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					A CV Risk Education Symposium
Integrating Total CV Risk
Management Into Clinical Practice
Welcome and Opening Remarks
      What Is the PCE?
 The Practicing Clinicians Exchange (PCE) is an
  innovative network of live educational activities and
  home study materials designed for NPs and PAs.
  This unique CME/CE format will provide NPs and
  PAs with educational opportunities built to meet
  real-world clinical needs

 The PCE’s goal is to provide practicing clinicians
  with comprehensive CME/CE programs in a variety
  of therapeutic areas, with opportunities to earn
  multiple CME/CE credits
      What Makes PCE Unique?
 Developed for NPs and PAs
 Symposium series integrated with live
  teleconference series and home study workbook
 Today’s symposium:
    Is case based
    Has been developed to meet your needs
    Includes case studies led by NPs and PAs
     (in concert with expert physician faculty)
    Includes full-panel Q&A sessions led by
     NPs and PAs
         Scientific Agenda

8:05 AM – 8:30 AM     The Case for Total CV Risk Management

8:30 AM – 9:30 AM     The Hypertension Component:
                      JNC 7 and Beyond

9:30 AM – 9:45 AM     Break

9:45 AM – 10:40 AM    The Dyslipidemia Component:
                      What Recent Clinical Trials Tell Us

10:40 AM – 11:35 AM   Managing Diabetes as a CHD Risk Equivalent

11:35 AM – 11:45 AM   Summary and Closing Remarks
       Why Are You Here Today?
 Which of today’s learning objectives are you
  most interested in?
  1. Explain the rationale for a global approach              ?
     to CV risk management
  2. Distinguish between primary and secondary
     CV risk management
  3. Extrapolate data from recent clinical trials to select
     appropriate pharmacologic and nonpharmacologic
     treatment for CV risk factors in clinical practice
  4. Apply current CV risk guidelines to clinical practice
  5. Employ techniques to help patients achieve CV risk
     management goals
Use your keypad to vote now!
The Case for Total
CV Risk Management
CV Risk:
The Scope of the Problem
                           Leading Causes of Death for All Males
                           and Females: United States, 2002

                                                                                Total CVD (preliminary)
                     500                                  494                   Cancer
                            434                                                 Accidents
Deaths (thousands)




                     400                                                        Chronic Lower
                                                                                  Respiratory Diseases
                                  289                                           Diabetes Mellitus
                     300                                        269
                                                                                Alzheimer’s Disease

                     200

                     100                 69     61                    64
                                                     34                    42     39
                       0
                                        Males                    Females

CVD = cardiovascular disease.
CDC/NCHS.
                               Prevalence of CHD by Age and Sex:
                               NHANES, 1999-2002
                                                      Males         Females
                          18                                                                  16.8
  Percent of Population




                          16
                          14
                          12                                        11.6         11.5
                                                                                                     10.3
                          10
                          8
                                                                                        6.3
                          6
                          4                             3.0                3.6

                          2               1.4                 1.6
                                0.0 0.3         0.2
                          0
                                 20-34    35-44         45-54    55-64           65-74         75+
                                                             Ages
NHANES = National Health and Nutrition Examination Survey. CDC/NCHS and NHLBI.
                               Prevalence of Stroke by Age and
                               Sex: NHANES, 1999-2002
                                                     Males         Females
                          14
  Percent of Population




                                                                                       12.0
                          12                                                                  11.5

                          10

                          8
                                                                             6.6 6.3
                          6

                          4                                        3.1 3.0
                                                             2.1
                          2                1.1 0.8     1.2
                                 0.4 0.3
                          0
                                 20-34     35-44       45-54    55-64        65-74      75+
                                                            Ages
CDC/NCHS and NHLBI.
                          Estimated Direct and Indirect Costs
                          of Cardiovascular Diseases
                          and Stroke: United States, 2005

                        450
                        400
  Billions of Dollars




                        350
                        300
                        250
                        200
                        150
                        100
                        50
                         0
                               Heart    Coronary   Stroke   Hyper-    Congestive   Total
                              Disease    Heart              tensive      Heart     CVD
                                        Disease             Disease     Failure

AHA. Heart Disease and Stroke Statistics—2005 Update.
CV Risk Factors:
An Intimate Interrelationship
          Impact of Elevated SBP and Total
          Cholesterol on CHD Mortality: MRFIT
                                              33.7
                                                                                           n = 202,620

    Age-Adjusted
   CHD Death Rates                                          21
     Per 10,000                        22.6                             17.1
                                                                                     12.7
                                                                                                            64% lower
    Person-years                                                                                  12.2
                                17.7
                                                                                                               risk
                                                     12.3
                                                                  8.3          9.6
                         16.7                                                               5.9             245
                                              10.9
                                                            8.5                                          221–244
                                                                        6.3          5.5
                  13.7                 7.9           7.9                                          203–220
                                                                  6                                         Cholesterol
                                                                               4.3
                                                                                            182–202          Quintile
                                 5            5.6
                                                            3.4         3.1           <182                   (mg/dL)
59% lower
   risk                                                                        91% lower
                         SBP Quintile (mm Hg)                                     risk
MRFIT= Multiple Risk Factor Intervention Trial; SBP = systolic blood pressure.
Adapted from Neaton JD, et al. Arch Intern Med. 1992;152:56-64.
                      Risk of CHD in Mild Hypertension by
                      Intensity of Associated Risk Factors
                                42                             40
       10-Year Probability of


                                36
                                30
            Event (%)




                                24                        21

                                18                14
                                             10
                                12
                                         6
                                 6   4

                                 0
Risk Factors
SBP 150-160 mm Hg                    +   +   +    +       +    +
TC 240-262 mg/dL                     −   +   +    +       +    +
HDL-C 33-35 mg/dL                    −   −   +    +       +    +
Diabetes                             −   −   −    +       +    +
Cigarette smoking                    −   −   −    −       +    +
ECG-LVH                              −   −   −    −       −    +
Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.
           Integrated Cellular
           Mechanisms of CVD

      Hypertension                  Dyslipidemia                   Diabetes


                            Endothelial Dysfunction


    NO Synthesis         COX Activity        Inflammation          Endothelin
   Vasoconstriction    Thromboxane A2       Leukocyte            Vasoconstriction
   Thrombosis          Prostaglandin H2      adhesion             Calcium
   Superoxide                                Endothelial           mobilization
                        Prostacyclin          permeability
                                              Foam cell
                                               formation
                                              T-cell activation

NO = nitric oxide; COX = cyclooxygenase.
Liao JK. Clin Chem. 1998;44:1799-1808. Libby P. J Intern Med. 2000;247:349-358.
Mason RP. Cerebrovasc Dis. 2003;16(suppl 3):11-17.
Examples of Clinical Trials That Are
Studying Multiple CV Risk Factors
            ASCOT: Study Design
                                       19,257                              ASCOT-BPLA
                            hypertensive patients (BPLA)                  Results reported
                                                                             in 2005
        amlodipine ±                    PROBE                      atenolol ±
         perindopril                                           bendroflumethiazide
                                         design
                                                                           ASCOT-LLA
                                10,305 patients (LLA)                     Results reported
                            TC ≤6.5 mmol/L (251 mg/dL)                       in 2003

        5168 patients                                               5137 patients
     atorvastatin 10 mg              Double-blind                     placebo

     Investigator-led, multinational randomized controlled trial
ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; BPLA = blood pressure–lowering arm;
LLA = lipid-lowering arm; PROBE = prospective randomized open blinded end points.
Adapted from Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.
           ASCOT: Patient Population Risk
           Factor Profile
    All patients in ASCOT had hypertension plus ≥3 risk factors for CHD
               Hypertension
             Aged ≥55 years
                       Male
Microalbuminuria/proteinuria
                    Smoker
      Family history of CHD
       Plasma TC:HDL-C ≥6
            Type 2 diabetes
  Certain ECG abnormalities
                        LVH
Prior cerebrovascular events
 Peripheral vascular disease

                               0   10   20   30   40    50    60    70    80    90     100
                                         Patients With Risk Factor (%)
ECG = electrocardiogram; LVH = left ventricular hypertrophy; TC = total cholesterol.
Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.
           ASCOT: Main Outcome Measure
 Combination of nonfatal MI and fatal CHD
 Results to be discussed later today




MI = myocardial infarction.
Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.
          Action to Control Cardiovascular
          Risk in Diabetes (ACCORD) Trial
 Randomized, multicenter clinical trial (75 sites in US and Canada),
  2x2 factorial design
 10,000 patients with type 2 diabetes (with and without existing CVD)
  at high risk for CVD events
 Will independently test 3 medical strategies to reduce CVD in
  patients with diabetes

               Intensive                                   Standard
A1C            <6%                                         <7.5%
SBP            <120 mm Hg                                  <140 mm Hg
Lipids         Statin to ↓ LDL                             Statin to ↓ LDL alone
               + fibrate to ↑HDL-C and ↓ TG

