steven d. atwood, m.d., facp internal medicine, springfield, mo satwood@pol.net the issue of...
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Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO satwood@pol.net
The Issue of Treating
Cholesterol in the Elderly
The Issue of Treating
Cholesterol in the Elderly
statins treatment in the elderly 2
Clipped From the Headlines
• Statin therapy associated with reduced mortality across all age groups, including very elderly
• Statin therapy in the elderly—the evidence mounts
• Statins safe for elderly patients. New findings offer reassurance about cholesterol drugs
statins treatment in the elderly 3
Clipped From the Headlines
statins treatment in the elderly 4
The Real World
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
LDL=190 HDL=60 TG=180
10 years on a statin vs. the cost of losing 2 years of good life to a nursing home
“I’m Old But I’m Not Dead Yet”
statins treatment in the elderly 5
Today’s Goal
• Should I Treat
• Why
• Which Statin
Atherosclerosis
Is an inflammatory,
proliferative,
thrombotic
disease that occurs in response to risk factor activation of the endothelium.
Cholesterol and specifically oxidized LDL forms the bulk of the plaque
Atherosclerosis
Is an inflammatory,
proliferative,
thrombotic
disease that occurs in response to risk factor activation of the endothelium.
Cholesterol and specifically oxidized LDL forms the bulk of the plaque
CRPMyeloperoxidase
FibrinogenPAI
Nitrous Oxide
anti-oxidants
statins treatment in the elderly 8
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
statins treatment in the elderly 9
Development of Atherosclerotic Plaques
Normal
Fatty streak
Foam cells
Lipid-rich plaque
Lipid core
Fibrous cap
Thrombus
statins treatment in the elderly 10
statins treatment in the elderly 11
statins treatment in the elderly 12
LumenFibrous Cap
Lipid Core
Lipid Core
Fibrous Cap
Lumen
Vulnerable Plaque
Stable Plaque
• Thick fibrous cap• Smooth muscle cells: more extracellular matrix• Lipid-poor plaque
• Thin fibrous cap• Inflammatory cell infiltrates: proteolytic activity• Lipid-rich plaque
Libby P. Circulation. 1995;91:2844-2850.
Vulnerable vs. Stable Atherosclerotic Plaques Like
Diabetic
Enhanced by statins
Lot of Plaque before occlude lumen
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Lower Cholesterol Levels Associated With Lower CHD Risk
0
25
50
75
100
125
150
204 205-234 235-264 265-294 295
Castelli WP. Am J Med. 1984;76:4-12.
CH
D I
ncid
en
ce p
er
1000
Serum Cholesterol (mg/100 mL)
The Framingham Heart Study
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statins treatment in the elderly 15
What is the molecular basis for use of a statin?
How is the statin working?
statins treatment in the elderly 16
Statin Biochemistry
HMG-CoA Reductase
HMG CoA binding domain
tetrameric complex
Zoomed in view active site
positive hole
hydrophobicbinding site N
ONa
O
F
CH3
CH3
OH OH
CH4
1) One of the body’s most highly regulated enzymes
2) All statins are false substrates
Tetramic complex
statins treatment in the elderly 18
statins treatment in the elderly 19
You are what you eat
Be Afraid, Be Very Afraid
First step of therapy is always diet
20
All the Players• Cholesterol can’t 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
LDL
• Good cholesterol = HDL
• Bad cholesterol = LDL
• A good (apoA) B bad (apoB)
• Big good Small / dense bad
statins treatment in the elderly 21
All the Players
• Cholesterol can’t 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
omega-3
cold water fish SMASH
plant, Olive , Canola unsaturated short chains
animal fat = bad trans fat
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All the Players To dissolve and move Lipoproteins 5 complexes 4 key proteins groups
apo-proteins A BCE B
statins treatment in the elderly 23
A lot of studies in elderly, statins benefited ~30%
statins treatment in the elderly 24
statins treatment in the elderly 25
Benefit seen
by 1 year
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Primary EndpointPrimary EndpointPrimary EndpointPrimary Endpoint
CHD death, Nonfatal MI, Fatal or Nonfatal StrokeCHD death, Nonfatal MI, Fatal or Nonfatal Stroke
YearsYears
00
55
1010
1515
2020
PlaceboPlaceboEvents = 473/2913 (16.2%)Events = 473/2913 (16.2%)
PlaceboPlaceboEvents = 473/2913 (16.2%)Events = 473/2913 (16.2%)
PravastatinEvents = 408/2891 (14.1%)
PravastatinEvents = 408/2891 (14.1%)
% With Event
% With Event
15% RRR(P = 0.014)15% RRR(P = 0.014)
00 11 22 33
NNT = 48NNT = 48
PROSPER Study Group. Lancet. 2002; 360:1623-30.PROSPER Study Group. Lancet. 2002; 360:1623-30.
