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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

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statins in renal failure

Statins in Renal Failure

Andrea Fox

Sunnybrook Health Science Center

May 2010

slide2
No jokes
  • No funny stories
  • No time
objectives
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
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
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
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
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
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
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

why no benefit
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
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
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
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
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
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
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
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)