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
LDLR recycling
Down regulate HMGCoA reductase
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 )
20
10
0
50th Percentile
Coronary Heart Disease ( % )
Frequency ( % )
30
Dallas Heart Study
0 50 100 150 200 250 300
PCSK946L Allele ( n=301 )
30
20
10
0
12
P=0.003
8
4
0
0 50 100 150 200 250 300
Plasma LDL Cholesterol in White Subjects ( mg/dL)
No
Yes
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
Vessel Lumen
LDL
Oxidation of Lipids
and ApoB
Aggregation
LDL
Endothelium
Hydrolysis of Phosphatidylcholine
to Lysophosphatidylcholine
Other Chemical Modifications
Modified LDL
Modified LDL are Pro inflammatory
Intima
Steinberg D et al. N Engl J Med 1989;320:915-924.
Macrophages and Foam Cells Express
Growth Factors and Proteinases
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
Cytokines
Macrophage
MCP-1
LDL
Modified
LDL
Foam Cell
Endothelium
Intima
Growth Factors
Metalloproteinases
Cell Proliferation
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
Statins
Synthesis
Hepatic
cholesterol
Biliary
cholesterol
Dietary
cholesterol
Intestinal
pool
Statins:The Evidence Base.
Placebo MI rate per 100 subjects per 5 years
Continuum
of risk
22.6 Secondary
prevention
12.9
HPS
8.44
7.9
2.8
Primary
prevention
4S
(simvastatin)
High-risk CHD patients
(high cholesterol)
CARE
(pravastatin)
LIPID
(pravastatin)
WOSCOPS
(pravastatin)
AFCAPS/TexCAPS
(lovastatin)
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)
CHD Risk Despite Statin Therapy
Clinical events*
Risk reduction Remaining
risk
vs placebo
Trial
Statin treatment
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
25
20
Secondary prevention
Primary prevention
Lipid-PI
4S-Rx
With CHD 15
Event
(%)
10
5
0
50
CARE-Rx
?
?
70
CARE-PI
Lipid-Rx
AFCAPS-Rx
90
4S-PI
WOS-Rx
WOS-PI
AFCAPS-PI
110 130 150
170
LDL-cholesterol (mg/dl)
190
210
PROVE-IT Trial
Intensive and Moderate Lipid-Lowering
after Acute Coronary Syndromes
Pravastatin 40mg
26.3%
CVD Endpoints
Population:
4162 patients within 10 days of
acute coronary syndrome
Treatment:
Standard: Pravastatin 40mg/day
mean LDL 2.46mmol/l
Intensive: Atorvastatin 80mg/day
mean LDL 1.6mmol/l
Primary endpoint:
Death , MI, unstable angina
requiring hospitalisation,
revascularisation and stroke
Follow-up:
18-36 months (mean 24 months)
Atorvastatin 80mg
22.4%
16% reduction
p=0.005
6
12
18
Months
24
30
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
Proportion of patients experiencing
major cardiovascular event
0.15
HR =
0.78(95%CI
(95% CI 0.69,
0.69, 0.89)
HR
0.78
0.89)
p=0.0002
P=0.0002
Atorvastatin 10 mg
Atorvastatin10mg
80 mg
Atorvastatin
Atorvastatin 80mg
0.10
0.05
Relative
riskreduction
reduction
22%
Relative risk
= 22%
0
0
1
2
3
Time (years)
4
5
6
*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
increased benefit








 
LDL cholesterol (mg/dl)
La Rosa et al NEJM March 2005
Meta-Analysis
Cardiovascular Outcomes
Intensive vs Moderate Statin Therapy
Population:
27,548 patients with
stable CVD in TNT and
IDEAL or acute coronary
syndrome, PROVE-ITTIMI-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.
Odds Ratio (95% CI)
PROVE IT-TIMI 22
A-TO-Z
TNT
IDEAL
OR, 0.84
95% CI, 0.77-0.91
p=0.00003
Total
.66
INTENSIVE
1
1.34
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
Odds Ratios (95% CI)
Trials
ASCOT-LLA
ALLHAT-LLT
PROSPER
HPS
GREACE
MIRACL
GISSI
LIPID
AFCAPS/TexCAPS
Post-CABG
CARE
WOSCOPS
4S
SMALL TRIALS
OVERALL (95% confidence interval)
0.2
0.79 (0.73-0.85)
0.4
0.6
0.8
Statin better
1.0
1.2 1.4
Control better
Amarenco et al. Stroke. 2004;35:2902-2909.
Heart Protection Study
Stroke Outcomes
Simvastatin
Incidence of stroke (%)
12
10
10.3
Placebo
10.4
* P<.05.
8
6
169
170
4.8 *
4
3.2
2
275
0
Prior cerebrovascular disease
n=3280
415
No prior cerebrovascular disease
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

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
Atorvastatin 80 mg
4200
patients
Double-blind placebo
5 years
Primary endpoint:
Time to first fatal
or non fatal stroke
Welch KMA, et al. 26th International Stroke Conference;
February 14-16, 2001, Ft Lauderdale, Fl, USA.
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, placebocontrolled 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%
% Patients
High-Dose Atorvastatin after Stroke
or Transient Ischaemic Attack
The SPARCL Trial
Years
SPARCL Investigators NEJM 2006; 355: 549-559