valentin fuster, m.d., ph.d. high risk population subclinical disease (hrp) & post-mi (polypill)...

High Risk Population Subclinical Disease (HRP) & Post-MI (Polypill)

Valentin Fuster, M.D., Ph.D.Valentin Fuster, M.D., Ph.D.

Dallas, Nov 13-6, 2013 No DisclosuresDallas, Nov 13-6, 2013 No Disclosures

High Risk Population Subclinical Disease (HRP)

1. Vulnerable Plaque – Invasive Approach ?

A) Restricted Population with Complex Disease

B) Mild Angiography, Significant IVUS & Pathology

2. Vulnerable Patient – Non-invasive Burden Approach

A) Large Population with Silent Disease

B) RF + Burden of Disease at 3D-US & CAC

C) What is next ?

Background of FREEDOM – Autopsy, Ex Vivo, Imaging

Data From FREEDOM – “No FREEDOM of Choice”

Strict Data From FREEDOM – 3 Exceptions of Choice?

Post FREEDOM Challenges – Timing, Polypill, Hybrid

Modified from G Niccoli et. al. JACC Cardiovasc Img. 2013;6:1108GW Stone, J Narula JACC: Cardiov. Imag. 2013:6;1124A Arbab-Zadeh, M Nakano, R Virmani, V Fuster, et. al. Circ. 2012;125:1147

1. Vulnerable Plaque ? B) Mild at Angiography, Significant at IVUS & Pathology

STABLE PLAQUE Angiogr., IVUS

UNSTABLE PLAQUE Angiogr., IVUS, Pathology

RUPTURED PLAQUE Pathology

Vulnerable Plaque – Invasive Approach ? A) Restricted Population with Complex Disease

D Butler. Nature. 2011;477:261 (UN. NCD). At Present

R. Beaglehole et. al. Lancet 2008;372:1988 - > 30% Across, 2030

V Fuster, BB Kelly, R Vedanthan , Circulation. 2011;123:1671








C) What is next ?





2. Vulnerable Patient – Non-invasive Burden A) Large Population & Silent Disease

D Butler. Nature. 2011;477:261 (UN. NCD). At PresentR. Beaglehole et. al. Lancet 2008;372:1988 - > 30% Across, 2030V Fuster, BB Kelly, R Vedanthan , Circulation. 2011;123:1671








C) What is next ?





PESA & AWHS PESA & AWHS HRP > 55y, HRP > 55y, 40-54y, n= 8,000 , FU 0,3,6 y 40-54y, n= 8,000 , FU 0,3,6 y N=6000 FU 3yN=6000 FU 3y

Omics (Framingham)Telomeres (S.blot, qPCR, Fresh)

a). Predictive ?b). Economics ?

c). Life Style & Imaging ? Pesa Systemic Score

B).

Carotid Plaque Burden, mm3 3D US - Manual Sweep 2D vs Transducer

Focal structure into the arterial lumen of at least 0.5 mm

or 50% of surrounding IMT value. 37% missed at Classical 2D CardioSCORE-R7-ApoA1, Apo B, B2M, CEA, CRP, Lp(a),Transferrin

H Sillesen, P Muntendam, E Falk, V Fuster et.al JACC Imag. 2012;7:681..

Calcification of the Coronary Arteries (CAC)

1. Cross Interaction Between Carotid Plaque Area & CAC

(n = 1480) (n = 1477) (n = 1479) (n = 1478)

Carotid Plaque Area Quartiles

IMT vs Focal: +IMT vs Focal: +Ilio-Femoral: +++ Ilio-Femoral: +++

U Baber, R Mehran, E Falk, V Fuster et al, 2013

2. PESA Systemic Score With Age And Gender(N=2578, Age 40-54yo, 35% Women)

LJ Jimenez Borregueva, AI Fernandez Ortiz, V Fuster et. al. 2013

P-value<.0001

0.0

5.0

10.0

15.0

1337 1229 1124 402High Risk 2445 2207 2023 737Intermediate Risk2049 1786 1603 555Low Risk

