Disclosure statement

Chronic Kidney Disease,

Cardiovascular Disease, I receive funding from Kidney Foundation of Canada,
Dyslipidemia and its CIHR, NIH and AKDTN in my capacity as researcher,
researcher,
reviewer or advisor.
advisor.
Management
I receive remuneration as a speaker or advisor,
advisor, totally or
Current state of the art partially,
partially, from the following pharmaceutical industries:

A Levin MD FRCPC FACP Amgen, Janssen-

Janssen-Ortho inc.,
inc., Genzyme,
Genzyme, Shire,
Shire, Abbott,
Professor of Medicine UBC Merck-
Merck-Frosst.
Frosst.
Nephrology

Learning Objectives Overview

ƒ The audience will understand ƒ Cardiovascular disease in CKD

• the physiology of CVD in CKD populations • Clinical observations
• Biological mechanisms
• the rationale for the SHARP study and the
findings of previous lipid lowering studies in
CKD populations ƒ Dyslipidemias in CKD
• the results of the SHARP study, strengths of
study design and issues related to results ƒ Clinical trials in different populations

ƒ Evidence base for therapy

Mortality increases exponentially Epidemiology of cardiovascular disease

as GFR declines in haemodialysis patients
Age-standardized rate of death from

15 14.14 100
any cause (per 100 person-yr)

14 1 million KP pts
13 11.36
12
Annual mortality (%)

11 10
10
9
8 1
7
6 4.76
5 0.1
4 Dialysis Male
3 Dialysis Female
2 0.76 1.08
1 0.01 Healthy Male
0
≥ 60 45-59 30-44 15-29 < 15 Healthy Female

Estimated GFR (ml/min/1.73m2) 25-34 35-44 45-54 55-64 65-74 75-84 >85
No. of events 25,803 11,669 7802 4408 1842 Age (years)
Go et al. NEJM 2004; 351:1296-305 Foley et al. AJKD 1998; 32:S112-9
Causes of death in dialysis patients Causes of death in dialysis patients
Other
Other Cancer 3.5%
Cancer 3.5%
15.6%
15.6% Infection Unknown
Infection Unknown 12.6%
12.6% 19.6%
19.6%
Stroke 5.5%
10.2% Stroke 5.5%
16.1% 10.2%
16.9% Acute MI 16.1%
Other cardiac 16.9% Acute MI
Other cardiac
Cardiac arrest
Cardiac arrest
USRDS 1996 Annual Data Report USRDS 1996 Annual Data Report

CVD in general populations: CVD in CKD populations

Risk factor reduction has positive impact ƒ Risk factor reduction has questionable impact
ƒ Risk factors • HTN
• HTN • DM
• DM • Dyslipidemia: under study
• Dyslipidemia • Smoking cessation: probable
• Smoking cessation ƒ Treatment strategies may be of benefit
ƒ Treatment strategies are of proven benefit • Blood pressure lowering
• Blood pressure lowering ►ACEi, ARB
► ACEi, ARB ►CCB
► Beta blockers ►Beta blockers: not tested specifically
► Calcium channel blockers • Statin therapy: questionable
• Glycemic control • ASA, antiplatelet agents:
• Statin therapy ► complications of use; not tested
• ASA, antiplatelet agents

Traditional risk factors and scoring CV risk in CKD higher

systems under-predict events in than general population
those with CKD Men Women
CKD Framingham CKD Framingham
(n=357) (n=2439) (n=517) (n=2812)
Framingham probability (%)
5-yr 6.0 ± 4.6 3.5 ± 3.6 1.9 ± 2.2 0.9 ± 1.6
10-yr 13.9 ± 9.8 8.2 ± 7.9 4.8 ± 5.4 2.5 ± 4.0

Outcomes (%)
Cardiac events
5-yr 9.8 3.7 5.1 1.4
10-yr 20.7 8.0 9.7 2.8
Mortality events
5-yr 14.8 3.5 9.4 2.3
10-yr 35.3 9.0 20.8 5.8

Gender, age, BP, cholesterol, diabetes, smoking

Weiner D et al. JACC 2007; 50(3): 217-24 Adapted from Weiner D et al. JACC 2007; 50(3): 217-24
 Framingham 10-yr predicted and Framingham 10-yr predicted and
observed cardiac event rates in CKD cohorts observed mortality rates in CKD cohorts
22 40
20
35
18
30
Cardiac events (%)

