Transcript Avapro Medical

Disclosures / Conflicts of Interest
Alfred K. Cheung, M.D.
None relevant to this topic
Lipid Control
Is it really needed in the ESRD patient?
ESRD: STATE OF THE ART AND CHARTING THE
CHALLENGES FOR THE FUTURE
April 23-26, 2009
Alfred K. Cheung, M.D.
Lipid Control
Is it really needed in the ESRD patient?
I don’t know
Unconventional Relationship
with Clinical Outcomes in HD Patients
• Blood pressure
• Hemoglobin
• Blood glucose
Is Dialysis World
round or flat?
Serum Cholesterol and CHD Death Rate in MRFIT (N=361,662)
Martin, Lancet 1986
Can LDL-C be too low?
(Atorvastatin 80 mg in PROVE-IT with achieved LDL <100 mg/dl)
Target 70-100
Wiviott , 2005
CAD Risk Reduction in 49 Randomized Trials
52
50
Risk reduction (%)
60
30
50
40
30
21
31
19
33
6+
19
20
10
Should be long
enough for HD
patients to benefit
3 to 5
6
1 to 2
0
8 to 29 30-55
LDL reduction (mg/dl)
Years in trial
>55
Law MR, 2003
Hemodialysis Patients
3.5
Relative Death Risk
3.0
N = 13,535
2.5
2.0
1.5
1.0
0.5
0.0
LT 100
Lowrie, 2002
100-150
150-200
200-250
250-300
300-350
Total Cholesterol (mg/dL)
GE 350
Relative Risk of Death
4
Total cholesterol
3.22
<160
3
160-199
2.33
200-239
2
>240 mg/dL
1
1
0
n = 206
0.76 0.71 0.62
213
130
Present
85
1
43
1.23
65
52
29
Absent
Inflammation / Malnutrition
Liu, CHOICE, 2004
Effect in Simvastatin on Total Mortality in Mild CKD
eGFR < 75
Total Mortality
eGFR ≥ 75
eGFR < 75
Major coronary events
eGFR ≥ 75
eGFR < 75
CHD death or
nonfatal MI
eGFR ≥ 75
● 4S post-hoc analysis
● 4444 patients with CHD
● 2314 (52%) CKD
eGFR < 75
CABG or PTCA
eGFR ≥ 75
eGFR < 75
Stroke
eGFR ≥ 75
0
0.5
Simvastatin
Better
1.0
1.5 2.0 2.5
3.0
Simvastatin
Worse
3.5
Chonchol AJKD, 2007
Die Deutsche Diabetes Dialyse Studie
4D Study: Effects of Statins on HD Patients
Prospective, randomized double-blind study with type II DM
Atorvastatin 20 mg QD
Placebo
1255
patients
Placebo
Wanner, NEJM. 2005;
4D
LDL-C Lowering by Atorvastatin in DM HD
LDL cholesterol (mg/dL)
140
120
Placebo
100
80
60
Atorvastatin
40
20
0
0
1
2
3
4
5
6
Years
Wanner, 2005
Primary composite end point
4D
(Cardiac death / MI / stroke)
Cumulative incidence (%)
60
 2X fatal stroke (13 vs. 27 events, p=0.04)
 32% in cardiac events
50
40
30
Placebo
20
Atorvastatin
RR reduction = 8% (0.77-1.10)
10
0
0
1
2
3
4
Years from Randomization
Wanner, 2005
5
5.5 years
A study to evaluate the Use of Rosuvastatin in subjects on Regular
hemodialysis: an Assessment of survival and CV events
(AURORA)
• 280 centers in 25 countries
• 2,776 HD patients (age 50-80 yrs)
~40% history of CVD
~25% DM (vs. 4D)
• Rosuvastatin (10 mg vs. placebo)
• ACM and CV events
Fellstrom, 2009
AURORA RESULTS
Decrease in LDL-C by 46%
No effect on primary outcome:
CV death + MI + stroke
Study of Heart and Renal Protection
• ~9,000 patients (~6000 CKD + ~3000 HD/PD)
• No lipid criteria (statin not obviously indicated)
• 19% DM (vs. 100% in 4D)
• No prior MI or coronary revascularization
• Simvastatin (20 mg) + ezetimibe (10 mg)
• Results?
• It is very difficult to prophesize, especially about the future
Why is lowering LDL-cholesterol
ineffective in improving clinical outcomes
in dialysis patients?
