rafael bitzur the bert w strassburger lipid center sheba ... · the bert w strassburger lipid...
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Case PresentationCase Presentation
Rafael BitzurThe Bert W Strassburger Lipid Center
Sheba Medical CenterTel Hashomer
Case PresentationCase Presentation
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
Case PresentationCase Presentation
Lipid profile
–TC 188 mg/dL
–LDL 90 mg/dL
–HDL 34 mg/dL
–TG 320 mg/dL
CK, GOT, GPT normal. No myalgia.
Case PresentationCase Presentation
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
Case PresentationCase Presentation
Treatment options
–Atorvastatin 80 mg instead of simva
–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
Case PresentationCase Presentation
Treatment options
–Atorvastatin 80 mg instead of simva
–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
N Engl J Med 2009;361.
Lipids with niacin (mg/dL)
• LDL-C
83 73
• HDL-C
43 50
ARBITERARBITER--HALTS 6 StudyHALTS 6 Study
N Engl J Med 2009;361.
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.
J Am Coll Cardiol 2009;54:1787–94
Oxford Niaspan StudyOxford Niaspan Study
J Am Coll Cardiol 2009;54:1787–94
Lipids in niacin groupLDL-C 85 69 mg/dL (-19%)HDL-C 39 48 mg/dL (+23%)
Oxford Niaspan StudyOxford Niaspan Study
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.
J Am Coll Cardiol 2009;54:1787–94
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
Case PresentationCase Presentation
Treatment options
–Atorvastatin 80 mg instead of simva
–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%
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
Case PresentationCase Presentation
Treatment options
–Atorvastatin 80 mg instead of simva
–Add fibrate
–Add niacin ER
–Omega 3