On-X Aortic Heart Valve. Advanced Features Greater Benefits

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1 On-X Aortic Heart Valve Advanced Features Greater Benefits

2 The Most Advanced Technology Pure On-X Carbon allows a natural design for reduced turbulence Organized Flow: Inlet Flare and Natural Length 90 Opening Angle 40 Closing Angle Leaflet Guards No Pannus Improved Pivot Washing Two Point Closure

3 Jack Bokros PhD, Founder Pioneer in Carbon Implant Manufacturing No other company has the industry pioneer who: Discovered isotropic pyrolytic carbon Developed manufacturing processes Designed other valves on market Continues to improve valves

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15 No Pannus 150,000 + Implants 18 Years No confirmed documented pannus

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20 Sizing of Mitral Valves On-X valves reach an optimal size at a smaller nominal size. There is much less regurgitation at any heart rate compared to the market leader.

21 Sizing of Mitral Valves Patient who is 2 M tall And weighs 100 Kilos Completed triathalon 10 months postop with On-X Conform-X mitral valve.

22 Sizing of Mitral Valves Less Mismatch Lowest Complication Rates

23 Lowest Complication Rates FDA trials: Least biased Same protocol Multicenter International Sequential enrollment Audited

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27 1 st Valve with Gradients < 10mmHg in every size

28 Body Surface Area (m 2 ) Patient Annulus EOA EOA EOA EOA 1.7 cm cm cm cm Very Little Mismatch EOAI > 0.75 EOAI< EOAI<0.65 Different publications list different parameters for acceptable IEOA in heart valves. 1,2 Severe mismatch (IEOA 0.6) has negative effects on outcomes. 1 References 1. Daneshvar SA, Rahimtoola SH. Valve prosthesispatient mismatch (VP-PM) a long-term perspective. JACC 2012;60: PibarotP, DumesnilJG. Valve prosthesis-patient mismatch, 1978 to JACC 2012;60: YezbickAB, Ho JK, Crowley R, et al. Echocardiographic signature of the On-X valve. Echocardiography 2008;25:

29 Long Term On-X Complication Rates Aortic Clinical Event (% per patient-year) PMA Study On-X 9 On-X Valve Long-Term Studies South Africa yrs Europe yrs Germany yrs Weighted Average Thromboembolism Thrombosis Hemorrhage Composite Rate All Mortality Valve-Related Mortality

30 South African Data OBJECTIVE: This study was undertaken to evaluate the performance of the On-X valve in a socioeconomically disadvantaged population where anticoagulation was generally poorly controlled and where infectious diseases such as tuberculosis and HIV/AIDS were common co-morbid. 42% NONCOMPLIANT or NO ANTICOAGULATION. LINEARISED RATES FOR VALVE RELATED COMPLICATIONS: MVR AVR DVR Thrombembolism Thrombosis Bleeding Endocarditis Valve related mortality

31 Summary of Benefits Lowest complication rates Largest measured areas Lowest gradients No pannus Lower INR proven safe for aortic valve

32 PROACT Update Current Status of the FDA Approved Reduced Anticoagulation Trial

33 PROACT Study Design and Results Data current to September 2014 Test Groups: High Risk AVR - INR FDA Approval April 2015 MVR - INR pending - about two years out Plus Baby Aspirin (81mg/day)

34 PROACT Objective To determine whether it is safe and effective to manage On-X valve patients with less aggressive anticoagulant therapy than is currently recommend by ACC/AHA guidelines. AVR current recommendation is an INR target of 2.5 with an acceptable range of 2.0 to 3.0.

