Steven%20D.%20Atwood,%20M.D.,%20FACP

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The Issue of Treating Cholesterol in
the Elderly

• Steven D. Atwood, M.D., FACP
• Internal Medicine, Springfield, MO
  satwood_at_pol.net

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Clipped From the Headlines

• Statin therapy associated with reduced mortality
  across all age groups, including very elderly
• Statin therapy in the elderlythe evidence
  mounts
• Statins safe for elderly patients. New findings
  offer reassurance about cholesterol drugs

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Clipped From the Headlines
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The Real World
Im Old But Im Not Dead Yet

• 80 y/o woman drives to office for yearly checkup
  controlled hypertension, fixed income, weighs
  110 A-Fib on diltiazem and coumadin
• 2 children in the area
• LDL190 HDL60 TG180 10 years
  on a statin vs.
  the cost of losing 2 years of good life to a
  nursing home

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Todays Goal

• Should I Treat
• Why
• Which Statin

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Atherosclerosis
Is an inflammatory,
proliferative,
thrombotic disease that occurs in
response to risk factor activation of
the endothelium.Chole
sterol and specifically oxidized LDL
forms the bulk of the plaque
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Atherosclerosis
CRPMyeloperoxidase
Is an inflammatory,
proliferative,
thrombotic disease that occurs in
response to risk factor activation of
the endothelium.Chole
sterol and specifically oxidized LDL
forms the bulk of the plaque
FibrinogenPAI
Nitrous Oxide
anti-oxidants
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Normal Arterial Wall
Tunica adventitia Tunica media Tunica intima
Endothelium Subendothelial connective
tissue Internal elastic membrane Smooth muscle
cells Elastic/collagen fibers External elastic
membrane
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Development of Atherosclerotic Plaques
Fatty streak
Normal
Lipid-rich plaque
Foam cells
Fibrous cap
Lipid core
Thrombus
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Vulnerable vs. Stable Atherosclerotic Plaques
Like Diabetic
Vulnerable Plaque
Lumen
Lipid Core

• Thin fibrous cap
• Inflammatory cell infiltrates
• proteolytic activity
• Lipid-rich plaque

Fibrous Cap
Enhanced by statins
Stable Plaque
Lumen

• Thick fibrous cap
• Smooth muscle cells
• more extracellular matrix
• Lipid-poor plaque

Lipid Core
Fibrous Cap
Lot of Plaque before occlude lumen
Libby P. Circulation. 1995912844-2850.
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Lower Cholesterol Levels Associated With Lower
CHD Risk
The Framingham Heart Study
150
125
100
CHD Incidence per 1000
75
50
25
0
265-294
? 204
205-234
235-264
? 295
Serum Cholesterol (mg/100 mL)
Castelli WP. Am J Med. 1984764-12.
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What is the molecular basis for use of a
statin?How is the statin working?
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Statin Biochemistry
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HMG-CoA Reductase
HMG CoA binding domain
Zoomed in view active site
1) One of the bodys most highly regulated
enzymes 2) All statins are false
substrates
positive hole
hydrophobic binding site
Tetramic complex
tetrameric complex
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You are what you eatBe Afraid, Be Very
AfraidFirst step of therapy is always
diet
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All the Players
LDL

• Cholesterol cant dissolve in water (blood)
• Cholesterol only comes from animals
  none in plants
• To dissolve and move Lipoproteins
• 5 complexes 4 key protein groups
• Good cholesterol HDL
• Bad cholesterol LDL
• A good (apoA) B bad (apoB)
• Big good Small / dense bad

• Good cholesterol HDL
• Bad cholesterol LDL

• A good (apoA) B bad (apoB)
• Big good Small / dense bad

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All the Players
omega-3 cold water fish SMASH plant, Olive
, Canola unsaturated short chainsanimal
fat bad trans fat

• Cholesterol cant dissolve in blood
• Cholesterol only comes from animals
  none in plants
• To dissolve and move Lipoproteins
• 5 complexes 4 key protein groups
• Good cholesterol Bad cholesterol
• A good B bad
• Big good Small / dense bad
• Bad fat Good fat

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All the Players To dissolve
and move Lipoproteins 5 complexes 4 key
proteins groups


apo-proteins A BCE B
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statins benefited 30
A lot of studies in elderly,
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Benefit seen by 1 year
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Primary Endpoint
CHD death, Nonfatal MI, Fatal or Nonfatal Stroke
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15 RRR (P 0.014)
Placebo Events 473/2913 (16.2)
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With Event
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NNT 48
Pravastatin Events 408/2891 (14.1)
5
0
0
1
2
3
Years
PROSPER Study Group. Lancet. 2002 3601623-30.
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Prosper

• The benefit of treatment in the elderly
• was the same as the benefit in the young

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Improvement at all levels of LDL

• If divide patients byhigh, medium, and low
  LDLEvent reduction similar for each group
• Seen in Prosper
• Seen in ALLHAT
• ALSO TREAT THE LOW LDL PATIENT ASCOT TRIAL

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Pravachol and Aspirin Pravigard
combination -- more than additive
Fatal or Non-Fatal MI
0.100
Placebo (158/1460)
0.075
0.050
Cumulative Proportion of Events
0.025
0.000
0
1
2
3
4
5
Relative Risk Reduction
Year
Meta-analysis
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Pharmacokinetics of HMG-CoA Reductase Inhibitors
Octanol/H2O Coefficient
Increased Conc. With Inhibitors
HMG-CoA
CYP450
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(cardiziem)
(sporanox)
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Effects of CYP 3A4 Inhibitors on Statin Serum
Concentrations
Simvastatin
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10 x
Elevations in Serum Concentrations Versus
Placebo
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5.0 x
3.9 x
5
0
Verapamil
Itraconazole
Erythromycin
Area under the concentration-time curve (AUC)
of active simvastatin acid
Kantola T et al. Clin Pharmacol Ther.
199864177-182. Neuvonen PJ et al. Clin
Pharmacol Ther. 199863322-341.
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Effects of Advancing Age on Drug Distribution
and Metabolism

