1. Severe Aortic Stenosis and TAVR
Joseph N. Wight, Jr, MD
MaineHealth Cardiology
Maine Medical Center
Clinical Assistant Professor
Department of Medicine
Tufts University School of Medicine
September 12, 2014

2. Disclosures
I will not discuss off label use or investigational use in my presentation.
I have no financial relationships to disclose.
Employee of MaineHealth Cardiology

3. Prevalence of Aortic Stenosis
16.5 Million People in US
Over the Age of 652
Aortic stenosis is estimated to be prevalent in up to 7% of the population over the age of 651
It is more likely to affect men than women; 80% of adults with symptomatic aortic stenosis are male3
Percentage Diagnosed with Aortic Stenosis
Aortic stenosis is a common public health problem affecting millions of people in the United States. It is estimated to be prevalent in up to 7% of the population over the age of It is also
more likely to affect men than women; 80% of adults with symptomatic aortic stenosis are male.

4. Aortic Stenosis Demographics
Aortic stenosis 2% US population >65yrs old
Aortic sclerosis 29% US population> 65 yrs old
Aortic sclerosis 50% greater risk of mortality and myocardial infarction.
Aortic sclerosis progresses to aortic stenosis in 9% over 5 years

5. What Causes Aortic Stenosis in Adults?
More Common
Age-Related Calcific Aortic Stenosis
Aortic stenosis in patients over the age of 65 is usually caused by calcific (calcium) deposits associated with aging
Rheumatic Fever
There are various causes of aortic stenosis. Aortic stenosis in patients over the age of 65 is usually caused by calcific (calcium) deposits associated with aging. It can also be caused by infection, rheumatic fever, or a congenital abnormality.
Adults who have had rheumatic fever may also be at risk for aortic stenosis
Congenital Abnormality
In some cases adults may develop aortic stenosis resulting from a congenital abnormality
Less Common

6. 3 Major Etiologies for aortic stenosis

9. Major Risk Factors
Independent clinical factors associated with degenerative aortic valve disease include the following:4
Increasing age
Male gender
Hypertension
Smoking
Elevated lipoprotein A
Elevated LDL cholesterol
Independent clinical factors associated with degenerative aortic valve disease include the following increasing age, male gender, hypertension, smoking, elevated lipoprotein A, elevated LDL cholesterol

10. Signs and Symptoms Heart Failure Carotid Parvus et Tardus Angina
Syncope
Carotid Parvus et Tardus
Laterally displaced PMI
Soft A2
Crescendo-Decrescendo systolic murmur
Timing of peak murmur and NOT intensity predicts severity

11. Aortic Stenosis Is Life Threatening and Progresses Rapidly
Literature shows
- Survival after onset of symptoms is 50% at 2 years and 20% at 5 years
- Surgical intervention for severe aortic stenosis should be performed promptly once even minor symptoms occur
Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1
Surgical intervention for severe aortic stenosis should be performed promptly once even minor symptoms occur1

12. Sobering Perspective 5-Year Survival8 Survival, %
Data shows a sobering perspective for inoperable patients: 5 year survival of breast cancer, lung cancer, prostate cancer, ovarian cancer and severe inoperable aortic stenosis
Breast
Cancer
Lung
Cancer
Colorectal
Cancer
Prostate
Cancer
Ovarian
Cancer
Severe
Inoperable AS*
*Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu, MD, Cleveland Clinic
5 year survival of breast cancer, lung cancer, prostate cancer, ovarian cancer and severe inoperable aortic stenosis

13. Echocardiographic Guidelines are the Gold Standard in Assessing Severe Aortic Stenosis6*
Echocardiographic guidelines are the gold standard in diagnosing a patient with severe aortic stenosis. According to the 2008 ACC/AHA guidelines, severe aortic stenosis is defined as aortic valve area (AVA) less than 1.0 cm2, mean gradient greater than 40 mmHg or jet velocity greater than 4.0 m/s.
*Doppler-Echocardiographic measurements
According to the 2014 ACC/AHA guidelines, severe aortic stenosis is defined as:
Aortic valve area (AVA) less than 1.0 cm2
Mean gradient greater than 40 mmHg or jet velocity greater than 4.0 m/s

14. Multiple Modalities May Be Used to Diagnose Severe Aortic Stenosis6
Trans-thoracic Echo (TTE)
Chest
X-ray
Electro-cardiogram
Cardiac Cath.
Auscultation
Multiple modalities may be used to diagnose severe aortic stenosis including review of a patient’s electrocardiogram, chest x-ray, cardiac catheterization, auscultation and transthoracic echocardiography (TTE).

