Important Highlights from The ACC Annual Meeting, March 29-31, 2014

Mohammed Fakhry AbdulMohsen, MD, MESC, FACCProfessor of Medicine and Cardiology,

At College of Medicine, UODConsultant Internist/Cardiologist,

King Fahd Hospital of the UniversityApril 21, 2014

1. Bariatric Surgery vs. Intensive Medical Therapy in Obese Diabetic Patients:

3-Year Outcomes

Philip R Schauer, Deepak L Bhatt, John P Kirwan, Kathy Wolski, Stacy A Brethauer, Sankar D Navaneethan, Ali Aminian,

Claire E Pothier, Ester SH Kim, Steve E Nissen, and Sangeeta R KashyapSTAMPEDE investigators

Cleveland ClinicBariatric and Metabolic Institute

Endocrinology, Diabetes and Metabolism

Results of the STAMPEDE Trial

1. STAMPEDE Trial

Background

• T2DM affects over 25 million individuals in the US, but < 50% of patients achieve adequate glycemic control on current pharmacotherapy.

• Observational studies show improvement in glycemic control and CV risk factors following bariatric surgery.

• Short-term (1-2 yrs.) RCTs, including the 1 year data of the STAMPEDE trial demonstrated remission of T2DM following bariatric surgery*.

• However, no long-term (>3 yrs) RCT data exist to compare the durability of bariatric surgery vs medical therapy for T2DM control.

1. STAMPEDE Trial

Objectives

1) Compare the durability of bariatric surgery vs medical therapy with respect to:

• Achieving biochemical resolution of T2DM

2) Compare differences between types of surgery

1. STAMPEDE Trial

EndpointsPrimary:Success rate of achieving HbA1c ≤ 6%

Secondary:• Change in fasting plasma glucose (FPG)

• Change in lipids, blood pressure, BMI

• Change in carotid intimal medial thickness

• Change in medications

• Safety and adverse events

• Quality of Life

1. STAMPEDE Trial

Intensive Medical Therapy:• Wt. management with diet and lifestyle.

• Antihyperglycemic agents and multiple insulin injections utilized to target HbA1c ≤6%

• Scheduled visits with nutrition, psychology and endocrinology per protocol

Bariatric Surgery

Roux-en-Y Gastric Bypass Sleeve Gastrectomy

Kashyap S, Schauer P, Bhatt D; Diabetes Obesity Metabolism2010 Sep;12(9):833

218 patients screened

50Intensive medical

therapy alone

50 Medical therapy

plussleeve gastrectomy

Population for 3-Year Analysis 40 48 49

150 randomized

STAMPEDE Trial: Flow of Patients

50Medical therapy

plusgastric bypass

1 withdrew consent prior to surgery

8 withdrew consent 2 Lost to follow-up

• HbA1c >7.0%• BMI 27- 43 kg/m2

• Age 20-60 years

91% retention

2 Lost to follow-up

Baseline CharacteristicsBaseline Characteristics

ParameterMedical Therapy(n=40)

Bypass (n=48)

Sleeve (n=49)

Age (yrs) 50.3 48.0 47.8

Females 67% 58% 78%

Duration of diabetes (yrs) 8.8 8.0 8.3

HbA1c (%) 9.0 9.3 9.5

Body Mass Index (kg/m2) 36.4 37.1 36.1

≥ 3 diabetes medications 61% 52% 46.9%

Insulin use 51.2% 46% 44.9%

Depression 32% 37% 46%

Microvascular complications 20% 42% 29%

Note: Based on analyzed population

Primary and Secondary Endpoints at 36 MonthsPrimary and Secondary Endpoints at 36 Months

ParameterMedical Therapy (n=40)

Bypass (n=48)

Sleeve (n=49)

P Value1

P Value2

HbA1c ≤ 6% 5% 37.5% 24.5% <0.001 0.012

HbA1c ≤ 6% (without DM meds) 0% 35.4% 20.4% <0.001 0.002

HbA1c ≤ 7% 40% 64.6% 65.3% 0.02 0.02

Change in FPG (mg/dL) -6 -85.5 -46 0.001 0.006

Relapse of glycemic control 80% 23.8% 50% 0.03 0.34

% change in HDL +4.6 +34.7 +35.0 <0.001 <0.001

% change in TG -21.5 -45.9 -31.5 0.01 0.01

% change in CIMT 0.048 0.013 0.017 0.36 0.49

1 Gastric Bypass vs Medical Therapy; 2 Sleeve vs Medical Therapy

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.50 3 6 12 24 36

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.50 3 6 12 24 36

Change in HbA1c

Change in HbA1c (%)

P<0.001

P<0.001

Value at Visit Baseline Month 6 Month 12 Month 24 Month 36Medical 9.0 (8.5) 7.1 (6.8) 7.5 (6.9) 7.7 (7.3) 8.4 (7.6)Gastric Bypass 9.3 (9.2) 6.3 (6.2) 6.3 (6.1) 6.5 (6.4) 6.7 (6.6)Sleeve 9.5 (8.9) 6.7 (6.4) 6.6 (6.4) 6.8 (6.8) 7.0 (6.6)

