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

Key Message 1 • Premature mortality and CVD are very common in CKD and ESRD 3

Current staging system for chronic kidney disease (CKD) Prevalence GFR Stage Description (1000s) (ml/min/1.73 m 2 ) Kidney damage with 1  90 5,600 normal or  GFR Kidney damage 2 60-89 5,700 with mild  GFR 3 Moderate  GFR 30-59 7,400 4 Severe  GFR 15-29 300 5 Kidney Failure < 15 or Dialysis 391 NKF-K/DOQI, 2002

CKD and ESRD are associated with exceedingly high mortality ESRD vs general population Stage 3-4 CKD vs general population Expected remaining life-years Mortality rate per 1000 pt-yr 60 250 Europe Stage 0 males Stage 0 females 50 US Whites Stage 3 males Stage 3 females 200 Stage 4 males Stage 4 females 40 General population 150 30 100 17.6 20 13.9 10.6 7.8 50 10 Dialysis 2.5 0 0 20 25 30 35 40 45 50 55 60 65 70 75 80 20-25 30-35 40-45 50-55 60-65 70-75 80-85 Age (years) Age groups Jager, from ERA-EDTA and USRDS data Alberta Kidney Disease Network, unpublished data

What do people with ESRD die of? Cardiovascular disease is a major cause ESRD, USA General population, USA Cardiovascular All other disease Cardiovascular All other 33.0% 31.0% disease 33.1% 42.0% Infection Self-harm Malignancy 3.6% 1.4% Malignancy Alzheimers 23.2% 4% Lung disease 3.1% 5.3% Withdrawal Infection 9% 12% USRDS, 2010 ADR National Vital Statistics Report, CDC 2010

…but “cardiovascular disease” is different for ESRD patients than the general pop’n CVD in ESRD CVD in general population Other cardiac 5% CVA AMI 10% 12% CVA CHF 25% 12% AMI 51% Other cardiac Arrhythmias/cardiac arrest 17% 61% CHF 7% USRDS, 2010 ADR Lloyd-Jones, Circulation 2009

Key Message 2 • LDL-C does not predict CV risk in patients with ESRD or advanced CKD 8

Prevalence of dyslipidemia in stages 1-4 CKD is a moving target 100 General population 90 CKD without protienuria 80 CKD with protienuria 70 60 50 40 30 20 10 0 LDL-C HDL-C Triglyc. Lp (a) >3.4 mmol/l <1.0 mmol/l >2.3 mmol/l >74 nmol/l • Prevalence varies: • As GFR decreases: • DM • lower LDL and TC • proteinuria • lower HDL • GFR • higher TG • higher non-HDL 9 Kasiske, AJKD 2001

Link between hyperlipidemia and CVD is complex in advanced CKD Men Screened for MRFIT (N=316 009) Prevalent HD Patients (N=11,167) 70 70 60 60 per 1000 over 10 y CAD mortality rate 50 50 40 40 30 30 20 20 10 10 0 0 3.6 4.6 5.7 6.7 7.8 8.8 3.1 - 3.6 - 4.1 - 4.7 - 5.2 - 5.7 - 3.6 3.9 4.4 4.9 5.4 6.5 Serum cholesterol (mmol/l) Serum cholesterol (mmol/l) Neaton, Arch Intern Med 1992; Iseki et al, Kidney Int 2002

Link between AMI and LDL is attenuated at lower eGFR N=868,450 GFR >90 GFR 60-89.9 HR 1.44 per mmol/l HR 1.22 per mmol/L GFR 15-29.9 GFR 30-59.9 HR 1.04 per mmol/L HR 1.20 per mmol/L

Key Message 3 • Relative benefit of statins for CV events appears similar in people with stage 1-3 CKD to those without CKD 12

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

Key Message 4 • No RCT demonstrates efficacy of statin (alone or in combination) for dialysis patients 14

Stud tudy d y design esign • Type 2 diabetes on dialysis for <24 mo • 18-80 years of age mean LDL-C reduction at 1y: 1.2 mmol/l • 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

Primar Primary y compo composit site e end po end point int RR 0.92 (95 % CI: 0.77-1.10, P=0.37) 60 CV death, non-fatal MI, any CVA Cumulative incidence 50 40 30 Placebo 20 (%) Atorvastatin 10 N=1255 0 0 1 2 3 4 5 5.5 years Years from Randomization Median follow-up time of 4 years Wanner et al, NEJM 2005

