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Lipid Disorders The Science and Art of Treatment in 2004. Alan Jansujwicz, M.D. DHMC Cardiology Update Symposium 2004. Session Outline. Background Review of Data to Support Current Lipid Treatment Paradigms Current Recommendations for Treatment Time for Questions (Hopefully). Introduction.

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Lipid disorders the science and art of treatment in 2004 l.jpg

Lipid DisordersThe Science and Art of Treatment in 2004

Alan Jansujwicz, M.D.

DHMC Cardiology Update Symposium 2004


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Session Outline

  • Background

  • Review of Data to Support Current Lipid Treatment Paradigms

  • Current Recommendations for Treatment

  • Time for Questions (Hopefully)


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Introduction

  • CHD remains the no. 1 killer in the U.S.

    • Eradicate CAD – life expectancy up to 84

    • Eradicate Cancer – life expectancy up to 80

  • Dyslipidemia plays a major role in CHD

  • Safe and effective treatments available

  • Less than ½ of eligible patients treated

  • Many who are initially treated, stop Rx


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Lipid Lowering Drugs and the Data

  • HMG Co-A Reductase Inhibitors

  • Niacin

  • Fibrates

  • Ezetimibe

  • Others


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HMG Co-A Reductase Inhibitors“Statins”

  • Drugs structurally similar to HMG-CoA

    • precursor of cholesterol

  • Competitive inhibitors of HMG-CoA reductase

    • last step in cholesterol synthesis

  • Lower serum LDL concentrations by:

    • Upregulating LDL receptor activity

    • Reducing LDL entry into the circulation

  • Most effective agents for lowering LDL

  • Impressive body of evidence for CHD treatment


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LDL Reduction by Individual Statins

In general, doubling dose = additional 6% reduction in LDL

Source: Gau G, Mayo Clinic Cardiovascular Review


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Chronic Statin TherapyInitial Major Secondary Prevention Studies

  • Scandinavian Simvastatin Survival Study (4S) – Lancet ‘94

    • 4444 patients with remote MI or Angina

    • Total Cholesterol 213-309 mg/dL

    • Simvastatin 20/40 mg vs placebo for 5.4 years

  • Cholesterol and Recurrent Events Trial (CARE) – NEJM ‘96

    • 4159 patients with remote MI

    • Total Cholesterol < 240 mg/dL, LDL 115-174 mg/dL

    • Pravachol 40 mg vs placebo for 5 years

  • Long-Term Intervention with Pravastatin (LIPID) – NEJM ‘98

    • 9014 patients with remote MI or Angina

    • Total Cholesterol 155 to 271 mg/dL

    • Pravachol 40 mg vs placebo for 6.1 years




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LIPID Trial – Risk of CHD Death

Time Delay to Benefit…

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, N Engl J Med 1998;339:1349-1357


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CARE Trial – CHD Events

Possible Lower Limit to Benefit…

Investigators postulated that there might be a “benefit floor”

Sacks, F. M. et al. N Engl J Med 1996;335:1001-1009


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Chronic Statin TherapyThe Heart Protection Study

  • 20K patients ages 40-80 years in the UK

  • Inclusion criteria of

    • Known CAD

    • Known PVD

    • Diabetes

    • Males > 65 with HTN (also a high risk group, but only 1%)

  • No upper or lower limit of serum cholesterol

  • Assigned to simvastatin 40 mg vs placebo

  • Direct LDL measured from nonfasting samples

  • Followed for average of 5 years

HPS Collaborative Group. Lancet 2002;360: 7-22.


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The Heart Protection StudyLipid Levels

  • Baseline Lipid Panel

    • Total Chol 228 mg/dL

    • dLDL 131 mg/dL (15% less than calculated LDL)

    • HDL 41 mg/dL

    • Trig 81 mg/dL

  • Average dLDL levels during 5 years of follow-up

    • Simvastatin 89 mg/dL (85% avg compliance)

    • Placebo 128 mg/dL (17% avg crossover)

**Below previously suggested floor to benefit**

HPS Collaborative Group. Lancet 2002;360: 7-22.