statins treatment in the elderly 27
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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Fatal or Non-Fatal MI
Placebo (158/1460)
Cu
mu
lati
ve P
rop
ort
ion
of
Ev
ents
0.000
0.025
0.050
0.075
0.100
0 1 2 3 4 5
Year
Prava (125/1436)ASA (626/5833)
Prava+ASA(445/5888)
31%*RRR
*Relative Risk Reduction
Meta-analysis
Pravachol and Aspirin = Pravigard combination -- more than additive
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statins treatment in the elderly 31
Pharmacokinetics of HMG-CoA Reductase InhibitorsPharmacokinetics of HMG-CoA Reductase Inhibitors
Increased Conc. With Inhibitors Increased Conc. With Inhibitors HMG-CoAHMG-CoA
Octanol/H2OCoefficient
Octanol/H2OCoefficient CYP450CYP450
YesYesSimvastatinSimvastatin 65.065.0 3A4/2D63A4/2D6
NoNoPravastatinPravastatin 0.20.2 NoNo
YesYesAtorvastatinAtorvastatin 15.015.0 3A43A4
YesYesFluvastatinFluvastatin 22.022.0 2C92C9
YesYesLovastatinLovastatin 16.016.0 3A43A4
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statins treatment in the elderly 33
statins treatment in the elderly 34
(cardiziem) (sporanox)
statins treatment in the elderly 35
Effects of CYP 3A4 Inhibitors on Statin Serum ConcentrationsEffects of CYP 3A4 Inhibitors on Statin Serum Concentrations
00
55
1010
1515
VerapamilVerapamil ItraconazoleItraconazole ErythromycinErythromycin
3.9 x3.9 x5.0 x5.0 x
10 x10 xElevations in
Serum Concentrations
Versus Placebo*
Elevations in Serum
Concentrations Versus
Placebo*
Kantola T et al. Clin Pharmacol Ther. 1998;64:177-182. Neuvonen PJ et al. Clin Pharmacol Ther. 1998;63:322-341. Kantola T et al. Clin Pharmacol Ther. 1998;64:177-182. Neuvonen PJ et al. Clin Pharmacol Ther. 1998;63:322-341.
* Area under the concentration-time curve (AUC) of active simvastatin acid* Area under the concentration-time curve (AUC) of active simvastatin acid
SimvastatinSimvastatin
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statins treatment in the elderly 37
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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 1) lipid solubility
2) increase serum levels via 3A4 up to 20 x increase e.g.. 5x with verapamil 5 125
3) damage to the needed cholesterol, ubiquinone prenalated proteins myopathy muscle cell death
1) for elderly known risk factors include: 1) age 2) muscle mass 3) obesity 4) female 5) impaired renal status
statins treatment in the elderly 40
Plavix
pro-drug activated by 3A4
Lipitor may diminish Plavix’s antiplatelet effect at least in the lab
1) Circulation 2003; 107: 1568-15692) Circulation 2003; 107: 32-37
3) Euro Heart J 24 (19) October 2003, 1744-1749 4) Circulation 2003;108:921-924
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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)
statins treatment in the elderly 42
Statin Pleiotropic Effects or non-Cholesterol Effects
1. Decrease inflammation– decrease CRP2. Decrease lipid oxidation3. Decrease thrombosis4. Decrease transplant rejection
(routinely use with transplants)5. Increase endothelial medial vasodilation
increased nitrous oxide production6. Increased osteoblastic activity (reduced hip fx)
statins treatment in the elderly 43
Statin Biochemistry
GTP enzyme anchors cell signaling proliferation production cytokines
thrombosis, inflammation, nitrous oxide production
statins treatment in the elderly 44
So Many Choices, So Little Time
• 6 types options for present statins39
■
statins treatment in the elderly 45
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
statins treatment in the elderly 46
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
7. hematuria
8. to much suppression
9. 2C9
10. superpower in most fragile
statins treatment in the elderly 47
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
LDL=190 TC=260 HDL=60 TG=180
10 years on a statin vs. the cost of losing 2 years of good life to a nursing home
statins treatment in the elderly 48
statins treatment in the elderly 49
statins treatment in the elderly 50
Risk Assessment: FHS Score for Men
<0 <10 11 12 13 14 15 26 27 38 49 5
10 611 812 1013 1214 1615 2016 25
17 30
Point Total10-Year
CHD Risk (%)
Low
Moderate
High
Risk Factor Points
1) Age 13
2) Total C 0
3) HDL-C 1
4) BP 2
5) Smoking 0
Point Total 16
www.nhlbi.nih.gov
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PRO: Clinically Demonstrated
Pros and Cons of a Statin in Elderly
1. 19% MI
2. 15% all key vascular events
3. # to treat for benefit < 50
4. CRP
5. benefit seen by year 1
7. osteoporosis FX
8. dementia
9. diabetes 10. similar all tertiles of LDL
(even low LDL levels benefited)
11. transplant rejection
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PRO: Demonstrated in Lab
Pros and Cons of a Statin in Elderly
1. thrombosis
2. endothelial function
3. osteoblasts clasts
4. Stabilize plaque
7. Inhibit PAI-1 which is primary inhibitor of fibrinolysis
8. Vasodilation NO
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CON
Pros and Cons of a Statin in Elderly
1. Adverse drug-drug rxn
2. Cost
3. One more pill
4. Muscle problem
5. T killer cells
6. Liver / kidney insufficiency
7. Quality of life
8. > 1 year see benefit
9. Overall death rate =
10.Life expectancy
“Probably the most important single pathological process underlying disability in old age is atherosclerosis”
JC Brocklehurst. The Atlas of Geriatric Medicine
statins treatment in the elderly 55
Prevent Heart Disease
Prevent Stroke
Increase length of life
Improve quality of life
Goals of Treating the Elderly
statins treatment in the elderly 56
Clinical example RX age 80
Less time in nursing home ($57k / yr) VSCost & supervision
Selection: drug-drug / proven / cost
57statins treatment in the elderly
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)
Prevention always the best treatment
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