Transcript LIPIDS - South Jersey Heart Group - 3

Prevention of a “Broken Heart”
Prevention of a “Broken Heart”
February 16 2005
Mario L Maiese DO FACC FACOI
Associate Professor UMDNJSOM
South Jersey Heart Group
www.sjhg.org
Email @ [email protected]
Hidden Overlap of Atherothrombotic
Disease
Coronary
Artery
Disease
40%
15%
16%
Cerebrovascular
Disease
9%
11%
38% overlap
( 2 vascular beds)
3%
6%
Peripheral Arterial Disease
Patients with one manifestation
often have coexistent disease in other vascular
beds
Ness J, Aronow WS. JAGS. 1999;47(10):1255-56.
Dyslipidemia:
Identify high-risk patients and determine
benefits of treatment.
Strategy and recommendations for obtaining
safe optimal aggressive treatment goals.
Atherothrombosis: A Progressive
Process
Normal
Fatty
Streak
Plaque
Rupture/
Occlusive
Fissure &
Fibrous Atherosclerotic
Thrombosis
Plaque
Plaque
Unstable
Angina
MI
Coronary
Death
Stroke
Clinically Silent
Effort Angina
Claudication
Increasing Age
Critical Leg
Ischemia
Courtesy of P Ganz.
Thrombotic
occlusion
Final Result
Normal
blush
“To a man with a hammer every
nail looks like it needs driving”.
…Mark Twain
Characteristics of Plaques Prone to Rupture
Fibrous cap
Media
Lumen
Lipid
area of
detail
core
"Vulnerable" plaque
– T-lymphocyte
Lumen
Lipid
core
– Macrophage foam cell (tissue factor +)
– "Activated" intimal SMC (HLA-DR+)
– Normal medial SMC
"Stable" plaque
Libby P. Circulation. 1995;91:2844-2850.
“If prevention is your goal
focus on the donut, not the hole”.
Lesion growth
Mechanism of Plaque Disruption in
Atherothrombosis
It is this "hidden disease" – the
presence of vulnerable plaques
throughout the coronary tree –
that is the target of long-term
treatment with high-dose
statins, aspirin, ACE inhibitors.
ABCs of CVD Risk Management
Intervention
A
• Antiplatelets/anticoagulants
• ACE inhibitors/ARBs
• Antianginals (b-blockers)
B
• BP control
•
Goals
• Treat all high-risk patients with one
or both of these (ASA, clopidogrel)
• Optimize BP especially if CVD,
type 2 diabetes, or low EF present
• Relieve anginal symptoms, allow
patient to exercise
• Aim for BP <130/85 mm Hg, or
<130/80 mm Hg for type 2
diabetes
• Post MI or low EF
CVD=cardiovascular disease; ACE=angiotensin converting enzyme;
ARB=angiotensin receptor blocker; BP=blood pressure; EF=ejection fraction;
MI=myocardial infarction.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
ABCs of CVD Risk Management
Intervention
C • Cholesterol
Management*
Goals
• LDL-C targets, ATP III
guidelines
– CHD, CHD risk
equivalents: <100 mg/dL*
– 2 RF: <130 mg/dL*
– 0-1 RF: <160 mg/dL
• HDL-C: 40 mg/dL (men)
50 mg/dL (women)
• TG: <150 mg/dL
• Cigarette-smoking cessation • Long-term smoking cessation
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
* Circulation July 13 2004; 110: 227-239.
ABCs of CVD Risk Management
Intervention
D • Dietary/weight
counseling
• Diabetes management
E • Exercise
• Education of patients
and families
Goals
• Achieve optimal BMI
•  saturated fats;  fruits,
vegetables, fiber (South
Beach)*
• Achieve HbA1c <7%
• Improve physical fitness
(aim for 30 min/d on most
days per week)
• Optimize awareness of
CAD risk factors
BMI=body mass index; HbA1c=glycosylated hemoglobin;
CAD=coronary artery disease.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105. *JAMA Nov 2004;2442-2490.
