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.

57th Annual Scientific Sessions of the American College of Cardiology

Chicago, Illinois / March 29 - April 1, 2008

Although relatively small and conducted in a very specialized population, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) study was closely dissected here this week during the scientific sessions for its relevance to clinical practice. In the recently published study, 720 patients with familial hypercholesterolemia, a relatively rare genetic predisposition for hypercholesterolemia, were followed with ultrasonography for changes in carotid intima wall thickness after being randomized to simvastatin 80 mg monotherapy or simvastatin 80 mg plus 10 mg ezetimibe (Kastelein et al. N Engl J Med 2008; 358(14):1431-43). Although the combination therapy, as expected, reduced LDL levels by an additional 16.5%, atherosclerosis as represented by carotid intima media thickness did not regress as it had in previous lipid-lowering studies.

Reaching Optimal Lipid Levels Remains Critical

This surprising result appears to be more relevant to theories about atherosclerotic plaque dynamics than clinical practice. The importance of reaching LDL goals is unchanged even in familial hypercholesterolemia.

“In these patients, even maximum statins will not achieve target LDL levels. [The addition of] ezetimibe is the only way to do this,” reported senior ENHANCE investigator Dr. John J.P. Kastelein, University Medical Center, Utrecht, The Netherlands. He stated that he does not intend to change his practice of using statins plus the cholesterol absorption inhibitor ezetimibe when combination therapy is required to reach treatment goals in those with familial hypercholesterolemia.

Although no poll is available, remarks here at the ACC indicate that most other experts believe that the importance of reaching LDL targets remains undiminished by the ENHANCE results and that ezetimibe should be added to statin therapy when maximum tolerated statin doses are not sufficient to reach those goals. The panellists invited to formally discuss ENHANCE results declared that the new data reinforce the importance of maximizing doses of statins, which have demonstrated mortality benefits, before adding ezetimibe, but it was repeatedly stated that LDL goals among current guidelines remain unchanged. In emphasizing maximum statin doses, the panellists were reacting to widespread practice in the US of combining a low-dose statin with ezetimibe. Facilitated by a combination pill that is available in the US, this same practice has been uncommon in Canada.

“Physicians should optimize therapy with maximally tolerated doses of statins in an attempt to get patients to target levels as dictated by their clinical risk. For those not able to get there either for side effects or drug interactions, it is time to reach for adjunctive medications,” reported panellist Dr. Patrick T. O’Gara, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Another panellist, Dr. Joseph Messer, Rush University Medical Center, Chicago, Illinois, also signalled that ENHANCE results should not be over-interpreted: “We all believe in the LDL hypothesis.”

In Canada, the current recommendations are to employ maximum tolerated doses of statins before adding an adjunctive therapy, such as ezetimibe, to reach target LDL levels. Although these recommendations are largely based on statin trials, the supporting data are overwhelming. The results of ENHANCE, which did not have a clinical end point, produce no change in this approach. The cholesterol absorption inhibitor remains an important tool for attaining LDL targets in the substantial proportion of patients who cannot reach them on statins alone.

In the most critical statements made here this week, aggressive combination therapy was challenged in the absence of evidence of a clear clinical benefit. However, even the most vocal of these critics, Dr. Harlan Krumholz, Professor of Cardiology, Yale School of Medicine, New Haven, Connecticut, acknowledged that surrogate end points are a necessary tool for advancing clinical therapies until clinical event trials can be conducted. One such trial currently underway, IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), is randomizing patients to ezetimibe 10 mg plus simvastatin 40 mg or simvastatin 40 mg alone and has already enrolled 11,000 of its planned study population of 18,000 patients. The primary end point of the secondary prevention trial is the composite of death, myocardial infarction (MI), rehospitalization for acute coronary syndrome or revascularization (occurring 30 days or more after the initial event).

In his more highly critical appraisal of the role of ezetimibe, Dr. Krumholz was adamant about informing patients of the limits of knowledge in cholesterol lowering. He reiterated that most of the evidence of benefit in LDL lowering has been generated by statins. When considering ezetimibe, he recommended that patients be informed that the LDL lowering with this agent has not yet been confirmed to be beneficial in a trial with clinical end points. While he acknowledged that there is a “very good chance” that patients may choose to take a therapy supported by surrogate end points, he indicated that they should do so in full possession of the information.

ENHANCE Findings: Carotid Intima Media

For lipid lowering, ezetimibe was highly effective in ENHANCE. Consistent with the studies which provided regulatory approval of this agent, an inhibitor of dietary cholesterol absorption, the addition of ezetimibe not only provided a 16.5% reduction in LDL but a 25.7% reduction in C-reactive protein, an important measure of inflammatory activity, and a 6.6% reduction in triglycerides. While these reductions would have predicted a pronounced slowing of intima media thickening based on a previous study in a familial hypercholesterolemia population, the lack of effect is less surprising with a detailed examination of differences in the study population. In the previous trial, ASAP (Atorvastatin vs. Simvastatin on Atherosclerosis Progression), patients had thicker intima media at baseline and less exposure to statins.

“In the ENHANCE study, the mean baseline measure of carotid intima media thickness was 0.7 mm, which is much thinner than that in the ASAP study and also thinner than expected. This finding supports the hypothesis that previous plaque lipid depletion is an explanation for the results of the ENHANCE study,” reported Dr. B. Greg Brown, Professor of Medicine, University of Washington, Seattle, and Dr. Allen J. Taylor, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Evaluating the findings of ENHANCE, they indicated that plausible explanations for the results and the previously demonstrated importance of LDL lowering should not eliminate ezetimibe as a tool in clinical practice (Brown GB, Taylor AJ. N Engl J Med 2008;358(14):1504-7). Not least of these explanations is the likelihood that there is a limit in intima media wall thickness regression due to the fibrous cap and scar tissue that is characteristic of atherosclerosis and unlikely to disappear regardless of lipid lowering.

Confirmed Safety

One reason to support the continued use of ezetimibe to reach LDL goals while awaiting clinical end point trials is its safety profile. In ENHANCE, the rate of adverse events was lower although not statistically different in the combination treatment arm than in the arm that received simvastatin alone (8.1% vs. 9.4%; P=0.56). The proportion who had to discontinue therapy due to consecutive elevations in alanine aminotransferase was also statistically indistinguishable (2.8% vs. 2.2%, respectively; P=0.62). Creatine kinase levels elevated greater than 10 times the upper limit of normal occurred in twice as many patients on the statin alone, but again, the difference was not significant (1.1% vs. 2.2%, respectively; P=0.25). Overall, Dr. Kastelein reported that there were “no safety issues raised for chronic combination therapy” in this study.

Summary

In a 720-patient trial conducted in patients with familial hypercholesterolemia, ezetimibe with simvastatin did not provide greater prevention of growth in the carotid intima media thickness than simvastatin alone despite greater reductions in LDL. This result, although unexpected, may be explained by the low baseline thickness of the intima media thickness in a patient population already aggressively treated with statins. As a surrogate end point, regression of intima media thickness has provided reassuring evidence of activity of lipid-lowering therapies but clinical events is the outcome that counts. The new findings do not affect the importance of reaching LDL targets with current therapies including ezetimibe.