Lipids as predictors of and treatment targets for cardiovascular diseases

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Lipids as predictors of and treatment targets for
cardiovascular diseases

• Dr. Mike Khan

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Topics of Discussion

• The burden of CHD
• CHD as a multifactorial and systemic disease
• Establishing the link between cholesterol and CVD
• Role of lipids in pathogenesis of atherosclerosis
• Molecular level- inflammation, lipid oxidation.
• Clinical level- role of lipid subfractions
• Trials of lipid-lowering
• Calculating future risk of CVD
• Public health
• ?tailored or individualised medicine
• Guidelines

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The scale of the problem
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ATHEROSCLEROTIC DISEASES - THE SCURGE OF THE
DEVELOPED WORLD

• Vascular Event Incidence and Prevalence
• Myocardial 0.56 of the population experience
  an MI per year Infarction 2.4 of the
  population have suffered an MI
• Stroke 0.24 of the population per year suffer a
  stroke for the first time 25 of men and 20
  of women over 45 years will have a stroke by
  the age of 85 years
• Peripheral Symptomatic PVD increases with
  age Vascular - 0.2 per year in men of
  35-45 years Disease - 7 of 50-75 year-olds

Office for National Statistics. Britain 1998.
HMSO, London 1998 Stroke Services and Research.
London 1996 Coronary heart disease statistics.
BHF 1995 Lancet 19973501469-65 Eur J Vasc
Surg 19882283-291.
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AtherothrombosisThe Leading Cause of Death
Worldwide
0
2
4
6
8
10
12
14
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Number of deaths (x 106)
In eight defined regions of the world, including
developed and developing areas.
Murray et al. Lancet 19973491269-1276.
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Not a new problem
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Angina probably first afflicted a   prosperous
cave man who very likely dropped dead ... after
gorging himself with a roast of venison and on
his way to date one of his harem Paul Dudley
White (1886-1973)
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Risk Factors for Atherothrombosis
Hypercoagulable states
Life-style (e.g., smoking, diet, lack of exercise)
Homocysteinaemia
Hyperlipidaemia
Insulin resistance
Diabetes
Infection?
Obesity
Age
Atherosclerosis
Hypertension
Gender
Genetics
Atherothrombotic Manifestations(MI, Ischemic
Stroke, Vascular Death)
American Heart Association. Heart and Stroke
Facts 1997 Statistical Supplement Wolf. Stroke
199021(suppl 2)II-4II-6 Laurila et al.
Arterioscler Thromb Vasc Biol 1997172910-2913
Grau et al. Stroke 1997281724-1729 Graham et
al. JAMA 19972771775-1781 Brigden. Postgrad
Med 1997101(5)249-262.
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Incidence of CHD in USA is declining

• Unfortunately, primarily due to effective
  employment of primary/secondary prevention
  treatments, rather than improved lifestyle.
• Broadly similar findings in Europe.

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Incidence of some CVD risk factors is increasing
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Diabesity- the new epidemic

• 200 million individuals world-wide have diabetes.
• Incidence is predicted to double over the next
  10-15 years.
• 80 will die early due to their disease,
  primarily as a result of atherothrombosis.

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Clustering of Risk Factors for Atherothrombosis
in Diabetes
Hypercoagulable states
Life-style (e.g., diet, lack of exercise)
Hyperuricaemia
Hyperlipidaemia
Insulin resistance
High glucose
Infection?
Obesity
Age
Atherosclerosis
Hypertension
Gender
Genetics
Atherothrombotic Manifestations(MI, Ischemic
Stroke, Vascular Death)
American Heart Association. Heart and Stroke
Facts 1997 Statistical Supplement Wolf. Stroke
199021(suppl 2)II-4II-6 Laurila et al.
Arterioscler Thromb Vasc Biol 1997172910-2913
Grau et al. Stroke 1997281724-1729 Graham et
al. JAMA 19972771775-1781 Brigden. Postgrad
Med 1997101(5)249-262.
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Genes are important
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So is diet!!
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Encourage healthy lifestyle and diet

• Health promotion.
• Links between weight and health may be
  misunderstood.
• The media play a key role.

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ATHEROSCLEROTIC DISEASE
Multiple Clinical Outcomes - One Underlying
Pathology
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Cholesterol level predicts CHD risk
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Cholesterol and CHD

• The relationship between plasma LDL-cholesterol
  and CHD risk is continuous and semilogarithmic.
• The absolute theoretical benefit of reducing
  cholesterol is greater at higher than at lower
  LDL-cholesterol levels.
• Also, because CHD is multifactorial, high risk
  individuals will derive greater absolute benefits
  from treatment than low risk individuals with the
  same LDL-cholesterol.
• Similar data from PROCAM, Framingham, MRFIT.