A1C = glycosylated hemoglobin. Available at: www.accordtrial.org/public/purpose.cfm.
           ACCORD: Main Outcome Measure
 First occurrence after randomization
  of a major CVD event
    Nonfatal MI
    Nonfatal stroke
    CV death
 Results to be published in 2010




Available at: www.accordtrial.org/public/purpose.cfm.
CV Risk Management:
What We Should Be Doing
         Primary and Secondary Prevention:
         Definitions
 Primary prevention
    Modification of risk factors or prevention of their
     development to prevent or delay the onset of CHD
 Secondary prevention
    Initiation of therapy to reduce recurrent CHD
     events and decrease cardiac mortality in patients
     with established CHD
 ―Primary and a half prevention‖*
    As patients with subclinical CHD are identified,
     the distinction between primary and secondary
     prevention becomes blurred

*Celermajer DS. JACC. 2005;45:1994-1996.
              Key Goals: JNC 7, NCEP, ADA,
              and AHA Guidelines
                                NCEP ATP III and
                   JNC 7         NCEP Report                 ADA*                            AHA
Blood         <140/90          NA                     <130/80          <140/90
pressure      <130/80 with                                             <130/85 with CHD or renal insufficiency
(mm Hg)       diabetes or                                              <130/80 with diabetes
              renal disease
LDL-C         NA               <160 if lower risk     <100             <160 if ≤1 risk factor
(mg/dL)                        <130† if moderate                       <130 if ≥2 risk factors and 10-year risk <20%
                               risk                                    <100 if ≥2 risk factors and 10-year risk ≥20%
                               <100‡ if high risk                      or diabetes
TG            NA               <150                   <150             Consider treatment after LDL-C goal reached;
(mg/dL)                                                                if 150-199, treat with diet and exercise;
                                                                       if 200, pharmacologic therapy
HDL-C         NA               40-60                  >40 in men       ≥40 in men
(mg/dL)                                               >50 in women     ≥50 in women
A1C (%)       NA               NA                     <7               <7
*For patients with diabetes. †Therapeutic option <100 mg/dL for patients at moderately high risk. ‡Therapeutic option
<70 mg/dL for patients at very high risk.
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35;S65-S67;S68-S71; Chobanian AV, et al.
JNC 7: Complete Report. 2003. Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206; Grundy SM
et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication No. 02-5215; Pearson TA, et al. Circulation.
2002;106:388-391.
          ACC/AHA ABC Approach to
          Primary and Secondary Prevention

               Antiplatelet therapy
               Anticoagulant therapy
      A
               Angiotensin-converting enzyme inhibitor
               Angiotensin receptor blocker
               Blood pressure control
      B        -blocker
               Cholesterol management
      C
               Cigarette smoking cessation
               Diet and weight management
      D
               Diabetes mellitus prevention and management
               Exercise
      E        Ejection fraction assessment and therapy

Complete sets of ACC/AHA guidelines available at www.acc.org and
www.americanheart.org.
Gluckman TJ, et al. Arch Intern Med. 2004;164:1490-1500.
       CV Risk Factor Evaluation:
       What to Consider
 ―Traditional‖ risk factors
 Framingham risk analysis
 Metabolic syndrome
 Atherosclerotic disease (or equivalence)
 ―Emerging‖ risk factors?

  More on these in the presentations to come!
      Conclusions: The Case for
      Total CV Risk Management
 CV disease remains the leading cause of death
  in both men and women in the US
 Framingham data show that CV risk factors tend to
  cluster—and that risk of death from CHD and stroke
  increases proportionately
 Endothelial dysfunction seems to be a key factor
  in the development of CV disease
 Recent clinical trials have given us a wealth of
  information with which to manage total CV risk
  and have led to updates of major clinical guidelines
Full Panel Q&A
The Hypertension Component:
JNC 7 and Beyond
                    Hypertension Affects Approximately
                    65 Million Americans: 28% of Adults
                   50                  Males       Females
                                                   40%
                                           38%
                   40
Hypertension (%)
 Population With




                         27%   27%                           29%   28%
                   30


                   20


                   10


                    0
                        Non-Hispanic      Non-Hispanic       Mexican
                           White             Black           American

Fields LE, et al. Hypertension. 2004;44:398-404.
                                            Blood Pressure: Lower Is Better
                                                      Ischemic Heart Disease Mortality
                                                           Age at Risk (Y)                                                              Age at Risk (Y)




                                                                             Ischemic Heart Disease Mortality
Ischemic Heart Disease Mortality




                                   256                          80-89                                           256                          80-89
                                   128                          70-79                                           128                          70-79
                                   64                           60-69                                           64                           60-69
                                   32                           50-59                                           32                           50-59
                                   16                                                                           16                           40-49
                                                                40-49
                                     8                                                                            8
                                     4                                                                            4
                                     2                                                                            2
                                     1                                                                            1
                                     0                                                                            0
                                          120 140 160 180                                                              70 80 90 100 110
                                         Usual Systolic BP (mm Hg)                                                    Usual Diastolic BP (mm Hg)

              BP = blood pressure.
              Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.
           JNC 7 Blood Pressure
           Classification

                                                 SBP                       DBP
                                               (mm Hg)                   (mm Hg)

Normal                                            <120             and     <80

Prehypertension                                120-139              or    80-89

Stage 1 hypertension                           140-159              or    90-99

Stage 2 hypertension                              ≥160              or    ≥100




DBP = diastolic blood pressure.
Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
           JNC 7 Goal Blood Pressures
 Most patients
   <140/90 mm Hg
 Patients with diabetes or chronic kidney disease
   <130/80 mm Hg
   Based mostly on observational data,
    not prospective clinical trials
 Patients with metabolic syndrome
   No specific recommendation
Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
          JNC 7: Algorithm for Hypertension
                                  LIFESTYLE MODIFICATIONS
                        Not at goal BP (<140/90 mm Hg or <130/80 mm Hg
                        for patients with diabetes or chronic kidney disease)
                                     INITIAL DRUG CHOICES

               Without Compelling Indications                  With Compelling Indications

   Stage 1 Hypertension           Stage 2 Hypertension           Drug(s) for Compelling
  Thiazide-type diuretics for     2-drug combinations for               Indications
     most; may consider          most (usually thiazide-type      Other antihypertensive
   ACEI, ARB, BB, CCB,              diuretics and ACEI,         drugs (diuretic, ACEI, ARB,
       or combination.            or ARB, or BB, or CCB).          BB, CCB) as needed.
              If not at goal BP, optimize dosages or add additional drugs until
           goal BP is achieved. Consider consultation with hypertension specialist.
Chobanian AV, et al. JNC 7: Complete Report. 2004.
Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
         Practicing Clinicians Case Study 1:
         A 33-Year-Old White Man Who
         Presents With Acute Back Pain
 Presents with acute low back pain following weekend
    racquetball game
   No other complaints
   ―Weekend warrior‖ lifestyle; nonsmoker; occasional ETOH
   Using this presentation to perform a CV risk assessment,
    you find
      BP:
        – 148/90 mm Hg (first reading)
        – 146/88 mm Hg (second reading)
      Height: 6' 0"; weight: 218 lb; waist: 39"
   You treat the acute low back pain and ask the patient to
    return for a more thorough evaluation of CV status
           Practicing Clinicians Case Study 1:
           Findings During Return Visit
 Family history not significant for CV disease
 High-sodium, high-fat diet
 Laboratory findings
      TC: 170 mg/dL
      LDL-C: 102 mg/dL
      HDL-C: 48 mg/dL
      TG: 100 mg/dL
      Fasting glucose: 96 mg/dL
      Serum creatinine: 0.9 mg/dL
       (GFR: 128 mL/min/1.73 m2)
      Dipstick: negative for protein
GFR = glomerular filtration rate.
          Practicing Clinicians
          Case Study 1: Decision Point
 Given the patient’s risk factor profile,
   how would you treat him?
   1. Prescribe diet/exercise regimen and
                                                                      ?
      determine in 3 to 4 months whether drug
      therapy is indicated
   2. Start a diuretic
   3. Start a diuretic and an ACE inhibitor
   4. Start a dihydropyridine CCB
Use your keypad to vote now!
ACE = angiotensin-converting enzyme; CCB = calcium channel blocker.
           JNC 7: Lifestyle Modifications to
           Prevent and Manage Hypertension

                                                      Approximate SBP
           Modification
                                                         Reduction
          Weight reduction                               5-20 mm Hg/10 kg

