Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin. The impact of increasing dose on lowering LDL cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B was investigated. Doubling the dose of each statin was accompanied by a 4% to 7% greater degree of lowering of all atherogenic lipids. A stronger correlation was observed between changes in LDL cholesterol and non-HDL cholesterol (r = 0.92, p <0.001) or apolipoprotein B (r = 0.76, p <0.001) than triglycerides (r = 0.14, p <0.001). On multivariate analysis, baseline lipid level (p <0.0001) and increasing statin dose (p <0.0001) were strong predictors of achieving treatment goals in high-risk patients. Increasing age was a strong independent predictor of achieving goal for all atherogenic lipids (p <0.0001). Achieving LDL cholesterol goals was also more likely in women (p <0.0001), patients with diabetes (p <0.0001), and patients without atherosclerotic disease (p = 0.0002). In contrast, normal triglyceride levels were more often observed in men (p <0.0001) and patients without diabetes mellitus (p = 0.03). In conclusion, doubling statin dose was associated with greater lowering of LDL cholesterol by 4% to 6% and non-HDL cholesterol by 3% to 6%. Greater lipid goal achievement with increasing dose supports the use of high-dose statin therapy for more effective cardiovascular prevention.
The unequivocal benefit of lowering low-density lipoprotein (LDL) cholesterol in clinical trials has led to the establishment of treatment goals by guideline committees. The degree of intensity of these goals is determined on the basis of a patient’s estimated global cardiovascular risk. Although the impact of increasing statin dose on lipid levels and goal attainment has been reported in small cohorts, the degree of incremental benefit has not been fully elucidated. An Individual Patient Meta-Analysis of Statin Therapy in At Risk Groups: Effects of Rosuvastatin, Atorvastatin and Simvastatin (VOYAGER) was conceived to use an individual patient meta-analysis to characterize the effect of individual statin agents on lipid levels using individual patient data from pooled clinical studies that involved the comparison of rosuvastatin with either atorvastatin or simvastatin, thus representing the 3 statins most commonly used in clinical practice. The objective of the current analysis was to determine the relation between increasing dose of each individual statin and their incremental ability to lower levels of atherogenic lipid parameters and achieve established treatment goals.
Methods
An individual patient meta-analysis was performed of 37 studies that involved fixed-dose comparisons of rosuvastatin with either atorvastatin or simvastatin and recorded lipid parameters at baseline and on therapy, for which individual patient data were available. Studies that were of <4 weeks in duration, were open-label extension, were observational, or were pharmacokinetic were not included. Only studies for which individual patient data were available were used. Studies were identified by a comprehensive search of the Cochrane Controlled Trials Registry, Medline (1999 to 2007), EMBASE (1999 to 2007) Citeline Trialtrove, and collection of all published research on rosuvastatin.
All lipid parameters were quantified on samples collected in the fasting state. Cholesterol and triglyceride quantitation was determined by enzymatic assay. LDL cholesterol was calculated using the Friedewald equation for patients with triglycerides ≤400 mg/dl and measured by β quantification for those with triglycerides >400 mg/dl. High-density lipoprotein (HDL) cholesterol was quantified after the precipitation of apolipoprotein (apo) B–containing lipoproteins. Levels of non-HDL cholesterol were calculated by the subtraction of HDL cholesterol from total cholesterol. Apo B and high-sensitivity C-reactive protein levels were quantified by immunonephelometry.
All statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). Demographic data are expressed as mean ± SD for continuous variables and as percentages for categorical variables. When a parameter was not normally distributed (triglycerides, C-reactive protein), it is expressed as median (interquartile range). In studies in which patients were force-titrated to higher doses at predefined intervals, each period was considered an exposure. For each lipid variable, percentage change was calculated from baseline to the end of each fixed dose period.
Changes in lipid parameters were compared using a single mixed-effects model that used fixed effects for trial and periods and for statin and doses and a random effect for trial and period-by-treatment interaction. The model was formulated in this way so that the contribution of each study was weighted by the inverse of its variance and to provide correct estimates of error terms for calculation of confidence intervals. Changes in lipid parameters are expressed as least squares mean ± SEM. Differences in percentage change of lipid parameters between each dose of rosuvastatin and each dose of atorvastatin or simvastatin were calculated using only those trials that directly randomized the treatments being compared.
Lipid goal achievement is expressed as the percentage of high-risk subjects with on-treatment values less than the specified target. Estimates of the differences between treatments for each on-treatment target were obtained using logistic regression analysis with terms for trial and period and for treatment used in the model. Only those studies that contributed to the specific comparison were used. For multivariate analyses, additional factors and all trials and periods were included in the logistic regression model. Partial correlation coefficients were used to measure the relation between changes in different atherogenic lipid parameters for the whole cohort using multivariate analysis of variance with trial and statin dose as factors. A p value <0.05 was considered statistically significant, without adjustment for multiple comparisons.