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A large number of clinical events occur in those
with below average cholesterol levels
Total Cholesterol Distribution HD vs Non-CHD
Population
Framingham Heart Study26-Year Follow-up
No CHD
35 of CHD Occurs in People with TClt5.0 mmol/L
CHD
4
6.5
7.7
5
Total Cholesterol (mmol/L)
Castelli WP. Atherosclerosis. 1996124(suppl)S1-S
9. ?1996 Reprinted with permission from Elsevier
Science.
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Cholesterol predicts risk of CHD even when other
factors accounted for
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LDL, HDL and Triglycerides

• LDL correlated better with CVD risk than TC.
• CVD risk inversely proportional to HDL.
• Low HDL and raised TG (atherogenic dyslipidaemia)
  strong predictor of risk.

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Calculating risk
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Natural history of atherosclerosis
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Pathogenesis of atherosclerosisRole of lipids

• Increased expression of cell adhesion molecules.
• Foam cell formation.
• Endothelial dysfunction.
• Engender and maintain chronic inflammation.
• Destabilise plaques.
• Pro-thrombotic.

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Pathogenesis of the atherosclerotic plaque

• Two increasingly convergent hypotheses
• Response to injury- first proposed by Ross and
  extended to a broader recognition as
  inflammation by Peter Libby and others.
• Smoking, hypertension, dyslipidaemia damage
  endothelium thus starting atherogenesis
• Lipid oxidation- pioneered by Daniel Steinberg
• Foam cell formation only occurs in the presence
  of modified lipoproteins
• Both intimately and inextricably linked

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LPL
Chylo-micron
Remnant
Apo E receptor
Gut
HDL
TG
TC
TG
HDL
CETP
VLDL
IDL
Liver
LPL
TC
LPL
TG
TG
LDL
Ox-LDL
LDL receptor
HDL
LDLr
SR-A
TC
Macrophage
Lipid metabolism
ABC1
Cholesterol uptake
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Reducing the risk of CHD

• Treatment of
• Hypertension
• Renin angiotensin system
• Dyslipidaemia
• Platelet adhesion
• Hormone replacement/manipulation

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Secondary prevention of CVD

• Angiographic regression studies
• 4S
• Landmark study.
• CARE
• Cholesterol-lowering reduced events in those with
  lower initial LDL levels
• LIPID
• Oxford Universitys Heart Protection study
• Largest study to date. To all intents and
  purposes benefit at any level of baseline LDL.
• Greek Atorvastatin and Coronary-heart-disease
  Evaluation (GREACE) Study

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Early Lipid-loweringPlaque regression studies

• Using traditional angiography
• FATS, UCSF-SCOR
• MAAS, MARS, CCAIT, PLAC-1, LCAS, REGRESS,
  Post-CABG
• Overall 10-20 improvement in some 12 of
  stenoses.

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Angiographic changes seem less spectacular than
events reductions

• Wrong analytical technique!
• Mean 2 year studies
• Too short.
• Vulnerable plaques may benefit most
• Plaques stabilise by lipid depletion and reduced
  inflammation.
• Improved endothelial function.
• Many plaques do not occlude the lumen.

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Dyslipidaemia- Trial evidence

• 4S, CARE, LIPID, Oxford HPS, Greace
• WOSCOPS, AFCAPS/TEXCAPS, ASCOT-LLA
• HSS, Va-HIT

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The 4S studyMean TC 6.75 mmol/l (LDL 4.9 mmol/l)
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The CARE studyMean TC 5.4 mmol/l (LDL 3.6mmol/l)
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HPS. (Previous MI, CVA, PVD or diabetes).even
when TClt5.0mmol/l Possibly down to TC of
3.5mmol/l!

• 15 454 men and 5082 women, with 9515 aged over
  65yrs at entry.
• 8510 (41) having had MI, 4869 (24) some other
  history of CHD, 3288 (16) cerebrovascular
  disease, 6748 (33) peripheral vascular disease,
  5963 (29) diabetes mellitus (of whom 3985 had no
  history of CHD and 8455 (41) treated
  hypertension.
• Baseline non-fasting cholesterol levels were less
  than 5.5 mmol/l in 7882 (38) participants, and
  LDL less than 3.0 mmol/l in 6888 (34).
• Randomly assigned to simvastatin 40 mg or placebo
  for a mean 5.5 years. Analysed by intention to
  treat.

