1. Cardiology Update 2013 New Anticoagulants Renal Denervation Wearable Defibrillators Radial access for Coronary Intervention Mitral Valve Clip Trans Aortic Valve Replacement

2. New Approaches for Preventing Stroke in Atrial Fibrillation

3. Anticoagulation Agents Stroke Prevention in Atrial Fibrillation VTEVTE – post- orthopedic surgery ACS Warfarin (Coumadin ® ) ◊ ◊ ◊ ◊ Dabigatran (Pradaxa ® ) ◊ Rivaroxaban (Xarelto ® ) ◊ ◊ ◊ Apixaban (Eliquis ® ) ◊ Phase III data published ◊ FDA approved indication

4. Anticoagulant Overview Indirect anticoagulants: UFH, LMWH, fondaparinux, warfarin Direct anticoagulants: Bivalirudin, argatroban, dabigatran, rivaroxaban, apixaban

5. New Oral AC – Sites of Action From: Eur Heart J 2011;32:1968-1976

6. 1-800-BAD-DRUG

7. DABIGATRAN

8. Dabigatran (Pradaxa ® ) Direct Thrombin Inhibitor FDA indication: stroke prevention for non- valvular AF Approved doses: – 150 mg BID – 75 mg BID for CrCl 15-30 mL/min Data: RE-LY (AF) and RE-COVER (VTE)

9. RE-LY Randomized, open-label, non-inferiority Dabigatran 110 mg BID vs 150 mg BID vs Warfarin in patients with non-valvular AFIB N = 18,113 – Age ~71 years, 63% male, 32% HF, 20% prior CVA/TIA – Mean CHADS 2 – 2.1 Median follow-up 2.0 years Mean TTR for warfarin = 64% (Rosendaal) Connolly SJ, et al. NEJM 2009;361:1139-51

10. RE-LY: Results Connolly SJ, et al. NEJM 2009;361:1139-51 Primary Outcome (Stroke or systemic embolism): Warfarin 1.69%/yr D 110 mg* 1.53%/yr D 150 mg*^ 1.11%/yr *Non-inferior to warfarin, P<0.001 ^Superior to warfarin and to D 110 mg P=0.005

11. RE-LY: Safety Connolly SJ, et al. NEJM 2009;361:1139-51

12. RE-LY: Safety Major Bleeding – Dabigatran 110 mg < Warf (20% RRR, P=0.003) Life-threatening Bleeding – Both Dabigatran doses were less than warfarin (P<0.05) GI Bleeding – Dabigatran 150 mg higher than both warfarin and Dabigatran 110 mg (P<0.05) Minor Bleeding – Dabigatran 110 mg less than both warfarin and 150 mg – Dabigatran 150 mg < warfarin Connolly SJ, et al. NEJM 2009;361:1139-51

13. RE-LY: Conclusions Dabigatran 110 mg BID – Non-inferior to warfarin for stroke prevention – Superior to warfarin for bleeding Dabigatran 150 mg BID – Superior to both warfarin and Dabigatran 110 mg BID for stroke prevention – Similar to warfarin for bleeding Connolly SJ, et al. NEJM 2009;361:1139-51

14. Dabigatran – VTE: RE-COVER Double-blind, double-dummy Warfarin versus dabigatran 150 mg BID for acute VTE (6 month duration) 55 yrs old, 59% male, 95% caucasian 69% DVT; 21% PE – ~ 25% were recurrent Non-inferior for VTE or related death (1º) Similar rates of major bleeding Not an FDA approved indication Schulman et al. NEJM 2009;361:2342-52

15. RIVAROXABAN

16. Rivaroxaban (Xarelto ® ) Factor Xa Inhibitor FDA Indication: – Stroke reduction in non-valvular atrial fibrillation – Prevention of DVT after knee or hip surgery Approved doses: – 20 mg QD and 15 mg QD (GFR 15 – 49mL/min) With evening meal – 10 mg QD after knee or hip replacement Data: – ROCKET AF, RECORD1-4, EINSTEIN

