High-dose rosuvastatin induces regression of coronary atherosclerosis, but it remains uncertain whether usual-dose statin has similar effects. We compared the effects of atorvastatin 20 mg/day versus rosuvastatin 10 mg/day on mild coronary atherosclerotic plaques (20% to 50% luminal narrowing and lesion length >10 mm) using intravascular ultrasound (IVUS). Three hundred fifty statin-naive patients with mild coronary atherosclerotic plaques were randomized to receive atorvastatin 20 mg/day or rosuvastatin 10 mg/day. IVUS examinations were performed at baseline and 6-month follow-up. Primary end point was percent change in total atheroma volume (TAV) defined as (TAV at 6 months − TAV at baseline)/(TAV at baseline) × 100. Evaluable IVUS was obtained for 271 patients (atorvastatin in 143, rosuvastatin in 128). Clinical characteristics, lipid levels, and IVUS measurements at baseline were similar between the 2 groups. At 6-month follow-up, percent change in TAV was significantly less in the atorvastatin group than in the rosuvastatin group (−3.9 ± 11.9% vs −7.4 ± 10.6%, respectively, p = 0.018). In contrast, change in percent atheroma volume was not different between the 2 groups (−0.3 ± 4.2 vs −1.1 ± 3.5, respectively, p = 0.157). Compared to baseline, TAV and TAV at the most diseased 10-mm subsegment were significantly decreased in the 2 groups (p <0.001). Changes in lipid profiles at 6-month follow-up were similar between the 2 groups. In conclusion, usual doses of atorvastatin and rosuvastatin induced significant regression of coronary atherosclerosis in statin-naive patients, with a greater decrease in favor of rosuvastatin.
Atorvastatin (10 to 20 mg/day) and rosuvastatin (10 mg/day) are commonly prescribed to prevent recurrent coronary events. However, little is known about whether this approach is as effective as high-dose statin therapy and whether plaque regression differences exist according to type of statin used. In the present study, we compared the effects of atorvastatin versus rosuvastatin therapy with equivalent potency on mild coronary atherosclerotic plaques using intravascular ultrasound (IVUS; atorvastatin versus rosuvastatin therapy with equivalent potency on mild coronary atherosclerotic plaques [ARTMAP] trial).
Methods
ARTMAP is a prospective, single-center, open-label, randomized comparison trial involving statin-naive patients ≥18 years old with clinically indicated percutaneous coronary intervention from September 2004 through June 2009. Patients were included if they had ≥1 atherosclerotic plaque with 20% to 50% luminal narrowing and lesion length >10 mm in a coronary artery by visual assessment that had not been subjected to intervention. Exclusion criteria included coronary artery bypass graft surgery, valvular heart disease, left ventricular ejection fraction <40%, any heart failure, renal insufficiency (serum creatinine >1.5 mg/dl), active liver disease, and any statin therapy in the previous 4 weeks. The study protocol was approved by our institutional review committee. All patients provided written informed consent.
Patients were randomized to receive atorvastatin 20 mg/day or rosuvastatin 10 mg/day after IVUS examination. The randomization code was generated by computer, and the study drug was administered after the procedure. Biochemical laboratory tests were performed at the time of admission and at 1- and 6-month follow-up periods. All patients were clinically monitored by laboratory measurements at 1 month and 3 and 6 months. Routine coronary angiography and IVUS examination at 6 months were requested for all patients.
The longest and least angulated target vessel meeting the inclusion criteria was selected. The region of interest was flanked by 2 anatomic landmarks (side branches) that were easily identifiable at follow-up. After intracoronary administration of nitroglycerin 0.2 mg, IVUS imaging was performed using a motorized transducer pullback system (0.5 mm/s) and a commercial scanner (SCIMED/Boston Scientific, Natick, Massachusetts) that consisted of a rotating 40-MHz transducer within a 3.2Fr imaging sheath. IVUS images were recorded on a computer disk and analyzed by personnel unaware of the study drug. After the 6-month treatment period, actively participating patients underwent repeat coronary angiography and IVUS examination.