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HPS

• Overall for a mean difference in LDL-C of 1.1
  mmol/l over 5 years.
• Reduced incidence of MI and stroke by about 25-
  regardless of age, sex, or cholesterol level.
• All cause mortality reduced by 12 and death from
  CVD by 17.
• 25 reduction in stroke (444 4.3 simvastatin
  vs 585 5.7 placebo plt0.0001).
• Those with pre-existing cerebrovascular disease
  did not experience significant reduction in
  stroke rate, but there was a 20 (8-29) reduction
  in the rate of any major vascular event (406
  24.7 vs 488 29.8 p0.001).
• NB- 17 of placebo group were on a statin of some
  kind.

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GREACE

• The GREek Atorvastatin and Coronary-heart-disease
  Evaluation (GREACE) study

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How early should one initiate statins?

• MIRACL
• A-Z

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MIRACL

• Myocardial Ischemia Reduction with Aggressive
  Cholesterol Lowering Trial.
• Subjects with an acute coronary syndrome within
  the previous 1-3 days, were randomized to
  atorvastatin 80 mg/d or placebo for 16 weeks.
• primary composite endpoint was reduced from 17.4
  to 14.8 (P 0.048) among the 3086 patients
  enrolled.

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Primary prevention studies

• WOSCOPS
• AFCAPS/TexCAPS
• ASCOT-LLA

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WOSCOPS

• 6595 men, 45 to 64 years of age, with a mean (/-
  SD) plasma cholesterol level of 7.0 /- 0.6
  mmol/l. After 4.9 years pravastatin lowered
  plasma cholesterol levels by 20 (LDL by 26).
• 31 reduction in risk of definite nonfatal MI
  28 in death from CHD and 32 in death from all
  cardiovascular causes.
• 22 reduction in the risk of death from any
  cause in the pravastatin group (P 0.051).

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AFCAPS/TexCAPS

• Mean TC level 5.71 mmol/L, LDL-C 3.89 mmol/L,
  mean HDL-C level 0.94 mmol/L for men and 1.03
  mmol/L for women and median (SD) triglyceride
  levels were 1.78 (0.86) mmol/L.
• After mean 5.2 years, lovastatin 20-40 mg daily
  reduced LDL-C by 25 to 2.96 mmol/L and increased
  HDL-C by 6 to 1.02 mmol/L.
• 25 reduction in cardiovascular events
• 8,000,000 in US would be eligible for statins on
  these criteria!!

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ALLHAT

• The Antihypertensive and Lipid-Lowering Treatment
  to Prevent Heart Attack Trial (ALLHAT-LLT).
• Pravastatin did not reduce either all-cause
  mortality or CHD significantly when compared with
  usual care in older participants with
  well-controlled hypertension and moderately
  elevated LDL-C. The results may be due to the
  modest differential in total cholesterol (9.6)
  and LDL-C (16.7) between pravastatin and usual
  care compared with prior statin trials supporting
  cardiovascular disease prevention.

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Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

• 19,342 hypertensive patients (40-79 years with at
  least three other CV risk factors randomised to
  one of two antihypertensive regimens.
• 10,305 with TC of 6.5 mmol/L or less randomised
  to additional atorvastatin 10 mg or placebo-
  ASCOT-LLA.

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Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
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ASCOT

• Stopped early (FU 3.3 yrs), as 154 events in the
  placebo group, but only 100 events with
  atorvastatin.
• Atorvastatin lowered total serum cholesterol by
  about 1.3 mmol/L compared with placebo at 12
  months, and by 1.1 mmol/L after 3 years of
  follow-up.
• Fatal and non-fatal stroke (89 vs 121 p0.024),
• Total cardiovascular events (389 vs 486,
  p0.0005),
• Total coronary events (178 vs 247, p0.0005).
• All cause mortality 185 deaths in the
  atorvastatin group and 212 in the placebo group
  p0.16).

