managing the late consequences of chd: what is the evidence for lipid management

Managing the late consequences of CHD: What is the evidence for lipid management

Prof Philip Barter

The Heart Research Institute

Sydney, Australia

Slides prepared and presented by

Serum Cholesterol and CHD in 361,662 US Men: MRFIT

6-Y

ear

CH

D D

eath

Rat

e pe

r 10

00 M

en

Serum Cholesterol (mg/dl)

0

2

4

6

8

10

12

14

16

18

140 160 180 200 220 240 260 280 300

Lipoprotein classes and atherosclerosis

Chylomicrons,VLDL, and theircatabolic remnants

LDL HDL

Pro-atherogenic Anti-atherogenic

Adhesion Molecule

Monocyte

Intima

Vessel Lumen

Endothelium

LDL

LDLMCP-1

Macrophage

Cytokines

Foam Cell

MODIFIED LDL

ROLE OF LDL IN CAUSING ATHEROSCLEROSIS

0

10

20

30

CARE-Pra

LIPID-Pra

4S-Sim

CARE-Plac

LIPID-Plac

4S-Plac

Statin Trials: LDL-C Levels vs Events Secondary Prevention

21090 110 130 150 170 190

LDL-C (mg/dL)

% w

ith C

HD

eve

nt

70

TNT-Ator10

TNT-Ator80

HPS-Plac

HPS-Sim

IDEAL-SimIDEAL-Ator

Med

ian

LDL-

C (

mg/

dL)

20

40

60

80

100

120

Rand 30 days 4 months 8 months 16 months Final

Pravastatin 40 mg(Median LDL-C 95 mg/dL)

Atorvastatin 80 mg(Median LDL-C 62 mg/dL)

49%

21%

P<0.001

Cannon CP, et al. N Engl J Med. 2004;350:1495-504

PROVE-IT:Changes From Baseline LDL-C

PROVE-IT: All-cause Mortality or Major CV Events in All Randomized Subjects

0 3 18 21 24 27 306 9 12 15

Months of follow-up

Pravastatin 40 mg(26.3%)

Atorvastatin 80 mg(22.4%)

16% RRR

P=0.005

30

25

20

15

10

5

0

% p

atie

nts

with

eve

nt

Cannon CP, et al. N Engl J Med. 2004;350:1495-504

Patient population: CHD LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L) Triglycerides 600 mg/dL (6.8 mmol/L)

Primary efficacy outcome measure: Time to occurrence of a major CV event:

– CHD death– Nonfatal, non-procedure-related MI– Resuscitated cardiac arrest– Fatal or nonfatal stroke

Atorvastatin 10 mg

Open-label run-inn=15,464

8 weeks1-8 weeks

Screening and wash-out

n=18,469

Atorvastatin 10 mgLDL-C target: 100 mg/dL (2.6 mmol/L)

Median follow-up = 4.9 years

Atorvastatin 80 mgLDL-C target: 75 mg/dL (1.9 mmol/L)

Double-blind periodn=10,001

LDL-C <130 mg/dL (<3.4 mmol/L)

n=4995

n=5006

Baseline

TNT-Study Design

FinalScreen 0 3 12 24 36 48 60

P<0.001

Baseline4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Mean LD

L-C (m

mol/L)

Mean LDL-C level = 101 mg/dL (2.6 mmol/L)

Mean LDL-C level = 77 mg/dL (2.0 mmol/L)

0

20

40

60

80

100

120

140

160

Study visit (months)

Mea

n LD

L-C

(m

g/dL

)

Atorvastatin 10 mg (n=5006)


LaRosa JC, et al. N Eng J Med. 2005;352

TNT-Changes in LDL-C By Treatment Group

HR = 0.78 (95% CI 0.69, 0.89)P=0.0002

Pro

port

ion

of p

atie

nts

expe

rienc

ing

maj

or

card

iova

scul

ar e

vent

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%


TNT-Primary Efficacy Outcome Measure: Major Cardiovascular Events

Pro

port

ion

of p

atie

nts

expe

rienc

ing

fata

l or

non

fata

l str

oke

0

0.01

0.02

0.04

0.03

HR = 0.75 (95%CI 0.59, 0.96)P=0.02

Relative risk reduction

= 25%

Atorvastatin 10 mg

Atorvastatin 80 mg

0 1 2 3 4 5 6Time (years)


TNT-Stroke (Fatal or nonfatal)