17. Rivaroxaban - AF Double blind comparison of warfarin versus rivaroxaban 20 mg QD* *15 mg QD in those with GFR 15-49 mL/min N = 14,264 Mean age 73, 60% men, 62% HF Mean CHADS 2 score = 3.5 Mean follow up: 1.9 yrs – Mean duration on therapy: 1.6 years Mean TTR: 55% Patel et al. NEJM 2011;365:883-91

18. Rivaroxaban - safety Overall – bleeding similar – Rivaroxaban 14.9%; warfarin 14.5% Rivaroxaban – – More rates of: Hgb drop of ≥ 2.0 g/dL, transfusions, critical bleeding* *intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular (compartment syndrome), or retroperitoneal – Less rates of: Intracranial hemorrhage, fatal bleeding Patel et al. NEJM 2011;365:883-91

19. Rivaroxaban – RECORD1-4 Arthoplasty studies comparing rivaroxaban to enoxaparin 40 mg QD Basis for approval of prevention of VTE after knee or hip arthroplasy Approved dose: – 10 mg QD, initial dose 6-10 hours post-surgery (if hemostasis is established) Hip – treat for 35 days Knee – treat for 12 days NEJM 2008;358:2765-75; Lancet 2008;372(9632):31-9; NEJM 2008;358(26):2776-86; Lancet 2009;373(9676):1673-80

20. EINSTEIN – Acute DVT Treatment Open-label, randomized, event driven, non- inferior analysis Rivaroxaban 15 mg BID x 3 weeks, 20 mg QD VS 1 mg/kg BID SC enoxaparin + open-label warfarin Primary efficacy and safety endpoints – recurrent VTE and clinically relevant bleeding NEJM 2010;363:2499-5010

21. Acute DVT and continued treatment NEJM 2010;363:2499-5010

22. Rivaroxaban and DVT/PE Now FDA approved for use as an alternative for wafarin in patients with DVT/PE Dosing: – Acute Treatment – 15 mg BID with food – Extended Treatment – 20 mg daily with food after day 22

23. APIXABAN

24. Apixaban (Eliquis ® ) Factor Xa Inhibitor FDA indication: Nonvalvular atrial fibrillation Data: AVERROES, ARISTOTLE

25. AVERROES Patient with AF “unsuitable” for VKA Apixaban 5 mg BID vs aspirin QD Primary outcome: stroke, systemic embolism Age 70 yrs, 59% male, 14% prior CVA/TIA, ~40% HF Mean CHADS 2 : 2.0 Mean follow up: 1.1 yrs NEJM 2011;364:806-17

26. AVERROES: Results NEJM 2011;364:806-17 * P<0.001 ** P=0.07 P=0.57

27. ARISTOTLE Randomized, double-blind, non-inferiority analysis Apixaban 5 mg BID versus warfarin N=18,201 Age 70 yrs, 65% male, 35% HF – Mean CHADS 2 = 2.1 Mean follow up: 1.8 yrs Mean TTR: 62% NEJM 2011;365:981-92

28. Results NEJM 2011;365:981-92

29. Monitoring Coagulation Assays – Routine labs - not needed – Other monitoring: Data evolving about what could be monitored Clinical Assessment

30. Reversal of anticoagulation No specific antidote Limited data Reversal with non-specific agents – Evolving knowledge of options: FEIBA ® (Factor VIII Inhibitor Bypassing Activity) rFVIIa PCC *No data for use in this clinical context – all in vitro/animal data. *Reserve for life-threatening bleeding Natural clearance – ~ 2-4 days Thromb Haemost 2012 May 25;108(2).