Value at Visit Baseline Month 6 Month 12 Month 24 Month 36Medical 9.0 (8.5) 7.1 (6.8) 7.5 (6.9) 7.7 (7.3) 8.4 (7.6)Gastric Bypass 9.3 (9.2) 6.3 (6.2) 6.3 (6.1) 6.5 (6.4) 6.7 (6.6)Sleeve 9.5 (8.9) 6.7 (6.4) 6.6 (6.4) 6.8 (6.8) 7.0 (6.6)

Medical

Sleeve Gastric Bypass

Change in Body Mass Index

Changein BMI

(Kg/M2)

-12.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

-12.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

90 3 6 12 24 360 3 6 12 24 369

P=0.006

P<0.001

P<0.001

Value at Visit Baseline Month 6 Month 12 Month 24 Month 36Medical 36.4 34.6 34.2 35.0 34.8Gastric Bypass 37.1 28.2 26.7 27.3 27.9Sleeve 36.1 28.3 27.1 27.9 29.2

Value at Visit Baseline Month 6 Month 12 Month 24 Month 36Medical 36.4 34.6 34.2 35.0 34.8Gastric Bypass 37.1 28.2 26.7 27.3 27.9Sleeve 36.1 28.3 27.1 27.9 29.2

Medical

Sleeve Gastric Bypass

0

10

20

30

40

50

60

Baseline Month 3 Month 6 Month 12 Month 24 Month 360

10

20

30

40

50

60

Baseline Month 3 Month 6 Month 12 Month 24 Month 36

Percentage of Patients on Insulin

% Patients

Medical 52 54 44 40 47 55Gastric Bypass 46 25 10 4 7 6Sleeve 45 16 6 8 9 8

Medical

Sleeve Gastric Bypass

Cardiovascular Medications atBaseline and Month 36

Cardiovascular Medications atBaseline and Month 36

CV medications number (%)

Medical Therapy(n=40)

Bypass (n=48)

Sleeve (n=49)

Baseline

None 0 (0) 3 (6.3) 2 (4.1)

1 - 2 19 (47.5) 17 (35.4) 28 (57.1)

> 3 21 (52.5) 28 (58.3) 19 (38.8)

Month 36

None 1 (2.5) 33 (68.8) * 21 (42.9) *

1 - 2 18 (45) 14 (29.2) 25 (51)

> 3 21 (52.5) 1 (2.1) 3 (6.1)

* P value <0.05 with Medical Therapy group as comparator

1. STAMPEDE Trial

-20-15-10

-505

1015202530 IMT

Gastric Bypass

Sleeve

Bodily Pain General Health

Physical Functioning

Role Limitations

Quality of Life

%

Physical Health Components

Adverse Events through 36 MonthsAdverse Events through 36 Months

Parameter Medical Therapy (n=43)

Bypass (n=50)

Sleeve (n=49)

GI complications 2 (5) 13 (26) 5 (4)

Re-op 0 2(4) 2(4)

Stroke 0 0 1 (2)

Retinopathy 0 1 (2) 2 (4)

Nephropathy 4 (9) 7 (14) 5 (10)

Foot ulcers 0 2 (4) 1 (2)

Excessive weight gain 7 (16) 0 0

1. STAMPEDE Trial

Summary

• Bariatric surgery was more effective than intensive medical therapy in achieving glycemic control (HbA1c < 6.0%) with weight loss as the primary determinant of this outcome.

• Many surgical patients achieved glycemic control without use of any diabetic medications (particularly insulin).

• Metabolic syndrome components (HDL, triglycerides, glucose, BMI) showed greater improvement after surgery.

• Marked improvement in quality of life.

1. STAMPEDE Trial

ConclusionBariatric surgery (gastric bypass or sleeve gastrectomy) should be considered as a treatment option for patients with uncontrolled T2DM and moderate to severe obesity (BMI > 30 Kg/M2) with results durable through 3 years of follow up.

Highlights from The ACC Annual Meeting, March 27, 2014

2. CoreValve US Pivotal Trial

A Randomized Comparison of Self-expanding Transcatheter (TAVR) and Surgical Aortic Valve

Replacement in Patients with Severe Aortic Stenosis Deemed High-Risk for Surgery.

• David H. Adams, MD• On Behalf of the US CoreValve Investigators

2. CoreValve US Pivotal Trial

• Background: Many Patients with Symptomatic Severe Aortic Stenosis are not Ideal Candidates for Surgery due to Increased Risks

• TAVR (TAVI) with a balloon expandable valve improved survival compared to medical therapy in inoperable patients

• TAVR with a balloon expandable valve had similar survival compared to surgery in patients at high risk for surgery

2. CoreValve US Pivotal Trial

Study Purpose:

• To assess the safety and effectiveness of TAVR with the Core Valve (Self-expanding) prosthesis compared

to surgical valve replacement in symptomatic patients with severe aortic stenosis at increased

surgical risk.

