High Risk Population
Subclinical Disease (HRP) & Post-MI (Polypill)
Valentin Fuster, M.D., Ph.D.
Dallas, 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 ?
1. Vulnerable Plaque ?
B) Mild at Angiography, Significant at IVUS & Pathology
STABLE PLAQUE
Angiogr., IVUS
UNSTABLE PLAQUE
Angiogr., IVUS, Pathology
RUPTURED PLAQUE
Pathology
Modified from G Niccoli et. al. JACC Cardiovasc Img. 2013;6:1108
GW Stone, J Narula JACC: Cardiov. Imag. 2013:6;1124
A Arbab-Zadeh, M Nakano, R Virmani, V Fuster, et. al. Circ. 2012;125:1147
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
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 ?
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 ?
2. Vulnerable Patient – Non-invasive Burden
A) Large Population & Silent 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
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 ?
B).
PESA & AWHS
40-54y, n= 8,000 , FU 0,3,6 y
HRP > 55y,
N=6000 FU 3y
c).
a). Predictive ?
b). Economics ?
Life Style & Imaging ?
Pesa Systemic Score
Omics (Framingham)
Telomeres (S.blot, qPCR, Fresh)
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
IMT vs Focal: +
Ilio-Femoral: +++
(n = 1480)
(n = 1477)
(n = 1479)
(n = 1478)
Carotid Plaque Area Quartiles
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
15.0
5.0
10.0
P-value<.0001
0.0
Cumulative Incidence, %
3a. Cumulative MACE by Framingham Score
0
365
2049
2445
1337
1786
2207
1229
Number at risk
Low Risk
Intermediate Risk
High Risk
730
Analysis time, Days
1603
2023
1124
U Baber, R Mehran, E Falk, V Fuster et al, 2013
1095
555
737
402
10.0
5.0
P-value<.0001
0.0
Cumulative Incidence, %
3b. Cumulative MACE by 2D US Carotid Plaque
0
500
1000
Analysis time, Days
No Plaque
Tertile 2
Tertile 1
Tertile 3
U Baber, R Mehran, E Falk, V Fuster et al, 2013
15.0
5.0
10.0
P-value<.0001
0.0
Cumulative Incidence, %
3c. Cumulative MACE by Coronary Calcium Score
0
365
730
1095
Analysis time, Days
CAC 0
CAC 100-400
CAC 0-100
CAC > 400
U Baber, R Mehran, E Falk, V Fuster et al, 2013
4a. Reclassification: INCORRECT, CORRECT
Status at
follow-up examination
Coronary artery calcium
Non-Case
Predicted
Framingham
<3%
3%-6%
>6%
Case
<3%
3%-6%
>6%
Predicted
Framingham plus score
Reclassified
Net correctly
reclassified
(%)
<3%
3%-6%
>6%
Increased
risk
Decreased
risk
2240
588
47
103
1465
180
0
308
672
411
815
7.21
27
13
1
1
59
8
1
27
68
29
22
3.41
NRI 10.62
2D ultra sound
Non-Case
<3%
3%-6%
>6%
Case
<3%
3%-6%
>6%
2234
554
44
108
1480
172
1
327
683
436
770
5.96
27
12
1
58
1
29
31
20
5.37
1
7
69
NRI 11.33
4b. 2D-US Transducer + CAC
Impact on Events (Intermediate FRS Group)
U Baber, R Mehran, E Falk, V Fuster et al, 2013
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 ?
C1).
PESA & AWHS
40-54y, n= 8,000 , FU 0,3,6 y
c).Life Style & Imaging ?
