Sunday, September 30 - OSU Center for Continuing … Presentations.pdfpayments plus additional bonuses ... and Lp(a) Vera Bittner, MD, MSPH, FACC ... CHD Stroke PAD DM MS CKD delta

Sunday, September 30

NOTES—

9/20/2012

1

Cardiology in the World of Accountable Care

Patrick T. O’Gara, MDBrigham and Women’s Hospital

Harvard Medical School

No Disclosures

Current Climate

Pressure to Lower Costs

• Current cost trend unsustainable

Healthcare Reform

• Patient Protection and Affordable Care Act

• Potential for major legislation In Massachusetts

• Accountable Care Organizations

• Bundled payments

Incentives and Penalties forPerformance

Risk Sharing • Increased medical expense risk borne by providers• Providers incentivized to keep populations healthy

Incentives for Collective Accountability

• Meaningful Use, decreased payments for readmissions, hospital acquired Infection, core measure compliance

Adapted from slide prepared by Center for Applied Research (CFAR)

Changing Landscape of Payment

Procedure Payment to provider

Episode of care

Payment to organization

Providers Facility Ancillaries

care organization

Post-discharge care

9/20/2012

2

Overview of ACO: Key Differences Between Accountable Care and Capitation

Accountable Care, Managed Care Different in Concept, Implication

Key Differences Between Capitation/Shared Savings

Patient Choice Payment Structure Value Capture

Patient joins HMO, coverage limited

Fixed PMPM payment

Provider retains all excess value

Capitation

Patients assigned to ACO are free to choose providers and sites of care

Pioneer ACO shifts to PMPM in Year 3, FFS in

Yrs 1&2

Pioneer ACO shares savings

with payer (CMS)

Key Differences between Pioneer

ACO and Capitation

Source: Advisory Board ‘Playbook for Accountable Care’, modified

to narrow subset of participating

providers

regardless of care volume

created by lowering

population cost

Invisible assignment, patient free to choose,

change providers at will

Fee for service payments plus

additional bonuses

Provider shares value from population

management successw/ payer

Shared Savings

Overview of ACO: What is an ACO? Population Management at the Heart of Shared Savings

The Medicare Shared Savings Program (MSSP or Original ACO) and Pioneer ACO models are payment models that incorporate utilization risk and require providers to engage in population management:

Shared Savings Payment

Cycle (Adapted for

Pioneer ACO)

1Assignment

Patients attributed to ACO based on terms of contracts

2

BillingProviders bill normally, receive standard fee-for-

service payments in Years 1&2. Population-based payments in Yr 3

ACO)

3

ComparisonThe targeted performance benchmark (total cost of care estimated for assigned population) is based on trending baseline expenditures using an expenditure growth rate

of a ‘matched’ national patient cohort

4Bonus/Losses

If total expenses are greater/less than targeted (dependent on quality scores), portion of

savings/losses shared by ACO

5Distribution

ACO responsible for dividing bonus payments among stakeholders

Source: Advisory Board ‘Playbook for Accountable Care’, modified

Overview of Pioneer ACO: Patient Alignment Eligibility

• Medicare FFS beneficiaries eligible for prospective alignment under Pioneer ACO are those who:

Have 12 months of Part A and Part B coverage during 3rd

alignment year (alignment year = the year before each f )

- -

performance year)Have no months of coverage under a private Medicare planHave no months of coverage in which Medicare was secondary payerAre resident in the U.S.Have at least 1 claim for a qualifying E&M service during alignment period

9/20/2012

3

Overview of Population Health Management

• Why we are doing this

• What population management means

• Who we are talking about

• Which strategies we are employing to be successful

• How you can contribute

Why we are doing this – rising costs can not be sustained

Why we are doing this – 4 population management contracts designed to lower cost

trend

9/20/2012

4

Why we are doing this – 4 population management contracts designed to lower cost trend

Total Medical Expense (TME)

TME

TME for comparator population

BCBS Example

TME in baseline period

TME

TME

TME

TME

TME in performance year

Target Trend = 0%

•Our initial focus is to control the health care cost trend of 60K patients who are

–Covered by one of our 4 trend management contracts; and,

Who we are talking about – initial focus on high risk patients

–Have a Brigham and Women’s PCP

~60K IPF patients

~3K high risk patients

•Our initial focus is to control the health care cost trend of 60K patients who are

– Covered by one of our 4 trend management contracts; and,

– Have a Brigham and Women’s PCP

•Our long term goal is to expand the population management systems to all Brigham and Women’s patients

Who we are talking about – initial focus on high risk patients

~100K patients w/ BWPO PCPs

~60K IPF patients

~3K high risk patients

~500K BWHC IP, Surg, EM, OV

9/20/2012

5

What population management means –coordinating care for a population of defined

patients•Population management programs focus on

–Collaborating within and across departments to id l ti t t dprovide seamless patient‐centered care

–Having effective communication and coordination

–Reducing unexplained variation

•Fundamental transformation of the way BWF delivers care to all of our patients

Longitudinal Care Episodic CarePrimary Care Specialty Care Hospital Care

Access to care

Patient portal/physician portal Optimize site of care (e.g. FH)

Extended hours/same day appointments/ New Patient Access Reduced low acuity

admissionsExpand virtual visit options

Focus on Value - Defined process standards in priority conditions(multidisciplinary teams, registries)

High risk care AppropriatenessRe-admissions

14 - 14 -

Design of care

High risk care management

Appropriateness (SCAMPS) Hospital Acquired

Conditions

100% preventive services Required patient decision aids

Hand-off standards

Continuity visit

EHR with decision support and order entry/Meaningful Use

Incentive programs (recognition, financial)

Data Management

Variance reporting/performance dashboards

Quality metrics: clinical outcomes, satisfaction

Costs/population Costs/episode

Adapted from Tim Ferris, MD 11/7 Performance Management Presentation

• Integrated Care Management Program (iCMP)– If you see the CMP icon and want to share or need information about a patient, contact their iCMP RNCC by clicking on the CMP

How you can contribute

Data Driven Care Redesign Review available data and help us interpret what it means

Participate in or lead care redesign process or care improvement initiatives

9/20/2012

6

Preparing for the FutureIndividually…Identify opportunities for:Costs savings StandardizationIncreased efficiency

Locally…Ensuring:The right patient in the right settingOptimal patient flowFocus on improved disease managementFocus on outcomes

Nationally…Create:Clinical pathwaysGuidelines for practice

Value Framework

Health Outcomes + Quality + Experience

C tValue =

Cost

1

Making Sense Of The Lipid “Subparticles”:

Non-HDL-C, Apo B, LDL-P, LDL size and Lp(a)

Vera Bittner, MD, MSPH, FACCProfessor of Medicine

Section Head, Preventive CardiologyDivision of Cardiovascular Disease

University of Alabama at Birmingham

Fourth Annual Contemporary Multi-Disciplinary Cardiovascular Medicine

September 28-30

Disclosures Current Research Grants:

– Sanofi: ODYSSEY

– GSK: STABILITY

– NIH/Abbott: AIM HIGH

– Roche: dal-Outcomes 1+2, ALECARDIO

– Amgen: School of Public Health Contract

Past Research Grants:– Atherogenics: ARISE

– Merck: Merck-112

– Pfizer: TNT, ILLUMINATE

Speakers’ Bureaus: None

Consultant: Pfizer, Amarin, Kowa, Liposcience

Stock Ownership: None

DSMB: Columbia University

Non-HDL-C and Apo-B

2

Two Ways of Capturing All Potentially Atherogenic Particles

Non-HDL-C = Total-C – HDL-C

VLDL VLDLR IDL LDL - Particles

Apolipoprotein B

Non-HDL-C and Apo-B Are Highly Correlated On And Off Therapy ACCESS Study (54 week, compares different statins)

N= 3,916; all had LDL>130 mg/dL, TG <400 mg/dL

Baseline: r = 0.914; On Treatment: r = 0.938

Ballantyne et al. AJC 2001;88:265–269

On Statins at Week 54

Can We Identify People With Non-HDL-C / Apo B Discordance?

Type I (mg/dl)

Type IIamg/dl)

Type IIb(mg/dl)

Type III (mg/dl)

Type IV (mg/dl)

Type V (mg/dl)

Predominant Particle CM LDL LDL + VLDL Remnant VLDL

VLDL + CM

Non-HDL-C 173 212 236 312 187 295

Apo B 48 136 153 104 118 96

Apo B/Non-HDL-CCorrelation 0.54 0.94 0.92 0.72 0.74 0.13

Data from Sniderman et al. Clin Sci 2008;114:149-155

ApoB/Non-HDL-C Correlation for normolipidemia: 0.92;Lipid values are means for this population

3

Non-HDL-C and Apo-B for Risk Prediction

Non-HDL-C and CHD Mortality

Patient level meta-analysis of 61 studies

Studies with HDL-C available included 1,496,000 py of F/U

IHD deaths: 3,020

HR (95% CI)

Prospective Studies Collaboration. Lancet 2007; 370: 1829–39

Apo B and CHD: Meta-Analysis6,320 CHD cases from 19 studies

Summary RR 1.99 (1.65-2.39) comparing top third vs. bottom third

Thompson / Danesh. J Int Med 2006;259: 481–492

4

Non-HDL-C and Apo-B Are Comparable Risk Predictors in Persons Without CVD N=91,307 (4499

cases), 22 studies

Regression stratified by sex and trial group

Adj. for age, SBP, smoking, DM, BMI

Analyses of non–HDL-C adj. for HDL-C, log TG

Analyses of apo B adj. for apo AI, log TG

Haz

ard

Rat

io

Non-HDL-C

HDL-C

Apo-B

Apo-A1

Emerging RF Collaboration. JAMA 2009;302:1993-2000

Non-HDL-C Vs. Apo-B: Which Is The Better Predictor?

Studies are heterogeneous– Apo-B is better

– Non-HDL-C is better

– Equivalent prognostic value

– Neither measure adds anything

Relative prognostic value depends on– Study design

– Patient characteristics

– Covariates

– Outcomes assessed

– Time frame of risk prediction

We need to understand better when Apo-B might provide additional prognostication

Non-HDL-C and Apo-B as Treatment Targets

5

What Are Current Treatment Goals?