TNT-Primary Endpoint

P-value

117 (2.3)

25 (0.5)

243 (4.9)

101 (2.0)

434 (8.7)

Atorvastatin 80 mg

155 (3.1)

26 (0.5)

308 (6.2)

127 (2.5)

548 (10.9)

Atorvastatin 10 mg

No. of patients (%)

0.0040.78Nonfatal MI

0.020.75Stroke

0.890.96Resuscitated

cardiac arrest

0.090.80CHD death

End point

0.78

HR

0.0002Major CV event


TNT-Safety

2 (0.04)3 (0.06)Rhabdomyolysis*

60 (1.2)9 (0.2)AST/ALT elevation >3 ULN

406 (8.1)

241 (4.8)

289 (5.8)

234 (4.7)

Treatment-related AEs

Treatment-related myalgia

No. of patients (%)



*No cases were considered by the investigator with direct responsibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria2 for rhabdomyolysis

2. Pasternak RC et al. Circulation. 2002;106:1024-1028

1. LaRosa JC, et al. N Eng J Med. 2005;352

TNT-Major CVE by on-treatment LDL Quintiles

0

2

4

6

8

10

12

14

16

Ma

jor

CV

E (

%)

< 1.6 1.8 2.2 2.5 > 2.7

LDL-C quintile (mmol/L)

TNT-Major CVE by on-treatment LDL Quintiles

0

2

4

6

8

10

12

14

16

Ma

jor

CV

E (

%)

< 1.6 1.8 2.2 2.5 > 2.7

LDL-C quintile (mmol/L)La Rosa et al. Am J Cardiol 2007; 100:747-752

0

1

2

3

4

5

6

7

8

All-

cau

se m

ort

alit

y (%

)TNT-All-cause mortality by on-treatment LDL Quintiles

< 1.6 1.8 2.2 2.5 > 2.7


0

1

2

3

4

No

n-C

V d

ea

ths

(%)

TNT-Non-CV mortality by on-treatment LDL Quintiles

< 1.6 1.8 2.2 2.5 > 2.7


0

2

4

6

8

10

12

14

16

4S(S40)

4S(P)

CARE(P40)

CARE(P)

LIPID(P40)

LIPID(P)

HPS(S40)

HPS(P)

Mor

talit

y (%

)

TNT(A10)

TNT(A80)

Cardiovascular Mortality in Secondary Prevention Studies

0

2

4

6

8

10

12

14

16

Mor

talit

y (%

)

4S(S40)

4S(P)

CARE(P40)

CARE(P)

LIPID(P40)

LIPID(P)

HPS(S40)

HPS(P)

TNT(A10)

TNT(A80)

Non-cardiovascular Mortality in Secondary Prevention Studies

Diabetic Subgroup in TNT

Atorva 10 mg

N=753

Atorva 80mg

N=748

CHD death 31 (4.1 %) 23 (3.1%)

Nonfatal non PR MI 61 (8.1%) 49 (6.6%)

Resuscitated Cardiac Arrest 0 (0.0%) 3 (0.4%)

Stroke 43 (5.7%) 28 (3.7%)

Total 135 (17.9%) 103 (13.8%)

Log-rank p

HR (95% CI)

0.0263

0.75 (0.58 , 0.97)

Shepherd et al, Diabetes Care 2006;29:1220.

Metabolic Syndrome Subgroup in TNT

Atorva 10 mg

N=1771

Atorva 80mg

N=1706

CHD death 47 (2.7%) 32 (1.9%)

Nonfatal non PR MI 145 (8.2%) 98 (5.7%)

Resuscitated Cardiac Arrest3 (0.2%) 6 (0.4%)

Total 195 (11%) 136 (8%)

Log-rank p

HR (95% CI)

0.0026

0.72 (0.57 , 0.89)

Deedwania et al. Lancet 2006

4.8-year follow-up

8888 patients

Patient population· Enrolled at 190 sites

throughout Scandinavia and the Netherlands

· Diagnosed with CHD· Previous hospitalization

with MI, and eligible for statin therapy

Open-label period with blinded end point evaluations

Atorvastatin 80 mg/day

Simvastatin 20 mg/day(titrated to 40 mg if required)

IDEAL - Protocol

Pedersen et al. Am J Cardiol. 2004;94:720-721; Pedersen et al. JAMA. 2005;294:2437-2445.