It is too
late to
treat !!
Hypothesis:
Atherosclerosis is not a major
problem in dialysis patients
Oxidative
Endothelial
stress
dysfunction
LIPIDS
Inflammation
Uremia
Abnormal
glucose
metabolism
Homocysteine
Fluid
HTN
Genetics
Phosphorus
Vascular
Too thin
calcification
Vitamin D
deficiency
Too Too
fat much
Vitamin K
Too much
ESA
Anemia deficiency
CVD
blood
VLDLr
Cholesterol ester
transfer protein
torcetrapib
Lecitin cholesterol
acyl-transferase
Dyslipidemia in Dialysis Patients
• Hypertriglyceridemia
– in lipoprotein remnants
– Total TG ~265 mg/dL in 4D; ~155 mg/dL in AURORA
• Low HDL and impaired anti-oxidant activity of HDL
• Abnormal LDL
– modified (oxidized, glycated, carbamylated)
Not responsive to statins
Triglycerides and HDL-C are Independent CAD Risk Factors
Hopkins , JACC, 2005
17.2
Odds Ratio
20
15
7.9
6.7
4.3
6.1
10
5.7
3.1
5
3.7
300+
1.1
2.2
1.3
0
<30
30-39
40-49
HDL Cholesterol (mg/dL)
1.0
50+
200-299
<200
Triglycerides
(mg/dL)
Fasting TG, HDL and Risk for CHD
New cardiac events
(per 1000 person-years)
The Helsinki Heart Study
16
14
12
10
8
6
4
2
0
67% reduction
ns
ns
TG 200+
TG <200
Placebo
Gemfibrozil
ns
TG <200
HDL-C 40+ mg/dl
TG 200+
HDL-C <40 mg/dl
Manninen, Circulation, 1992.
LDL-cholesterol
Tentative Practice Guidelines
for Dyslipidemia in HD Patients
• Would not discontinue statins; consider initiating statin for LDL-C
>130 mg/dL (reduce lovastatin dose by 50%)
• For total TG >500 mg/dL
– w-3 FA 3-4 gm QD
– gemfibrozil 600 mg QD (beware of fenofibrate)
• Niacin is a reasonable alternative
– decrease TG
– increase HDL-C
– decrease small dense LDL
Conclusions in ESRD Patients
• Serum total and LDL-cholesterol levels are not usually high
• Despite lowering of LDL-cholesterol levels, there is no
convincing evidence for benefits or harm associated with
statin use
• There are other dyslipidemia that may be more atherogenic
in uremia (e.g., hypertriglyceridemia associated with
retention of lipoprotein remnants; low HDL levels and
activities as result of uremic modifications)
• Future clinical research should concentrate on these other
dyslipidemic states
Lipid Control
Is it really needed in the ESRD patient?
CANNOT SAY “YES” IN 2009
NOT total cholesterol or LDL-cholesterol
ADA/ACC 2008 Consensus Statement:
Treatment Goals in Patients With Cardiometabolic Risk
Goals
Highest-Risk Patients
♥ Known CVD
♥ Diabetes plus ≥1 additional major
LDL-C
Non–HDL-C
Apo B
<70 mg/dL
<100 mg/dL
<80 mg/dL
<100 mg/dL
<130 mg/dL
<90 mg/dL
CVD risk factor
High-Risk Patients
♥ ≥2 major CVD risk factors, no
♥
diabetes or known CVD but
Diabetes but no other major CVD
risk factors
“In individuals on statin therapy who continue to have low HDL-C or
elevated non–HDL-C, especially if Apo B levels remain elevated,
combination therapy is recommended. The preferred agent to use
Brunzell JD, et al. JACC 2008; 51:1512.
ADA and ACC Consensus Statement
Treatment Recomendations
• A statin is the initial drug of choice.
• If LDL goal not reached consider adding:
– ezetimibe
– bile acid sequestrants (can raise TG)
– niacin
• Low HDL-C or elevated non-HDL-C, especially if apoB
remains elevated:
– combination therapy is recommended
– niacin first choice
Brunzell JD, et al. JACC 2008; 51:1512.
ADA and ACC Consensus Statement
Treatment Recomendations
• Fibrates have been shown to reduce CVD events in some
studies but not total mortality
• N-3 fatty acid therapy
– CVD outcome data are lacking for hypertriglyceridemic
patients
– Clear reduction in CV risk in other studies
• Severe hypertriglyceridemia :
–
–
–
–
fat restriction
fibrate
niacin
high-dose n-3 FA (4 g / day)
Brunzell JD, et al. JACC 2008; 51:1512.
