The efFects of Pharmacological management of lipids in patients with CKD

Andrew Monson FY118/9/14

The SHARP (Study of Heart and Renal Protection) trial

• Background

• Methodology

• Interpretation / Limitations

• Guidelines

Statins

• HMG-CoA reductase inhibitors• Meta-analyses of RCTs undertaken mainly in

patients without CKD (CTT) show statin therapy reduces risk of1,2:

• Major coronary events (MI or death from CHD)• Ischaemic strokes• Coronary revascularisations

• Approx 20% reduction of risk for each 1mmol/L reduction in LDL cholesterol

CKD

• eGFR > 60mL/min – CVS disease primarily atherosclerotic– Proportional effects of statin therapy independent of

renal function

• eGFR < 30mL/min – cardiovascular pathology differs– Vascular stiffness and calcification– Structural heart disease– Sympathetic over activity contributing to an increased

risk of arrhythmia and HF

Key question

• Does LDL-cholesterol lowering therapy remain effective as renal impairment progresses?

• The SHARP trial (double blind RCT) 3

– Aimed to assess safety and efficacy of reducing LDL cholesterol in 9270 patients with CKD

– Simvastatin + Ezetimibe VS Placebo

– Published in Lancet 2011

Method• Patients ≥ 40 years old with CKD• 6 week single blind placebo only

• Non-compliers excluded at this point

• Randomisation– Subsequently balanced for:

• Age• Sex• Ethnicity• Dialysis (33%) vs non-dialysis (67%)• Prior vascular disease• Previous DM• Systolic BP• Creatinine• Total Cholesterol

Randomisation• Initially 3 groups

– 20mg Simvastatin– 20mg Simvastatin / 10mg Ezetimibe– Placebo

• After year 1 Simvastatin group “re-randomised” into the other 2 groups– 9270 patients

• Double dummy method– Year 1 all patients 2 tablets– Year 2 all patients 1 tablet

• “Intention to treat”

Follow Up

• Primary Outcome: Major atherosclerotic events– Non-fatal MI, CHD death– non-hameorrhagic stroke– revascularisation procedures (coronary / non-)

• Monitored for Adverse events• SE’s (myalgia, raised CK, raised transaminases, hepatitis,

Gallstones, Pancreatitis• Cancer• Progression of renal disease• Compliance

• FU median 4.9 years (Minimum 4 years)

Results (SHARP)

Mean reduction in LDL-C among the treatment group was 0.83mmol/l (32 mg/dl) compared to placebo

Results

Overall: • Statin plus ezetimibe therapy was associated

with a statistically significant 17% RR reduction of the primary outcome of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke, or any revascularization) compared with placebo

• (RR 0.83; 95% CI 0.74–0.94)

Results

• No significant reduction in renal disease progression

• No significant increase in adverse side effects between the 2 groups

Overall

• 33% (n=3023) were receiving maintenance dialysis at randomization

• The remaining 67% (n=6247) CKD patients had a mean eGFR of 27 ml/min/1.73m2

Dialysis

• Combination treatment did not significantly reduce the risk of the primary outcome in the subgroup of over 3000 patients treated with dialysis (ESRF) at baseline

Author Interpretation

• “Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.”

Author Interpretation

“After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not.”

• Study claims that the differences in effects between subgroups were not statistically significant

Not so SHARP

• Funding – Merck/Schering-Plough Pharma– Manufacture Simvastatin/Ezetemibe dual therapy

• Despite claims, unable to demonstrate significant benefit in dialysis patient subgroup

• Unable to evaluate effects of statin alone in early stage CKD and pre-dialysis

Previous Studies

• AURORA• 4D

• Failed to find statistically significant reduction in events using statin therapies 4,5

– Haemodialysis patients only

Conclusion

• Simvastatin/Ezetimibe reduces cardiovascular events in patients with CKD who do not have ESRD

• Possible that this reduction is what would be expected with a statin alone

• In keeping with previous studies SHARP demonstrates that Statin based treatment provides minimal or no benefit in patients with ESRD

KDIGO Guidelines (2013) 6

• “In adults aged ≥50 years with eGFR <60 ml/min/1.73 m2 but not treated with chronic dialysis or kidney transplantation, we recommend treatment with a statin or statin/ezetimibe combination. (1A)”

• “In adults aged ≥ 50 years with CKD and eGFR ≥ 60 ml/min/1.73 m2 (GFR categories G1-G2) we recommend treatment with a statin. (1B)”

• “In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated. (2A)”

Questions?

References1) Cholesterol Treatment Trialists’ (CTT) Collaborators. Effi cacy andsafety of cholesterol-lowering treatment: prospective meta-analysisof data from 90 056 participants in 14 randomised trials of statins.Lancet 2005; 366: 1267–78.2) Cholesterol Treatment Trialists’ (CTT) Collaboration. Effi cacyand safety of more intensive lowering of LDL cholesterol:a meta-analysis of data from 170 000 participants in 26 randomisedtrials. Lancet 2010; 376: 1670–81.3) Baigent C, Landray MJ, Reith C et al. The effects of lowering LDLcholesterol with simvastatin plus ezetimibe in patients with chronickidney disease (Study of Heart and Renal Protection): a randomisedplacebo-controlled trial. Lancet 2011; 377: 2181–2192.4) Fellstrom BC, Jardine AG, Schmieder RE et al. Rosuvastatin andcardiovascular events in patients undergoing hemodialysis. N Engl J Med2009; 360: 1395–1407.5) Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238–248.6) http://www.kdigo.org/clinical_practice_guidelines/Lipids/KDIGO%20Lipid%20Management%20Guideline%202013.pdf