Kastelein JJP et al. Simvastatin with or without ezetimibe in familial hypercholesterolaemia. New Engl J Med 2008; 358: 1431-1443 (The ENHANCE study 3rd April 2008)
The short answer to the question above is – not a lot. The ENHANCE study used a surrogate outcome measure and did not look at outcomes important to patients. There remains no evidence that ezetimibe▼ either alone or added to a statin affects the risk of cardiovascular events. However ENHANCE has been extremely controversial so this blog expands on our previous blog and sets the study in context.
What is the background to this?
Having elevated blood levels of low-density lipoprotein (LDL) is one of several risk factors for cardiovascular (CV) disease such as myocardial infarction (MI) and stroke. Several statins, notably simvastatin in the Heart Protection Study and atorvastatin in CARDS, have been shown to reduce LDL levels and (of far greater importance to patients) the risk of CV events. But is LDL-lowering the be-all and end-all, and is it a case of “the lower the better”?
There is some evidence, such as the PROVE-IT study, that using high dose atorvastatin may reduce CV risk and mortality in very high risk patients (those in PROVE-IT were included within a few days of developing acute coronary syndrome). However, there are limitations to this study (not least that the comparator was pravastatin 40 mg). Moreover, the benefits on death rates seen in PROVE-IT were not seen with the use of high dose statins in stable patients in the IDEAL and TNT studies. It is important to note that, although substantial reductions in LDL levels were seen in these studies, the comparison was between high and standard doses of statins, not different LDL targets.
Substantial reductions in LDL levels (around 37% on average) can be achieved with simvastatin 40 mg or atorvastatin 10 mg. Achieving greater reductions in LDL levels requires the use of much higher doses of statin, which increases the risk of side effects.
Ezetimibe▼ reduces blood LDL levels by reducing cholesterol re-absorption (whereas statins reduce its synthesis). When added to statin therapy, ezetimibe▼ lowers LDL levels further than with the statin alone. Although this might be expected to reduce the risk of CV events, there are currently no published data to say whether or not ezetimibe▼ alone or added to a statin helps people live longer or reduces their chance of having a CV event (see below).
The ENHANCE study recruited patients with familial hypercholesterolaemia, with extremely high LDL levels at entry (more than 8 mmol/L). These patients were therefore not typical of most patients looked after by primary care health professionals, or secondary care professionals other than specialist cardiologists, lipidologists, etc
The primary and secondary outcomes of the ENHANCE study were related to the effect of ezetimibe▼ 10mg plus simvastatin 80mg versus simvastatin 80mg alone on the intima-media thickness of the carotid artery.
What did this study find?
After two years of treatment, there were no statistically significant differences observed between the two study groups for the primary or secondary outcomes. The primary endpoint was the mean increase in carotid artery intima-media thickness. The increase in the ezetimibe▼ plus simvastatin group was nearly double that seen in the simvastatin-only group, but this observed difference probably arose by chance (mean increase ± Standard Error [SE] was 0.0111±0.0038 mm in the combination group compared with 0.0058±0.0037 mm in the simavstatin-only group, P value = 0.29).
This was despite a substantial difference in LDL levels in the two groups (a reduction from 8.25 mmol/L to 3.65 mmol/L in the combination group, compared to a reduction from 8.22 mmol/l to 4.98 mmol/L in the simvastatin-only group).
There were no major differences in adverse effects rates or rates of discontinuation of medication in the two groups. The study was not designed to look at patient-oriented outcomes such as rates of CV events or death
This study has been the subject of controversy, as discussed by Ben Goldacre in his Bad Science blog. In particular, as pointed out to the co-sponsors of the study in a strongly worded letter from the US House of Representatives Committee on Energy and Commerce, the trial was registered very late with the public trials register, and the endpoints in the register entry were at first different from those originally described. Moreover, there was a substantial delay between the completion of the study in April 2006 and the publication of the results in January 2008. The results presented in the NEJM paper appear to be consistent with the endpoints originally planned. The study has implications for the use of ezetimibe▼ but wider lessons can also be learned.
So what? – the role of ezetimibe▼
The primary endpoint used is a surrogate endpoint. As Brown and Taylor discuss in an accompanying NEJM editorial, although a reduction in carotid intima-media thickness does not guarantee a reduction in the rate of cardiovascular events, it seems unlikely that a reduction in events can be expected without one. Although ezetimibe▼ effectively lowers LDL levels, there are currently no published data to say whether or not ezetimibe▼ alone or added to a statin helps people live longer or live better. At this stage it is impossible to know with any degree of certainty whether ezetimibe▼ will be beneficial to patients at risk of CV events. The IMPROVE-IT trial, which compares the effect on CV outcomes of ezetimibe▼ 10 mg plus plus simvastatin 40 mg with the effect of simvastatin 40 mg alone, should answer this question. However, it is not expected to be completed until 2012.
As we have previously blogged, ezetimibe has been considered by NICE. It advises that ezetimibe▼ monotherapy is an option for the treatment of adults with who would otherwise be initiated on statin therapy (as in NICE guidance TA 94) but who are unable to do so because statins are contraindicated or they were unable to tolerate them.