35 Inclusion Criteria Adults Isolated AVR and MVR Concomitant cardiac surgery allowed Risk groups for AVR defined by cardiac rhythm, ejection fraction, atrial and ventricular dimensions, previous thrombotic or neurologic event, spontaneous echo contrast in atrium, hypercoagulability Full informed consent and agreement to follow-up requirements

36 Exclusion Criteria Multiple valve replacement (MV repair is OK) Active endocarditis Terminal illness Emergency cases Inability to return for follow-up Persons unable to give adequate consent

37 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 Lack of platelet response to aspirin or clopidogrel Women receiving estrogen replacement therapy Hypercoagulability

38 PROACT Enrollment by Group as of Nov 1, 2014 Overall Patients Enrolled 1266 Test 391 Control 404 Pending 4 Removed 467 High Risk AVR Enrolled 425 Test 185 Control 190 Pending 0 Removed* 50 Mitral Enrolled 292 Test 107 Control 112 Pending** 4 Data as of 3/1/2013 Removed 69

39 Active Centers Center Tacoma General, Tacoma, WA St. Francis, Indianapolis, IN Maine Medical, Portland, ME Emory University, Atlanta, GA Tucson VA, Tucson, AZ Sentara, Norfolk, VA St. Joseph Mercy, Ann Arbor, MI Duke University, Durham, NC University of Arizona, Tucson, AZ UT Southwestern, Dallas, TX University of Florida, Gainesville, FL Florida Hospital, Orlando, FL Oklahoma VA, Oklahoma City, OK University of British Columbia, Vancouver, BC Providence Heart, Portland, OR Loma Linda University, Loma Linda, CA Rex Cardiovascular, Raleigh, NC New Mexico Heart, Albuquerque, NM University of Alberta, Edmonton, AL Center Forsyth, Winston-Salem, NC Mary Washington, Fredericksburg, VA Beth Israel Deaconess, Boston, MA Baylor, Dallas, TX St. Luke s Roosevelt, New York, NY Texas Cardiac, Lubbock, TX Cotton-O Neil, Topeka, KS Ohio State University, Columbus, OH Cleveland Clinic Foundation, Cleveland, OH London Health Sciences, Hamilton, ON Cardiac Surgical Associates, Kissimmee, FL Texas Heart Institute, Houston, TX Johns Hopkins University, Baltimore, MD Washington University, St. Louis, MO Montefiore Hospital, New York University of Oklahoma, Oklahoma City, OK Swedish Health System, Seattle, WA University of Pittsburgh, Pittsburgh, PA Hartford Hospital, Hartford, CT

40 Reasons for Removal Before Randomization Reason AVR High Risk Adverse event exclusion 10 Early death 8 Different valve used/double 10 Patient/physician withdrawn 11 Protocol exclusion discovered 3 No surgery 4 Lost to follow-up 3 Explant 1

41 Summary 1-Year Echo Results Mean Std. Dev. Property Size /29 Peak Gradient (mmhg) Mean Gradient (mmhg) EOA (cm 2 ) Indexed EOA All are routine echoes on asymptomatic patients.

42 Home INR Compliance Percent reporting Control 96% (182/190) Treatment 97% (176/181 4 withdrawn at randomization) Average days between readings 9 both groups

43 Home INR Results AVR High (p<0.0001) Control N= Test N= Mean Median Stdev (p<0.001) Low 14.8% (2.5% <1.5) 10.6% In Range 70.4% 64.1% ( %) High 14.8% 25.3% (2.9% >3.0) Total Readings

44 INR Distributions AVR High Risk 60% 50% 40% Percent 30% 20% Control Treatment 10% 0% INR

45 Randomized Patients and Years Group Patients Mean Yrs Follow-Up Patient Yrs AVR High Risk Total Treatment Control

46 AVR High Risk Group Postrandomization Events Event Control (ptyr=878.6) ( ) Test (ptyr=766.2) ( ) Rate Ratio 95% CI P-value N Rate (%/ptyr) N Rate (%/ptyr) (test/control) Major Bleed Cerebral Bleed Minor Bleed Total Bleed <0.001 Ischemic Stroke TIA Neurologic Event Peripheral TE Thrombosis Major bleed, TE, thrombosis(aats Guideline) Primary Endpoint Sudden Death Valve-related death Total Mortality