Pesa Systemic Score
e). Omics (Framingham)
Telomeres (S.blot, qPCR, Fresh)
HRP > 55y,
N=7000 FU 3y
a). Predictive ?
b). Economics ?
d). 5 More Yrs of Follow-Up
C2). In-vivo, Diabetic Carotid - PET/MRI
RR Moustafa, J Rudd et. al. Circ Cardiov. Imag. 2010;3:536
R Corti & V Fuster EHJ 2011 (April 19) JD Spence. Circ. 2013;127:739
Diffuse: Inflammatory / Lipid – Transcr. Doppler: M-emboli / Stroke
C3). DBD & Traditional CV Risk Factors
White 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, 2013
5. 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
1
3
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;123:1650
F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274 – Healthy Lifestyle
High Risk Population
Subclinical Disease (HRP) & Post-MI (Polypill)
Valentin Fuster, M.D., Ph.D.
Dallas, Nov 13-6, 2013
No Disclosures
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.
2) Promoting Cardiovascular Health
Worldwide
2012
Circ. 2011;123:1671
Scientific American, May 2014 (In Press)
2012
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) Low-Compliance vs Low-Adherence
Definition of Terms
Compliance, Implies
Passive Participation
by The Patient (Life Style
or Behavior, fluctuates).
Adherence, Implies
Active Participation by
The Patient (Drugs,
around the Clock)
JM Castellano, R Copeland-Halperin, V Fuster, Global Health. 2013;8:263
L 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.
2). TRIALS TARGETS FOR RISK FACTOR CONTROL?
Risk Factors - Proportion of Participants at Goal % – 1 year
Hb A1C
Meet Goals
Base FU
Trials
LDL
SBP
DBP
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
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) 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;161:719
WHO. Adherence to Long-Term: evidence for Action, 2003
S Schuster et.al. Z Kardiol.1997;86:273- N Danchin et.al AHJ 2005;150:1147
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
New England Health Institute (NEHI) Research Brief: August 2009.
MC Roebuck, et al. Health Aff. 2011;30(1):91 – MI-FREE AHA Nov 2011
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) 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;47:1873
3CA 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
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).The Adherence Estimator For a New Prescription
Concerns
Commitment
Cost
CA McHorney. Curr Med Res Opin. 2009;25(1):215
Medication Adherence. Merck 2011.
2). Who Should Focus on These Patients
and Promote Adherence
Medication Adherence. Merck 2011.
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) CNIC-FERRER POLYPILL FOR 2ary PREVENTION.
FOOD INTERACTION
FOCUS 1 & 2
PHARMACOKINETIC
INTERACTION WITH ASPIRIN
BIO-EQUIVALENCE
Argentina
Brazil
Paraguay
Italy
Spain
ASA, Statin, ACE-Inhibitor
PHARMACOKINETIC
INTERACTION WITH
SYMVASTATIN
PHARMACODINAMIC
INTERACTION WITH RAMIPRIL
PHARMACODYNAMIC
INTERACTION WITH
SYMVASTATIN
G Sanz, V Fuster Am. H J 2011;162:811
Semin.Thor.Cardiov.Surg 2011;23:24
Nature Rev Cardiology, 2013-In Press
PHARMACOKINETIC
INTERACTION WITH RAMIPRIL
PHARMACODYNAMIC
INTERACTION WITH ASPIRIN
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
Secondary Prevention
ASA 75 mg, Lisinopril 10 mg,
Simv. 20 mg, Aten. 50 mg
Red Heart Pill 2
Primary Prevention
ASA 75 mg, Lisinopril 10 mg,
Simv. 20 mg, Hctz. 12.5 mg
Cardia
India
Ramitorva
Primary Prevention
ASA 100 mg, Simv 20 mg,Ram 5mg
Aten. 50 mg, Hctz. 12.5 mg
Zyduscadila
India
Zycad
Secondary Prevention
Dr Reddy’s
India
UMPIRE
Alborz Darou
Iran
ASA 75 mg, Atorv. 10 mg,
Ram 5mg, Metoprolol 50 mg
Polyran 1
ASA 81 mg, Atorv. 20 mg,
Prim / Secon. Prevention? Enalapril 5mg, Hctz 25 mg
Polyran 2
ASA 81 mg, Ator 20 mg,
Prim / Secon. Prevention? Valsartan 40mg, Hctz 25 mg
CNIC-FERRER
Spain
Trinomia
Secondary prevention
ASA 100 mg, Simv. 40 mg,
Ram 2.5 / 5 / 10 mg
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) A Community Call
Population Ageing & Cost
The Lancet NCD Action (G Alleyne et. al.) Lancet. 2013;381:566
2) A Community Call
The 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)
Valentin Fuster, M.D., Ph.D.