15. Continuity Equation-Conservation of Mass
Echocardiography:
Continuity Equation-Conservation of Mass

17. Echocardiography: 3D Planimetry

19. Not so classic aortic stenosis

20. 1. Low Flow, Low Gradient Severe AS 2
1. Low Flow, Low Gradient Severe AS 2. Paradoxical Low Flow, Low Gradient Severe AS

22. Low Flow, Low Gradient AS
Low gradient with a small calculated valve area in the setting of poor systolic function. This may result in lack of referral for AVR because of the low gradient.
Dobutamine Stress Echo:
By increasing cardiac output, we can determine if the AS is severe by reassessing the gradient across the aortic valve (increases) AND the aortic valve area (decreases).
Assess myocardial contractile reserve
Does the cardiac output improve by 20% or more.
Critical for decision making regarding aortic valve replacement.

23. Paradoxical Low Flow and/or Low Gradient Severe Aortic Stenosis1
Some patients with severe aortic stenosis based on valve area have a lower than expected gradient (e.g. mean gradient < 30 mmHg) despite preserved LV ejection fraction (e.g. EF > 50%)
Up to 35% of patients with severe aortic stenosis present with low flow, low gradient
These low gradients often lead to an underestimation of the severity of the disease, so many of these patients do not undergo surgical aortic valve replacement
According to the 2008 ACC/AHA guidelines, severe aortic stenosis is defined as aortic valve area (AVA) less than 1.0 cm2, mean gradient greater than 40 mmHg or jet velocity greater than 4.0 m/s. In patients with low cardiac output, a low gradient (< 40 mmHg) may be present. In this case, accurate differentiation between true and pseudo severe aortic stenosis is necessary. Dobutamine stress echocardiography should be used to better define the severity of the aortic stenosis in this circumstance.
Dobutamine stress in low gradient, low ejection fraction AS
Chambers, Heart April; 92(4): 554–558

24. Stages of Valvular AS. ACC/AHA 2104 Valve Guidelines
Nishimura R A et al. Circulation. 2014;129:e521-e643
Copyright © American Heart Association, Inc. All rights reserved.

25. Summary of Recommendations for AS: Timing of Intervention.
Nishimura R A et al. Circulation. 2014;129:e521-e643
Copyright © American Heart Association, Inc. All rights reserved.

26. Aortic Valve Replacement Greatly Improves Survival
Patient Survival16
AVR, No Symptoms
AVR, Symptoms
No AVR, No Symptoms
No AVR, Symptoms
Study data demonstrate that early and late outcomes were similarly good in both symptomatic and asymptomatic patients
It is important to note that among asymptomatic patients with SAS, omission of surgical treatment was the most important risk factor for late mortality
Years
Study data demonstrate that early and late outcomes were similarly good in both symptomatic and asymptomatic patients
It is important to note that among asymptomatic patients with SAS, omission of surgical treatment was the most important risk factor for late mortality

27. Options for Aortic Valve Replacement
Inoperable OR High Risk
Patients Suitable for Open Chest Surgery
Transcatheter Aortic Valve Replacement (TAVR)
Surgical Aortic Valve Replacement
(sAVR)
Minimal Incision Valve Surgery
(MIVS)
Transfemoral Approach

28. Prosthetic Heart Valves

29. Tilting Disc Valve

30. Bio-prosthetic Valve

31. Low Percentage of Aortic Valve Surgery
Aortic Valve Replacement
No Aortic Valve Replacement
Studies show at least 40% of SAS patients are not treated with an AVR9-15
Studies show at least 40% of patients with severe AS are not treated with an AVR9-15

32. Summary of Recommendations for AS: Choice of Surgical or Transcatheter Intervention.
Nishimura R A et al. Circulation. 2014;129:e521-e643
Copyright © American Heart Association, Inc. All rights reserved.

