Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

European Society of Cardiology Congress 2008

Munich, Germany / August 30-September 3, 2008

Results of the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study presented here at the ESC 2008 and concurrently published online indicate that lipids are not a major mediator of events in patients who have advanced to aortic stenosis (Rossebo et al. N Engl J Med 2008 Sep 2; Epub ahead of print). This refutes the SEAS study hypothesis, but this type of result is expected to be an increasingly common phenomenon. The success of lipid lowering in patients with conventional forms of cardiovascular (CV) disease has led to studies in a broad number of new indications where benefit is less assured. Aortic stenosis may be one of these.

“Statins are extraordinary drugs but they are being pushed to their outer limits. It is asking a lot of lipid lowering drugs when the horse has been out of the barn,” observed Dr. Eugene Braunwald, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. As a pre-eminent cardiologist invited by the ESC to discuss the results of SEAS immediately after they were presented, Dr. Braunwald stated, “[This] trial provides a clear negative answer to this interesting question [of whether intensive lipid lowering could prevent events in patients with mild to moderate aortic stenosis]. The question now is would lipid lowering started earlier in the process be preventive.”

SEAS: Lipid-lowering Benefit Confirmed

The point Dr. Braunwald stressed was that the lack of activity in these new applications seen in the SEAS results has no relevance to the proven benefit in established applications. He, like others, stressed that the guideline goals for secondary prevention in patients with established CV disease or with diabetes or for primary prevention in those with risk factors are evidence-based and remain unchanged. These goals are independent of statin therapies although statins are considered first-line for LDL lowering due to their safety and efficacy. However, Dr. Braunwald endorsed combination therapies, like the one employed in SEAS, if needed to reach and sustain LDL at goal.

In the double-blind SEAS trial, 1873 patients with mild-to-moderate asymptomatic aortic stenosis were randomized to simvastatin 40 mg plus ezetimibe 10 mg or placebo. The primary outcome was a composite of death from CV causes, aortic valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina, heart failure, coronary artery bypass graft, percutaneous coronary intervention and nonhemorrhagic stroke. Patients were followed for a median of 52.2 months with some patients followed up to seven years.

“The therapy was quite effective. Within eight weeks, there was a 61.3% mean reduction in LDL but no change in the placebo group,” reported Dr. Terje R. Pedersen, Center for Preventive Health, Ulleval University Hospital, University of Oslo, Norway. Over the course of the more than four years of follow-up, the mean LDL reduction among those on the simvastatin/ezetimibe combination was 53.8% vs. 3.8% in the placebo group.

The incidence of the primary outcome was lower on the LDL-lowering therapy (35.3%) than on placebo (38.2%), but the difference did not reach significance (hazard ratio [HR] 0.96%, 95% CI: 0.83-1.112; P=0.59). When comparing specific events, the intensive lipid lowering had almost no effect on aortic valve replacement (28.3% vs. 29.9%) even though it produced a significant 22% relative risk reduction in ischemic CV events (15.7% vs. 20.1%, HR 0.78, 95% CI: 0.63-0.97; P=0.02). Although the differences did not reach statistical significance, often perhaps due to a low number of events, the numerical advantage was in favour of intensive lipid lowering in the vast majority of CV outcomes.

Table 1. SEAS: Lipid Findings

Cancer Anomaly Dismissed

An unexpected finding from SEAS, announced more than a month ago, was an apparent increased risk of cancer for intensive lipid lowering relative to placebo, which reached marginal statistical significance (4.1% vs. 2.5%; P=0.05). This finding prompted an intensive evaluation of other data in order to determine whether this was a previously overlooked risk or a simple play of chance. These subsequent analyses have been consistent in concluding that the finding was an anomaly. In an analysis of more than 20,000 patients participating in clinical trials under lead author Prof. Richard Peto, Professor of Medical Satistics and Epidemiology, University of Oxford, UK, which was published online simultaneously with the SEAS data, the conclusion was that the data “do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer” (Peto et al. N Engl J Med 2008 Sep 2;Epub ahead of print).

The same conclusion was drawn by Dr. Braunwald. In addition to the data published in the New England Journal of Medicine, he cited a number of reasons to discount an increased cancer risk. One is the absence of any pattern across a broad array of cancers, many of which have different etiologies. More importantly, there was no increased risk of cancer over time “which would be expected if the treatment was a cancer cause,” Dr. Braunwald told delegates.

Lipid Lowering First and Foremost

Just as importantly, the findings of SEAS should not be allowed to diminish the rigor with which physicians attempt to treat LDL to current goals, according to Dr. Braunwald. Several other experts, including Dr. Lawrence Leiter, Head, Division of Endocrinology and Metabolism, St. Michael’s Hospital, and Professor of Medicine, University of Toronto, Ontario, and Dr. Pedersen emphasized the same point. While statins are very effective at reducing LDL, Dr. Leiter pointed out that many patients, particularly those at high risk who have the lowest treatment goals, cannot get their LDL low enough on a single therapy. Other agents, such as niacin, may provide some additional LDL lowering when combined with statin, but even a relatively modest dose of ezetimibe can provide a major reduction in LDL when added to a statin with few or no additional side effects.

“The evidence that a lower LDL is better has been a consistent message across the many lipid-lowering studies,” confirmed Dr. Pedersen, senior author of the landmark 4S (Scandinavian Simvastatin Survival Study). “We are in the position of saving lives by ensuring that patients at high risk of CV disease are at their goal.”

As lipid lowering is tested in areas that are not directly dependent on vascular events, more disappointments can be expected. In SEAS, the result is not likely to be related to the therapy but simply to the fact that lipid lowering is not beneficial in this population. Again, it is possible that the opportunity for benefit from lipid lowering has already passed in this disease process. As discussed by lipid experts, this should not influence treatment goals where benefit has been seen.

Summary

The SEAS study tested the hypothesis that intensive lipid lowering reduces the risk of adverse clinical events in patients with mild to moderate aortic stenosis. The double-blind, placebo-controlled trial was unable to show a significant overall benefit even though the simvastatin/ezetimibe combination, as expected, did reduce LDL by more than 60% and the rate of ischemic events by 22% relative to placebo. There has been concern that this study will reduce the rigor with which patients are treated to LDL goals. In response, several experts emphasized that these goals are evidence-based and stressed the importance of treating to goal, including using combination therapies such as simvastatin/ezetimibe when statins alone are not sufficient.