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Endpoint Trials with the Statins
Nonfatal MI or CHD death ischemic
events Downs JR et al. JAMA 19982791615-1622.
Shepherd J et al. N Engl J Med 19993331301-1307.
Scandinavian Simvastatin Study Group. Lancet
19943441383-1389. Sacks FM et al. N Engl J
Med 19963351001-1009. LIPID Study Group. N
Engl J Med 19983391349-1357. Schwartz GG et
al. JAMA 20012851711-1718. Pitt B et al. N
Engl J Med 199934170-76.
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CHD Trials in Diabetic Subjects Subgroup
Analyses
CHD RiskReduction(overall)
CHD RiskReduction(diabetes)
Drug
No.
Study
Primary Prevention AFCAPS/TexCAPS CARDS ASCOT-LLA
HPS Secondary Prevention CARE 4S LIPID 4S-Extende
d Greace HPS
Lovastatin Atorvastatin Atorvastatin Simvastatin
Pravastatin Simvastatin Pravastatin Simvastatin
Atorvastatin Simvastatin
43 37 (at 3 yrs) 36 (at 3 yrs) (?50 at
5yrs) 33 25 55 19 42 62 22
37 ---- 24 ----- 23 32 25 32 47 24
239 2838 2532 2912 586 202 782 483 313 3051
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Are statins special?

• POSCH
• Even partial ileal bypass can reduce cholesterol
  and thereby CHD events.
• But, latency to benefit gt 3 years.
• Probably extent of reduction in LDL is the key.

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Things may appear similar at first glance
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Evidence for raising HDL

• The Cholesterol Lowering Atherosclerosis Study
  demonstrated beneficial effect of
  colestipol/niacin on coronary atherosclerosis
  using a panel-determined global coronary change
  score.

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Cholesterol flux more important than HDL level

• Carriers of apoAI(Milano), have reduced levels of
  LDL and reduced HDL and total apoAI. Infusions of
  the ApoAI(Milano) variant given to patients with
  coronary atherosclerosis appear to lead to
  disease regression and reduced plaque size.
• Attention should be focused on the removal of
  cholesterol from plaques rather than simply
  desiring to raise HDL concentrations in patients

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Triglycerides?

• Harder
• GISSI-Prevention study of 11 324 patients showed
  a marked decrease in risk of sudden cardiac death
  as well as a reduction in all-cause mortality in
  the group taking a highly purified form of
  omega-3 fatty acids, despite the use of other
  secondary prevention drugs, including
  beta-blockers and lipid-lowering therapy.

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Lipids and PVD

• Aggressive LDL-lowering can improve outcomes in
  PVD.
• REGRESS
• Post-CABG
• LDL-apharesis studies

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Lipids and Stroke

• Regression of carotid artery lesions.
• ACAPS, PLAC-II, KAPS, CAIUS
• Stroke reduced in CHD secondary/primary
  prevention trials.
• 4S, CARE, WOSCOPS
• Stroke reduced in HPS.

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Stroke

• Epidemiologic studies found no or little
  association cholesterol levels and stroke.
• Randomized show that LDL lowering decreased the
  risk of stroke, in diabetic or hypertensive
  patients with normal' LDL cholesterol at
  baseline, and in patients with CHD, with
  respectively 48, 27 and 25 reduction in stroke
  incidence.
• Meta-analysis suggests that the greater the LDL
  cholesterol reduction, the greater the
  intima-media thickness and stroke risk
  reductions.
• Prevention of recurrent stroke still to be
  proven- but prevention of CHD more than justifies
  treating all patients with any form of CVD with
  cholesterol-lowering!!
• SPARCL (The Stroke Prevention by Aggressive
  Reduction in Cholesterol Levels) awaited in next
  few months

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Lipids vs hypertension

• The absolute benefit of pravastatin treatment of
  hyperlipidaemia is less in the primary prevention
  of CHD than in secondary prevention, but is
  similar to that for primary prevention of stroke
  by treatment of mild to moderate hypertension in
  middle-aged men (WOSCOPS compared with MRC trial).

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Is initial LDL level relevant?

• Biology of atherogenesis suggests that for
  individuals with confirmed CVD, LDL must be too
  high, whatever the level.
• Evidence from trials is increasingly supporting
  this view.
• Treatment initiation should be based on global
  risk assessment.
• Framingham equation or other.

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Is lower better?

• Post-CABG
• LDL 2.4 mmol/l group has less angiographic
  progression than 3.5mmol/l group.
• AVERT
• 2.0mmol/l vs 3.0mmol/l (36 less ischaemic
  events).
• ASTEROID
• Differs in that no control group- just before and
  after treatment. Use of IVUS
• 40mg rosuvastatin- mean LDL reduction by 53 (on
  Rx average level 1.6mmol/l), HDL elevation of
  14.
• First trial to clearly show regression in
  coronary artery. Mean change in percent atheroma
  volume was 0.98 (plt0.001 compared with
  baseline). However several randomised trials
  (this wasnt) have shown regression in carotids.