31. Cardiovascular Disease and Sudden Cardiac Arrest: Risk Stratification and Treatment

32. SCD and Out of Hospital Cardiac Arrest SCD accounts for 450,000 deaths annually in the US (1) Each year there are an estimated 295,000 EMS-treated out-of-hospital cardiac arrests in the United States (2) Approximately 60% of unexpected cardiac deaths are treated by EMS (2) Buxton, et al. JACC., 50:1150-1157, 2007. (1) AHA Heart Disease and Stroke Statistics-2010 update (2)

33. Out of Hospital Cardiac Arrest Median reported survival to D/C after out of hospital cardiac arrest with any first recorded rhythm is 6.4% (1) Incidence of lay-responder defibrillation with AED is 2.1% (2010) (2) Nichol et al. Circ, April 21, 2008.(1) Weisfeldt, Myron, L., JACC, 55:1713-20, 2010. (2)

34. Out of Hospital Cardiac Arrest Factors determining survival after out of hospital cardiac arrest Time between collapse and start of resuscitation Time to defibrillation Availability of AED’s in public

35. Home Use of Automated External Defibrillators for Sudden Cardiac Arrest (HAT Trial) Bardy et al conducted a large RCT of 7001 patients to test the hypothesis that an AED in the home would reduce all-cause mortality above that achieved from a conventional lay response to SCA Patients with history of anterior MI, who were not candidates for an ICD, were either assigned to receive the control response (calling EMS with family member performing CPR) or, use of an AED (followed by calling EMS and performing CPR) for SCA occurring in the home Patients were required to have a live-in companion willing to call EMS, perform CPR and use an AED Bardy, et al., NEJM 58: 2008.

36. 228 patients in the control group died 222 patients in the AED group died 117 of these deaths occurred at home 58 of them were witnessed AED’s were used on only 32 of these patients Only 14 received an appropriate shock Only 4 survived to hospital discharge Home Use of Automated External Defibrillators for Sudden Cardiac Arrest (HAT Trial) Bardy, et al., NEJM 58: 2008.

37. Gaps in SCD Protection? Most from ventricular tachyarrhythmias Outpatient defibrillation possibilities: -- Home AED -- EMS (Emergency Medical Services) -- ICD Most SCD occurs in patient groups not indicated for ICD treatment

38. ICD Purgatory/WCD Indications Post Myocardial Infarction with low EF (<35%) < 40 days after MI < 90 post CABG < 90 post PTCA Non-ischemic cardiomyopathy < 3 months from diagnosis (90-270 days) ICD requires explantation Pre transplant, NYHA Class IV Emerging, untested indications

39. FDA Indications for Use The LifeVest System is indicated for adult patients who are at risk for sudden cardiac arrest and are not candidates for or who refuse an implantable defibrillator.

40. LifeVest A Proven Treatment Option

41. Gel capsules Defibrillation electrode ECG electrode Dry, comfortable electrodes

42. LifeVest Features Self gelling defibrillation electrodes No gel, no adhesive ECG electrodes Lightweight (1.8 lb monitor) Consciousness test before shock 150-joule biphasic shock Captures ECG 30 seconds before event Stores up to 75 minutes of ECG

43. Alarm Sequence 1.Arrhythmia detected, activating vibration alert (continues throughout sequence). 2.Siren alerts begin (continues throughout sequence). 3.Siren alerts get louder. 4.Patient audible prompt: “Electrical shock possible.” 5.Gel release. 6.Bystander audible prompt: "Do not touch patient.” 7.Treatment shock.

44. SS FB SS FB SS FB SS FB - 24 seconds between top and bottom - onset shockrecovery

45. LifeVest Experience Experience with over 75,000 patients Average duration of use is 2 1/2 months Median daily use is 95% Survival After Deployment >94%

46. LifeVest Experience First shock conversion success: 98%. Shocked event survival (conscious ER arrival or stayed at home): 94%. Most (77%) treated within 60 seconds (remaining delayed from response button use or VT programming

47. Survival with AED 4-7% (1) In-hospital survival 13-17% (2) Casino 74% (3) WCD 92-94% Survival Statistics (1)Nichol et al. Circ, April 21, 2008. (2)Peberdy, et al, RESUSCITATION 58 (2003) 297-308 (3)Valenzuela et al., NEJM. Oct 26, 1206-9, 2000.

