Advantage of Fixed Dose Combination Lipid Lowering ...perkicabangmalang.org/assets/files/1. dr...

JOHN DOE, MD

SUBTITLE 32 PT ARIAL BOLD ITALICS

Advantage of Fixed Dose Combination Lipid

Lowering Treatment Focus:

Ischaemic Coronary Heart Disease

DADANG HENDRAWAN

Introduction

• Cardiovascular diseases (CVDs)

are the leading causes of death in

the world

• 10% of the global disease burden

is attributed to CVD

• Out of the 17.3 million CV deaths in

2008, heart attacks were

responsible for 7.3 million and

strokes for 6.2 million deaths

Libby P. N Engl J Med 2013;368:2004-2013WHO Global atlas on CVD prevention and control 2011

OH 2017

Foamcells

Fattystreak

Intermediatelesion Atheroma

Fibrousplaque

Complicatedlesion/rupture

Smooth muscleand collagen

From first decade From third decade From fourth decade

Growth mainly by lipid accumulation Thrombosis,

haematoma

Endothelial dysfunction

Kiechl S et al. Eradicate Cardiovascular Disease 2008

Atherosclerosis: Natural history

OH 2017

4

Unmet need

5

Doubling statin dose but not doubling

LDL lowering potency

Liver

Cholesterol Pool(Micelles)

NPC1L1 Remnant Receptors

Cholesterol

HMG-CoA

CMR

CM

Statins X 1

3

LDL Receptor

Expression

1 Inhibition of HMG-CoA reductase

activity

2 Reduction of hepatic cholesterol

3 Increased LDL receptorexpression

4 Increased clearance of LDL-C

Statin: Mechanism of Action

LDL-C

Atheroma

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; NPC1L1 = Niemann-Pick C1-like 1; CMR = chylomicronremnant.

Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

Cholesterol Pool

2

4

Statins Inhibit Synthesis of Cholesterol

Blood

Eze Inhibits Absorption of Cholesterol in the Small Intestine

Liver

Blood



Cholesterol

HMG-CoA

CMR

CM

Ezetimibe

X1

3

5

4

LDL Receptor

Expression

2

1 Inhibition of NPC1L1

activity

2 Reduction of

cholesterol

transported to the liver

3

4

5

Reduction of hepatic cholesterol

Increased LDL receptor

expression Increased clearance

of LDL-C

2

Ezetimibe: Mechanism of Action

LDL-C

Atheroma

NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant.Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

Cholesterol Pool

Liver



Cholesterol

HMG-CoA

CMR

CM

Statins

Ezetimibe

X

2

LDL Receptor

Expression

1

2

3

Reduction of hepatic cholesterol

Increased LDL receptor expression

Increased clearance of plasmaLDL-

C

Together, ezetimibe in combination

with a statin provides:

LDL-C

Atheroma

NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant.

Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

1 Cholesterol Pool

3

Ezetimibe & Statins Have Complementary MoA

Blood

X

Clinical Data for Ezetimibe/Atorvastatin:

Effect of Ezetimibe Coadministered With

Atorvastatin in 628 Patients With

Primary Hypercholesterolemia

Ballantyne CM et al. Circulation. 2003;107:2409–2415.

2 3 4b 5 6 7

84 12

8

20–2–4

Visit 1

Week –16 to –6

Q1 Q2

Adapted with permission from Ballantyne CM et al.1

aBaseline LDL-C 145 to 250 mg/dL (~3.7 to 6.5 mmol/L) and triglycerides ≤350 mg/dL (~4.0 mmol/L).bRandom assignment to double-blind treatment occurred at visit4.

NCEP = National Cholesterol Education Program; Q1 = first qualifying calculated LDL-C value; Q2 = second qualifying calculated

LDL-C value; blood samples for Q1 and Q2 were collected at least 1 week apart.

1. Ballantyne CM et al. Circulation. 2003;107:2409–2415.

Phase I

Screening Phase

Phase II

Prerandomization

Phase

DRUG WASHOUT

and Dietary Stabilization on

NCEP Step I Diet

PLACEBO

Run-in

Plus Diet

(4 weeks)

Patients with primary hypercholesterolemiaa

Phase III: Randomization Phase

ACTIVE TREATMENT PLUS DIET

(12 weeks)

Study Design

RANDOMIZATION

Placebo (n=60)

Ezetimibe 10 mg (n=65)

Atorvastatin 10 mg (n=60)

Ezetimibe/atorvastatin 10/10 mg (n=65)







Subjects :

• Men, women ≥ 18 y.o

• LDL-C145-250 mg/dL, TG ≤ 350 mg/dL

• Ezetimibe + atorvastatin was more effective in reducing mean LDL-C than was atorvastatin alone (–56% vs –44%

respectively, pooled across all doses); P<0.01.

• Mean pooled untreated baseline LDL-C was 182 mg/dL (~4.7 mmol/L) for the group receiving ezetimibe + atorvastatin

(n=255) and 181 mg/dL (~4.7 mmol/L) for the group receiving atorvastatin(n=248).

aP<0.01 for combination therapy vs corresponding dose of atorvastatin alone.

