g lipid lowering in ckd
TRANSCRIPT
Lipid lowering therapy in CKD What is the evidence?
Conall O’ Seaghdha
Renal Meeting
Royal North Shore Hospital
29/08/07
Case for Discussion
• 72 male type II DM ESKD 2ary DN
• PMHx HTN Gout
• No symptoms CHD
• Meds ACE / NSA / BB / Diuretic
• Total Chol 5.0mmol/l LDL Chol 3.4 mmol/l
• ?Statin
Patients with known CHD, or other high-risk condition (e.g. diabetes
mellitus)
Cholesterol Treatment Trialists’ (CTT) Collaboration
• 90 000 trial participants
• 14 000 major vascular events
– 8 000 major coronary events
– 6 000 coronary revascularisations
– 3 000 strokes
• 5 000 cancers
• 8 000 deaths
Proportional effects on MAJOR VASCULAR EVENTS* by mean difference in LDL cholesterol
* MI, coronary death, stroke or coronary revascularisation
Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005
End pointTreatment-arm
events, %(n=45 054)
Control-arm events, % (n=45
002
Relative risk(95% CI)
Any major vascular event
14.1 17.8 0.79 (0.77-0.81)
Any major coronary event
7.4 9.8 0.77 (0.74-0.80)
•Nonfatal MI 4.4 6.2 0.74 (0.70-0.79)
•CHD death 3.4 4.4 0.81 (0.75-0.87)
Any coronary revascularization
5.8 7.6 0.76 (0.73-0.80)
•CABG 1.6 2.2 0.75 (0.69-0.82)
•PTCA 1.1 1.5 0.79 (0.69-0.90)
•Unspecified 3.1 3.9 0.76 (0.69-0.84)
Any stroke 3.0 3.7 0.83 (0.78-0.88)
Proportional effects on major vascular events per 1mmol/L LDL-cholesterol reduction
Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005
Cause of deathTreatment-arm
events, % (n=45 054)
Control-arm events, % (n=45 002)
Relative risk(95% CI)
All-cause 8.5 9.7 0.88 (0.84-0.91)
Coronary heart disease 3.4 4.4 0.81 (0.76-0.85)
Any non-coronary-heart-disease
1.2 1.3 0.93 (0.83-1.03)
Stroke 0.6 0.6 0.91 (0.74-1.11)
Other vascular 0.6 0.7 0.95 (0.78-1.16)
Any vascular 4.7 5.7 0.83 (0.79-0.87)
Any nonvascular 3.8 4.0 0.95 (0.90-1.01)
Cancer 2.4 2.4 1.01 (0.91-1.12)
Proportional effects on cause-specific mortality per 1mmol/L LDL-cholesterol reduction
Main results of the CTT meta-analysis
• Vascular benefits are proportional to the size in the reduction in LDL cholesterol
• Timing of benefits of lowering cholesterol– 11% reduction in first year– 25-30% reduction each successive year
• For each outcome, proportional benefits similar irrespective of age, gender, lipid profile, history of vascular disease, and other prognostic factors
• No excess risk of cancer or other non-vascular causes of death
Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005
Groups Treatment-arm events, %
Control-arm events, %
Rate Reduction(95% CI)
<3.5 mmol/l 1130 (6.8) 1443 (8.7) 24% (16%, 32%)
3.5-4.5 mmol/l 1374 (7.3) 1814 (9.6) 23% (17%, 29%)
>4.5 mmol/l
Overall
801 (9.3)
3337 (7.4)
1120 (12.9)
4420 (9.8)
22% (15%, 28%)
23% (20%, 26%)
Proportional effects on major coronary events per 1-mmol/L LDL-cholesterol reduction subdivided by
baseline LDL cholesterol
K/DOQI Stages of Chronic Kidney Disease
Stage GFR (ml/min/1.73m2) Comment
1* >90 Hypertension
Structural problem
2* 60-89 Hypertension
Structural problem
3 30-59 Complications
Progression/Referral
4 15-29 More Complications
Referral/Preparation
5 0-14 RRT/Conservative
Benefits of pravastatin on major coronary event or revascularisation in the CARE, LIPID and
WOSCOPS trials, by eGFR
eGFR
(ml/min/1.73m2)Relative risk
95% confidence interval
<60 0.79 0.71-0.88
60-89.9 0.81 0.74-0.88
>90 0.85 0.71-1.01
Pravastatin Pooling Project Tonelli et al. Circulation 2004;110;1557-1563
Among patients with known CHD, proportional benefits of statins appear