Secondary· Cardiovascular/coronary events

· Cerebrovascular events

· PAD

· Hospitalization with primary diagnosis of CHF

· All-cause mortality

Primary· Time to occurrence of a major coronary

event− CHD death− Nonfatal MI− Resuscitated cardiac arrest

Mean LDL-C = 104 mg/dL (2.7 mmol/L)

Pedersen et al. JAMA. 2005;294:2437-2445.

0

70

80

90

100

110

120

130

Baseline Week 12 Year 1 Year 2 Year 3 Year 4 Year 5

LDL-

C (

mg/

dL)

AtorvastatinSimvastatin

0

1.8

2.0

2.3

2.6

2.8

3.1

3.4

LDL-C

(mm

ol/L)

Mean LDL-C = 81 mg/dL (2.1 mmol/L)

IDEAL: Effect of Treatment On LDL-C

IDEAL: Composite End PointsC

umu

lativ

e H

azar

d (%

)

0

4

8

12

16 Simvastatin

Atorvastatin

HR=0.89, P=.07

Cum

ula

tive

Haz

ard

(%)

HR=0.87, P=.02

Years Since Randomization

Cum

ula

tive

Haz

ard

(%)

0 1 2 3 4 50

10

20

30

40

HR=0.84, P<.001C

umu

lativ

e H

azar

d (%

)HR=0.84, P<.001

Any CHD

Major Coronary EventMajor Coronary Event

Any Cardiovascular Disease

Major Cardiovascular DiseaseMajor Cardiovascular Disease

Years Since Randomization0 1 2 3 4 5

0

10

20

30

40



0

4

8

12

16

Pedersen et al. JAMA. 2005;294:2437-2445.

MIRACL Study Design

4 months

3073patients

Atorvastatin 80 mg

Non-Q-wave infarction or unstable angina

Randomised 24–96 hours from admission

Exclusions: Planned CABG/PTCA Prior Q-wave <28 days CABG <3 months,

PTCA <6 months IIIb/IV CHF TC >3.1 mmol/L

(270mg/dL)

Patient population

Primary end point: Time to ischaemic events (CHD death, non-

fatal MI, cardiac arrest, documented angina requiring hospitalisation)

Usual care + double-blindplacebo

Schwartz et al; JAMA. 2001;285:1711-1718.

MIRACL Results

Effects on LDL-C:

Placebo group 124 mg/dlAtorvastatin group 74 mg/dl


MIRACL Results

Effects on primary endpoint(death, non-fatal MI, cardiac arrest, recurrent ischemia requiring hospitalisation)

Placebo group 17.4%Atorvastatin group 14.8%

16% reduction (p< 0.05)


MIRACL Results

Effects on stroke(secondary endpoint)

Placebo group 24Atorvastatin group 12

(p< 0.05)


MIRACL Conclusion

MIRACL provides convincing evidence of the benefits of commencing aggressive LDL lowering very early in patients with acute coronary syndromes


ARMYDA trial: Study design

153 patients

Stable AnginaPositive stress testIndication to PCINo previous statin treatment

Atorvastatin 40 mg/day

N=76

PlaceboN=77

PCI R

ando

miz

atio

n Clinical

Follow-up

7 days

1° Blood samplebefore PCI

2°-3° Blood samples8 and 24 h post-PCI

30 days

CK MB, Tn-I, Myoglobin

Pasceri et al, 2004; Circulation 110:674-678

Primary end point

Incidence of MI, defined as post-PCI increase of CK-MB > 2 times UNL


Post-PCI incidence of myocardial infarction (CK-MB> 2 times UNL)

P=0.025

ARMYDA trial: Primary end point

0

5

10

15

20

Atorvastatin Placebo

CK

-MB

(%

)

18

5


The ARMYDA randomized trial demonstrates that a short pretreatment with atorvastatin decreases the incidence of myocardial injury during coronary intervention compared with placebo, thereby improving clinical outcome

These results have the potential to influence practice patterns concerning pharmacological therapy prior to percutaneous coronary revascularization

ARMYDA trial: Conclusions


End pointTreatment-arm(n=84573)

Control-arm (n=84565)

Relative risk(95% CI)

Any major vascular event

10973 13350 0.78 (0.76-0.80)

Any major coronary event

5105 6512 0.75 (0.70-0.82)

Any stroke 2302 2680 0.82 (0.74-0.92)

All statin clinical outcome trialsRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol

(26 Trials; 169,138 subjects; 24,323 events)

CTT Collaborators. Lancet. 2010; 376:1670-1681.

