Rossebø AB, et al for the SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359 (early online publication, September 2nd 2008: 10.1056/NEJMoa0804602)
This trial doesn’t tell us that ezetimibe▼ helps people live longer or live better, but raises concerns about it possibly increasing the risk of cancer. These concerns are unproven when considered alongside other large, ongoing trials of ezetimibe▼. A large, high-quality meta-analysis suggests that statins do not increase the risk of cancer.
Action – It would seem sensible to use ezetimibe▼ only with caution as there is no published evidence of its benefit on clinically important outcomes such as cardiovascular events and its long-term safety is unknown. Prescribers should continue to use statins first-line in most patients who require a lipid-lowering agent. As ezetimibe▼ is a black triangle drug, all suspected adverse drug reactions should be reported to the MHRA.
What is the background to this? – Ezetimibe▼ lowers LDL-cholesterol levels. Although this might be expected to reduce the risk of cardiovascular events, until recently there have been 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 cardiovascular event. Concerns about translating cholesterol-lowering effects directly to cardiovascular outcome data have been expressed following the recent randomised controlled trial, ENHANCE. This did not find a reduction in carotid intima medial thickness with the addition of ezetimibe▼ 10mg to simvastatin 80mg in people with familial hypercholesterolaemia. See previous blog for details.
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial is the first study of ezetimibe▼ looking at clinical outcomes to be published. This compared simvastatin 40mg plus ezetimibe 10mg daily, with placebo in people with asymptomatic stenosis of the aortic valve. Hyperlipidaemia has been suggested as a risk factor for aortic stenosis, but lipid-lowering studies have had conflicting results. However, the SEAS study unexpectedly raised concerns about the safety of ezetimibe▼, because, as was first reported by the FDA in August 2008, there was an increased incidence of cancer in the active treatment group.
What does this study claim? – Simvastatin plus ezetimibe▼ had no impact on the progression of aortic stenosis or on cardiovascular events in general (with the exception of coronary artery bypass grafting). The primary composite outcome of combined aortic-valve events and ischaemic events was reached in 35.3% of the simvastatin plus ezetimibe▼ group compared with 38.2% of the placebo group (Hazard ratio [HR] 0.96; 95% confidence intervals [95%CI] 0.83 – 1.12; P=0.59). Median follow-up was 52.2 months.
There was an unexpected 55% increase in new cancers seen in the simvastatin plus ezetimibe▼ group compared with the placebo group (10.8% vs. 7.0%, HR 1.55; 95% CI 1.13 – 2.12; P=0.01; NNH = 26). An increase in a variety of cancers (including prostate, gastrointestinal and skin) was seen, and death from cancer also increased (4.1% vs. 2.5%, HR 1.67; 95% CI 1.00 to 2.79), although this was at the limits of conventional levels of statistical significance (P=0.05).
How does this relate to other studies?
The Cholesterol Treatment Trialists (CTT) meta-analysis included data on more than 90,000 patients randomised to either statin therapy or control treatment for approximately 5 years in 14 trials. CTT found no increased cancer risk with statin treatment.
The unexpected finding of an increased risk of cancer with simvastatin plus ezetimibe▼ in SEAS was explored further in an accompanying analysis by the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Oxford University.
The CTSU authors noted that the excess risk of cancers seen in the SEAS trial is based on only small numbers of patients so the range of uncertainty around the relative risk is wide. They suggest that if there were a true adverse effect of simvastatin plus ezetimibe▼ on the incidence of cancer, the excess should be dominated by a few particular types of cancer and the relative risk should increase significantly with duration of follow-up; neither of these were the case.
To explore the possibility of an increased risk of cancer with simvastain plus ezetimibe▼, the CTSU analysis compared the incidence of cancer in the SEAS trial with cancer data from two larger ongoing trials also investigated simvastatin plus ezetimibe▼: SHARP and IMPROVE-IT. An accompanying editorial points out that none of these three trials was designed primarily to address cancer risk. However, cancer mortality would be expected to be a reliable endpoint.
Together, the SHARP and IMPROVE-IT trials involve about four times as much information about the incidence of cancer as the SEAS data alone. In the SHARP and IMPROVE-IT trials combined, there was no significant excess incidence of cancer (Relative Risk [RR] 0.96; 95%CI 0.82 to 1.12, P=0.61) either overall or at a particular site, and no suggestion of an emerging trend with duration of follow-up. There was a non-significant increase in cancer mortality, but this had much wider 95% CIs (RR 1.34 (95% CI, 0.98 to 1.84, P=0.07).