47 5-Year Kaplan Meier Event Free Rates Event Control (ptyr=878.6) ( ) Test (ptyr=766.2) ( ) P-value Rate (%) Std Error (%) Rate (%) Std Error (%) Major Bleed Minor Bleed Total Bleed <0.001 Ischemic Stroke TIA Neurologic Event Peripheral TE Thrombosis Major bleed, TE, thrombosis(aats Guideline) Primary Endpoint Sudden Death Valve-related death Total Mortality

48 Cerebral Event Analysis Event Test (ptyr = 766.2) Control (ptyr = 878.6) Rate Ratio N Rate (%/ptyr) N Rate (%/ptyr) (test/control) 95% CI p-value Hemorrhagic Stroke Death Long-term > NA NA NA days Short-term 3days NA NA NA Ischemic Stroke Death NA NA NA Long-term > days Short-term days Total Stroke

49 Relationship of TE to Bleed 50,0% INR versus Event Rate 40,0% Percent 30,0% 20,0% Bleeding Rate TE Rate 10,0% 0,0% INR

50 Conclusions and Events PROACT trial interim results from the High Risk AVR group establish that lower target INR is associated with 65% reduction of bleeding events. Risk of TE events has not increased Puskas publication in April 2014 in JCTVS On-X aortic mechanical valve may be maintained at lower INR ( ) with FDA approval and CE mark MVR group enrollment and follow-up continues.

51 THE END

52 Objections to PROACT Sample size too small Home monitoring is required to get these results We still need to be more concerned about TE than we do about bleeding; i.e. TE is a more severe event than bleeding

53 Sample Size Too Small The study was design to give statistical power on the composite rate of bleeding and TE events resulting in: Type I error of <0.05 Type II error of <0.20 This is the standard acceptable power for hypothesis testing The sample size objection comes from the concept of testing individual rates for non-inferiority (Doing this for valve thrombosis, for example, creates an impractical study.) AATS/STS guidelines state that the composite rate represents a more accurate assessment of total hazard of thrombogenicity and anticoagulation. This also comes from refusal to apply the central limit theorem of statistics which is the founding principle of statistics.

54 Home Monitoring is Required This objection ignores basic principles of scientific method If one holds all variables constant except the one you are studying, then the results apply to the variable you are studying and only to that variable. In PROACT home monitoring is a constant and only INR target varies, thus the results apply to INR target and home monitoring is not relevant to these results.

55 INR Home Monitoring In a meta-analysis, researchers pooled data from 14 trials (total, 3049 patients) Thromboembolic events were reduced significantly by self-monitoring (by 43%) or self-management (by 73%) Major hemorrhage was reduced significantly by selfmonitoring (by 44%), but not by self-management All-cause mortality rates were significantly lower with self-management by 63% than with clinical management Heneghan C et al. Self-monitoring of oral anticoagulation: A systematic review and meta-analysis. Lancet 2006 Feb 4; 367:

56 Self Monitoring and Self Management When all data for self-monitoring and selfmanagement was pooled, patients who obtained their INR values at home: 55% fewer thromboembolic events 35% fewer major hemorrhages 39% decrease in all-cause mortality Heneghan C et al. Self-monitoring of oral anticoagulation: A systematic review and meta-analysis. Lancet 2006 Feb 4; 367:

57 What happens if home monitoring is removed? If Heneghan s analysis is correct, then TE s will essentially double Major bleeding will increase by 35% The composite will increase by ~42% Current composite data are: Control 5.80%/ptyr, test 4.57%/ptyr, difference 1.23 New rate would be current times 1.42: Control 8.24%/ptyr, test 6.49%/ptyr, difference 1.75 Remove home monitoring and the results get more significant If anything home monitoring made our task more difficult not more easy

58 Relative Severity of TE and Bleeding Mortality of ischemic stroke ~10% The aggressive use of TPA has greatly reduced the overall effects of ischemic stroke (TE) Recovery is faster and more complete these days Mortality has been reduced in the last decade Mortality of hemorrhagic stroke between 60-80% Improved medical management has reduced this slightly recently, but it is still much higher than for TE Recovery remains a problem as TPA can t help Hemorrhagic stroke is only 5 to 10% of all major bleeding and only about 10% of all stroke Consequently TE is still more feared than bleeding Is that truly justifiable? Probably not but it is real.

