Rafael Bitzur The Bert W Strassburger Lipid Center Sheba ... · The Bert W Strassburger Lipid...

Case PresentationCase Presentation

Rafael BitzurThe Bert W Strassburger Lipid Center

Sheba Medical CenterTel Hashomer


50 YO man

NSTEMI treated with PCI 1 month ago

Medical History:

– Obesity: BMI 32, waist circumference 110 cm

– HTN: well controlled with ACE-I and β-blocker

– IFG (fasting glucose 108 mg/dL, HbA1c 6.3%)

– Dyslipidemia treated with simvastatin 20 mg


Lipid profile

–TC 188 mg/dL

–LDL 90 mg/dL

–HDL 34 mg/dL

–TG 320 mg/dL

CK, GOT, GPT normal. No myalgia.


Treatment options (+TLC)

–Atorvastatin 80 mg instead of simva

–Add fibrate

–Add niacin ER

–Add Omega 3

o` l e dyrz dnjlz?

BraunwaldBraunwald (1996)(1996)

Deaths/100 patients/monthDeaths/100 patients/month

Time (months after hospital admission)Time (months after hospital admission)

Risk of death in patients with CHD is Risk of death in patients with CHD is greatest greatest earlyearly after an ACSafter an ACS

Acute MIAcute MIUnstable anginaUnstable anginaStable anginaStable angina

00

55

1010

1515

2020

2525

00 11 22 33 44 55 66

00 44 88 1212 1616

1515

1010

55

00

Cumulative incidence (%)Cumulative incidence (%)

Time since randomisation (weeks)Time since randomisation (weeks)

AtorvastatinAtorvastatin

PlaceboPlacebo 17.4%17.4%

14.8%14.8%

RRR = 16%RRR = 16%pp=0.048=0.048

Time to first occurrence of Time to first occurrence of composite endpoint of:composite endpoint of:

MIRACL: Primary efficacy measureMIRACL: Primary efficacy measure

95% 95% CI CI = 0.701= 0.701––0.9990.999 Death (any cause)Death (any cause) NonNon--fatal MIfatal MI Resuscitated cardiac arrestResuscitated cardiac arrest Worsening angina with new Worsening angina with new

objective evidence and urgent objective evidence and urgent rehospitalisationrehospitalisation

JAMA. 2001;285:1711

NNT = 38

PROVE ITPROVE IT--TIMI 22: Early benefit with TIMI 22: Early benefit with intensive lipid loweringintensive lipid lowering

Ray KK and Cannon CP Am J Cardiol. 2005;96(suppl):54F-60F.Adapted from Cannon CP et al. N Engl J Med. 2004;350:1495-504.

30

20

3 6 9 12 30

10

015 18 21 24 27

40 mg Pravastatin80 mg Atorvastatin

P = 0.03 at 4 mos

Follow-up (months)

Death or major

CV event (%)

0

N = 4162 with ACS

NNT = 25

16% RRR at 2 years16% RRR at 2 years(p = 0.005)(p = 0.005)

A to Z: Primary EndpointA to Z: Primary EndpointComposite CV Death, MI, ACS or StrokeComposite CV Death, MI, ACS or Stroke

0 1 4 8 12 16 20 24Month from Randomization

0

5

10

15

20

KM

Rat

e (%

)

P/S20Rate = 16.7%

S40/80Rate = 14.4%

HR 0.89

p = 0.14

CI 0.76 – 1.04

652 primary events

JAMA. 2004;292:1307

CRP CRP -- EFFECT ONLY IN ACS?EFFECT ONLY IN ACS?LDLLDL--C, CRP, and Early Clinical Benefit in A to Z, C, CRP, and Early Clinical Benefit in A to Z,

MIRACL, and PROVE ITMIRACL, and PROVE IT––TIMI 22TIMI 22

* Measured 120 days after randomization.† Measured 90 days after randomization.

Adapted from Nissen. JAMA. 2004;292:1365, with permission.

Number of patients randomized 4497 3086 4162

Early* LDL achieved on treatment, mg/dL 62 72 62

Early* LDL cholesterol differential, mg/dL 62 63 33

CRP differential, % 0/17 34 38

Early event reduction, % 0* 16* 18†

A-to-Z MIRACL PROVE IT

HighHigh--Dose Statin Treatment Dose Statin Treatment RreducesRreduces OxOx--LDL MarkersLDL Markers

Tsimikas S et al. Circulation. 2004;110:1406-12.

OxPL = oxidized phospholipidsIC-IgG, -IgM = immune complexes with IgG and IgM, respectivelyMyocardial Ischemia Reduction with Aggressive Cholesterol Lowering

MIRACL study subgroup analysis, N = 2341 with ACS, atorvastatin 80 mg for 16 weeks

ApoB-100AtorvastatinPlacebo

Total apoB-OxPLAtorvastatinPlacebo

Total apoB-IC IgGAtorvastatinPlacebo

Total apoB-IC IgMAtorvastatinPlacebo

% change–40 –20 0 20 40

Mean 95% CI

–33.0 –34.2, –31.85.8 4.6, 7.0

–29.7 –31.5, –28.0–0.2 –2.3, 1.9

–29.5 –31.9, –27.02.1 –1.1, 5.4

–25.7 –28.1, –23.313.2 9.3, 17.3


Treatment options


–Add fibrate

–Add niacin ER

–Omega 3

TG Level Is Significant CVD Risk Factor: TG Level Is Significant CVD Risk Factor: MetaMeta--Analysis of 29 StudiesAnalysis of 29 Studies

Circulation. 2007;115:450-458

*Individuals in top vs. bottom third of usual log-TG values; adjusted for at least age, sex, smoking status, and lipid concentrations; also adjusted for BP (in most studies).