Stein, Sniderman, Laskarzewski. AJC 2005;96:36K-43KBrunzell et al. Diabetes Care 2008;31:811-822

Risk Category(10 year risk)

LDL-C(mg/dL)

Non-HDL-C (mg/dL; if TG 200-500

mg/dL)

Apo B(mg/dL)

>20% <100(optional <70)

<130(optional <100)

<90(optional <80)

10-20% (>2 RF) < 130(optional <100)

<160(optional <130)

<105 or <110 (optional <90)

<10% (2+ RF) <130 <160 <105 or <110

0-1 RF <160 <190 <120 or <130

Optional goals favored by ADA/ACC Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk

Change in Non-HDL-C With Therapy and CHD Risk

Meta-analysis of 30 trials– 14 statin trials, 7 fibrate trials, 6 niacin trials, 1

resin trial, 1 diet trial, 1 ileal bypass trial

Study level data (not patient level)

Mean F/U 4.5 years

CHD event = nonfatal MI or CHD death– Angina and revascularization not included

1:1 relationship between mean % change in non-HDL-C and % decrease in CHD events

Robinson J et al. JACC 2009;53:316–22

Statins: Effect on Non-HDL-C and Apo B

11 statin trials

17,035 subjects

% change with therapy

Population %ileachieved

LDL-C Non-HDL-C Apo-BConcentration Achieved

99 mg/dL 127 mg/dL 102 mg/dL

%ile Achieved 21 29 55Sniderman A. J Clin Lipidol2008;2:36–42

6

MERCURY II: Beware of the Y-Intercept …

To achieve an apo-B target of <90 mg/dL, we need to aim for the optional non-HDL-C goal (<100 mg/dL) in statin-treated patients

16 weeks of Rx

Ballantyne et al. JACC 2008;52:626-632

Distance from LDL-C and Non-HDL-C Goals in the US – NHANES 2003-2004

0

20

40

60

80

100

CHD Stroke PAD DM MS CKD

delta LDL-C

delta non-HDL

ATP III goals prior to white paper– Stroke, PAD, DM, CKD* = CHD Equivalents

– Goals for metabolic syndrome calculated by FRS

Distance from goal calculated for those not at goal (≈50%)

*CKD: Cockroft-Gault CrCl<60

mg/

dL

Ghandehari et al. AHJ 2008;156:112-9

LDL Particle Number and Size

7

LDL-Particles Are Heterogeneous22-29 nm in size, 1 Apo-B per particleSize of the predominant LDL particles

determines the classification– Small: 22-25.5 nm– Intermediate: 25.6-26.5 nm– Large: 26.6-28.5 nm

Two Major Subclass Patterns:– Pattern A: >25.5 nm– Pattern B: ≤25.5 nm– Some authors define a third “AB”, “C” or

“intermediate” pattern

Sacks and Campos. JCEM 2003;88:4525-4532

LDL Fractionation Is Not StandardizedMultiple clinical (GGE, VAP, NMR) and

bench methods - no gold standard

Few comparative studies, highly variable analysis methods

Correlations for size from 0.67-0.92

Concordance in identifying LDL patterns 7-94%

Comparability of methods appears to vary by type of patient population

Chung et al. Atherosclerosis 2009;205:342–348

Large LDL Are AtherogenicLarge LDL relates to atherosclerosis in non-

human primates– Rudel LL et al.. JLR 1986;27:465-474

Patients with FH have large LDL– Patsch et al. JLR 1982;23:1196–205

Normolipidemic men with CHD have large LDL– Campos et al. ATVB 1995;15:1043–8

CARE Study: large, not small LDL predicted risk in patients with MI– Campos et. Al. JAMA 2001;286:1468–74.

8

Small Dense LDL Are AtherogenicLess cholesterol per particle than larger LDL

Proposed atherogenic characteristics:– Long residence time in plasma

– ↑ Oxidizability

– ↑ Arterial proteoglycan binding

– ↑ Permeability through the endothelial barrier

Often present in patients with CHD

Often present in DM, low HDL-C / high TG, insulin resistance / metabolic syndrome

Sacks and Campos. JCEM 2003;88:4525-4532

LDL-Particles and CV riskMany studies show that

– Small LDL particle size correlates with risk

– LDL Pattern B correlates with risk

– LDL particle number correlates with risk

BUT

Size and number are interrelated which is the real correlate of risk?

Small, Dense LDL and IHD Risk in MenProspective Results From the Quebec Cardiovascular Study

LowHigh

01234567

Large SmallLDL particle size

6.2

2.1

1.0 1.0

Ris

k of

IHD

Circulation 1997;95:69-75

Apo-B as continuous variable single best predictor in multivariate model

LDL size as a continuous variable not significant after Apo-B adjustment

9

MESA: LDL and IMT N=5538, multi-

ethnic

Detailed particle analysis by NMR

Cross-sectional correlation with IMT

Inverse correlation between large and small LDL-P (r = -0.63)

Correlates of small LDL-P– LDL-C: r = 0.4

– LDL-size: r = -0.91

Correlates of large LDL-P– LDL-C: r = 0.27

– LDL-size: r = 0.87

Unadjusted analysis of LDL (per SD) vs IMT (m):– Total LDL-P: + 40.2 (p<0.001)

– Small LDL-P: + 31.7 (p<0.001)

– Large LDL-P: + 4.9 (p=NS)

Mora et al. Atherosclerosis 2007;192:211–217

920

950

980

1010

1040

Q1 Q2 Q3 Q4 Q5

Large LDL-P Quintiles

Ptrend = 0.94 Ptrend <0.001

Adj. for age, sex Adj. for age,sex, small LDL-P

IMT

(m

icro

ns)

MESA: Large + Small LDL-P Correlate With IMT

Mora et al. Atherosclerosis 2007;192:211–217

Mutually Adjusted

∆ IMT (m) per SD in LDL-P

Small: +39.1

Large: +42.9

VA-HIT: LDL-P and CHD Events

OR 95% CI p OR 95% CI p

Univariate

Total LDL-P 1.2 1.05-1.37 0.0006 1.28 1.12-1.47 0.0003

Small LDL-P 1.11 0.98-1.27 NS 1.17 1.02-1.34 0.03

Large LDL-P 1.08 0.95-1.23 NS 1.06 0.93-1.22 NS

Multivariate

Small LDL-P 1.44 1.20-1.73 <0.0001 1.41 1.14-1.73 0.001

Large LDL-P 1.31 1.09-1.57 0.003 1.34 1.11-1.62 0.002

Otvos et al. Circulation 2006;113:1556-63

Baseline On Trial

OR per SD of LDL-PCo-variates: treatment group, age, HTN, smoking, BMI, and DM.

10

Conclusions

There is lipoprotein-related risk beyond LDL-C

Assess this risk by estimating the number of atherogenic particles– Non-HDL-C

– Apo B

– LDL-P

None of the 3 clearly superior to the others for risk prediction; may be complementary

All 3 need to be validated as treatment targets

Lipoprotein (a)

Lp(a) Structure

Homologous to Protease Region of Plasminogen

Homologous to Kringle 5 of Plasminogen

LDL Particle

10 Different Types of PlasminogenKringle 4-like Repeats

2 to >40 Copies of Kringle 4 Type 2 Domain (varies by apo(a) Isoform)

Disulfide Bond

Apo B 100

11

Lp(a) Population Distribution

Genetically determined

Skewed distribution

Marked ethnic variation in Lp(a) concentration and (a) isoforms

50 mg/dL = 80th %ile(in Whites)

Concentration: Median(mg/dL)

IQ Range (mg/dL)

Non-Hispanic Whites

12 5-32

Chinese 11 4-22

Japanese 13 5-26

Hispanics 19 8-43

Blacks 39 19-69

Nordestgaard BG et al. EHJ Oct 21, 2010: doi:10.1093/eurheartj/ehq386

Lp(a) – Measurement (NHLBI) It is essential that Lp(a) assays used in clinical and

epidemiologic studies be validated for their ability to provide accurate values independently of the size of apo(a) in the samples.

The expression of Lp(a) values in terms of total Lp(a) mass (mg/dL) should be abandoned as this reflects protein component of Lp(a) and not its lipid and carbohydrate content.

To correctly reflect the number of Lp(a) particles and to compare data from different studies, the values should be expressed in terms of nmol/L of Lp(a).

Marcovina SM, et al. Clin Chem 2003;49:1785-1796

Emerging RF Collaboration N= 126,634 in 36

prospective studies

1.3 million py F/U

9336 incident CHD events

1903 ischemic strokes

8114 non-vascular deaths

Adj. for age, sex, SBP, smoking, DM, BMI and TC

JAMA 2009;302:412-423

Nonfatal MI and CHD Death Ischemic Stroke Nonvascular Death

Per SD: RR 1.13 (1.09-1.18) Per SD: RR 1.10 (1.02-1.18)

SD = 3.5 fold higher level

12

Lp(a) Risk Modulated by LDL-C RxFATS Posthoc Analysis

Black Bars: ≤10% LDL-C Reduction; Gray Bars: >10% LDL-C Reduction

Maher et al. JAMA 1995;274:1771-1774

Current GuidelinesATP III: Consider more aggressive LDL-C target in

individuals with high Lp(a)– ATP III Guidelines 2001

NHLBI: screen individuals at intermediate risk; no specific treatment recommendations– Clin Chem 2003;49:1785-1796

USPSTF: Insufficient data– Annals IM 2009;151:474-482 and 496-507

EAS: screen intermediate and high risk patients and treat those with high levels (Niacin, possibly apheresis)– European Heart Journal (2011) 32, 1769–1818

9/20/2012

1

Approach to the Patient with a Family History of

Premature CVD



No Disclosures

Prevention• Primordial

Prevent the development of risk factors

• PrimaryPrevent 1st occurrence of clinical event in persons at risk

• SecondaryPrevent recurrent events in patients with manifest disease

Ideal CV Health

Health Behaviors Health Factors• Non-smoking ● TC < 200• BMI < 25 BP < 120/80• BMI < 25 ● BP < 120/80• Physical activity ● FBS < 100• Diet

9/20/2012

2

Attributes of Ideal CV Health• Smoking never/quit > 12 mos 73• BMI < 25 kg/m2 33• Physical act > 150 min/week 45 • Healthy diet 4 5 comp’nts < 0 5

Prevalence (%)

• Healthy diet 4-5 comp nts < 0.5• T Chol < 200 mg/dL 45• BP < 120/80 42• FBS < 100 mg/dL 58

Prevalence of Ideal CV Health in US Populations ~ 5%

Lifetime Risk of CV DeathMen, Age 55

Berry JD et al. NEJM 2012; 366:321-9

Lifetime Risk of CV DeathWomen, Age 55

Berry JD et al. NEJM 2012; 366:321-9

9/20/2012

3

Prevalence of Conventional Risk Factors in Patients with Coronary Heart Disease (N = 87,869)

19.4 %

8.9 %

4 Risk Factors(< 1 %)

No Risk Factors

3 Risk FactorsSmokingHTNCholesterolDM

43.0 %

27.8 %

1 Risk Factor

2 Risk Factors 62.4 %

Khot U et al, JAMA 2003;290:898-904

Lipoprotein(a)

Homocysteine

IL-6

TC

LDLC

sICAM-1

Risk Factors for Future Cardiovascular Events: WHS

8

0 1.0 2.0 4.0 6.0

SAA

Apo B

TC: HDLC

hs-CRP

hs-CRP + TC: HDLC

Relative Risk of Future Cardiovascular Events

Ridker et al, N Engl J Med 2000;342:836-43

25.0

30.0

Moving Toward an hs-CRP Modified Framingham Risk Score

ngha

m R

isk

ngha

m R

isk

9

0.0

5.0

10.0

15.0

20.0

10-20 5-10 <5 <0.50.5-1.0

1.0-3.03.0-10.0

>10.0

Calculated Framingham 10Calculated Framingham 10--Year RiskYear Risk

Ridker PM, Wilson PWF, Grundy SM. Circulation 2004;109:2818-2925

CR

P M

odifi

ed F

ram

inC

RP

Mod

ified

Fra

min

9/20/2012

4

Age-adjusted prevalence (%) of CAC ≥100 by FH of premature CHD category and increasing number of risk factors.

