FAQ
ENHANCE trial: is there a role for ezetimibe in managing dyslipidemia?
The results of the ENHANCE (Ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression) have been published in the New England Journal of Medicine and have been accompanied by editorials and response from the lay press. Ezetimibe, a drug that inhibits intestinal absorption of cholesterol, is marked alone (Zetia) and in combination with simvastatin, a statin (Vytorin).
Annual prescriptions for both medications have steadily increased in the United States since their introduction to market. According to a cohort study conducted by Jackevicius and colleagues, ezetimibe prescriptions have increased by an average of 27,200 per month (2002 to 2006) and ezetimibe/simvastatin prescriptions have increased by an average of 61,000 per month (2004 to 2006) in the United States. Prescriptions for ezetimibe have also increased in Canada (from 2003 to 2006), but not to the degree that they have in the United States (p<0.001). Furthermore, this cohort study reveals that during the same time period, prescriptions for statins decreased from 86.5% to 80.8% of total prescriptions for lipid lowering therapy in the United States. There was no appreciable change in statin prescriptions in Canada. The authors report that monthly costs associated with ezetimibe therapy in December 2006 were $261, 479, 000 in the United States and $6,640,354 in Canada.
Literature review
ENHANCE was a randomized, double blind, active controlled, multicenter trial conducted to determine whether or not ezetimibe plus simvastatin compared to simvastatin alone reduced the progression of atherosclerosis. Subjects with familial hypercholesterolemia and low-density lipoprotein (LDL) values of 210 mg/dL or above were randomized to ezetimibe 10 mg/simvastatin 80 mg (n=357) or simvastatin 80 mg plus placebo (n=363) for 24 months following a 6-week washout/run-in period. The primary outcome measure was a surrogate endpoint for atherosclerosis progress, mean carotid-artery-intima-media thickness assessed by ultrasound. Main secondary outcomes included the regression in mean carotid-artery-intima-media thickness compared to baseline, proportion of subjects with new carotid artery plaques greater than 1.3 mm, change from baseline to week 24 in mean maximal carotid-artery-intima-media thickness, and average change in thickness of the carotid and femoral arteries from baseline.
Enrolled subjects had an average age of 45 years, and 80% received previous statin therapy. Efficacy results were based on an intention to treat analysis and included all subjects who had carotid-artery-intima-media thickness assessed after baseline; ezetimibe/simvastatin (n=322), simvastatin/placebo (n=320). The mean carotid-artery-intima-media thickness was 0.0058 mm for simvastatin-treated subjects vs. 0.0111 mm in the combination therapy group (difference 0.0053 mm, p=0.29). No differences were found in secondary endpoints for ezetimibe/simvastatin (n=322) vs. simvastin (n=320): regression in thickness occurred in 146 (45.3%) and 142 (44.4%) subjects, respectively (p=0.92), new plaque formation was noted in 15 (4.7%) and 9 (2.8%), respectively (p=0.20), and no difference was seen between groups for mean maximal carotid-artery-intima-media thickness (p=0.27) or thickness of femoral or carotid arteries (p>0.05 for all comparisons).
Both regimens were well tolerated with similar discontinuation rates from therapy. No difference was found in terms of elevations in hepatic transaminases, elevated creatinine kinase, or development of myopathy. The combination therapy was associated with lower average LDL readings compared to simvastatin alone (141 vs. 197 mg/dL, difference 16.5%, p<0.01). In addition, C-reactive protein was reduced to a greater extent with combination therapy (difference 25.7%, p<0.01), as were triglycerides (difference 6.6%, p<0.01).
The authors concluded that combination therapy did not lead to significant changes in mean carotid-artery-intima-media thickness as compared to simvastatin alone.
Clinical controversy
The ENHANCE trial has been a source of clinical controversy since the preliminary results were released in January 2008. Two editorials accompany the electronic posting of the ENHANCE publication. Brown and Taylor also discuss the utility of carotid-artery-intima-media thickness as a surrogate marker for atherosclerosis. Their review of previously conducted trials found that a majority of trials have demonstrated that carotid-artery-intima-media thickness correlates to atherosclerosis (measured by angiography). The editorialists comment that the fact combination therapy did not reduce thickness to a greater extent than monotherapy could have to do with the extensive use of statins prior to enrollment (80% in each group). Finally, it is suggested that the ENHANCE results question the common belief that lower LDL is better and suggest that how LDL is reduced may also be important.