Core laboratory personnel (CVRF, Seoul, Korea) blinded to treatment assignment analyzed all IVUS images using validated software (EchoPlaque 3.0, Indec Systems, Mountain View, California). A technician selected a distal branch site as the beginning point for analysis, and manual planimetry was used to trace the leading edges of the luminal and external elastic membrane (EEM) borders every 1 mm in the region of interest. Total atheroma volume (TAV) was calculated as the sum of differences between EEM and lumen cross-sectional areas (CSAs) across all evaluable slices. Normalized TAV was calculated as the product of the mean atheroma area and median segment length in the entire population. Percent atheroma volume (PAV) was calculated as PAV = (Σ[EEM CSA − lumen CSA ]/ΣEEM CSA ) × 100. To observe the variability of the IVUS measurements, intra- and interobserver coefficients of variation were calculated in 20 randomly selected lesions. Inter- and intraobserver coefficients of variation were 0.07 and 0.06 mm 3 for total lumen volume and 0.04 and 0.03 mm 3 for total vessel volume, respectively.
The primary end point was percent change in TAV defined as (TAV at 6 months minus TAV at baseline)/(TAV at baseline) × 100. Secondary end points included change in TAV (TAV at 6 months minus TAV at baseline), change in PAV (PAV at 6 months minus PAV at baseline), and change in TAV within the most diseased baseline 10-mm subsegment and percent change from baseline in lipid levels.
A sample size of approximately 140 patients per treatment group was calculated to provide 80% power (assuming an SD of 19%) to detect a difference of 6.4% with a significance level of 0.05 using a 2-sided test. With an anticipated dropout rate of 20%, a final sample size of 175 patients per treatment group (total 350 patients) was specified to provide an adequate number of evaluable patients. Continuous variables are expressed as mean ± SD or median with interquartile range, whereas categorical variables are expressed as frequency. Continuous variables were compared using paired t test or Wilcoxon rank-sum test for changes in each group and unpaired t test or Mann–Whitney U test for differences between the 2 groups. IVUS end points were analyzed using an analysis of covariance model with baseline IVUS values as a covariate and treatment group as a fixed factor. Statistical significance was defined as a 2-sided p value <0.05.
Results
As shown in Figure 1 , 350 patients were randomized to receive atorvastatin 20 mg/day (n = 178) or rosuvastatin 10 mg/day (n = 172) during the study period. IVUS follow-up was performed in 302 patients (86.3%). Of these, 271 patients (atorvastatin in 143, rosuvastatin in 128) had an evaluable baseline IVUS and a follow-up IVUS and comprised the study population.
Baseline clinical characteristics were not different between the 2 groups, except age ( Table 1 ). Lipid levels were also similar between the 2 groups ( Table 2 ). At 6-month follow-up, total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were significantly decreased in the 2 groups (p <0.001), whereas high-density lipoprotein cholesterol levels were significantly increased (p <0.001). High-sensitivity C-reactive protein levels at 6 months were comparable between the 2 groups (p = 0.263).
| Characteristics | Atorvastatin | Rosuvastatin | p Value |
|---|---|---|---|
| (n = 143) | (n = 128) | ||
| Age (years) | 57.6 ± 7.6 | 55.3 ± 9.4 | 0.024 |
| Men/women | 117/26 | 106/22 | 0.874 |
| Current smoker | 71 (49.7%) | 56 (43.8%) | 0.345 |
| Diabetes mellitus | 26 (18.2%) | 26 (20.3%) | 0.770 |
| Hypertension | 70 (49.0%) | 64 (50%) | 0.903 |
| Acute myocardial infarction | 47 (32.9%) | 45 (35.2%) | 0.893 |