Nasir K et al. Circulation 2004;110:2150-2156

Prevalence (%) of age-, gender-, and race-adjusted CAC ≥75th percentile according to FamHx of premature CHD among ethnic groups in individuals classified as low-to-intermediate risk

by FRS.

Nasir K et al. Circulation 2007;116:619-626

Lifetime Risk of CV Death for Men at 55

Bachmann J M et al. Circulation 2012;125:3092-3098

9/20/2012

5

Lifetime Risk of CV Death for Men at 45

Bachmann J M et al. Circulation 2012;125:3092-3098

Figure 1

Y Chromosome Haplogroups

Lancet 2012; 379:915-22

Figure 2

Haplogroup IDifferential Expression

Lancet 2012; 379:915-22

9/20/2012

6

Reynolds Risk CalculatorGenderAgeDo you currently smoke? Systolic Blood Pressure (SBP) mm/HgTotal Cholesterol mg/DL (or) mmol/LHDL Cholesterol mg/DL (or) mmol/L High Sensitivity C-Reactive Protein (hsCRP) mg/LDid your Mother or Father have a heart attack

before age 60 ?YesNo

1

CRP: When and Why?





September 28-30

Disclosures related to this presentation:

I was part of the “NLA Expert Panel” that I will cite later in the talk.

Mora S, Ridker PM. AJC 2006;97(2A) (www.AJConline.org)

CRP-triggered oxidation of LDL cholesterol

CRP-induced PAI-1 expression stabilizes PAI-1 mRNA

CRP attenuates NO production, decreases eNOS

expression

CRP-induced production of cell adhesion molecules MCP-1, ET-1

CRP-mediated LDL uptake by macrophages

CRP localization in atherosclerotic but not normal intima

CRP-induced complement activation

CRP-dependent monocyte recruitment into arterial

wall

CRP-induced production of tissue factor in monocytes

CRP-based blunting of endothelial vasoreactivity

Is CRP a Risk Marker or a Risk Factor?

2

Three major questions:

Is hs-CRP easily and reliably measured?

Does it predict risk independent of traditional risk factors?– People without disease / people with

diseaseDoes a strategy targeting individuals

with high hs-CRP change outcomes?

Measurement: Classification Accuracy is Similar for CRP and Total Cholesterol

N=113 with multiple TC and CRP measurements

CRP and cholesterol divided into 4 ranges

Agreement between measurements assessed

Ockene et al. Clin Chem 2001;47:444-450

Patient Characteristics / Conditions Associated With ↑ or ↓ hs-CRP

Pearson et al. CDC/AHA guidelines. Circulation 2003;107:499-511

3



Does hs-CRP predict risk independent of traditional risk factors?– People without disease / people with



< 1.0

1.0-3.0

> 3.0

0

5

10

15

20

25

10+ 5-9 2-4 0-1

11

5.53.1

1

21

11

3.31.8

22

14

5.7

2.5

hs-CRP(mg/L)

Framingham 10-Year Risk (%)

Ridker PM et al. N Engl J Med 2002;347:1557-1565

Women’s Health Study: CRP Adds Prognostic Information To The FRS

F/U: 8 years; Outcome: CV events

ERFC: CRP Predicts Incident CHD

Adj. for age, sex, study, SBP, smoking, DM, BMI, log TG, non-HDL-C, HDL-C, alcoholAdj. for age, sex, study

The Emerging Risk Factors Collaboration. Lancet 2009;374 (published online Dec 2009)

4

ERFC: CRP vs Traditional RF

Risk per SD usual value for ln CRP, SBP, TC, non-HDL-C (mutually adjusted)

The Emerging Risk Factors Collaboration. Lancet 2010;374 (Web Appendix)

CRP Change with Treatment and Progression of CAD by IVUS

REVERSAL StudyN=502RCT of 40 mg prava

vs 80 mg atorva

Nissen et al NEJM 2005;352:29-38

REVERSAL: Joint Effects of LDL-C and CRP change on Atheroma Volume

-4

-2

0

2

4

6

8

LDL-C & CRP>median

LDL-C <median,CRP>median

LDL-C>median,CRP<median

LDL-C & CRP<median

Total Atheroma Volume

Nissen et al NEJM 2005;352:29-38

5

Ridker PM et al. N Engl J Med 2005;352:20-28

Incidence of Recurrent MI or CHD Death by Achieved Levels of LDL-C and CRP

Rec

urre

nt M

I or C

oron

ary

Dea

th(%

)

Follow-up (Years)0.0 0.5 1.0 1.5 2.0 2.5

LDL 70 mg/dl, CRP 2 mg/L

LDL 70 mg/dl, CRP <2 mg/LLDL <70 mg/dl, CRP 2 mg/L

LDL <70 mg/dl, CRP <2 mg/L

0.00

0.02

0.04

0.06

0.08

0.10

PROVE IT–TIMI 22



Does hs-CRP predict risk independent of traditional risk factors?– People without disease / people with



AFCAPS/TexCAPS PostHoc Analysis

Study Group Lovastatin

(Event Rate)

Placebo

(Event Rate)

NNT

Low LDL-C/low CRP 0.025 0.022 _

Low LDL-C/high CRP 0.029 0.051 48

High LDL-C/low CRP 0.020 0.050 33

High LDL-C/high CRP 0.038 0.055 58

Ridker et al. NEJM 2001;344:1959-65

6

Jupiter Trial Design

Rosuvastatin (N = 8901)

Placebo (N = 8901)4-week Run-in

• No History of CAD• Men > 55 • Women > 65 • LDL-C < 130 mg/dL• CRP > 2 mg/L

• Primary EP: First CVD Event

• MI • Stroke• Unstable Angina • CVD • Death• CABG/PTCA

End of Study Visit

Biannual Follow-up Visits

Safety Visit

Randomization Visit

Screening Visit

CRPLFT

HbA1c

LipidsCRP

HbA1c

LipidsCRPLFTs

LipidsCRP

Ridker PM. N Engl J Med. 2003;108:2292-7.

Endpoints

Primary End Point: First Major Cardiovascular Event

No. at Risk

Rosuvastatin 8901 8631 8412 6540 3893 1958 1353 983 538 157

Placebo 8901 8621 8353 6508 3872 1963 1333 955 531 174

Cu

mu

lati

ve I

nci

den

ce

0.08

0.06

0.04

0.02

0.000 1 2 3 4

Years

Placebo

Rosuvastatin

p < 0.00001

Ridker PM et al. N Engl J Med. 2008;359:2195-207.

HR 0.56, 95% CI 0.46-0.69P < 0.00001

- 44 %

Jupiter Subgroups (1o EP)

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

Women

Age > 70

Framingham Risk < 10 %

Black, Hispanic, Other

LDLC < 100 mg/dL

No Hypertension

All Participants

N HR (95%CI)

6,801 0.54 (0.37-0.80)

5,695 0.61 (0.46-0.82)

8,882 0.56 (0.38-0.83)

5,117 0.63 (0.41-0.98)

6,269 0.66 (0.47-0.92)

7,586 0.62 (0.44-0.87)

17,802 0.56 (0.46-0.69)

BMI < 25 mg/m2 4,073 0.59 (0.40-0.87)

No metabolic Syndrome 10,296 0.49 (0.37-0.65)

Elevated hsCRP Only 6,375 0.63 (0.44-0.92)

Understudied Subgroups

“Low Risk” Subgroups

7

ACCF/AHA 2010: Measurement of hs-CRP

JACC 2010;56;2182-2199

8

NLA Recommendations

Initial Clinical AssessmentOn Treatment Management

Decisions

Journal of Clinical Lipidology 2011;5:338–367

9/18/2012

1

HDL: Should We AIM‐High or Not?or Not?

Robert A. Vogel, M.D., F.A.C.C.

Clinical Professor of Medicine

University of Colorado

Disclosures: None

Castelli WP, et al, JAMA 1986;256:2835

Framingham Heart Study: 4-Year CHD Risk in Men 50-70 Years Old by LDL-C and HDL-C

2

2.5

3

HDL-CRis

k

0

0.5

1

1.5

2

100 160 220

25456585

LDL-C

Rel

ativ

e C

HD

R

Barter P et al, NEJM 2007;356:1301

Cardiovascular Events in the TNT Trial by LDL and HDL Cholesterol

8%

10%

12%

E

0%

2%

4%

6%

LDL <70 LDL 70‐100 LDL >100

HDL <38HDL 38‐42HDL 43‐47HDL 48‐54HDL >54

Major CVE

9/18/2012

2

0 8

0.9

1

1.1

Voight BF et al, Lancet 2012

Genes Associated with Increased HDL‐C and Risk of MI in 20 Studies (N=116,303)

MI

Per 1mmol ↑HDL‐C

0.4

0.5

0.6

0.7

0.8

LIPG 396Ser 14 Common SNPs

Predicted

ObservedHR for

Endothelial lipase

Mackey RH et al, J Am Coll Cardiol 2012

MESA Study: Correlation of CHD Risk with HDL Particle Concentration (N=5598, 45‐84 yrs)

0.6

0.8

1

RF Corrected

0

0.2

0.4

HDL Cholesterol

HDL Particle Conc

LDL/HDL Particle Conc Correction

Virani SS et al (ACC 3/11)

Discrimination of Lipid + Other Parameters for Carotid Plaque in 1005 Retired NFL

Players

Rat

io 1.5

2

2.5P =NS P <0.05

P = NS

Odd

s R

0

0.5

1

LDL‐C

Non‐HDL‐C

LDL‐P

HDL‐C

HDL‐P CR

P

PLAC2

P = NS

9/18/2012

3

ApoA-I Milano: mean HDL-C = 17 mg/dl, CHD risk = 0%

Nissen SE et al, JAMA 2003;290:2292

Effect of 5 Weekly Infusions of ApoA-I Milano on IVUS Plaque Volume in 47 ACS Subjects

‐4%

‐2%

0%

‐6%Placebo Low Dose High Dose

Antiatherogenic Properties of HDL• Reverse cholesterol transport

• Prolongs half-life of prostacyclin (PGI2)

• Protects LDL-C from oxidation (some HDL)( )

• Decreases endothelial expression of cell adhesion molecules in response to cytokines (some HDL)

• Antithrombotic (some HDL)

Xia et al. J Biol Chem. 1999;274:33143-33147. Pirich, et al. Thromb Res 1997;88:41-49.