               DASH diet                                     8-14 mm Hg

          Sodium reduction                                    2-8 mm Hg

           Physical activity                                  4-9 mm Hg

Moderate alcohol consumption                                  2-4 mm Hg

DASH = Dietary Approaches to Stop Hypertension.
Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
      Practicing Clinicians
      Case Study 1: Decision Point
 The patient tells you he has been too
  stressed with work and family
  obligations to seriously follow his
                                                   ?
  diet/exercise regimen. What would you do next?
  1. Start a -blocker
  2. Start a diuretic
  3. Start a diuretic and an ACE inhibitor
  4. Start a dihydropyridine CCB
Use your keypad to vote now!
         Practicing Clinicians Case Study 1:
         CV Risk Management Pearls
 Lifestyle modifications alone may be sufficient
  for a young patient with stage 1 hypertension and
  no other CV risk factors (expert opinion)
 If lifestyle modifications do not achieve goal
  BP within 3-4 months, pharmacologic therapy can
  be prescribed (expert opinion)
 Excellent clinical trial outcome data prove that
  lowering BP with several classes of drugs, including
  ACEIs, ARBs, β-blockers, CCBs, and thiazide-type
  diuretics, will all reduce the complications of
  hypertension (JNC 7)
  ARB = angiotensin receptor blocker.
                                Newer Versus Older Agents:
                                ALLHAT
                               Primary End Point: Fatal CHD or Nonfatal MI
                               16
   Cumulative Event Rate (%)




                                        Chlorthalidone
                                        Amlodipine
                               12
                                        Lisinopril
                                        N = 33,357
                                8

                                                                        RR (95% CI)       P value
                                4                                A/C   0.98 (0.90-1.07)     .65
                                                                 L/C   0.99 (0.91-1.08)     .81
                                0
                                    0    1       2        3       4          5        6           7
                                                     Time to Event (years)
ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
                                Newer Versus Older Antihypertensive
                                Agents: ASCOT-BPLA
                              Primary End Point: Nonfatal MI and Fatal CHD
                              5.0         Atenolol-based regimen   No. of events: 474
   Proportion of Events (%)




                                          Amlodipine-based regimen No. of events: 429
                              4.0

                              3.0

                              2.0
                                                                HR = 0.90 (0.79-1.02)
                              1.0                               P = .1052*
                                                                N = 19,257
                              0.0
                                    0.0       1.0        2.0        3.0       4.0       5.0
                                                               Years
*Trial stopped early, after 5.5 years’ median follow-up
Dahlöf B, et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.
               ASCOT-BPLA: Summary of All
               End Points
                                                                                              Unadjusted Hazard
   Primary                                                                                      Ratio (95% CI)
   Nonfatal MI (including silent) + fatal CHD                                                  0.90 (0.79-1.02)
   Secondary
   Nonfatal MI (excluding silent) + fatal CHD                                                   0.87 (0.76-1.00)
   Total coronary end point                                                                     0.87 (0.79-0.96)
   Total CV events and procedures                                                               0.84 (0.78-0.90)
   All-cause mortality                                                                          0.89 (0.81-0.99)
   CV mortality                                                                                 0.76 (0.65-0.90)
   Fatal and nonfatal stroke                                                                    0.77 (0.66-0.89)
   Fatal and nonfatal heart failure                                                             0.84 (0.66-1.05)
   Tertiary
   Silent MI                                                                                    1.27 (0.80-2.00)
   Unstable angina                                                                              0.68 (0.51-0.92)
   Chronic stable angina                                                                        0.98 (0.81-1.19)
   Peripheral arterial disease                                                                  0.65 (0.52-0.81)
   Life-threatening arrhythmias                                                                 1.07 (0.62-1.85)
   New-onset diabetes mellitus                                                                  0.70 (0.63-0.78)
   New-onset renal impairment                                                                   0.85 (0.75-0.97)
   Post hoc
   Primary end point + coronary revasc procs                                                    0.86 (0.77-0.96)
   CV death + MI + stroke                                                                       0.84 (0.76-0.92)

                                0.50         0.70        1.00                1.45        2.00
                         Amlodipine-based regimen better                Atenolol-based regimen better
Area of the yellow squares is proportional to the amount of statistical information.
Dahlöf B, et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.
        Practicing Clinicians Case Study 2:
        49-Year-Old White Woman With
        ―Resistant‖ Hypertension
 Presents for routine follow-up of BP
 Family history: type 2 diabetes; father had MI (age 45)
 Nonsmoker; no ETOH use; history of cystic renal disease
 Physical examination
    BP: 158/95 mm Hg
    Height: 5' 6"; weight: 142 lb; waist: 34"
 Laboratory values
    Lipid profile: within normal limits
    TG: 144 mg/dL
    Fasting glucose: 98 mg/dL
    Serum creatinine: 1.3 mg/dL (GFR: 44 mL/min/1.73 m2)
    Dipstick: negative for protein
 Medication
    Enalapril 40 mg/d
       Practicing Clinicians
       Case Study 2: Decision Point
 Given this patient’s risk factor profile,
  what goal would you have for her BP?
  1. <140/90 mm Hg
                                              ?
  2. <130/85 mm Hg
  3. <130/80 mm Hg
  4. <120/80 mm Hg
Use your keypad to vote now!
      Practicing Clinicians
      Case Study 2: Decision Point
 Because the patient has chronic
  renal disease, the BP goal is
  <130/80 mm Hg. What would you do to         ?
  get this patient there?
  1. Reemphasize diet/exercise therapy and
     reevaluate in 3 months
  2. Switch from an ACE inhibitor to an ARB
  3. Add a thiazide diuretic
  4. Add a dihydropyridine CCB
Use your keypad to vote now!
            Practicing Clinicians Case Study 2:
            CV Risk Management Pearls
 If BP is >20/10 mm Hg above goal, consider starting
  with 2 agents, perhaps in a combination pill
 If patient still not at goal BP, optimize dosages
  or add additional drugs until goal is achieved
 ―Compelling indications‖ may dictate treatment
  choices




Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
          ESH-ESC Guidelines:
          Effective Combinations
          of Antihypertensive Agents
                                     Diuretics


                                                          Angiotensin
            β-Blockers                                     Receptor
                                                          Antagonists




             α-Blockers                                  Calcium
                                                        Antagonists


                                  ACE Inhibitors

ESH = European Society of Hypertension; ESC = European Society of Cardiology.
Adapted from ESH-ESC Guidelines Committee. J Hypertens. 2003;21:1011-1053.
           JNC 7: Compelling Indications for
           Antihypertensive Drug Classes

                                                    Recommended Drugs
                                                                                  Aldo
Compelling Indication                Diuretic      BB      ACEI         ARB   CCB ANT
Heart failure                             •          •       •           •         •
Post MI                                              •       •                     •
High coronary
disease risk                              •          •       •                 •
Diabetes                                  •          •       •           •     •
Chronic kidney disease                                       •           •
Recurrent stroke
prevention                                •                  •
Aldo ANT = aldosterone antagonist.
Chobanian AV, et al. JNC 7: Complete Report. 2004.
Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
      Practicing Clinicians Case Study 2:
      Decision Point
 You add a thiazide diuretic to the ACE
  inhibitor regimen, but BP is still
  >130/80 mm Hg. What would you do now?
                                           ?
  1. Maximize dosage of diuretic and
     reevaluate in 3 months
  2. Add a CCB to the current regimen
  3. Add an ARB to the current regimen
  4. Add an aldosterone blocker to the
     current regimen
Use your keypad to vote now!
           Practicing Clinicians Case Study 2:
           CV Risk Management Pearls
 Addition of a thiazide diuretic markedly improves
  the response to -blockers, ACE inhibitors, ARBs,
  and CCBs, especially in salt-sensitive populations
    Has been some concern about thiazide diuretics
     and increased risk for diabetes
 Addition of a CCB would be another option
  for this patient



Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
                              Multiple Antihypertensive
                              Agents Are Needed to Achieve
                              Target BP: ALLHAT
                                  1 Drug    2 Drugs   3 Drugs       % Controlled <140/90 mm Hg

                            100
   Percentage of Patients




                            80

                            60

                            40

                            20

                             0
                            Baseline       6 Months   1 Year     3 Years       5 Years

Adapted from Cushman WC, et al. J Clin Hypertens. 2002;4:393-404.
           Practicing Clinicians Case Study 2:
           CV Risk Management Pearls
 If goal BP is not achieved despite use of 3-drug regimen
   that includes a diuretic, consider:
     Pseudoresistance: white coat, wrong cuff
     Nonadherence
     Volume overload: excess salt intake, progressive renal
      damage, inadequate diuretic therapy
     Drug-related causes: dosages too low, wrong type of
      diuretic, use of short-acting drugs, drug interactions,
      NSAIDs, sympathomimetics, ―alternative‖ therapies,
      illicit drugs, etc
     Treatable causes: sleep apnea, renovascular disease,
      coarctation of aorta, glucocorticoid excess states, etc
Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
           JNC 7 Guidelines
           for Measurement of BP

Method                                           Brief Description
In-office                   Two readings, 5 minutes apart, sitting in chair.
                            Confirm elevated reading in contralateral arm.