18Fr delivery system

4 valve sizes (18-29 mm annular range)

TransfemoralSubclavianDirect Aortic

Study Device and Access Routes

22

2. CoreValve US Pivotal Trial

Primary Endpoint:• All-cause mortality at 1 year

• Non-inferiority Testing: TAVR with the CoreValve prosthesis was non-inferior to SAVR after 1 year for all-cause mortality with a 7.5% non-inferiority margin.

2. CoreValve US Pivotal Trial

• Secondary Endpoints:Hierarchical (Graded- Categorized) Testing of Secondary Endpoints:

• Δ mean gradient baseline to 1 year (non-inferior)

• Δ effective orifice area baseline to 1 year (non-inferior)

• Δ NYHA class baseline to 1 year (non-inferior)

2. CoreValve US Pivotal Trial

Inclusion Criteria:• NYHA functional class II or greater

• Severe aortic stenosis: AVA ≤ 0.8 cm2 or AVAI ≤ 0.5 cm2/m2 AND mean gradient > 40 mm Hg.

• Risk of death at 30 days after surgery was ≥ 15% and the risk of death or irreversible complications within 30 days was < 50%

Study Disposition

CharacteristicTAVRN=390

SAVRN=357

Age, years 83.1 ± 7.1 83.2 ± 6.4

Men, % 53.1 52.4

STS Predicted Risk of Mortality, % 7.3 ± 3.0 7.5 ± 3.4

Logistic EuroSCORE, % 17.7 ± 13.1 18.6 ± 13.0

NYHA Class III/IV, % 85.6 86.8

Diabetes Mellitus, % 34.9* 45.4*

Insulin Requiring Diabetes, % 11.0 13.2

Prior Stroke, % 12.6 14.0

STS Severe Chronic Lung Disease, % 13.3 9.0

Baseline Demographics

*P < 0.01

28

Highlights from The ACC Annual Meeting, March 27, 2014

3. Renal Denervation in Patients with Uncontrolled Hypertension:

Results of the SYMPLICITY HTN 3 Trial

Deepak L. Bhatt, M.D., M.P.H., David E. Kandzari, M.D., William W. O’Neill, M.D., Ralph D'Agostino, Ph.D., John M. Flack, M.D., M.P.H., Barry T. Katzen, M.D., Martin B. Leon, M.D., Minglei Liu, Ph.D., Laura Mauri, M.D., M.Sc., Manuela Negoita, M.D., Sidney A. Cohen, M.D., Ph.D., Suzanne Oparil, M.D., Krishna Rocha-Singh, M.D., Raymond R. Townsend, M.D., George L. Bakris, M.D., for the SYMPLICITY HTN-3 Investigators

SYMPLICITY HTN 3 Trial

Background:• Hypertension is growing in prevalence worldwide due to

aging of the population and prevalence of obesity .

• Approximately 10% of patients with diagnosed hypertension have “resistant” hypertension.

• The sympathetic nervous system appears to play an important role in resistant hypertension.

• Prior non-blinded studies have suggested that catheter-based renal artery denervation reduces BP in resistant hypertension.

SYMPLICITY HTN 3 Trial

Trial Objectives:• SYMPLICITY HTN-3 is the first prospective, multi-center,

randomized, blinded, sham controlled study to evaluate both the safety and efficacy of percutaneous renal artery denervation in patients with severe treatment-resistant hypertension.

• The trial included 535 patients enrolled by 88 participating US centers.

SYMPLICITY HTN 3 Trial

SYMPLICITY HTN 3 Trial

Inclusion Criteria:• Age ≥18 and ≤80 years.

• Stable medication regimen including full tolerated doses of ≥3 antihypertensive medications of different classes, including a diuretic.

• Office SBP ≥160 mm Hg based on an average of 3 BP readings.

• Written informed consent

SYMPLICITY HTN 3 Trial

Exclusion Criteria:• ABPM 24 hour → average SBP <135 mm Hg

• eGFR of <45 mL/min

• Main renal arteries <4 mm diameter or <20 mm treatable length

• Renal artery stenosis >50% or aneurysm in either renal artery

• History of prior renal artery intervention

SYMPLICITY HTN 3 Trial

Primary Endpoints: 1. The rate of the Major Adverse Events (MAE) in the treatment group compared with an Objective Performance Criterion (OPC=9.8%)

2. MAE was defined as all-cause mortality, end stage renal disease, embolic event resulting in end-organ damage, renal artery or other vascular complication, hypertensive crisis through 30 days, or new renal artery stenosis within 6 months.

“Our Lord, Let Not Our Hearts Deviate After You Have Guided Us, and grant us mercy from You. Truly, You are the Best Granter.” Surat A`L Imran; verse 8

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آية: العظيم 8عمران الله صدق