Atorva = atorvastatin.

Adapted with permission from Ballantyne CM et al.1


Ezetimibe in Combination With

Atorvastatin 10 mg Reduced Mean LDL-C by 53%1

-7 0

-6 0

-5 0

-4 0

-1 0

-2 0

-3 0

0

Mea

n C

han

ge

in L

DL-C

Fro

m U

ntrea

ted

Bas

elin

e,%

–

53a

–

37 –

42–

45–

54

Ezetimibe +

Atorvastatin

10 mg 10 mg 20 mg 40 mg 80 mg

Atorvastatin

Efficacy of ezetimibe + the lowest dose of atorvastatin wassimilar

to that of the highest dose of atorvastatin

Mean Change in LDL-

C From Untreated

Baseline With:

Ezetimibe +

Atorva 20

mg

–54%a

Ezetimibe +

Atorva 40

mg

–56%a

Ezetimibe +

Atorva 80

mg

–61%a

P <

0.01

P <

0.01

P <

0.01

Ezetimibe/Atorvastatin Provided Significantly Greater Reduction in

Total-C, Apo B, Non–HDL-C, and TG and Increase in HDL-C

Compared with Atorvastatin Monotherapy1

-60

-50

-40

-30

0

-10

-20

10

20

Total-C TG

–41

–32–36

74

–25

–52

–41

P<0.01

–33

P<0.01

HDL-C

P<0.01

Ezetimibe/atorvastatin (pooled)n=255

Apo B Non–HDL-C

Atorvastatin (pooled)

n=248

Me

an

Pe

rce

nt

Ch

an

ge

F

rom

Ba

se

lin

e

a

aMedian percent change from baseline.

Total-C = total cholesterol; ApoB = apolipoprotein B; TG = triglycerides.


P<0.01

–45

P<0.01


Efficacy and Safety of Ezetimibe Added on to

Atorvastatin (20 mg) Versus Uptitration of

Atorvastatin (to 40 mg) in

Hypercholesterolemic Patients at Moderately

High Risk for Coronary Heart Disease (TEMPO

Study)

Conard SE et al. Am J Cardiol. 2008;102:1489–1494.

Study Design

CHD = coronary heart disease; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III.

1. Conard SE et al. Am J Cardiol. 2008;102:1489–1494.

Atorvastatin 20 mg

Visit 1 Week 0 Week 6

Randomization

(LDL-C 100–160 mg/dL, [~2.6–4.1 mmol/L] and

triglycerides ≤350 mg/dL [~≤4.0 mmol/L])

Run-in Double-Blind Period

Patients with hypercholesterolemia at moderately high risk of

CHD

(based on NCEP ATP III criteria)



1. Conard SE et al. Am J Cardiol. 2008;102:1489–

1494.

Ezetimibe/Atorvastatin 10/20 mg Provided Greater Additional

LDL-C Reduction vs Doubling Atorvastatin Dose to 40 mg1


(mean on-statin baseline LDL-C = 120mg/dL,

~3.1 mmol/L)

Atorvastatin 20 mg titrated to 40 mg (n=92)

(mean on-statin baseline LDL-C = 118 mg/dL,

~3.1 mmol/L)

0

–10

–

40

10

LDL-

C

–20

–30–31%

–11%

P<0.001

Me

an

Ch

an

ge F

rom

Sta

tin

-Tre

ate

d B

as

elin

e,%

Patients Reaching LDL-C <100 mg/dL, at 6 weeks, as a Result

of Greater LDL-C Reduction

Ezetimibe/atorvastatin 10/20 mg

(n=92)

Atorvastatin 40 mg

(n=92)

84%49%

Mean Statin-Treated Baseline

LDL-C: 120 mg/dL (~3.1

mmol/L)

Mean Statin-Treated Baseline

LDL-C: 118 mg/dL (~3.1

mmol/L)

P<0.001

Greater Percentage of Patients Reached LDL-C <100 mg/dL With

Ezetimibe/Atorvastatin 10/20 mg vs Doubling Atorvastatin Dose to 40 mg1

The mean decrease in LDL-C from statin-treated baseline was 31% with ezetimibe/atorvastatin

10/20 mg

compared with 11% with atorvastatin 40 mg; P<0.001.

1. Conard SE et al. Am J Cardiol. 2008;102:1489–1494.


Efficacy and Safety of Ezetimibe Added on to

Atorvastatin (40 mg) Compared With Uptitration of

Atorvastatin (to 80 mg) in Hypercholesterolemic

Patients at High Risk of Coronary Heart Disease

(EZ-PATH Study)

Leiter LA et al. Am J Cardiol. 2008;102:1495–1501.