So what?- wider lessons
Two editorials in JAMA explore the wider lessons to be learned from the ENHANCE study and the associated debacle.
Greenland and Lloyd-Jones are highly critical of the motives they impute to the sponsors for conducting ENHANCE. They say that, given the limitations of the information ENHANCE could provide, one reasonable conclusion is that it was conducted primarily or exclusively as a marketing tool, so that the (expected) positive results could be used to persuade clinicians to prescribe ezetimibe▼. The editorialists are also critical of the lay media presentation of the results, which (in some US publications at least) were taken as proving the entire cholesterol-CV disease hypothesis incorrect. This could lead to distress among patients, and even to harm if patients were to stop or start medication inappropriately as a result. Finally, the editorialists recommend that leading organisations concerned with science and/or medicine and patient care must be scrupulous to avoid conflicts of interest, real or perceived.
Psaty and Lumley compare the fates of ezetimibe▼ and torcetrapib. Unlike statins and ezetimibe▼, torcetrapib targeted high density lipoprotein (HDL). In contrast to LDL, higher blood levels of HDL are associated with a lower CV risk. Torcetrapib is highly effective at increasing HDL levels. However, the drug has never been approved for use.
The ILLUMINATE trial compared torcetrapib plus atorvastatin with atorvastatin alone in some 15,000 patients at high cardiovascular risk. Although patients in the combination group had mean HDL levels 0.73 mmol/L higher and mean LDL levels 0.51 mmol/L lower than patients taking atorvastatin, interim analysis showed a 25% greater risk of major cardiovascular events in the combination group – equivalent to an extra 12 CV events and an extra three deaths per 1000 person-years of use. The ILLUMINATE trial was stopped early and the manufacturer halted the development of torcetrapib.
The editorialists comment:
The differences in histories of ezetimibe▼ and torcetrapib, both drugs designed to alter lipid levels and prevent cardiovascular events, are striking. Ezetimibe▼ was approved and marketed aggressively. The randomized clinical trials evaluating its effects on atherosclerosis and clinical events have been slow to be reported or started. Torcetrapib was never approved. A large, long-term randomized trial evaluating its association with major cardiovascular events was well under way before approval… ….If torcetrapib had been approved solely on the basis of its ability to increase HDL cholesterol levels, the drug might have been marketed for many years before the increase in cardiovascular events was detected.
It is salutary to compare the impact of ENHANCE with the widespread media reporting of the ASTEROID study. ASTEROID was a not dissimilar but non-comparative study which showed a reduction in atheroma volume in patients treated with rosuvastatin 40 mg daily. More recently, the METEOR study, which had the same endpoints and duration as ENHANCE, found a reduced rate of thickening of the carotid intima-media. But there are as yet no published studies which have examined whether or not rosuvastatin reduces the risk of CV events and all-cause death in the type of patients for whom it is commonly prescribed. It has recently been announced (29th March) that the JUPITER, a placebo-controlled primary prevention study of rosuvastatin 20 mg in lower-CV-risk patients, has been terminated early due to observed beneficial effects on CV mortality and morbidity. However, details are not yet available, nor do we know how rosuvastatin would compare with simvastatin.
More information on lipid management, including the arguments for and against fixed cholesterol targets or aiming for a “meaningful drop” in cholesterol concentrations, can be found on the lipids section of NPC. The great majority of patients will achieve a good reduction in their total cholesterol, and meet the Quality and Outcomes Framework (QOF) standard of 5 mmol/L total cholesterol or less, on simvastatin 40 mg a day alone. This is well tolerated and has a low acquisition cost to the NHS. Ezetimibe▼ is not licensed for primary or secondary prevention of cardiovascular events.
Health professionals should think carefully before adding ezetimibe or following other strategies to chase ever lower LDL levels. Those who consider using ezetimibe should take the NICE technology appraisal covering ezetimibe▼ in hypercholesterolaemia fully into account when deciding on treatment. Ezetimibe▼ is a “black triangle” drug under intensive surveillance by the MHRA. Health care professionals (and patients) are therefore requested to report all suspected adverse reactions to ezetimibe▼ to the MHRA.
More broadly, health professionals should be wary of studies which report only surrogate outcomes and should not allow themselves to be led astray by associated marketing activities
Patients: 720 patients with familial hypercholesterolaemia
Intervention and comparison: 80 mg simvastatin daily plus either placebo or ezetimibe▼ 10 mg daily, for 24 months
Outcome and results: The primary outcome was the mean (± Standard Error [SE]) change in the carotid-artery intima-media thickness. This was 0.0111±0.0038 mm in the combination group and 0.0058±0.0037 mm in the simavstatin-only group, P = 0.29 (not statistically significant). LDL levels were reduced in both groups from 8.25 mmol/L to 3.65 mmol/L in the combination group, compared to a reduction from 8.22 mmol/l to 4.98 mmol/L in the simvastatin-only group
Sponsorship: The study was supported by Merck and Schering-Plough.