Results
Thirty-seven studies were identified that involved comparisons of rosuvastatin with either atorvastatin or simvastatin on lipid levels. Because 11 studies involved forced titration to higher statin doses, there was a total of 38,199 exposures to individual doses of statin agents, among the population of 32,258 patients. The clinical characteristics and biochemical parameters at baseline of the entire cohort are listed in Table 1 . Subjects had an average age of 60 years, with an equal distribution of gender and a predominance of Caucasians. A high prevalence of established atherosclerotic disease and high cardiovascular risk was present: 57% of the subjects were considered “high risk,” defined as having either atherogenic dyslipidemia (triglycerides ≥150 mg/dl and HDL cholesterol <40 mg/dl), documented atherosclerotic cardiovascular disease (coronary artery disease, peripheral arterial disease, carotid artery disease, or abdominal aortic aneurysm), or diabetes. Subjects demonstrated elevated levels of atherogenic lipid parameters, including LDL cholesterol, triglycerides, and non-HDL cholesterol. HDL cholesterol and high-sensitivity C-reactive protein levels were within normal limits.
| Parameter | Cohort (n = 32,258) |
|---|---|
| Age (years) | 60.0 ± 11.1 |
| Men | 56.7% |
| Caucasian | 79.9% |
| Black | 5.1% |
| Oriental Asian | 5.6% |
| High-risk patient ⁎ | 67.1% |
| Diabetes mellitus | 27.5% |
| Atherogenic dyslipidemia † | 18.8% |
| Atherosclerotic disease | 48.0% |
| Low-density lipoprotein cholesterol (mg/dl) | 170.9 ± 38.7 |
| High-density lipoprotein cholesterol (mg/dl) | 48.7 ± 12.7 |
| Triglycerides (mg/dl) | 161.2 (120.4–215.0) |
| Non-high-density lipoprotein cholesterol (mg/dl) | 205.2 ± 41.8 |
| Apo B (mg/dl) | 159.3 ± 37.2 |
| C-reactive protein (mg/L) | 0.38 (0.15–0.93) |
⁎ Established atherosclerotic disease, diabetes, or triglycerides >150 mg/dl or HDL <40 mg/dl.
The impact of increasing dose of each statin on LDL cholesterol levels is summarized in Figure 1 and Table 2 . Increasing doses of all agents predictably resulted in an incremental benefit in terms of LDL cholesterol reduction. Despite differences in the efficacy of each individual agent, the incremental impact of dose doubling was comparable, with a 5% to 7% increase in LDL cholesterol lowering. The impact of increasing statin dose on the likelihood of achieving treatment goals was investigated in high-risk patients (n = 21,656; Table 3 ). In general, a greater percentage of patients achieved treatment goals using increasing doses of all agents or in the setting of lower levels at baseline ( Table 3 ). The lack of incremental benefit observed at the highest doses of rosuvastatin and simvastatin was primarily observed in those with lower LDL cholesterol levels at baseline and probably reflects the higher likelihood that they would meet their goal. After controlling for statin dose and baseline LDL cholesterol level, multivariate analysis revealed that predictors of achieving an LDL cholesterol goal of <100 mg/dl included female gender (p <0.0001), increasing age (p <0.0001), diabetes (p <0.0001), and the lack of documented atherosclerotic cardiovascular disease (p = 0.0002). Increasing statin dose was not associated with a significant increase in subject withdrawal due to adverse events.
| Treatment | Least Squares Mean (SE) % Change from Baseline | |||
|---|---|---|---|---|
| LDL-C | Non-HDL-C | Triglycerides | Apo B ⁎ | |
| Rosuvastatin (mg) | ||||
| 5 (n = 670) | −38.8 ± 0.9 | −35.4 ± 0.8 | −15.2 ± 1.4 | −30.2 ± 0.8 |
| 10 (n = 11,690) | −44.1 ± 0.6 | −40.2 ± 0.5 | −18.7 ± 0.5 | −34.5 ± 0.4 |
| 20 (n = 3,554) | −49.5 ± 0.5 | −45.1 ± 0.4 | −20.1 ± 0.7 | −39.0 ± 0.4 |
| 40 (n = 2,983) | −54.7 ± 0.4 | −49.9 ± 0.3 | −21.9 ± 1.0 | −42.9 ± 0.6 |
| Atorvastatin (mg) | ||||
| 10 (n = 7,837) | −35.5 ± 0.6 | −32.8 ± 0.5 | −16.4 ± 0.5 | −27.6 ± 0.4 |
| 20 (n = 3,908) | −41.4 ± 0.5 | −38.2 ± 0.5 | −18.9 ± 0.6 | −33.3 ± 0.4 |
| 40 (n = 1,324) | −46.2 ± 0.5 | −42.6 ± 0.5 | −20.7 ± 1.2 | −36.7 ± 0.7 |
| 80 (n = 2,072) | −50.2 ± 0.4 | −46.6 ± 0.4 | −25.0 ± 1.1 | −40.8 ± 0.6 |
| Simvastatin (mg) | ||||
| 10 (n = 165) | −27.4 ± 1.4 | −24.8 ± 1.2 | −9.3 ± 2.5 | −20.1 ± 1.4 |
| 20 (n = 2,929) | −33.0 ± 0.6 | −30.1 ± 0.5 | −12.7 ± 0.7 | −25.3 ± 0.6 |
| 40 (n = 548) | −38.9 ± 0.9 | −35.0 ± 0.8 | −13.3 ± 1.4 | −30.0 ± 0.8 |
| 80 (n = 479) | −45.0 ± 1.0 | −40.5 ± 0.9 | −14.1 ± 1.8 | −34.1 ± 1.0 |
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