9/18/2012

4

Lifestyle Means for Increasing Lifestyle Means for Increasing HDLHDL--CC

Metaanalysis of 42 Trials• Alcohol (5-15%)

• Exercise (5-10%, 2 drinks per day = 10 miles jogged/week

• Weight loss (0.35mg/dl per ↓1kg)

Rimm EB, BMJ 1999;319:1523

• Tobacco cessation (4 mg/dl)

• MUFA

• Stopping androgen and progesterone

Metaanalysis of CHD Mortality in Fibrate Trials

HHS

VAHIT

BIP

DIASDIAS

LEADER

FIELD

Total

0.2 0.5 1 2 3Hazard Ratio

0.96

ACCORD Trial in High‐Risk Subjects with Type 2 Diabetes Mellitus

IntensiveGlycemicControl

5128

Lipid BP

Placebo Fibrate Intensive Standard

1383 1374 11931178Control

StandardGlycemicControl

5123

237123622753 2765

13911370 11781184

10,251

47335518

9/18/2012

5

ACCORD Trial in High‐Risk Subjects with Type 2 Diabetes Mellitus: Fenofibrate vs. Placebo

Comparison of ACCORD subgroup results with those from prior fibrate studies

Trial(Drug)

Primary Endpoint: Entire Cohort (P‐value)

Lipid Subgroup Criterion

Primary Endpoint: Subgroup

HHS (Gemfibrozil)‐34% (0.02)

TG > 200 mg/dlLDL‐C/HDL‐C > 5.0

‐71%5.0

BIP (Bezafibrate) ‐7.3% (0.24)

TG > 200 mg/dl‐39.5%

FIELD(Fenofibrate) ‐11% (0.16)

TG > 204 mg/dlHDL‐C < 42 mg/dl ‐27%

ACCORD(Fenofibrate) ‐8% (0.32)

TG > 204 mg/dlHDL‐C < 34 mg/dl ‐31%

Brown BG, et al. NEJM 2001;345:1583

HDL Atherosclerosis Treatment Study (HATS):Effect of Simvastatin + Niacin in 160 Subjects with Low

HDL

81012

Placebo

Simva/NiacinP<0.03

‐20246

HDL‐C %DS CVE's

Simva/Niacin

P<0.01

Δ Δ(mg/dl) (Death, MI, CVA, Revasc)

P<0.001

9/18/2012

6

NEJM 2011;365:2255

AIM‐HIGH Study: Niacin 1.5‐2.0g in 3414 Subjects with CHD and LDL‐C 40‐80 mg/dl

10%

15%

20%

25%

-20%

-15%

-10%

-5%

0%

5%

LDL-C HDL-C TG MACE

HDL and Reverse Cholesterol Transport

Nascent HDL HDL3 HDL2a HDL2b

A-I PL C A-I C PLCE A-II

LCAT LCAT A-I C PL

CE CE CE

A-I C PLCE CE CECE CE CE

LCAT

TG

Liver

Intestine

Extrahepatic

TissueABCA1

ABCG1

CETP

B/E Particle UptakeSR-B1

Liver

Chylo VLDL VLDL

LDLCE

TG

ILLUMINATE Study: Torcetrapib + Atorva vs. Atorva in 15,067 Subjects with CHD

(18 months of planned 5‐year study)

40%

60%

80%

ffect

‐40%

‐20%

0%

20%

40%

LDL HDL SBP CVE Death

Treatm

ent E

f

9/18/2012

7

Bhatt DL et al, AHA 11/10

DEFINE Trial: Anacetrapib (100mg) vs. Placebo in 1625 Subjects (55% prior CHD) over 76 Weeks

ange

(%) BUT: Dal‐Outcomes trial was

(‐) and showed no correlation between HDL‐C and CV risk

Rel

ativ

e C

h

P = 0.4 P = 0.048

Ballantyne CM et al, Circulation 1999;99:736

Effect of Statin Therapy on Coronary Events Depending upon Initial HDL‐C Level

25%

30%

35%

Statin

Pl b

0%

5%

10%

15%

20%

4S WOSCOPS AFCAPS

Placebo

HDL>51 HDL<39

HDL>42 HDL<42

HDL>39 HDL<35

CVE

Investigational HDL Agents

• ApoA-1 Milano• ApoA-1-mimetic peptides• Trimeric ApoA-1• HDL delipidation• Other CETP inhibitors• L-4F, D-4F peptides (4-Φala peptides)• Phospholipid mimetics

NOTES—

9/20/2012

1

Statins and Making Sense of the New FDA Labeling



No Disclosures

• FDA announced safety label change for statin medications raising concerns for:

• Cognitive impairmentg p• Increase blood sugar and hemoglobin

A1c (HbA1c)*

• Drug interactions (lovastatin specific)

*Does not include pravastatin

http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm 2

OVERALL SURVIVAL

atie

n ts

aliv

e

100

95Simvastatin

30%Placebo

4S: Total Mortality/Overall Survival 4S: Total Mortality/Overall Survival

ents

aliv

e

Adapted from Scandinavian Simvastatin Survival Study Group Lancet1994;344:1383-1389.

%of

pa 90

85

00 1 2 3 4 5 6

Years since randomization

30%risk reduction

P=0.0003

More people quit the placebo

than the statin

% p

atie

9/20/2012

2

Statins Reduce All-Cause Death: Meta-Analysis of 14 Trials

Cause of death

3.4 0.81

0.910.950 93

Vascular causes:

StrokeOther vascular

Any non CHD vascular

0.60.61 2 1 3

0.70.6

4.4

Events (%)Treatment

(n = 45,054)Control

(n = 45,002) Treatment better

Controlbetter

CHD

Cholesterol Treatment Trialists’ Collaboration

0.93

Any vascular

Any non-CHD vascular 1.2

4.7

2.40.20.11.13.8

8.5 9.7

4.01.20.10.32.4

5.7

1.3

Nonvascular causes:Cancer

Respiratory

0.83

1.010.820.890.870.95

0.88

TraumaOther/unknown

Any nonvascular

Any death

1.51.00.5

CTT Collaborators. Lancet. 2005;366:1267-1278.

Relative risk

All-Cause Death or Major CV Events in All Randomized Subjects

%

PravastatinPravastatin 40mg40mg(26.3%)(26.3%)

3030

2525

2020

00 33 1818 2121 2424 2727 303066 99 1212 1515

% with

Event

Months of Follow-up

AtorvastatinAtorvastatin 80mg80mg(22.4%)(22.4%)

16% RR16% RR(P = 0.005)(P = 0.005)

1515

1010

55

00

Cannon CP et al. NEJM 2004Cannon CP et al. NEJM 2004

2008: JUPITER

• Largest primary prevention trial to date– n = 17,802 men & women – Inclusion criteria

• no evidence CVDDM• no DM

• LDL <130 mg/dL• hs-CRP ≥2.0 mg/L

– Rosuvastatin 20 mg daily vs. placebo– Dx DM: physician report

Ridker, P.M. et al. N. Engl. J. Med. 359, 2195–2207 (2008). 6

9/20/2012

3

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901HR 0.56, 95% CI 0.46-0.69

P < 0.00001

- 44 %0.06

0.08

ence

Ridker et al NEJM 2008

Rosuvastatin 142 / 8901

0 1 2 3 40.00

0.02

0.04

Cum

ulat

ive

Inci

de

Follow-up (years)

Incident Diabetes in Jupiter

Ridker PM et al. Lancet 2012

Incident Diabetes in Jupiter

Ridker PM et al. Lancet 2012

9/20/2012

4

JUPITER: Outcomes

Ridker PM et al Lancet 2012

2008: JUPITER

• Increase in physician-reported new-onset diabetes by 26% over median of 1.9y– Rosuvastatin, n = 270 (3.0%)– Placebo n = 216 (2 4%)Placebo, n = 216 (2.4%)– OR 1.26 (95% CI 1.04-1.51)

11

2010 Meta-Analysis: Sattar et al.

• Statins associated with 9% increase in DM (95% CI 2-17%; I2 =11%)

Sattar, N. et al. Lancet 375, 735–742 (2010). 12

9/20/2012

5

2010: Sattar et al.

• Statins included:– Pravastatin

• WOSCOPS, LIPID, PROSPER, ALLHAT-LLT (all 40 mg)• MEGA (10-20 mg), GISSI PREVENZION (20 mg)

– Lovastatin• AFCAPS/TexCAPS (20-40 mg)

– Simvastatin• HPS (40 mg), 4S (20-40 mg)

– Atorvastatin• ASCOT-LLA (10 mg),

– Rosuvastatin• JUPITER (20 mg), CORONA (20 mg), GISSI HF (10 mg)

13

2010 Meta-Analysis: Sattar et al.

• Risk according to statin

n = 7,773

Sattar, N. et al. Lancet 375, 735–742 (2010). 14

n = 18,815

n = 24,714

n = 33,627

n = 6,211

2011 Meta-Analysis: Preiss et al.

Preiss, D. et al. JAMA 305, 2556–2564 (2011). 15

9/20/2012

6

2011: Preiss et al.

• Risks vs. benefits of intensive-dose therapy (compared with moderate-dose)– NNH

• DM = 498– NNT

• All CV events = 155• CV death = 1087• Non-fatal MI = 578• Non-fatal stroke = 1538• Revascularizations = 171

16

2011: Waters et al.

• Risk of new-onset DM increases with risk factors• Patients with metabolic syndrome most at risk for DM

while on statin

Waters, D.D. et al. J. Am. Coll. Cardiol. 57, 1535–1545 (2011). 17

Benefits of Statins

• Primary prevention– Reduction in total mortality, 12-17%– Reduction in CVD morbidity

• Coronary events 30%• Coronary events, ~30%• Strokes, ~20%• Revascularizations, ~33%

– Emphasis on high-risk patients

Minder, C.M. et al. Arch. Intern. Med. 171, 1593–1594 (2011).National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Circulation 106, 3143–3421 (2002).