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No evidence of a threshold
4S-Pl
4S-Rx
LIPID-Pl
CARE-Pl
LIPID-Rx
HPS-Pl
CARE-Rx
WOSCOPS-Pl
HPS-Rx
WOSCOPS-Rx
TNT-80mg
ASCOT-PL
AFCAPS-Pl
ASCOT-Rx
AFCAPS-Rx
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Lower really is better

• Reversal
• Prove-IT
• TNT

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Reversal of Atherosclerosis with Aggressive Lipid
Lowering REVERSAL

• 654 patients randomised to 40 mg of pravastatin
  or 80 mg of atorvastatin.
• Baseline LDL mean 3.89 mmol/L was reduced to
  2.85 mmol/L in the pravastatin group and to 2.05
  mmol/L in the atorvastatin group (Plt.001).
• C-reactive protein decreased 5.2 with
  pravastatin and 36.4 with atorvastatin (Plt.001).
  
• The primary end point (percentage change in
  atheroma volume) showed a significantly lower
  progression rate in the atorvastatin (intensive)
  group (P .02)

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PROVE-IT The Pravastatin or Atorvastatin
Evaluation and Infection Therapy trial
(PROVE-IT/TIMI-22)

• men and women aged 18 years or older who had been
  hospitalized for an acute coronary syndrome,
  either acute myocardial infarction (AMI) with or
  without ST-segment elevation or high risk
  unstable angina within the preceeding 10 days.
• N4162

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PROVE-IT

• In patients with acute coronary syndromes,
  aggressive lipid-lowering using atorvastatin 80
  mg/day provided greater protection against death
  or major cardiovascular events than did moderate
  lipid-lowering using pravastatin 40 mg/day.
• Lowering LDL-cholesterol level to around
  1.6mmol/l with atorvastatin resulted in a further
  16 reduction in cardiovascular end points.

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PROVE-IT likely benefits

• Estimated benefit of aggressive cholesterol
  lowering
• Atorvastatin 80 mg resulted in an additional 18
  reduction in nonfatal MI and CHD death beyond
  treatment with pravastatin 40 mg over 24 months
  of treatment.
• Extrapolation of the event rate after 12 months
  of treatment yielded an approximate additional
  22 reduction in major CHD events in the
  atorvastatin group at 5 years.
• Based on clinical trials of gt4 years of
  pravastatin therapy (CHD relative risk reduction
  24, the expected relative risk reduction for
  atorvastatin 80-mg therapy would therefore be
  expected to be approximately 46.

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TNT (Treat to New Targets Trial)

• Randomised double-blind, trial to test efficacy
  and safety of lowering LDL-C below 2.6 mmol/l
  (100 mg/dl) in patients with stable coronary
  heart disease (CHD), over median 4.9 yrs FU.
• 10,001 patients with clinically evident CHD and
  LDL lt 3.4 mmol/l randomised to 10 mg or 80 mg of
  atorvastatin per day.
• The primary end point was a first major CVD event
  (CHD death, nonfatal MI, fatal or nonfatal
  stroke).
• Mean LDL cholesterol levels were 2.0 mmol/l
  (77mg/dl) and 2.6 mmol/l (101mg/dl) mmol/l in the
  80 and 10mg treatment groups respectively.
• Persistent raise in in transaminases in 0.2 on
  10 mg and 1.2 on 80 mg.
• A primary event occurred in 434 patients (8.7)
  vs 548 patients (10.9) for 80 and 10mg
  atorvastatin.
• Absolute reduction in major CVD events of 2.2
  (22 relative reduction in risk) Plt0.001.
• No difference in total mortality.
• Intensive lipid-lowering in patients with stable
  CHD provides significant additional clinical
  benefit, though at the expense of a greater
  incidence of elevated ALT levels.

