Download Management of Ischemic Heart Disease in High

Prevention in the Elderly:
Good Clinical Care or Oxymoron?
Daniel E. Forman, MD
Associate Professor, Harvard Medical School
Director, Cardiac Rehabilitation and The Exercise Testing Laboratory
Division of Cardiovascular Medicine, Brigham and Women’s Hospital
Physician Scientist, New England Geriatric Research, Education, and Clinical Center,
Veterans Affairs Boston Healthcare System
Chair, Council on Cardiovascular Care for Older Adults,
American College of Cardiology
Burgeoning Population of Elderly
80
Adults >65 yrs (Millions)
Between 2000-2050
389%  population > age 85
US Census Bureau
Increasing Life Expectancy
Improvements in acute care, prevention, and medical technology.
Over ½ the current U.S. population can anticipate living to age 80
% total U.S. population
Percent U.S. Population Aged ≥65 years
•
Between 2000-2050
389%  population > age 85
•
>½ the current U.S. population can anticipate
living to age 80
UN World Population Prospects, 2008
% total Chinese population
Percent Chinese Population Aged ≥65 years
Population Reference Bureau,
http://www.prb.org
Compression of Morbidity
J. Fries, 1980
Percentage of Population
Prevalence of Cardiovascular Disease
in
the
U.S.
100
90
80
70
60
50
40
30
20
10
0
20-24
25-34
35-44
45-54
Men
55-64
Women
65-74
75+
NHANES III
CVD Hospitalizations and Mortality
>65 yo (~13% of the population)
●
disproportionate CV events & mortality
___Admissions___
Total *
>65 yrs
Acute MI
Deaths
>65 yrs
858
65.5%
81.2%
1280
53.5%
85.7%
Arrhythmias
731
71.0%
73.3%
Heart failure
1040
77.4%
92.7%
Cerebrovascular Dz
1044
72.6%
74.6%
Coronary disease
* in thousands
National Hospital Discharge Survey, 2000
U.S. Cardiovascular Procedures
Number of Procedures*
Total
Diagnostic catheterization
1322
PCI
1265
637
50.4%
Coronary bypass surgery
469
Permanent pacemaker
180
Implantable defibrillator
Endarterectomy
103
82
65 years
659
49.9%
265
56.5%
155
86.1%
91
50
54.6%
79.6%
* in thousands
AHA, Heart Disease and Stroke Statistics , 2008 Update, www.amhrt.org/statistics/index.html
Insidious Subclinical CV Disease
• Functional Decline: Aerobic, Strength, Endurance
• Cognitive Decline
• Renal Insufficiency
• ↑ “Geriatric Syndromes”
– Confusion, Syncope, Falls
•
ACS: Geriatric Cardiology
Patient wishes
POLYPHARMACY
Conundrum
•Cognition
•Independence
•Frailty
COMPLICATIONS
Arrhythmias
Bleeding
Stroke
Rupture
Renal failure
PRESENTATION
(Delayed)
Atypical symptoms
AGE-RELATED PHYSIOLOGY
(dyspnea, confusion)
Ventricular-vascular stiffness
Abnl ECG
Systolic limits
Diastolic limits
Conduction abnl
COMORBIDITIES
Renal insufficiency
Pulmonary
Anemia
Hypertension
GIB
Cancers
Strokes
Prevention in Relation to Aging
?
Prevention in Relation to Aging
• “Prevention” to help achieve an
aging course that better preserves
functional capacity (physical,
cognitive, emotional), quality of
living, and self-efficacy despite
senescence.
• A career opportunity…
Age as a risk factor for CVD
Aging Physiology: Predictable CV
Disease
Physiologic Changes
↑ Central arterial stiffness
Delayed early LV filling
↑ Central arterial stiffness
Clinical Syndrome
Isolated systolic hypertension
Heart Failure with Preserved
Ejection Fraction
↓Neurohormonal regulation
↓ Baroreflex sensitivity
Orthostatic hypotension
↑ LV stiffness → ↑LV pressure
↑ Atrial pressure/size
Atrial fibrillation
Central arterial stiffness
↑ Central arterial stiffness
Endothelial dysfunction
Coronary Artery Disease (CAD)
Chymase
Oxidative Stress
E. Lakatta
Telomeres
– Specialized structure at the end of
chromosomes that shorten with each
replication until cells’ biological capacity is
compromised.
– Size inversely correlates to oxidative stress
and areas of high cell turnover (areas of
higher cell repair).