18

9/20/2012

7

Take Home Message

• Statins are associated with new-onset DM, but are not a proven cause of DM

B fit f t ti ti t t i h• Benefits of statins continue to outweigh risks in properly selected, high-risk primary and secondary prevention populations

19

NOTES—

9/18/2012

1

What’s New in Hypertension:JNC‐8

Robert A. Vogel, M.D., F.A.C.C.li i l f f di iClinical Professor of MedicineUniversity of ColoradoDenver, Colorado, USA

Disclosures: None

How Should BP be Measured?

• Office, home, or ABPM?• What does BP variability mean?• Importance of SBP vs. DBP

Mansoor et al. J Hum Hypertens 1996;10:87

White‐Coat Hypertensive Response with Age

9/18/2012

2

240

200

160

Ambulatory BP in a 78 y.o. man

190/90re (m

mHg)

120

80

40

012:00 15:00 18:00 21:00 24:00 03:00 6:00 0 9:00

12:00TIME

150/80 No dipping

105/60

190/90

Bloo

d Pressu

SBP DBP

Dolan E,et al. HYPERTENSION 2005;46:156

Adjusted 5‐ year Risk of CV Death in 5292 Patients by Clinic and Ambulatory SBP

Rothwell, PM et al. Lancet 2011; 377:1681

The Relation Between Visit‐to‐Visit Variability in Systolic Blood Pressure and Risk of Subsequent Stroke in the UK‐TIA Trial

9/18/2012

3

Mortality Risk with Systolic Pressure at Fixed Diastolic Pressure

180/68

Staessen et al; Lancet, 2000

180/92

What are the BP Goals?

• Most patients: <140/90 (JNC 7, VA‐DoD)

• Diabetes: <130/80 (JNC 7)

<140/80 (VA DoD)<140/80 (VA‐DoD)

• CKD: <130/80 (JNC 7) <140/90 (VA‐DoD)

• CVD: <130/80 (AHA)

Vasan RS et al, NEJM 2001;345:1291

10‐Year CVEs in 6859 Framingham Heart Study Subjects Initially Free of HTN and CVD

130‐140 mmHg <120‐130 mmHg <120 mmHg

9/18/2012

4

Outcome Tight control (<130mmHg)

Usual control (130‐140 mmHg)

Uncontrolled (>140mmHg)

Death MI or stroke 12 7% 12 6% 19 8%

INVEST: Blood Pressure Control in 6400 Subjects with Type 2 Diabetes Mellitus

Death, MI, or stroke (primary end point)

12.7% 12.6% 19.8%

All‐cause mortality* 11.0% 10.2% 15.4%

Cooper‐DeHoff RM et al. JAMA 2010; 304:61‐68.

* Extended follow‐up: risk of all‐cause mortality was slightly higher in the tight‐control group vs. the usual‐control group (22.8% vs. 21.8%; adjusted HR 1.15; 95% CI 1.01‐1.32).

Systolic Blood Pressure (mmHg)

Incide

nce of Primary

Outcome (%

)

Diastolic Blood Pressure (mmHg)

Incide

nce of Primary

Outcome (%

)

Messerli F: Lower is better for the brain, kidney, and retina but not for the heart

Denardo SJ, et al. Am J Med 2010; 123:719

Death, MI or Stroke in 22, 576 Treated Hypertensives with CHD, age > 50 (INVEST Trial)

9/18/2012

5

How Should HTN be Treated?

JNC 7: Treatment Overview

Messerli F et al, JACC

Metaanalysis Antihypertensive Tx

‐6

‐4

‐2

0HCTZ ACE‐I ARB BB CCB

mHg)

‐16

‐14

‐12

‐10

‐8

6

SBP

DBP

Chan

ge BP (m

m

9/18/2012

6

Law et. BMJ 2009;338:b1665

CHD and Strokes in Drug Comparison Trials

Webb, AJS et al. Lancet 2010; 375:906‐915

Change in Coefficient of Variation in Systolic BP at Follow‐up Compared with Baseline

Am J Med 2009; 122:290‐300

Incremental Blood Pressure‐Lowering Effects of Adding A Drug or Doubling the Dose

(11,000 patients in 42 trials) Add a Different Drug Double Dose

9/18/2012

7

NICE /BHS HTN Guidelines

SBP

Step 1: 140‐160 ACE /ARB (<55y); CCB or Diur (>55y)

St 2 >160 ACE/ARB+CCB CCB+DiStep 2: >160 ACE/ARB+CCB or CCB+Diur

Step 3: ACE/ARB+CCB+Diur

Step 4: add: α‐B, BB, hydral, clon, minox

w/u: HTN, NSAIDS, OSA, renovasc

NOTES—

1

Physical Activity in the Primary Prevention of CVD





September 28-30

Disclosures related to this presentation: None

Outline

Physical activity and inactivity in the US

Observational data linking PA to CVD

Change in PA / Fitness and Outcomes

What can physicians / health care providers do?

2

Eating alone will not keep a man well; he must also take exercise….

And it is necessary, … to proportion exercise to bulk of food, to the constitution of the patient, to the age of the individual, to the season of the year, to the changes in the winds, (and) to the situation of the region in which the patient resides, ...

Hippocrates, 400 B.C.

Definitions Physical activity: A behavior that is any bodily movement

produced by the contraction of skeletal muscles that substantially increases energy expenditure.– Measurement difficult– Generally ascertained by self-report in large prospective studies

Physical inactivity: A behavioral state of not achieving, on a regular basis, a certain minimal common standard of physical activity.

Physical fitness: An attained set of attributes (i.e., cardiorespiratory endurance; flexibility; body composition; skeletal muscle endurance strength) that relates to the ability to perform physical activity.– Can be precisely measured– Strong inherited / familial component (30-50% of the variation in

cardiorespiratory fitness levels among untrained sedentary individuals can be explained by genetic and shared lifestyle factors)

Intensity of PA

Moderate PA (3-5.9 METS)

Brisk walking (≥3 mph)

Water aerobics

Bicycling (<10 mph)

Tennis (doubles)

Ballroom dancing

General gardening

Vigorous PA (≥6 METS)

Race-walking, jogging, or running

Swimming laps

Tennis (singles)

Aerobic dancing

Bicycling (≥10 mph)

Jumping rope

Heavy gardening

Hiking uphill or with heavy backpack

www.health.gove/paguidelines

3

Are We Meeting PA Goals?2007 Prevalence

"Healthy People 2010" objectives

– Moderate PA at least 5 days a week for 30 min a day

OR

– Vigorous PA at least 3 days a week for 20 min a day

http://apps.nccd.cdc.gov/PASurveillance/StateSumV.asp?Year=2007[3/11/2012 5:45:38 PM]

Prevalence of Physical Inactivity 2008

CDC website, accessed 3/11/2012

Benefits of PA

Focus on

Mortality

CHD / CVD

www.health.gov/paguidelines

4

MI in London Busmen 1949-1958

Morris JN, Heady JA, Raffle PAB, Roberts CG, Parks JN.

Coronary heart disease and physical activity at work.

Lancet 1953;ii:1053-1057 and 1111-1120

Paffenbarger RS,Jr et al. Int J Epidemiol. 2001; 30(5):1184-92

Physical Fitness and All Cause MortalityCooper Clinic: 10,224 men, 3,120 women; F/U 8 years

Blair SN et al. JAMA 1989;262:2395-2401

Q1=lowest fitness quintile, Q5=highest fitness quintile

Cardiorespiratory Fitness and All Cause Mortality

33 studies

102,980 participants

Age 37-51 y

6,910 deaths

F/U 1.1-26 y

Kodama et al. JAMA. 2009;301:2024-2035

Summary RR: 0.87 (0.84-0.90)

RR per 1 MET higher max. physical capacity

5

ObeseNormal Weight

Fit vs. Fat: CVD Mortality in the Nurses’ Health Study

Ris

k fo

r D

eath

Hu FB et al. N Engl J Med 2004;351:2694-2703 Slide modified from www.lipids.online.org

1.9

2.5

4.7

1.5

2.1

4.3

1.0

1.6

2.9

Physical Activity(hours/week)

<1.0 1.0–3.4 3.5

Overweight

Walking and CV Events

Hazard Ratio0.69 (0.61-0.77)

Hamer Br J Sports Med 2008;42:238–243

Men

Women

Walking and All Cause Mortality

Hamer Br J Sports Med 2008;42:238–243

Hazard Ratio0.68 (0.59-0.78)

Men

Women

6

Unfit–Fit Fit–FitUnfit–Unfit

Changes in Physical Fitness and CVD Mortality: Aerobic Center Longitudinal Study

Blair SN et al. JAMA 1995;273:1093-1098 (adapted from www.lipidsonline)

Mo

rta

lity

Ra

te

87 deaths in 9,777 men

4.9 years between exams

Fitness at Two Exams

65.0

31.4

14.2

* Lifestyle: achieve/maintain ≥7% reduction of initial body weight via diet + moderate-intensity physical activity (≥150 minutes/week)

DPP: Benefit of Diet & Exercise or Metformin on Diabetes Prevention

DPP Research Group. NEJM 2002;346:393-403

Year

N = 3234 with IFG and IGTwithout diabetes

0

0

10

20

30

40

1 2 3 4

Placebo

Metformin

Lifestyle*Cumulativeincidence of

diabetes(%)

31%

58%

P(vs. placebo)

<0.001

<0.001

Weight DecreaseLoss in Risk0.2 lbs4.6 lbs - 31%12.3 lbs - 58%

Look AHEAD4 Year Results

Weight

Fitness

Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575

NIDDK RCT in Type II DM 16 clinical centers N = 5,145

– 1st pt randomized: 8/01– Recruitment complete: 4/04

Compares– Intensive Lifestyle

Intervention (ILI)– Diabetes Support and

Education (DSE) 1o EP: CV Morb & Mort Planned F/U of 13.5 y to

12/31/14

7

2008 PA Guidelines Some PA is better than none

Substantial Health Benefits:– ≥ 150 min (2.5 hrs) a week of moderate-

intensity PA or – ≥ 75 min/week of vigorous-intensity PA or– equivalent combination of moderate and

vigorous aerobic PA– Should be performed in bouts of ≥10 min– Should be spread throughout the week.

Additional Health Benefits:– Increase aerobic PA to 300 min (5 hrs) a

week of moderate-intensity– or 150 min/week of vigorous-intensity

aerobic physical activity– or equivalent combination of moderate-

and vigorous-intensity PA.

Muscle-Strengthening Activities– Moderate or high intensity– Involve all major muscle groups– 2 or more days a week.