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RRR = 13%

RRR = 18%

RRR = 25%

RRR = 24%

The Heart Protection StudyMajor Outcomes

All risk reductions statistically significant


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The Heart Protection StudySafety Measures

p = ns

p = ns

p = ns

p = ns


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Chronic Statin TherapyPrimary Prevention

  • WOSCOPS – NEJM ’95

    • 6595 men, age 45 to 64, with no documented CAD

    • Total cholesterol at least 252 mg/dL

    • Pravachol 40 mg vs placebo for 4.9 years

    • Primary Endpoint – Nonfatal MI or Death from CHD

  • AFCAPS/TexCAPS – JAMA ’98

    • 997 women (age 55-73) and 5608 men (age 45-73)

    • No documented CAD or PVD

    • Total cholesterol 180 to 264 mg/dL

    • Lovastatin 20/40 mg vs placebo for 5.2 years

    • Primary Endpoint – MI, USA, or Sudden Cardiac Death


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Primary Prevention TrialsLipid Lowering Results

26%

25%

WOS – RRR 31%, due to reduction in nonfatal MI and CHD death

AFCAPS – RRR 37%, due to difference in nonfatal events


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Acute Statin Therapy

  • MIRACL – JAMA 2001

    • 3086 patients undergoing noninvasive ACS treatment

    • Total cholesterol less than 270 mg/dL; no lower limit

    • Atorvastatin 80 mg vs placebo for 16 weeks

  • PROVE-IT – NEJM 2004

    • 4162 patients undergoing mostly invasive ACS treatment

    • Total cholesterol less than 240 mg/dL (naïve), 200 mg/dL (Rx)

    • Atorvastatin 80 mg vs Pravastatin 40 mg for 2 years

  • A to Z – JAMA 2004

    • 4497 patients with acute NSTEMI or STEMI (complicated trial)

    • Total cholesterol less than 250 mg/dL; no lower limit

    • Simva 40(1mo)/80 mg vs Placebo(4mo)/Simva 20 mg for 2 years


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MIRACL Trial Results

RRR = 16% in Treatment Group at 16 weeks (p=0.048)

Higher baseline LDL not predictive of increased event rate

No significant association between % change in LDL and event rate


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PROVE-IT and AtoZ Results

Similar Reductions in LDL achieved in both trials

RRR = 16% in PROVE-IT met significance

RRR = 11% in A to Z did not meet significance

Limitations in A to Z design likely responsible for lack of significant outcome


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LDL Levels and CHD RiskLower is Better!

4S-PL

4S-Rx

LIPID-PL

CARE-PL

AtoZ-PL

LIPID-Rx

AtoZ-Rx

HPS-PL

CARE-Rx

HPS-Rx

WOS-PL

PROV-Rx

PROV-PL

AF-PL

WOS-Rx

AF-Rx


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Niacin

  • Cholesterol-lowering effect 1st reported in 1955

  • Reduces LDL (5-25%) by decreasing peripheral mobilization of FFAs from adipose tissue

  • Most effective drug available clinically for raising HDL (15-35%)

  • Also effective for reducing triglycerides (25-50%)

  • Reduces Lp(a) by 30%

  • Converts small, dense LDL to large, buoyant LDL


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Niacin

  • Pitfalls with niacin therapy

    • Cutaneous flushing, pruritis, nausea, abd pain

    • Hepatotoxicity

    • Glucose intolerance

    • Increase risk of myositis if used with statin

    • Minimal hard endpoint outcome data


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Niacin Outcome Data Trials

  • Coronary Drug Project –JACC 1986

    • 8,000+ men, post-MI, Rx with 1 of 5 drugs or placebo

    • Patients treated for 6 years (some arms stopped early)

    • Patients subsequently followed for 9+ years post-Rx

  • HDL Atherosclerosis Treatment Study – NEJM 2001

    • 160 patients with established CAD

    • Low HDL (31 mg/dL), “normal” LDL (125 mg/dL)

    • Four Rx regimens: Placebo, N+S, AV, N+S+AV

    • Followed for 3 years for clinical or angiographic events

    • All but 14 patients underwent an end of trial angiogram


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Coronary Drug ProjectLong-Term Mortality Benefit of Niacin

100

90

80

70

Niacin

60

Survival (%)

50

Placebo

40

30

P = 0.0012

20

10

16

14

12

10

6

8

4

0

2

Years of follow-up

Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

source = www.lipidsonline.org


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HDL-Atherosclerosis Treatment Study (HATS)Niacin and Statin Outcome Trial

RRR = 89% p < 0.05

LDL 116

LDL 75

LDL 112

LDL 79

HDL 34

HDL 40

HDL 33

HDL 36


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Fibrates

  • Class of drugs which resemble short chain fatty acids

  • Increase oxidation of fatty acids in muscle and liver

  • Most effective class of drugs for lowering triglycerides

  • Increase size of LDL particles and enhance removal

  • May increase HDL-mediated reverse cholesterol transport

  • Reduce levels of plasminogen activator inhibitor type I

  • Currently available drugs in U.S.

