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