Methods

The present 6-week, multicenter (United States [n = 19], Puerto Rico [n = 1], Canada [n = 7], Hungary [n = 3], Denmark [n = 3], Peru [n = 3], Poland [n = 10], Columbia [n = 3], Finland n = 5], and Croatia [n = 3]), randomized, double-blind, parallel-arm study of the EfficACy and SafeTy of Ezetimibe Added On to Rosuvastatin Versus Up Titration of Rosuvastatin in Hypercholesterolemic Patients at Risk for Coronary Heart Disease (ACTE) was conducted from January 23, 2009 to May 9, 2010 ( clinical trials.gov identifier NCT00783263 ). The trial was conducted in accordance with principles of Good Clinical Practice and all local and/or national regulations and directives. The appropriate institutional review boards approved the protocol (study 139), and all participants provided written informed consent before enrollment.

The subjects included in the present study were hypercholesterolemic men and women aged 18 to 79 years with a moderately high risk (subjects with ≥2 risk factors conferring a 10-year risk of CHD of 10% to 20%, as estimated from the Framingham risk scores), high risk without AVD (subjects with CHD risk equivalents such as diabetes mellitus or ≥2 risk factors conferring a 10-year risk of CHD >20%, as estimated from the Framingham risk scores), or high risk with AVD (subjects with established CHD or patients with CHD risk equivalents and other AVD [peripheral arterial disease, atherosclerotic aortic disease, or carotid artery disease]). Eligible subjects included those taking rosuvastatin 5 mg or 10 mg or lipid-lowering therapy of equal or lesser potency for ≥6 weeks before screening, or treatment-naïve subjects (no statin and/or ezetimibe for the 6 weeks before the prescreen visit). The moderately high-risk and high-risk subjects without AVD were required to have a LDL cholesterol level of ≥100 mg/dl but ≤160 mg/dl (2.6 and 4.2 mmol/L, respectively) before randomization. An LDL cholesterol level of ≥70 mg/dl but ≤160 mg/dl (1.8 and 4.2 mmol/L, respectively) was required for those at high risk of CHD with AVD. Fasting triglyceride levels of <350 mg/dl were also required. The main exclusion criteria included previous significant myopathy or rhabdomyolysis with ezetimibe or any statin or hypersensitivity or intolerance to ezetimibe or rosuvastatin; prespecified cardiovascular diseases (congestive heart failure [New York Heart Association class III or IV], unstable angina pectoris, myocardial infarction, coronary artery bypass surgery, angioplasty, or uncontrolled or severe peripheral artery disease within 3 months of the rosuvastatin run-in period); disorders of the hematologic, digestive, or central nervous systems, including cerebrovascular disease and degenerative disease that would limit study evaluation or participation; uncontrolled hypertension; intestinal malabsorption; uncontrolled endocrine or metabolic diseases known to influence serum lipids or lipoproteins; treatment with prohibited concomitant therapies (i.e., lipid-lowering agents, including fish oils, within 6 weeks of run-in or fibrates within 8 weeks of run-in; itraconazole, cyclosporine, lopinavir, or ritonavir; systemic corticosteroids within 6 weeks of run-in); current active liver disease or alanine aminotransferase and/or aspartate aminotransferase levels ≥2 times the upper limit of normal); creatine kinase levels >3 times the upper limit of normal; and estimated glomerular filtration rate ≤30 ml/min/1.73 m ² using the 4-variable Modification of Diet in Renal Disease equation, nephrotic syndrome, or other clinically significant renal disease.