Number at risk0 365 730 1095

Analysis time, Days

3a. Cumulative MACE by Framingham Score

Cu

mu

lati

ve I

nci

den

ce,

%


Analysis time, Days

3b. Cumulative MACE by 2D US Carotid Plaque

No Plaque Tertile 1Tertile 2 Tertile 3

0.0

5.0

10.0

0 500 1000

Cu

mu

lati

ve I

nci

den

ce,

%P-value<.0001


P-value<.0001

0.0

5.0

10.0

15.0

0 365 730 1095

Analysis time, Days

3c. Cumulative MACE by Coronary Calcium Score

Cum

ulat

ive

Inci

denc

e, %

CAC 0 CAC 0-100CAC 100-400 CAC > 400


Status at follow-up examination

Predicted Framingham

Predicted Framingham plus score

ReclassifiedNet correctly reclassified

(%)<3% 3%-6% >6%Increased

riskDecreased

risk

Coronary artery calciumNon-Case <3% 2240 103 0 411 815 7.21

3%-6% 588 1465 308>6% 47 180 672

Case <3% 27 1 1 29 22 3.41

3%-6% 13 59 27>6% 1 8 68

NRI 10.622D ultra sound

Non-Case <3% 2234 108 1 436 770 5.96

3%-6% 554 1480 327>6% 44 172 683

Case <3% 27 1 1 31 20 5.37

3%-6% 12 58 29>6% 1 7 69

NRI 11.33

4a. Reclassification: INCORRECT, CORRECT

CACS

4b. 2D-US Transducer + CAC Impact on Events (Intermediate FRS Group)









C) What is next ?





PESA & AWHS PESA & AWHS HRP > 55y,HRP > 55y, 40-54y, n= 8,000 , FU 0,3,6 y 40-54y, n= 8,000 , FU 0,3,6 y N=7000 FU 3yN=7000 FU 3y

e). Omics (Framingham)Telomeres (S.blot, qPCR, Fresh)

a). Predictive ?b). Economics ?

c).Life Style & Imaging ? Pesa Systemic Score

C1).

d). 5 More Yrs of Follow-Up

C2). In-vivo, Diabetic Carotid - PET/MRI

RR Moustafa, J Rudd et. al. Circ Cardiov. Imag. 2010;3:536R Corti & V Fuster EHJ 2011 (April 19) JD Spence. Circ. 2013;127:739Diffuse: Inflammatory / Lipid – Transcr. Doppler: M-emboli / Stroke

C3). DBD & Traditional CV Risk FactorsWhite Matter Lesion Volume and Cognitive Decline

1. V Novak, I Hajjar. Nat. Rev. Cardiol. 2010;7:686(HMS)2. WB White et al.Circ 2011;124:2312 (Farmington,Yale)

3. AHA/ASA, Stroke 2011; 42:2672 - WHO - Dementia report 2012

4. JB Toledo et al. Brain July 10, 20135. C Russo et. al. Circ. 2013;128:1105 6. JR Kizer Circ 2013;128:1045 Ischemia affects 60 to 90% of patients with Alzheimer’s

C4). Aging / Senescence Cellular Telomere & Telomerase

B Niemann et. al. JACC 2011; 57: 577. R Madonna, R De Caterina et. al EHJ 2011;32:1190 (Houston &Chieti, Italy)JC Kovacic, EG Nabel, V Fuster – Circ. 2011;123:1650F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274 – Healthy Lifestyle

1

3

High Risk Population Subclinical Disease (HRP) & Post-MI (Polypill)



Post-MI Polypll – 14 Comments Compliance / Adherence ( Rx ) & Economics

1. From Warnings to Promoting Health (2)

2. Low-Compliance vs Low-Adherence

Definition, Quantification Worldwide (2)

Clinical & Economic Impact of Low Adherence (2)

The Causes or 7 Tenets of Low-Adherence (2)

3. Aiming at New Approaches

The Adherence Estimator & Communication (2)

Polypill & Adherence (2)

A Community Call (2)

1) Major Documents on Global CV Health

Promoting Cardiovascular Health in the Developing World; A Critical Challenge to Achieve Global Health. Ed. V Fuster and B Kelly. IOM of the Natl. Academies. Natl . Academies Press. Washington DC.2010.

