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PACE CV Master Programme Advanced CV Risk Management in

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PACE CV Master Programme Advanced CV Risk Management in Powered By Docstoc
					                Master Class:
                Advanced CV Risk management in cardiology
                June 17-18, 2011, London


Presentation topic

The case for intensive lipid management:
    The opportunities and issues for
               cardiologists
   Slide lecture prepared and held by:

  Prof. John Betteridge
  University College London
 A Survey of 246 Suggested
   Coronary Risk Factors
Paul N. Hopkins and Roger R. Williams

  Department of Internal Medicine,
 Cardiology Division, University of Utah
            Medical Center,
   Salt Lake City, UT 84132 (USA)

        Atherosclerosis 1981
BMJ   1975, 4 500-502
   The Fate of LDL




LDLR

       PCSK9 prevents
                        Down regulate HMGCoA reductase
       LDLR recycling
                         Reduce LDL receptor synthesis
                          Esterified by ACAT (storage)
                FH3: mutations in PCSK9
     Proprotein convertase subtilisin/kexin type 9
• PCSK9 is a protease which binds to LDL-R and directs them to
  lysosomes for degradation, rather than recycling to cell surface
• Loss of function (non-sense and some mis-sense) mutations lead to
  LDL levels
    – 2.6% of US blacks, LDL 28%, CHD 88%
    – 3.2% of US whites, LDL 15%, CHD 47%
          • (Cohen et al. NEJM 2006;354:1264)
• Rare gain of function (other mis-sense) mutations described which
  lead to severe FH
    – D374Y accounts for 2% of FH in UK
    – phenotype generally more severe than HeFH due to LDLR mutations
    – true homozygotes not described?
• Statins increase PCSK9 as well as LDLR activity – counterproductive
• Potential therapeutic target




 Tall, NEJM 2006;354:1310Horton et al. Trends Biochem Sci 2006;32:71Zhang et al. PNAS 2008;105:13045
          Familial
    Hypercholesterolaemia
Autosomal dominant inheritance
Xanthomata
Premature vascular disease
Elevated low density lipoprotein levels
Genetic defect at the LDL receptor
                     LDL-C Distribution and CAD Incidence
                    Presence or Absence of PCSK9 46L Allele
              No PCSK946L Allele ( n=9223 )                                            Dallas Heart Study
                    30           50th Percentile
                                                                                  12




                                                   Coronary Heart Disease ( % )
                    20
  Frequency ( % )




                    10                                                                        P=0.003
                     0                                                            8
                       0 50 100 150 200 250 300
                    PCSK946L Allele ( n=301 )
                    30                                                            4
                    20
                    10
                                                                                  0
                     0
          0 50 100 150 200 250 300                                                       No    Yes
Plasma LDL Cholesterol in White Subjects ( mg/dL)                                        PCSK946L
                           COHEN et al. New Engl J Med 354:1264, 2006
             LDL and Atherogenesis
LDL Readily Enter the Artery Wall Where They May be Modified

                         LDL                           Vessel Lumen



                                                             Endothelium
   Oxidation of Lipids   LDL   Hydrolysis of Phosphatidylcholine
            and ApoB           to Lysophosphatidylcholine

           Aggregation         Other Chemical Modifications


                     Modified LDL
                                                              Intima
          Modified LDL are Pro inflammatory

                               Steinberg D et al. N Engl J Med 1989;320:915-924.
Macrophages and Foam Cells Express
 Growth Factors and Proteinases

Monocyte                                  Vessel Lumen
                             LDL


Adhesion                                       Endothelium
                MCP-1
Molecules                    LDL
                                                    Intima
                Modified
 Cytokines        LDL            Growth Factors
                                Metalloproteinases


                                 Cell Proliferation
 Macrophage
                Foam Cell       Matrix Degradation

                            Ross R. N Engl J Med 1999;340:115-126.
From Association to
      Cause
Cholesterol and CHD
   strength
   dose response
   independent
   consistent
   plausible mechanism
   predictive
   reversible
     Problems with Early Trials
• Available drugs of limited efficacy, poorly
  tolerated or both.
  small differences between control and treated
  groups
• Clinical trial science poorly developed.
   low end-point numbers
   poor data collection
   Lack of definitive outcomes:
   small reduction in CHD events
  (mainly non-fatal MI)
   no effect on overall mortality
              Effects of Statins
                                     Plasma LDL


                    LDL receptors



                 Synthesis
      Statins
                        Hepatic
                       cholesterol

Biliary
cholesterol

Dietary                Intestinal
cholesterol            pool
                                                 Statins:The Evidence Base.
Continuum
  of risk
 Placebo MI rate per 100 subjects per 5 years




