CVD Critical Pathways Group2006 Teleconferences

This activity is supported by an educational grant from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.

October 11, 2006

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Faculty

Gregg C. Fonarow, MDEliot Corday Professor of Medicine

and Cardiovascular Science

Director, Ahmanson-UCLA Cardiomyopathy Center

UCLA Division of Cardiology

UCLA Medical Center

Los Angeles, California

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Disclosure StatementThe Network for Continuing Medical Education requires

that CME faculty disclose, during the planning of an

activity, the existence of any personal financial or other

relationships they or their spouses/partners have with

the commercial supporter of the activity or with the

manufacturer of any commercial product or service

discussed in the activity.

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Faculty Disclosure Statement

Gregg C. Fonarow, MD, has served as a consultant to and has received research support and honoraria from Bristol-Myers Squibb Company, GlaxoSmithKline, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, and Scios, Inc.

W. Frank Peacock, MD, FACEP, of the Cleveland Clinic in Cleveland, Ohio reports no such relationships.

Diabetes and Metabolic Syndrome in Patients

Hospitalized With CVD

Gregg C. Fonarow, MD

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Polling Question #1

1. Yes, always

2. Yes, most of the time

3. No

Do you screen for diabetes and metabolic syndrome in patients hospitalized with an acute event associated with cardiovascular disease?

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Diagnose by presence of 3 or more risk factors

Adapted with permission from Grundy SM, et al. Circulation. 2005;112:2735-2752.

AHA/NHLBI-Modified ATP III Criteria for the Metabolic Syndrome

Risk Factor Defining Level

Abdominal obesity Waist circumference*Men >40 inWomen >35 in

Triglycerides, mg/dL 150

HDL-C, mg/dLMen <40Women <50

BP, mm Hg 130/≥85

Fasting glucose, mg/dL 100

*Lower cutpoints for Asian Americans.

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Metabolic Syndrome:Prevalence of Components*

● Abdominal obesity 44%● Hypertriglyceridemia 33%● Low HDL cholesterol 40%● High blood pressure or medication use 39%● High fasting glucose† or medication use 31%

*US adults aged 20 years and older (NHANES 1999-2000 data).†Fasting plasma glucose 100 mg/dL.

Ford ES, et al. Diabetes Care. 2004;27:2444-2449.

~64 million US residents had the metabolic syndrome in 2000

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1 in 4 Adults Have Diabetes or the Metabolic Syndrome

~64

14.6

6.

2

Undiagnosed

diabetes*

Diagnosed

diabetes*

Metabolic

syndrome†

Population at risk (millions)12

8

4

0

35

15

50

25

Diagnosed diabetes

Metabolic syndrome

White Black Hispanic Other

White Black Hispanic Other

Prevalence, %,

age ≥18 yrs

Prevalence, %,

age ≥20 yrs

Mokdad AH, et al. JAMA. 2003;289:76-79.Ford ES, et al. JAMA. 2002;287:356-359.Ford ES, et al. Diabetes Care. 2004;27:2444-2449.

10

6

2

30

20

10

*2005 US data, NIDDK, NIH.†Based on revised NCEP/ATP III definition (NHANES 2000 data).

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Risk Factors Associated With the Metabolic Syndrome (NHANES 1999-2000)

90.9

73.9 77.0

41.5

73.9

15.1

36.6

14.924.9

7.2

26.5

5.6

0

20

40

60

80

100

High W

aist

Circum

fere

nce High

Trigly

cerid

es

Low HDL-C

High F

astin

g

Gluco

se

High B

P

CVD His

tory

Per

cen

tag

e

Metabolic syndrome

Without metabolic syndrome

Adapted from Ford ES, et al. JAMA. 2002;287:356-359.

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Metabolic Syndrome Predicts Incidence of Diabetes Independently of Impaired Glucose Tolerance

San Antonio Heart Study (N = 1734 )

Lorenzo C, et al. Diabetes Care. 2003;26:3153-3156.

*ATP III definition.

60

50

40

30

20

10

0No Yes

Metabolic syndrome*

Diabetes,%

P = .018

P <.0001

P <.0001

Impaired Glucose Tolerance

YesNo

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Follow-up, Years

Cu

mu

lati

ve H

azar

d,

%

121086420

RR = 3.55 (95% CI, 1.96-6.43)

0

5

10

15

866288

852279

834234

292100

YesNo

Metabolic Syndrome?*

Metabolic Syndrome

Controls

*Based on factor analysis; men in highest quarter of distribution of the metabolic syndrome factor were considered to have metabolic syndrome. Reproduced with permission from Lakka HM, et al. JAMA. 2002;288:2709-2716.