| Unstable angina pectoris | 52 (36.4%) | 41 (32.0%) | 0.622 |
| Stable angina pectoris | 44 (30.8%) | 42 (32.8%) | 0.794 |
| Target coronary artery | 0.574 | ||
| Left anterior descending | 57 (39.9%) | 44 (34.3%) | |
| Left circumflex | 38 (26.6%) | 34 (26.6%) | |
| Right | 48 (33.6%) | 50 (39.1%) | |
| Medications at time of follow-up | |||
| Aspirin | 143 (100%) | 128 (100%) | 1.000 |
| Clopidogrel | 124 (86.7%) | 116 (90.6%) | 0.680 |
| Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker | 48 (33.6%) | 38 (30.0%) | 0.434 |
| β Blockers | 71 (49.7%) | 67 (52.3%) | 0.807 |
| Calcium channel antagonists | 108 (75.5%) | 102 (79.7%) | 0.653 |
| Characteristics | Atorvastatin | Rosuvastatin | p Value Between Groups |
|---|---|---|---|
| (n = 143) | (n = 128) | ||
| Total cholesterol (mg/dl) | |||
| Baseline | 183 ± 36 | 186 ± 34 | 0.495 |
| 6 months | 128 ± 23 | 126 ± 25 | 0.510 |
| Change from baseline (%) | −29 ± 14 | −31 ± 13 | 0.095 |
| Low-density lipoprotein cholesterol (mg/dl) | |||
| Baseline | 110 ± 31 | 109 ± 31 | 0.755 |
| 6 months | 56 ± 18 | 53 ± 18 | 0.232 |
| Change from baseline (%) | −47 ± 18 | −49 ± 17 | 0.256 |
| High-density lipoprotein cholesterol (mg/dl) | |||
| Baseline | 40 ± 13 | 40 ± 9 | 0.994 |
| 6 months | 47 ± 12 | 47 ± 11 | 0.795 |
| Change from baseline (%) | 19 ± 25 | 20 ± 25 | 0.752 |
| Triglyceride cholesterol (mg/dl) | |||
| Baseline | 165 ± 93 | 182 ± 121 | 0.196 |
| 6 months | 122 ± 67 | 125 ± 65 | 0.702 |
| Change from baseline (%) | −16 ± 38 | −19 ± 44 | 0.554 |
| High-sensitivity C-reactive protein at 6 months (mg/L) | 1.6 ± 3.2 | 1.2 ± 1.9 | 0.263 |
IVUS data are presented in Table 3 . IVUS-measured lengths were 32.6 ± 7.1 mm in the atorvastatin group and 34.3 ± 7.3 mm in the rosuvastatin group (p = 0.055). Baseline IVUS measurements were not different between the 2 groups. At 6-month follow-up, TAV, normalized TAV, and TAV at the most diseased 10-mm subsegment were significantly decreased in the 2 groups (p <0.001). In contrast, PAV was significantly decreased in the rosuvastatin group (p = 0.001) but not in the atorvastatin group (p = 0.359).
| Characteristics | Atorvastatin | Rosuvastatin | p Value Between Groups |
|---|---|---|---|
| (n = 143) | (n = 128) | ||
| Total atheroma volume (mm 3 ) | |||
| Baseline | 215 ± 89 | 229 ± 94 | 0.226 |
| Follow-up | 205 ± 85 | 210 ± 86 | 0.655 |
| Nominal change (interquartile range) | −6.7 (−27.0 to 4.6) | −15.6 (−34.2 to −0.9) | 0.012 ⁎ |
| p value compared to baseline | <0.001 | <0.001 | |
| Percent change (primary end point) | −3.9 ± 11.9 | −7.4 ± 10.6 | 0.018 † |
| Normalized total atheroma volume (mm 3 ) | |||
| Baseline | 220 ± 80 | 220 ± 69 | 0.994 |
| Follow-up | 211 ± 78 | 201 ± 63 | 0.280 |
| Nominal change (95% confidence interval) | −9.6 (−14.4 to −4.8) | −18.2 (−22.6 to −13.7) | 0.021 † |
| p value compared to baseline | <0.001 | <0.001 | |
| Percent change | −3.9 ± 11.9 | −7.5 ± 10.7 | 0.017 † |
| Percent atheroma volume (%) | |||
| Baseline | 42.3 ± 8.6 | 43.3 ± 9.6 | 0.991 |
| Follow-up | 43.0 ± 8.7 | 42.3 ± 9.7 | 0.523 |
| Nominal change (95% confidence interval) | −0.3 (−1.0 to 0.4) | −1.0 (−1.7 to −0.4) | 0.157 † |
| p value compared to baseline | 0.359 | 0.001 | |
| Percent change | −0.2 ± 10.7 | −2.2 ± 8.7 | 0.117 † |
| Atheroma volume in 10-mm subsegment with greatest disease severity (mm 3 ) | |||
| Baseline | 74.9 ± 26.8 | 76.1 ± 25.2 | 0.706 |
| Follow-up | 70.7 ± 26.9 | 68.0 ± 23.6 | 0.378 |
| Nominal change (95% confidence interval) | −4.2 (−6.1 to −2.2) | −8.1 (−10.2 to −5.9) | 0.014 † |
| p value compared to baseline | <0.001 | <0.001 | |
| Percent change (interquartile range) | −4.8 (−13.6 to 3.8) | −9.5 (−9.5 to −0.7) | 0.011 ⁎ |
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