Number of Events

Any coronaryrevascularisation

5353 6807 0.71 (0.65-0.78)

Any stroke 572 663 0.74 (0.59-0.92)

End pointAggressive(n=19829)

Moderate (n=19783)


Any major vascular event

3837 4416 0.72 (0.66-0.78)

Any major coronary event

1725 1973 0.74 (0.65-0.85)

Effects of aggressive vs moderate therapy with

statins

Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events)

Number of Events

Any coronaryrevascularisation

2250 2741 0.66 (0.60-0.73)


SubgroupTreatment-arm(n=84573)



Type 1 diabetes 145 192 0.77 (0.58-1.01)

Type 2 diabetes 2494 2920 0.80 (0.74-0.86)

All statin clinical outcome trials: effects in diabetesRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL)

reduction in LDL-cholesterol

(26 Trials; 169,138 subjects; 24,323 events)

Number of Events

No diabetes 8272 10163 0.78 (0.75-0.81)



Type 1 diabetes 8 8 0.74 (0.02-22.21)

Type 2 diabetes 703 792 0.76 (0.59-0.98)

Number of Events

No diabetes 3126 3616 0.71 (0.63-0.80)

Aggressive vs moderate statin therapy:

effects in diabetesRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in

LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events)

Aggressive(n=19829)

Moderate (n=19783)Subgroup


Baseline LDL-CTreatment-arm(n=84573)



< 2 mmol/L 910 1012 0.78 (0.61-0.99)

2 - 2.5 mmol/L 1528 1729 0.77 (0.67-0.89)

All statin clinical outcome trials:

effects of baseline LDL-CRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events)

Number of Events

2.5 - 3.0 mmol/L 1866 2225 0.77 (0.70-0.85)

3 - 3.5 mmol/L 2007 2454 0.76 (0.70-0.82)

> 3.5 mmol/L 4508 5736 0.80 (0.76-0.83)

Heterogeneity trend test: p=0.3CTT Collaborators. Lancet. 2010; 376:1670-1681.

Baseline LDL-CTreatment-arm(n=84573)



< 2 mmol/L 704 795 0.71 (0.52-0.98)

2 - 2.5 mmol/L 1189 1317 0.77 (0.64-0.94)

Aggressive vs moderate therapy:

effects of baseline LDL-CRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; 39612 subjects; 8,253 events)

Number of Events

2.5 - 3.0 mmol/L 1065 1203 0.81 (0.67-0.97)

3 - 3.5 mmol/L 517 633 0.61 (0.46-0.81)

> 3.5 mmol/L 303 398 0.64 (0.47-0.86)

Heterogeneity trend test: p=0.2CTT Collaborators. Lancet. 2010; 376:1670-1681.

Treatment-arm(n=84573)



Male 8712 10725 0.77 (0.74-0.80)

Female 2494 2920 0.80 (0.74-0.86)

All statin clinical outcome trials:

effects of genderRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events)

Number of Events

Subgroup

Heterogeneity trend test: p=0.04


Duration (years)Treatment-arm(n=84573)



Year 0-1 3497 3952 0.88 (0.84-0.93)

Year 1-2 2112 2645 0.77 (0.73-0.82)

All clinical outcome trials:

effects of duration of treatmentRelative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events)

Number of Events

Year 2-3 1763 2318 0.73 (0.69-0.78)

Year 3-4 1508 1954 0.72 (0.68-0.77)

Year 4-5 1224 1486 0.77 (0.72-0.83)

Year 5+ 869 995 0.76 (0.69-0.85)


Effects of other subgroups on the ability of statins to reduce major vascular events

No effect of:

• Prior vascular disease• Age• Blood pressure• BMI• Smoking• Estimated GFR


Comparison Treatment-arm Control-arm Relative risk (95% CI)

More vs less statin5 trials (n=39,612)

1466 1472 1.02 (0.89-1.18)

Statin vs Control21 Trials (n=129,526

3594 3592 1.00 (0.95-1.04)

All statin clinical outcome trials: effects on Cancer

Relative risk of cancer per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol

Cancer incidence

All 26 trials(n=169,138)

5060 5064 1.00 (0.96-1.04)


managing the late consequences of chd: what is the evidence for lipid management

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