- Email: [email protected]
Comparison of the effects of atorvastatin versus simvastatin on subclinical atherosclerosis in primary preventionas determined by electronbeam tomography
Comparison of the Effects of Atorvastatin Versus Simvastatin on Subclinical Atherosclerosis in Primary Prevention as Determined by Electron Beam Tomography Harvey S. Hecht,
MD,
and S. Mitchell Harman,
MD, PhD
This study was designed to evaluate the effects of lipidlowering therapy by atorvastatin versus simvastatin on calcified plaque progression, as determined by serial electron beam tomography (EBT), in primary prevention patients. In this observational study, serial EBT was performed before and after 1.2 years of atorvastatin (n ⴝ 103) and simavastatin therapy (n ⴝ 46); ⬃50% of each group was on niacin as well, in similar doses. There were no differences in demographic parameters between the groups. Total, low-density lipoprotein (LDL), and non– high-density lipoprotein (HDL) cholesterol were significantly higher in the atorvastatin group before treatment. Before treatment, EBT calcium score and volume scores were 469 and 378, respectively, in the atorvastatin patients, and 388 and 307, respectively, in the simvastatin patients (p ⴝ NS, atorvastatin vs simvastatin). After treatment, there were no differences in any
lipid or EBT values between the groups. Post-treatment total cholesterol and LDL cholesterol were 156 and 79 mg/dl, respectively, in the atorvastatin cohort and 154 and 76 mg/dl, respectively, in the simvastatin group (p ⴝ NS). Calcium score and volume progressed 10.8%/ year and 8.5%/year, respectively, in the atorvastatin group, and 7.5%/year and 7.8%/year in the simvastatin group (p ⴝ NS, atorvastatin vs simvastatin). We conclude that aggressive treatment with atorvastatin and simvastatin in the primary prevention population, to similar lipid levels, is associated with equal progression of EBT-determined calcified plaque. This suggests that these hydroxymethylglutaryl coenzyme A reductase inhibitors exhibit a “class effect” with respect to progression of subclinical atherosclerosis. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;91:42– 45)
unclear whether different hydroxymethylglucoenzyme A (HMG-CoA) reductase inhibitors Ihavettarylispreferential beneficial qualities, or if there is a
vestigators. All patients gave consent for their data to be used in subsequent analyses. None had a history of clinical CAD. Hypertension was defined by current or recommended use of antihypertensive medications. Smoking was defined as current tobacco usage and diabetes by current or recommended use of diet or medication to reduce blood sugar. Family history of CAD was defined as established CAD in first-degree male relatives ⬍56 years or female relatives ⬍66 years of age. Body mass index was calculated as weight (kilograms) divided by height (square meters). Serum lipid measurements were obtained at the time of both EBT evaluations. Imaging: EBT was performed using an Imatron C-150 scanner (South San Francisco, California). Forty contiguous 3-mm slices were acquired during a single breathhold beginning at the carina with a 350-mm scan field, 100 ms/slice scan time, and triggered at 80% of the RR interval. Three contiguous pixels with an attenuation coefficient of ⬎130 Hounsfield units were the minimum requirements for a calcium deposit. The coronary artery calcium score, corresponding to the amount of plaque, was calculated with the Agatston method1 by a technologist and reviewed by a physician blinded to all clinical data. The calcium volume score, a parameter of plaque burden that is density independent, was calculated according to method used by Callister et al.2 The calcium percentile, an age- and gender-corrected index of plaque
“class effect” common to all, assuming equal reduction of lipid abnormalities. The goal of this study was to compare the effects of the 2 most commonly prescribed HMG-CoA reductase inhibitors, atorvastatin and simvastatin, on progression of subclinical coronary artery disease (CAD) in asymptomatic patients, as measured by serial electron beam tomography (EBT) determined calcified plaque burden.
