The opportunities and issues for cardiologists Prof John Betteridge University College London Slide lecture prepared and held by Master Class Advanced CV Risk management in cardiology ID: 930610
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Slide1
The case for intensive lipid management:
The opportunities and issues for cardiologists
Prof. John Betteridge
University College London
Slide lecture prepared and held by:
Master
Class: Advanced CV Risk management in cardiologyJune 17-18, 2011, London
Presentation topic
Slide2A 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
Slide3BMJ 1975, 4 500-502
Slide4Down regulate HMGCoA reductase
Reduce LDL receptor synthesis
Esterified by ACAT (storage)
The Fate of LDLPCSK9 preventsLDLR recyclingLDLR
Slide5FH3: mutations in PCSK9
Proprotein
convertase subtilisin
/kexin type 9PCSK9 is a protease which binds to LDL-R and directs them to lysosomes for degradation, rather than recycling to cell surfaceLoss of function (non-sense and some mis-sense) mutations lead to
LDL levels2.6% 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 mutationstrue homozygotes not described?Statins increase PCSK9 as well as LDLR activity – counterproductivePotential therapeutic targetTall, NEJM 2006;354:1310Horton et al. Trends
Biochem
Sci
2006;32:71Zhang
et al. PNAS 2008;105:13045
Slide6Familial Hypercholesterolaemia
Autosomal
dominant inheritance
XanthomataPremature vascular diseaseElevated low density lipoprotein levelsGenetic defect at the LDL receptor
Slide7COHEN et al. New Engl J Med 354:1264, 2006
P=0.003
No Yes
PCSK9
46L
Coronary Heart Disease ( % )12
8
4
0
Frequency ( % )
Plasma LDL Cholesterol in White Subjects ( mg/dL)
No
PCSK9
46L
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
50
th
Percentile
PCSK9
46L
Allele
( n=301 )
LDL-C Distribution and CAD Incidence Presence or Absence of PCSK9
46L
Allele
Dallas Heart Study
Slide8LDL and Atherogenesis
Steinberg D et al.
N Engl J Med
1989;320:915-924.
Endothelium
Vessel Lumen
LDL
LDL Readily Enter the Artery Wall Where They May be Modified
LDL
Intima
Modified LDL
Modified LDL are Pro inflammatory
Hydrolysis of Phosphatidylcholine
to Lysophosphatidylcholine
Other Chemical Modifications
Oxidation of Lipids
and ApoB
Aggregation
Slide9LDL
LDL
Endothelium
Vessel Lumen
Monocyte
Macrophage
Adhesion
Molecules
Macrophages and Foam Cells Express
Growth Factors and Proteinases
Foam Cell
Intima
Modified
LDL
Cytokines
Cell Proliferation
Matrix Degradation
Growth Factors
Metalloproteinases
Ross R.
N Engl J Med
1999;340:115-126.
MCP-1
Slide10From Association to Cause
Cholesterol and CHD
strength
dose response independent consistent
plausible mechanism predictive reversible
Slide11Problems 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
Slide12Dietary
cholesterol
Biliary
cholesterol
Effects of Statins
Intestinal pool
LDL receptors
Hepatic
cholesterol
Synthesis
Plasma LDL
Statins
Slide13High-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)
Primary
prevention
Secondary
prevention
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
Placebo MI rate per 100 subjects per 5 years
HPS
Slide14CHD 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%
Slide15Early Primary and Secondary CVD Prevention Trials
With CHD
Event
(%)?
25
20
15
10
5
0
50
70
90
110
130
150
170
190
210
Secondary prevention
Primary prevention
4S-PI
4S-Rx
Lipid-PI
CARE-PI
Lipid-Rx
WOS-Rx
WOS-PI
AFCAPS-PI
AFCAPS-Rx
CARE-Rx
LDL-cholesterol (mg/dl)
?
Slide16PROVE-IT Trial
Intensive and Moderate Lipid-Lowering after Acute Coronary Syndromes
Population:
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/l
Primary endpoint:Death , MI, unstable angina requiring hospitalisation, revascularisation and stroke
Follow-up:18-36 months (mean 24 months)
Cannon et al N Engl J Med April 8
th
2004
Pravastatin 40mg
26.3%
16% reduction
p=0.005
CVD Endpoints
24
30
18
Months
12
6
Atorvastatin 80mg
22.4%
Slide17Intensive 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
Slide18La Rosa et al NEJM March 2005
Treat to New Targets: Lipid Effects
Slide19Primary 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=0.0002Proportion of patients experiencing major cardiovascular event
00.05
0.100.15Atorvastatin 10 mg
Atorvastatin 80 mg
0 1 2 3 4 5 6
Time (years)
Relative risk reduction = 22%
HR 0.78 (95%CI 0.69, 0.89) p=0.0002
Atorvastatin 10mg
Atorvastatin 80mg
Relative risk reduction 22%
Slide20Statin
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
La Rosa et al NEJM March 2005
Events (%)
LDL cholesterol (mg/dl)
Slide21Meta-Analysis
Cardiovascular Outcomes
Intensive vs Moderate Statin Therapy
Population: 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, 0.84
95% CI, 0.77-0.91
p=0.00003
.66
1
1.34
Slide22Implications 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
Slide23Statins and Stroke Reduction
A Meta-Analysis
Amarenco et al. Stroke. 2004;35:2902-2909.
ASCOT-LLA
ALLHAT-LLT
PROSPER
HPS
GREACE
MIRACL
GISSI
LIPID
AFCAPS/TexCAPS
Post-CABG
CARE
WOSCOPS
4S
SMALL 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
Slide24Heart
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 disease
n=3280
No prior cerebrovascular disease
n=17,256
Incidence of stroke (%)
169
275
170
415
Slide25SPARCL: 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 CADEndarterectomy in prior monthSubarachnoid hemorrhage
4200
patients
Primary endpoint:
Time to first fatal
or non fatal stroke
5 years
Welch KMA, et al. 26th International Stroke Conference;
February 14-16, 2001, Ft Lauderdale, Fl, USA.
Double-blind placebo
Atorvastatin 80 mg
Slide26High-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 CHDDesign:
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
% Patients
SPARCL Investigators NEJM 2006; 355: 549-559