16

Mortality rate (%)

14 25
12
20
10
8 15
6 10
4
5
2
0 0
Framingham- CKD cohorts Framingham- CKD cohorts Framingham- CKD cohorts Framingham- CKD cohorts
predicted observed predicted observed predicted observed predicted observed
Men Women Men Women
Adapted from Weiner D et al. JACC 2007; 50(3): 217-24 Adapted from Weiner D et al. JACC 2007; 50(3): 217-24

Traditional and non-traditional

Structural and functional changes
risk factors in CVD
in cardiovascular system in CKD
Large vessels - Conduit
ƒ Atherosclerosis
ƒ Arteriosclerosis Cardiomyopathy
• Calcification (risk)
LV wall thickness
• Stiffness (risk)
Cavity volume
Small vessels – Resistance
Myocyte number
ƒ Arteriolar wall thickening
ƒ SMC hypertrophy Fibrosis
ƒ Endothelial dysfunction

Adapted from and with permission D. Wheeler Stenvinkel P. Clin J Am Soc Nephrol 3: 505-521, 2008. doi: 10.2215/CJN.03670807

Common factors associated with

Focus on dyslipidemia
adverse outcomes in CVD and CKD
ƒ Traditional ƒ “Non-traditional”
• Hypertension • Anemia
ƒ Patterns of dyslipidemia in CKD
• Diabetes • iPTH excess
• Dyslipidemia • Calcium phosphate ƒ Evidence from RCTs of statins in CKD
• Family history abnormalities
• Smoking • Vitamin D deficiency
• Obesity • Kidney function
• Albuminuria/
Proteinuria
Total cholesterol and CV mortality among Total cholesterol and all-cause mortality
350,000 men: MRFIT prospective study among 12,000 haemodialysis patients

2.0 5
Relative risk of CHD death

Relative risk of death

3
1.0
2

0.5 1

0
<100 100-150 151-200 201-250 251-300 301-350 >350
4.0 5.0 6.0 7.0 (2.56 mmol/L) (8.96 mmol/L)
Total cholesterol (mg/dL)
Usual total cholesterol (mmol/L)

Martin et al. Lancet 1986; 2(8513):933-36 Lowrie & Lew AJKD 1990; 15:458-82

Serum cholesterol and relative hazard of death CRIB study: Total cholesterol and 4-year
mortality among 370 pre-dialysis patients
1.15
20
HD n=5,522 CV death
1.10 Non-CV death
PD n=2,291
15
Mortality (%)

1.05
Hazard

10
1.00

0.95 5

0.90 0
110 150 180 220 260 300 340 <3.2 3.2-4.0 4.0-4.5 4.5-6.0 >6.0
(2.82 mmol/L) (8.70 mmol/L)
Total cholesterol (mg/dL)
Quintile of baseline cholesterol (mmol/L)

Adapted from UK Renal Registry Landray et al. AJKD 2001; 38:537-46

Vascular disease in CKD patients Lipid abnormalities in CKD patients

ƒ Epidemiological associations with cholesterol Group Cholesterol Triglycerides HDL

• No direct relationship between cholesterol and
cardiovascular outcomes Stage 3-5 CKD
• High cholesterol does not equal high risk
Haemodialysis
BUT CAPD

Transplant recipients
• Little data on LDL-cholesterol or other lipid fractions
• Little data on cardiovascular outcomes Nephrotic syndrome
• Little data in CKD populations not receiving dialysis

Adapted from D Wheeler 2010

 Prevalence of dyslipidemia: Lipid-lowering agents in CKD:
Haemodialysis vs. peritoneal dialysis Safety issues
Lipid measurement HD PD Agent GFR 60-90 GFR 15-59 GFR <15 Notes
n=16,507 n=1,708
Statin OK OK ↓ 50% Start at low doses

Cholesterol ≥ 6.2 mmol/L 9.5% 25.7%* Fibrate ↓ 50% ↓ 75% Avoid Except Gemfibrozil

Bile acid OK OK OK
Triglycerides ≥ 2.2 mmol/L 28.9% 41.2%* sequestrant

Nicotinic acid OK OK ↓ 50% 35% renal excretion

HDL-C ≤ 0.9 mmol/L 44.3% 38.3% Ezetimibe OK OK OK

* P<0.0001 vs. haemodialysis

Fox CS, Clin Nephrol 2004; 61:229-307 KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations; 2006