49. Summary Constant monitoring and protection of SCD with superb results: 98% first shock conversion Designed for transitional SCD risk periods (the coverage “gaps” in ICD policy) Medicare and numerous insurances, including many Medicaid programs, cover wearable defibrillator use Allows time to determine long term course of treatment as well as ensuring patient returns for follow-up visit

50. Renal Sympathetic Denervation: Resistant Hypertension and Beyond 50

51. Introduction HTN is a major morbid condition and public concern. Approximately 30-40% of the adult population in the developed world suffer from this condition. Over 65 million Americans (half of whom are > 60 years old) suffer from HTN. It is the leading cause of mortality worldwide causing 7.5 million deaths annually. Every 20/10 mmHg increase in BP is associated with doubling of CV mortality. Adherence to life-long pharmacological therapy to an asymptomatic disease is challenging necessitating the development of new therapies. 51

52. Introduction - Definition Resistant HTN: failure to achieve goal BP in patients who are adhering to use of adequate doses of three antihypertensive agents from different classes, including a diuretic. 52 T. Rousan OUHSC

53. Introduction – Pathophysiology Renal efferent and afferent nerves play a major role in the initiation and maintenance of essential hypertension. Efferent sympathetic outflow stimulates renin release, increases tubular sodium reabsorption, and reduces renal blood flow. Afferent signals from the kidneys modulate central sympathetic outflow and thereby directly contribute to neurogenic HTN. 53

54. 54

55. Introduction Surgical sympathectomy was developed in the 1920s for the treatment of severe hypertension. Thoracolumbar sympathectomy (resection of the sympathetic ganglia D2-L2 ± splanchiectomy) was first performed in 1938 for the treatment of severe HTN. 55

56. Introduction – Surgical Sympathectomy The operation resulted in a decrease in BP (21 mmHg systolic and 15 mmHg diastolic in the surgical group compared to an increase by 7 mmHg and zero in the control group). It resulted in significant improvement in headache and resolution of papilledema and retinopathy. Orthostatic hypotension was a major side effect (occurring in all patients post-op and persisting in 20% of the survivors). Mortality rate (by the end of 10 years) was 41% (mean survival 46 months) in the surgical group and 47% (mean survival 45 months) in the control group. 56

57. Symplicity HTN-1 A nonrandomized, open-label, proof-of- concept study. Enrolled 153 patients at 19 investigational sites in Australia, Europe, and the United States between 6/2007, and 5/2010 (initial patient enrollment was 6/2007-11/2008). Primary efficacy end-point: Change in office BP. 57

58. Symplicity HTN-1 - Procedure 58

59. Symplicity HTN-1 – Results/Efficacy 59 T. Rousan OUHSC

60. Symplicity HTN-1 - Results/Efficacy 60 T. Rousan OUHSC

61. Symplicity HTN-2 Multicentre, prospective, randomized trial. Inclusion criteria: – 18-85 years old. – BP > 160 mmHg (> 150 mmHg in DMII) despite taking 3 antihypertensive drug classes, 1 of which was a diuretic, at target or maximal tolerated dose. Exclusion criteria: – eGFR< 45 mL/min per 1. 73 m2 – Type 1 DM – Contraindications to MRI – Substantial stenotic valvular heart disease – Pregnancy or planned pregnancy during the study – A history of MI, unstable angina, or CVA in the previous 6 months. 61 Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. Dec 4;376(9756):1903-1909. T. Rousan OUHSC

62. Symplicity HTN-2 – Results/Efficacy 62

63. Symplicity HTN-2 - Results/Efficacy 63

64. Symplicity HTN-3 The SYMPLICITY HTN-3 Trial is a regulatory study designed as a prospective, randomized, masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of resistant hypertension. 64