33. What is TAVR-Transcatheter Aortic Valve Replacement?
An aortic valve replacement as an alternative to traditional thoracotomy.
Less invasive than traditional thoracotomy for patients considered too high risk for traditional surgery.
If a cardiac surgeon determines that you are too sick for open-heart surgery and if medicine is not helping you feel better, TAVR may be an alternative. This less invasive procedure allows your aortic valve to be replaced with a new valve while your heart is still beating.

34. Two TAVR Options Edwards Sapien Valve Stainless Steel Frame
More Aortic Regurg, less AV block/PPM
Better for severe bulky calcification.
Medtronic CoreValve
Nitinol Frame-self expanding
Less Aortic Regurg, More heart block/PPM

36. TAVR Multimodality imaging

37. PARTNER Study Design Cohort A Cohort B N = 358 Inoperable High Risk
Symptomatic Severe Aortic Stenosis
Cohort A
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
Cohort B
N = 179
N = 358
Inoperable
Standard
Therapy
ASSESSMENT: Transfemoral Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
1:1 Randomization VS
Yes No
Total = 1,057 patients
High Risk
N = 699
2 Parallel Trials: Individually Powered
ASSESSMENT: Transfemoral Access
Transapical (TA)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR
AVR
Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority)
TA TAVR VS
N = 248
N = 104
N = 103
N = 244

38. PARTNER Trial B Exclusion Criteria:
bicuspid or noncalcified aortic valve
acute myocardial infarction
substantial coronary artery disease requiring revascularization
left ventricular ejection fraction of less than 20%
a diameter of the aortic annulus of less than 18 mm or more than 25 mm
severe (>3+) mitral or aortic regurgitation
a transient ischemic attack or stroke within the previous 6 months
severe renal insufficiency (creatinine greater than 3 or on dialysis).
Iliac-femoral anatomy precluding safe sheath insertion

39. PARTNER Trial B Primary End-Points: Death from any cause
Rate of a hierarchical composite of the time to death from any cause or the time to the first repeat hospitalization from aortic valve disease or procedure related complication

40. PARTNER Trial B Secondary End-Points:
the rate of death from cardiovascular causes
NYHA functional class
The distance covered during a 6-minute walk test
Valve performance (assessed by echocardiography)
The rates of myocardial infarction, stroke, acute kidney injury, vascular complications, and bleeding

41. Characteristics of an Inoperable Patient Cohort B
TAVR patients may present with some of the following:
Severe, symptomatic native aortic valve stenosis
Old age
Frailty
History of stroke/CVA
History of syncope
Reduced EF
Heavily calcified aorta
Prior CABG
Prior chest radiation
History of AFib
History of CAD
Prior open chest surgery
History of COPD
Fatigue, slow gait
History of renal insufficiency
Peripheral vascular disease
Diabetes and hypertension

42. “Standard Medical Therapy”
179 Patients assigned
Balloon Valvuloplasty perfomed in 114 (63.7%) patients in first 30 days and 36 (20.1%) additional patients 30 days after randomization.
12 (6.7%) underwent AVR!
5 (2.8%) LV apex to Aorta conduit

43. TAVR Group 179 Patients 6 did not undergo TAVR
2 died before implantation
2 unsuccessful transfemoral access
2 aortic valve annulus was to large

44. Cohort B Survival THE PARTNER TRIAL COHORT B
Despite frequent BAV (78.8%), standard therapy failed to alter the dismal natural course of the disease.
The Edwards SAPIEN transcatheter heart valve demonstrated an absolute reduction in mortality of 25% at two years.
THE PARTNER TRIAL COHORT B

45. Edwards SAPIEN THV Improved Cardiac Function
The dramatic reduction in mean gradient in the Edwards SAPIEN transcatheter heart valve arm of Cohort B was sustained out to two years. The mean gradient worsened over time for the patients in the standard therapy group, with no sustained hemodynamic benefit from BAV.
Error bars = ± 1 Std Dev
THE PARTNER TRIAL COHORT B