Once eligible, patients were assigned to receive run-in open-label rosuvastatin 5 or 10 mg/day for 4 weeks (5 weeks for those switching medication or treatment naïve) according to their cardiovascular risk, current use of lipid-lowering therapy, and LDL level at screening. Patients were stratified according to their run-in treatment (stratum I, rosuvastatin 5 mg; stratum II, rosuvastatin 10 mg). The subjects in each stratum who were not at their NCEP ATP III recommended LDL cholesterol target before randomization (<100 mg/dl for moderately high- or high-risk subjects without AVD, <70 mg/dl for high-risk subjects with AVD) were centrally randomized using an interactive voice response system into equal-size double-blind treatment groups of ezetimibe 10 mg added to the run-in dose of rosuvastatin or up-titration of the run-in dose of rosuvastatin for 6 weeks. All subjects were instructed to follow the NCEP ATP III therapeutic lifestyle changes or a similar cholesterol-lowering diet throughout the study. All subjects, investigators, and study personnel were kept unaware of the treatment allocation until the study was complete, the review of the subject-level data was finished, and the data file was locked.

The primary efficacy end point was the percentage of change from baseline in LDL cholesterol evaluated in the overall population (pooled across doses). The evaluation of this end point for each stratum separately, and the percentage of subjects reaching the NCEP ATP III recommended LDL cholesterol targets in the overall population (pooled across doses) constituted the key secondary efficacy end points. Other secondary efficacy end points included the percentage of subjects reaching the NCEP ATP III recommended LDL cholesterol targets evaluated in each stratum separately; the percentage of subjects achieving an LDL cholesterol level of <70 mg/dl in the overall population and in each stratum separately; and the percentage of change from baseline in other lipids, lipoproteins, and high-sensitivity C-reactive protein evaluated in the overall population and in each stratum separately. Safety and tolerability were assessed by review of all safety parameters, including adverse experiences and laboratory values.

The primary and secondary efficacy analyses included the full analysis set population and included all randomized subjects receiving ≥1 dose of blinded study treatment, with baseline data available. The percentage of change from baseline in LDL cholesterol after 6 weeks was analyzed using longitudinal data analysis, which included the baseline and calculated postbaseline percentage of change from the baseline measurements as response variables and terms for treatment, time, stratum, and the interaction of time by treatment. A similar method was used to evaluate the key and other secondary end points involving the percentage of change from baseline. Data for triglycerides and high-sensitivity C-reactive protein were log-transformed because of the non-normal distribution. The percentage of subjects reaching the prespecified LDL cholesterol targets, in the overall population and in each stratum, was analyzed using a logistic regression model with terms for treatment, stratum (for overall population only), and baseline LDL cholesterol category (3 levels: <100, 100 to <130, and ≥130 mg/dl). Sensitivity analyses that excluded those subjects from the full analysis set population who had met the LDL cholesterol entrance criteria 1 week before randomization but were at the prespecified target at randomization were also performed for the primary and key secondary efficacy variables. Subgroup analyses were performed for the primary end point to assess the consistency of the treatment effect across the various prespecified subgroups.

For the primary efficacy end point, with 200 patients/group (pooled doses), the study had ≥99% power to detect a 10% anticipated difference, assuming a SD of 19% (α level of 0.05, 2-sided). With 90 patients/group (stratum I) and 110 patients/group (stratum II), the study had 95% power to detect a difference of 10%, assuming a SD of 18% for stratum I and 20% for stratum II (α level of 0.05, 2-sided). A closed testing procedure was used to control for multiplicity across the primary and key secondary end points. Statistical significance for treatment comparisons related to key secondary end points was only considered if the treatment difference for the primary end point was significant (p ≤0.05), and a step down ordered testing procedure was performed in the following order: (1) percentage of change in LDL cholesterol from baseline in each stratum and (2) percentage of subjects reaching their LDL cholesterol target in the overall population. A closed testing procedure was also used to step down from the overall population (across strata) to each stratum for the other secondary end point analyses.

Safety was evaluated using the all-patients-as-treated population, including all randomized subjects who had received ≥1 dose of the study treatment. The prespecified safety end points of special interest for the present study were subject to inferential testing for statistical significance, with p values and 95% confidence intervals provided for between-group comparisons using a stratified Miettinen and Nurminen method. In addition, 95% confidence intervals for between-group differences were provided for the broad AE categories including ≥1 AEs, drug related AEs, serious AEs, and discontinuations because of an AE.