65. Symplicity HTN-3 Estimated Enrollment: 530 patients (2:1 enrollment). Study Start Date: 9/2011 Estimated Primary Completion Date: 3/2013 (Final data collection date for primary outcome measure). Eighty-seven study locations in the U.S. 65 T. Rousan OUHSC

66. … Beyond Resistant HTN 66 T. Rousan OUHSC

67. Chronic heart failure. HTN and symptomatic atrial fibrillation. Ventricular arrhythmias. Metabolic syndrome. Glucose metabolism. Secondary Prevention for Patients After Percutaneous Coronary Intervention. Polycystic ovary syndrome. Obstructive sleep apnea. Hypertension (initial therapy). 67 T. Rousan OUHSC

68. Renal Denervation & Heart Failure 68

69. Renal Denervation & Heart Failure Renal Artery Denervation in Chronic Heart Failure Study (REACH) – Estimated Primary Completion Date: August 2014 Renal Sympathetic Modification in Patients With Heart Failure – Estimated Study Completion Date: April 2017 69 Bilateral renal denervation can be conducted safely in patients with chronic systolic heart failure. Results suggested improvements in both symptoms and exercise capacity. T. Rousan OUHSC

70. Renal Denervation & Afib 70 Electrical and structural remodeling are important synergistic contributors to the Afib substrate. Studies have indicated that angiotensin II and aldosterone might be involved in atrial structural and electrical remodeling in patients with Afib. HTN is associated with LVH, left atrial enlargement, and slowing of the atrial conduction velocity. Renal artery denervation was shown to decrease Afib episodes in animal models.

71. 71

72. Renal Denervation & Afib 72 T. Rousan OUHSC

73. Renal Denervation & Afib Renal artery denervation reduces systolic and diastolic blood pressure in patients with drug-resistant hypertension and reduces AF recurrences when combined with PVI. Adjunctive Renal Sympathetic Denervation to Modify Hypertension as Upstream Therapy in the Treatment of Atrial Fibrillation (H-FIB) – Estimated Study Completion Date: July 2017 Renal Sympathetic Denervation in Patients With Hypertension and Symptomatic Atrial Fibrillation (RSDforAF) – Estimated Study Completion Date: July 2015 73 Is bilateral renal denervation (as a sole procedure) safe and effective in controlling afib and reducing recurrence? T. Rousan OUHSC

74. Renal Denervation & Glucose Metabolism 74 Activation of the sympathetic nervous system contributes to insulin resistance, the metabolic syndrome, is associated with central obesity and risk of developing DM. Inhibition of the sympathetic nervous system by moxonidine has been shown to improve glucose metabolism. Renal sympathetic denervation decreases whole body norepinephrine spillover. It is plausible to speculate that renal sympathetic denervation may have a substantial effect on glucose metabolism.

75. Fifty patients with therapy resistant HTN were enrolled (13 control and 37 therapy [renal denervation] groups). SBP and DBP, fasting glucose, insulin, C peptide, hemoglobin A1c, calculated insulin sensitivity, and glucose levels during OGT test were measured before and 1 and 3 months after treatment. 75

76. 76 T. Rousan OUHSC

77. Renal Denervation & Glucose Metabolism Denervation of the REnal Artery in Metabolic Syndrome (DREAMS) – Estimated Study Completion Date: May 2014 Renal Sympathetic Modification in Patients With Metabolic Syndrome – Estimated Study Completion Date: August 2016 77 Renal denervation improves glucose metabolism and insulin sensitivity.

