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19 August 2011
The SHARP RCT of ezetimibe plus simvastatin▼* in patients with chronic kidney disease (CKD), which was previously reported in a Merck press release in 2010, has now been published in full. Although, ezetimibe plus simvastatin reduced the risk of major cardiovascular (CV) events compared with placebo at around 5 years, we still do not know if addition of ezetimibe to simvastatin offers any safety or efficacy advantage over simvastatin alone (at the same or increased dose).
*Note: The MHRA has advised that the black triangle (▼) refers to intensive monitoring being requested only when simvastatin is used in children and adolescents (10–17 years), in line with the licensed paediatric dosing recommendation.
Action
This study provides no reason to change practice with regard to the prescribing of lipid-lowering drugs, with simvastatin 40mg/day remaining a good first choice option for most circumstances. Ezetimibe has a limited role, according to NICE guidance, for the treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia in the following circumstances:
- Where statins are contraindicated or not tolerated
- In conjunction with a statin where serum total or LDL-cholesterol is not appropriately controlled by initial statin therapy (after appropriate dose titration or because dose titration is limited by intolerance) and when consideration is being given to changing the initial statin therapy to an alternative statin.
Prescribers and prescribing managers should review local prescribing trends for statins and ezetimibe as suggested in the document ‘Key therapeutic topics – Medicines management options for local implementation’, produced by the NPC as part of the QIPP programme.
What does NICE guidance currently say about lipid modification in CKD?
NICE guidelines for CKD recommends that the use of statin therapy for the prevention of CV disease in people with CKD should not differ from its use in people without CKD. Treatment decisions should be based on existing risk tables for people with and without diabetes, with the understanding that the Framingham risk tables significantly underestimate CV risk in people with CKD. Statins should be offered for the secondary prevention of CV disease irrespective of baseline lipid values. Ezetimibe and ezetimibe plus simvastatin (Inegy) are not specifically currently licensed for use in patients with CKD.
NICE guidance on lipid modification recommends use of simvastatin 40mg/day for secondary prevention of CV events and for primary prevention in adults who have a 20% or greater 10-year risk of developing CV disease. For secondary prevention, in patients without acute coronary syndrome prescribers should consider increasing the dose of simvastatin to 80mg/day (or a drug of similar efficacy and acquisition cost) only in patients whose total cholesterol is greater than or equal to 4mmol/L and also whose LDL-cholesterol is greater than or equal to 2mmol/L.
What is the background to this study? Merck issued an initial press release about the SHARP (Study of Heart and Renal Protection) RCT in 2010, which we have discussed in MeReC Rapid Review 2162. We had also previously highlighted in MeReC Rapid Review 1722 that the evidence for the clinical efficacy of ezetimibe was based on surrogate outcomes (i.e. cholesterol lowering) and that there was no direct clinical evidence that ezetimibe improves patient-oriented outcomes.
Prior to the SHARP RCT discussed in this article, there were no studies that specifically aimed to look at lipid-lowering regimens in people with CKD.
What did the SHARP study claim?
Over a median duration of 4.9 years, 9,270 patients with CKD were randomised to simvastatin 20mg plus ezetimibe 10 mg daily or placebo. Fewer participants taking ezetimibe plus simvastatin met the key outcome (see outcomes and results below ) of a first major atherosclerotic event (non-fatal MI or coronary death, non-haemorrhagic stroke, or arterial revascularisation) compared with those allocated to placebo (11.3% vs. 13.4%; risk ratio [RR] 0·83, 95% confidence interval [CI] 0·74 to 0·94; p=0·0021).
The excess risk of myopathy was two per 10,000 patients per year of treatment with the ezetimibe plus simvastatin combination compared with placebo (9 [0·2%] vs. 5 [0·1%]) and was not statistically significant (p-value not quoted).
The published results of the SHARP study reported that use of ezetimibe plus simvastatin was not associated with an increased incidence of any cancer (438 [9·4%] vs. 439 [9·5%], p=0·89) or cancer-related death (2.8% vs. 2.5%, p=0.26) compared with placebo over 4.9 years. This provides further reassurance about the risk of cancer with ezetimibe in line with the data discussed in MeReC Rapid Review No. 366.
What are the implications of the SHARP study? Although the study identified a benefit for ezetimibe plus simvastatin over placebo in patients with CKD, the lack of a simvastatin alone arm in the study, means that we still do not have any evidence that addition of ezetimibe to simvastatin offers any safety or efficacy advantage over simvastatin alone, either at the same dose or at an increased dose, when used in accordance with NICE guidance. This is the case for patients with CKD and for other patients for whom lipid-modifying therapy is appropriate.
Design
Randomised, double-blind, placebo-controlled trial
Patients
Patients (n=9,270; mean age 62 years) with CKD and more than one previous measurement of serum or plasma creatinine of at least 150 micromol/L (1·7 mg/dL) if male, or 130 micromol/L (1·5 mg/dL) if female, were included. At randomisation, 3,023 patients were on maintenance dialysis.
Intervention and comparison
SHARP compared the efficacy and safety of the combination of ezetimibe plus simvastatin with placebo in people with CKD but who had no known history of myocardial infarction (MI) or coronary revascularisation. Patients were randomised to simvastatin 20mg plus ezetimibe 10 mg daily (n=4,650; 4,193 initially plus 457 after one year) or placebo (n=4,620; 4,191 initially plus 429 after one year). The 886 additional patients that were incorporated after one year into the two main study arms were initially allocated simvastatin alone as part of a safety analysis. The median duration of follow-up was 4·9 years for surviving patients.
Outcomes and results
The key outcome was first major atherosclerotic event (non-fatal MI or coronary death, non-haemorrhagic stroke, or arterial revascularisation) as reported above. The study also confirms the main outcome reported through a Merck press release in 2010 that ezetimibe plus simvastatin was significantly more effective than placebo in reducing major CV events, even when the patients initially allocated simvastatin alone were excluded (15.2% vs. 17.9%, RR 0.84, 95% CI 0.75 to 0.93, p=0.001; number needed to treat [NNT] 37 over 4.9 years). This appears to have been the initial primary outcome in the study protocol, but was changed during the study to major atherosclerotic events..
In addition, there was no significant excess of death from any non-vascular cause (14·4% vs.13·2%, RR 1.09, 95%CI 0.98 to 1.21, p=0·13). Please see the published paper for full details about the study’s outcomes and results.
Sponsorship
Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.
Further information can be found on NHS Evidence and in the cardiovascular disease – lipids NPC e-learning section.
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