G Lipid Lowering In Ckd

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


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


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



1* >90Hypertension

Structural problem

2* 60-89Hypertension

Structural problem

3 30-59Complications


4 15-29More Complications



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



Acute MI13%

Cardiac Arrest21%

Other Cardiac20%

Stroke7%

Infection16%

Cancer19%

Other4%




Acute MI13%

Cardiac Arrest21%

Other Cardiac20%

Stroke7%

Infection16%

Cancer19%

Other4%


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


Baseline Characteristics of Patients


Median Level of Low-Density Lipoprotein (LDL) Cholesterol


Estimated Cumulative Incidence of the Composite Primary End Point


Rates of Primary and Secondary End Points


Adverse Events


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



1* >90 Hypertension

Structural problem

2* 60-89 Hypertension

Structural problem

3 30-59 Complications


4 15-29 More Complications



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

Health & Medicine

G Lipid Lowering In Ckd