78. 78

79. Conclusions The mechanisms of hypertension are complex and mutifactorial. The “ neuroadrenergic hypothesis ” has led to the advent of renal sympathetic denervation as a promising procedure for the treatment of resistant HTN. This procedure will lead to a paradigm shift in the management of a variety of diseases. The results of the current and undergoing trials should be taken with “ guarded optimism ” awaiting long-term efficacy and safety follow-up results. 79

82. log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Bleeding & Outcomes N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B Rao SV, et al. Am J Cardiol. 2005 Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity

83. Transfusion in ACS N=24,111 pts from PURSUIT, PARAGON B, GUSTO IIb Rao SV, et. al., JAMA 2004

85. NSTE-ACS and STEMI (n=7021) Radial Access (n=3507) Femoral Access (n=3514) Primary Outcome: Death, MI, stroke or non-CABG-related Major Bleeding at 30 days Randomization RIVAL Study Design Key Inclusion: Intact dual circulation of hand required Interventionalist experienced with both (minimum 50 radial procedures in last year) Jolly SS et al. Am Heart J. 2011;161:254-60. Blinded Adjudication of Outcomes

86. Primary and Secondary Outcomes Radial (n=3507) % Femoral (n=3514) % HR 95% CI P Primary Outcome Death, MI, Stroke, Non-CABG Major Bleed 3.74.00.920.72-1.170.50 Secondary Outcomes Death, MI, Stroke 3.2 0.980.77-1.280.90 Non-CABG Major Bleeding 0.70.90.730.43-1.230.23

87. Other Outcomes Other Outcomes Radial (n=3507) % Femoral (n=3514) % P Major Vascular Access Site Complications 1.43.7 <0.0001 Access site Cross-over (%) 7.62.0<0.0001 PCI Procedure duration (min) 35340.62 Fluoroscopy time (min) 9.38.0<0.0001

88. Conclusion No significant difference between radial and femoral access in primary outcome of death, MI, stroke or non- CABG major bleeding No significant difference between radial and femoral access in primary outcome of death, MI, stroke or non- CABG major bleeding Rates of primary outcome appeared to be lower with radial compared to femoral access in high volume radial centres and STEMI Rates of primary outcome appeared to be lower with radial compared to femoral access in high volume radial centres and STEMI Radial had fewer major vascular complications with similar PCI success Radial had fewer major vascular complications with similar PCI success

89. Radial versus Femoral Randomized Investigation in ST Elevation Acute Coronary Syndrome the RIFLE STEACS study F R

90. RIFLE STEACS - flow chart Design DESIGN: Prospective, randomized (1:1), parallel group, multi-center trial. INCLUSION CRITERIA: all ST Elevation Myocardial infarction (STEMI) eligible for primary percutaneous coronary intervention. ESCLUSION CRITERIA: contraindication to any of both percutaneous arterial access. international normalized ratio (INR) > 2.0. 1001 patients enrolled between January 2009 and July 2011 in 4 clinical sites in Italy Clinical follow-up at 1 month in 100% Femoral arm (N=501) Radial arm (N=500) Femoral arm (N=534) Radial arm (N=467) Clinical follow-up at 1 month in 100% Intention-to-treat analysis 4.7% 1.4%

91. p = 0.020 30-day MACCE rate RIFLE STEACS – results p = 1.000p = 0.604p = 0.725 9.2% 5.2% 1.4% 1.2% 1.8% 1.2% 0.6% 0.8%

92. 30-day bleeding rate RIFLE STEACS – results p = 1.000 12.2% 6.8% 2.6% 5.4% 5.2% p = 0.026 7.8% 47% p = 0.002

93. Radial access in patients with STEMI is associated with significant clinical benefit, in terms of both bleeding and cardiac mortality. Radial approach should thus no more be considered a valid alternative to femoral one, but become the recommended access site for STEMI (international guideline). RIFLE STEACS - conclusions

94. Horizons-AMI RadialFemoralP value 30 day death reinfarction 1.0%4.3%P=0.02 Major Bleed3.4%7.6%P=0.03 MACE2.0%5.6%P=0.02 1 year death reinfarction 4.0%7.8%P=0.05 1 year MACE6.0%12.4%P=0.01