                                                                                       High-risk CHD patients
                                                                            4S
                                                22.6 Secondary         (simvastatin)
                                                                                        (high cholesterol)
                                                     prevention
                                                                                           Majority of
                                                                         CARE               CHD patients
                                                12.9       HPS        (pravastatin)          (broad range of
                                                                         LIPID                  cholesterol levels)
                                                8.44                  (pravastatin)
                                                                                               Patients at high risk
                                                7.9                    WOSCOPS                   of CHD (high
                                                        Primary       (pravastatin)
                                                       prevention                                   cholesterol)

                                                2.8                 AFCAPS/TexCAPS                 Patients at low
                                                                       (lovastatin)                  risk of CHD
                                                                                                        (low HDL-C)
        CHD Risk Despite Statin Therapy

                                                            Clinical events*
                                                        Risk reduction Remaining
Trial                           Statin treatment          vs placebo     risk
WOSCOPS** (6595)               Pravastatin 40 mg            31%          69%
AFCAPS/TexCAPS** (6605)        Lovastatin 20 or 40 mg       40%          60%
ASCOT-LLA** (10,305)           Atorvastatin 10 mg           38%          62%
4S** (4444)                    Simvastatin 20 mg            26%          74%
CARE*** (4159)                 Pravastatin 40 mg            24%          76%
LIPID*** (9014)                Pravastatin 40 mg            24%          76%
HPS*** (20,536)                Simvastatin 40 mg            27%          73%
PROSPER*** (5804)              Pravastatin 40 mg            24%          76%

  *Nonfatal myocardial infarction and coronary death; **Primary prevention
  trial; ***Secondary prevention trial
    Early Primary and Secondary
       CVD Prevention Trials
                                                 4S-PI
        25     Secondary prevention
               Primary prevention
        20                        Lipid-PI
                          4S-Rx
With CHD 15
                                       CARE-PI
 Event
                   CARE-Rx
   (%)   10                     Lipid-Rx
                                                     WOS-PI
                                           WOS-Rx
         5     ?       AFCAPS-Rx
               ?                            AFCAPS-PI
         0
          50   70     90   110 130 150       170     190   210
                           LDL-cholesterol (mg/dl)
            PROVE-IT Trial
 Intensive and Moderate Lipid-Lowering
    after Acute Coronary Syndromes
Population:
4162 patients within 10 days of                    Pravastatin 40mg
acute coronary syndrome                                 26.3%
Treatment:




                                   CVD Endpoints
Standard: Pravastatin 40mg/day
mean LDL 2.46mmol/l
Intensive: Atorvastatin 80mg/day                           Atorvastatin 80mg
mean LDL 1.6mmol/l                                               22.4%
Primary endpoint:                                         16% reduction
Death , MI, unstable angina                                  p=0.005
requiring hospitalisation,
revascularisation and stroke
Follow-up:                                          6    12    18     24   30
18-36 months (mean 24 months)                             Months

                              Cannon et al N Engl J Med April 8th 2004
    Intensive Lipid Lowering with Atorvastatin
     in Patients with Stable Coronary Disease
         Treat to New Targets Trial (TNT)

Population: 10,001 patients with CHD: previous MI, angina with
    objective evidence of atherosclerotic CHD, coronary
    revascularization.
Protocol: 15464 CHD patients, LDL-C 130-250mg/dl (3.4-6.5mmol/l)
    8 week run-in treatment with atorvastatin 10 mg/day. 5461 excluded.
    If LDL -C <130mg/dl randomised to either atorvastatin 10mg/dl or
    80mg/day. Median follow-up 4.9yrs.
Primary end point: Occurrence of first CVD event; CHD death, non-
    fatal, non procedure - related MI, resuscitation after cardiac arrest,
    fatal or non fatal stroke.
.


                                      La Rosa et al NEJM March 2005
Treat to New Targets: Lipid Effects




               La Rosa et al NEJM March 2005
                                       Primary Efficacy Outcome Measure:
                                        First Major Cardiovascular Event*
                                                      TNT
                                      0.15
Proportion of patients experiencing




                                                 HR 0.78 (95% CI 0.69,
                                                 HR = 0.78(95%CI 0.69, 0.89)
                                                 0.89)
                                                 p=0.0002
    major cardiovascular event




                                                 P=0.0002
                                                     Atorvastatin 10 mg
                                      0.10           Atorvastatin 80
                                                   Atorvastatin 10mgmg
                                                   Atorvastatin 80mg