METHODS
Subjects: One hundred forty-nine consecutive asymptomatic patients with EBT evidence for subclinical atherosclerosis, who were treated with atorvastatin or simvastatin alone or in combination with niacin and who underwent repeat EBT evaluation, comprised the patient population. This was an observational study, not a randomized trial; serial EBT evaluation and lipid-lowering agents and doses employed were chosen by the treating physicians based on practice patterns, and not according to criteria set by the inFrom the Beth Israel Medical Center, New York, New York; and Kronos Longevity Research Institute, Phoenix, Arizona. Manuscript received July 2, 2002; revised manuscript received and accepted August 12, 2002. Address for reprints: Harvey S. Hecht, MD, P.O. Box 450, Brookside, New Jersey 07926. E-mail: [email protected].
42
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 1, 2003
0002-9149/03/$–see front matter PII S0002-9149(02)02995-8
TABLE 1 Demographics, Lipid, and EBT Values Atorvastatin (n ⫽ 103) Age (yrs) Men (%) Women (%) BMI (kg/m2) Hypertension (%) Diabetes (%) Family history (%) Smoking (%) Dose (mg) Niacin No. (%) Dose (mg) Scan interval Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Non-HDL cholesterol (mg/dl) Total/HDL cholesterol EBT calcium score EBT volume score EBT percentile
58.3 ⫾ 7.6 79 (77%) 24 (23%) 27.3 ⫾ 4.5 31 (30%) 2 (2%) 61 (59%) 6 (6%) 14.2 ⫾ 8.1 57 (55%) 1890 ⫾ 1171 1.18 ⫾ 0.28 216.5 ⫾ 41.4 137.2 ⫾ 37.3 50.6 ⫾ 16.3 143.9 ⫾ 78.9 165.9 ⫾ 39.3 4.6 ⫾ 1.3 469.1 ⫾ 483.0 377.5 ⫾ 385.7 80.1 ⫾ 16.0
Simvastatin (n ⫽ 46)
p Value
59.2 ⫾ 9.0 41 (89%) 5 (11%) 27.5 ⫾ 4.6 12 (26%) 4 (9%) 28 (61%) 2 (4%) 23.7 ⫾ 11.8
NS NS NS NS NS NS NS NS
24 (52%) 1875 ⫾ 899 1.24 ⫾ 0.33 199.7 ⫾ 33.3 121.2 ⫾ 32.6 48.7 ⫾ 12.7 163.0 ⫾ 148.5 150.9 ⫾ 31.4 4.3 ⫾ 1.1 388.3 ⫾ 468.9 306.9 ⫾ 361.3 73.4 ⫾ 16.1
NS NS NS ⬍0.05 ⬍0.05 NS NS ⬍0.05 NS NS NS ⬍0.05
BMI ⫽ body mass index.
burden prematurity shown to be powerfully related to prognosis,3 was derived from the University of Illinois asymptomatic patient database. The pre- and posttreatment EBT studies were evaluated side-by-side for comparability of analysis by an experienced observer (HSH). Changes in coronary calcium and calcium volume scores were calculated on an absolute basis and as a percent change per year. To avoid skewing the data by large percent changes in a few individual patients with low scores, the percent changes per year for the treated and untreated groups were calculated by dividing the mean annualized changes by the mean baseline values for the groups as a whole, rather than by the mean of the percent change per year for each individual patient. Laboratory values: Fasting total cholesterol (TC) and triglycerides were determined using enzymatic methods on samples drawn on the same day as the EBT procedure. High-density lipoprotein (HDL) cholesterol was measured after precipitation of apolipoprotein B particles. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from TC. Treatment: HMG-CoA reductase inhibitors were used to lower LDL cholesterol, and niacin derivatives to increase HDL cholesterol and lower triglycerides. The choice of atorvastatin or simvastatin was based upon physician or patient preference, as well as insurance and cost considerations. Aspirin, appropriate diet, weight loss, and exercise were recommended for all patients, as well as tobacco cessation, and tight control of diabetes and hypertension. Statistical analysis. All statistical analyses were performed using STATVIEW v.4.1 (SAS Institute, Cary, North Carolina). Chi-square analysis with Fisher’s
exact test was employed for differences in distribution of qualitative variables between groups and analysis of variance with Fisher’s least significance difference tests to detect significance of difference between atorvastatin- and simvastatin-treated patients. Repeated measures analysis of variance with a 2-way model was employed to detect both the significance of differences from visit 1 to visit 2 and the effect of atorvastatin versus simvastatin on lipid and EBT values. The level of significance was set at p ⬍0.05 (2-tailed).