Cardiovascular Disease Mortality and the Metabolic Syndrome

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Clustering of Risk Factors Increases Mortalityin Post-CABG Patients: 8-Year Follow-up

Obesity, Diabetes, Hypertension, Hypertriglyceridemia

Sprecher DL, Pearce GL. J Am Coll Cardiol. 2000;36:1159-1165.

50

45

40

35

30

25

20

15

10

5

00 1 2 3 4

Number of Risk Factors

Mo

rtal

ity

, %

P <.001 for relationship of increasingnumber of risk factors to mortality

MenWomen

N = 6428; deaths = 860.

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Overweight

Overweight and Obesity Increase the Risk of Cardiovascular Disease Mortality

Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment.

Calle EE, et al. N Engl J Med. 1999;341:1097-1105.

Normal weight Obese

Rel

ativ

e R

isk

of

Car

dio

vasc

ula

r D

isea

se M

ort

alit

y

0.6

3.0

2.6

2.2

1.8

1.4

1.0

>18 25 30 >40

BMI, kg/m2

WomenMen

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The Ticking Clock: CV Risk Before Glucose

Nurses’ Health Study; 20-year follow-up of 117,629 women

Hu FB, et al. Diabetes Care. 2002;25:1129-1134.

Rel

ativ

e ri

sk o

fM

I o

r st

roke

No diabetesthroughout

study

Risk of event prior to diabetes

diagnosis

Risk of eventafter

diabetesdiagnosis

Diabetesat baseline

5.03.7

2.8

1.0

6

4

2

0

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Association of Insulin Resistance With Cardiovascular Risk Factors and Atherosclerosis

Central Obesity

Glucose intolerance

• AGEsHypertension Endothelial

dysfunction• VCAM,E-selectin

• NO Impaired

thrombolysis• PAI-1• tPA

Atherosclerosis

Inflammation• CRP• IL-6

Insulin resistance

Dyslipidemia• Low HDL

• Small, dense LDL particles

• Hyper-triglyceridemia

McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718.

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Waist Circumference Correlates With BP and Insulin Resistance

768 men with fasting glucose ≤126 mg/dL (≤7 mmol/L)

Siani A, et al. Am J Hypertens. 2002;15:780-786.

P <.001 for trend in each parameter.

50

40

30

20

10

0

50

40

30

20

10

0I II III IV V I II III IV V

High blood pressure Insulin resistance

Quintiles of Waist Circumference

%

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Link Between Hyperglycemia and Poor Hospital Outcomes

Clement S et al. Diabetes Care. 2004;27:553-591.

Metabolic stress response

Stress hormones and peptides

Prolonged hospital stay Disability Death

Glucose Insulin

FFA Ketones Lactate

Immune dysfunction

Infection dissemination

Reactive O2 species

Transcription factors

Secondary mediatorsCellular injury/apoptosisInflammation

Tissue damageAltered tissue/wound repair

AcidosisInfarction/ischemia

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Increasing Glucose Levels Increase Long-Term Mortality in ACS

Bhadriraju S, et al. Am J Cardiol. 2006;97:1573-1577.

OPUS-TIMI 16 trial; 10,288 patients with ACS

Quartile 1=<101 mg/dLQuartile 2=101–120.6 mg/dLQuartile 3=120.6–157 mg/dL Quartile 4=>157 mg/dL

1

.95

.9

.85

Days of Follow-up

Cu

mu

lati

ve S

urv

ival

0 100 200 300

Quartile 1

Quartile 2

Quartile 3

Quartile 4

P for trend across group=0.006

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Hyperglycemia Increases In-Hospital Complications and Long-Term Mortality

1. Foo K, et al. Heart. 2003;89:512-516.2. Kosiborod M, et al. Circulation. 2005;111:3078-3086.

N=2,127 patients with AMI or unstable angina1

Multivariate Predictors of Left Ventricular Failure

Variable Comparison Odds Ratio P Value

Glucose Q1 1.00

Q2 1.10 (0.66 to 1.86)

Q3 1.73 (1.06 to 2.83)

Q4 2.80 (1.74 to 4.50)

<.0001

Q 1=≤5.8 mmol/L; Q2= ≤7.2; Q3=≤10.0; Q4=>10.0.