AURORA: study design Screening Treatment 0 Month: – 14 days 3 6 12 6-monthly 2 Visit: 1 3 4 5 Final † 6 Rosuvastatin 10 mg daily (n~1391) Patients (n~2750) Inclusion criteria • ESRD, on HD for ≥3 mo • 50 – 80 years Randomization 1:1 Exclusion criteria • Statin within 6 months • KTx expected within 1y • CK or ALT >3xULN Matching placebo (n~1385) mean LDL-C reduction at 1y: 1.1 mmol/l Fellström B et al, Curr Control Trials Cardiovasc Med 2005

AURORA: primary endpoint CV death, non-fatal MI, or stroke 40 Placebo 35 30 Rosuvastatin Cumulative 25 incidence of 20 primary endpoint (%) 15 HR=0.96 (95% CI 0.84 – 1.11), p=0.59 10 5 0 N=2774 0 1 2 3 4 5 Years from randomization No. at risk: Rosuvastatin 1390 1152 962 826 551 148 Placebo 1384 1163 952 809 534 153 Fellström B et al, NEJM 2009

SHARP: study design Screening Treatment 0 Month: 0 12 2 Final † Men: SCr ≥150 µmol/L Women: SCr ≥130 µmol/L) Eze 10/ Simva 20 (n=4193) or ESRD (HD or PD) Age ≥40 years Simva 20 (n=1054) No history of MI/CABG/PTCA Placebo (n=4191) Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated mean LDL-C reduction at 2.5y - non-ESRD 1.0 mmol/l - ESRD 0.6 mmol/l Baigent et al, Lancet 2011

Eze/simva significantly reduced risk of major atherosclerotic events 25 Proportion suffering event (%) coronary death, any MI, non-hemorrhagic stroke, coronary revasc. 20 Placebo RR 0.83 (0.74 – 0.94) 15 p=0.0022 Eze/simva 10 5 N=9270 0 0 1 2 3 4 5 Years of follow-up Baigent et al, Lancet 2011

SHARP: Major Atherosclerotic Events Event Eze/simv Placebo Risk ratio & 95% CI (n=4650) (n=4620) 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 Placebo better better Baigent et al, Lancet 2011

Results similar when other CV events included Event Eze/simv Placebo Risk ratio & 95% CI (n=4650) (n=4620) 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) 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) 0.6 0.8 1.0 1.2 1.4 Eze/simv Placebo better better Baigent et al, Lancet 2011

SHARP: Major Atherosclerotic Events by renal status at randomization Eze/simv Placebo Risk ratio & 95% CI (n=4650) (n=4620) 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) No significant heterogeneity between 0.6 0.8 1.0 1.2 1.4 non-dialysis and dialysis patients (p=0.25) Eze/simv Placebo better better Baigent et al, Lancet 2011

ACM 0.009 0.009 0.89 (0.82, 0.97) CV 0.08 0.08 death 0.86 (0.78, 0.95) less MACE 0.0001 0.0001 benefit in 0.77 (0.70, 0.84) ESRD MI 0.03 0.03 0.76 (0.68, 0.86) Stroke 0.07 0.07 0.86 (0.62, 1.20) Palmer, Ann Intern Med in press

ACM 0.009 CV 0.08 death Statins improve outcomes in stage 1-4 CKD MACE benefits are smaller/questionable for dialysis patients 0.0001 MI 0.03 Stroke 0.07 Palmer, Ann Intern Med in press

Is CKD 1-4 a CHD risk equivalent? status quo: diabetes is a risk equivalent and thus trumps CKD 25 25 20 20 15 15 AMI per MI 1000 pt-y Diabetes 10 GR<60 10 GFR<45 GFR<45 + Upr 5 5 None 0 0 MI Diabetes GFR<60 None N=1,268,029 ESRD excluded No MI No MI & no diabetes

What if CKD 1-4 trumped diabetes when assessing CHD risk equivalency? 25 20 15 10 5 0 MI GR<60 GFR<45 GFR<45 + Upr Diabetes None N=1,268,029 No MI No MI & no CKD ESRD excluded

High case fatality rate High event rate ✔ ✔ = risk equivalency status Proven treatment efficacy ✔ for CKD stage 1-4? i.e initiate statin for all? or all >40 y.o? Grundy, Diabetes Care 2006

How should statins be adjusted after Rx, in CKD 1-4 patients? • Treat-to- • no direct evidence • labor intensive target: • more costly • pop’n at high risk for toxicity • lower LDL ≠ better outcomes vs • Fire-and- • simple forget: • 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”