96. © 2013 EuroIntervention. All rights reserved. EuroIntervention 2013; 8-online publish-ahead-of-print January 2013 Consensus document on the radial approach in percutaneous cardiovascular interventions: position paper by the European Association of Percutaneous Cardiovascular Interventions and Working Groups on Acute Cardiac Care** and Thrombosis of the European Society of Cardiology

97. Cost of bleeding GUSTO IIb Length of stay Dollars No bleeding5.4 days$14,282 Mild6.9 days$21,676 Moderate15.0 days$45,798 Severe16.4 days$66,564

102. Dr. Scott’s Cocktail 1.3000 units UFH 2.2.5 mg Verapamil 3.300 mcg NTG 4.Alternative agents – diltiazem / nicardipine

103. Why Switch to Radial Access? Better Clinical Outcomes Improved Survival Reduced Vascular complications Cost Reduced length of stay Reduced cost of complication Reduced hospital cost Patient Preference

104. Other reasons for Radial Access Save the back of cath lab and nursing staff It sounds less invasive to patients You will get patient referrals from word of mouth. Warfarin issue Help Doctor Scott’s REM sleep pattern

105. MitraClip Therapy First-in-Class Percutaneous Mitral Valve Repair System Clinical evidence demonstrates: – Positive safety profile – Reduction in mitral regurgitation – Favorable left ventricular remodeling – Improvement in patient symptoms – Reduction in hospitalizations for heart failure

106. Mitral Regurgitation Etiologies Source: Enriquez-Sarano, M et al. Lancet. 2009;373:1382-94. Causes Degenerative MR –Also known as primary or organic MR –Usually caused by an anatomic defect of one or more structures comprising the mitral valve apparatus—the annulus, the leaflets, the chordae tendineae, and the papillary muscles. Functional MR –Also known as secondary MR –Results from left ventricular (LV) dysfunction and dilation, which causes otherwise normal valve components to fail and results in MR. Normal Mitral Valve Degenerative MR: Prolapse Degenerative MR: Flail Functional MR

107. MR Progresses to Heart Failure Increasing Mitral Regurgitation Increase Load/Stress Muscle Damage/Loss Dysfunction of left ventricle Dilation of left ventricle MR initiates a cascade of events progressing to heart failure, then death, if untreated 2,3 1 Cioffi G, et al. Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure. European Journal of Heart Failure 2005 Dec;7(7):1112-7 2 Grigioni F, et al. Outcomes in mitral regurgitation due to flail leaflets a multicenter European study. JACC Cardiovasc Imaging. 2008 Mar;1(2):133-41 3 Enriquez-Sarano M, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med. 2005 Mar 3;352(9):875-83 1 year mortality up to 57% 1

108. Moderate or Severe Valvular Disease Is Common and Increases With Age Mitral regurgitation is the most common type of heart valve insufficiency in the US 1,2 – Prevalence increases with increasing age, from 0.5% for 18-44 yr olds rising to 9.3% for ≥75 year olds (p<.0001) 1. Heart Disease and Stroke Statistics 2010 Update: A Report From the American Heart Association. Circulation. 2010;121:e46-e215. 2. Nkomo et al. Burden of Valvular Heart Diseases: A Population-based Study, Lancet, 2006; 368: 1005-11. Prevalence of Valvular Heart Disease by Age

109. Mitral Regurgitation 2009 U.S. Prevalence A Largely Untreated Patient Population Total MR Patients 1,2 Eligible for Treatment 3,4 (MR Grade ≥3+) 4,100,000 1,700,000 Annual MV Surgery 5 Annual Incidence 3 (MR Grade ≥3+) 250,000 30,000 Only 2% Treated Surgically 14% Newly Diagnosed Each Year 1,670,000 84% Untreated Large and Growing Clinical Unmet Need

110. Of surgical candidates, up to 50% of patients are not referred to surgery, even if a surgical indication exists 2 Factors prohibiting Surgery include 6 : Impaired LVEF High operative risk Multiple comorbidities Advanced age Many patients are not considered appropriate candidates for mitral valve surgery Large portion of mitral regurgitation patients are left untreated—ineligible for surgical treatment or denied surgical intervention 1-2 49% High-Risk Patients*,3-5 (860K) 49% Surgical Candidates (850K) 2% Surgical Patients (30K) * Data on file Abbott Vascular.