The CTSU authors concluded that the available results from these other trials of simvastatin plus ezetimibe▼ do not support the hypothesis generated by SEAS (i.e. that ezetimibe▼ plus simvastatin increases the risk of cancer). The accompanying editorial strikes a more cautious tone. It notes that although the 95% CIs derived from the analysis rule out (at conventional levels of statistical significance) the possibility that the combination increases the risk of cancer by more than about 12%, they cannot exclude a relative increase of as much as 84% in the risk of cancer-related death. The editorialist says that using interim data from SHARP and IMPROVE-IT is problematic, and that additional data are needed to adequately address whether simvastatin plus ezetimibe▼ is associated with an increased risk of death from cancer. He suggests such data should be provided by completed randomised trials that have been prospectively designed to address these safety issues.
There remains no good evidence that ezetimibe▼ either alone or added to a statin reduces the risk of cardiovascular events compared to a statin alone. There was a 22% relative reduction in risk of ischaemic cardiac events seen in SEAS from the combination compared with placebo, but this is in line with what we would expect to see from simvastatin 40mg alone. In any case, because the primary outcome did not achieve statistical significance, there are good statistical reasons for being very cautious about accepting observed benefits in secondary outcomes. It is worth remembering that torcetrapib also produced impressive benefits in blood lipids, but was associated with a 25% increase in major cardiovascular events (see previous blog).
What about harms? Although a 55% increased risk of cancer was seen in SEAS, the P value of 0.01 indicates that there is a 1 in 100 possibility that this was a chance finding. The data currently available suggest that such a large increase in the risk of cancer is unlikely. However, further data are required to clarify this important safety issue.
With no direct evidence of benefits and some remaining, but unproven, questions about safety, one must consider cost. Adding ezetimibe▼ to statin therapy substantially increases the cost to the NHS. NICE guidance on ezetimibe▼ seems sensible. This is to use ezetimibe▼ monotherapy only if statins are contraindicated or not tolerated, and to use ezetimibe▼ in combination with a statin in some limited circumstances where statins have not appropriately controlled cholesterol levels, despite appropriate dose titration and consideration of switching stains. Note that NICE guidance on lipid-lowering does not recommend that patients should be expected to achieve specific lipid targets (see previous blog), although guidance for patients with type 2 diabetes or familial hypercholesterolaemia is slightly different.
Study details – SEAS
Design: Double blind randomised controlled trial. It is not possible to determine if allocation was concealed.
Patients:1,873 patients (mean age 67) with mild-to-moderate, asymptomatic aortic stenosis, as assessed on echocardiography. Patients with other cardiovascular disease or diabetes were excluded.
Interventions/comparators: 40mg of simvastatin plus 10mg of ezetimibe▼ or placebo daily.
The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, non-fatal myocardial infarction, hospitalisation for unstable angina, heart failure, coronary-artery bypass grafting (CABG), percutaneous coronary intervention, and non-haemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischaemic cardiovascular events. Median duration of follow-up was 52.2 months.
The primary outcome occurred in 35.3% of the simvastatin plus ezetimibe▼ group compared with 38.2% in the placebo group (hazard ratio [HR] 0.96; 95% CI 0.83 to 1.12; P =0.59). Aortic-valve replacement was performed in 267 (28.3%) of the simvastatin plus ezetimibe▼ group and 278 (29.9%) of the placebo group (HR 1.00; 95% CI 0.84 – 1.18; P=0.97). Fewer ischaemic cardiovascular events occurred in the simvastatin plus ezetimibe▼ group than in the placebo group (15.7% vs. 20.1%; HR 0.78; 95% CI 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent CABG.
Cancer occurred more frequently in the simvastatin plus ezetimibe▼ group. Incident cancer (including recurrent cancer) was diagnosed in 105 patients (11.1%) of the simvastatin plus placebo group compared with 70 patients (7.5%) in the placebo group (P=0.01). Incident cancer (excluding recurrent cancer) occurred in 7.0% and 10.8% of patients, respectively (P=0.01). An increase in a variety of cancers (including prostate, gastrointestinal and skin) was seen, and death from cancer also increased (4.1% vs. 2.5%, HR 1.67; 95% CI 1.00 to 2.79), although this was at the limits of conventional levels of statistical significance (P=0.05). During the entire follow-up period, the mean percent reduction in LDL-cholesterol was 53.8% in the simvastatin plus ezetimibe▼ group and 3.8% in the placebo group
Study details – SHARP
The Study of Heart and Renal Protection (SHARP) is comparing simvastatin 20mg plus ezetimibe 10mg daily with placebo in 9,264 patients with chronic kidney disease. Cancer data was unblended in July 2008 when there was a mean follow-up period of 2.7 years.
Study details – IMPROVE-IT
The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), is comparing simvastatin 40mg plus ezetimibe 10mg with simvastatin 40mg daily in patients with acute coronary syndrome. Recruitment is ongoing. Cancer data was unblinded in July 2008 when 11,353 (of a planned 18,000) patients had been followed-up for a mean period of 1.0 year.
The SEAS trial was sponsored by Merck and Schering-Plough Pharmaceuticals. CTSU, Oxford received research funding from Merck and Schering-Plough to carry out this work.