• Shorter at vessel bifurcations
Arterial Phenotypic Changes with Aging
 Vascular thickening
↓ Elastin, ↑ Collagen, ↑Calcium
↑ Advanced Glycation –
Endproducts (AGE)
↑ Smooth muscle cell migration
 Endothelial performance
↓ Vasomotor responses
↓ Athero-inhibiting benefit
Senescent flow mechanics:
lower threshold to disease
• Differences in vascular stiffness and endothelium
• Flow mechanics and atherosclerosis
• Broad Implications: CAD, Stroke, Kidney Disease
Blood Pressure and Age
Pulse
pressure
National Health and Nutrition Examination Survey
Cardiovascular Mortality
Myocardial Changes with Aging
Aorta
stiff and
dilated
LV Hypertrophy
LA
dilates
Valves
thicken
LVH and
stiffening
• More vulnerable to
ischemia
• Diastolic filling
changes
• More vulnerable to
arrhythmia
• Ventricular Hypertrophy & Stiffening
LV diastolic pressure
--Impedes Ventricular Filling
Endsystole
Stiff
AGING
Enddiastole
LV diastolic volume
--Congestion as
blood backs
into the lungs
Normal
Risk Factor Burden
Over a Lifetime
Prostate
CA
Breast
CA
19%
12.5%
Lloyd-Jones D, et al. Circulation 2006;113:791-98
Predictability and Complexity of CVD With Aging
Risk Factors:
Duration and
Number
• ↑ Cholesterol,
HTN, DM,
Tobacco,
Sedentary,
Obesity
Aging Physiology:
• Oxidative Stress
• ↓ telomere length
Socioeconomic:
• Lifestyle (exercise, diet, isolation)
• Financial
Multiple Concurrent Diseases
• Heart Failure
• CAD, Valvular Dz
• Arrhythmia (afib)
• Hypertension (PP)
•
•
•
•
•
•
•
DM, Metabolic Synd
Infections
Renal Insufficiency
Anemia
COPD, Sarcopenia
Depression
Cognitive Change
Comorbidity
Frailty
Disability
↓Cognition
↑Depression
↓ Weight
↑ Weakness
↑ Muscle Wasting
↓Physical Function
↑Fatigue
“Old Age”
still many years of life ahead
• Men
• Women
Lifetable
75 yo —
80 yo —
85 yo —
90 yo —
75.2 yrs
80.4 yrs
men women
10.5 12.5
7.9 9.5
5.9 6.6
4.3 5.0
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Barbara Walters:
Regis Philbin:
Birthdate: 9/25/29
Birthdate: 8/25/31
Prevention starts in middle age
• Diet, Weight, Physical Activity, Stress
• Pollution, Sleep, Tobacco, ETOH
• DM, HTN, Inflammation
• Screening
• ASA, BP, cholesterol
Primary Prevention:
Ventricular Stiffness
Arbab-Zadeh A et al. Circulation 2004;110:1799-1805
Physical capacity varies significantly
with lifelong patterns
VO2max in older endurance
athletes
Key Implication:
Healthy older adults retain the
ability to respond to a habitual
exercise stimulus with an  in
maximal aerobic capacity
Heath et al., J. Appl. Physiol. 51: 634-40, 1981
Oxidative Stress
Relative MitoSox Fluorescence
Anti-Oxidants
• Resveratrol
Caloric Restriction and Longevity
(mouse model)
Roth GS. J Am Geriatr Soc 2005;53:S280-283
Calorie Restriction and Diastolic Function:
Echo Parameters
WD (N=25)
CR (N=22)
p-value
F. shortening
36%
34%
NS
E-peak, cm/s
64.3
70.8
NS
A-peak, cm/s
53.0
45.7
0.011
E/A
1.24
1.61
0.001
DT, ms
192.6
173.8
0.012
E’Sept cm/s
9.7
11.8
0.02
E’Lat cm/s
10.2
14.3
0.001
WD=Western diet;
CR=Calorie restriction
T Meyer, MD, L Fontana,
JACC 2006;47:398-402
Age-Associated Physiologic Changes
Cardiac
Non-Cardiac
Heart Failure, CAD,
HTN, Arrhythmia,
Vascular Stiffening,
Valvular Disease,
LVH, Conduction Abnl,
Lipid Abnl, Inflammation
Diabetes,
Anemia,
Renal Failure,
COPD, Infections,
 Cognition,
Depression
Lifestyle (risk)
• Sedentary
• Diet; High Fat, High
Salt
• Altered Sleep
• Over Sedation
Age-Associated Physiologic Changes
• Falls
• Cognitive/Functional ∆
• Confusion
• Incontinence
• Fatigue
• Independence
Cardiac
Non-Cardiac
Heart Failure, CAD,
HTN, Arrhythmia,
Vascular Stiffening,
Valvular Disease,
LVH, Conduction Abnl,
Lipid Abnl, Inflammation
Diabetes,
Anemia,
Renal Failure,
COPD, Infections,
 Cognition,
Depression
Lifestyle (risk)
• Sedentary
• Diet; High Fat, High
Salt
• Altered Sleep
• Over Sedation
CVD Prevention for Elderly
• Cardiac Disease arises from the substrate of aging…
• Cardiac Disease is intrinsically linked to non-cardiac
pathophysiology
•Blood pressure
•Exercise
•Cholesterol
•Obesity
Heterogenity of
Patients
• Frail to Robust
–
–
–
–
Medications
Cognition
Multi-morbidity
Frailty (speed, strength, wt loss, ↓acuity)
Treatment has to fit the needs of the patient:
Patient-Centered Care??
