The PROACT Trial: valve choice has changed

Transcription

1 The PROACT Trial: valve choice has changed Marc W. Gerdisch, MD On behalf of the PROACT Investigators; Chief Cardiovascular and Thoracic Surgery Co-director Franciscan Heart Valve Center Cardiac Surgery Associates St Francis Heart Center Indianapolis

2 Faculty disclosure Marc W. Gerdisch, MD I disclose the following financial relationships: Consultant and/or advisory board: On-X Life Technologies, Atricure, CorMatrix Cardiovascular Paid speaker: Medtronic, On-X Life Technologies, Atricure, CorMatrix Cardiovascular Equity positions: Atricure, CorMatrix Cardiovascular

3

4 Innovation in Aortic Valve Surgery Pyrolitic Carbon Bileaflet Valves 1977 St Jude 1988 Carbomedics 1996 On-X Life Technologies

5 Dr. Jack Bokros

6 one of the nuclear carbons was Thromboresistant Durable Stable Pyrolite Carbon

7 Silicon-Alloyed Pyrolytic Carbon

8 MCRI (Medical Carbon Research) formed in 1994 On-X Carbon

9 Enlarged pivot

10 Enlarged pivot in motion

11 J Heart Valve Dis 2006;15:80-86

12 South African Trial (Williams, 2004)

13 REDUCED ANTICOAGULATION AFTER MECHANICAL VALVE REPLACEMENT: PROACT RANDOMIZED FDA TRIAL

14 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.

15 ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease After AVR with bileaflet mechanical or Medtronic Hall prostheses warfarin is indicated to achieve an INR of 2.0 to 3.0. (Level of Evidence: B) The addition of aspirin 75 to 100 mg once daily to therapeutic warfarin is recommended for all patients with mechanical heart valves. (Level of Evidence: B)

16 PROACT Study Design Multicenter RCT; FDA IDE trial All patients receive standard anticoagulation therapy for 90 postoperative days At 3 months, randomized to low dose anticoagulation ( test ) vs standard therapy ( control ) groups Primary Endpoints (at 800 pt/yrs; mean 5 yrs F/U): 1) sum of stroke, TIA, peripheral TE, valve thrombosis and major bleeding events, defined per AATS/STS guidelines 2) all-cause mortality Non-inferiority hypothesis with margin 1.5% (absolute)

17 3 Limbs of PROACT Early postop period (three months), standard therapy per AHA/ACC: warfarin plus ASA 81 mg/day. High risk AVR INR 1.5 to 2.0, plus 81 mg/day aspirin Low risk AVR Clopidogrel 75 mg/day, plus aspirin 325 mg/day 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 provided home monitoring after three months

18 Sample Size Initial design: 200 patients per group followed 5 years maximum Amended design: 100 patients followed for an average of 8 years in AVR low risk and MVR 6 groups (3 test and 3 control) for a total of 800 patients

19 Study Centers Tacoma General, Tacoma Baylor, Dallas St. Francis, Indianapolis St. Luke s Roosevelt, New York Emory University, Atlanta Beth Israel Deaconess, Boston Maine Medical, Portland, ME Forsyth, Winston-Salem Tucson VA, Tucson Texas Cardiac, Lubbock Sentara, Norfolk Cotton-O Neil, Topeka University of Arizona, Tucson Mary Washington, Fredericksburg Duke University, Durham Ohio State University, Columbus St. Joseph Mercy, Ann Arbor Cardiac Surg. Assoc, Kissimmee UT Southwestern, Dallas Cleveland Clinic Foundation, Cleveland University of Florida, Gainesville Texas Heart Institute, Houston Oklahoma VA, Oklahoma City University of Alberta, Edmonton Florida Hospital, Orlando Washington University, St. Louis WakeMed, Raleigh Johns Hopkins Univ., Baltimore Providence Heart, Portland, OR University of Oklahoma, OK City Loma Linda Univ., Loma Linda London Health Sciences, Ontario UBC, Vancouver SE Texas Cardiovascular, Humble New Mexico Heart, Albuquerque Aurora Health Care, Milwaukee

20 PROACT Enrollment by Group Overall Patients Enrolled 1247 Test 385 Control 391 Pending 7 Removed 464 Low Risk AVR Enrolled 549 Test 98 Control 99 Pending** 7 Removed 345 High Risk AVR Enrolled 425 Test 185 Control 190 Pending 0 Removed* 50 Mitral Enrolled 273 Test 102 Control 102 Pending 0 Removed 69 Data as of 3/1/2013 *Removed from trial prior to randomization for cause

21 AVR High Risk Group: Inclusion Isolated AVR with/without other concomitant cardiac surgery (CABG, maze, MV repair, etc.) Adult, informed consent, agree to follow-up

22 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

23 AVR High Risk Criteria Clinical and Laboratory 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 Estrogen replacement therapy Hypercoagulability Inadequate platelet response to aspirin or clopidogrel (as follows)

24 Hypercoagulability 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

25 Drug Response Tests Urine 11 dehydro-thromboxane B2 must be reduced after aspirin treatment ( 298 pg thromboxane/mg creatinine), P2Y12 must be reduced after clopidogrel treatment ( 35 % inhibition; VerifyNow) Testing done after at least 5 days of aspirin and clopidogrel, either prior to surgery or days postoperatively.