Results

Of the 1,925 participants screened, 440 were administered the study drug, with 197 (44.8%) receiving rosuvastatin 5 mg and 243 (55.2%) receiving rosuvastatin 10 mg during the 4- to 5-week open label run-in period ( Figure 1 ). The subjects receiving rosuvastatin 5 mg during the run-in period (stratum I) were randomized to rosuvastatin 5 mg plus ezetimibe 10 mg add-on or rosuvastatin up-titration to 10 mg. Those receiving rosuvastatin 10 mg (stratum II) were randomized to rosuvastatin 10 mg plus ezetimibe 10 mg add-on or rosuvastatin up-titration to 20 mg. Overall, 3.2% of participants receiving ezetimibe add-on to rosuvastatin discontinued the study: 2.3% because of AEs, 0.5% were lost to follow-up, and 0.5% withdrew consent. For the participants allocated to rosuvastatin up-titration, 2.3% discontinued the study: 0.5% because of AEs, 0.5% were lost to follow-up, and 1.4% withdrew consent. Compliance was high and similar between the treatment groups. The overall mean compliance was 98.5%, with >94% of patients of all treatment groups achieving >95% compliance with the study therapy.

Participant distribution. *A subject could be excluded for >1 reason. EZ = ezetimibe; FAS = full analysis set (included all randomized patients with baseline and ≥1 valid postbaseline evaluation); LDL-C = low-density lipoprotein cholesterol; PP = per protocol (protocol violators removed from full analysis set population); Rosuva = rosuvastatin.

The baseline characteristics and risk factors were generally similar within each rosuvastatin 5 or 10 mg run-in stratum ( Table 1 ). The mean age of the participants in the present study was 61 years, and most participants were white (77%) and men (62%). Of the 440 subjects randomized, 68% were at high risk with AVD, 18% were at high risk without AVD, and 15% were at moderately high risk. The baseline lipid parameters and high-sensitivity C-reactive protein levels were generally well balanced across all groups ( Table 2 ). A total of 73 participants (17%) met the LDL cholesterol entrance criteria during screening but had LDL cholesterol levels below the entrance criteria (<100 mg/dl for moderately high-/high-risk subjects without AVD, and <70 mg/dl for high-risk subjects with AVD) at randomization.

The addition of ezetimibe 10 mg to the run-in dose of rosuvastatin produced significantly greater percent reductions in LDL cholesterol than rosuvastatin up-titration for the pooled data analysis (primary efficacy end point), as well as for the comparisons within each stratum (key secondary end points; Table 3 ). Sensitivity analysis using the subset of subjects who were above their LDL cholesterol target at baseline was consistent with these results, with rosuvastatin plus ezetimibe add-on lowering LDL cholesterol 14% more than that observed with rosuvastatin up-titration (−21.5% vs −7.6%, p <0.001). Analysis of the pooled data showed a significantly larger percentage of achievement of the prespecified LDL cholesterol levels (<100 mg/dl for moderately high-/high-risk subjects without AVD and <70 mg/dl for high-risk subjects with AVD) with rosuvastatin plus ezetimibe add-on than with rosuvastatin up-titration (adjusted odds ratio 4.5, p <0.001; Figure 2 ). Similar results were seen when each rosuvastatin run-in stratum was analyzed individually (rosuvastatin 5 mg plus ezetimibe add-on vs rosuvastatin 10 mg, adjusted odds ratio 3.1, p <0.001; rosuvastatin 10 mg plus ezetimibe add-on vs rosuvastatin 20 mg, adjusted odds ratio 6.5, p <0.001; Figure 2 ). Regardless of risk status, attainment of LDL cholesterol <70 mg/dl was also significantly greater for subjects receiving rosuvastatin plus ezetimibe add-on than for those with the rosuvastatin dose doubled (pooled across doses, adjusted odds ratio 8.0; rosuvastatin 5 mg plus ezetimibe add-on vs rosuvastatin 10 mg, adjusted odds ratio 5.1; rosuvastatin 10 mg plus ezetimibe add-on vs rosuvastatin 20 mg, adjusted odds ratio 11.4; p <0.001 for all comparisons; Figure 3 ). The evaluation of other lipid parameters showed significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B with rosuvastatin plus ezetimibe add-on compared to rosuvastatin up-titration; the reductions in triglycerides were similar ( Table 3 ). Pooled across the strata, the percentage of change from baseline in high-density lipoprotein cholesterol and apolipoprotein AI was small and comparable between treatments. The changes in the lipid and lipoprotein ratios and high-sensitivity C-reactive protein are listed in Table 3 . The treatment effect for ezetimibe added to stable rosuvastatin 5 or 10 mg compared to rosuvastatin up-titration was generally consistent across all prespecified subgroups of age, gender, race, risk group, baseline LDL cholesterol level, baseline LDL cholesterol level with a cutoff of 20 mg/dl above the target, baseline triglycerides, and metabolic syndrome/diabetes status ( Figure 4 ).