Proportional effects on major vascular events

4S Study: The first major statin trial per mmol/L LDL cholesterol reduction
Coronary Death or Non-fatal MI Events (%) RR & CI Rate Reduction
Endpoint Treatment Control (95% CI)
Non-fatal MI 2,001 (4.4) 2,769 (6.2) 26% (21%, 30%)
100
% of patients without events

CHD death 1,548 (3.4) 1,960 (4.4) 19% (13%, 25%)

Simvastatin Any major coronary event 3,337 (7.4) 4,420 (9.8) 23% (20%, 26%)

90 (n=2,221) CABG 713 (3.3) 1,006 (4.7) 25% (18%, 31%)

PTCA 510 (2.4) 658 (3.1) 21% (11%, 31%)
Unknown 1,397 (3.1) 1,770 (3.9) 24% (16%, 31%)
80 Placebo 34% Any coronary revasc. 2,620 (5.8) 3,434 (7.6) 24% (20%, 27%)
(n=2,223) risk reduction
P <0.00001 Haemorrhagic stroke 105 (0.2) 99 (0.2) -5% (-41%, 22%)
70 Presumed ischaemic stroke 1,235 (2.8) 1,518 (3.4) 19% (11%, 26%)

0 Any stroke 1,340 (3.0) 1,617 (3.7) 17% (12%, 22%)

0 1 2 3 4 5 Any major vascular event 6,354 (14.1) 7,994 (17.8) 21% (19%, 23%)
Years after randomization 0.5 1.0 1.5
90,056 participants in 14 randomised trials

4S Study Group. Lancet 1994; 344:1383-89 Baigent et al. (Cholesterol Trialists Collaboration). Lancet 2005; 366:1276-78

Treatment of dyslipidemia Post-hoc subgroup analysis of data

in CKD patients from Pravastatin Pooling Project (PPP)
ƒ 3 double-blind RCTs
The evidence base:
(pravastatin 40 mg vs. placebo)
1. Post-hoc analysis of trials which • CARE – secondary prevention
included CKD patients • LIPID – secondary prevention
2. Kidney transplant patients • WOSCOPS – primary prevention

3. Dialysis patients ƒ CKD classified based on K/DOQI criteria:

4. CKD patients not on dialysis • GFR > 60 ml/min/1.73m2 (n=15,209)
• GFR 30-59.9 ml/min/1.73m2 (n=4,491)
Tonelli et al. Circulation 2004; 110:1557-63
 Pravastatin reduced CVD events and
total mortality in stage 3 CKD
(eGFR 30-59.9 ml/min)
Odds ratio (95% CI)
Primary outcome
All patients
Secondary prevention Effect of statins on cardiovascular events in stage 1-5 CKD
Primary prevention

Total mortality
All patients
Secondary prevention
Primary prevention
Favours statin Favours placebo
0.0 0.4 0.6 0.8 1.0 1.2 1.4
Favours statin
Tonelli et al. Circulation 2004; 110:1557-63 Strippoli G et al. BMJ 2008; 336:645-51

Effect of statins on all cause mortality in stage 1-5 CKD Effect of statins on all cause mortality in stage 1-5 CKD

Effect of statins on CV mortality in stage 1-5 CKD Vast of

Effect majority of CV
statins on patients had
mortality in eGFR > 30
stage 1-5 ml/min
CKD
and overt vascular disease

Favours statin Favours placebo Favours statin Favours placebo

Strippoli G et al. BMJ 2008; 336:645-51 Strippoli G et al. BMJ 2008; 336:645-51

Large-scale statin studies in

ALERT: LDL-cholesterol
enrolling CKD patients
ƒ ALERT 4.5
Mean LDL-cholesterol (mmol/L)

• 2100 renal transplant patients Placebo

• Fluvastatin vs. placebo; mean FU 5.1 years 4.0
• Results published Lancet June 2003
ƒ 4D Fluvastatin
3.5 treatment
• 1300 diabetic haemodialysis patients started in
• Atorvastatin vs. placebo; ongoing placebo
• Results published NEJM June 2005 3.0 group
ƒ AURORA
• 2700 haemodialysis patients 2.5 Fluvastatin
• Rosuvastatin vs. placebo
• Results published in NEJM April 2009 . 2.0
ƒ SHARP 0 1 2 3 4 5 6 7 8
• 9000 CKD patients (pre-dialysis or dialysis)
• Ezetimibe/simvastatin vs. placebo Years since randomization
• Results presented at ASN Nov 2010
Holdaas H et al. Lancet 2003; 361:2024-31
 ALERT: Principal results - efficacy ALERT: Cumulative incidence of
Fluvastatin Placebo Risk ratio major adverse cardiac events
(n=1050) (n=1052) (95% CI) 20
ITT analysis
ƒ Primary endpoint 112 134 0.83