Ambulatory                  Indicated for evaluation of ―white-coat‖
BP monitoring               hypertension. Absence of 10%-20% BP decrease
                            during sleep may indicate increased CVD risk.
Self-measurement Provides information on response to therapy.
                 May help improve adherence to therapy and
                 evaluate ―white-coat‖ hypertension.
Chobanian AV, et al. JNC 7: Complete Report. 2003.
Available at: http://hyper.ahajournals.org/cgi/content/full/42/6/1206.
      How Will JNC 8 Differ From JNC 7?
 Will <140/90 (or <130/80) mm Hg still be
  considered ―normal‖ blood pressure?
 Will ASCOT-BPLA change the initial approach
  to therapy? For example:
    Should CCBs and ACEIs be preferred as
     initial therapy over BBs and diuretics?
    Should we avoid starting therapy with
     a BB or diuretic in patients at metabolic
     risk for diabetes?
      Conclusion: Practicing Clinicians
      Hypertension Cases
 Consider every office visit an opportunity to
  screen for CV risk factors—regardless of the
  presenting complaint
 Counsel patients with hypertension and other
  CV risk factors on health-promoting lifestyle
  modifications
 Compelling indications may warrant use of
  specific agents (eg, ACEIs, ARBs, -blockers,
  CCBs, diuretics)
 Treatment with 2 or more agents is particularly
  important to control BP in high-risk patients
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BREAK
The Dyslipidemia Component:
What Recent Clinical Trials Tell Us
           Lipoprotein Classes




Chylomicrons, VLDL,                      LDL                           HDL
 and their catabolic
     remnants
       >30 nm                       20–22 nm                        9–15 nm
                 Potentially                                      Potentially
              pro-inflammatory                                anti-inflammatory
VLDL = very low density lipoprotein.
Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Colome C, et al.
Atherosclerosis. 2000;149:295-302; Doi H, et al. Circulation. 2000;102:670-676.
          National Cholesterol
          Education Program (NCEP)
          Management Guidelines
 Obtain a fasting lipid profile in all patients. For those who
  have had an MI, obtain a fasting lipid profile within 24 hours
  of admission
 Start therapeutic lifestyle changes in all patients, including:
    Reduced intakes of saturated fats (<7% of total calories)
      and cholesterol (<200 mg/d)
    Increased physical activity
    Weight reduction
    Add plant stanols/sterols (2 g/d) and viscous fiber
      (10-25 g/d) to enhance LDL-C lowering

NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at:
http://www.nhlbi.nih.gov/guidelines/cholesterol/.
          NCEP Management Guidelines
          (cont’d)
 For primary and secondary prevention, use statins first-line to
    achieve LDL-C goal
   If patient remains above LDL-C goal, intensify statin therapy—
    and add a second LDL-C–lowering agent, if needed
   If TG 150 mg/dL or HDL-C <40 mg/dL:
       Emphasize weight management, physical activity,
        smoking cessation
   If TG 200-499 mg/dL after initiation of LDL-C–lowering therapy:
       Calculate non-HDL-C as secondary target
       Consider adding nicotinic acid or a fibrate
   If TG 500 mg/dL
       Very low-fat diet, weight reduction, increased physical activity
       Consider treating with nicotinic acid or a fibrate before LDL-C–
        lowering therapy
NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at:
http://www.nhlbi.nih.gov/guidelines/cholesterol/.
            Risk Profile Assessment
            for LDL-C Lowering
            Use a risk assessment tool* for patients with 2 RFs
                              10-year CHD Risk
     0                     10%                     20%
               0-1 RF
                                     2 RFs

                                                          CHD or Risk
                                                          Equivalent†

*Such as the Framingham Risk Score (FRS).
†Includesdiabetes, non-coronary atherosclerotic vascular disease, and 20% 10-year
CHD risk by the FRS.
NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at:
http://www.nhlbi.nih.gov/guidelines/cholesterol/.
          Major Independent CHD Risk
          Factors
 Cigarette smoking
 BP ≥140/90 mm Hg (or taking antihypertensive
  medication)
 Low HDL-C (<40 mg/dL)
 Family history of premature CHD
    <55 years in first-degree male relative
    <65 years in first-degree female relative
 Age
    Men ≥45 years
    Women ≥55 years
Grundy SM, et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication
No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/.
          CHD Risk ―Equivalents‖ Point to
          >20% 10-year Risk for a CHD Event
 Diabetes
 Other clinical atherosclerotic disease
    Peripheral arterial disease
    Abdominal aortic aneurysm
    Carotid artery disease
 ≥2 risk factors with 10-year risk for hard CHD >20%




Grundy SM, et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication
No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/.
      Practicing Clinicians Case Study 3:
      44-Year-Old Hispanic Man
      Who Wants to Quit Smoking
 Wife and children are ―hassling‖ him to quit smoking
 22 pack-year history; has tried to quit several times
  in recent years
 Father died of MI at age 53
 Physical examination
    Height 5'8"; weight 164 lb; waist 34"
    BP: 160/95 mm Hg on first reading,
     158/91 mm Hg on second reading
    Lungs clear to auscultation
         Practicing Clinicians
         Case Study 3: Decision Point
 What would be your best next step in
  this case?
  1. Order a lipid profile
                                                ?
  2. Order advanced lipid testing to evaluate
     LDL-C particle size and number
  3. Order a 2-hr postprandial glucose test
  4. Order EBCT to assess coronary calcium
Use your keypad to vote now!

EBCT = electron beam computed tomography.
       Practicing Clinicians
       Case Study 3: Laboratory Values
 Lipid profile
   TC 205 mg/dL; LDL 140 mg/dL; HDL 40 mg/dL;
    TG 125 mg/dL
 Other laboratory values
   Glucose 91 mg/dL (fasting)
   Creatinine 1.2 mg/dL (GFR: 68 mL/min/1.73 m2)
   UA negative for protein
       Practicing Clinicians
       Case Study 3: Decision Point
 Is this patient a candidate for lipid-lowering
  therapy?
  1. Yes
                                                   ?
  2. No


Use your keypad to vote now!
              Practicing Clinicians Case Study 3:
              Risk for Fatal or Nonfatal CHD
              Over the Next 10 Years in Men*
   Age (y)     Points
                            SBP (mmHg) Untreated Treated      Smoking             Age (y)
   20-34         -9            <120        0        0          status 20-39 40-49 50-59 60-69            70-79
   35-39         -4           120-129      0        1       Nonsmoker   0     0     0     0                0
   40-44          0           130-139      1        2       Smoker      8     5     3     1                1
   45-49          3           140-159      1        2
   50-54          6            160        2        3                   Point Total   10-Year Risk (%)
                                                                           <0               <1
   55-59          8          HDL (mg/dL)      Points                        0                1
   60-64         10             60             -1                          1                1
   65-69         11               50-59         0                           2                1
                                  40-49         1                           3                1
   70-74         12
                                                                            4                1
   75-79         13               <40           2                           5                2
                                                                            6                2
               Age       Age         Age       Age       Age
                                                                            7                3
 TC (mg/dL)   20-39 y   40-49 y     50-59 y   60-69 y   70-79 y
                                                                            8                4
    <160         0         0           0         0         0                9                5
  160-199        4         3           2         1         0               10                6
  200-239        7         5           3         1         0               11                8
  240-279        9         6           4         2         1               12               10
                                                                           13               12
    280        11         8           5         3         1
                                                                           14               16
*A separate Framingham risk calculator exists for women.                   15               20
NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at:             16               25
http://www.nhlbi.nih.gov/guidelines/cholesterol/.                         17              30
       Practicing Clinicians CV Management
       Pearls: Disadvantages
       of Framingham Risk Calculator
 Lack of sensitivity for patients with:
   A severe single risk factor
   Multiple lifestyle risk factors
   Metabolic syndrome
   Presence of emerging risk factors
 Overestimates the risk of age
 May underestimate risk in women
 Does not predict risk of stroke
         ASCOT-LLA: Clinical Question
 Is atorvastatin 10 mg/d, when compared with
   placebo, beneficial for primary prevention of
   CHD in patients treated for hypertension who are
   not conventionally deemed dyslipidemic and who
   have at least 3 additional CV risk factors?




ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial─Lipid Lowering Arm.
Sever PS, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.
            ASCOT-LLA: Primary End Point
            (Nonfatal MI and Fatal CHD)
            in Patients With Treated Hypertension
        4
                      Placebo                No. of events: 154
                      Atorvastatin 10 mg/d No. of events: 100
        3                                                                         36%


        2


        1
                                                HR = 0.64 (95% CI, 0.50-0.83)
                                                P = .0005*
        0
            0.0    0.5      1.0      1.5       2.0     2.5      3.0         3.5
                                       Years
*Trial stopped early, after 3.3 years’ median follow-up
Sever PS, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.
                                          ASCOT-LLA: Secondary End Points
                           Fatal and Nonfatal Stroke                      All CV Events and Procedures                            All Coronary Events
                                                          No. of events                                  No. of events                                  No. of events

                                     Placebo                     121                Placebo                      486               Placebo                     247
                                     Atorvastatin 10 mg           89                Atorvastatin 10 mg           389               Atorvastatin 10 mg          178
                           3                                              12                                             6
Cumulative Incidence (%)




                                                                          10                                             5
                                                                 27%                                             21%                                           29%
                           2                                              8                                              4


                                                                          6                                              3


                           1                                              4                                              2

                                                  P = .0236               2                        P = .0005             1                       P = .0005
                                     HR = 0.73 (CI, 0.56-0.96)                       HR = 0.79 (CI, 0.59-0.90)                      HR = 0.71 (CI, 0.59-0.86)
                           0                                              0                                              0
                               0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5                 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5               0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
                                          Years                                           Years                                         Years
              Sever PS, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.
          Practicing Clinicians Case Study 3:
          CV Risk Management Pearls
 Recall that the majority of patients with hypertension
  have at least 2 additional risk factors
 Make a full assessment of all treatable risk factors,
  including lipid and glucose metabolism
 For patients with hypertension and at least 3 additional
  CV risk factors (eg, BP ≥140/90 mm Hg, smoking, low
  HDL-C, family history of premature CHD), NCEP ATP III
  update recommends an optional LDL-C goal <100 mg/dL
  in addition to BP and other CV risk management
Glazer NL, et al. Am J Hypertens. 2005;18:759-766; Grundy SM, et al. Circulation.
2004;110:227-239; Pearson TA, et al. Circulation. 2002;106:388-391; Sever PS, et al,
for the ASCOT Investigators. Lancet. 2003;361:1149-1158; Williams B. J Am Coll
Cardiol. 2005;45:813-827.
           Therapeutic Goals for LDL-C
           at Various Risk Levels:
           NCEP ATP III and NCEP 2004

 Risk Level                                          LDL-C Goal (mg/dL)
 High risk: CHD or CHD risk equivalent               <100
 Very high risk                                      <70 (therapeutic option)
 Moderate risk: multiple (2) risk factors           <130
 Moderately high risk                                <100 (therapeutic option)

 Lower risk: <2 risk factors                         <160
 In patients at moderate or high risk, NCEP 2004 update advises that
 lipid-lowering therapy should result in at least a 30%-40% reduction in
 LDL-C.

Grundy SM, et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication
No. 02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/.
           NCEP ATP III Update (2004):
           New Risk Levels

 Risk Level                                        Risk Factors
 Very high risk                    Established CVD + multiple risk factors
                                   (diabetes; continued cigarette smoking;
                                   metabolic syndrome; acute coronary
                                   syndrome)

 Moderately high risk              Advancing age; >2 risk factors (continued
                                   cigarette smoking; strongly positive family
                                   history of premature atherosclerotic CVD;
                                   high TG, elevated non–HDL-C; low HDL-C;
                                   metabolic syndrome; emerging risk factors)



Grundy SM, et al. Circulation. 2004;110:227-239.
          NCEP ATP III Classification of
          Other Lipoprotein Levels
         Total Cholesterol                             HDL-Cholesterol*
 Level (mg/dL)       Classification             Level (mg/dL)    Classification
     <200              Desirable                      <40             Low
    200-239         Borderline High                   ≥60            High
      240                High                  *AHA recommends ≥40 in men and
                                                ≥50 in women
                 Triglycerides
      Level (mg/dL)       Classification
          <150               Normal
        150-199           Borderline High
        200-499                High
          500              Very High
Pearson TA, et al. Circulation. 2002;106:388-391.
NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at:
http://www.nhlbi.nih.gov/guidelines/cholesterol/.
    Coronary Artery Calcification
    as Assessed by EBCT
 No Calcification    Severe Calcification

                    LAD




Left Main                             LCX
      Practicing Clinicians Case Study 4:
      A 77-Year-Old African American
      Woman With Recent Acute MI
 77-year-old African American woman, S/P AMI
  1 week ago
 PMHx: ASHD, HTN, osteoarthritis
 Presents for routine evaluation after hospital
  discharge
 V/S: T 98.4oF orally, P 72, R 18,
  BP 135/92 mm Hg, SaO2 92% RA, BMI 24
 Current medications:
    Metoprolol 100 mg qd, HCTZ 25 mg qd,
     ASA 81 mg qd, atorvastatin 20 mg qd
       Practicing Clinicians Case Study 4:
       Additional Patient Data
 Basic Metabolic Panel:         LFTs:
    Fasting glucose 89 mg/dL       AST 24 u/L
    BUN 13 mg/dL                   ALT 20 u/L
    Creatinine 0.6 mg/dL        Lipid panel:
    Sodium 136 meq/dL              TC 180 mg/dL
    Potassium 4.0 meq/dL           TG 138 mg/dL
    Chloride 98 meq/dL             LDL-C 101 mg/dL
    CO2 27 meq/dL                  HDL-C 43 mg/dL
 CBC:
    WBC 6.6 THDS/CMM
    Hemoglobin 12.9 g/dL
    Hematocrit 37.1%
    Platelets 234 THDS/CMM
      Practicing Clinicians Case Study 4:
      Decision Point
 What should you consider first?
  1. Order a high-sensitivity CRP test
  2. Perform 10-year Framingham risk assessment
                                                    ?
  3. Aggressively escalate statin dosage to lower
     LDL-C below 70 mg/dL
  4. Counsel patient regarding target lifestyle
     changes and advise that you will re-evaluate
     her in 3 to 6 months
Use your keypad to vote now!
          PROVE-IT–TIMI 22: Clinical
          Question
 Does intensive lipid-lowering with atorvastatin
   80 mg/d provide greater protection against
   death or major CV events than standard
   lipid-lowering with pravastatin 40 mg/d in
   patients who recently had an ACS?




ACS = acute coronary syndrome; PROVE-IT–TIMI 22 = Pravastatin or Atorvastatin
Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22.
Cannon C, et al. N Engl J Med. 2004;350:1495-1504.
                               PROVE IT–TIMI 22 Primary End Point:
                               Death From Any Cause
                               or Major CV Event
                               30
                                                  Pravastatin                                 16%
     Patients With Event (%)




                               25               40 mg/d (26.3%)

                               20
                                                                         Atorvastatin
                               15                                      80 mg/d (22.4%)

                               10
                                                             16% HRR (95% CI, 5%-26%)
                               5                             P = .005

                               0
                                    0   3   6    9      12   15   18      21   24   27   30
    N = 4162                                         Follow-up (months)

HRR = hazard ratio reduction.
Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
          REVERSAL: Clinical Question
 Does intensive lipid-lowering therapy with
   atorvastatin 80 mg/d, when compared with moderate
   lipid-lowering therapy with pravastatin 40 mg/d,
   reduce the progression of coronary atherosclerosis?




REVERSAL = Reversal of Atherosclerosis with Aggressive Lipid Lowering.
Nissen SE, et al, for the REVERSAL Investigators. JAMA. 2004;291:1071-1080.
                        REVERSAL Primary End Point:
                        Percentage Change
                        in Atheroma Volume
                                             P = .02
                       3.0                                     2.7%†
 Atheroma Volume (%)




                       2.5
  Median Change in




                       2.0
                       1.5
                       1.0
                       0.5
                         0
                       -0.5      -0.4%*
                       -1.0   Atorvastatin                 Pravastatin
                               (80 mg/d)                    (40 mg/d)
                                (n = 253)                    (n = 249)

*No progression vs baseline (P = .98).
†Net progression vs baseline (P = .001).

Nissen SE, et al, for the REVERSAL Investigators. JAMA. 2004;291:1071-1080.
          MRC/BHF Heart Protection Study
          (HPS): Clinical Question
 Does simvastatin 40 mg/d, when compared
   with placebo, cause a significant reduction
   in CHD events in patients at high risk
   (eg, because of prior MI, diabetes, hypertension)?