ADA and ACC Consensus Statement
Treatment Recommendations: Niacin
• Niacin decreased CVD in the Coronary Drug Project and
total mortality in an extended follow up
• Niacin in combination with bile-acid sequestrants or statin
was associated with regression of atherosclerosis and CVD
events in several studies
– FATS, HATS, ARBITER 2, CLAS
• In diabetes the use of low dose niacin (1500 mg/day) does
not significantly increase A1C levels
Brunzell JD, et al. JACC 2008; 51:1512.
Potential Mechanism of Statin
Benefit in Kidney Disease
• Inhibit mesangial proliferation
• Inhibit induction of TGF- and increase in
extracellular matrix
• Inhibition of induction of MCP-1
• Decrease in inflammation and oxidative stress
• Ameliorate podocyte damage
• Hemodynamic effects on endothelial function and
vasodilation
Fried L, et al. Kidney Int. 2008;74:571-576.
Statins for Improving
Renal Outcomes: Meta-analysis
 39,704 participants (27 studies)
 21 studies with data for eGFR and 20 for albuminuria or proteinuria
 Change in mean differences for eGFR was significant: 1.22 ml/min
per yr slower in statin recipients
 Subgroup analysis: benefit of statin was significant in studies of
participants with CVD but not in populations with diabetic or
hypertensive kidney disease or glomerulonephritis
 Reduction in albuminuria or proteinuria as a result of statin therapy
was also significant:
0.58 Units of SD greater
decrease in statin recipients
Sandhu S, et al. JASN. 2006;17:2006-2016.
Meta-analysis: Lipid Reduction Shown
to Reduce Albuminuria and Proteinuria
Study, Year
Excretion <30 mg/d
Asselbergs et al., 2004
Dalla Nora et al., 2003
Fried et al., 2001
Subtotal of WMD
Statin
Sample
Size, n
Effect
(95% CI), %
Pravastatin
Atorvastatin
Simvastatin
864
25
39
12 (-1 to 25)
-70 (-171 to 31)
-5 (-90 to 81)
2 (-32 to -35)
Excretion, 30-299 mg/d
Buemi et al., 2000
Lintott et al., 1995
Nakamura et al., 2001
Nielsen et al., 1993
Tonolo et al., 1997
Zhang et al., 1995
Subtotal of WMD
Fluvastatin
Fluvastatin
Cerivastatin
Simvastatin
Simvastatin
Pravastatin
21
42
60
18
20
20
-73 (-136 to -10)
-81 (-217 to 55)
-61 (-106 to -16)
-44 (-113 to 25)
-50 (-93 to -7)
-8 (-61 to 45)
-48 (-71 to -25)
Excretion 300 mg/d
Hommei et al., 1992
Lam et al., 1995
Lee et al., 2002
Lee et al., 2005
Nakamura et al., 2002
Thomas et al., 1993
Subtotal of WMD
Simvastatin
Lovastatin
Pravastatin
Pravastatin
Cerivastatin
Simvastatin
21
36
66
82
40
30
-5 (-137 to 128)
-32 (-102 to 38)
-47 (-64 to -29)
-62 (-79 to -45)
-67 (-87 to -48)
20 (-28 to 67)
-47 (-67 to -26)
-0.9
Douglas K, et al. Ann Intern Med. 2006;145:117-124.
WMD
Favors Statin
0.0
0.3
Favors Placebo
Cumulative Incidence, %
VA-HIT: Cumulative Incidence of
CHD Death and Nonfatal MI
25
Placebo
20
15
Gemfibrozil
10
5
0
0
1
2
3
4
5
6
Year
Rubins HB, et al. N Engl J Med. 1999;341:410-418.
Statins decreases CV events in Patients with normal
LDL-C
• JUPITER
• Comparative Atorvastatin Pleiotropic Effects
• However, no effect in HD patients (11% decrease in CRP
in AURORA, not ine 4D)
Rate of Change in MDRD-GFR
in Pravastatin CKD Recipients
Loss of Kidney Function
Faster than Placebo
Loss of Kidney Function
Slower than Placebo
N=690 (20.4%)
GFR < 60, no proteinuria
GFR < 60, proteinuria
GFR < 50, no proteinuria
GFR < 50, proteinuria
GFR < 40, no proteinuria
GFR < 40, proteinuria
-2.5
-1.5
- 0.5
0.5
Rate of Kidney Function Loss
mL/min/1.73m2
Tonelli M, et al. JASN. 2003;14:1605-1613.