Circ. 2011;123:1671 Scientific American, May 2014 (In Press)

2012 2012

2) Promoting Cardiovascular HealthWorldwide

JM Castellano, R Copeland-Halperin, V Fuster, Global Health. 2013;8:263L Osterberg, et. al. N Engl J Med. 2005;353:487.GN Varghese et. al. Drug Benefit Trends. 2008;20:17.National Council on Patient Information and Education. August 2007.

1) Low-Compliance vs Low-Adherence Definition of Terms

Compliance, Implies Passive Participationby The Patient (Life Style or Behavior, fluctuates).

Adherence, Implies Active Participation by The Patient (Drugs, around the Clock)

2). TRIALS TARGETS FOR RISK FACTOR CONTROL?

Risk Factors - Proportion of Participants at Goal % – 1 year

Trials LDL SBP DBP Hb A1C Meet Goals Base FU

BARI-2D 75 56 70 52 14 20

COURAGE 51 55 55 59 12 19

FREEDOM 55 63 53 55 12 20

Freedom, Bari-2D, Courage Investigators, 2013 (In Press)PURE (S Yusuf et al.) Lancet 2011; Aug 28 - Poor Countries,7% !!!NHANES, AHA, NHLBI-JNC-7, NHLBI-NCEP P Muntner, V Fuster et al., AHJ 2011; 161: 719

1) Projected Impact Of Polypill Use Among US Adults:Adherence and a 9 Year Event Rate – CAD & Stroke

P Muntner, V Fuster, M Woodward et. al. Am Heart J. 2011;161:719WHO. Adherence to Long-Term: evidence for Action, 2003S Schuster et.al. Z Kardiol.1997;86:273- N Danchin et.al AHJ 2005;150:1147

New England Health Institute (NEHI) Research Brief: August 2009. MC Roebuck, et al. Health Aff. 2011;30(1):91 – MI-FREE AHA Nov 2011

2) The Cost of Low-Adherence in the US could be up to $300 Billion Each Year

Medication Adherence May Lead to Lower Health Care Use and Costs Despite Increased Drug Spending

1) TENETS OF LOW ADHERENCE TO MEDICATIONS –“NO”

1. There is no such thing as a “non-adherent personality.”1

2. Patients - 83%- don’t tell physicians of their adherence.

Physicians -74%- believe their patients are adherent.2

3. Adherence to prescription medications is largely not

related to compliance or self-care and lifestyle.3

4. Effects of demographics - age, gender, education, &

income - on adherence are small.4

1D Hevey. 2007 2KL Lapane Am J Manag Care 2007;13:613 - AL Goldberg, Soc Sci Med 1998;47:18733CA McHurney, Curr Med Res Opin 2009; 25:21 4MR DiMateo , Med Care 2004; 42:200

2) TENETS OF LOW ADHERENCE TO MEDICATIONS –“YES”

5. Patients want to know why the medication is prescribed,

duration, possible side effects, what could happen if they

don’t take it, and cost / affordability.5

6. Health care professionals should communicate less poorly

on prescription medications - av. 49 sec, appropiate 3%.6

7. Taking medications is a decision-making process. Patients

actively decide about their medications.7

5 CA McHurney, Cur Med Res Opin 2009;25:215 BJ Bailey, Progr Cardiov Nurs 1997; 12:23 - DK Ziegler, Arch Int Med 2001;161:706 6 DM Tarn, Patient Educ Cours 2008; 72:311, Arch Int Med 2006; 166:1855 7 SL William, Clin Interv Aging 2007; 25:453

CA McHorney. Curr Med Res Opin. 2009;25(1):215 Medication Adherence. Merck 2011.

1).The Adherence Estimator For a New Prescription

Concerns

Commitment

Cost

Medication Adherence. Merck 2011.

2). Who Should Focus on These Patients and Promote Adherence

1) CNIC-FERRER POLYPILL FOR 2ary PREVENTION.

