PROACT: P rospective R andomized O n-X A nticoagulation C linical T rial – 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. - PowerPoint PPT Presentation
PROACT: PROACT: P P rospective rospective R R andomized andomized O O n- n- X X A A nticoagulation nticoagulation C C linical linical T T rial – rial – Reduced Anticoagulation for a Reduced Anticoagulation for a Mechanical Heart Valve Mechanical Heart Valve John D. Puskas MD, FACS, FACC John D. Puskas MD, FACS, FACC Emory University Emory University International Principal Investigator International Principal Investigator On Behalf of the PROACT Investigators On Behalf of the PROACT Investigators
Reduced Anticoagulation for a Mechanical Reduced Anticoagulation for a Mechanical Heart ValveHeart Valve
John D. Puskas MD, FACS, FACCJohn D. Puskas MD, FACS, FACC Emory University Emory University
International Principal InvestigatorInternational Principal InvestigatorOn Behalf of the PROACT InvestigatorsOn Behalf of the PROACT Investigators
Disclosure SlideDisclosure 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 ObjectivePROACT 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)
04/21/23 – slide 5
PROACT Study DesignPROACT 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 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 Groups3 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
InclusionInclusion
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
ExclusionExclusion
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 CriteriaAVR High Risk Criteria
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
HypercoagulabilityHypercoagulability
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 TestsDrug 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 CentersActive Centers
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
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
Data as of 2/28/2011
PROACT Enrollment by Group
Enrollment Process AVR High RiskEnrollment Process AVR High Risk- Closed -- Closed -
90 day: RandomizeProvide, train, test home monitor.
Discharge/30 dayComplete and submit home monitor
paperwork
Surgery
AVR HIGH RISK Enrollmentpreop or up to 60 days postop
ControlTest
Removal Before RandomizationRemoval 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 GroupAge and Gender AVR High Risk Group
Group Age (years) % Male
AVR High Risk 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
No differences between high risk control and test.
Etiology Of Native Valve PathologyEtiology 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 LesionsNative Valve Lesions
AVR High N=435
N (%)
Stenosis 227(52)
Regurgitation 92(21)
Mixed 101(23)
Other 12(3)
Preoperative NYHA ClassPreoperative NYHA Class
NYHA Class AVR High (N=435)
N (%)
I 89(20)
II 167(38)
III 120(28)
IV 26(6)
Unknown/Missing 34(8)
Clinical Conditions Causing Clinical Conditions Causing “High Risk” Status in AVR Patients“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 ResultsAbnormal Laboratory Test ResultsTest 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 Comparisons of AVR High Risk Groups – Native PathologyGroups – 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 Comparisons of AVR High Risk Groups – Valve LesionGroups – 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 Comparisons of AVR High Risk Groups – NYHA ClassificationGroups – 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 Comparisons of AVR High Risk Groups – Clinical Risk FactorsGroups – 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 Comparisons of AVR High Risk Groups – Laboratory TestsGroups – 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 ComplianceHome INR CompliancePatients testing and reporting by groupPatients 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 ResultsHome INR ResultsHigh 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
Low (< 2.0) 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
Total INR readings 26,383
INR Distribution High Risk AVRINR Distribution High Risk AVR
Randomized Patients and YearsRandomized 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 AVR High Risk (435)N Rate (%)