CHD Risk Ratio* (95% CI)

1.72 (1.56-1.90)21

Duration of follow-up≥10 years 5902<10 years 4256

SexMale 7728Female 1994

Fasting statusFasting 7484Nonfasting 2674

Adjusted for HDLYes 4469No 5689

N = 262,525Groups CHD Cases

TG Level Remains CVD Risk Factor TG Level Remains CVD Risk Factor in Patients On Statins: TNTin Patients On Statins: TNT

0

0.2

0.4

0.6

0.8

1

1.2

LDL<70 mg/dl LDL>70 mg/dl

TG<150 mg/dlTG>150 mg/dl

Adjusted HRs of death, MI, and recurrent ACS between 30 days and 2 years of follow-up*

*Adjusted for age, gender, low HDL-C, smoking, HTN, obesity, DM, prior statin therapy, prior ACS, PVD, treatment effect

JACC 2008;51:724–30

Diet for Metabolic DyslipidemiaDiet for Metabolic Dyslipidemia

NEJM 2008;359:229-41

Outcomes in Fibrate Trials:Outcomes in Fibrate Trials:Diabetes / Metabolic SyndromeDiabetes / Metabolic Syndrome

Trial N Control DrugRel.RR P

Primary Prevention

HHS* 292 13.0% 3.9% 71% .005

Secondary Prevention

BIP† 1470 18.4% 14.1% 25% .03

VA-HIT‡ 769 29.4% 21.2% 32% .004Rel. RR indicates relative risk reduction*Patients with triglycerides >204 mg/dL and an LDL/HDL >5†Patients with the metabolic syndrome; baseline HDL-C, 33 mg/dL; triglycerides, 170 mg/dL‡Patients with diabetes; baseline HDL-C, 31 mg/dL; triglycerides, 164 mg/dL

Major CVDEvent Rate

* Circulation. 1992;85:37-45.† Arch Intern Med. 2005;165:1154-1160.‡ Arch Intern Med. 2002;162:2597-2604.

Fibrate Trials: Fibrate Trials: Diabetic or Metabolic Diabetic or Metabolic SyndromeSyndrome SubanalysesSubanalyses

-71

-25-32

-80-70-60-50-40-30-20-10

0

HH

S*

BIP

**

VA

-H

IT**

*

RRR in MACE

*Patients with triglycerides >204 mg/dL and an LDL/HDL >5* * Patients with the metabolic syndrome; baseline HDL-C, 33 mg/dL; triglycerides, 170 mg/dL* * * Patients with diabetes; baseline HDL-C, 31 mg/dL; triglycerides, 164 mg/dL

%

6%

5%

0

1

2

3

4

5

6

7

8

Placebo Fenofibrate

Even

t Rat

e, %

11% ReductionP=.16

FIELD: Primary End PointFIELD: Primary End PointNonfatal MI, or CHD DeathNonfatal MI, or CHD Death

Lancet. 2005;366:1849-1861

Fibrates: WhatFibrates: What’’s in Store?s in Store?

ACCORD:

– Fenofibrate+statin vs. statin in 9750 patients with

DM2

– Due 2011


Treatment options


–Add fibrate

–Add niacin ER

–Omega 3

Lipid Effects of Niacin ExtendedLipid Effects of Niacin Extended--ReleaseRelease

Am J Cardiol 1998;82:74U-81U.

Most potent agent for HDL: 20%+; nonlinear Favorable effects on LDL-particle density LDL (linear), TG, and Lp(a)

Chan

ge

from

Base

line

(%) -8 -13

-22 -21-16

2930242116

10

-21

-32-44-39

-14-5

-26

-3-12

-30-25

-17

HDLHDL--CC

LDLLDL--CCLp(a)Lp(a)

TGTG

3020100

-10-20-30-40-50

mg500 1000 1500 2000 2500 3000

Coronary Drug ProjectCoronary Drug ProjectLongLong--Term Mortality Benefit of Niacin in PostTerm Mortality Benefit of Niacin in Post--MI PatientsMI Patients

Niacin

Placebo

P = 0.0012

100908070605040302010

0 2 4 6 8 10 12 14 16

Years of follow-up

Surv

ival

(%

)

J Am Coll Cardiol 1986;8:1245–1255

15 years: 4% absolute reduction in mortalityNNT = 25

NIACIN: Clinical EventsNIACIN: Clinical Events

NEJM 2001;345:1583-1592

90

80

70

76%

RR = 0.10P = .03

0 1 2 3

97%

All placebos

Simvastatin–Niacin

Composite End Point (Death from Coronary Causes, Nonfatal MI, Stroke, or Revascularization for Worsening Ischemia)

Pat

ient

s w

ith E

vent

(%)

0

2

4

6

8

10

12

Statin +Placebo

Statin +Niacin ER

9.6

3.8

RR = 0.4P = .20

Circulation 2004;110:3512-3517.