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IDEAL (Incremental Decrease in End Points Through
Aggressive Lipid Lowering)

• To compare a standard and aggressive lipid
  lowering strategy on CVD risk in those with prior
  MI.
• Prospective, randomized, open-label, blinded
  end-point evaluation trial conducted at 190
  ambulatory cardiology care and specialist
  practices in northern Europe between March 1999
  and March 2005.
• 8888 patients, 80 years or less with prior MI
  randomised to atorvastatin 80 mg/d (n 4439), or
  simvastatin 20 mg/d (n 4449), with a median
  follow-up of 4.8 years.
• Primary endpoint was occurrence of a major
  coronary event (coronary death, confirmed
  nonfatal acute MI, or cardiac arrest with
  resuscitation).
• Mean on-drug LDL-C were 2.6mmol/l in the
  simvastatin group and 2.08mmol/l in the
  atorvastatin group.
• Major coronary event in 463 on simvastatin
  (10.4) and 411 on atorvastatin (9.3) P 0.07
  (not significant) nonfatal MI in 321 (7.2) and
  267 (6.0) (P 0.02).
• Major cardiovascular events in 608 and 533 in 2
  groups, respectively (p .02) occurrence of any
  coronary event reported in 1059 on simvastatin
  and 898 on atorvastatin ( Plt.001).
• More atorvastatin patients withdrew due to
  nonserious adverse events transaminase elevation
  resulted in 43 (1.0) vs 5 (0.1) withdrawals
  (Plt.001).
• There were no differences in cardiovascular or
  all-cause mortality. Patients with MI may benefit
  from intensive lowering of LDL-C without an
  increase in noncardiovascular mortality or other
  serious adverse reactions.

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ASTEROID

• LDL below 1.6mmol/ appear safe and may produce
  improved plaque regression, but concerns over
  study design.

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What about the elderly?

• CVD causes 70 of deaths over 75 years of age.
• 4S and CARE support treating over 65 years.
• In CARE and LIPID reduction of major CV events
  greater in 65-75 year olds.
• HPS shows effectiveness up to 75 years.
• Primary prevention less clear though AFCAPS
  included men up to 75 years.
• PROSPER, recruited men and women 72-80 years
• randomised to pravastatin or placebo.

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Elderly diabetics

• HPS in diabetics before and after the age of 70
  years and CARDS in diabetics aged up to 75 years.

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Children

• Until recently, in children under age 10, the
  focus of treatment has been on dietary and
  lifestyle adjustments. For children older than 10
  years, bile acid-binding resins were also
  recommended if LDL-C levels remained high after
  dietary adjustment. However, the lipid-lowering
  effect of bile acid-binding resins is modest at
  best and long-term compliance is often poor.
• HMG-CoA reductase inhibitors (statins) are first
  choice in the treatment of adult
  hypercholesterolemia.
• In the last few years, several randomized trials
  have shown that statins are also effective in
  reducing LDL cholesterol levels in children and
  seem safe at least in the short term.
• Another novel development is the
  cholesterol-lowering agent, ezetimibe, which
  inhibits cholesterol absorption in the intestine.
  Although efficacy and safety data in children are
  still lacking, ezetimibe has a good safety
  profile in adults, either as monotherapy or in
  combination with a statin.
• Fibrates and nicotinic acid are not generally
  advocated due to side effect profile except in
  extreme circumstances.

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Who should not receive statins?

• Trials increasingly support benefit of statins
  even in low risk groups.
• As low as 9 predicted 10 year CHD risk.
• Economic restraints are a major force in devising
  new guidelines.
• Level of risk at which to consider drugs, and
  then target level of risk factor to be achieved.

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What are the targets for lipid guidelines!! UK

• TC lt 5 mmol/l 4
• TC/HDL 4
• LDL 3 mmol/l 2
• TG 2 mmol/l
• HDL 1.1 and 1.3 mmol/l
• Consider aspirin or clopidogrel
• Consider ACE-I

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However more treatments needed

• While statin therapy does offer significant
  clinical benefit, 60-70 of major CVD events are
  still not prevented.
• Ever lower LDL levels are likely not the answer
• Raise HDL/reduce triglycerides
• Treat inflammation/oxidation

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NCEP- ATPIII

• Secondary prevention
• LDL ? 2.6 mmol/l
• Primary prevention-
• CHD risk equivalents (Diabetes, non-coronary CVD,
  10 year Framingham CHD risk gt 20)- LDL ? 2.6
  mmol/l
• Intermediate (10-20 10 year risk)- LDL ? 3.4
  mmol/l
• Secondary non-HDL goals of 0.8 mmol/l higher than
  LDL goal

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Latest NCEP

• In light of new trials- PROVE-IT, ASCOT-LLA,
  CARDS.
• Proposed that for very high risk patients one
  should consider a target of lt1.7 mmol/l.