Relevance of Social Context
Aging is affected by many
dimensions of life
• Physiological as well as Cultural
– Religion, Community,
Architecture (Housing, Urban)
– Regional differences
• Socioeconomics
• Family
Heterogeneous Assumptions
Regarding Living and
Feeling Well
Different Perception of Care
•
•
•
•
Imaging
Procedures
1995
2005
Technology
Pharmacological
Imaging
Lifestyle
Benefit vs Risk Conundrum
• Which elderly would benefit most from
prevention?
• Are there markers to determine who would
benefit most from aggressive therapy?
Relative risk reduction
Relative
Risk
Reduction
Control
Intervention
Absolute
Risk
Reduction
Absolute risk reduction
But also greater inatrogenesis and complexity of management
Blood Pressure
• Systolic BP
• Poorly controlled in most elderly (often
require 2 meds)
• Reduced CV endpoints
– Effects on mortality inconsistent, especially
with advancing age
– Side effects, cost
HYVET
Protocol Age 80-105 with stage 2 HTN
Perindopril 4 mg/d
Perindopril 2 mg/d
Indapamide SR 1.5 mg/d
Placebo
double-blind
open FU
goal BP: <150/80 mmHg
Placebo
Placebo
Placebo
–2
–1
0
+3
+6
+9
+12
+18
+24
+60 mo.
Beckett NG et al, NEJM. 2008; 358: 1887-98
HYVET
trial in the very elderly
HR
95% CI
P value
All stroke
- 34%
0.46 - 0.95
0.025
Total mortality
- 28%
0.59 - 0.88
0.001
Fatal stroke
- 45%
0.33 - 0.93
0.021
Cardiovascular mortality
- 27%
0.55-0.97
0.029
Heart failure
- 72%
0.17-0.48
<0.001
Cardiovascular events
- 37%
0.51-0.71
<0.001
Per Protocol
Beckett N. N Engl J Med. 2008;358.
Key Points
• CVA, CVD improved (benefits manifest quickly)
• Progression to Heart Failure, CAD improved
• Still:
– Side effects, cost, polypharmacy remain notorious
impediments
– Therapeutic targets still unclear
• Non-pharmacological therapies are important
BP-Lowering Treatment Trialists
Comparisons in respect to CV events, CV mortality, and total mortality
BP Difference
Relative Risk
(mm Hg)
RR (95% CI)
Major CV events
ACEI vs D/BB
CA vs D/BB
ACEI vs CA
CV mortality
ACEI vs D/BB
2/0
1/0
1/1
1.02 (0.98, 1.07)
1.04 (0.99, 1.08)
0.97 (0.95, 1.03)
2/0
1.03 (0.95, 1.11)
CA vs D/BB
1/0
1.05 (0.97, 1.13)
ACEI vs CA
1/1
1.03 (0.94, 1.13)
2/0
1/0
1/1
1.00 (0.95, 1.05)
Total mortality
ACEI vs D/BB
CA vs D/BB
ACEI vs CA
0.99 (0.95, 1.04)
1.04 (0.98, 1.10)
0.5
1.0
2.0
Favors First Listed Favors Second Listed
Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.
Are there other BP treatment
endpoints to consider??
I Hajjar et al. Arch Intern Med. 2012; 172 (5):442
Gray Zones….
• Intermittent application of most standard
therapies that are used for younger adults.