Drazen and colleagues have published similar comments and also mention that future data from Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) will provide much needed insight into the place in therapy of ezetimibe. IMPROVE-IT will evaluate the same drugs in high-risk subjects with coronary artery disease with a composite primary outcome of cardiovascular death, myocardial infarction, nonfatal stroke, rehospitalization for acute coronary syndrome, or revascularization. The estimated completion date for IMPROVE-IT is June 2012.
Data suppression?
Part of the press surrounding ENHANCE involves allegations of potential data suppression by Schering-Plough Corporation. The Congressional Committee on Energy and Commerce has sent 2 letters to the company inquiring about the delay in releasing results for presentation. The first letter, dated December 2007, stated that ENHANCE ended in April 2006, and data were not published or presented as of December 2007. The Congressional Committee was also concerned about a discrepancy in endpoints for the trial based on information contained at http://www.clinicaltrials.gov; the endpoint differed from that described in the initial study design. ENHANCE also was not registered at http://www.clinicaltrials.gov until October 2007 (18 months after completion).
The second letter (January 2008) raises concerns about the lack of benefit seen with combination therapy, while the company was actively promoting the drug to consumers via direct-to-consumer advertisements. The committee requested copies of the advertisements, financial records, and communication between the company and the primary investigator for ENHANCE.
Additional information uncovered by Congress reveals the primary investigator was kept out of important meetings involving trial design, notably the change in endpoints. A series of e-mails have been found in which the investigator expresses concern about the lack of release of the findings.
Implications for practice
Currently, no data are available to support that ezetimibe alone or in combination with statins leads to significant improvements in clinically important outcomes such as mortality, stroke, or coronary artery disease. ENHANCE data, based on a surrogate marker of atherosclerosis, suggest that ezetimibe does not induce regression of atherosclerosis. Future trials, notably the IMPROVE-IT will provide further insight and much needed outcome data.
In light of current data, editorialists suggest that patients who need further reduction in LDL despite statin therapy should be managed with diet and exercise and the addition of niacin, fibrates, or bile acid sequestrants if needed. Ezetimibe’s role should be limited to patients who cannot tolerate or are not otherwise candidates for other agents.
References
Jackevicius CA, Tu JV, Ross JS, Ko DT, Krumholz HM. Use of ezetimibe in the United States and Canada [published online ahead of print March 30, 2008]. N Engl J Med. doi:10.1056/NEJMsa0801461.
Bereson A. Journal issues warnings on two cholesterol drugs. New York Times. March 30, 2008. http://www.nytimes.com/2008/03/30/business/30cnd-vytorin.html?ref=business. Accessed April 1, 2008.
Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia [published online ahead of print March 30, 2008]. N Engl J Med. doi: 10.1056/NEJMoa0800742.
Drazen JM, Jarcho JA, Morrissey S, Curfman GD. Cholesterol lowering and ezetimibe [published online ahead of print March 30, 2008]. N Engl J Med. doi:10.1056/NEJMe0801842.
Brown BG, Taylor AJ. Does ENHANCE diminish confidence in lowering LDL or in ezetimibe? N Engl J Med. 2008;358(14):1504-7.
American College of Cardiology statement on ENHANCE trial. http://www.acc.org/enhance.htm. Accessed April 1, 2008.
US National Institutes of Health. Clinical trials.gov. IMPROVE-IT: examining outcomes in subjects with acute coronary syndrome: Vytorin (ezetimibe/simvastatin) vs. simvastatin (Study P04103). Available at: http://clinicaltrials.gov/show/NCT00202878. Accessed April 1, 2008.
The House Committee on Energy and Commerce. News release. Dingell, Stupak to continue ENHANCE trial investigation: study results show no benefit from brand-name drug. http://energycommerce.house.gov/Press_110/110nr171.shtml. Accessed April 1, 2008.