BHF = British Heart Foundation; CHD = coronary heart disease; MI = myocardial
infarction; MRC = Medical Research Council.
HPS Collaborative Group. Lancet. 2002;360:7-22.
                                HPS: Key Findings
Average Change From Baseline




                                 5      CHD       All-cause
                                       Events     Mortality
                                 0
     at End of Study (%)




                                –5

                               –10

                               –15                   –13%
                               –20                  P = .0003

                               –25

                               –30      –27%
                                                          N = 20,536
                                      P <.0001


HPS Collaborative Group. Lancet. 2002;360:7-22.
            CTT Meta-analysis: Cause-Specific
            Mortality per mmol/L LDL-C Reduction
                                 Events
                       Treatment       Control                            Risk Reduction
Cause of Death          (45,054)      (45,002)                                 (CI)
Vascular causes:
CHD                   1548 (3.4%)      1960 (4.4%)                         0.81 (0.76-0.85)
 Stroke                 265 (0.6%)       291 (0.6%)                        0.91 (0.74-1.11)
 Other vascular         289 (0.6%)       302 (0.7%)                        0.95 (0.78-1.16)
Any non-CHD                                                                0.93 (0.83-1.03)
                        554 (1.2%)       593 (1.3%)
vascular
Any vascular          2102 (4.7%)      2553 (5.7%)                         0.83 (0.79-0.87)

Any non-vascular 1730 (3.8%)           1801 (4.0%)                         0.95 (0.90-1.01)
Any death        3832 (8.5%)           4354 (9.7%)                         0.88 (0.84-0.91)

                                                  0.5         1.0       1.5
                                             Treatment Better     Control Better Effect P <.0001
CTT = Cholesterol Treatment Trialists.
Baigent C, et al; Cholesterol Treatment Trialists’ Collaborators. Lancet. 2005;366:1267-1278.
      Practicing Clinicians
      Case Study 4: Decision Point
 You elect to titrate the statin upward to lower
  LDL-C below 70 mg/dL. However, the
  patient complains of minor muscle aches.
                                                       ?
  What should you do now?
  1. Stop the statin immediately
  2. Reduce the statin dose back to 20 mg qd
  3. Keep the patient on the statin at the increased
     dose and order a CK
  4. Immediately refer the patient to a cardiologist
Use your keypad to vote now!
      Practicing Clinicians
      Case Study 4: Decision Point
 The CK results are 460 ng/dL. Should you
  1. Stop the statin immediately?
  2. Give the patient a 3-week washout
                                                       ?
     period and then attempt to re-start the statin?
  3. Return the patient to the initial, lower statin dose?
  4. Keep the patient on the statin, and advise her of
     the increased risk and the need for more frequent
     monitoring?

Use your keypad to vote now!
          Practicing Clinicians Case Study 4:
          CV Risk Management Pearls—
          Rhabdomyolysis
 CK levels must rise >10-fold for risk of stopping
  statin therapy to outweigh benefit
    More than 474,468,000 Rx written for statins
     through 2001 (excluding cerivastatin)
    42 cases of fatal rhabdomyolysis reported
     (excluding cerivastatin)
 ~ 2 cases of minor rhabdomyolysis per 1,000 statin
  patients, none requiring treatment
    Discontinuation rates due to elevated CK
      – <1 per 10,000
 Fatal rhabdomyolysis incidence <1 per 1,000,000
Staffa JA, et al. N Engl J Med. 2002;346:539-540.
          ―Emerging‖ Risk Factors:
          Lipid and Non-Lipid
   Triglycerides                              Inflammatory markers
   Lipoprotein remnants                        (eg, CRP)
   Lipoprotein(a)                             Thrombogenic hemostatic
   Small LDL particles                         factors
   HDL subspecies                             Impaired fasting glucose
   Apolipoproteins                            Homocysteine
      Apolipoprotein B
      Apolipoprotein A1
Keep in mind that 80%-90% of CHD is due to standard risk factors

Khot UN, et al. JAMA. 2003;290:898-904; NCEP ATP III. 2002. NIH Publication No.
02-5215. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/; Pearson TA, et
al. Circulation. 2003;107:499-511.
         Conclusion: Practicing Clinicians
         Dyslipidemia Cases
 Since NCEP ATP III, there have been a number of major
    clinical trials of statins with end points highly relevant to
    clinical practice
   Based on these trials, NCEP ATP III now recommends
    optional LDL-C goals of:
      <70 mg/dL for patients at very high risk
      <100 mg/dL for patients at moderately high risk
   Further, NCEP ATP III now advises that lipid-lowering
    therapy should result in at least a 30% to 40% reduction
    in LDL-C in moderate- or high-risk patients
   CK levels must rise >10-fold (>1500 mg/dL) for risk of
    stopping statin therapy to outweigh benefit
   Assessment of emerging risk factors is optional but
    may be valuable in selected cases
Full Panel Q&A
Managing Diabetes
as a CHD Risk Equivalent
                       Age-Adjusted Prevalence of Heart Disease
                       and Stroke Among Adults Aged 35 Years
                       With and Without Diabetes: US, 1999-2001

                  40                                     No Diabetes
                                                         Diabetes
                  35
 Prevalence (%)




                  30
                  25
                  20
                  15
                  10
                  5
                  0
                       Coronary Heart   Stroke   Other Heart
                          Disease                Conditions

CDC. MMWR. 2003;52:1065-1070.
           Established Modifiable CV Risk
           Factors in Type 2 Diabetes
                                      UKPDS 23

                   Variables                                      P Value*
          LDL-C, HDL-C, TG                                         <.0001
          Hemoglobin A1C                                             .0003
          SBP                                                        .0032
          Smoking, FPG                                               .016
Adjusted for age and sex in 2693 white patients with type 2 DM with dependent variable
as time to first event.
*Significant for CAD (n = 280). P values are significance of risk factors after controlling for
all other risk factors in model.
Turner RC, et al. BMJ. 1998;316:823-828.
                  CV Risk Factor Control Among
                  Adults With Diagnosed Diabetes
                       Fewer than half of adults with diabetes achieve
                             treatment goals for CV risk factors
                                                            NHANES III (n = 1204)
                  60                                        NHANES 1999-2000 (n = 370)
                  50                                             48.2
                          44.3
     Adults (%)




                  40             37.0            35.8     33.9
                                          29.0
                  30

                  20

                  10                                                         5.2   7.3

                   0
                           A1C Level    Blood Pressure Total Cholesterol* Achieved all 3
                             <7%        <130/80 mm Hg     <200 mg/dL      treatment goals
*LDL-C and TG not evaluated.
Saydah SH, et al. JAMA. 2004;291:335-342.
       Practicing Clinicians Case Study 5:
       62-Year-Old Hispanic Woman
       With PVD and Hypertension
 Medications
    Valsartan 160 mg/d
    Hydrochlorothiazide 25 mg/d
    Clopidogrel 75 mg/d
 Physical examination
    BP: 136/78 mm Hg
    Height 5'4"; weight 159 lb; BMI 27.3 kg/m2
    1+ peripheral pulses
 Laboratory values
    Fasting plasma glucose 116 mg/dL
    Potassium 5.1 mEq/L; BUN 24 mg/dL; creatinine 1.3 mg/dL
     (GFR: 42 mL/min/1.73 m2)
    Urinalysis: microalbuminuria (210 μg/mg creatinine)
    TC 198 mg/dL; LDL 118 mg/dL; HDL 52 mg/dL; TG 142 mg/dL
 ECG: LVH with repolarization abnormality
       Practicing Clinicians Case Study 5:
       Decision Point
 Given this patient’s CV risk factor
  profile, what would you do at this point?
   1. Switch from a thiazide to spironolactone
                                                 ?
   2. Order an oral glucose tolerance test
   3. Switch from an ARB to an ACEI
   4. Order advanced lipid testing
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         Practicing Clinicians Case Study 5
         CV Risk Management Pearls:
         Testing for Diabetes in Adults
 Consider for all patients age ≥45 years, especially if BMI >25 kg/m2
 Consider at a younger age or carry out more frequently in
   overweight patients (BMI >25 kg/m2) and have additional risk
   factors, such as:
     Habitually physically inactive
     First-degree relative with diabetes
     Member of a high-risk ethnic population (eg, African American,
       Latino, Native American, Asian American, Pacific Islander)
     Hypertensive (140/90 mm Hg)
     HDL-C level <35 mg/dL and/or a TG level >250 mg/dL
     IGT or IFG on previous testing
     Other clinical conditions associated with insulin resistance
     History of vascular disease
ADA. Diabetes Care. 2004;27(suppl 1):S15-35.
         Natural History of Type 2 Diabetes
                                         0         5         10        15
   Years from -10            -5
   diagnosis                Onset    Diagnosis


  Insulin resistance

  Insulin secretion
                            “Metabolic Syndrome”
         Impaired fasting
             glucose
Post-meal glucose
                                       Microvascular complications
  Fasting glucose
                                    Cardiovascular complications
             Pre-diabetes                    Type 2 diabetes
Nathan DM. N Engl J Med. 2002;347:1342-1349; Ramlo-Halsted BA, Edelman SV. Prim
Care. 1999;26:771-789.
       Practicing Clinicians Case Study 5:
       Decision Point
 The patient’s 2-h plasma glucose is 206 mg/dL
  (first test) and 212 mg/dL (second test), and
  you diagnose diabetes. In addition to glucose
  management, what would you do now?
                                                   ?
   1. Establish BP control, then treat LDL-C
      to <100 mg/dL
   2. Treat LDL-C to <70 mg/dL, then establish
      BP control
   3. Address BP and LDL-C abnormalities
      simultaneously
   4. Perform comprehensive quantitative CV risk
      assessment prior to additional therapy
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            HPS: Major Vascular Events
            by LDL-C and Prior Diabetes