59 Clinical Factors For mechanical valves the best practice is to find the balance between bleeding and TE that presents the optimum composite rate These events are either transient, major reversible or permanent Neurological TE s are considered more important overall than bleeding events Transient (minor) bleeding is essentially ignored by the society guidelines Neurological events (hemorrhagic or ischemic) are actually the most critical 5 9

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

61 Societal Benefits of Reduced Events Fewer patients having events Is good for patients and their families Reduces human resource burden on healthcare system by having fewer readmissions Reduces costs of healthcare Each major bleed saved represents $25,000 health care savings per most recent CMS data 1% reduction in bleeding per patient-year among 20,000 patients = cost savings $5 million annually Without increase in TE, bleeding is absolutely important 6 1

62 Guidance Organizations American Heart Association American College of Cardiology American College of Chest Physicians European Society of Cardiology British Cardiovascular Society ANZ Cardiovascular Society Many other local societies

63 Conditions for Anticoagulation Deep vein thrombosis Orthopedic surgery (particularly in legs) Pulmonary embolism Stroke Percutaneous coronary intervention Acute coronary syndrome Coronary artery disease CABG Acute MI Atrial fibrillation Heart valves

64 Atrial Fibrillation To anticoagulate or not to anticoagulate? When you anticoagulate what is the preferred therapy? Warfarin at INR 2.5 (range 2-3), or NOAC (non-valvular afib only) Add aspirin to warfarin if desired, not to NOAC

65 Aortic Heart Valves Tissue valves: 3 months warfarin at 2.5 (2-3), or none at all depending on the organization Aspirin if desired If another reason for anticoagulation then follow those rules Mechanical valves Bileaflet and tilting disc Permanent warfarin at 2.5 (2-3) Add an aspirin (some guidance yes, some optional) With additional risk warfarin at 3.0 ( ) Older valves Permanent warfarin at 3.0 ( ) Add an aspirin (some guidance yes, some optional)

66 Labeling On-X Aortic Valve Labeling : Anticoagulation Patients with an On-X valve in the aortic valve position should be maintained on long-term warfarin anticoagulation which should achieve an International Normalized Ratio (INR) of for the first 3 months after valve replacement surgery, after which the INR should be reduced to Patients with an On-X valve in the mitral valve position or in multiple valve positions should be maintained at an INR of continuously after valve replacement surgery. The addition of a daily aspirin at a dose from 75 to 100 mg is also recommended for patients with an On-X valve in any valve position, unless there is a contraindication to the use of aspirin. Studies show that stable control of INR provides better clinical results and that patients should be regularly monitored. The use of home monitoring to accomplish stable INR control is recommended.

67 Our Advise Anticoagulant management is a mutual decision between a patient and his/her physician(s). It is not our decision. The decision takes into account patient condition, desire, abilities, and many other factors that we are not privy to. They do not need to follow our labeling recommendation, but should not manage anticoagulation any less aggressively than our label states. If comorbidities exist that dictate higher INR levels than in our label, then those higher levels should be used. Example: On-X aortic valve in a patient with afib and a risk score 2 or above should have a 2.5 INR target, but not 3.0. In this instance follow the afib guideline not the heart valve guideline.

68 On-X Heart Valves Implant Techniques

69 On-X Aortic Valve Sizing DO NOT OVERSIZE the On-X aortic valve There is intra-annular carbon and the valve cannot be oversized. The gradients are all less than 10 mm HG 2. The best sizing with the grey sizers occurs AFTER sutures are in place especially if pledgets are used. With the gold sizers, sizing can be estimated prior to suture placement. 3. Tie three equidistant sutures preferably at the low points of the sinus to prevent one side of the intraannular carbon from popping up.

