Disclosure Slide

PROACT: Prospective Randomized On-X Anticoagulation Clinical Trial –Reduced Anticoagulation for a Mechanical Heart ValveJohn D. Puskas MD, FACS, FACC Emory UniversityInternational Principal InvestigatorOn 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)

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 • 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 • 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 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 • 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

PROACT Study Centers

PROACT Enrollment by Group Data as of 2/28/2011

AVR HIGH RISK Enrollment preop or up to 60 days postop Surgery Discharge/30 day Complete and submit home monitor paperwork 90 day: Randomize Provide, train, test home monitor. Enrollment Process AVR High Risk- Closed - Test Control

Removal Before Randomization

Age and Gender AVR High Risk Group No differences between high risk control and test.

Etiology Of Native Valve Pathology

Native Valve Lesions

Preoperative NYHA Class

Clinical Conditions Causing “High Risk” Status in AVR Patients

Abnormal Laboratory Test Results Patients with only laboratory high risk criteria.

Comparisons of AVR High Risk Groups – Native Pathology

Comparisons of AVR High Risk Groups – Valve Lesion

Comparisons of AVR High Risk Groups – NYHA Classification p-value by Chi Square test = 0.406.

Comparisons of AVR High Risk Groups – Clinical Risk Factors

Comparisons of AVR High Risk Groups – Laboratory Tests

Home INR CompliancePatients testing and reporting by group Initial Reporting Current Reporting AVR High Control – 88.3% Test – 87.6% • AVR High • Control – 91.6% • Test – 91.9%

Home INR Results Total INR readings 26,383

INR Distribution High Risk AVR

Randomized Patients and Years

Patients Withdrawn After Randomization

AVR High Risk EventsAfter Randomization (Intent to Treat)

AVR High Risk Bleeding and TE Comparisons Intent to Treat vs. Per Protocol

INR Status Among High Risk AVR Patients High Risk AVR Control 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 • 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

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.

Disclosure Slide