RESULTS
Demographics (Table 1): There were no differences in risk factor distribution between the 2 groups. Men predominated and a family history of premature CAD was frequently noted (⬃60%). Hypertension was considerably more common than smoking or diabetes. The atorvastatin dose was lower than that of simvastatin, reflecting their difference in potency. Similar percentages of patients were on niacin, in almost identical doses. The interscan interval was 1.2 years for atorvastatin and simvastatin patients. Lipid and EBT values (Table 1): Before treatment, TC, LDL cholesterol, and non-HDL cholesterol were significantly higher in the atorvastatin group. There were no differences in HDL cholesterol, triglycerides, and TC/HDL ratio. EBT calcium score and volume score were similar. EBT percentile was high in both groups, reflecting the severity of the underlying subclinical atherosclerosis, but was significantly higher in the atorvastatin cohort. After treatment (Table 2), there were no differences in any of the lipid parameters. There were no differences in calcium score or volume between groups after treatment. Percent change in lipid and EBT parameters: The 2 cohorts achieved equally dramatic improvement in all lipid parameters (Table 2). There were no significant differences in the mean annualized rates of progression for either calcium score (10.8% vs 7.5%) or volume score (8.5% vs 7.8%) (Table 3). Validation of EBT for tracking progression: Validation of EBT to track changes in plaque burden is provided in Figure 1, which demonstrates the highly significant correlation between serial scans, performed 1.2 ⫾ 0.3 years apart, in 182 treated patients, of both the calcium score (r ⫽ 0.982, p ⬍0.0001) and volume (r ⫽ 0.981, p ⬍0.0001). This extraordinarily strong fit demonstrates the consistency of the method and its potential for evaluating disease progression.
DISCUSSION This study demonstrates that aggressive treatment with atorvastatin and simvastatin is associated with similar outcomes as measured by calcified plaque
PREVENTIVE CARDIOLOGY/EBT EVALUATION OF ATORVASTATIN VS SIMVASTATIN
43
TABLE 2 Change in Lipid Values Atorvastatin
Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Non-HDL cholesterol (mg/dl) TC/HDL cholesterol
†
Simvastatin ‡
Pre*
Post
%Change
Pre*
Post
% Change
216.5 137.2 50.6 143.9 165.9 4.6
156.0 79.1 57.0 100.1 99.0 2.9
⫺26.2 ⫺39.8 ⫹15.6 ⫺22.1 ⫺38.3 ⫺34.1
199.7 121.2 48.7 163.3 150.9 4.3
153.7 75.7 54.9 114.8 98.8 3.0
⫺22.2 ⫺34.7 ⫹14.9 ⫺18.8 ⫺34.3 ⫺29.8
*Pre versus post: all p ⬍0.0001. † Atorvastatin post versus simvastatin post: all p ⫽ NS ‡ Atorvastatin percent change versus simvastatin percent change: all p ⫽ NS.