                                                               Rate ratio (95% CI)
LDL-C and            Simvastatin        Placebo            Statin better      Placebo better
Diabetes             (n = 10,269)     (n = 10,267)
<116 mg/dL
   Diabetes          191 (15.7%)      252 (20.9%)
   No diabetes       407 (18.8%)      504 (22.9%)


116 mg/dL
   Diabetes          410 (23.3%)      496 (27.9%)
   No diabetes      1025 (20.0%)     1333 (26.2%)

All Patients        2033 (19.8%)     2585 (25.2%)                             0.76 (0.72-0.81)
                                                                              P <.0001

                                                     0.4    0.6   0.8   1.0     1.2   1.4


HPS Collaborative Group. Lancet. 2003;361:2005-2016.
          CARDS Trial: Clinical Question
 Is atorvastatin 10 mg/d, when compared with
   placebo, beneficial for primary prevention of major
   CV events in patients with type 2 diabetes who
   do not have high levels of LDL-C?




CARDS = Collaborative Atorvastatin Diabetes Study.
Colhoun HM, et al. Lancet. 2004;364:685-696.
                                CARDS Primary End Point:
                                Major Cardiovascular Events
                           15
                                         Placebo        No. of events: 127
   Cumulative Hazard (%)




                                         Atorvastatin   No. of events: 83
                           10       N = 2838                                       37%



                            5

                                                                    RRR 37% (95% CI, 17%-52%)
                                                                    P = .001
                            0
                                0         1         2           3         4     4.75

                                                        Years
RRR = relative risk reduction.
Colhoun HM, et al. Lancet. 2004;364:685-696.
                                      UKPDS: Tight Glucose Versus Tight
                                      BP Control and CV Outcomes
                                         Tight glucose control                           Tight BP control
                                          (goal <6.0 mmol/L or 108 mg/dL)                (average 144/82 mm Hg)

                                                           Any Diabetic            DM            Microvascular
                                         Stroke             End Point             Deaths         Complications
  Relative Risk Reduction (%)




                                 0

                                         5%
                                -10
                                                                                  10%
                                                              12%
                                -20
                                                                     24%
                                -30                                   *
                                                                                        32%           32%
                                -40                                                     *                   37%
                                                                                                              *
                                              44%
                                -50            *                      *P <.05 compared to tight glucose control

UKPDS = United Kingdom Prospective Diabetes Study.
Bakris GL, et al. Am J Kidney Dis. 2000;36:646-661.
          Steno-2: Interventions
          for Intensive Treatment Group
 Low-fat diet
 Exercise
 Smoking cessation
 ACE inhibitor or ARB
 Multivitamin
 Aspirin
 A1C goal <6.5%
 Initial blood pressure goal <140/85 mm Hg
  (goals revised during study)
 Atorvastatin or equivalent statin and/or fibrate


Gaede P, et al. N Engl J Med. 2003;348:383-393.
                      Steno-2 Study: Kaplan-Meier
                      Estimates of Composite End Point
                     60
                              P = .007
                     50
 Primary Composite




                                                          Conventional therapy
    End Point (%)




                     40

                     30

                     20

                     10
                                                            Intensive therapy

                     0
                          0      12      24    36    48      60    72     84     96
                                              Follow-up (months)

Gaede P, et al. N Engl J Med. 2003;348:383-393.
                                    PROACTIVE Primary End Point*
                               25             Placebo        No. of events: 572
    Proportion of Events (%)



                                              Pioglitazone   No. of events: 514
                               20
                                        N = 5238
                               15

                               10

                               5                                  HR = 0.90 (95% CI, 0.80-1.02)
                                                                  P = .095
                                0
                                    0         6      12      18        24       30       36
                                              Time From Randomization (months)
*Death from any cause, nonfatal MI (including silent MI), stroke, ACS, leg amputation,
coronary revascularization, or revascularization of the leg.
PROACTIVE = PROspective pioglitAzone Clinical Trial In macroVascular Events.
Dormandy JA, et al. Lancet. 2005;366:1279-1289.
                                    PROACTIVE Secondary End Point*
                               25             Placebo        No. of events: 358
    Proportion of Events (%)




                                              Pioglitazone   No. of events: 301
                               20
                                        N = 5238
                               15

                               10

                               5                                  HR = 0.84 (95% CI, 0.72-0.98)
                                                                  P = .027
                                0
                                    0        6       12      18        24       30       36
                                              Time From Randomization (months)


*Death from any cause, nonfatal MI (excluding silent MI), or stroke.
Dormandy JA, et al. Lancet. 2005;366:1279-1289.
      Practicing Clinicians Case Study 6:
      50-Year-Old White Man With HTN
      and Family History of Premature CAD
 50-year-old white man with family history of
  premature CAD (father had MI at age 52)
 Presents for evaluation and recommendations
 PMH
    HTN for 5 yrs; treated with ARB
    No known CAD, DM, or thyroid disease
 Height: 5' 10", weight 211 lbs, waist 39"
 Blood pressure: 148/94 mm Hg
 24 pack-year history smoking
 No regular exercise program
      Practicing Clinicians Case Study 6:
      Additional Data
 Stressful job as manager in an investment firm
 Often ―eats on the run‖
 Laboratory studies reveal:
    Lipids:
      – TG 484 mg/dL
      – TC 272 mg/dL
      – HDL 35 mg/dL
      – LDL 140 mg/dL
    Fasting glucose 158 mg/dL
    Renal, hepatic, and thyroid function WNL
 ECG unremarkable
      Practicing Clinicians Case Study 6:
      Decision Point
 Which of the following findings suggest
  that this patient may have the metabolic
  syndrome?
                                                  ?
   1. TG 484 mg/dL, HDL 35 mg/dL, fasting glucose
      158 mg/dL
   2. TG 484 mg/dL, HDL 35 mg/dL, LDL 140 mg/dL
   3. Family history premature CAD, smoking history,
      TC 272 mg/dL
   4. Absence of thyroid disease, BP 148/94 mm Hg,
      TC 272 mg/dL
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           Definition of the Metabolic
           Syndrome: 2005 Update
Risk factor*                Categorical Cut-points
↑ Waist                     ≥102 cm (≥40 in) in men†
circumference               ≥88 cm (≥35 in) in women†
↑ TG                        ≥150 mg/dL (or drug treatment for)
↓ HDL-C                     <40 mg/dL in men (or drug treatment for)
                            <50 mg/dL in women (or drug treatment for)
↑ BP                        ≥130 mm Hg SBP or ≥85 mm Hg DBP
                            (or drug treatment for)
↑ Fasting glucose           ≥100 mg/dL (or drug treatment for)
*Presence of 3 or more of these factors identifies the metabolic syndrome.
†A lower threshold can be used for patients especially prone to insulin resistance,

particularly Asian Americans.
Grundy SM, et al. Circulation. 2005;112:2735-2752.
NOTE: The ADA recently issued a statement calling for a critical appraisal of the
metabolic syndrome. Kahn R, et al. Diabetologia. 2005;48:1684-1699.
          Management of the Metabolic
          Syndrome: 2005 Update
 Weight reduction
 Increased physical activity
 Modification of atherogenic diet
 Drug therapy for dyslipidemia
 Drug therapy for hypertension
 Aspirin or clopidogrel for prothrombotic state
 Lifestyle changes to lower serum glucose
   (if diabetes has developed, drug therapy may
   also be needed to reduce A1C to ADA goal of <7%)

Grundy SM, et al. Circulation. 2005;112:2735-2752.
          Association of MI and Stroke
          With the Metabolic Syndrome
 Analyzed 10,357 subjects                                      3.0
  from NHANES III
                                                                                    2.16†
 Applied NCEP ATP III                                                      2.01*




                                                   Odds Ratio
                                                                2.0
  criteria for the metabolic
  syndrome
                                                                1.0
 Determined relationship
  of the metabolic
  syndrome to MI and                                              0
                                                                             MI     Stroke
  stroke                                                        *P <.0001
                                                                †P <.0002




Ninomiya JK, et al. Circulation. 2004;109:42-46.
       Practicing Clinicians Case Study 6:
       Decision Point
 The patient proves to have diabetes, on top
  of being a smoker, having HTN, and having
  the metabolic syndrome. A1C is 7.8%.               ?
  What would you prescribe at this point for lipid
  management?
   1. Fenofibrate
   2. Fenofibrate and a statin
   3. Extended-release niacin and a statin
   4. Intensive statin therapy
Use your keypad to vote now!
             Non-HDL-C as a Secondary Target
                                     LDL-C Goal                       Non-HDL-C Goal
Risk Level
                                     (mg/dL)                          (mg/dL)
High risk: CHD or CHD risk           <100                             <130
equivalent
Very high risk                       <70 (therapeutic option)         <100 (therapeutic option)