Patients with event (%)

(cardiac death, (0.64-1.06) 15 P= 0.139
non-fatal MI or N=2,102 Placebo
17%
CABG/PCI) 10

ƒ Cardiac death or 70 104 0.65 Fluvastatin

5
non-fatal MI (0.48-0.88)

ƒ Renal endpoint 182 165 1.10 0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0
(graft loss or 2x (0.89-1.36)
serum creatinine) Years since randomization

Mean LDL-cholesterol difference 1.0 mmol/L Holdaas H et al. Lancet 2003; 361:2024-31 Holdaas H et al. Lancet 2003; 361:2024-31

ALERT: Cumulative incidence of ALERT+extension: Occurrence of MACE

cardiac death or non-fatal definite MI 20
15
Cumulative incidence (%)
ITT analysis Placebo
15
Patients with event (%)

P= 0.005
10 N=2,102 Placebo P=0.036
35% 10
Fluvastatin
End of
5 5 Core Study
Fluvastatin

0
0 0 1 2 3 4 5 6 7
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0
No. at risk
Years since randomization
Years since randomization Fluvastatin 1050 1009 974 930 885 836 755 691
Placebo 1052 1018 972 929 878 846 743 679
Holdaas H et al. Lancet 2003; 361:2024-31 Holdaas H et al. Am J Transplant. 2005; 5:2929

4D and AURORA: 4D: Eligibility

RCTs of statins in dialysis patients
examining CV events or death ƒ Type 2 diabetes on dialysis for no more than
24 months
ƒ Males or females
ƒ 18-80 years of age
ƒ LDL-C: > 80 mg/dL (2.1 mmol/L) and
≤ 190 mg/dL (4.9 mmol/L)
N Engl J Med. 2005 Jul 21;353:238-48.
ƒ Triglycerides: ≤ 1000 mg/dL (11.8 mmol/L)
ƒ No cardiovascular events in 3 months
N Engl J Med. 2009 Apr 2;360(14):1395-407. prior to screening

Wanner C et al. N Engl J Med 2005; 353:238-48

 4D: Effect on LDL-C 4D: Primary composite endpoint
140 60
Relative Risk Reduction 8%
120

Cumulative incidence (%)

50 (95% CI: 0.77-1.10, P=0.37) Placebo
Placebo
100 40
LDL-C (mg/dL)

Atorvastatin
80 Mean 40 mg/dL (1 mmol/L) 30

60 20
Atorvastatin
Median follow-up
40 10 time of 4 years

20 0
0 1 2 3 4 5 5.5
0 Years from randomization
No. at risk
0 1 2 3 4 5 6 Placebo 636 532 383 252 136 51 29
Time of visit (years) Atorvastatin 619 515 378 252 136 58 19

Wanner C et al. N Engl J Med 2005; 353:238-48 Wanner C et al. N Engl J Med 2005; 353:238-48

4D: Primary endpoint Risk reductions in 4D were predictable

Endpoint Placebo Atorvastatin RR
(n=636) (n=619) (95% CI) Outcome Predicted† RR Observed RR (95% CI)

Primary endpoint 0.83 0.92 (0.77-1.10)

Primary endpoint 243 226 0.92 (0.77-1.10)*
Cardiac events 0.84 0.82 (0.68-0.99)

Cardiac death 149 121 Stroke 0.75 1.33 (0.90-1.97)

Non-fatal MI 79 70 All-cause mortality 0.93 0.93 (0.79-1.08)

Fatal stroke 13 27
† Rate ratio predicted based on a difference of ~1.0 mmol/L at 1 year
Non-fatal stroke 32 33 after randomization in the 4D trial, as derived from the results of the
Cholesterol Treatment Trialists’ (CTT) meta-analysis.