TABLE 3 Annualized Change in EBT Values Atorvastatin
Calcium score Volume score
Simvastatin
Pre*
Post†
% Change/Yr‡
Pre*
Post
% Change/Yr
469.1 377.5
528.9 415.3
⫹10.8 ⫹8.5
388.3 306.9
424.6 336.6
⫹7.5 ⫹7.8
*Pre versus post: all p ⬍0.0001. † Atorvastatin post versus simvastatin post: all p ⫽ NS. ‡ Atorvastatin percent change per year versus simvastatin percent change per year: all p ⫽ NS.
progression in a primary prevention population. This suggests that, in doses producing similar improvements in lipid profiles, they manifest a class effect with respect to progression of subclinical atherosclerosis, rather than a property unique to a particular drug. Comparison with prior studies: The present study represents the largest series of statin-treated patients evaluated by serial EBT scans, and is the only study with detailed lipid analyses. The reported annualized rate of progression in untreated patients has ranged from 24% to 52%.4 – 6 Maher et al4 reported a 24% annual increase in 35 patients, of whom only 15 had a baseline calcium score ⬎20. Callister et al5 reported a 52%/year progression of calcium volume in 44 untreated asymptomatic patients, 25% in 40 statintreated patients whose LDL cholesterol remained ⬎120 mg/dl, and a 7% decrease associated with achieved LDL cholesterol ⬍120 mg/day in 65 subjects. Budoff et al6 reported a 39% annual progression of calcium score in 81 untreated asymptomatic patients irrespective of risk factors, and 15% progression in 62 statin-treated subjects. Importantly, calcium progression appears to be associated with a worse prognosis. In a follow-up of 225 subjects, there was a relative risk for a cardiac event of 13.4 in those patients whose calcium score progressed ⬎10% versus ⬍10%/year.6 In a second study of 269 subjects, 91% of cardiac events (20 of 22) were associated with progression (41 ⫾ 10% increase in calcium volume) and almost 50% were in patients who progressed despite achieving an LDL cholesterol of ⬍120 mg/dl.7 Calcified plaque may increase as the result of new plaque formation with subsequent calcification, which would appear more ominous, or by calcification of previously existing plaque. The poorer 44 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 91
FIGURE 1. Correlation of EBT plaque burden measured 1.2 ⴞ 0.3 years apart in 182 treated patients. Top panel, calcium score: Y ⴝ ⴚ6.6 ⴙ 1.15 X, r ⴝ 0.982, p <0.0001. Bottom panel, volume score: Y ⴝ ⴚ6.1 ⴙ 1.1 X, r ⴝ 0.98, p <0.0001.
prognosis associated with calcified plaque progression6,7 suggests the former mechanism. Our results differ from the mean 7% decrease in volume score JANUARY 1, 2003
reported by Callister et al5 in patients who achieved a LDL cholesterol of ⬍120 mg/dl (100 ⫾ 17 mg/L), but who had a considerably higher baseline volume score (980 ⫾ 1,611). No other studies, with or without treatment, have reported a mean decrease in calcium or volume scores. The present results are closer to the 15% increase in calcium score reported by Budoff et al,6 in statin-treated patients with baseline calcium scores similar to the present study (mean calcium score 392). Lipid values were not reported in that study. The slightly different percent change analysis in the present study may contribute to differences from other studies. Aggressive lipid treatment: Statins were employed to decrease LDL cholesterol and niacin was used to increase HDL cholesterol and lower triglyceride levels. National Cholesterol Education Program Adult Treatment Panel III secondary prevention treatment goals8 were achieved in 90% of this asymptomatic, primary prevention population with high calcified plaque burdens. This aggressive treatment approach is justified by the high annual event rates (4%/year), equal to or greater than patients with established CAD, in patients with high calcium scores and percentiles.3 Further support is lent by studies demonstrating a relative risk of 8 for scores ⬎270, after adjusting for all risk factors,9 and odds ratios from 14.3 to 20.2 for scores ranging from ⬎80 to ⬎600, which are 3 to 7 times greater than that for the National Cholesterol Education Progam risk factors.10 Calcium percentile has been recommended as a replacement for age in the Framingham risk score11 and is being increasingly recommended for risk assessment.12,13 Atorvastatin versus simvastatin: The validity of this study is