111. MitraClip System The MitraClip System is supported by robust clinical evidence – Establishes vertical coaptation while capturing the leaflets and drawing them together – Repositionable to allow real-time MR assessment prior to deployment – Supported by data from the EVEREST clinical trial program* and numerous real-world studies * Data on file Abbott Vascular.

112. MitraClip Therapy Broad Spectrum of Experience EVEREST II (Randomized Controlled Trial) EVEREST (High Risk Cohort^) ACCESS EU (Europe) 178 patients Device time – 146 minutes Implant rate – 89% 211 patients Device time – 127 minutes Implant rate – 95% = DMR = FMR 567 patients Procedure time – 117 minutes Implant rate – 99% ^ Enrolled by February 28, 2010 Data on file Abbott Vascular, April 12, 2011 Source: Schillinger, W. ACCESS-EUROPE Phase I: A Post Market Study of the MitraClip System for the Treatment of Significant Mitral Regurgitation in Europe: Analysis of Outcomes at 1 Year. ESC 2012; August 25-29, 2012; Munich, Germany.

113. EVEREST II RCT Results Published in NEJM Summary – EVEREST II RCT When percutaneous repair is compared to surgery – Percutaneous repair provides superior safety and similar clinical outcomes – Surgery provides more complete MR reduction Summary – 24 Month Follow-up 78% of percutaneous patients are free from surgery at 2 years Both percutaneous and surgical treatment reduced MR and demonstrated meaningful clinical benefits through 2 years – Significantly improved LV volumes and NYHA Functional Class No loss of device integrity through 2 years Follow-up is ongoing

114. EVEREST High Surgical Risk Cohort (n=211) Results EVEREST High Surgical Risk Cohort Mitral Regurgitation Grade Everest II RCT – AATS 2012 N=180 1 Year (Matched Cases) N=137 Everest II High Surgical Risk Cohort NYHA Functional Class *Within group difference (p<0.05), †Between group difference at 1 year (p<0.05), ‡Between group difference at 2 year (p<0.05) Everest II RCT – ACC 2011Investigational Device only in the US. Not available for sale in the U.S. EVEREST High Surgical Risk Cohort NYHA Functional Class N=211 1 Year (Matched Cases) N=143 EVEREST High Surgical Risk Cohort Left Ventricular End Diastolic and Systolic Volumes N=131 (matched) 1 Year (Matched Cases) N=131 (matched) 81% p < 0.0001 Everest II RCT – AATS 2012 81% p < 0.001 p < 0.0001 Everest II RCT – AATS 2012 p < 0.0001 Mean (mL) Favorable Reverse LV Remodeling Significant Reduction In The Rate Of Hospitalization For Heart Failure Clinically Significant Improvement in NYHA Functional Class Clinically Significant Reduction of Mitral Regurgitation

115. EVEREST High Surgical Risk Cohort Summary Robust clinical evidence in a large cohort of high surgical risk patients – Prospective, multi-center clinical trial – Independent Core Lab assessed MR and LV measurement MitraClip device reduced MR and demonstrated significant clinical benefits at 1 year follow up – Reduction in LV volumes – Improvement in NYHA Functional Class – Reduction in the Rate Of Hospitalization for Heart Failure High Surgical Risk Cohort

116. MitraClip Therapy First-in-Class Percutaneous Mitral Valve Repair System Clinical evidence demonstrates: – Positive safety profile – Reduction in mitral regurgitation – Favorable left ventricular remodeling – Improvement in patient symptoms – Reduction in hospitalizations for heart failure