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The case for intensive lipid management:The opportunities and issues for
cardiologists
Prof. John BetteridgeUniversity College London
Slide lecture prepared and held by:
Master Class: Advanced CV Risk management in cardiologyJune 17-18, 2011, London
Presentation topic
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
Down regulate HMGCoA reductaseReduce LDL receptor synthesis
Esterified by ACAT (storage)
The Fate of LDL
PCSK9 preventsLDLR recycling
LDLR
FH3: mutations in PCSK9Proprotein 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 inheritanceXanthomataPremature vascular diseaseElevated low density lipoprotein levelsGenetic defect at the LDL receptor
COHEN et al. New Engl J Med 354:1264, 2006
P=0.003
No Yes
PCSK946L
Coro
nary
Heart
Dis
ease
( %
)
12
8
4
0
Freq
uen
cy (
% )
Plasma LDL Cholesterol in White Subjects ( mg/dL)
No PCSK946L Allele ( n=9223 )
30
20
10
0
30
20
10
0
0 50 100 150 200 250 300
0 50 100 150 200 250 300
50th Percentile
PCSK946L Allele ( n=301 )
LDL-C Distribution and CAD Incidence Presence or Absence of PCSK9 46L Allele
Dallas Heart Study
LDL and Atherogenesis
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel LumenLDL
LDL Readily Enter the Artery Wall Where They May be Modified
LDL
Intima
Modified LDL
Modified LDL are Pro inflammatory
Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine
Other Chemical Modifications
Oxidation of Lipidsand ApoB
Aggregation
LDL
LDLEndothelium
Vessel LumenMonocyte
Macrophage
AdhesionMolecules
Macrophages and Foam Cells Express Growth Factors and Proteinases
Foam Cell
IntimaModified
LDLCytokines
Cell ProliferationMatrix Degradation
Growth FactorsMetalloproteinases
Ross R. N Engl J Med 1999;340:115-126.
MCP-1MCP-1
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
Dietary cholesterol
Biliarycholesterol
Effects of Statins
Intestinal pool
LDL receptors
Hepaticcholesterol
Synthesis
Plasma LDL
Statins
High-risk CHD patients (high cholesterol)
Majority of CHD patients (broad range of cholesterol levels)
Patients at high risk of CHD (high cholesterol)
Patients at low risk of CHD (low HDL-C)
Primaryprevention
Secondaryprevention
Statins:The Evidence Base.
WOSCOPS(pravastatin)
AFCAPS/TexCAPS(lovastatin)
4S(simvastatin)
CARE (pravastatin)
LIPID
(pravastatin)
Continuum of risk
22.6
12.9
8.44
7.9
2.8
Pla
ceb
o M
I ra
te p
er
10
0 s
ub
jects
per
5
years
HPS
CHD Risk Despite Statin Therapy
Trial Statin treatment
Clinical events*
Risk reduction vs placebo
WOSCOPS** (6595) Pravastatin 40 mg 31%
AFCAPS/TexCAPS** (6605) Lovastatin 20 or 40 mg
40%
ASCOT-LLA** (10,305) Atorvastatin 10 mg 38%
4S** (4444) Simvastatin 20 mg 26%
CARE*** (4159) Pravastatin 40 mg 24%
LIPID*** (9014) Pravastatin 40 mg 24%
HPS*** (20,536) Simvastatin 40 mg 27%
PROSPER*** (5804) Pravastatin 40 mg 24%
*Nonfatal myocardial infarction and coronary death; **Primary prevention trial; ***Secondary prevention trial
Remaining
risk
69%
60%
62%
74%
76%
76%
73%
76%
Early Primary and Secondary CVD Prevention
Trials
With CHDEvent(%)
?
25
20
15
10
5
050 70 90 110 130 150 170 190 210
Secondary preventionPrimary prevention
4S-PI
4S-RxLipid-PI
CARE-PI
Lipid-RxWOS-Rx WOS-PI
AFCAPS-PIAFCAPS-Rx
CARE-Rx
LDL-cholesterol (mg/dl)
?