–
–
–
–
J-curve
Orthostasis
Energy
Mood/appetite/confusion
The significance of functional
capacity
• Functional Decline: key determinant of CV health as
well as a gauge of health and/or therapeutic benefit
Preventive benefits of exercise
Exercise: Pleotropic Benefits
• Exercise as an essential aspect of homeostasis
 Restores/preserves healthful physiology
– Anti-oxidant, anti-inflammatory
– Plaque Stability, Metabolism
– Bone and joint stability, Behavioral
• Anti-aging
 remodeling, endothelial responsiveness
  diastolic performance
  bone/muscle
Reinforce other Risk Factor
Modification Goals
•
•
•
•
•
Blood pressure
Obesity
Hypercholesterolemia
Insulin sensitivity
Cognition
Physical Activity and CVD Risk in Women
% of Risk Reduction Explained by Various Risk Factors
All Risk Factors
59%
Inflammatory Markers
32.6%
27.1%
Blood Pressure/ Hypertension
Traditional Lipids
19.1%
15.5%
Novel Lipids
10.1%
Body Mass Index
8.9%
Hemoglobin A1c/ Diabetes
0.7%
Homocysteine
0
10
20
30
40
50
% Risk Reduction
Mora et al, Circ 2007;116: 2110
60
70
Modifiable
Vascular
Stiffness with
Exercise
Tanaka H, et al. Circ. 2000; 102:1270-5
Modifiable Ventricular Stiffness with Exercise
Edelmann et al. JACC. 2011;58:1780-91
•Aging
•Diabetes
•Starvation
•Renal Dz
•Cancer
•COPD
•Aging
•Diabetes
•Starvation
•Renal Dz
•Cancer
•COPD
Exercise!!
Mitochondria Architecture
Before and After Resistance Training
Pre Training
M
Post Training
M
Z band
M
What kind of exercise?
• Intensity, Frequency
Mode (Aerobic, Strength, Inspiratory, Tai chi)
• Each has different physiological benefits
–
–
–
–
–
–
Aerobic
Strength
Balance
Respiratory
Cognition
Genetic
707
nonsmoking
retired men,
ages 61-81
12 year follow-up:
Those who walked <1 mile/day
were nearly twice as likely to
die as those who walked >2
miles a day
PCI compared with Exercise Training
Exercise Rx
Event
EventFree
free
Survival
Stent Rx
survival
(%)
Exercise Capacity, Symptoms, Costs: Superior with exercise training
R. Hambrecht, Circulation. 2004;109:1271-8
Strength training to modify aerobic
changes in older HF patients
Results
Pre-Ex
Post-Ex
p-value
Peak VO2 (ml O2/min)
906±65
1066±69
p<.05
Ventilatory Anaerobic
Threshold (VAT)
671±34
755±34
p<.04
6 Min Walk (m)
388±13
452±7
p<.0007
No significant changes in BMI, RER, or heart rate
• Resistance training
improves muscle
strength and endurance
by 25% to 100% in men
and women of all ages
Exercise as Therapy
• Mortality, Morbidity, Impact other RF (e.g., BP
and weight
• Coaching: aerobic, strength, balance
– Safety (especially in context of frailty and
multi-morbidity)
• Behavior
• Logistics
• Cost
Ironically: Relatively Few Older Patients
are Referred to CR
Suaya J, et al. Circulation. 2007;116:1653-62
Paradigm of Cardiac Rehabilitation
(1970’s-1980’s)
• Is it still relevant?
– Completed MI
– Ischemic cardiomyopathy
• Pro-ischemic
• Pro-arrhythmic
• Hemodynamically unstable
Obstacles to Exercise:
paradoxical behaviors
Cardiac Rehabilitation and Survival
Cumulative Mortality Rate
N=601,099
21-34% Mortality
Reduction
• Advanced ages
• Socioeconomic
range
• Severity of dz
• Extent of
comorbidity
Months from Discharge
Suaya JA, et al. JACC. 2009
Other Relevant CR Endpoints
• Risk Factors
• Functional Capacity
– Physical
– Cognitive
• QOL,  Self-efficacy, Dyspnea, Energy
• Rehospitalization
Multiple Therapeutic Concerns
Addressed in Cardiac Rehabilitation
• Compliance, Education, Polypharmacology
• Depression, ETOH
• Sleep, OSA
• Diet (esp. in relation to fluctuating psychosocial circumstances)
Expanding Role of Cardiac
Rehabilitation in a Capitated
Medical Environment World
Statins
(hydroxy-3-methylglutaryl co-enzyme A reductase
inhibitor)
• Cholesterol benefits
• Pleotropic benefits
– Potent anti-atherogenic
benefit
– Anti-inflammatory
– Anti-oxidant
• Favorable safety
profile
Epidemiological Distortion
• Low cholesterol, good or bad?
