Blog entry by Arif Khwaja
Final data from the Study of Heart and Renal Protection (SHARP) was presented at this weeks UK Renal Association and published in the Lancet online this week.The SHARP study was an RCT that involved 9270 patients with chronic kidney disease (of whom 3023 participants were dialysis-dependent), who were randomly assigned to receive simvastatin 20 mg daily plus ezetimibe 10 mg daily, or placebo, and followed up for a median of 4·9 years. There was a significant 17% proportional reduction (RR 0·83, 95% CI 0·74—0·94; log-rank p=0·0021) in major atherosclerotic events (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or arterial revascularisation) among those allocated to active treatment. There was also a significant one-fifth reduction in major vascular events (ie, major atherosclerotic events plus non-coronary cardiac deaths) amongst patients randomised to active lipid-lowering treatment. Whilst at first sight the effect appears more convincing in the non-dialysis population there is no statistical difference in outcomes between the dialysis and non-dialysis population. Reassuringly lipid lowering was safe and was not associated with cancer or rhabdomyolysis. As in previous trials there was a slight excess of haemorrhagic stroke in the lipid lowering group. there was no effect on CKD progression with lipid lowering.
The obvious question that arises is why do the results of SHARP appear to be positive when previous studies in the dialysis (4D and AURORA) population appear to be negative. However coronary revascularisation was not part of the primary endpoint in 4D and AURORA and the authors argue convincingly that the LDL-cholesterol-weighted proportional effects in AURORA, 4D and SHARP were statistically compatible for non-fatal myocardial infarction, non-fatal haemorrhagic stroke, non-fatal non-haemorrhagic stroke. Thus the results of SHARP are consistent with the effects of Cholesterol Treatment Trialists' (CTT) Collaboration metanalysis that shows statin therapy reduces the risk of myocardial infarction or coronary death, stroke, or coronary revascularisation by about a 20% per 1mmol/l reduction in LDL cholesterol. Furthermore the SHARP study included a large number of non-dialysis patients in whom the pathophysiology of cardiovascular disease maybe more similar to the general population.
So where does this leave the practicing clinician ? It seems that there is now good evidence to support lipid lowering in CKD patients as a primary prevention therapy to reduce cardiovascular events. This seems to be clear for the non-dialysis population ( even if they progress to renal replacement therapy) but the evidence is perhaps less clear in those on lifelong dialysis. For those who dont have access to ezetimibe the overall potency of the simvastatin+ezetimibe combination was broadly equivalent to atorvastatin 20 mg daily, rosuvastatin 10 mg daily, and fluvastatin 40—80 mg daily.