Lipid lowering treatment in CKD Marcello Tonelli MD SM FRCPC - - PowerPoint PPT Presentation

Lipid lowering treatment in CKD

Marcello Tonelli MD SM FRCPC

Alberta Kidney Disease Network University of Alberta

Disclosure: advisory boards for Merck Associated honoraria were donated to charity

Outl Outline ine

• CKD and ESRD are high risk populations
• Link between LDL-C and outcomes in CKD
• Evidence for efficacy of statins (alone/combination):
• in CKD
• in ESRD (dialysis)
• not kidney transplant recipients
• Implications for practice

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Key Message 1

• Premature mortality and CVD are very

common in CKD and ESRD

Current staging system for chronic kidney disease (CKD)

Prevalence (1000s) 391 < 15 or Dialysis Kidney Failure 5 300 15-29 Severe  GFR 4 7,400 30-59 Moderate  GFR 3 5,700 60-89 Kidney damage with mild  GFR 2 5,600  90

Kidney damage with normal or  GFR

1 GFR

(ml/min/1.73 m2)

Description Stage

NKF-K/DOQI, 2002

CKD and ESRD are associated with exceedingly high mortality

ESRD vs general population Stage 3-4 CKD vs general population

Jager, from ERA-EDTA and USRDS data Alberta Kidney Disease Network, unpublished data

50 60 40 30 20 10 20 25 30 35 40 45 50 55 60 65 70 75 80

General population Dialysis

7.8 10.6 13.9 17.6 2.5

Expected remaining life-years Age (years)

Europe US Whites

250 80-85 200 150 100 50 70-75 60-65 50-55 40-45 30-35 20-25 Age groups

Stage 0 males Stage 3 males Stage 4 males Stage 0 females Stage 3 females Stage 4 females

Mortality rate per 1000 pt-yr

What do people with ESRD die of?

Cardiovascular disease is a major cause

USRDS, 2010 ADR National Vital Statistics Report, CDC 2010

Cardiovascular disease 42.0% Infection 3.6% Withdrawal 9% All other 33.0% Malignancy 4% Cardiovascular disease 31.0% All other 33.1% Malignancy 23.2% Lung disease 5.3%

Self-harm 1.4% Alzheimers

3.1%

Infection 12%

ESRD, USA General population, USA

…but “cardiovascular disease” is different for ESRD patients than the general pop’n

CVD in ESRD CVD in general population

USRDS, 2010 ADR Lloyd-Jones, Circulation 2009

AMI 12% CHF 7% Arrhythmias/cardiac arrest 61% Other cardiac 5% CVA 10% Other cardiac 17% CVA 25% AMI 51% CHF 12%

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Key Message 2

• LDL-C does not predict CV risk in patients

with ESRD or advanced CKD

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Prevalence of dyslipidemia in stages 1-4 CKD is a moving target

• Prevalence varies:
• DM
• proteinuria
• GFR

Kasiske, AJKD 2001

• As GFR decreases:
• lower LDL and TC
• lower HDL
• higher TG
• higher non-HDL

10 20 30 40 50 60 70 80 90 100 General population CKD without protienuria CKD with protienuria

LDL-C

>3.4 mmol/l

HDL-C

<1.0 mmol/l

Triglyc.

>2.3 mmol/l

Lp (a)

>74 nmol/l

Link between hyperlipidemia and CVD is complex in advanced CKD

Neaton, Arch Intern Med 1992; Iseki et al, Kidney Int 2002

Men Screened for MRFIT (N=316 009) Serum cholesterol (mmol/l) CAD mortality rate per 1000 over 10 y 3.6 4.6 5.7 6.7 7.8 70 60 50 40 30 20 10 8.8 Prevalent HD Patients (N=11,167) 10 20 30 40 50 60 70

3.1 - 3.6 3.6 - 3.9 4.1 - 4.4 4.7 - 4.9 5.2 - 5.4 5.7 - 6.5

Serum cholesterol (mmol/l)

Link between AMI and LDL is attenuated at lower eGFR

GFR >90

HR 1.44 per mmol/l

GFR 60-89.9

HR 1.22 per mmol/L

GFR 15-29.9

HR 1.04 per mmol/L

GFR 30-59.9

HR 1.20 per mmol/L

N=868,450

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Key Message 3

• Relative benefit of statins for CV events

appears similar in people with stage 1-3 CKD to those without CKD

Summary of literature: benefits of statins in CKD 1-4

• Consistent RRR of 20-25% for CV events
• Consistent RRR of 15-20% for mortality
• ARR greater in CKD populations

N=36,033

Palmer, Ann Intern Med in press

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Key Message 4

• No RCT demonstrates efficacy of statin

(alone or in combination) for dialysis patients

Stud tudy d y design esign

• Type 2 diabetes on dialysis for <24 mo
• 18-80 years of age
• LDL-C 2.1 - 4.9 mmol/L
• No CV events in 3 mo prior to screening
• Could be on lipid lowering Rx prior to randomization

Wanner C et al, Kidney Blood Press Res 2004

mean LDL-C reduction at 1y: 1.2 mmol/l

Primar Primary y compo composit site e end po end point int

RR 0.92 (95 % CI: 0.77-1.10, P=0.37)

Median follow-up time of 4 years

Cumulative incidence (%) 10 20 30 40 50 60 1 2 3 4 5 5.5 years Placebo Atorvastatin

Years from Randomization CV death, non-fatal MI, any CVA

N=1255

Wanner et al, NEJM 2005

AURORA: study design

Matching placebo (n~1385) Screening 6-monthly 6 Final† Patients (n~2750) Inclusion criteria

