2 December 2010
A press release from Merck reports the results of a study showing that ezetimibe/simvastatin (10/20mg daily) was more effective than placebo in reducing the risk of major cardiovascular (CV) events over a period of five years in people with chronic kidney disease (CKD). If the fully published study study is found to be robust, then this will provide evidence that ezetimibe/simvastatin can reduce the risk of patient-oriented outcomes in people with CKD compared with placebo. This still does not address the more important issue of whether there is any meaningful efficacy or safety advantage of this combination compared with the current first choice treatment of using simvastatin▼* alone. However, these results may provide reassurance that ezetimibe is unlikely to be associated with an increased risk of cancer.
Since the release of this Stop Press, we have reviewed the full study (SHARP RCT), which was published in June 2011 and examined whether it confirms the key outcome measures outlined in the Merck press release discussed here. For more in depth review of the study and its implications please see MeReC Rapid Review No. 4270.
*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 recently licensed paediatric dosing recommendation.
This study provides no reason to change practice with regard to the prescribing of lipid-lowering drugs. 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 should review, and where appropriate, revise prescribing of ezetimibe to ensure it is in line with NICE guidance.
What does NICE guidance currently say about lipid modification in 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.
NICE guidelines for CKD states that their insufficient evidence for the routine use of statins to prevent or ameliorate CKD. The use of statin therapy for the primary prevention of CV disease in people with CKD should not differ from its use in people without CKD and should be based on existing risk tables for people with and without diabetes. It should be understood that the Framingham risk tables significantly underestimate risk in people with CKD. Statins should be offered for the secondary prevention of CVD irrespective of baseline lipid values.
Ezetimibe and ezetimibe/simvastatin (Inegy®) are not currently licensed for use in patients with CKD.
What is the background to this new evidence?
We have previously highlighted in MeReC Stop Press 1722 that the evidence for the clinical efficacy of ezetimibe is based on surrogate outcomes (i.e. cholesterol lowering) and that there is no direct clinical evidence that ezetimibe reduces patient-oriented outcomes. Concerns have been expressed about a possible link between ezetimibe use and cancer, although the MHRA advised in 2008 that current data were insufficient to draw conclusions. Furthermore, post-marketing adverse event reports did not find any increased risk of cancer with ezetimibe compared with statins, either alone or when taken in combination with simvastatin (see MeReC Rapid Review No. 366).
What does this study show?
Results of the SHARP study were presented at the recent American Society of Nephrology annual meeting. The study was a randomised controlled trial of more than 9,000 patients with CKD, who received either a combination of ezetimibe 10mg/simvastatin 20mg, placebo, or (for the first year only) simvastatin 20mg only (patients in this group were reallocated to one of the other groups after the first year). The press release reports that ezetimibe/simvastatin was significantly more effective than placebo in reducing major CV events (15.2% vs. 17.9%, P=0.0010; NNT 37 over 4.9 years), and that incidences of cancer and any other adverse effects were similar between the treatment groups.
Of course, we really want to know whether the addition of ezetimibe to simvastatin offers any clinical advantage over the use of simvastatin alone (at the same or increased dose). Unfortunately, the absence of a simvastatin only group throughout the full treatment period means that we still do not know the answer to this question.
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