Cooperative Cardiovascular Project; N=141,680 elderly patients hospitalized

with AMI2

1.00.90.80.70.60.50.40.30.20.10.0

70 120 170 220 270 320 370Glucose (mg/dl)

Mo

rtal

ity

Rat

e

Diabetes: No

P <.001 for interaction

Diabetes: Yes

One-Year Mortality

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Inpatient Management of Hyperglycemia and Diabetes

Upper Limits for Glycemic Targets

Noncritical Care Units

Intensive Care Unit Preprandial Maximal Glucose

110 mg/dL (6.1 mmol/L) 110 mg/dL (6.1 mmol/L) 180 mg/dL (10.0 mmol/L)

American College of Endocrinology Task Force on Inpatient Diabetes and Metabolic Control

• Values above 180 mg/dL are an indication to monitor glucose levels more frequently to determine need, if any, for more intensive intervention

• Targets for non-ICU patients are supported only by prospective observational studies

• Separate targets for pregnant patients (not shown)

American College of Endocrinology. Endocr Pract. 2004;10:77-82.

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Inpatient Management of Metabolic Syndrome

Evaluate all patients with hyperglycemia for metabolic syndrome

Patients with hyperglycemia but no diabetes diagnosis during hospitalization should receive a written plan for follow-up testing after discharge

Treatment of the metabolic syndrome often requires more than one pharmacotherapeutic agent for each component

Interventions aimed at reducing the burden of obesity in the US would reduce the risk for metabolic syndrome

Selig PM. AACN Clin Issues. 2006;17:79-85.

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Hypertension

Type 2 diabetes

Dyslipidemia

Risk factorsCoronary

heart disease

Treat the complications?

Managecoronary heart

disease risk

Adapted with permission from Després JP, et al. BMJ. 2001;322:716-720.

Management of Cardiovascular Risk in Patients With Abdominal Obesity

Treat the cause

Abdominally obesepatient at increasedcardiometabolic risk

Knowler WM, et al; Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

Effect of Interventions on Weight Change andRisk of Diabetes and Metabolic Syndrome

Diabetes Prevention Program

-8

-0.1

Wei

gh

t C

han

ge,

kg

-6

-4

-2

0

PB(n = 1082)

LS(n = 1079)

MET(n = 1073)

-5.6*

-2.1*

*P <.001 vs placebo

% R

edu

ctio

n in

In

cid

ence

of

Dia

bet

es

-60

-40

-20

MET LS

-58*

-31

*P <.05 vs metformin

-50

-40

-30

-20

-10

0MET LS

Red

uct

ion

in R

isk

of

Met

abo

lic S

ynd

rom

e, %

-17%†

-41%*

Risk of developing metabolic syndrome

n=1523

LS = lifestyle intervention; MET = metformin; PB = placebo.

Orchard TJ, et al; Diabetes Prevention Program Research Group. Ann Intern Med. 2005;142:611-619.

*P <.001; †P = .03

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Current Approaches to Treating Obesity

Diet, exercise, and behavioral therapy continue to be the mainstays of obesity treatment

Short-term efficacy of pharmacotherapy has been noted in clinical trials

Side effects of pharmacologic therapy vary and may impact administration

Surgery is reserved for morbidly obese patients with comorbidities

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Most Widely Prescribed Drugs for Treating Obesity

*Approved for OTC use in January 2006.

Adapted from Yanovski SZ, Yanovski JA. N Engl J Med. 2002;346:591-602.

Phentermine

Year Approved

Approved Use

DEA Schedule

1997Long termIV

1973Short termIV

1999Long termNone

Generic Name

Sibutramine

Orlistat*

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Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors

NCEP ATP III

definitionof the

metabolicsyndrome

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Antihypertensives

Oral antidiabetic agents

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Brain

Food intake

Rimonabant

Adipocyte

Rimonabant, the First CB1 Blocker:May Affect Multiple Targets

Rimonabant, the First CB1 Blocker:May Affect Multiple Targets

Central Peripheral

CB1CB1

Adiponectin: Insulin resistance Triglycerides Glucose tolerance HDL cholesterol

Weight loss

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1 year 1045Obese or overweight withtype 2 diabetes

RIO-Diabetes

1 year 1036Obese or overweight withuntreated dyslipidemia

(diabetes excluded)

RIO-Lipids

2 years1507Obese or overweightwith/without comorbidities

(except diabetes)

RIO-Europe

1+1 year

Re-randomized

3045Obese or overweightwith/without comorbidities

(except diabetes)

RIO-North America

DesignPopulationStudy

Rimonabant In Overweight/Obesity Trials

N

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Placebo-subtracted Change in Metabolic Syndrome Parameters in 4 Rimonabant Trials

Mean (+ SEM)

**

*

*

* **

*

** * *

1. Pi-Sunyer FX, et al. JAMA. 2006;295:761-775.2. Van Gaal LF, et al. Lancet. 2005;365:1389-1397.3. Després JP, et al. N Engl J Med. 2005;353:2121-2134. 4. Scheen AF. Presented at: 65th Annual Scientific Sessions of the ADA;

June 12, 2005; San Diego, Calif.