1.5
2.5
3.5
4.5
Effect of Atorvastatin on Inflammation in Patients with Type 2
Diabetes Mellitus on Hemodialysis
p=0.001
Krane V, et al. Kidney Int 2008.
p=0.71
Dosing Modifications for Lipid-Lowering Drugs in CKD
GFR 60-90
ml/min/1.73m2
GFR 15-59
ml/min/1.73m2
GFR <15
ml/min/1.73m2
No
No
No
Fluvastatin
No
Not defined
Not defined
Lovastatin
No
 to 50%
 to 50%
Pravastatin
No
No
No
Rosuvastatin
No
5-10 mg
5-10 mg
Simvastatin
No
No
5 mg
No
No
No
No
 to 50%
No
No
No
No
 to 25%
 to 50%
No
No
No
Avoid
Gemfibrozil
No
No
No
Omega-3 FAs
No
No
No
Agent
Statins
Atorvastatin
Nonstatins
Nicotinic acid
Cholestyramine
Colesevelam
Ezetimibe
Fenofibrate
Harper CR. J Am Coll Cardiol. 2008;51:2375-2384..
Notes
 dose to one-half at GFR
<30 ml/min/1.73 m2
 dose to one-half at GFR
<30 ml/min/1.73 m2
Start at 10 mg/day for GFR <60 ml/min/1.73 m2
Start at 5 mg/day for GFR
<30 ml/min/1.73 m2, max dose 10 mg/day
Start at 5 mg if GFR
< 10 ml/min/1.73 m2
34% kidney excretion
Not absorbed
Not absorbed
May  serum creatinine
NLA recommends a dose of 600 mg/day for
GFR 15-59 ml/min/1.73m2
How Should We Treat Them?
Lipid Disorder
Therapeutic Option
Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2)
Elevated LDL-C
1. Atorvastatin, add ezetimibe if not at LDL-C goal
2. Fluvastatin, add ezetimibe if not at LDL-C goal
Mixed dyslipidemia
(not at non-HDL goal)
1. Atorvastatin ofrfluvastatin + ezetimibe
2. Fluvastatin + gemfibrozil 600 mg/day + ezetimibe if not at non
HDL goal
3. Statin + omega 3 fatty acids, add ezetimibe if not at non-HDL goal
4. Statin + fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal
1. Gemfibrozil 600 mg/day
Very high triglycerides (triglyceride 500 mg/dl) 2. Omega-3 fatty acids 3-4 g/day
3. Fenofibrate 48 mg/day
CKD stage 5 (hemodialysis or GFR <15 ml/min/1.73 m2)
Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C
Elevated LDL-C
goal
Mixed dyslipidemia
Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or
omega-3 fatty acids 3-4 g/day if not at non-HDL goal
Very high triglycerides
Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day
Harper CR. J Am Coll Cardiol. 2008;51:2375-2384.
Drug Interactions
Statin
Metabolic pathway
Drug interactions
Atorvastatin
CYP450 3A4
CYA, digoxin, fibric acid, niacin,
erythromycin, antifungals
Fluvastatin
CYP450 2C9
Omeprazole, phenytoin, ranitidine,
rifampicin
Pravastatin
Minimally metabolized
Gemfibrozil
Rosuvastatin
CYP450 2C9
CYA, gemfibrozil
(not extensively
metabolized)
Simvastatin
Agarwal R. Mayo Clin Proc. 2007;82:1381-1390.
CYP450 3A4
Amiodarone, CYA, gemfibrozil,
antifungals, erythromycin, HIV
protease inhibitors, verapamil
How Should We Treat Them?
