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									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
  Email @
 Hidden Overlap of Atherothrombotic
       Coronary                                  Cerebrovascular
        Artery        40%     15%      16%           Disease
                        11%         3%

    38% overlap                           Peripheral Arterial Disease
( 2 vascular beds)

           Patients with one manifestation
   often have coexistent disease in other vascular
                            Ness J, Aronow WS. JAGS. 1999;47(10):1255-56.

Identify high-risk patients and determine
  benefits of treatment.

Strategy and recommendations for obtaining
  safe optimal aggressive treatment goals.
 Atherothrombosis: A Progressive
                              Occlusive      Rupture/
          Fatty     Fibrous Atherosclerotic  Fissure &       Unstable
Normal   Streak     Plaque      Plaque      Thrombosis        Angina




Clinically Silent     Effort Angina
                                                         Critical Leg
                      Claudication                        Ischemia

            Increasing Age                                  Courtesy of P Ganz.

        Final Result

“To a man with a hammer every
 nail looks like it needs driving”.
                   …Mark Twain
    Characteristics of Plaques Prone to Rupture
                                                Fibrous cap

                      area of
                       detail                core

                 "Vulnerable" plaque

                       Lumen                                  – T-lymphocyte
                                     Lipid                    – 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
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                                             Goals
A    • Antiplatelets/anticoagulants                     • Treat all high-risk patients with one
                                                          or both of these (ASA, clopidogrel)
     • ACE inhibitors/ARBs                              • Optimize BP especially if CVD,
                                                          type 2 diabetes, or low EF present
                                                        • Relieve anginal symptoms, allow
     • Antianginals (b-blockers)                          patient to exercise

B    • BP control                                       • Aim for BP <130/85 mm Hg, or
                                                          <130/80 mm Hg for type 2
     •                                                  • 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                                        Goals
 C • Cholesterol                                    • LDL-C targets, ATP III
     Management*                                      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                                       Goals
D • Dietary/weight                              • Achieve optimal BMI
    counseling                                  •  saturated fats;  fruits,
                                                  vegetables, fiber (South
    • Diabetes management                       • Achieve HbA1c <7%

E • Exercise                                    • Improve physical fitness
                                                  (aim for 30 min/d on most
                                                  days per week)
    • Education of patients                     • Optimize awareness of
      and families                                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

   LDL-C          Non HDL-C

                JAMA 2001; 285: 2486-2497.
• 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

                          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
        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              Optional goal
risk factors including DM, tobacco dependence,
MetS,or severe or poorly controlled risk factors (eg    < 70mg/dL.
HBP or recent MI, ACS or recurrent symptoms on Tx.
Moderate Risk: Two or more risk factors (10-            < 130mg/dL.
yr risk < 10%).
High Moderate Risk: Two or more risk                    < 100mg/dL.
factors (10-yr risk > 10%).

              Circulation July 13 2004; 110: 227-239.
 NCEP III Update Based on 5 Clinical Trials
Trial Name                         Statin Therapy             Summary
HPS: Heart Protection              Simvastatin 40mg     20,536 subjects, 5 years, 30%
Study.                             vs placebo           reduction LDL-C, significant
Lancet 2002; 360: 7-22                                  reduction of CV events.
                                                        Even with starting LDL-C < 100
PROSPER: Prospective Study         Provastatin 40mg     5,804 subjects, 3.2 years, 27%
of provastatin in the elderly at   vs placebo           decrease in LDL-C, significant
risk. Lancet 2002; 360:1623-30.                         reduction of CV events.

ALLHAT: Anti-hypertensive and      Provastatin vs       10,355 subjects, No significant
lipid-lowering treatment to        usual care           difference.
prevent heart attack trial.
JAMA 2002; 288: 2998-3007.
ASCOT-LLA: Anglo-                  Atorvastatin 10 mg   10,305 hypertensive subjects,
Scandinavian cardiac outcomes      vs placebo           29% decrease in LDL-C,
trial lipid lowering arm.                               terminated early because of a
Lancet 2003; 361: 1149-1158                             significant reduction in CV
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 Lipid-
        Lowering Therapy

• Before NCEP ATP III Update.

• Will be even more difficult reaching LDL-C
  goals post update.

       The CARDS data strongly
demonstrateas the safety and benefits
 of statin therapy in T2DM regardless
              of baseline LDL-C.
Comparative Efficacy of Available
Available Statins                    % LDL-C reduction
Rosuvastatin 5mg
Atorvastatin       10mg                33-39%
Simvastatin        20mg
Lovastatin         40mg
Pravastatin        40mg
Fluvastatin        80mg
                         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

“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-HDL-
C 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

               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
 • 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 cholesterol-
  lowering efficacy.
• Listen to the patient first (muscle pain
  weakness or stiffness).
• Negative placebo situation
    Positive placebo effect
• Temporarily stop, reduce the dose or
  switch (every other day dosing is
  frequently as effective with reduced side
              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
 (Cardio) Level

         1 mg/L     3 mg/L            10 mg/L                                     >100 mg/L

        Low    Moderate      High                  Acute Phase Response
        Risk    Risk         Risk            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
  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.
          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]
• 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.
“Preventing a Broken Heart”
   …The time is now!
                Sample Case 1
• Male, age 62.                  Access Risk: “Setting”
  Original Lipid Panel as of     CHD Risk calculation
  TC = 210, HDL-C = 25,          Goals of therapy:
   LDL-C = 124. TG = 307         (Based on NCEP ATP III updated)
  Non HDL-C = 210 - 25 = 185
                                 • LDL-C
• Lipid Panel as of 1/2005: on   • Non-HDL-C
  TriCor 145 mg and Lipitor
• TC = 148, HDL-C = 23, LDL-C
  = 67, TG = 291 Non HDL-C
  = 125                          • 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.                                What is the plan?
• Female now age 45 with - FH
  no other risk factors, quite fit.
  Chest CT for Calcium = 0.
                                      What does NCEP III recommend?
• 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.
            Sample Case 3.
• TC = 364               • What do you want to
• Triglycerides = 219      know?
• HDL-C = 39
• VLDL -C (calculated)
  = 44
• LDL-C = 281
• Non HDL-C = 364 -
  39 = 325
            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.
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by Mario L Maiese
Relationship Between LDL-C and
 HDL-C Levels & Coronary Risk

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