Cholesterol Management
…per NCEP III Guidelines
PRIMARY GOAL:
LDL-C
SECONDARY GOAL:
Non HDL-C
JAMA 2001; 285: 2486-2497.
Non-HDL-C
• Provides a measure of all the cholesterol in
atherogenic particles including LDL-C, Apo B, LP(a)
and TG-rich particles in VLDL,VLDL remnants and
intermediately dense lipoproteins.
• Introduced as the secondary target of therapy in
patients with high TG (> 200mg/dL) per NCEP ATP
III.
JAMA 2001; 285: 2486-2497.
NCEP III Non HDL-C Goal
• Non-HDL-C = TC - HDL-C
• Goal Non-HDL-C is 30mg > LDL-C goal
Must be remembered that LDL-C and non
HDL-C goals are surrogates for the
number 1 lipid risk factor which is Apo B
(a marker of atherogenic lipoproteins).
Modifications to NCEP III
• TLC was re-emphasized.
• Use of the Framingham CAD risk
calculator was recommended.
Circulation July 13 2004; 110: 227-239
Coronary Artery Disease
Calculator
Modifications to NCEP III
Risk Category
LDL-C Goal
High Risk: CHD,PAD, Carotid vasc. Dx, AAA or < 100mg/dL.
CHD risk equivalents (DM or 10-yr CHD risk > 20%)
Very High Risk: Above plus having multiple
risk factors including DM, tobacco dependence,
MetS,or severe or poorly controlled risk factors (eg
HBP or recent MI, ACS or recurrent symptoms on Tx.
Moderate Risk: Two or more risk factors (10-
Optional goal
< 70mg/dL.
< 130mg/dL.
yr risk < 10%).
High Moderate Risk: Two or more risk
factors (10-yr risk > 10%).
Circulation July 13 2004; 110: 227-239.
< 100mg/dL.
NCEP III Update Based on 5 Clinical Trials
Trial Name
Statin Therapy
Summary
HPS: Heart Protection
Study.
Lancet 2002; 360: 7-22
Simvastatin 40mg
vs placebo
20,536 subjects, 5 years, 30%
reduction LDL-C, significant
reduction of CV events.
Even with starting LDL-C < 100
PROSPER: Prospective Study
of provastatin in the elderly at
risk. Lancet 2002; 360:1623-30.
Provastatin 40mg
vs placebo
5,804 subjects, 3.2 years, 27%
decrease in LDL-C, significant
reduction of CV events.
ALLHAT: Anti-hypertensive and
lipid-lowering treatment to
prevent heart attack trial.
JAMA 2002; 288: 2998-3007.
Provastatin vs
usual care
10,355 subjects, No significant
difference.
ASCOT-LLA: AngloScandinavian cardiac outcomes
trial lipid lowering arm.
Lancet 2003; 361: 1149-1158
Atorvastatin 10 mg
vs placebo
10,305 hypertensive subjects,
29% decrease in LDL-C,
terminated early because of a
significant reduction in CV
events.
JAMA 2001; 285: 2486-2497.
Safety Analysis of Intensive Tx
• Among subjects treated with intensive statin therapy
following ACS, there were lower rates of clinical
events in those patients who achieved LDL-C < 60
mg/dL (or < 40 mg/dL) compared with those in the >
80-100 mg/dL range.
• Lipid levels well below the current guidelines were not
associated with worse safety outcomes.
• Therefore, there is no need to reduce statin dosage if
the LDL-C levels are below target goal.
Circulation 2004;110:III-498. Abstract 2340.
“Very High Risk” Patients
The updated NCEP III definition of “high
risk” requires established CVD plus:
• Multiple risk factors (especially diabetes).
• Severe and poorly controlled risk factors
(especially continued cigarette smoking).
• Multiple risk factors for MetS (especially
high TG >200 plus non HDL-C >
130mg/dL with low HDL-C [< 40mg/dL]).
• Patients with ACS.
The Forgotten Cardiac Risk Factor:
Noncompliance With LipidLowering Therapy
• Before NCEP ATP III Update.
• Will be even more difficult reaching LDL-C
goals post update.