• Decreased protein binding
• Increased volume of distribution for
  lipophilic drugs
• Decreased phase 1 (CPY 450) oxidation

Mayersohn M. Special Pharmacokinetic
Considerations in the Elderly in Evans WE
et.al. Eds. Applied Pharmacokinetics Principles
of Therapeutic Drug Monitoring, 2nd edition.
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• MYOPATHY
• lipid solubility
• increase serum levels via 3A4 up to 20 x
  increase e.g.. 5x with verapamil 5 125
  
• damage to the needed cholesterol, ubiquinone
  prenalated proteins myopathy muscle cell
  death
• for elderly known risk factors include
• 1) age
• 2) muscle mass
• 3) obesity
• 4) female
• 5) impaired renal status

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Plavix

• pro-drug activated by 3A4
• Lipitor may diminish Plavixs antiplatelet
  effect at least in the lab 1) Circulation
  2003 107 1568-1569 2) Circulation 2003 107
  32-37
• 3) Euro Heart J 24 (19) October
  2003, 1744-1749 4) Circulation
  2003108921-924

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Pleiotropic Effects or non-Cholesterol effects

• 1. Unstable angina (stabilize plaque)
• 2. DM 30 less (Pravachol woscops )
• 3. Osteoporosis (reduced hip fractures)
• 4. Stroke (Vasodilation - ?
  NO)
• 5. Less dementia (maybe-conflicting data)

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Statin Pleiotropic Effects or
non-Cholesterol Effects

• Decrease inflammation decrease CRP
• Decrease lipid oxidation
• Decrease thrombosis
• Decrease transplant rejection
  (routinely use with transplants)
• Increase endothelial medial vasodilation
  increased nitrous oxide production
• Increased osteoblastic activity (reduced hip
  fx)

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Statin Biochemistry
GTP enzyme anchors cell signaling
proliferation production cytokines thrombosis
, inflammation, nitrous oxide production
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So Many Choices, So Little Time

• 6 types options for present
  statins

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Prescription Options list

• 39 statin combinations
• Statins vary by 1. Side effects
• 2. Potency for
  lipids
• 3. Potency for
  Plieotropic effects
  4. Cost
• Geriatric side effects may be the major issue
  how is it metabolized
  does it have the best pleiotropic
  effect cost
  is the statin proven to help in the elderly

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Issues of Crestor in Elderly

1. lack of data
2. long half life
3. rhabdomyolysis
4. trouble clearing FDA
5. triple level in Asians
6. proteinuria

1. hematuria
2. to much suppression
3. 2C9
4. superpower in most fragile

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The Real World

• 80 y/o woman drives to office for yearly checkup
  controlled hypertension on med, BP 130/80fixed
  income, never smoked, A-Fib on diltiaziem
  coumadinweighs 110
• 2 children in the area
• LDL190 TC260 HDL60 TG180
  10 years on a statin
  vs. the cost of losing 2 years of good life to
  a nursing home

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Risk Assessment FHS Score for Men
Point Total
10-Year CHD Risk ()

• Risk Factor Points
• Age 13
• Total C 0
• HDL-C 1
• BP 2
• Smoking 0
• Point Total 16

lt0 lt1 0 1 1 1 2 1 3 1 4 1 5 2 6 2 7 3 8
4 9 5 10 6 11 8 12 10 13 12 14 16 15 20 16
25 ?17 ?30
Low
Moderate
www.nhlbi.nih.gov
High
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Pros and Cons of a Statin in Elderly

• PRO Clinically Demonstrated

• ? osteoporosis FX
• ? dementia
• ? diabetes
• ? similar all tertiles of LDL (even low LDL
  levels benefited)
• ? transplant rejection

1. 19 ? MI
2. 15 ? all key vascular events
3. to treat for benefit lt 50
4. ? CRP
5. benefit seen by year 1

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Pros and Cons of a Statin in Elderly

• PRO Demonstrated in Lab

• Inhibit PAI-1 which is primary inhibitor of
  fibrinolysis
• ? Vasodilation ? NO

• ? thrombosis
• ? endothelial function
• ? osteoblasts ? clasts
• Stabilize plaque

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Pros and Cons of a Statin in Elderly

• CON

1. Adverse drug-drug rxn
2. Cost
3. One more pill
4. Muscle problem
5. ? T killer cells
6. Liver / kidney insufficiency

• Quality of life
• gt 1 year see benefit
• Overall death rate
• Life expectancy

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Probably the most important single pathological
process underlying disability in old age is
atherosclerosis
JC Brocklehurst. The Atlas of Geriatric Medicine
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Goals of Treating the Elderly

• Prevent Heart Disease
• Prevent Stroke
• Increase length of life
• Improve quality of life

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Clinical example RX age 80

• Less time in nursing home (57k / yr)
• VS
• Cost supervision
• Selection drug-drug / proven / cost

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Prevention always the best treatment
Superior doctors prevent the disease.
Mediocre doctors treat the disease before
evident. Inferior doctors treat the
full-blown disease. --Huang Lee
Nai-Ching (2600 BC, First Chinese Medical Text)