G Sanz, V Fuster Am. H J 2011;162:811 Semin.Thor.Cardiov.Surg 2011;23:24 Nature Rev Cardiology, 2013-In Press

ASA, Statin, ACE-Inhibitor ArgentinaBrazilParaguayItalySpain

FOCUS 1 & 2

UMPIRE: High Risk, Two Polypills as FOCUS +Hctz or Atenolol vs Usual Care 86% Adherence vs 65%, Lower BP and LDL-C - Events NS --- JAMA 2013;310:918

2). POLYPILL STUDIES PUBLISHED OR IN COURSE

Company Polypill Active components

Red Heart Pill 1 ASA 75 mg, Lisinopril 10 mg, Dr Reddy’s Secondary Prevention Simv. 20 mg, Aten. 50 mg

India UMPIRE Red Heart Pill 2 ASA 75 mg, Lisinopril 10 mg,

Primary Prevention Simv. 20 mg, Hctz. 12.5 mg

Cardia Ramitorva ASA 100 mg, Simv 20 mg,Ram 5mg India Primary Prevention Aten. 50 mg, Hctz. 12.5 mg

Zyduscadila Zycad ASA 75 mg, Atorv. 10 mg, India Secondary Prevention Ram 5mg, Metoprolol 50 mg

Polyran 1 ASA 81 mg, Atorv. 20 mg, Alborz Darou Prim / Secon. Prevention? Enalapril 5mg, Hctz 25 mg

Iran Polyran 2 ASA 81 mg, Ator 20 mg,

Prim / Secon. Prevention? Valsartan 40mg, Hctz 25 mg CNIC-FERRER Trinomia ASA 100 mg, Simv. 40 mg, Spain Secondary prevention Ram 2.5 / 5 / 10 mg

1) A Community CallPopulation Ageing & Cost

The Lancet NCD Action (G Alleyne et. al.) Lancet. 2013;381:566

2) A Community CallThe Message

A. Compliance & Adherence are a Marathon, Not a Sprint

B. Compliance & Adherence are the Key Drivers Enabling Patients to Achieve Their Treatment Goals

World Health Organization 2003-2011

High Risk Population Subclinical Disease (HRP) & MI (Polypill)



U Baber, R Mehran, V Fuster et al, 2013








C) What is next ?





C3). Cortical Atrophy (Alzheimer’s), White Matter Abnormalities & Lacunar Stroke

JC Kovacic, V Fuster et. al. Circulation. 2011;123:1900 MA Lim et. al. Clin Geriatr Med. 2009;25:191.

C4). The Hallmarks of Aging

Aging is characterized by a progressive loss of

physiological integrity, leading to impaired

function and increased vulnerability to death.

This deterioration is the primary risk factor for

major human pathologies, including cancer,

diabetes, cardiovascular disorders, and

neurodegenerative diseases

C Lopez-Otin et al., Cell 2013; 153:1194

Aging Is The Leading Risk Factor For Most Serious Chronic Disabilities

T Tchkonia et. al. J Clin Invest. 2013;123:966

ENVIRONMENTAL OXIDATIVE STRESS

F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274

Induction of telomere shortening

Smoking Alcohol abuse Obesity Sedentary lifestyle Mental stress

Inhibition of telomere shortening

Healthy lifestyle

Promoting Health and Improving Survival IntoVery Old Age

The identification of strategies that can promote

health and productivity into old age is one of the

most important challenges facing public health.

The current study’s findings, which suggest that

modifiable social and behavioral factors increase

survival among older people, but only when achieved early in life, preferably in childhood

MM Glymour, TL Osypuk. BMJ 2012; 345:e6452








C) What is next ?





1) UN Targets Top Killers – 4 Warnings

D Butler. Nature. 2011;477:261 (UN. NCD). At PresentR. Beaglehole et. al. Lancet 2008;372:1988 - > 30% Across, 2030PREMISE (S Mendis et al) Bull. WHO 2005, 2007- LM-I, Pop / $ High V Fuster et al, Circ. 2011;123:1671 – H-I $ Rx / Prom. Health High

Global Health. 2013;8:263

% Patients, Non-Adherence / Compliance

2a) Manhattan Project 2a) Manhattan Project Quantificacion, Low-Adherence / Low-Quantificacion, Low-Adherence / Low-Compliance Compliance