dependent on the comparability of the 2 groups, which were not prospectively randomized. Table 1 demonstrates their remarkable similarity. Significantly higher TC, LDL cholesterol and non- HDL cholesterol were noted in the atorvastatin group (Table 2), probably reflecting preferential use of the more potent agent in patients with higher values. However, the differences, although significant, were not large. There were no differences in calcium or volume scores. The calcium percentile was slightly, but significantly, higher in the atorvastatin group, but both represent very large, premature plaque burdens. The post-treatment lipid values and the percent change in lipid values speak strongly for the comparability of therapy (Table 2); there were no differences in any of the post-treatment lipid parameters between the 2 groups, and the percent change in EBT parameters was similar (Table 3). Because combination therapy was used in approximately 50% of both groups, the relative effects on plaque burden of the HMG-CoA reductase inhibitors and niacin cannot be differentiated. The presence of data supporting the impact of the HMG-CoA reductase inhibitors on EBT plaque burden progression6,7
and the lack of data for niacin does not at all discount the possibility that niacin is effective, especially in view of the documented effects of niacin on angiographic regression.14 Although we have demonstrated similar plaque progression in patients on a statin alone compared with statin and niacin combination therapy (unpublished data), the combination therapy group had a much higher incidence of combined metabolic disorders related to HDL cholesterol and triglycerides, and might have had more progression without the addition of niacin. In the present study, the dosages and percentages of patients on niacin were virtually identical, and there were no differences in either the pre- or post-treatment HDL cholesterol and triglyceride levels between the 2 groups. It is, therefore, reasonable to assign either the presence or absence of a difference in plaque progression to either a unique or “class effect” of atorvastatin or simvastatin. The similar plaque progression supports the “class effect” hypothesis, but does not differentiate between LDL cholesterol lowering and pleiotropic components.15,16 1. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–823. 2. Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electronbeam CT volumetric method. Radiology 1998;208:807–814. 3. Raggi P, Callister TQ, Cooil B, He Z, Lippolis NJ, Russo DJ, Zelinger A, Mahmarian JJ. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron beam computed tomography. Circulation 2000; 101:850 –855. 4. Maher JE, Bielak LF, Raz JA, Sheedy PF, Schwartz RS, Peyser PA. Progression of coronary artery calcification: a pilot study. Mayo Clin Proc 1999;74:347– 355. 5. Callister T, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998;339:1972–1978. 6. Budoff MJ, Lane KL, Bakhsheshi H, Mao S, Grassmann BO, Friedman BC, Brundage BH. Rates of progression of coronary calcium by electron beam tomography. Am J Cardiol 2000;86:8 –11. 7. Budoff MJ, Raggi P. Coronary artery disease progression assessed by electron beam computed tomography. Am J Cardiol 2001;88(suppl):51E–55E. 8. Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 9. Wong ND, Hsu JC, Detrano RC, Diamond G, Eisenberg H, Gardin JM. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol 2000;86:495–498. 10. Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:1253–1260. 11. Grundy SM. Coronary plaque as a replacement for age as a risk factor in global risk assessment. Am J Cardiol 2001;88(suppl):8E–11E. 12. Hecht HS, Rodgers GP, Rumberger JA, Achenbach S, Agatston AA, Berman DS, Brown BG, Budoff MJ, Callister TQ, Castelli WP, et al. Practice guidelines for electron beam tomography: a report of the Society of Atherosclerosis Imaging. Am J Cardiol 2000;86:705–706. 13. Greenland P, Smith SC, Grundy SM. Improving coronary heart disease assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–1867. 14. Brown BG, Zhao X, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993;87:1781–1791. 15. LaRosa JC. Pleiotropic effects of statins and their clinical significance. Am J Cardiol 2001;88:291–293. 16. Faggiotto A, Paoletti R. Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins? Curr Atheroscler Rep 2000;2:20 –25.