* P=0.37
Wanner C et al. N Engl J Med 2005; 353:238-48 Baigent, Landray & Wheeler. Semin Dial 2007; 20:498-503

AURORA AURORA: Primary endpoint

Kaplan-Meier estimate of time-first major CV event
Rosuvastatin and cardiovascular events in
patients undergoing haemodialysis 40
Placebo
35
Cumulative incidence of

ƒ Study population: 2,776 patients on maintenance

primary endpoint (%)

30
haemodialysis 25
Rosuvastatin

ƒ Treatment: Rosuvastatin 10 mg/d vs. 20

placebo 15
HR=0.96
ƒ LDL-C difference: 1.05 mmol/L difference in LDL-C 10 p=0.59
5
ƒ Follow-up: 3.8 years (median)
0
ƒ Primary endpoint: Combined primary endpoint 0 1 2 3 4 5
was death from CV causes, No. at risk: Years from randomization
Rosuvastatin1,390 1,152 962 826 551 148
non-fatal MI, or non-fatal stroke Placebo 1,384 1,163 952 809 534 153
Fellström BC et al. N Engl J Med 2009; 360:1395-407 Fellström BC et al. N Engl J Med 2009; 360:1395-407
Why were 4D and AURORA negative? Vascular disease in CKD patients
Results of previous trials
1. Lack of power
ƒ Subgroup analyses suggest benefit among individuals
2. Excluded the highest-risk patients with mild CKD and established vascular disease
3. Non-precision of CV end points ƒ 2 trials in ESRD suggest that any benefit may be
somewhat less than is seen in populations without CKD
4. High drop-out rates
5. Statins don’t work in dialysis patients BUT

a. “Different” cardiovascular disease

ƒ Trials have been too small to exclude moderate benefits
b. “Statin resistance” ƒ No data in CKD populations not receiving dialysis

Adapted from Strippoli GF et al. NEJM 2009; 360:1455-57

Pilot Studies:UK HARP I and II SHARP: Rationale

ƒ Risk of vascular events is high among
ƒ 448 and 208 CKD pts in UK: patients with chronic kidney disease
• Non dialysis, dialysis and transplant pts ƒ Lack of clear association between
ƒ Study 1: Simva and ASA 2x 2 factorial x 1 yr cholesterol level and vascular disease risk
• Effective in LDL lowering (26% reduction) ƒ Pattern of vascular disease is atypical,
• Safe : no indications of toxicity with a large proportion being non-
ƒ Study 2: Simva and Eze vs Simva alone x 6 m atherosclerotic
• Safe and effective ƒ Previous trials of LDL-lowering therapy in
• Additional 21% lowering with Eze chronic kidney disease are inconclusive
• No toxicity
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10 and
Baigent C, et al: Am J Kidney Dis 2005; 45(3):473-84 www.SHARPInfo.org

Study of Heart and Renal Protection

Randomized trial to assess the effects of lowering SHARP: Eligibility
LDL-C among 9,438 patients with CKD ƒ History of chronic kidney disease
ƒ Study population: 9438 CKD patients, • not on dialysis: elevated creatinine on 2 occasions
(3056 dialysis, 6382 pre-dialysis)
► Men: ≥1.7 mg/dL (150 µmol/L)
ƒ Treatment: Simvastatin 20 mg + ► Women: ≥1.5 mg/dL (130 µmol/L)
ezetimibe 10 mg daily • on dialysis: haemodialysis or peritoneal dialysis
vs. placebo
ƒ Age ≥ 40 years
ƒ LDL-C difference: 0.85 mmol at 2.5 years
ƒ No history of myocardial infarction or coronary
ƒ Follow-up: 4 years revascularization
ƒ Primary endpoint: Major atherosclerotic events defined ƒ Uncertainty: LDL-lowering treatment not
as a combination of MI, coronary definitely indicated or contraindicated
death, & ischemic stroke or any
revascularization procedure
Am Heart J 2010;160-785-794.e10 www.SHARPInfo.org
 SHARP: Assessment of LDL-lowering
The results of the Study of Heart
and Renal Protection (SHARP)

Colin Baigent, Martin Landray

on behalf of the SHARP Investigators

Disclosure: SHARP was sponsored, designed, run,

and analysed by the University of Oxford. Funding was
received from Merck, the UK MRC, British Heart
Foundation, and Australian NHMRC.