26 Patients Withdrawn Before Randomization (n=50) Reason AVR High Risk Adverse event exclusion 10 Early death 8 Explant 1 Different valve used/double 10 Patient/physician withdrawn 11 Other protocol exclusion 3 No surgery 4 Lost to follow-up 3

27 Age and Gender, AVR High Risk Randomized Groups Group Age (years) % Male Control 55.8 ± 12.0 (22-85) 81.0 Test 54.1 ± 13.0 (20-83) 80.0 p = p = 0.898

28 Comparison 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) Ejection Fraction < 30% 7 (4) 9 (5) Estrogen Therapy 2 (1) 4 (2) Left Atrial Diameter > 50mm 22 (12) 15 (8) Neurological Events 9 (5) 6 (3) Spontaneous Echo Contrasts 2 (1) 0 (0) Ventricular Aneurysm 1 (0.5) 1 (0.5) 0.464

29 Comparison of AVR High Risk Groups: Abnormal Laboratory Tests Laboratory Test AVR High Risk p-value Control - N (%) Test - N (%) AT-III Activity 24 (13) 28 (15) Factor VIII Activity 1 (0.5) 1 (0.5) Factor V Leiden Mutation 3 (2) 5 (3) Protein C Activity 9 (5) 9 (5) Prothrombin Mutation 3 (2) 4 (2) Protein S Activity 3 (2) 3 (2) P2Y12 Inhibition 52 (27) 42 (23) Urine Thromboxane 69 (36) 84 (45) 0.092

30 Home INR Compliance Percent reporting Control 96% (182/190) Treatment 97% (176/181) Average days between readings 9 both groups Frequency Control (%) Treatment (%) Weekly or more /month or more /month or more /month or less /month or less 7 7

31 INR Distributions AVR High Risk 60% 50% 40% Percent 30% 20% Control (2.0 to 3.0) Treatment (1.5 to 2.0) 10% 0% INR

32 Follow-up of Randomized Patients to Date Type Group Patients Mean Yrs Follow-up Patient Years AVR High All Test Control

33 Patients Withdrawn After Randomization (n=68) Reason AVR High Risk Test Control Death 10 9 Patient withdrawal 12 6 Physician withdrawal 6 1 Lost to follow-up 10 5 Explant 6 2 Adverse Event 1 0

34 Cross-over After Randomization (n=11) 11 test patients had neurological events (5 stroke, 6 TIA) and crossed over to control group, per FDA protocol Protocol does not allow for cross-over from control to test group.

35 Adverse Events After Randomization (Intent to Treat) Event Test (ptyr = 675.2) Control (ptyr = 755.7) Rate Ratio 95% CI P- value N Rate (%/ptyr) N Rate (%/ptyr) (test/control ) Major Bleed Minor Bleed Total Bleed < Ischemic Stroke TIA Stroke + TIA Peripheral TE Thrombosis Primary Endpoint (Major bleed, stroke/tia/te, thrombosis) All Bleeding & Thrombus Valve-related death (incl. sudden) Total Mortality The p-value results from a loglinear/poisson regression model with an offset of log(years of follow-up).

36 Stroke Event Test (ptyr = 675.2) Control (ptyr = 755.4) N Rate (%/ptyr) N Rate (%/ptyr) (test/control) Rate Ratio 95% CI p-value Hemorrhagic Stroke Death Long-term >3 days NA NA NA Short-term NA NA NA 3days Ischemic Stroke Death NA NA NA Long-term >3 days Short-term 3days

37

38 Relationship of TE to Bleed 70,0% INR versus Event Rate 60,0% 50,0% Event Rate 40,0% 30,0% 20,0% TE Bleeding 10,0% 0,0% INR

39 Conclusions PROACT trial interim results from the High Risk AVR group establish that lower target INR is associated with lower incidence of bleeding events. Risk of TE events is not increased. Tight INR control important to limit adverse events. This aortic bileaflet mechanical valve may be safely managed at INR 1.5-2, with ASA 81 mg/d

40 Anatomic Sewing Ring

41

42

43

44

45

46

47

48

49 Thank you