46. Cohort B HF Improvement
The vast majority of patients treated with the Edwards SAPIEN THV (who initially presented in NYHA class III or IV) were alive at 12 months. But perhaps as important, they were now mildly symptomatic or asymptomatic in class II or I, respectively.
83% of the Edwards SAPIEN THV patients were classified as NYHA class I or II at two years. Improvement was observed as early as 30 days (P < .0001)
The patients in the standard therapy arm didn’t fare as well; the majority who did survive at 1 year still presented with NYHA class III or IV symptoms.
THE PARTNER TRIAL COHORT B

47. Complications THE PARTNER TRIAL COHORT B
The Edwards SAPIEN THV was associated with a higher incidence of stroke, major vascular complications and major bleeding at two years.
Standard therapy demonstrated higher all-cause mortality as well as death or repeat hospitalization at two years.
Stroke was defined as follows: Neurological deficit lasting ≥ 24 hours or lasting less than 24 hours with a brain imaging study showing an infarction.
Major vascular complications were defined as any thoracic aortic dissection, access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, or hematoma) leading to either death, need for significant blood transfusion (> 3 units), or percutaneous or surgical intervention, and/or distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage.
Bleeding event is defined as ≥ 2 units within the index procedure.
THE PARTNER TRIAL COHORT B

48. PARTNER Study Design Cohort A Cohort B N = 358 Inoperable High Risk
Symptomatic Severe Aortic Stenosis
Cohort A
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
Cohort B
N = 179
N = 358
Inoperable
Standard
Therapy
ASSESSMENT: Transfemoral Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
1:1 Randomization VS
Yes No
Total = 1,057 patients
High Risk
N = 699
2 Parallel Trials: Individually Powered
ASSESSMENT: Transfemoral Access
Transapical (TA)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR
AVR
Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority)
TA TAVR VS
N = 248
N = 104
N = 103
N = 244

49. Cohort A: All-Cause Mortality
HR [95% CI] = 0.93 [0.74, 1.15]
p (log rank) = 0.483
44.8%
34.6%
44.2%
26.8%
33.7%
24.3%
No. at Risk
TAVR
348
298
261
239
222
187
149
AVR
351
252
236
223
202
174
142

50. Months Post Randomization
Cohort A: Strokes
3.2%
6.0%
9.3%
8.2%
HR [95% CI] = 1.09 [0.62, 1.91]
p (log rank) = 0.763
4.9%
7.7%
Months Post Randomization
No. at Risk
TAVR
348
287
250
228
211
176
139
351
246
230
217
197
169
AVR

51. CoreValve US Pivotal Trials Iliofemoral Access > 18 Fr Sheath
Extreme Risk
High Risk
CoreValve
Iliofemoral
Iliofemoral Access > 18 Fr Sheath No
Yes
Randomization 1:1
Non-Iliofemoral
Versus
SAVR
N=487
N=147
TCT 2013 LBCT
Extreme Risk Study | Iliofemoral Pivotal

52. Extreme Risk Study | Iliofemoral Pivotal
Study Purpose
Study Purpose: To evaluate the safety and efficacy of the CoreValve THV for the treatment of patients with symptomatic severe aortic stenosis in whom the predicted risk of operative mortality or serious, irreversible morbidity was 50% or greater at 30 days
Risk Determined by: Two Clinical Site Cardiac Surgeons and One Interventional Cardiologist
Risk Confirmed by: Two Screening Committee Cardiac Surgeons and One Interventional Cardiologist
Primary Endpoint: All Cause Mortality or Major Stroke at 12 Months
TCT 2013 LBCT
Extreme Risk Study | Iliofemoral Pivotal

53. Inclusion and Exclusion Criteria
Inclusion Criteria:
Severe aortic stenosis: AVA ≤ 0.8 cm2 or AVAI ≤ 0.5 cm2/m2 AND mean gradient > 40 mm Hg or peak velocity > 4 m/sec at rest or with dobutamine stress (if LVEF < 50%)
NYHA functional class II or greater
Exclusion Criteria (selected):
Recent active GI bleed (3 mos), stroke (6 mos), or MI (30 days)
Creatinine clearance < 20 mL/min
Significant untreated coronary artery disease
LVEF < 20%
Life expectancy < 1 year due to co-morbidities
TCT 2013 LBCT
Extreme Risk Study | Iliofemoral Pivotal