HDL Cholesterol, %

7.2 8.9 8.1 8.4

-20

-15

-10

-5

0

5

10

%

Waist Circumference, cm

-3.6-4.2

-4.7

-3.3

-6

-5

-4

-3

-2

-1

0

cm

Triglycerides, %

-13.2-15.1

-12.4-16.4

-20

-15

-10

-5

0

5

10

%

Systolic Blood Pressure, mm Hg

-1.2-1.7

-2.3

-0.2

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

mm

Hg

*P <.001

*P <.001

*P <.001

RIO-North America1

RIO-Europe2

RIO-Lipids3

RIO-Diabetes4

NS

NS

*P <.05

*P <.05

N = >6600; ITT, LOCF

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RIO-North America: Change in Metabolic Syndrome Status

Pi-Sunyer FX, et al. JAMA. 2006;295:761-775.

Baseline

1-Year Treatment

ITT, LOCF

Pa

tie

nts

, %

31.7%34.8%

29.2%

21.2%

0

10

20

30

40

Placebo Rimonabant 20 mg

P <.001

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Pooled RIO Studies: Overall Safety

Year 1 Year 2

Subjects discontinued due to adverse event

Subjects with any serious adverse event*

Subjects with any adverse event

4.7%

5.4%

77.0%

4.5%

4.7%

74.4%

4.7%

4.5%

76.7%86.0%82.9%81.8%

13.8%8.8%7.2%

5.9%5.4%4.2%

(n = 466)

Placebo

(n = 663)

Rimonabant5 mg

(n = 688)

Rimonabant20 mg

Rimonabant20 mg

(n = 2503)(n = 1602) (n = 2520)

Rimonabant5 mg

Placebo

Includes all deaths occurring in all four RIO studies:4 on placebo, 3 on rimonabant 5 mg, 4 on rimonabant 20 mg.

RIO-North

America

RIO-Europe

RIO-Lipids

RIO-Diabetes

RIO-North

America

RIO-Europe

Scheen A, et al. Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 12, 2005; San Diego, Calif.

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Summary● The prevalence of obesity and diabetes is increasing

dramatically

● Metabolic syndrome, a precursor to CVD and diabetes, also is increasing dramatically

● Obesity is a major risk factor for diabetes and CVD, and the driving force behind the metabolic syndrome

● Weight reduction and exercise are the cornerstone of cardiometabolic risk reduction

● Pharmacotherapy can be used along with lifestyle intervention to reduce cardiometabolic risk factors

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Featured Institution

Cleveland Clinic FoundationCleveland, Ohio

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35

Polling Question #2

1. We are currently on the same item

2. We have since moved to the next checkbox on the checklist

3. We have progressed by more than one item on the checklist

4. ACS pathways are up-to-date and regularly followed

If you participated in a previous teleconference, how much progress have you made since then?

(Please refer to the checklists on the next 3 slides.)

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36

Progress Checklist:Immediate Goals

Assemble team and set up meeting of working group

Develop draft pathways

Circulate pathways to all cardiology, ED, and CV nursing staff for comments

Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff for comments

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37

Progress Checklist:Short-term Goals/Activities

Finalize critical pathways

Launch critical pathways

Circulate memo

Grand rounds/conference: Cardiology/IM

Grand rounds/conference: Emergency Dept.

Grand rounds/conference: Nursing

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38

Progress Checklist:Long-term Goals/Activities

Monitor data: Which registry?

NRMI

AHA Get With the Guidelines

ACC National Cardiovascular Data Registry

CRUSADE

GRACE

REACH

Other

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39

Question-and-Answer Session

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40

Concluding RemarksGregg C. Fonarow, MD

Next Program Highlights From the

2006 Transcatheter Cardiovascular Therapeutics (TCT) Conference

Christopher P. Cannon, MDWednesday, November 8, 2006

12:00 Noon Eastern Time (9:00 AM Pacific Time)