What can health care providers do?

National Physical Activity Plan, 2010

Images from Google, downloaded 3/11/2012

9/18/2012

1

Resistant HypertensionRobert A. Vogel, M.D., F.A.C.C.Clinical Professor of Medicine

University of ColoradoDenver, Colorado, USA

Disclosures: None

Definition of Resistant Hypertension

• Blood pressure above goal on:Blood pressure above goal on:• Optimal dose of >3 anti-HTN

drugs of different classes,• Including >1 diuretic

What are the BP Goals?• Most patients: <140/90 (JNC 7, VA-DoD)• Diabetes: <130/80 (JNC 7)

<140/80 (VA DoD)<140/80 (VA-DoD)• CKD: <130/80 (JNC 7)

<140/90 (VA-DoD)• CVD: <130/80 (AHA)

9/18/2012

2

Messerli F et al, JACC (in press)

Metaanalysis of BP Reductions Achieved by Classes of Drug

6

‐4

‐2

0HCTZ ACE‐I ARB BB CCB

mH

g)

‐16

‐14

‐12

‐10

‐8

‐6

SBP

DBP

Cha

nge

BP

(mm

Mean decrease = 12/8

Efficacy of Antihypertensive Therapy

Staessen et al; Lancet, 2000

9/18/2012

3

Resistant HTN ≠ Uncontrolled HTN

- 40-50% hypertensive patients need > 3 meds

- 20-25% of hypertensive patients are resistant

- 50% are uncontrolled

Questions to Ask if BP is above Goal

• Was BP measured correctly (cuff size, calcified arteries, pre-measurement rest period)?

• Does this patient have white-coat HTN?• Is this patient taking his/her meds?• Am I prescribing the right meds and doses?• Does this patient take substances or have

conditions that prevent effective treatment?• Is this patient restricting salt and trying to lose

weight?

Substances Causing Resistant Hypertension

• NSAIDS• Sympathomimetics (e.g. decongestives)•Oral contraceptives• Adrenal steroids

E th iti• Erythropoeitin• Cyclosporin and tacrolimus• Licorice• Herbals (e.g. ginsend, yohimbine, ma huang,

bitter orange• Alcohol• Excess salt

9/18/2012

4

Conditions Causing Resistant Hypertension

• Older age• Obesity• DM• OSAOSA• CKD• Renal artery stenosis• Cushing’s syndrome• Primary aldosteronism• Pheochromocytoma• Aortic coarctation

NICE /BHS HTN Guidelines

SBP

Step 1: 140‐160 ACE /ARB (<55y); CCB or Diur (>55y)

St 2 >160 ACE/ARB+CCB CCB+DiStep 2: >160 ACE/ARB+CCB or CCB+Diur

Step 3: ACE/ARB+CCB+Diur

Step 4: add: α‐B, BB, hydral, clon, minox

w/u: HTN, NSAIDS, OSA, renovasc

Third Drug Must be a Diuretic!!!• Expanded blood volume underlies most resistant HTN

• Start with hydrochlorothiazide 25mg

• Change to clorthalidone 25mg (MSBP↓ 5/8 mmHg)*

• Add amiloride 2.5mg (BP↓ 31/15 mmHg, monitor K+)

• Change to a loop diuretic (furosemide→torsemide)

(furosemide BP↓32/11 c/w standard regimen)

• Add spironolactone 12.5-50mg (BP↓ 25/12 mmHg c/w

standard regimen including diuretic)

Calhoun DA et al. Circulation 2008;51:1403 *c/w HCTZ 50mg **HCTZ 25mg

9/18/2012

5

Final Drugs to be Added in Resistant Hypertension

(pt on ACE/ARB + CCB + Diuretic)

• β-Blocker: carvedilol, labetolol, nibevolol• Hydralazine (reflex sympathetic

stimulation)• Clonidine (withdrawal HTN)• α-Blocker (e.g. prazosin, doxazosin

(↑CHF in ALLHAT))• Minoxidil (fluid retention)

Grobbee et al, Br Med J 1986;293:27

Metaanalysis of the Effect of Salt Restriction on Blood Pressure

Appel et al, NEJM 1997

DASH Trial: Effect of Diet on Blood Pressure

Decrease = 7/4 mmHg

9/18/2012

6

Stevens VJ et al, Ann Intern Med 2001;134:1

Weight Loss and BP in 1191 Overweight (110-165% Ideal) Subjects with High Normal BP

Sustained weight loss (4.4kg) = 8/6 mmHg

Renal Artery Denervation

Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A scientific statement from the American Heart Association Professional

AHA Scientific Statement

Circulation 2008 Jun 24;117(25):e510-26.

Education Committee of the Council for High Blood Pressure Research

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM

1

Calcium and Vitamin D Supplements: Friend or Foe to the

HeartVera Bittner, MD, MSPH

Professor of Medicine

Section Head, Preventive Cardiology



September 28-30


Vitamin D and Calcium Metabolism, Reference Intakes,

Definition of Deficiency

2

Vitamin DStructure

Hollick MF. NEJM 2007;357:266-81and Ann Epidemiol 2009;19:73–78

Vit D3- In milk and OJ

- UV irradiation of 7-dehydrocholesterol from lanolin

Vit D2- Most supplements

- UV irradiation of ergosterol from yeast

Metabolism

25(OH)D = 25-hydroxyvitamin D

1,25(OH)2D = 1,25 dihydroxyvitamin D

LPS = lipopolysaccharide

PTH = parathyroid hormone

TLR = toll like receptor

VDR = vitamin D receptor

Hollick MF. NEJM 2007;357:266-81and Ann Epidemiol 2009;19:73–78

Dietary Reference Intakes for Vit D and Calcium

IOM Report Brief 2010http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx

3

How Much Dietary* Vit D Do We Get?Data from NHANES 1988-1994

Females

Males

Yetley E Am J Clin Nutr 2008; 88(suppl):558S-64S*Includes supplements; general MVI use in NHANES 99-00:NH White 40% > NH Blacks 23% > Mex Am 20%

Determination of Vitamin D Status 25(OH)D is the major circulating form of Vit D

Half life: 2–3 weeks

25(OH)D = Σ Vit D intake and Vit D produced from sun exposure

25(OH)D is the only Vit D metabolite that is used to determine whether a patient is Vit D deficient, sufficient or intoxicated (no need to differentiate between D2 and D3)

Hollick MF. NEJM 2007;357:266-81 and Ann Epidemiol 2009;19:73–78

How is “Normal” Defined?

Observational data: serum PTH values begin to increase with 25(OH)D concentrations <29.8 ng/ml

Supplementation studies show little decrease in PTH after 25(OH)D is above 20 ng/ml

Holick MF. J ClinEndocrinol Metab 2005;90:210

4

Why Not Measure 1,25(OH)2 Vit D? Short half-life (4-6 hours)

Concentration 1000-fold lower than 25(OH) Vitamin D

Vit D deficiency lower ionized calcium increased PTH 1,25 hydroxylase in kidney is UPREGULATED in Vit D deficiency 1,25(OH)2 measurement may mask Vit D deficiency

Only useful in diagnosing inherited and acquired disorders of Vit D metabolism

Hollick MF. NEJM 2007;357:266-81 and Ann Epidemiol 2009;19:73–78

Prevalence and Common Causes of Low Vit D

Prevalence Estimates of Vit D Deficiency or Insufficiency

1 billion people worldwide

40-100% of elderly US men and women living in the community

>50% of women taking medications for osteoporosis

40-50% adolescents

32% healthy students, attendings, residents in a Boston hospital

70-80% of pregnant women and their infants

93% of ED patients with muscle and bone pain

…

Hollick MF. NEJM 2007;357:266-81

5

Causes of Vit D Deficiency Decreased skin synthesis

– Aging / SPF / Skin pigment / Northern Latitude Obesity Sequestration Malabsorption Liver dysfunction

– Decreased hydroxylation CKD

– Decreased hydroxylation Nephrotic syndrome

– Urinary loss Increased catabolism

– HAART, glucocorticoids, anticonvulsants, anti-rejection medications, hyperthyroidism, …


Potential Links To Disease

Rickets

http://www.univie.ac.at/cga/art/rickets.JPG

6

Reported Musculoskeletal Benefits of Vit DWHI Ca plus D RCT

– Reduced hip fracture HR 0.71 (0.52-0.97)– BUT: Increased kidney stones HR 1.17 (1.02-0.97)

Swiss Trial of Institutionalized Elderly– Improved muscle strength with supplementation in

122 elderly women (p<0.01)– 49% reduction in falls (p<0.01)

Vit D and Statin Myalgia– Resolution of myalgia in 35/38 vitamin D deficient

patients who received supplements– No control group

Jackson et al. NEJM 2006;354:669-83Bischoff H et al. J Bone Miner Res 2003;18:343–351Ahmed et al. Translational Research 2009;153:11-16

TNT: No Relationship Between Vitamin D and Myalgia

Posthoc Substudy of TNT Trial

N=1,509 CHD patients

Atorva 10 mg vs. Atorva 80 mg daily

Vit D levels at baseline

Median F/U 4.9 years

Bittner V et al. ACC Poster presentation 3/2010, Atlanta, GA

Normal Vit D

Deficient Vit D

P-value

Incidence of myalgia (n,%)

95 (12.2%)

61 (8.3%)

NS

Discontinuation due to myalgia(n,%)

9(1.1%)

10(1.3%)

NS

Baseline Vitamin D and Myalgia

Low 25(OH) Vitamin D has been Linked to Many Non-Skeletal Diseases …

CVD and total mortality

Hypertension

Obesity

Diabetes mellitus

Metabolic syndrome

Multiple sclerosis

Breast, colon, prostate cancer

Immune disorders (Crohn’s, RA, …)


7

Potential Mechanisms: Vit D and CVD Inhibition of vascular smooth muscle

cell proliferation

Suppression of vascular calcification

Downregulation of proinflammatory cytokines

Up-regulation of anti-inflammatory cytokines

Negative endocrine regulator of the renin-angiotensin system


Potential Mechanisms Linking Calcium to CVD

Wang et al Am J Cardiovasc Drugs 2012; doi: 10.2165

Effect on HTN, DM, CACProspective Observational Data

8

Vit D Levels Predict Incident HTN 613 men from the Health Professionals’ Follow-Up Study

1198 women from the Nurses’ Health Study

F/U 4-8 years

Forman et al Hypertension 2007;49:1063-1069

Measured 25(OH)D in ng/ml≥30 15-29 <15

Men

Person-Years 865 1295 122

# of cases 22 33 6

RR (95% CI) 1.0 1.12 (0.51-2.48) 6.13 (1.0-37.8)

