Terry Jacobsen, MD

1
LDL - How low can you go?

• Terry Jacobsen, MD
• Director, Office of Health Promotion and Disease
  Prevention
• Emory University
• Atlanta, GA
• Anthony Gotto, MD
• Dean, Cornell University Medical College
• New York City, NY

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LDL-How low can you go?
Is lower really better?

• "The Lower the Better" in Hypercholesterolemia
  Therapy
• A Reliable Clinical Guideline?

Jacobson TA. Ann Intern Med 2000 133549-554
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LDL-How low can you go?
Epidemiology

• Studies show curvilinear relationship
• PROCAM Prospective Cardiovascular Munster Study
  
• MRFIT Multiple Risk Factor Intervention Trial
• The mean lipid level for a CHD survivor is
  between 120 and 140 mg/dL.
• A diminishing returns model of benefit as lipid
  levels are lowered.

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LDL-How low can you go?
Secondary prevention trials

• CARE Cholesterol and Recurrent Events trial
• No cardioprotective benefit in reducing LDL from
  124 mg/dL to 71 mg/dL
• LIPID Long-Term Intervention with Pravastatin in
  Ischaemic Disease study
• Showed only a 16 relative risk reduction in
  patients with LDL below 135 mg/dL

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LDL-How low can you go?
4S trial

• Reductions in relative risk were independent of
  baseline LDL cholesterol levels
• -35 in patients with LDL lt169 mg/dL
• -36 in patients with LDL gt206 mg/dL

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LDL-How low can you go?
Post-CABG trial

• Patients with saphenous vein grafts randomized
  to
• moderate therapy (LDL lt130)
• aggressive therapy (LDL lt100)
• 4 year results no significant difference in
  non-fatal MI or cardiovascular death

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LDL-How low can you go?
Primary prevention

• WOSCOPS
• (West Of Scotland COronary Prevention Study)
• AFCAPS/TexCAPS
• (Air Force/Texas Coronary Atherosclerosis
  Prevention Study)
• No evidence that the higher dose led to greater
  reduction of events.

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LDL-How low can you go?
More isnt better

• The pharmacoeconomics also mitigate that maybe
  we cant afford to get patients as low as
  possible. That maybe we need to focus in on other
  risk factors after we do drive LDL levels to
  goal.
• Terry Jacobsen, MD
• Director, Office of Health Promotion and Disease
  Prevention
• Emory University
• Atlanta, GA

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LDL-How low can you go?
2 to 1

• The Lipid Research Clinic (LRC) trial established
  the 2 to 1 relation between
• cholesterol reduction and risk reduction.
• AFCAPS/TexCAPS (Air Force/Texas Coronary
  Atherosclerosis Prevention Study) did not show a
  linear relationship, but also did not show a
  threshold.

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LDL-How low can you go?
Hazards of subgroup analyses

• Subgroup analyses are hypothesis generating, not
  conclusive.
• What is the real premise of the trial?
• Who benefited from therapy?
• AFCAPS/TexCAPS LDLgt130 w/HDLlt50
• CARE LDL gt160 w/established CAD

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LDL-How low can you go?
Two questions

• If you start at LDL gt120 or 200, should you be
  more aggressive?
• 2) With LDL 100-130, are you getting benefit by
  being more aggressive?
• Must wait for TNT, SEARCH, OXFORD trials

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LDL-How low can you go?
Goals arent everything

• LRC study showed no incremental reduction after
  30 LDL reduction.
• Many trials didnt reach NCEP goals, but did show
  benefit.
• Goals are important for populations, but
  advocating beyond them is premature.

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LDL-How low can you go?
Other factors

• Are there adverse consequences of a large LDL
  reduction?
• Are there dangers of hemorrhagic stroke?
• Are there other properties of statin therapy?
• Need to look at other risk factors as
  aggressively.

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LDL-How low can you go?
Treating to target

• Some patients LDL simply cant be lowered to an
  acceptable target level.
• You can see benefit without reaching target, but
  would you see more if LDL were lower?
• We may never be able to completely answer the
  question.