Conclusion:
The CARDS data strongly
demonstrateas the safety and benefits
of statin therapy in T2DM regardless
of baseline LDL-C.
Comparative Efficacy of Available
Statins
Available Statins
% LDL-C reduction
Rosuvastatin 5mg
Atorvastatin
10mg
Simvastatin
20mg
Lovastatin
40mg
Pravastatin
40mg
Fluvastatin
80mg
33-39%
Roberts WC. Am J Cardiol. 1997; 80: 106-107.
Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997; 2: 7-16.
Even with optimal statin treatment:
----30- 40% reduction in CV events with
statins.
“There is 50% to 60% risk we’re
not addressing”.
Preliminary data suggests that
combination therapy is much more
efficacious in ↓ CV events (> 75%) not surprising given that the lipid
lowering effect is much greater.
Be aggressive with
combination therapies.
In insulin resistant patients with abnormalities of the
TG/HDL-C axis statin/Zetia/TriCor would solve the
overwhelming majority of lipoprotein abnormalities
seen in most patients (getting to LDL-C and non-HDLC goals (apoB surrogate markers).
Efficacy of HDL-C Increasing Compounds
• Fibrates reduce major coronary events and increase
HDL-C without significant toxicity.
• Niacin has a more potent effect on HDL-C levels, but
data on CV event reduction are limited.
• HDL-C will probably be the “next target” over the next 10
years.
J Am Coll Cardiol January 18 2005; 45: 185-197.
AFREGS: Armed Forces Regression Study
A combination of 3 drugs aimed at
increasing HDL-C (niacin, fibrates and
cholestyramine):
• Improves cholesterol profiles.
• Helps halt angiographic progression of
coronary stenosis.
• May help prevent CV events.
Ann Intern Med January 18 2005; 142: 95-104.
Adverse Effects of Statins
• Myalgias (muscle pains), which is seen in 2% to
4% of patients.
• Myopathy (10x NL CPK) including
rhabdomyolysis (> 10,000 CPK) is very rare:
Incidence =0.5-1 in 10,000 patients.
• Increased values in liver function tests (LFTs)
in ~ 1% of patients, significant elevations > than
3x NL up to 2% or 2.5% with the highest doses
of statins.
Adverse Effects of Therapy
• Risk usually increases with dose escalation.
• Risk is higher in women, older age (> 60),
dehydration or those with underlying renal or
liver disease.
• Risk increases with combination therapy.
• Risk is not directly proportional to cholesterollowering efficacy.
Management
• Listen to the patient first (muscle pain
weakness or stiffness).
• Negative placebo situation
Balance
Positive placebo effect
• Temporarily stop, reduce the dose or
switch (every other day dosing is
frequently as effective with reduced side
effcts).
Take Home Points
• In nearly all cases increased LFTs and myopathy are
reversed after discontinuation of the statin or fibrate.
• Fenofibrate (Tricor) is safe in combination with all
statins (though more expensive). Gemfibrozil (Lopid)
in combo increases statin levels and possibly CPK
levels and muscle symptoms with all statins except
fluvastatin and minimally with pravastatin.
• Niacin in combination with statins appears to have a
much lower risk of myopathy.
Clinical concerns (side effects,
cost and tolerability) must always
be balanced in each individual
case with benefit.
Assess and Identify Risk
“Are you done with that?”
STELLAR trial,
• Rosuvastatin (Crestor) blew away all the
other statins in its ability to reduce the
atherogenic lipoproteins so prevalent in
metabolic syndrome patients.
(Am J Cardiol 2005;95:360–366)
Clinical Application of hs-CRP for Cardiovascular Risk Prediction
hs-CRP
(Cardio) Level
1 mg/L
Low
Risk
3 mg/L
Moderate
Risk
10 mg/L
High
Risk
>100 mg/L
Acute Phase Response
Ignore Value, Repeat Test in 2 weeks
Risk Category
Adapted from Pearson TA, et al. AHA-CDC Scientific Statement.
Circulation. 2003;107:499-511.