Women

Person-Years 2207 2317 335

# of cases 58 60 11

RR (95% CI) 1.0 0.85 (0.53-1.34) 2.67 (1.05-6.79)

Model adjusted for age, BMI, physical activity, race, menopausal status

Vit D, Calcium and Incident DM Nurses Health Study

N = 83,779 women without DM

F/U 20 y – n = 4,843 with incident DM

Multivariate adjusted risks by quartile

Highest vs. lowest Vit D intake (suppl)– Adj. RR 0.87 (0.75–1.00)

Highest vs. lowest calcium intake– Adj. RR 0.82 (0.72–0.92)

<600 mg / <400 IU vs >1200 mg / >800 IU– Adj. RR 0.67 (0.49–0.9)

Pittas et al. Diabetes Care 2006;29:650–656

Vit D Predicts Incident CAC Multi-Ethnic Study of Athero (MESA)

– N = 1,370 (46% men), no CVD

– Mean age: 64 y; F/U 3 years

CAC data:– 53% had CAC at baseline

– 21% developed de novo CAC

25(OH) Vit D concentration:– mean 21.4±11.3 ng/ml

– 27% had level <15 ng/ml

No relation to prevalent CAC

Incident CAC per 10 ng/ml change:– RR (adj.) 1.23 (1.00-1.52), p = 0.049

deBoer et al. JASN 2009;20:1805-812

9

Effects on CV Events and Mortality

Prospective Observational Data

Vitamin D and MI in MenThe Health Professionals F/U Study

N = 51,529 men

Age 40-75 yo in 1986

N = 18,225 provided sample in 1993-95

477 MI by 2004

Matched for other risk factors including lipids

P for trend 0.02

Rel

ativ

e R

isk

of M

I

Serum Vitamin D (ng/ml)Giovanucci. Arch IM 2008; 168(11):1174-1180

Low Vit D: CV and All Cause Mortality LURIC Study

Latitude 49o 29’

N = 3,258– Adm. for cath

– 70% men

– Mean age 62

F/U 7.7 years

Deaths:– 737 died (22.6%)

– 463 CV deaths

Dobnig et al. Arch IM 2008;168:1340-1349

HR 2.08 [95% CI 1.60-2.70] HR 2.22 [95% CI 1.57-3.13]

10

Low Vit D: Increased Mortality NHANES 1988-94

Median F/U 8.7 y

N=13,331

1,806 deaths– CVD 777 (43%)

– Cancer 424 (23%)

Melamed et al. Arch IM 2008;168:1629-1637

Mortality Q4 (>32.1 ng/ml) Q1 (<17.8 ng/ml)All Cause* 1 1.26 (1.08-1.46)

CVD 1 1.20 (0.87-1.64)

Cancer 1 0.91 (0.63-1.31)

Infectious Disease 1 0.84 (0.38-1.86)

TNT: No Relationship Between Vit D and CV Outcomes

Posthoc Substudy

N=1,509 CHD patients

Atorva 10 mg vs. Atorva 80 mg daily

Vit D levels at baseline• Deficient <15 ng/ml

• Insufficient 15-<30 ng/ml

Median F/U 4.9 years

Bittner V et al. AHJ 2012;164:387-93

Dietary CaIntake and CV Risk

Meta-analysis of Prospective Cohort Studies

Wang et al Am J Cardiovasc Drugs 2012; doi: 10.2165

CAD

Stroke

11

How You Get Your Calcium May MatterHeidelberg EPIC Cohort European Prospective

Investigation into Cancer and Nutrition

N = 23,980 Age 35-64 y Free of major CVD events Average F/U 11 years Multivariate Cox regression

models (HR and 95% CI)Supplements

Dairy Calcium

Li et alHeart 2012;98:920-925

Clinical Trials

Meta-Analysis: Vit D Supplementation and Total Mortality

18 RCT; 4,777 deaths; F/U 5.7 years

Autier et al. Arch IM 2007;167:1730-1737

12

WHI RCT: No Decrease in CV Events N = 36,282 PMP

women

Age 50-79 years

Randomized to – Ca 500 mg + D3 200 IU

taken BID

– vs. Placebo BID

F/U 7 years– Poor adherence: 60%

took ≥80% of tabs at end of trial

Some favorable intermediate endpoints– 2.6% lower LDL-C

– 0.3% lower waist and weight (less weight gain)

– BUT: 0.4% higher BP

MI or CHD death– HR 1.04 (95% CI 0.92-1.18)

Stroke– HR 0.95 (95% CI 0.82-1.10)

Hsia et al. Circulation 2007; 115:846-854

Meta-Analysis: Ca Supplementation andCV Events 5 trials with patient level

data, 11 with trial level data– Estimates for CV outcomes

similar

Age >40 y, duration >1 y

Type and dose of Casupplement variable, no Vit D

Median F/U 3.6-4 years

No trials designed specifically for CV endpoints

Bolland et al. BMJ 2010;341:c3691

Why the Discrepancy Between Observational and Interventional Data? Confounding by

healthier lifestyles

Publication bias against negative studies

Over-reliance on 2o rather than 1o prevention

Etiologic period not captured

Insufficient length of intervention and F/U

Inappropriate supplement doses

Unsuitable cohorts for testing the hypothesis

Importance of genotypic differences

Alice H. Lichtenstein, MD

J Lipid Res 2009;50:S429-433

13

My Conclusions Vitamin D deficiency is common Vitamin D intake and calcium intake tend to be

below recommended levels There are many good reasons to treat vitamin D

deficiency or recommend higher calcium intake

BUT

It is unclear whether systematic treatment of vitamin D deficiency will prevent atherosclerosis, cardiovascular events and improve mortality

More studies are needed on the cardiovascular and mortality effects of calcium supplementation opposed to dietary calcium intake

“Hope springs eternal that a single or combination nutrient supplement will be identified to dramatically reduce CVD risk and will require no more dietary restraint or physical exertion than the quick sideward twist of the wrist (open container) and front hand bend (insert pill in mouth).”

Alice H. Lichtenstein, MDJ Lipid Res 2009;50:S429-433

9/18/2012

1

Predicting CVD Risk: Biomarkers vs. Imaging

Robert A Vogel M DRobert A. Vogel, M.D. Clinical Professor of Medicine

University of Colorado

Disclosures: NFL Consultant

Benjamin EJ et al, JACC 2010

ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults

Class I Class llA Class IIB

Risk Score ECG (HTN & DM) Hgb-A1C

F il Hi t Mi lb (HTN & DM) Mi lb ( th )Family History Microalb (HTN & DM) Microalb (others)

CRP (>50/60, LDL<130) CRP (int risk)

CAC (10-20% risk) CAC (6-10% risk)

CIMT (int risk) LpPLA2

ABI (int risk)

Ridker PM et al, N Engl J Med 2002;347:1557

Framingham Estimate vs. Actual CHD Risk in the Women’s Health Study

nts

FRS includes: age, gender, SBP, TC, HDL, DM, smoking

CH

D E

ve

Framingham Estimate of 10-Year Risk

FRS excludes:family historyethnic bkgdobesityinsulin sensregional risk

9/18/2012

2

Leber A et al, Am Heart J 2008;155:154: Ballantyne CM et al. Circulation. 2004;109:837 ; Roman MJ et al, Circulation2004;110:III-798; Folsom AR et al, Arch Intern Med 2008;168:1333; Ridker PM et al, NEJM 2002;347:1557

Discrimination Value of Non-Framingham Risk Factors in Healthy Subjects: Dichotomous Analysis

4

5

6

7

D E

vent

s

Very good

0

1

2

3

4

Lp PLA2

CIMT CRP Fm History

Carotid Plaque

CAC >75%

HR

for C

HD

Good

Poor

Reynolds Risk Index: Which adds more: Family History of CHD or CRP?

55 yo maleRis

k

55 yo male nonsmoker TC 210, HDL 45, SBP 140 7% 11% 8% 14%10

-Yr C

HD

Ridker PM et al, Am J Cardiol 2010;106:204

JUPITER Trial: Decrease in CVE with Rosuvastatin vs. Placebo According to Baseline CRP

0 60.70.80.9

1

suva vs. Pbo

ed

↓60% ↓38% ↓39%

00.10.20.30.40.50.6

CRP <2 CRP 2.0-3.6 CRP 3.6-6.3 CRP >6.3

Relative Risk Ro

s

Unteste

9/18/2012

3

Blankstein R et al, JACC 2011;58:364

MESA Study: CAC Score and CIMT vs. CHD Events in 5627 Asymptomatic Subjects with LDL-C <130

000

Pt Y

ears

CAC Score CIMT

CH

D E

vent

s / 1

Arad Y et al, J Am Coll Cardiol 2005;46:158

St. Francis Heart Study: CHD Events in 4,613 Asymptomatic Subjects 50-70 Years Old by

CAC and Framingham Risk

25%30%35%40%

Agatston Score10

0%5%

10%15%20%25%

<10% 10-20% >20%

01--75>75

CH

D E

vent

s /

Year

s

Framingham 10-Year CHD Risk

Intermediate Risk

12:1 discrimination

Nasir K et al, J Am Coll Cardiol

Ethnic Differences in the 10-Year Prognostic Value of CAC for Death in

14,812 Subjects Referred for Screening

50

600-1011-100101-400

CAC Score

e

an

ic

n

0

10

20

30

40

CAC >100 White AA Hispanic Asian

401-1000>1000

(% Subjects) Relative Risk of Death by CAC Score

Whi

teA

A

His

paAs

ian

9/18/2012

4

Raggi P et al, ATVB 2004;24:1272

MI-free Survival in 495 Subjects on Statins by 2-Year CAC Progression

<15% change

>15% change

Roman MJ et al, Circulation 2004;110:III-798, O’Leary DH et al, NEJM 1999;340:14

CIMT and Carotid Plaque for Assessing CVD Risk in 5858 Subjects >65 Years Old

R fo

r CVD

Adju

sted

HR

Fowkes FG et al, JAMA 2008;300:197

CV Mortality and ABI: Metaanalysis of 16 Studies with 480,00 Person‐year Follow‐up

8

4

CV Mortality vs. ABI

2

1

.5

<0.6 0.6‐.7 0.7‐.8 0.8‐.9 0.9‐1 1‐1.1 1.1‐1.2 1.2‐1.3 1.3‐1.4 >1.4

NEW ABNORMAL RANGE

9/18/2012

5

Gender: MaleFemale

Diabetes: YesNo

Subgroups # Studies Risk RR (95% CI) p

Meta-analysis of Proteinuria and CV Risk in 26 Studies (169,949 Subjects)

Level of Micro*Albumin: Macro**

Adjust: Age, SexMultiple

•30-300 mg/d•>300 Mg/d

Risk Ratio (95% CI)Verdon PV et al, PLoS Med 2008;5:e207

Studies Evaluating Association of Lp-PLA2 with Incident CHD

HR 1 78 tertile 3 vsGeneral populationBallantyne

RR 1.18 per 1 SD ↑WOSCOPS subgroup 580 cases, 1160 controls

Packard et al

Findings*SubjectsStudy

HR 1.23 per 1 SD ↑General population97 cases, 837 controls

Koenig et al

HR 1.97 4th vs 1st quartile

General population418 cases, 1820 controls

Oei et al

HR 1.78 tertile 3 vs. tertile 1

General population608 cases, 740 controls

Ballantyne et al

*Adjusted relative risk (RR) or hazard ratio (HR)

Packard CJ et al. N Engl J Med. 2000;343:1148-55.Ballantyne CM et al. Circulation. 2004;109:837-42.