    • Gemfibrozil

    • Fenofibrate (less risk of myopathy when used with a statin)

  • ADRs: GI, ED, myopathy (CRF)


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Major Fibrate Therapy Trials

  • Helsinki Heart Study – NEJM 1987

    • Primary prevention trial

    • 4,081 dyslipidemic (non-HDL > 200 mg/dL) men, age 40 to 55

    • Gemfibrozil 600 mg bid vs Placebo for 5 years

    • Primary endpoint – CHD death or nonfatal MI

  • VA-HIT – NEJM 1999

    • Secondary prevention trial

    • 2,531 men with documented CAD in the VA system

    • HDL < 40 mg/dL and LDL < 140 mg/dL

    • Gemfibrozil 600 mg bid vs Placebo for 5.1 years

    • Primary endpoint – CHD death or nonfatal MI


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Major Fibrate TrialsOutcome Data

RRR = 34%

RRR = 66%

RRR = 22%

* HHS-Post Hoc: Subgroup with TG > 200 mg/dL and HDL < 42 mg/dL

** All results met statistical significance


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Ezetimibe

  • 1st in new class of cholesterol absorption inhibitors

  • Likely works by binding to and blocking the sterol transporter on the intestinal brush border

  • Results in increased LDL-R activity and LDL clearance

  • Drug and its metabolites circulate enterohepatically with little systemic penetration

  • Potential toxicities essentially limited to liver

  • Does not induce or inhibit cytochrome P450 system

  • Single dosing option of 10 mg once daily


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Lipid Lowering with Ezetimibe

Ballantyne CM. Circulation 2003; 107: 2409-2415.


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Lipid Risk AssessmentNCEP ATP III + Recent Update

  • Obtain a fasting lipoprotein profile on all adults aged 20 years or older (repeat every 5 years)

  • Assess for CHD, CHD risk equivalents, and risk factors for developing CHD

  • Framingham Risk Assessment for intermediate risk patients

  • Assess for the metabolic syndrome

  • Consider emerging risk factors (i.e. hs-CRP)

NCEP. JAMA 2001; 285(19): 2486-97.


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LDL Cholesterol

< 70 Optimal in HRP

< 100 Optimal

100-129 Near Optimal

130-159 Borderline High

160-189 High

190+ Very High

HDL Cholesterol

< 40 Low

60+ High

Total Cholesterol

< 200 Desirable

200-239 Borderline High

240+ High

Triglycerides

< 150 normal

150-199 Borderline High

200-499 High

500+ Very High

Lipoprotein Profile Classification


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CHD and CHD Risk Equivalents

  • CHD

  • CHD Risk Equivalents

    • Peripheral Vascular Disease

    • Abdominal Aortic Aneurysm

    • Symptomatic Carotid Arterial Disease

    • Diabetes

    • Framingham 10-year risk 20+%


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Major Risk FactorsATP III

  • Cigarette Smoking

  • Hypertension (140+/90+ or on meds)

  • Low HDL Cholesterol (< 40 mg/dL)

  • FH of Premature CAD

    • Male 1st degree relative < 55

    • Female 1st degree relative < 65

  • Personal Age

    • Male 45+

    • Female 55+


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Framingham Risk AssessmentFor Intermediate Risk Patients

  • Gender Specific

  • Calculates risk based on

    • Age

    • Total Cholesterol (age stratified)

    • Current Smoking Status (age stratified)

    • HDL Cholesterol

    • Systolic Blood Pressure (Rx or no Rx)

  • Overall point score allows for calculation of 10 year risk of a CHD event

  • Framingham Risk stratifies patients into

    • CHD equivalent 10-year risk > 20%

    • Moderately high risk 10-year risk 10-20%

    • Intermediate Risk 10-year risk < 10%


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The Metabolic SyndromeAny 3 of the following

  • Abdominal Obesity (waist circumference)

    • Men > 40 inches

    • Women > 35 inches

  • Triglycerides 150+ mg/dL

  • HDL

    • Men < 40 mg/dL

    • Women < 50 mg/dL

  • Blood Pressure 130+/85+ mm Hg

  • Fasting Glucose 110+ mg/dL


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Risk StratificationUpdate to ATP III

  • Very High Risk

    • CHD + multiple risk factors (diabetes)

    • CHD + poorly controlled risk factor (smoking)

