Statins in Renal Failure Andrea Fox Sunnybrook Health Science Center May 2010
No jokes • No funny stories • No time
Objectives • Discuss why the use of Statins in Stage 5 chronic kidney disease is controversial • Outline the two studies that produced unexpected outcomes • Provide a few practical tips from our practice at Sunnybrook HSC
What is the issue? • High mortality in patients on maintenance dialysis • 80% have known cardiovascular disease at initiation of renal replacement therapy • Have elevated CRP levels • Benefits of statins in the general population are well known in cardiovascular and cerebrovascular disease- Are dialysis patients different?
Expect the Unexpected • Stage 3 kidney patients may receive benefit. • Some evidence exists from large statin trials that included stage 3 patients that the benefit is similar or greater than the general population (post hoc subgroup analysis) • Studies have not backed up assumptions that statins will reduce events and death in patients on dialysis (Stage 5)
Observational studies • Several observational studies have suggested that statins are associated with decreased mortality • DOPPS (Dialysis Outcome and Practice Patterns Study) has shown this in 7365 prevalent hemodialysis patients • Patients who used statins had • 31% lower relative risk of death (p=0.0001) • 23% lower cardiac mortality risk (p=0.03)
4D study • The first powered RCT to address the issue: Do statins prevent CV events in dialysis patients? • 1255 German patients with type 2 DM on hemodialysis • Compared atorvastatin 20mg daily with placebo • Composite outcome of death from cardiac causes, nonfatal MI and stroke
AURORA • RCT, double blind, 2776 patients aged 50-80 yrs on hemodialysis • Compared rosuvastatin 10mg daily with placebo • Primary end point: time to major CV events (death from CV causes, nonfatal MI or nonfatal stroke) • Secondary endpoints included change in lipids and CRP levels.
Study comments • Both trials significantly reduced LDL-C levels (43% and 42%) • Both trials showed decrease in CRP in statin group vs. a rise in placebo group • Statin use did NOT statistically prevent the composite primary outcome in either study AURORA-LDL lowering
Primary Endpoint AURORA 4D
Why no benefit? • Lots of drop out/drop in in both studies • AURORA excluded patients who may have benefitted most from statin therapy • Statistical power
A Different Patient • Or… are statins truly not effective in dialysis patients? • Dialysis patients are different • Lipid profile (normal LDL) • Extensive calcification common • CV deaths are different • Sudden death, arrhythmias, cardiomyopathy • Atherosclerotic plaque rupture is less common • Are we too late?
Safety • Rhabdomyolysis • no increase seen in muscle related adverse events or rhabdomyolysis vs. placebo • Cancer • No increase in new cancer diagnoses • Liver Function • No increases in liver function tests or new liver disease
Safety: stroke risk 4D: • an increase in fatal stroke risk was seen in the atorvastatin group vs placebo (27 events vs. 13, p= 0.04) AURORA: • “marginal” increase in hemorrhagic stroke in patients with DM who received rosuvastatin (12 events vs. 2, P=0.07)
SHARP • Study of Heart and Renal Protection • 9000 patients (pre-dialysis, hemodialysis, peritoneal dialysis) • Patients may have received prior statin therapy • Evaluating effect of combined simvastatin/ezetimibe therapy • Expected to report in 2010-11
Practically speaking… • Statins are used in dialysis patients, usually initiated by other services (post MI, post stroke) • We often reduce higher doses (i.e.. Atorvastatin 80mg daily reduced to 40 mg) • Rosuvastatin (Crestor®) dosing: • Health Canada recommends starting dose of 5 mg in patients with renal failure • Monograph says 40 mg dose contraindicated in patients with Cr Cl < 30ml/minute (March 2010)
Conclusion? • Lowering LDL-C with statins in hemodialysis patients does not necessarily reduce CV or stroke risk • CV disease in patients on chronic dialysis differs from the general population • No clear answer on how to use statins in this population
References • Fellstrom, Jardine et al; Rosuvastatin and cardiovascular events in patients undergoing hemodialysis, NEJM 2009;360(14): 1395-1407 (AURORA) • Tonelli, Shurraw; In the Literature, Commentary on AURORA study; Am J Kidney Disease, 2010;55(2):237-240 • Wanner, Drane et al. Atorvastatin in patients with type 2 diabetes undergoing hemodialysis. NEJM. 2005;353(3);238-248 (4D) • Mason, Bailie et al. HMG_coenzyme A reductase inhibitor use is associated with mortality reduction in hemodialysis patients. Am J Kidney Disease 2005;45(1):119-126 (DOPPS)