G Lipid Lowering In Ckd

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  • G Lipid Lowering In Ckd

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

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