similar irrespective of eGFR
Summary: patients at high risk of atherosclerotic major vascular events
• Select for statin therapy on basis of risk of atherosclerotic major vascular events, not just CHD
• Aim for substantial reduction in LDL cholesterol rather than “treating to a target”
• For patients with CHD, extrapolation of evidence to those with mild CKD seems reasonable
K/DOQI Stages of Chronic Kidney Disease
Stage GFR (ml/min/1.73m2) Comment
1* >90Hypertension
Structural problem
2* 60-89Hypertension
Structural problem
3 30-59Complications
Progression/Referral
4 15-29More Complications
Referral/Preparation
5 0-14 RRT/Conservative
Cardiovascular Mortality in Dialysis Patients
Sarnak, M. J. et al. Circulation 2003;108:2154-2169
Reverse Epidemiology: Cholesterol
Lowrie EG Am J Kidney Dis 15:458-482, 1990
Traditional and Non-Traditional Risk Factors in Uremia
• Older age• Male sex
• Hypertension• Higher LDL Cholesterol• Lower HDL Cholesterol
• Diabetes• Smoking
• Physical inactivity• Menopause
• Family history of CVD• LVH
• Albuminuria• Homocysteine• Lipoprotein (a) and
apolipoprotein (a) isoforms• Lipoprotein remnants• Anaemia• Abnormal calcium / phosphate
metabolism• ECF volume overload• Electrolyte imbalance• Oxiditive stress• Inflammation (CRP)• Malnutrition• Thrombogenic factors• Sleep disturbances• Altered NO / Endothelin balance
Sarnak, M. J. et al. Circulation 2003;108:2154-2169
Causes of death in dialysis patients
Causes of Death in Dialysis Patients
Acute MI13%
Cardiac Arrest21%
Other Cardiac20%
Stroke7%
Infection16%
Cancer19%
Other4%
USRDS 1996 Annual Data Report
Causes of death in dialysis patients
Causes of Death in Dialysis Patients
Acute MI13%
Cardiac Arrest21%
Other Cardiac20%
Stroke7%
Infection16%
Cancer19%
Other4%
USRDS 1996 Annual Data Report
Causes of death in dialysis patients
Causes of Death in Dialysis Patients
Acute MI13%
Cardiac Arrest21%
Other Cardiac20%
Stroke7%
Infection16%
Cancer19%
Other4%
USRDS 1996 Annual Data Report
Left Ventricular Hypertrophy
• Concentric hypertrophy
• Eccentric hypertrophy
ECHO findings predict survival in haemodialysis patients
Parfrey P et al NDT 1996
Coronary Calcification in Dialysis Patients
Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis
Christoph Wanner, M.D., Vera Krane, M.D., Winfried Marz, M.D., Manfred Olschewski, M.Sc., Johannes F.E. Mann, M.D., Gunther Ruf, M.D., Eberhard Ritz, M.D. and the
German Diabetes and Dialysis Study Investigators
N Engl J MedVolume 353;3:238-248
July 21, 2005
Study Design
• Patients with Type 2 DM aged 18 to 80 years on haemodialysis for under 2 years
• 178 centres in Germany• Lipid-lowering meds discontinued at enrollment & 4-week placebo
run-in• Double-blind atorvastatin 20mg vs matching placebo• Data recorded at 4 weeks & 6-monthly intervals thereafter• Academic investigators• Data collected by 2 contract research organisations supported by
Pfizer• University-based, independent statistician• If LDL cholesterol fell <1.3 mmol/l, dose reduced to 10mg• Study drug could be replaced with statin if primary endpoint reached
Exclusion Criteria
• LDL Cholesterol <2.1 mmol/l or > 4.9mmol/l• Triglycerides > 11.3 mmol/l• LFT’s > 3 times ULN• Haematopoeitic or systemic disease unrelated to ESKD• Vascular intervention, CCF or MI in prior 3 months• Unsuccessful kidney transplantation• HTN resistant to therapy (>200/110 mmHg)
Endpoints
• Primary Endpoints– Composite death from cardiac causes, fatal stroke, nonfatal