Lipid Disorder
Therapeutic Option
Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2)
Elevated LDL-C
1. Atorvastatin, add ezetimibe if not at LDL-C goal
2. Fluvastatin, add ezetimibe if not at LDL-C goal
Mixed dyslipidemia
(not at non-HDL goal)
1. Atorvastatin ofrfluvastatin + ezetimibe
2. Fluvastatin + gemfibrozil 600 mg/day + ezetimibe if not at non
HDL goal
3. Statin + omega 3 fatty acids, add ezetimibe if not at non-HDL goal
4. Statin + fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal
1. Gemfibrozil 600 mg/day
Very high triglycerides (triglyceride 500 mg/dl) 2. Omega-3 fatty acids 3-4 g/day
3. Fenofibrate 48 mg/day
CKD stage 5 (hemodialysis or GFR <15 ml/min/1.73 m2)
Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C
Elevated LDL-C
goal
Mixed dyslipidemia
Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or
omega-3 fatty acids 3-4 g/day if not at non-HDL goal
Very high triglycerides
Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day
Harper CR. J Am Coll Cardiol. 2008;51:2375-2384.
Apolipoprotein abnormalities in CRF
•
•
•
•
•
↓ ApoA-1, ↓ ApoA-2
↓ ApoE
↓ Apo CII/CIII ratio
↑ ApoB
↑ LP(a)
49
Triglycerides and TG-Rich LP Metabolism In CRF
• ↑ plasma VLDL, ↓ VLDL and CM clearance,
• ↑ plasma IDL and CM remnants
• ↑ plasma triglyceride
• ↓ adipose tissue triglyceride
• TG-enrichment of LDL and HDL
50
Lipoprotein Lipase Deficiency (LPL)
• ↓ LPL expression and activity in muscle, myocardium and fat
tissue (CRF rats)
(Vaziri, Liang, Kidney Int 50:1928-1935, 1996; Vaziri et al AJP 273:F929-930, 1997)
• Contributing factors: ↑ PTH, ↓ physical activity, uremic
endocrinopathies, ↓ ApoC II/C III ratio,
↑ pre-B HDL, ↓ HDL-2, chronic heparin use, ?uremic
inhibitor(s)
• Consequences:
- deficient delipidation of VLDL and CM
- ↓ fat tissue TG
- ↑ plasma TG
- lipid fuel availability to muscles
51
VLDL Receptor Deficiency
• ↓ VLDLr mRNA and protein in skeletal muscle
and fat tissue in CRF rats
(Vaziri, Liang, Kidney Int 51:913-919, 1997)
• CRF-induced VLDLr deficiency is unrelated to
↑ PTH
(Liang, Oveisi, Vaziri, Kidney Int 53: 626-630, 1998)
• Consequences:
- ↓ VLDL clearance
- ↑ plasma VLDL
52
Hepatic Lipase Deficiency in CKD
• ↓ Hepatic lipase mRN and activity in CRF rats
(Klin et al, JCI 97:2167-2173, 1996; Sato, Liang, Vaziri, KI 64:1780-1786, 2003)
• Deficiency linked to 2° hyperparathyroidism
(Klin et al)
• Consequences:
- ↑ IDL (↓ IDL→ LDL conversion),
- ↑ LDL-TG,
- ↑ HDL-TG
53
Downregulation of LDL Receptor-Related Protein
(LRP) in CKD
• ↓ Hepatic LRP mRNA and protein abundance in CRF rats
(Kim C, Vaziri ND. Kidney Int 67:1028-1032, 2003)
• Consequences:
- ↓ Clearance and ↑ plasma chylomicron remnants
(prolonged Post-prandial hyperlipidemia)
54
HDL- Metabolism in CRF
• ↓ HDL-3 maturation to HDL-2
• ↑ Pre-Beta HDL
• ↓ HDL-cholesterol
• ↑ HDL triglyceride
• Impaired HDL function
55
1-Apo A-I and Apo A-II In CRF
• ↓ Plasma ApoA-I and -II in CRF humans and animals
• ↓ Hepatic Apo A-I gene expression in CRF rats
(Vaziri, Ding, Liang NDT 14:1462-1466, 1999)
• Consequence:
- ↓ plasma HDL
56
3- Lecithin Cholesterol Acyltransferase
(LCAT)
-Made by liver, secreted in plasma LCAT -Catalyzes extra-cellular:
A- Hydrolysis of sn-2 Fatty acid in
phospholipids (phospholipase-2)
&
B- Esterification of free cholesterol
(acyltransferase activity)
57
Anti-atherogenic Actions of HDL
A- Reverse cholesterol - lipid transport
B- Antioxidant/anti-inflammatory actions
a. ApoA-I mediated extraction of oxidized phospholipids
from lipoproteins and cell membrane
b. LCAT-mediated hydrolysis of proinflammatory
oxidized phospholipids (AA at sn-2)
c. Prevention of LDL oxidation and destruction of
oxidized phospholipids by paraoxonase-1 & GPX
d. Inactivation of PAF and PAF-like phospholipids by
acetyl hydrolase (anti-inflammatory / anti-thrombotic)
58
PAF
Conclusions (2/3)
• These abnormalities are compounded by concomitant
proteinuria (or ? PD) which can raise plasma chol by upregulating HMG-CoA reductase & lowering LDLr.