www.SHARPInfo.org www.SHARPInfo.org

SHARP: Baseline characteristics Lipid values at randomization

Not on dialysis On dialysis All patients
Characteristic Mean (SD) or %
Age 62 (12) Number with baseline LDL-C 6,149 (96%) 2,895 (95%) 9,044 (96%)
analyzed
Men 63%
Total cholesterol (mg/dL) 194 ± 45 179 ± 45 189 ± 45
Systolic BP (mm Hg) 139 (22) LDL-C (mg/dL) 111 ± 33 100 ± 33 108 ± 34
Diastolic BP (mm Hg) 79 (13) (2.85 mmol/L) (2.57 mmol/L) (2.77 mol/L)
Body mass index 27 (6) HDL-C (mg/dL) 44 ± 13 42 ± 13 43 ± 13
Current smoker 13% Triglycerides (mg/dL) 206 ± 146 206 ± 164 206 ± 152
Apo B (mg/dL) 99 ± 25 92 ± 26 96 ± 26
Vascular disease 15% Apo A1 (mg/dL) 136 ± 29 129 ± 27 134 ± 29
Diabetes mellitus 23%
Apo B:apo A1 0.75 ± 0.23 0.74 ± 0.24 0.75 ± 0.24
Non-dialysis patients only (n=6247)
eGFR (ml/min/1.73m2) 27 (13) To convert milligrams per decilitre to millimoles per litre, multiply by 0.02586 for cholesterol
and by 0.01129 for triglycerides; to convert apolipoprotein A1 and B from milligrams per
Albuminuria 80% decilitre to grams per litre, divide by 100.
www.SHARPInfo.org Am Heart J 2010;160-785-794.e10

SHARP: Baseline paper and

data analysis plan SHARP: Main outcomes
ƒ Key outcome
ƒ Major atherosclerotic events (coronary death, MI,
non-haemorrhagic stroke, or any revascularization)
ƒ Subsidiary outcomes
Am Heart J 2010;160-785-794.e10
ƒ Major vascular events (cardiac death, MI, any
ƒ 1-year LDL-C reduction of 30 mg/dL (0.77 mmol/L) with stroke, or any revascularization)
simvastatin 20 mg alone and of 43 mg/dL (1.10 mmol/L) ƒ Components of major atherosclerotic events
with eze/simv 10/20mg
ƒ Main renal outcome
ƒ Confirmation of safety of ezetimibe when added to
ƒ End stage renal disease (dialysis or transplant)
simvastatin (1-year results)
ƒ Revised data analysis plan published as an appendix
before unblinding of main results
www.SHARPInfo.org
SHARP: Major Atherosclerotic Events SHARP: Major Atherosclerotic Events
Event Eze/simv Placebo Risk ratio & 95% CI
(n=4650) (n=4620)
25 
Major coronary event  213  (4.6%)  230  (5.0%) 
Proportion suffering event (%) 

Non‐hemorrhagic stroke  131  (2.8%)  174  (3.8%) 

20  Risk ratio 0.83 (0.74 – 0.94)  Any revascularization  284  (6.1%)  352  (7.6%) 
Logrank 2P=0.0022  Major atherosclerotic event  526  (11.3%)  619  (13.4%)  16.5% SE 5.4 
Placebo  reduction 
(p=0.0022) 
15 
Eze/simv Other cardiac death  162  (3.5%)  182  (3.9%) 
Hemorrhagic stroke  45  (1.0%)  37  (0.8%) 
10 
Other major vascular events  207  (4.5%)  218  (4.7%)  5.4% SE 9.4 
reduction 
(p=0.57) 
5  Major vascular event  701  (15.1%)  814  (17.6%)  15.3% SE 4.7 
reduction 
(p=0.0012) 

0  0.6  0.8  1.0  1.2  1.4 

0  1  2  3  4  5  Eze/simv Placebo 
Years of follow‐up  better  better 
www.SHARPInfo.org www.SHARPInfo.org