MI or nonfatal stroke, whichever occurred first• Fatal MI, sudden death,death d/t CCF, CAD within 1 mo
intervention or all other deaths attributed to CAD• Sudden Death: unexpected death in a patient without
persistent hyperkalemia (> 7.5meq/l) pre-dialysis
• Secondary Endpoints– Death from all causes– All cardiac events combined– All cerebrovascular events combined
Study Protocol
Wanner, C. et al. N Engl J Med 2005;353:238-248
Baseline Characteristics of Patients
Wanner, C. et al. N Engl J Med 2005;353:238-248
Baseline Characteristics of Patients
Wanner, C. et al. N Engl J Med 2005;353:238-248
Median Level of Low-Density Lipoprotein (LDL) Cholesterol
Wanner, C. et al. N Engl J Med 2005;353:238-248
Estimated Cumulative Incidence of the Composite Primary End Point
Wanner, C. et al. N Engl J Med 2005;353:238-248
Rates of Primary and Secondary End Points
Wanner, C. et al. N Engl J Med 2005;353:238-248
Adverse Events
Wanner, C. et al. N Engl J Med 2005;353:238-248
Trialist’s Conclusions
• Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis
• In patients with Type 2 DM on haemodialysis with LDL Cholesterol levels 2.1 to 4.9 mmol/l, routine statin treatment to reduce the primary outcome of death from cardiac causes is not warranted
Different causes of death in 4D and CTT
Cause of death 4D CTT
CHD 9% 42%
Other cardiac 35% 7%
Stroke 6% 7%
Non-vascular 50% 44%
Expected versus observed effects on endpoints in the 4D trial
Endpoint Expected Observed
Primary endpoint 0.83 0.92 (0.77-1.10)
Cardiac events 0.84 0.82 (0.68-0.99)
Stroke 0.75 1.33 (0.90-1.97)
All-cause mortality 0.93 0.93 (0.79-1.08)
Effects of statins in dialysis patients
• High absolute risk of “cardiovascular disease”, BUT atypical vasculopathy (stiff arteries, calcification, LV disease)
• Effects of lowering cholesterol are unclear from existing epidemiology and 4D
• Need for further trials, such as AURORA and SHARP
K/DOQI Stages of Chronic Kidney Disease
Stage GFR (ml/min/1.73m2) Comment
1* >90 Hypertension
Structural problem
2* 60-89 Hypertension
Structural problem
3 30-59 Complications
Progression/Referral
4 15-29 More Complications
Referral/Preparation
5 0-14 RRT/Conservative
Effects of statins in pre-dialysis patients with CKD 3-5 but without known CHD
• Effects of lowering cholesterol unknown
• Matter of judgement whether to extrapolate from 4D or CTT
• Hence need SHARP, which will involve ~ 6000 such patients
SHARP Study of Heart and Renal Protection
• Eligibility– Patients with CKD (Cr > 133mmol/l in women or > 150mmol/l in
men), or in dialysis– Age >40– No history of MI or coronary revascularisation
• Simvastatin 20mg/ezetimibe 10mg daily vs placebo
• Target of 9000 patients (6000 pre-dialysis, 3000 dialysis)
• Primary endpoint: major vascular events (MI or cardiac death, stroke or revascularisation)
• Endpoint driven stopping: 1100 primary events
AURORA
*A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis an Assesment of survival and cardiovascular events
• Eligibility– Age 50-80– Haemodialysis for at least 3 months
• Rosuvastatin 10mg daily vs. placebo
• 2750 haemodialysis patients recruited
• Primary endpoint “major cardiovascular event” (cardiovascular death, non-fatal MI, non-fatal stroke)
• Endpoint driven stopping: 620 events
Transplant patients
• 2000 transplant patients• Total cholesterol 4 - 9 mmol/l• 5-6 year follow-up• Primary endpoint MACE
– Cardiac death – Non-fatal MI – Coronary intervention
• Intention to treat analysis