Moderate risk: multiple (2)         <130                             <160
risk factors
Moderately high risk                 <100 (therapeutic option)        <130 (therapeutic option)

Lower risk: <2 risk factors          <160                             <190

Triglyceride levels 200-499 mg/dL identify non-HDL-C as a secondary target of therapy. Goals for non-
HDL-C are 30 mg/dL higher than those for LDL-C.
Non-HDL-C = TC – HDL-C = LDL-C + VLDL.
NCEP ATP III. 2002. NIH Publication No. 02-5215.
Grundy SM, et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication No. 02-5215.
Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/.
      Practicing Clinicians Case Study 6:
      Initial Management Plan
 Lifestyle management
    Diet, exercise, and smoking cessation
 Fenofibrate 145 mg/d
 Simvastatin 20 mg/d
 Metformin 500 mg bid
 ASA 81 mg/d
 Fish oil 1 g bid
          Treatment of Hypertriglyceridemia
          With Fibrates
 Mechanism of Action                             Agents
     Decreased hepatic secretion                      Gemfibrozil
      of VLDL                                          Fenofibrate
     Decreased release of FFA
      from adipose tissue                         Effects on Lipids
     PPAR activation                                  Increase/decrease LDL
        – Nuclear hormone receptor                     Decrease TGs
          gene superfamily
                                                       Increase HDL
        – Function as a transcription
          activator/suppressor for
          genes involved in
          lipoprotein metabolism


FFA = free fatty acids; PPAR = peroxisome proliferator-activated receptor.
            FIELD: Primary Outcome

                        Placebo          Fenofibrate
                       (n = 4900)         (n = 4895)             HR         P
End Point
                          n (%)              n (%)            (95% CI)    Value
CHD death/               288 (6)            256 (5)             0.89       .16
nonfatal MI                                                 (0.75-1.05)
CHD death                 93 (2)            110 (2)             1.19       .22
                                                            (0.90-1.57)
Nonfatal MI              207 (4)            158 (3)             0.76      .010
                                                            (0.62-0.94)


FIELD = Fenofibrate Intervention and Event Lowering in Diabetes.
FIELD Study Investigators. Lancet. 2005;366:1849-1861.
                           VA-HIT Study: Effect of Gemfibrozil on
                           CHD Death, Nonfatal MI, or Stroke
                                    24% RR                    Placebo
                      45       (95% CI, -0.1%-43%)
                                     P = .05                  Gemfibrozil
                      40
Event Incidence (%)




                              36                                     24% RR
                      35                                         (95% CI, 6%-30%)
                      30                             28              P = .009

                      25                                    23
                      20                                                            18
                      15
                      10
                       5
                       0
                              Diabetic Patients           Nondiabetic Patients
                                  n = 627                      n = 1904
 VA-HIT = Veterans Affairs Cooperative Studies Program High-Density Lipoprotein
 Cholesterol Intervention Trial
 Rubins HB, et al. N Engl J Med. 1999;341:410–418.
        Practicing Clinicians Case Study 6:
        Further Options If Lipids Still Not at Goal

        Option                              Caveat
Intensify statin regimen   Little data on use of high doses in diabetes

                           No outcome data for ezetimibe in patients
Add ezetimibe              with diabetes; when used with statin, levels
                           of hepatic enzymes may increase
Add bile acid sequestrant May raise triglyceride level
                           Can increase glucose level in diabetics; be
Add extended-release
                           sure diabetes is well controlled, use low
niacin
                           dosage, have patient follow glucose closely
                           May cause weight gain, fluid retention;
Add pioglitazone
                           requires knowledge of LV function
      Combination Therapy in CV Risk
      Management
 Frequently necessary, especially with more
  aggressive 2004 NCEP Update goals
 Need to answer 3 specific questions when
  making decisions for combination treatment
    Safety
    Efficacy
    Cost
 Limitations of fixed-dose combination therapy
  include potential difficulty in titration and
  determining the cause of adverse effects
            Predictors of Adherence With
            Concomitant Antihypertensive
            and Lipid-Lowering Medications
                   Demographics*                                Therapy Initiation*
                                                       Start AHT/LLT
            Age (18-44)            1.00 (ref group)                               1.34 (P <.001)
                                                              (0-30 d)
            Age (55-64)           1.56 (P <.001)       Start AHT/LLT
                                                                                  1.09 (P = .25)
                                                             (31-60 d)
            Age (65-74)            1.27 (P = .004)     Start AHT/LLT              1.00 (ref group)
                                                             (61-90 d)
           Sex (female)            0.91 (P = .02)          No. of Concomitant Meds*
                                                                   0              1.96 (P <.001)
                No CAD             1.00 (ref group)                1              1.61 (P <.001)
CAD Level 1 (angina or
coronary angiography)              0.96 (P = .73)                  2              1.30 (P <.001)
   CAD Level 2 (PTCA,              1.20 (P = .001)                 3-5            1.23 (P <.001)
CABG, or chronic CHD)
 CAD Level 3 (acute MI)            1.28 (P = .003)                 6            1.00 (ref group)
                0.5   1        2.0 2.5                       0.5  1        2.0     2.5
            Nonadherent           Adherent               Nonadherent             Adherent
*Odds ratio (95% CI).
AHT = antihypertensive therapy; LLT = lipid-lowering therapy.
Chapman RH, et al. Arch Intern Med. 2005;165:1147-1152.
           Adherence to Simultaneous
           Antihypertensive and Lipid-Regulating
           Drug Therapy

                                                                 38%
          40 −
          35 −
          30 −                                 27%

          25 −           23%
          20 −
          15 −
          10 −
           5−
           0−
                      LRD First,           AHD First,         AHD + LRD
                     AHD Added             LRD Added           Initiated
                                                            Simultaneously
AHD = antihypertensive drug; LRD = lipid-regulating drug.
Adapted from Schwartz JS, et al. ACC 2003. Poster.
                         Adherence to Antihypertensive
                         Therapy With Combination Pill

                                    80.8       P <.001
  Possession Ratio (%)



                         81
   Overall Medication




                         80
                         79
                         78
                         77
                         76
                         75                                        73.8
                         74
                         73
                         72
                         71
                         70
                          0
                                 Amlodipine/                  ACE Inhibitor/
                                  Benazepril                     DCCB
                                 Combination                  Concurrently


DCCB = dihydropyridine calcium channel blocker.
Taylor AA, Shoheiber O. Congest Heart Fail. 2003;9:324-332.
                        Adherence Decreases in Patients
                        Switched to Separate Oral
                        Antidiabetic Agents

                  100
                               82
                                                           77
                   80
  Adherence (%)




                   60                            54

                   40

                   20

                    0
                          Monotherapy    Switched to   Switched to
                          (n = 33,567)    Gly + Met      Gly/Met
                                          (n = 1815)    (n = 105)
Adherence = days supplied/total days.
Melikian C, et al. Clin Ther. 2002;24:460-467.
          Combination Drugs for Treatment
          of Diabetes, Dyslipidemia,
          and Hypertension

           Condition                           Combination Product
                                           Antihypertensive/diuretic*
          Hypertension                     Benazepril/amlodipine
                                           Trandolapril/verapamil

                                           Ezetimibe/simvastatin
           Dyslipidemia
                                           Lovastatin/niacin

                                           Metformin/glipizide
                                           Metformin/glyburide
             Diabetes
                                           Pioglitazone/metformin
                                           Rosiglitazone/metformin

 Hypertension/Dyslipidemia                   Amlodipine/atorvastatin
*Established combinations of diuretics and antihypertensive agents too numerous to list.
Adapted from Leichter SB, Thomas S. Clin Diab. 2003;21:175-178.
       Conclusion: Diabetes Cases
 As of NHANES 1999-2000, only ~ 7% of patients with
  diabetes were achieving all 3 of the following
  CV risk management goals:
    A1C <7%
    BP <130/80 mm Hg
    TC <200 mg/dL (LDL-C and TG not evaluated)
 CV risk management in patients with diabetes is an
  important process requiring a full arsenal of clinical
  information, especially renal and cardiac function
 Adherence in patients with multiple CV risk factors may
  be significantly improved with combination therapy
 Remember the importance of total CV risk management
Full Panel Q&A
Summary and Closing Remarks
      A Reminder–and Thanks
 Please be sure to complete your CME/CE
  evaluation form and give it to a representative
  of CE Alliance as you leave
 Thanks for coming!
A CV Risk Education Symposium
Integrating Total CV Risk
Management Into Clinical Practice

				
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