Table 3

Percentage of change from treated baseline at week 6 in lipid parameters and high-sensitivity C-reactive protein (full analysis set population)

Parameter	Percentage of Change from Treated Baseline ⁎						Treatment Difference †
	Stratum I (R5 run-in)		Stratum II (R10 run-in)		Pooled		Stratum I	Stratum II	Pooled
	R5 + EZ10 (n = 98) ‡	R10 (n = 96) ‡	R10 + EZ10 (n = 121) ‡	R20 (n = 121) ‡	All R5,10 + EZ10 (n = 219) ‡	All R10,20 (n = 217) ‡	R5 + EZ10 vs R10	R10 + EZ10 vs R20	All R + EZ10 vs all R
Low-density lipoprotein cholesterol	−17.9	−5.6	−23.7	−6.3	−21.0	−5.7	−12.3 §	−17.5 §	−15.2 §
Total cholesterol	−10.7	−3.9	−14.3	−4.1	−12.6	−3.9	−6.8 ¶	−10.1 §	−8.7 §
Non–high-density lipoprotein cholesterol	−13.6	−5.2	−20.5	−5.7	−17.1	−5.2	−8.4 ∥	−14.8 §	−12.0 §
Triglycerides	−1.6	−3.6	−9.8	−2.9	−6.3	−3.2	1.9	−7.0	−3.1
Apolipoprotein B	−11.8	−5.2	−15.7	−4.0	−13.8	−4.4	−6.6 ∥	−11.6 §	−9.4 §
High-density lipoprotein cholesterol	−2.7	1.8	1.6	1.9	−0.5	1.7	−4.5 #	−0.3	−2.1
Apolipoprotein AI	2.5	0.3	0.0	1.0	−1.2	0.6	−2.8	−1.0	−1.8
Low-density lipoprotein/high-density lipoprotein cholesterol	−13.8	−5.8	−24.1	−6.3	−19.4	−6.2	−7.9 ∥	−17.8 §	−13.2 §
Total/high-density lipoprotein cholesterol	−5.5	−4.1	−14.9	−4.3	−10.7	−4.2	−1.4	−10.6 §	−6.4 ¶
Non–high-density lipoprotein/high-density lipoprotein cholesterol	−7.1	−5.1	−20.8	−5.1	−14.6	−5.1	−2.0	−15.7 §	−9.5 ¶
Apolipoprotein B/apolipoprotein AI	−8.3	−4.8	−14.6	−3.7	−11.8	−4.2	−3.5	−10.8 §	−7.5 §
High-sensitivity C-reactive protein	−13.1	−13.4	−13.2	−14.1	−14.1	−13.0	0.4	0.8	−1.1

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