HATSARBITER 2

Composite End Point (MI, UAP, CVA, Sudden Death, Coronary or peripheral revascularization)

0

100

YEARS

% F

ree

of E

vent

ARBITERARBITER--HALTS 6 StudyHALTS 6 Study

363 CHD/equivalent patients with low HDL-C (<50

mg/dl men, <55 mg/dl women)

– All on statin with LDL-C<100 mg/dl

Primary end point: change in cIMT after 14

months

The trial was terminated early, on the basis of

efficacy

N Engl J Med 2009;361.

ARBITERARBITER--HALTS 6 studyHALTS 6 study


Lipids with niacin (mg/dL)

• LDL-C

83 73

• HDL-C

43 50

ARBITERARBITER--HALTS 6 StudyHALTS 6 Study


Oxford Niaspan StudyOxford Niaspan Study

71 statin-treated patients with HDL-C<40 mg/dl

and DM2 + CHD or carotid/peripheral

atherosclerosis.

2 g daily modified-release NA vs. placebo

Primary end point: change in carotid artery wall

area quantified by MRI, after 1 year.




Lipids in niacin groupLDL-C 85 69 mg/dL (-19%)HDL-C 39 48 mg/dL (+23%)


Inverse relationship between the HDL-C and wall area,

and no relationship between the LDL-C and wall area.

– Increases in HDL-C may be beneficial

Flow-mediated dilation of the brachial artery showed a

favorable trend with niacin.

Aortic distensibility and glyceryl-trinitrate-mediated

brachial reactivity did not change significantly with niacin.


NIA PlaqueNIA Plaque studystudy

145 patients with clinically evident atherosclerosis, treated with a statin to ATP III LDL-C targets.

– Randomized to 1500 mg extended-release niacin or placebo.

Both arms improved

No significant difference between the two treatment arms in MRI outcomes, including carotid arterial wall volume and measurements of the lipid core.

Sibley et al. AHA 2009

Sibley et al. AHA 2009

NIA Plaque: Change in lipid parametersNIA Plaque: Change in lipid parameters

Lipid measure (mg/dL)

Statin + placebo, baseline

Statin + placebo, 18 mo

Statin+ER niacin,

baseline

Statin+ER niacin, 18 mo

p (between groups)

LDL-C 86 77 88 67 0.03

HDL-C 55 49 55 58 <0.001

TG 123 93 115 84 0.02

Niacin: What’s in Store?

HPS2-THRIVE:

– Niacin and a blocker of PG D2 on top of statin

therapy in 20,000 patients

AIM-HIGH:

– Simvastatin+Niaspan vs. Simvastatin in 3300

patients with CVD, low HDL and high TG

Due 2012


Treatment options


–Add fibrate

–Add niacin ER

–Omega 3

OmegaOmega--3 and Lipids in Patients with 3 and Lipids in Patients with TG >500 mg/dlTG >500 mg/dl

Pooled analysis: Harris WS et al. J Cardiovasc Risk 1997;4:385-391. Pownall HJ et al. Atherosclerosis 1999;143:285-297.

Placebo Omega-3 Acid Ethyl Esters (4 g/day)

Baseline(mg/dL)

TG816

HDL-C22

Non-HDL-C

27

Chol296

VLDL-C175

LDL-C89

P<0.0001P=0.0002

P=0.0015P=0.0059

P<0.0001

P<0.0001

-45.0

6.70.0

9.1

-3.6-13.8

-9.7-1.7 -0.9

-42.0

-4.8

45.0

-60%

-40%

-20%

0%

20%

40%

60%

Dietary Supplementation With Dietary Supplementation With OmegaOmega--3 Fatty Acids After MI3 Fatty Acids After MI

GISSIGISSI--PrevenzionePrevenzione

Lancet. 1999;354:447-455.

0

5

10

15

20

Placebo (n = 2828)Omega-3 fatty acids 1 g

(n = 2836)

Death/Nonfatal MI/

Nonfatal Stroke

Even

t Rat

e (%

)15% Reduction

P = .023

20% ReductionP = .008

CVD Death/Nonfatal MI/

Nonfatal Stroke

Months1 2 3 4 5 6

mg/d

L

Months1 2 3 4 5 6

mg/d

L

GISSIGISSI--Prevenzione: Prevenzione: Effects of EPA+DHA on Serum LipidsEffects of EPA+DHA on Serum Lipids

HDL Cholesterol Triglycerides

n-3Control

n-3Control

38404244464850

140145150155160165170

Circulation 2002;105:1897-1903.

No Difference 5% Difference


Treatment options


–Add fibrate

–Add niacin ER

–Omega 3

Rafael Bitzur The Bert W Strassburger Lipid Center Sheba ... · The Bert W Strassburger Lipid...

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