat vs. Per Protocol
Event
Intent to Treat
Control
Per Protocol
Test
Control
Test
n
%/ptyr
n
%/ptyr
n
%/ptyr
n
%/ptyr
Major Bleed
13
4.19
8
2.77
2
0.92
3
1.52
Minor Bleed
15
4.83
9
3.12
4
1.84
3
1.52
Total Bleed
28
9.01
17
5.89
6
2.76
6
3.04
CVA
1
0.32
4
1.39
1
0.46
0
0.00
TIA
2
0.64
5
1.73
0
0.00
2
1.01
Peripheral
Embolism
1
0.32
2
0.69
1
0.46
1
0.51
All TE
4
1.29
11
3.81
2
0.92
3
1.52
Major Events
14
4.51
12
4.16
3
1.38
3
1.52
All Events
32
10.30
29
10.04
8
3.68
9
4.56
INR Status Among High Risk AVR Patients
High Risk AVR Control
 Bleed
 15/29 (51.7%) Above
Target
 Average 3.3
 Major Bleed
 9/13 (69.2%) Above Target
 Average 4.3
 TE
 1/4 (25%) Below Target
 Average 2.5
 CVA
 1 at 2.0 INR
High Risk AVR Test
 Bleed
 9/17 (52.9%) Above Target
 Average 2.8
 Major Bleed
 5/7 (71.4%) Above Target
 Average 3.5
 TE
 6/11 (54.6%) Below Target
 Average 1.6
 CVA
 3/4 (75%) Below Target
 Average 1.5
Interim Adverse Event Analyses--Summary
 No significant differences to date in either
bleeding or TE
 Non-inferiority hypothesis supported
 Comparison of intent to treat and per
protocol results illustrates importance of
anticoagulation within target range.
 Bleeding events more common than TE
 Potential benefit from reducing INR
Conclusions
 PROACT trial interim results from the
High Risk AVR group suggest that lower
target INR may be associated with lower
incidence of bleeding events.
 Longer follow-up in this ongoing trial will
reveal whether this lower risk of bleeding
comes at an acceptable risk of TE events.
 Tight INR control important to limit
adverse events.