PROVE-IT proves it for
inflammation
Table 1. Age-adjusted Event Rates According to LDL
and CRP Level Achieved with Statin Therapy.
Individually
Together
LDL-C > 70 4.0
LDL-C >70, CRP >2
4.6
LDL-C < 70 2.7
LDL-C < 70, CRP >2
3.1
CRP > 2
3.9
LDL-C >70, CRP < 2
3.2
CRP < 2
2.8
LDL-C < 70, CRP < 2
2.4
N Engl J Med January 6 2005; 352: 20-28.
TLC
The Problem:
“Will power only lasts 3 weeks and in
addition it is alcohol soluble.”
….Don’t have a pill for diet & exercise.
Medical Treatment (Based
on the Guidelines) is
determined by risk
• LDL-C goals: Usually statins first
Non- HDL-C goals: Will usually
necessitate combination tx
[fenofibrate &/or ezetimibe – preferred]
STATINS
COMBINATION THERAPY
GEMS
• NCEP states that when Non HDL-C is not
achieved on lifestyle and a statin, that is
when the benefit outweighs any risk of
adding a fibrate or niacin of the statin.
• Combinations of statins, ezetimibe and
fibrates (fenofibrate) seems to be the best.
CONCLUSIONS
“Preventing a Broken Heart”
…The time is now!
Sample Case 1
• Male, age 62.
Original Lipid Panel as of
9/2004:
TC = 210, HDL-C = 25,
LDL-C = 124. TG = 307
Non HDL-C = 210 - 25 = 185
• Lipid Panel as of 1/2005: on
TriCor 145 mg and Lipitor
20mg
• TC = 148, HDL-C = 23, LDL-C
= 67, TG = 291 Non HDL-C
= 125
Access Risk: “Setting”
CHD Risk calculation
Goals of therapy:
(Based on NCEP ATP III updated)
• LDL-C
• Non-HDL-C
Treatment:
• TLC
• Meds
No preventive cardiologist or
lipidologist can make accurate
assessments of RISK without
clinical details, including history
and physical examination. Docs
too often loose tract of the
essential fact that every bit of
advice we offer patients will
depend on the risk of that patient.
Sample Case 2
• Friend of mine: (1995), TC
272, TG 39, HDL-C 93, LDL-C
171.
• Female now age 45 with - FH
no other risk factors, quite fit.
Chest CT for Calcium = 0.
• Now: TC 335, TG 172, LDL-C
202, HDL-C 116.
Non HDL-C = 335 - 116 = 219
EBT Calcium score still is 0.
Hs-CRP 0.9, LP(a) 70.
What is the plan?
What does NCEP III recommend?
Sample Case 3.
•
•
•
•
TC = 364
Triglycerides = 219
HDL-C = 39
VLDL -C (calculated)
= 44
• LDL-C = 281
• Non HDL-C = 364 39 = 325
• What do you want to
know?
Tx Plan for Case 3
• 1) TLC: Mediterranean or South Beach diet and > 30 60 minutes aerobics daily. Take a treadmill exercise test
before starting serious exercise.
• 2) Crestor 20 mg daily along with Zetia 10 mg daily.
• 3) Wait two weeks, recheck lipids and if Non HDL-C still
abnormal start TriCor 160 mg daily.
• 3) Daily ASA (81mg).
• 4) Daily omega-3 FA supplement (Coromega, etc): Also
have option to push omega-3 FA to higher doses (3-6
gm) to help with the TG, will also increase HDL-C.
• 5) Must have a BP < 130/85 If up use an ACEI or ARB.
• 6) If obese and will not exercise, start metformin and
titrate to 2 gms daily.
Cure all Med
Survival of the Fittest
• More than 150 years after Darwin’s published
theory of evolution…
• Evidence continues to mount.
• There is a direct relationship of survival to
physical fitness.
Myers J et al. Exercise capacity and mortality among
men referred for exercise testing. N Engl J Med 2002; 346: 793-801.
Exercise
Photo Album
by Mario L Maiese
Relationship Between LDL-C and
HDL-C Levels & Coronary Risk