• Dysregulation of lipid metabolism and inflammation
work in concert to promote atherosclerosis.
• Atherosclerosis in ESRD is primarily driven by
inflammation which tends to lower plasma chol.
• Consequently, therapeutic strategies should be directed
at amelioration of oxidative stress & inflammation &
HDL and TG metabolism (as opposed to chol-lowering
Rx).
59
Hypertriglyceridemia in ESRD
VLDL
IDL
TG
LPL
FFA
LPL
CM
CM
remnant
TG
Decreased LPL activity and VLDL receptor; therefore retain
remnant particles, which are putatively highly atherogenic
Dyslipidemia in ESRD
Parameter
Hemodialysis
Total cholesterol

LDL cholesterol

HDL cholesterol

Non-HDL cholesterol

TG

Lp(a)

ApoA-I

ApoA-IV

ApoB
Kwan BC, et al. J Am Soc Nephrol. 2007;18:1246-1261.

Fasting Triglycerides and Incident CVD Risk
Meta-Analysis of Prospective Studies
Men (unadjusted - 16 studies)
Men (adjusted for HDL - 6 studies)
Women (unadjusted - 5 studies)
Women (adjusted for HDL - 2 studies)
0.8
1
1.2
1.4
1.6
1.8
2
RR (per mM TG increase)
Austin , Am J Cardiol 1998
2.2
0.35
•
**
0.3
•
0.25
0.2
0.15
*
•
0.1
0.05
•
0
•
RLP isolated from postprandial plasma
of patients with high RLP (>75th
percentile).
RLP and other fractions incubated
with confluent HUVEC
ICAM-1, VCAM-1, tissue factor
mRNA and on cell surface all
increased similarly.
Plasma sICAM-1 and sVCAM-1
higher in these patients.
Possibly mediated by increased NFκB, intracellular oxidation.
C
on
tr
ol
R
LP RL
P
+
B
ou Vit
nd E
To TG
ta L
lT
G
L
LD
L
Cell Surface Expression
of VCAM-1
Remnant-like lipoproteins activate
endothelial cells
* p <0.05 vs control
** p <0.005 vs control
Doi H, et al. Circulation 2000; 102:670
The Fenofibrate Intervention and Event
Lowering in Diabetes Trial
 N = 9.795 type II DM
 No clear indication for lipidlowering drugs
 Baseline LDL-C = 119 mg/dL; TG
= 154 mg/dL
 Fenofibrate 200 mg QD
 Subgroup TG >200 mg/dL: HR =
0.77 (p=0.01)
 Subgroup TG >200 mg/dL + low
HDL-C: HR = 0.73 (p=0.005)
Unadj.
Adjusted
for statin
Lancet , 2005. Diabetic Care, 2009
Potential Caveats of AURORA
• Exclude patients on statins (who might need
statins)
• Low event rates (selection bias against patients
who needed statins)
• Age 50-80 yrs
SPACE
(Secondary Prevention with Antioxidants of CVD in ESRD)
•
•
•
•
196 HD patients with CVD
Vitamin E (800 IU/d) vs. placebo
Median F/U: 1.4 yrs
1° endpoint: Composite of MI / unstable angina / ischemic
stroke / PVD
• Vitamin E arm:
– RR = 0.46 [0.27-0.78]; p=0.014 for 1° endpoint
• No difference in mortality or individual CVD
Boaz, Lancet, 2000
JUPITER
Ridker P, Lancet, 2009
N-Acetylcysteine (NAC) in Hemodialysis
•
•
•
•
134 HD patients (including DM + CVD)
NAC 600 mg BID vs. placebo
Median F/U 14.5 (1–24) months
1° endpoint: Composite of CVD death / MI / coronary
revascularization / ischemic stroke / PVD surgery
RESULTS:
• 28% of NAC vs. 47% of placebo reached 1° endpoint (RR =
0.60 [0.38-0.95]; p=0.03)
• No difference in total mortality
Tepel, Circ, 2003