Atorvastatin 40 mg

Week -5 to -4 Week 0 Week 6

Run-in Double-Blind Period


Study Design

Patients with hypercholesterolemia at high risk of

CHD (based on NCEP ATP III criteria)


Randomization

(LDL-C 70–160 mg/dL [~1.8–4.1 mmol/L] and

triglycerides ≤350 mg/dL [~4.0 mmol/L])

NCEP ATP III = National Cholesterol Education ProgramAdult Treatment Panel III.

1. Leiter LA et al. Am J Cardiol. 2008;102:1495–1501.

Adapted with permission from Leiter LA etal.1

1. Leiter LA et al. Am J Cardiol. 2008;102:1495–

1501.

Ezetimibe/Atorvastatin 10/40 mg Provided Greater Additional

LDL-C Reduction vs Doubling Atorvastatin Dose to 80 mg1


Mean on-statin baseline LDL-C = 89 mg/dL

(~2.3 mmol/L )

Atorvastatin 40 mg titrated to 80 mg (n=279)

Mean on-statin baseline LDL-C = 90 mg/dL

(~2.3 mmol/L)

Me

an

Ch

an

ge F

rom

Sta

tin

-Tre

ate

d B

as

elin

e,%

–

20

–

30

0

–10

10

LDL-

C

–11%

–27%

P<0.001

Ezetimibe/atorvastatin 10/40 mg

(n=277)Atorvastatin 80 mg

(n=279)

74%32%

Mean Statin-Treated

Baseline LDL-C: 89 mg/dL (~2.3

mmol/L)

Mean Statin-Treated

Baseline LDL-C: 90 mg/dL (~2.3

mmol/L)

P<0.001

The mean decrease in LDL-C from statin-treated baseline was 27% with ezetimibe/atorvastatin

10/40 mg compared with 11% with atorvastatin 80 mg; P<0.001.1. Leiter LA et al. Am J Cardiol. 2008;102:1495–1501.

More Than Twice as Many Patients Reached LDL-C <70 mg/dL With

Ezetimibe/ Atorvastatin 10/40 mg vs Doubling Atorvastatin Dose to 80 mg1

Patients Reaching LDL-C <70 mg/dL at 6 weeks, as a Result

of Greater LDL-C Reduction

Plaque Regression With Cholesterol Absorption Inhibitor

or Synthesis Inhibitor Evaluated by Intravascular

Ultrasound (PRECISE-IVUS)

Tsujita K, Sugiyama S, Sumida H, et al. Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary

Plaque Regression in Patients With Percutaneous Coronary Intervention.:The Multicenter Randomized Controlled PRECISE-

IVUS Trial. J Am Coll Cardiol 2015;66: 495–507.

Study Design

Month 0 Month 9-12

Primary endpoint: the absolute change in % coronary atheroma

volume from baseline to follow-up.

• To evaluate the effects of ezetimibe plus

atorvastatin vs atorvastatin monotherapy

on the lipid profile and coronary

atherosclerosis in Japanese patients (n=246)

who underwent percutaneous coronary

intervention (PCI).

• Inclusion criteria:

o Aged 30 - 85 years with CAD

o After having undergone successful

coronary angiography or PCI under

IVUS guidance to treat ACS or stable

angina pectoris (SAP).

o LDL-C level at entry of >100 mg/dl

LDL-C and Lipid Changes

• The combination of atorvastatin/ezetimiberesulted in lower levels of LDL-C than atorvastatin monotherapy [63.2 ± 16.3 mg/dl (1.62 ± 0.4 mmol/L) vs. 73.3 ± 20.3 mg/dl (1.89 ± 0.5 mmol/L); p < 0.001].

PRECISE-IVUS = Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound

• The atorvastatin/ezetimibe group had a greater proportion of patients who achieved LDL-C levels <70 mg/dl (1.8 mmol/L) (72% vs. 47%; p = 0.001) compared to atorvastatin monotherapy group.

LZ group = atorvastatin/ezetimibe group; L group = atorvastatin monotherapy group

PRECISE-IVUS: IVUS images at baseline and follow-up

LZ group = atorvastatin/ezetimibe group; L group = atorvastatin monotherapy group

Relationship between achieved LDL-C levels and the median change in

percent atheroma volume in several intravascular ultrasound trials.

Conclusions

• Hyperlipidemia is a risk factor for CHD.1

• Many patients, including those on statins, have elevated LDL-C or non–HDL-C levels.2,3

• Ezetimibe lowers cholesterol through a mechanism that is

complementary to that of statins.4

• Ezetimibe/atorvastatin, as an adjunct to diet and exercise, is a therapeutic option to help manage

hyperlipidemia in statin-treated patients.5

• Ezetimibe/atorvastatin may be an effective therapeutic option to help reduce the risk of

cardiovascular events in patients with CHD.5

CHD = coronary heart disease.1. NCEP ATP III Expert Panel. Circulation. 2002;106:3143–3421. 2. Gitt AK et al. Eur J Prev Cardiol. 2011;19:221–230. 3. Santos RD et al.

Atherosclerosis.2012;224:150–153. 4. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278. 5. Data on

file, MSD.

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