SHARP: Major Atherosclerotic Events

SHARP: Effects in subgroups by renal status at randomization

ƒ Among 8384 patients originally Eze/simv Placebo Risk ratio & 95% CI

randomized to eze/simv vs. placebo, major (n=4650) (n=4620)

vascular events risk ratio = 0.84 (95% CI Non‐dialysis (n=6247) 296  (9.5%)  373  (11.9%) 
Dialysis (n=3023) 230  (15.0%)  246  (16.5%) 
0.75 – 0.93; P=0.0010)
Major atherosclerotic event  526  (11.3%)  619  (13.4%)  16.5% SE 5.4 
reduction 
(p=0.0022) 
ƒ Similar reductions in major atherosclerotic No significant heterogeneity
0.6  0.8  1.0  1.2  1.4 
events in all subgroups studied (including between non-dialysis and dialysis
patients (p=0.25)
Eze/simv Placebo 
non-dialysis and dialysis patients) better  better 

www.SHARPInfo.org www.SHARPInfo.org

SHARP: Cause‐specific mortality  SHARP: Cancer incidence 
Event Eze/simv Placebo Risk ratio & 95% CI
(n=4650) (n=4620)
25 
Coronary  91  (2.0%)  90  (1.9%) 
Other cardiac  162  (3.5%)  182  (3.9%) 
Proportion suffering event (%) 

Subtotal: Any cardiac  253  (5.4%)  272  (5.9%)  7.4% SE 8.4 

reduction  20 
Stroke  68  (1.5%)  78  (1.7%)  (p=0.38) 
Risk ratio 0.99 (0.87 – 1.13) 
Other vascular  40  (0.9%)  38  (0.8%) 
Subtotal: Any vascular  361  (7.8%)  388  (8.4%)  7.3% SE 7.0  Logrank 2P=0.89
reduction  15 
(p=0.30) 
Cancer  150  (3.2%)  128  (2.8%) 
Renal  164  (3.5%)  173  (3.7%)  Eze/simv
Other non‐vascular 354 (7.6%)  311 (6.7%) 
10  Placebo 
Subtotal: Any non‐vascular  668  (14.4%)  612  (13.2%)  8.6% SE 5.8 
increase 
(p=0.14) 
Unknown cause  113  (2.4%)  115  (2.5%) 
1.9% SE 4.2  5 
Total: Any death  1142  (24.6%)  1115  (24.1%)  increase 
(p=0.65) 

0.6  0.8  1.0  1.2  1.4  0 

Eze/simv Placebo 0  1  2  3  4  5 
better  better 
www.SHARPInfo.org Years of follow‐up  www.SHARPInfo.org
 SHARP: Safety SHARP: Conclusions as presented
at ASN 2010
ƒ Treatment eze/simv reduced the risk of major
Eze/simv Placebo atherosclerotic events by 17%
(n=4650) (n=4620)
• Consistent with meta-analysis of previous statin trials
Myopathy
ƒ No increase in risk of myopathy, liver and biliary disorders,
CK >10 x but ≤40 x ULN 17 (0.4%) 16 (0.3%) cancer, or non-vascular mortality
CK >40 x ULN 4 (0.1%) 5 (0.1%) ƒ No substantial effect on kidney disease progression
Hepatitis 21 (0.5%) 18 (0.4%) ƒ Similar proportional reductions in all subgroups (including
Persistently elevated ALT/AST >3x ULN 30 (0.6%) 26 (0.6%) among dialysis and non-dialysis patients)
Complications of gallstones 85 (1.8%) 76 (1.6%) ƒ Only 2/3 compliance, for this result, and estimated full
Other hospitalization for gallstones 21 (0.5%) 30 (0.6%) compliance would reduce the risk of major atherosclerotic
Pancreatitis without gallstones 12 (0.3%) 17 (0.4%) events by one quarter, avoiding 30–40 events per 1000
treated for 5 years

www.SHARPInfo.org www.SHARPInfo.org

Lipid lowering in CKD patients

Why were 4D and AURORA negative? Summary of the current evidence
post SHARP
CKD Stage Atherosclerosis reduction
1. Lack of power
Stage 1 Yes*
2. Excluded the highest-risk patients Stage 2 Yes*
Stage 3 Yes*
3. Non-precision of CV end points
Stage 4 Yes
4. High drop-out rates
Stage 5 Yes
Dialysis Yes
Transplant Yes

Adapted from Stripolli GF et al. NEJM 2009; 360:1455-57 * Post-hoc analysis among patients with vascular disease

Caveats
ƒ CKD patients do have traditional atherosclerotic
disease, this appears to be amenable to
therapies effective in general populations.

ƒ CKD patients have complex vascular disease in

addition to conventional atherosclerotic disease
(stiffening, calcification etc), which is likely not
amenable to lipid lowering strategies.

ƒ To improve mortality, we will need to better

understand and address these additional
processes.