    • CHD + metabolic syndrome

    • CHD + ACS

  • High Risk

    • CHD

    • CHD Equivalents

  • Moderately High Risk

    • 2+ Risk Factors + Framingham Risk of 10-20%

  • Intermediate Risk

    • 2+ Risk Factors + Framingham Risk of < 10%

  • Low Risk

    • 0-1 Risk Factor


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LDL Treatment Based on Risk Stratification

  • Very High Risk Patient

    • Optional LDL goal of < 70 mg/dL

    • Standard LDL goal of < 100 mg/dL

    • For LDL ≥ 100 mg/dL, initiate both lifestyle changes and drug treatment

    • For LDL < 100 mg/dL, lifestyle changes are indicated, drug Rx is therapeutic option


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LDL Treatment Based on Risk Stratification

  • High Risk Patient (CHD / CHD Equivalent)

    • LDL goal of < 100 mg/dL

    • For LDL ≥ 100 mg/dL, initiate both lifestyle changes and drug treatment

    • For high TG / low HDL, consider adding niacin or fibrate to statin


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LDL Treatment Based on Risk Stratification

  • Moderately High Risk Patients

    • 2+ RFs and 10-year risk 10-20%

    • Optional LDL goal of < 100 mg/dL

    • Standard LDL goal of < 130 mg/dL

    • For LDL ≥ 130 mg/dL, initiate both lifestyle changes and drug treatment

    • For LDL 100 to 129 mg/dL, lifestyle changes are indicated, drug Rx is therapeutic option


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LDL Treatment Based on Risk Stratification

  • Intermediate Risk Patients

    • 2+ RFs and 10-year risk < 10%

    • LDL goal < 130 mg/dL

    • For LDL ≥ 130 mg/dL, initiate lifestyle changes

    • For LDL ≥ 160 mg/dL, initiate both lifestyle changes and drug Rx


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LDL Treatment Based on Risk Stratification

  • Low Risk Patients

    • 0 to 1 risk factor

    • LDL goal < 160 mg/dL

    • For LDL ≥ 160 mg/dL, initiate lifestyle changes, drug Rx optional

    • For LDL ≥ 190 mg/dL, initiate both lifestyle changes and drug Rx


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Secondary Goal – Non HDL Cholesterol

  • Elevated triglycerides are an independent risk factor for CHD (meta-analyses)

  • Non HDL cholesterol captures risk of both LDL and triglycerides

  • Non HDL goals are set 30 mg/dL higher than LDL goals

    • High risk non HDL goal < 130 mg/dL

    • Int risk non HDL goal < 160 mg/dL

    • Low risk non HDL goal < 190 mg/dL


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hs-CRP

  • Large body of evidence now supports CRP as in independent predictor of CHD risk

  • However, the data all comes from post hoc analysis of lipid-lowering trials and observational trials

  • Probably most useful in identifying moderately high risk patients who may be at greater risk than predicted by traditional risk assessment


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hs-CRP

  • hs-CRP measurement is now a Class IIa recommendation in two subgroups of patients

    • Moderately high risk Framingham patients (10-20% risk)

    • Patients with known CAD for risk assessment of future events


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Measuring and Using hs-CRP

  • Measure twice, two weeks apart, in metabolically stable patients

  • Tertiles of risk

    • Low risk < 1 mg/dL

    • Intermediate risk 1-3 mg/dL

    • High risk > 3 mg/dL

  • High risk CRP results in moderately high risk patients and in those with CHD should result in intensification of treatment

  • hs-CRP values > 10 mg/dL indicate an ongoing inflammatory or infectious process and should not be used


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When to Stop Treatment

  • Statins and Ezetimibe

    • Myopathy - Muscle aches with CK > 10x ULN

    • Abnormal LFTs – 3x ULN

    • Pregnancy and Breast Feeding

  • Niacin

    • Abnormal LFTs (3x ULN) or chronic liver disease

    • Gout

    • Poorly controlled diabetes

    • Pregnancy

  • Fibrates

    • Chronic liver dysfunction or renal failure

    • Abnormal LFTs or myopathy

    • Pregnancy


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Summary

  • Recent clinical trials have confirmed the log-linear relationship between CHD risk and LDL cholesterol at lower levels

  • This relationship means that risk reduction is independent of initial cholesterol levels and is dependent only on absolute reduction in levels

  • This has led to more aggressive lipid lowering benchmarks, especially in certain high risk groups

  • Additionally, novel risk factors such as hs-CRP have become available which allow us to further stratify certain risk populations

  • The charge remains to identify and effectively treat our dyslipidemic patients over the long-term


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