PROVE-IT TrialIntensive and Moderate Lipid-Lowering
after Acute Coronary SyndromesPopulation:4162 patients within 10 days of acute coronary syndromeTreatment:Standard: Pravastatin 40mg/day mean LDL 2.46mmol/l Intensive: Atorvastatin 80mg/day mean LDL 1.6mmol/lPrimary endpoint:Death , MI, unstable angina requiring hospitalisation, revascularisation and strokeFollow-up:18-36 months (mean 24 months)
Cannon et al N Engl J Med April 8th 2004
Pravastatin 40mg 26.3%
16% reduction p=0.005C
VD
En
dp
oin
ts
24 3018
Months126
Atorvastatin 80mg 22.4%
Intensive Lipid Lowering with Atorvastatin in Patients with Stable
Coronary DiseaseTreat 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
La Rosa et al NEJM March 2005
Treat to New Targets: Lipid Effects
Primary Efficacy Outcome Measure: First Major Cardiovascular Event*
TNT
*CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke
HR = 0.78 (95% CI 0.69, 0.89)P=0.0002
Pro
port
ion
of
pati
en
ts
exp
eri
en
cin
g m
ajo
r card
iovascu
lar
even
t
0
0.05
0.10
0.15
Atorvastatin 10 mg
Atorvastatin 80 mg
0 1 2 3 4 5 6Time (years)
Relative risk reduction = 22%
HR 0.78 (95%CI 0.69, 0.89) p=0.0002
Atorvastatin 10mgAtorvastatin 80mg
Relative risk reduction 22%
Statin Therapy in Secondary Prevention Trials Event Rates Against
LDL-CNew 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 increased benefit
La Rosa et al NEJM March 2005
Even
t s (
%)
LDL cholesterol (mg/dl)
Meta-AnalysisCardiovascular Outcomes
Intensive vs Moderate Statin TherapyPopulation: 27,548 patients with
stable CVD in TNT and IDEAL or acute coronary syndrome, PROVE-IT-TIMI-22, and A-to-Z
Results: 16% odds reduction in
coronary death or myocardial infarction, p<0.0001.
No difference in total or non-cardiovascular mortality.
Cannon et al J Am Coll Cardiol, 2006; 48: 438-445
INTENSIVE MODERATE
PROVE IT-TIMI 22
A-TO-Z
TNT
IDEAL
Total
Odds Ratio (95% CI)
OR, 0.8495% CI, 0.77-0.91p=0.00003
.66 1 1.34
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
Amarenco et al. Stroke. 2004;35:2902-2909.
ASCOT-LLAALLHAT-LLT
PROSPERHPSGREACEMIRACLGISSILIPID
AFCAPS/TexCAPSPost-CABGCAREWOSCOPS4SSMALL TRIALS
OVERALL (95% confidence interval)0.79 (0.73-0.85)
Odds Ratios (95% CI)Trials
0.2 0.4 0.6 0.8 1.0 1.2 1.4
Across 26 trials, statins reduced stroke by 21% (P<.0001), with no evidence of heterogeneity between trials
Statin better Control better
Heart Protection Study Stroke Outcomes
HPS Collaborative Group. Lancet. 2004;363:757-767.
* P<.05.
*
Simvastatin Placebo
10.4
4.8
3.2
10.3
0
2
4
6
8
10
12
Prior cerebrovascular diseasen=3280
No prior cerebrovascular diseasen=17,256
Incid
en
ce o
f str
oke (
%)
169
275
170
415
SPARCL: Does Robust Lipid Lowering Reduce the Occurrence of
Stroke in Patients without CHD?
Patient population
Stroke/TIA 1-6 months prior
LDL 100-190 mg/dL (2.6-4.9 mmol/L) Exclusions:
Age <18 years Hx of CAD Endarterectomy in
prior month Subarachnoid
hemorrhage
4200patients
4200patients
Primary endpoint: Time to first fatal or non fatal stroke
5 years5 years
Welch KMA, et al. 26th International Stroke Conference; February 14-16, 2001, Ft Lauderdale, Fl, USA.
Double-blind placebo
Atorvastatin 80 mg
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-controlled trial comparing atorvastatin 80mg/day to placebo. Median follow-up 4.9years.
Primary endpoint: Time to first nonfatal or fatal
strokeResults: 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
% P
ati
ents
SPARCL Investigators NEJM 2006; 355: 549-559