                                      0.05



                                                                           Relative risk reduction 22%
                                                                          Relative risk reduction = 22%
                                        0

                                             0         1        2        3         4        5        6
                                                                    Time (years)
                                      *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac
                                      arrest, fatal or nonfatal stroke
Statin Therapy in Secondary Prevention
   Trials Event Rates Against LDL-C
        New Insights from TNT
Statin trials show highly
  significant reductions in                                      
  CHD events and stroke.            
  The lower the LDL the
  better.                                        
Despite these dramatic                              
  effects there remains a                         
  significant residual risk.                 
                                            
                                        
TNT has demonstrated
  that more intensive LDL
  lowering results in                   LDL cholesterol (mg/dl)
  increased benefit
                               La Rosa et al NEJM March 2005
                 Meta-Analysis
           Cardiovascular Outcomes
     Intensive vs Moderate Statin Therapy
Population:
                                                   Odds Ratio (95% CI)
  27,548 patients with
   stable CVD in TNT and      PROVE IT-TIMI 22
   IDEAL or acute coronary
   syndrome, PROVE-IT-        A-TO-Z
   TIMI-22, and A-to-Z
Results:                      TNT
  16% odds reduction in
   coronary death or          IDEAL
   myocardial infarction,                                       OR, 0.84
                                                                95% CI, 0.77-0.91
   p<0.0001.                  Total
                                                                p=0.00003
  No difference in total or
                                             .66            1               1.34
   non-cardiovascular
   mortality.                                INTENSIVE          MODERATE

                        Cannon et al J Am Coll Cardiol, 2006; 48: 438-445
   Implications of Recent Trials
Adult Treatment Panel III Guidelines


           High Risk CVD:
    Initiate statin therapy regardless of
    baseline LDL-C;
    LDL goal <70mg/dl (1.8mmol/L)




                         Circulation 2004;110 227
           Statins and Stroke Reduction
                  A Meta-Analysis
Across 26 trials, statins reduced stroke by 21% (P<.0001), with no
evidence of heterogeneity between trials
Trials                                                      Odds Ratios (95% CI)

ASCOT-LLA
ALLHAT-LLT
PROSPER
HPS
GREACE
MIRACL
GISSI
LIPID
AFCAPS/TexCAPS
Post-CABG
CARE
WOSCOPS
4S
SMALL TRIALS

OVERALL (95% confidence interval)   0.79 (0.73-0.85)
                       0.2                  0.4           0.6     0.8   1.0   1.2 1.4
                                                       Statin better     Control better

                                    Amarenco et al. Stroke. 2004;35:2902-2909.
                                   Heart Protection Study
                                            Stroke Outcomes

                                                 Simvastatin         Placebo
                          12
                                     10.3          10.4
Incidence of stroke (%)




                          10

                          8                                                     * P<.05.
                                     169           170
                          6
                                                                                           4.8 *
                          4                                                3.2
                          2                                               275              415

                          0
                               Prior cerebrovascular disease     No prior cerebrovascular disease
                                          n=3280                             n=17,256
                                                          HPS Collaborative Group. Lancet. 2004;363:757-767.
      SPARCL: Does Robust Lipid Lowering
      Reduce the Occurrence of Stroke in
            Patients without CHD?
Patient population                              Atorvastatin 80 mg
                              4200
   Stroke/TIA 1-6 months    patients
    prior
   LDL 100-190 mg/dL                           Double-blind placebo
    (2.6-4.9 mmol/L)
   Exclusions:
                                                            5 years
        Age <18 years
         Hx of CAD
                                               Primary endpoint:
     

        Endarterectomy in
         prior month                           Time to first fatal
        Subarachnoid
         hemorrhage                            or non fatal stroke
                             Welch KMA, et al. 26th International Stroke Conference;
                             February 14-16, 2001, Ft Lauderdale, Fl, USA.
         High-Dose Atorvastatin after Stroke
            or Transient Ischaemic Attack
                  The SPARCL Trial
Population:
   4731 patients with stroke or TIA
   one to six months before study
   entry. LDL-C 2.6-4.9mmol/l and no
   known CHD
Design:
   Randomised, double-blind, placebo-



                                         % Patients
   controlled trial comparing
   atorvastatin 80mg/day to placebo.
   Median follow-up 4.9years.
Primary endpoint:
   Time to first nonfatal or fatal
   stroke
Results:
   11.2% patients (265) on drug and
   13.1% (311) on placebo had an event
   HR, 0.84 (95%CI 0.71-0.99) p=0.03.
   5 year absolute risk reduction 2.2%                 Years
                                SPARCL Investigators NEJM 2006; 355: 549-559

				
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