Koenig W et al. Circulation. 2004;110:1903-8.Oei H-HS et al. Circulation. 2005;111:570-5.

Virani SS et al (ACC 3/11)

Discrimination of Lipid + Other Parameters for Carotid Plaque in 1005 Retired NFL Players

Rat

io 1.5

2

2.5P =NS P <0.05

P = NS

Odd

s R

0

0.5

1

LDL‐C

Non‐HDL‐C

LDL‐P

HDL‐C

HDL‐P CR

P

PLAC2

P = NS

9/18/2012

6

Screening of 55 Former NFL Players

• Age: 53 years

• LDL‐C >160 mg/dl: 5%

• SBP >160 mmHg: 15%

• CAC: >400: 15% >1000: 7%• CAC: >400: 15%, >1000: 7%

• Carotid plaque: 7%

• Dilated aorta: 4%

• Lung mass: 9%

Boone J

Circulating Micro‐RNAs and Risk of MIJ Am Coll Cardiol. 2012;60(4):290‐299. doi:10.1016/j.jacc.2012.03.056

Figure Legend:

FRS + Fm Hx

Low Risk Interm Risk High Risk

1o Prevention Risk Assessment:Summary

Low Risk Interm Risk High RiskCAC ScoreABI (Smoker) ABI (DM)Carotid US

Updates on CVD Prevention Guidelines in Women Laxmi Mehta, MD

1

Cardiac Rehab in 2012





September 28-30


Cardiac Rehab:Definition, Components,

Indications

2

“The term cardiac rehabilitation refers to coordinated, multifaceted interventions designed to optimize a cardiac patient’s physical, psychological, and social functioning, in addition to stabilizing, slowing, or even reversing the progression of the underlying atherosclerotic processes, thereby reducing morbidity and mortality.”

Balady et al. Circulation 2000;102:1069 –1073

What Is Cardiac Rehabilitation?

AHA/AACVPR Scientific Statement 2007: Core Components of CR

Patient assessment and treatment plan

Nutritional Counseling and Weight Management

Blood Pressure Management

Lipid Management

Diabetes Management

Tobacco Cessation

Psychosocial Management

Physical Activity Counseling Exercise Training

Balady et al. Circulation 2007;115:2675-2682

Referral to CR is a Class I Recommendation in AHA/ACC Guidelines

STEMI Guideline

CABG Guideline

PCI Guideline

Secondary Prevention Guideline

Women and CVD Guideline

UA/NSTEMI Guideline

…

3

CMS has expanded CR Eligibility*Before 2006Eligible

S/P MI

S/P CABG

Stable Angina

Not Eligible

S/P PTCA

Heart Failure

S/P Cardiac Tx

Since 2006Eligible

S/P MI / ACS

S/P CABG

S/P PCI

Stable Angina

S/P Valve Surgery

S/P Cardiac Tx

Not Eligible

Heart Failure*As defined by CMS

Outcome Domains in CRAACVPR Consensus Statement 2004

Behavioral– Physical activity, diet habits, smoking, stress

management techniques

Clinical– Functional capacity, lipid levels, blood pressure,

hemoglobin A1C, BMI, depression screen

Health– Morbidity and mortality– “Patient centered”: health status, health-related QOL

Service– Utilization rates, costs, patient and staff satisfaction

Sanderson et al. JCRP 2004;24:68-79

Cardiac Rehab: Morbidity and Mortality

4

Cochrane Review of RCTsMeta-analysis of RCT’s with >6 m F/U

– Before 1990: 40% / 1990’s: 43% / Since 2000: 17% N = 8,940 patients in 48 trials

– Age range 48-71 years (median 55 years)– 20% women, few minorities– Patients generally “low risk”

Taylor et al. Am J Med. 2004;116:682– 692

OR 95% CI P-valueTotal mortality 0.80 0.68 – 0.93 0.005

Cardiac mortality 0.74 0.61 – 0.96 0.002

Non-fatal MI 0.79 0.59 – 1.09 0.15

CABG 0.87 0.65 – 1.06 0.3

PCI 0.81 0.49 – 1.34 0.4

Cochrane Review of RCTs: Update 2011Meta-analysis of RCT’s with >6 m F/U N = 10,794 patients in 47 trials

– Age range 46-84 years; generally “low risk”– 20% women, few minorities– Considerable loss to F/U or drop out (33/47 studies had

>80% F/U) F/U time is important:

Heran BS et al. Cochrane Library 2011, Issue 8

RR6-12 m

95% CI RR>12 m

95% CI

Total mortality 0.82 0.67 – 1.01 0.87 0.75 – 0.99

CV mortality 0.93 0.71 – 1.21 0.74 0.63 – 0.87

Hospital Admission

0.69 0.51 – 0.93 0.69 0.87 – 1.11

CR Prevents MIMeta-analysis of 63 Secondary Prevention RCT’s Results comparable in different settings

– Group vs individual– Comprehensive CR– Exercise only– Risk factor counseling / education without exercise

Clark et al. Ann Int Med 2005;143:659-672

OR 95% CI

Total mortality 0.85 0.77 – 0.94

Myocardial infarction 0.83 0.74 – 0.94

5

Are Prior Clinical Trial Data Applicable? Different demographics

– Older, women, minorities

Different acute MI treatment– Revascularization / lytics

More NSTEMI than STEMI

Different “secondary prevention” medications– ASA, Plavix, BB, ACE-I, statin

Shorter time from event to enrollment

Worse LV function

More co-morbidities– DM, obesity, CKD, arthritis, ….

CR Outcomes: Observational Data

Trials not ethical– Few subgroups with “equipoise” (e.g. HF ACTION)

Observational data = real life data

Can be continuously monitored

BUT

Data subject to bias and confounding

Methods to overcome these:– Propensity matching

– Multivariable regression modeling

– Use of instrumental variables

CR Use and Mortality N = 601,099 Medicare Beneficiaries

Propensity matched mortality analysis (70,040 matched pairs)

F/U for mortality 1-5 years

12% participated

24 ± 12.4 sessions

Use vs Non-use:

5 y RRR -34%

More vs less:

5 y RRR -19%

Suaya JA et al. JACC 2009;54:25–33

6

Dose Matters Sample of Medicare

Claims Data 2000-2005

All patients who attended at least 1 CR session– Mean age 74, 64% men,

95% white

– 61% post CABG, 21% post MI, 15% stable angina

Outcomes: Death; MI– Analyses adjusted for

demographics and co-morbidities

Hammill et al. Circ 2010;121:63-70

Mortality

1-11

12-23

36+

Mortality by Propensity to Participate in CRData from Olmsted County

-78%

-72%-67% -63%

Population attributable risk = proportion of deaths attributable to non-participation in CRQuartile 1- 0.29 / Quartile 2 - 0.28 / Quartile 3 - 0.17 / Quartile 4 - 0.17

Witt et al. JACC 2004;44:988-996

CR and the Decline in CHD Mortality: USA 1980 - 2000

US Adults age 25-84 years 341,745 fewer CHD deaths in 2000 than in 1980

– >50% decline in age-adjusted death rates for men and women

47% of decrease attributed to treatments, 44% to decline in risk factors

Estimated Impact of CR:– 4,650 fewer deaths after MI in 2000 (participation rate 21%)– 1,655 fewer deaths after CABG or PCI in 2000 (participation

rate 32%)– Risk reduction comparable to post-event ASA, BB, ACE-I,

statin, warfarin– Risk reduction comparable to acute thrombolysis and

revascularization

Ford ES et al. NEJM 2007;356:2388-98

7

CR UtilizationReferral Enrollment Adherence

Low Referral Rates in GWTG Hospitals 72,817 CR-eligible patients discharged between 1/00 and 9/07

Overall referral rate: 56%

Wide variation between hospitals -<20% referral rate in >1/3 hospitals

CR utilization is much lower than other 2o prevention measures

Referral Rates by Hospital

Brown TM et al. JACC 2009;54:515-521

Low Enrollment in Medicare Patients N=267,427 Medicare patients

– S/P MI or CABG 1997– Survived ≥30 days post D/C

Negative predictors of CR:– Older age– Women– Nonwhites– Co-morbidities (incl. HF,

previous stroke, DM, cancer)

Positive predictors of CR:– CABG– Higher household income– Higher level of education– Shorter distance to the

nearest CR facility 9-fold variation among States

– Idaho 6.6% Nebraska 53.5%– Average 18.7%Suaya et al. Circulation 2007;116 – www.americanheart.org

Overall CR use– S/P MI: 13.9% / S/P CABG: 31%

8

Low CR Attendance Rates in the Medicare Population

≈50% attended >24 sessions18% attended 36 sessions

Hammill et al. Circ 2010;121:63-70

Factors Associated with Failure to Complete CR

Non-MedicalAOR (95% CI)

MedicalAOR (95% CI)

Gender (female) 0.6 (0.38-0.99)

Working 2.1 (1.09-4.00)

High risk 4.2 (1.37-13.03)

Diabetes 0.5 (0.32-0.89)

Obesity 2.5 (1.56-3.93)

Smoking 2.1 (1.29-3.58)

6-min walk (<median) 1.7 (1.04-2.93) 1.9 (1.02-3.46)

Sanderson BK, et al. JCRP 2003;23:281-89

• Completion rate: 304/526 58%• Drop-outs: 37% medical reasons, 63% non-medical

Conclusions

CR improves morbidity and mortality– CR also improves behavioral and clinical

outcomes, health status and health related QOL

CR remains underutilized– Low referral, enrollment and adherence rates

– Significant health care disparities

Need to remove barriers to traditional CR

Need to explore new delivery models– Research / Policy

9

Circulation 2011;124:2951-60

Circulation2012;125:1321-1329

NOTES—

Documents

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