After ENHANCE: is more LDL cholesterol lowering even better?

After much speculation, to the point of congressional involvement, regarding the reasons for the delay in reporting the results of a relatively small trial of carotidartery imaging in patients with familial hypercholesterolemia (FH), a brief top-line synopsis was released this year on January 14 (1 ). The study, called ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia), was designed to determine if an anticipated additional reduction in LDLcholesterol (LDLc) of 18% when ezetimibe 10 mg was added to 80 mg of simvastatin (Vytorin 10/80 mg) versus 80 mg simvastatin alone would result in either less progression or more regression of carotid atherosclerosis as measured by intima-media thickening (cIMT). The study was conducted over a 2-year period and enrolled 720 FH patients, with roughly equal numbers of men and women, mean age 45 years. Although patients had very high LDLc concentrations of nearly 320 mg/dL (8.32 mmol/L) after all lipid-lowering agents were washed out, more than 80% had been on prior statin treatment, including high-dose treatment, for many years before entry into the trial. The changes in cIMT after 2 years did not significantly differ from baseline for either treatment group or from one treatment group to the other. The popular press contacted selected “experts” who gave flamboyant, misleading, and sometimes self-serving or agenda-driven comments (2 ) interpreting the results either as a failure of the mechanism by which LDLc was decreased, or as evidence that LDLc reduction itself was not an effective way to ameliorate the course of atherosclerosis. The complete details of ENHANCE have now been published (3 ), and a more complete evaluation is possible. A number of critical flaws in the trial are apparent. The most important determinant of any clinical trial such as ENHANCE is the presence of disease in patients at baseline. For example, in testing the efficacy of an antibiotic it is crucial to recruit patients with an infection; otherwise, no matter how good the antibiotic, it will be impossible to show it is better than even a placebo! Unfortunately, because the design of the ENHANCE trial was based mainly on a prior cIMT trial in FH patients, ASAP (Atorvastatin versus Simvastatin on Atherosclerosis Progression), no minimum cIMT entry criteria were used in ENHANCE, as there have been for most other trials. The baseline cIMT from ASAP was 0.93 mm and was projected to be similar in ENHANCE. When baseline cIMT was analyzed after completion of the trial, the cIMT in ENHANCE, 0.69 mm, was found to be significantly lower than that observed in other trials. In comparison, another recent cIMT trial in non-FH patients with no prior statin exposure, METEOR (Rosuvastatin on Progression of cIMT in Low-Risk Individuals with Subclinical Atherosclerosis), which compared placebo to 40 mg of rosuvastatin (expected LDLc reduction of approximately 50%), required study patients to have a minimum of 1.2 mm in the maximum cIMT measurement and no prior exposure to statins. Thus the majority of patients in the ENHANCE trial had minimal carotid atherosclerosis and would not have qualified for a trial like METEOR. Because ASAP patients were recruited in 1997, only a few had received prior statin therapy, and because atorvastatin had just been cleared for general use and the top dose of simvastatin at the time was 40 mg, none of the ASAP patients had been on the aggressive treatment that was more standard by the time of the ENHANCE enrollment period. The second critical factor for demonstrating the superiority of one treatment to another is that one of the treatment groups must show a statistically significant worsening or improvement compared to the other group in the variable selected for measurement as a disease indicator (in this case the cIMT). ENHANCE was designed to have a power of 90% to detect a difference of 0.05 mm in cIMT between groups within the 2 year trial period. In ASAP, the study on which ENHANCE was based, the progression in cIMT during the 2-year trial period in the simvastatin 40-mg treatment group (expected LDLc decrease 40%) was 0.036 mm. At the end of the 2-year ENHANCE trial the change in cIMT was substantially less than projected in both groups, 0.011 mm in the Vytorin group and Medpace Reference Labs, Cincinnati, OH. Address correspondence to the author at: Medpace Reference Labs, 4620 Wesley Ave, Cincinnati, OH 45212. e-mail [email protected]. Received February 28, 2008; accepted March 4, 2008. Previously published online at DOI: 10.1373/clinchem.2008.104893 Clinical Chemistry 54:6 940–942 (2008) Perspectives