PM Ho, BMC Cardiov. Discord. 2006;6:48 – Arch.Int.Med. 2006;166: 1842-MIRH Chapman, Arch Inter Med 2005;165:1147- BP & Lipid Rx AS Gadkari AS, et. al. Curr Med Res Opin. 2010;26(3):648Data available from Merck, MI-FREE, AHA Nov 2011

Adherence Decreases Signicantly Over the First 6 Months2b) Timing - Adherence Decreases

Significantly Over the First 6 Months (40%)

A Critical Window of Opportunity

2c)2c) Quantificacion –Quantificacion – Worldwide CHD / Stroke Worldwide CHD / Stroke (N=153996) Non-Adherence to MedicationsNon-Adherence to MedicationsCV drug category High-income Upper-middle Lower-middle Low-income Overall

(%) income (%) income (%) (%)

Antiplatelets 62.0 24.6 21.9 8.8 25.3

Beta blockers 40.0 25.4 10.2 9.7 17.4

ACE inhibitors 49.8 30.0 11.1 5.2 19.5ARBs

BP-lowering 73.8 48.4 37.4 19.2 41.8agents

Statins 66.5 17.6 4.3 3.3 14.6

All decreasing trends from higher- to lower-income, p<0.0001

PURE (S Yusuf et al.) – Lancet 2011; Aug 28

WHO. Adherence to long-term therapies: evidence for action. 2003. N Col et. al. Arch Intern Med. 1990;150(4):841.DL Hershman et al. Breast Cancer Res Treat. 2011;126(2):529.

WHO. Adherence to Long-Term: evidence for Action, 2003N Col et al. Arch Intern Med. 1990;150:841 – MI-FREE, AHA N 2011Dl Hershman et al Breast Cancer Res Treat. 2011;126:529 DDl Hershman et al. Breast Cancer Res Treat. 2001;126:52

N1a) Low-Adherence is a Major Inefficiency

In Our Health Care System

German MITRA Registry (MI, 6067)German MITRA Registry (MI, 6067) French Registry (MI, 2320)French Registry (MI, 2320)

N=6067

S Schuster et al. Z Kardiol. 1997;86:273 N Danchin et al AHJ 2005;150:1147

N=2320

1b) Patient’s Lack Of Adherence To Medication 1b) Patient’s Lack Of Adherence To Medication

Study 1

Economy and Health Economy and Health system characteristics:system characteristics:• GNIGNI• Health care accesibilityHealth care accesibility• Out-of pocket expenditureOut-of pocket expenditure• Treatment accesibilityTreatment accesibility• Treatment affordabilityTreatment affordability• Prices of foodsPrices of foods

Patient’s characteristics:Patient’s characteristics:• DemographicsDemographics• Psycosocial factorsPsycosocial factors• Healths statusHealths status• Clinical variablesClinical variables• Blood sampleBlood sample

1) The FOCUS project: study 1 (N=4000)1) The FOCUS project: study 1 (N=4000)

PEP: PEP: Adherence test Adherence test (Morisky-Green(Morisky-Green))

Study 2

Study 1PolypillPolypill

3 drugs separately3 drugs separately

RandomizationRandomization Final visitFinal visit6-9 6-9 monthsmonths

1st visit1st visit

MedicationMedication

2nd visit2nd visit1month1month

Clinical statusClinical statusBlood pressureBlood pressureBlood sampleBlood sampleAdverse effectsAdverse effectsAdherence testAdherence testPill countingPill counting

PEPPEP: Adherence test: Adherence test Pill countingPill countingSEP: SEP: Blood pressureBlood pressure Lipid profileLipid profile Adverse effectsAdverse effects

3rd visit 3rd visit 4 month4 month

1)The FOCUS Project: Study 2 Design (N=1340)1)The FOCUS Project: Study 2 Design (N=1340)

valentin fuster, m.d., ph.d. high risk population subclinical disease (hrp) & post-mi (polypill)...

Documents

burden of disease

freedom of choice strict

restricted population

background of freedom

silent disease b rf

complex disease d butler

post freedom challenges

hybrid slide