• ESRD, on HD for ≥3 mo
• 50–80 years

Exclusion criteria

• Statin within 6 months
• KTx expected within 1y
• CK or ALT >3xULN

–14 days 1 2 6 4 Month: Visit: Rosuvastatin 10 mg daily (n~1391) 3 3 12 5 Treatment

Fellström B et al, Curr Control Trials Cardiovasc Med 2005

Randomization 1:1

mean LDL-C reduction at 1y: 1.1 mmol/l

Placebo

AURORA: primary endpoint

CV death, non-fatal MI, or stroke

• No. at risk:

Rosuvastatin 1390 1152 962 826 551 148 Placebo 1384 1163 952 809 534 153 Cumulative incidence of primary endpoint (%) Years from randomization

Rosuvastatin HR=0.96 (95% CI 0.84–1.11), p=0.59

5 10 15 20 25 30 35 40 1 2 3 4 5

Fellström B et al, NEJM 2009

N=2774

SHARP: study design

Placebo (n=4191) Screening Final†

Men: SCr ≥150 µmol/L Women: SCr ≥130 µmol/L)

• r ESRD (HD or PD)

Age ≥40 years No history of MI/CABG/PTCA Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated

2 Month: Eze 10/ Simva 20 (n=4193) 12 Treatment Simva 20 (n=1054)

mean LDL-C reduction at 2.5y

• non-ESRD 1.0 mmol/l
• ESRD 0.6 mmol/l

Baigent et al, Lancet 2011

1 2 3 4 5

Years of follow-up

5 10 15 20 25

Proportion suffering event (%)

RR 0.83 (0.74 – 0.94) p=0.0022 Placebo Eze/simva

Eze/simva significantly reduced risk of major atherosclerotic events

coronary death, any MI, non-hemorrhagic stroke, coronary revasc. N=9270

Baigent et al, Lancet 2011

SHARP: Major Atherosclerotic Events

Risk ratio & 95% CI Event Placebo Eze/simv (n=4620) (n=4650)

Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) 0.6 0.8 1.0 1.2 1.4

Eze/simv better Placebo better

Baigent et al, Lancet 2011

Results similar when other CV events included

Risk ratio & 95% CI Event Placebo Eze/simv (n=4620) (n=4650)

Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) 0.6 0.8 1.0 1.2 1.4

Eze/simv better Placebo better

Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhagic stroke 45 (1.0%) 37 (0.8%) Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=0.57) Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=0.0012)

Baigent et al, Lancet 2011

Risk ratio & 95% CI Placebo Eze/simv Eze/simv better Placebo better (n=4620) (n=4650)

Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246 (16.5%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) 0.6 0.8 1.0 1.2 1.4

SHARP: Major Atherosclerotic Events by renal status at randomization

No significant heterogeneity between non-dialysis and dialysis patients (p=0.25)

Baigent et al, Lancet 2011

Palmer, Ann Intern Med in press

0.009 0.03 0.07 0.08 0.0001

ACM CV death MACE MI Stroke less benefit in ESRD

0.89 (0.82, 0.97) 0.86 (0.78, 0.95) 0.77 (0.70, 0.84) 0.76 (0.68, 0.86) 0.86 (0.62, 1.20)

0.009 0.03 0.07 0.08 0.0001

Palmer, Ann Intern Med in press

0.009 0.03 0.07 0.08 0.0001

ACM CV death MACE MI Stroke Statins improve outcomes in stage 1-4 CKD benefits are smaller/questionable for dialysis patients

Is CKD 1-4 a CHD risk equivalent?

5 10 15 20 25

MI Diabetes GFR<60 None

5 10 15 20 25 MI Diabetes GR<60 GFR<45 GFR<45 + Upr None

status quo: diabetes is a risk equivalent and thus trumps CKD

N=1,268,029

ESRD excluded No MI No MI & no diabetes

AMI per 1000 pt-y

What if CKD 1-4 trumped diabetes when assessing CHD risk equivalency?

5 10 15 20 25 MI GR<60 GFR<45 GFR<45 + Upr Diabetes None

No MI & no CKD No MI N=1,268,029

ESRD excluded

Grundy, Diabetes Care 2006

High event rate High case fatality rate Proven treatment efficacy

✔ ✔ ✔

= risk equivalency status for CKD stage 1-4? i.e initiate statin for all?

• r all >40 y.o?

How should statins be adjusted after Rx, in CKD 1-4 patients?

• Treat-to-

target: vs

• Fire-and-

forget:

• no direct evidence
• labor intensive
• more costly
• pop’n at high risk for toxicity
• lower LDL ≠ better outcomes
• simple
• evidence-based
• focus on treating pts at risk

Summary and opinion

• Statins will not solve CVD in dialysis patients
• benefit is uncertain
• new Rx may be worthwhile in selected pts
• no evidence to stop statins at ESRD onset
• For both ESRD and CKD:
• importance of “appropriate adherence”

Summary and opinion

• Initiation: consider CKD as risk equivalent or as

heavily weighted factor in global risk assessment

• Maintenance: “fire-and-forget”
• prescribe an adequate starting dose to all at risk
• ?initial Rx based on regimens safely used in RCTs
• prava 40 / simva 40 / atorva 20 / simva 20 + eze 10
• These findings emphasize the need for early

identification and treatment of CKD pts at risk

Acknowledgements

• Christoph Wanner
• Bengt Fellstrom
• SHARP investigators
• Province of Alberta A-ARP
• Alberta Heritage Foundation for Medical Research
• Canada Research Chairs Program