70 On-X Aortic Valve Pannus Protection Learning to implant the intra-annular flare can be a challenging change to aortic implant. The intra-annular flare of the On-X aortic valve is the reason there have been no official confirmed reports of pannus ingrowth in On-X valves in more than 15 years. Pannus is a common occurrence with other valves.

71 On-X Aortic Valve Sizing 1 The On-X aortic valve cylindrical sizer is 0.8 mm larger than the stated size. 19 sizer is 19.8 mm outer diameter 21 sizer is 21.8 mm 23 sizer is 23.8 mm 25 sizer is 25.8 mm The On-X aortic replica sizer is the exact size of the valve. RIGHT SIZE all gradients < 10mmHg DO NOT OVERSIZE!!!

72 On-X Aortic Valve Sizing 2 RESIZE AFTER sutures are in place especially if pledgets are used with the On-X REPLICA sizer. If the sizer is tight, go down one size.

73 On-X Aortic Valve Sizing 3 Tie three equidistant sutures first before tying all the sutures stabilize the On-X aortic valve in the annulus to prevent pop up.

74 Snare Method Many surgeons employ the use of three snares (tourniquets) at the nadirs (low points) of the sinuses to secure the valve in the annulus before tying sutures for any aortic prosthesis. The sutures in between the snares are tied first and then the sutures at the three snares are tied. Technique developed for other valve brand: Baumgartner FJ, Omari BO, Stuart L, et al. Reversible snaring for proper prosthetic seating during valve replacement. Ann Thorac Surg 1998;66:957-58

75 Suture Methods The most commonly used method for On-X aortic valves is non-everting mattress sutures with pledgets introduced from the ventricular side of the annulus. All other suture methods have been used as well. Everting sutures decrease annular size. Pledgets decrease annular size.

76 Pledget Position If the On-X aortic valve is properly sized, the pledgets will lie behind the intra-annular carbon and out of the outflow tract. Some surgeons do not use pledgets with the generous On-X valve PTFE cuffs.

77 On-X Mitral Valve Sizing Sizes 23 and 25 On-X mitral valve sizers are cylindrical in shape. Sizes 27/29 and 31/33 On-X mitral valve sizers are conical in shape. These sizers will accommodate the large sized mitrals.

78 On-X Conform-X Mitral Valve Sizing Proper sizing of the On-X Conform- X Mitral Valve: If size 25 On-X mitral valve sizer fits, the valve will fit. The outer diameter of the leaflet guard is 25 mm. This valve size will accommodate most mitral valve patients. The cuff outer diameter is about 37 mm. On-X surgeons report no interference of mitral leaflet guards in the left ventricular outflow tract.

79 On-X Mitral Valve Orientation The leaflet axis of the On-X mitral valve should be aligned anti-anatomically the same as all bi-leaflet mitral valves. The gap in the leaflet guard will be positioned toward the LVOT or the aortic valve in this orientation.

80 On-X Mitral Valve Tips Tie 3 or 4 equidistant sutures to prevent pop up of one side of the mitral leaflet guards before tying all sutures Tie 1/3 to 1/2 the sutures before attempting rotation. Attempt rotation before all sutures are tied when all sutures are tied, tension on the rotation rings can make it harder to rotate. Leave long suture ends to provide countertraction to rotation. Orient the gap in the leaflet guard toward the aortic valve.

81 On-X Double Valve Implants The On-X mitral valve leaflet guards do not interfere with the LVOT On-X valve aortic cuffs and mitral cuffs do not interfere with each other during mitral implant. Suture method does not seem to matter.

82 The advanced natural design of the On-X valve provides greater flow area and reduced turbulence for lower complication rates and smoother flow. The design features present a difference in implant technique that is easily mastered and used worldwide. On-X Aortic Heart Valve Approved with Lowered INR