Dallas, Nov 13-6, 2013
No Disclosures
U Baber, R Mehran, V Fuster et al, 2013
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 ?
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
Induction of telomere
shortening
Smoking
Alcohol abuse
Obesity
Sedentary lifestyle
Mental stress
Inhibition of telomere
shortening
Healthy lifestyle
F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274
Promoting Health and Improving Survival Into
Very 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
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 ?
1) UN Targets Top Killers – 4 Warnings
D Butler. Nature. 2011;477:261 (UN. NCD). At Present
R. Beaglehole et. al. Lancet 2008;372:1988 - > 30% Across, 2030
PREMISE (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
2a) Manhattan Project
Quantificacion, Low-Adherence / Low-Compliance
% Patients, Non-Adherence / Compliance
2b)
Timing
Adherence
Decreases
Adherence Decreases Signicantly Over the First 6 Months
Significantly
Over the First 6 Months (40%)
A Critical Window of Opportunity
PM Ho, BMC Cardiov. Discord. 2006;6:48 – Arch.Int.Med. 2006;166: 1842-MI
RH Chapman, Arch Inter Med 2005;165:1147- BP & Lipid Rx
AS Gadkari AS, et. al. Curr Med Res Opin. 2010;26(3):648
Data available from Merck, MI-FREE, AHA Nov 2011
2c) Quantificacion – Worldwide CHD / Stroke (N=153996)
Non-Adherence to Medications
CV drug category
High-income
(%)
Upper-middle
income (%)
Lower-middle
income (%)
Low-income
(%)
Overall
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
ARBs
49.8
30.0
11.1
5.2
19.5
BP-lowering
agents
73.8
48.4
37.4
19.2
41.8
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
1a) Low-Adherence isN a Major Inefficiency
In Our Health Care System
WHO.Adherence
Adherence
to long-term
therapies:
evidence
for action. 2003.
WHO.
to Long-Term:
evidence
for Action,
2003
Coletet.
Arch
Intern
1990;150(4):841.
NNCol
al. al.
Arch
Intern
Med.Med.
1990;150:841
– MI-FREE, AHA N 2011
Dl
Hershman
et al
Cancer
Res Treat.
2011;126:529
DL
Hershman
etBreast
al. Breast
Cancer
Res Treat.
2011;126(2):529.
DDl Hershman et al. Breast Cancer Res Treat. 2001;126:52
1b) Patient’s Lack Of Adherence To Medication
German MITRA Registry (MI, 6067)
N=6067
S Schuster et al. Z Kardiol. 1997;86:273
French Registry (MI, 2320)
N=2320
N Danchin et al AHJ 2005;150:1147
1) The FOCUS project: study 1 (N=4000)
Study 2
Study 1
Economy and Health
system characteristics:
• GNI
• Health care accesibility
• Out-of pocket expenditure
• Treatment accesibility
• Treatment affordability
• Prices of foods
Patient’s characteristics:
• Demographics
• Psycosocial factors
• Healths status
• Clinical variables
• Blood sample
PEP:
Adherence test
(Morisky-Green)
1)The FOCUS Project: Study 2 Design (N=1340)
Randomization
2nd visit
1st visit 1month
Final visit
6-9
months
3rd visit
4 month
3 drugs separately
Study 1
Polypill
Clinical status
Medication Blood pressure
Blood sample
Adverse effects
Adherence test
Pill counting
PEP: Adherence test
Pill counting
SEP: Blood pressure
Lipid profile
Adverse effects