54. All Cause Mortality or Major Stroke Months Post-Procedure
Primary Endpoint
All Cause Mortality or Major Stroke
P <
Performance Goal = 43%
All Cause Mortality or Major Stroke
9.3% [6.7,12.0]
25.5%
[21.6,29.4]
Months Post-Procedure
TCT 2013 LBCT
Extreme Risk Study | Iliofemoral Pivotal

55. Percentage of Patients Extreme Risk Study | Iliofemoral Pivotal
NYHA Class Survivors
90% of Patients Improved at Least 1 NYHA Class by 1 Year
60% of Patients Improved at Least 2 NYHA Classes by 1 Year
Percentage of Patients
TCT 2013 LBCT
Extreme Risk Study | Iliofemoral Pivotal

56. Extreme Risk Study | Iliofemoral Pivotal
Secondary Endpoints
Events*
1 Month
1 Year
Any Stroke, %
3.9
6.7
Major, %
2.4
4.1
Minor, %
1.7
3.1
Myocardial Infarction, %
1.3
2.0
Reintervention, %
VARC Bleeding, %
35.1
41.4
Life Threatening or Disabling, %
11.7
16.6
24.1
27.6
Major Vascular Complications, %
8.3
8.5
Permanent Pacemaker Implant, %
22.2
27.1
Per ACC Guidelines, %
17.4
19.9
* Percentages obtained from Kaplan Meier estimates
TCT 2013 LBCT
Extreme Risk Study | Iliofemoral Pivotal

57. Core Valve Trial 57

58. Study Disposition

59. Primary Endpoint: 1 Year All-cause Mortality
ACC 2014
19.1%
4.5%
Surgical
14.2%
P = 0.04 for superiority
3.3%
Transcatheter 59

60. 2-Year All-cause Mortality
ACC 2014

62. Major Stroke 62

63. Other Endpoints Events* 1 Month 1 Year TAVR SAVR P Value
Vascular complications (major), %
5.9
1.7
0.003
6.2
2.0
0.004
Pacemaker implant, %
19.8
7.1
<0.001
22.3
11.3
Bleeding
(life threatening or disabling),%
13.6
35.0
16.6
38.4
New onset or worsening atrial fibrillation, %
11.7
30.5
15.9
32.7
Acute kidney injury, %
6.0
15.1
* Percentages reported are Kaplan-Meier estimates and log-rank P values 63

64. MMC Heart Valve Clinic Marco Diaz, MD John Lualdi,MD
David Butzell, MD Merle Kellett, MD
Reed Quinn, MD Scott Buchanan, MD
David Burkey, MD

65. Evaluate the aortic valvular complex using echocardiography
Following Patient Referral, the TAVR Team will Perform Further Evaluation 1 2 3 4 5
Confirm the patient is diagnosed with severe symptomatic native aortic stenosis
Confirm the patient has been independently evaluated by two cardiac surgeons and meets the indication for TAVR
Evaluate the aortic valvular complex using echocardiography
Evaluate the peripheral vasculature and aortic valvular complex using MDCT
Evaluate the peripheral vasculature and aortic valvular complex using catheterization
Note: Evaluation using CT is typically not done unless the Heart Team confirms that patient is a candidate for TAVR

66. Key Takeaways
Aortic Stenosis is prevalent with a high morbidity and mortality when symptomatic and aortic valve replacement is the only treatment associated with improved outcomes.
Asymptomatic low risk patients will benefit from surgical AVR.
Low gradient does not necessarily exclude severe aortic stenosis, even when the ejection fraction is normal!!
TAVR is an excellent alternative to traditional Aortic Valve Surgery but increased risk of stroke and vascular injury and the need for a permanent pacemaker.
MMC Heart Team has performed over 100 TAVR procedures in three years with excellent outcomes.

67. Thank You!