Major Secondary Prevention Statin
Study
Trials
Treatment; duration; % elderly
Risk Reduction
≥65 yrs
<65 yrs
-28% death
-42% CHD
death
-35%
events
4S
(4444)
Simvastatin 20-40 mg
5.4 yrs
23% elderly (65-70)
-34% death
-43% CHD
death
-34%
events
CARE
(4159)
Pravastatin 40 mg
5 yrs
31% elderly
-45% CHD
death
-23%
events
NS CHD
death
-19%
events
PROVE-IT
(4162)
Atorvastatin 80 mg
Pravastatin 40 mg
2 yrs; 30% elderly
-20%
events
-21%
events
Primary and
Secondary
Prevention
HPS (20,536)
(10,697 ≥65 yrs)
(5806 ≥70 yrs)
(1265 75-80)
Simvastatin 40 mg
5 years
Benefits even for those
with baseline chol <100
All-cause mortality -13%
Vasc death 17%
Vasc events -25%
Revascularization -29%
-5% absolute risk reduction
in the 75-80 yr population
PROSPER (5,804)
(70-82 yrs)
Pravastatin 40 mg
3.2 years
-24% CHD death
-15% events
-2.1% absolute reduction of
CHD events
Statins to Prevent Mortality in Older
Adults
Hierarchical Bayesian Meta-Analysis
N=19, 569, age 65-82
Statin therapy reduced the incidence of all-cause mortality by 22%. # needed
to treat: 28.
Afilalo J, J Am Coll Cardiol 2008;51:37–45)
Age-Specific Impact May be
Benefits
of Statins post AMI
Relevant in Advanced Age
Hazard Ratio
Age 80
yrs
Age
Foody JM, et al. J Am Geriatr Soc. 2006; 54(3): 421–430
Probability of Prescribing Statins
Relative to Age and Baseline Risk
(396,077 Ontario Residents with known CAD)
Highest risk patients
are the Lo
least likely to
receive a statin
Probability of
Statin Use
Low
Median
High
• CVA
• PAD
Age
Ko DT, JAMA 2004;291:1864–70
Effect of Statin Withdrawal on MMSE
• 18 pts with mild cognitive
impairment or dementia on
statins
• Mean age 77 yrs, 78% women
• Statins withdrawn for a mean
of 4.8 weeks
• Change in MMSE score:
18.8 ± 5.6 to 22.4 ± 5.1
mean increase 19%, p < 0.001
J Am Geriatr Soc 2010;58:1214-6
Statin Therapy, Muscle Function, and
Falls Risk in Community-Dwelling
Older Adults
D Scott, et al. QJ Med. 2009;102:625-33
• Statins exacerbating muscle decline and
proclivity to falls
Utility of Statins for Nonagenarians
Clas
s
Recommendation
LOE
IIa
It is reasonable to use statins for secondary prevention
in robust nonagenarians who value length of life.
D
IIb
Statins may be considered for secondary prevention in
nonagenarians of average health who value length of
life.
Statins may be considered for secondary prevention in
robust nonagenarians who value quality of life
D
III
Statins are not indicated for secondary prevention in
nonagenarians in frail health.
Statins are not indicated for primary prevention in
nonagenarians regardless of health status.
D
Michael Rich, Washington University
Unresolved Issues
• Dose, Type
• Clinical goals
• Side effects
– Cognition
– Myalgias
– Diabetes
• 2 years for trial benefits
Obesity
in US Adults
2003
Obesity
in US Adults
2003
Epidemiological Distortion
• Is weight loss good or bad?
Obesity
• Over a third of adults are obese (likely
underestimate):
physical activity and  metabolism.
• Weight loss protective but also a risk.
• Weight reduction:
– blood pressure control
– insulin sensitivity
– physical function
Diabetes Prevention Program
31%
58%
• 7% weight loss
• 150 minutes exercise/week
WC Knowler et al, NEJM. 2002;346:393-403
How to Increase Age-Specific Relevance of
Evidence Based Medicine?
• Mortality endpoints often less relevant to seniors than
quality of life
– ↓ Hospitalizations; Improved transitions
– ↑ Personal independence; ↓disability,
↓dependency
– Relieve symptoms, ↑ functional capacity
– ↓ Costs
– Improve manner and quality of death
Multimorbidity
Depression
COPD
Heart Failure
Conclusions
• Prevention of aging, Prevention of CVD
– National and International
– Primary, Secondary
– Best to start early
• BP, exercise, cholesterol, weight control
important prevention goals
• Better risk stratification needed
• Broad effects of meds need to be better studied
• Therapeutic goals and clinical endpoints
pertinent to elderly need to be clarified.
Biology