PREVENTIVE CARDIOLOGY/EBT EVALUATION OF ATORVASTATIN VS SIMVASTATIN
45
MD,
and S. Mitchell Harman,
MD, PhD
This study was designed to evaluate the effects of lipidlowering therapy by atorvastatin versus simvastatin on calcified plaque progression, as determined by serial electron beam tomography (EBT), in primary prevention patients. In this observational study, serial EBT was performed before and after 1.2 years of atorvastatin (n ⴝ 103) and simavastatin therapy (n ⴝ 46); ⬃50% of each group was on niacin as well, in similar doses. There were no differences in demographic parameters between the groups. Total, low-density lipoprotein (LDL), and non– high-density lipoprotein (HDL) cholesterol were significantly higher in the atorvastatin group before treatment. Before treatment, EBT calcium score and volume scores were 469 and 378, respectively, in the atorvastatin patients, and 388 and 307, respectively, in the simvastatin patients (p ⴝ NS, atorvastatin vs simvastatin). After treatment, there were no differences in any
lipid or EBT values between the groups. Post-treatment total cholesterol and LDL cholesterol were 156 and 79 mg/dl, respectively, in the atorvastatin cohort and 154 and 76 mg/dl, respectively, in the simvastatin group (p ⴝ NS). Calcium score and volume progressed 10.8%/ year and 8.5%/year, respectively, in the atorvastatin group, and 7.5%/year and 7.8%/year in the simvastatin group (p ⴝ NS, atorvastatin vs simvastatin). We conclude that aggressive treatment with atorvastatin and simvastatin in the primary prevention population, to similar lipid levels, is associated with equal progression of EBT-determined calcified plaque. This suggests that these hydroxymethylglutaryl coenzyme A reductase inhibitors exhibit a “class effect” with respect to progression of subclinical atherosclerosis. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;91:42– 45)
unclear whether different hydroxymethylglucoenzyme A (HMG-CoA) reductase inhibitors Ihavettarylispreferential beneficial qualities, or if there is a
vestigators. All patients gave consent for their data to be used in subsequent analyses. None had a history of clinical CAD. Hypertension was defined by current or recommended use of antihypertensive medications. Smoking was defined as current tobacco usage and diabetes by current or recommended use of diet or medication to reduce blood sugar. Family history of CAD was defined as established CAD in first-degree male relatives ⬍56 years or female relatives ⬍66 years of age. Body mass index was calculated as weight (kilograms) divided by height (square meters). Serum lipid measurements were obtained at the time of both EBT evaluations. Imaging: EBT was performed using an Imatron C-150 scanner (South San Francisco, California). Forty contiguous 3-mm slices were acquired during a single breathhold beginning at the carina with a 350-mm scan field, 100 ms/slice scan time, and triggered at 80% of the RR interval. Three contiguous pixels with an attenuation coefficient of ⬎130 Hounsfield units were the minimum requirements for a calcium deposit. The coronary artery calcium score, corresponding to the amount of plaque, was calculated with the Agatston method1 by a technologist and reviewed by a physician blinded to all clinical data. The calcium volume score, a parameter of plaque burden that is density independent, was calculated according to method used by Callister et al.2 The calcium percentile, an age- and gender-corrected index of plaque
“class effect” common to all, assuming equal reduction of lipid abnormalities. The goal of this study was to compare the effects of the 2 most commonly prescribed HMG-CoA reductase inhibitors, atorvastatin and simvastatin, on progression of subclinical coronary artery disease (CAD) in asymptomatic patients, as measured by serial electron beam tomography (EBT) determined calcified plaque burden.
METHODS
Subjects: One hundred forty-nine consecutive asymptomatic patients with EBT evidence for subclinical atherosclerosis, who were treated with atorvastatin or simvastatin alone or in combination with niacin and who underwent repeat EBT evaluation, comprised the patient population. This was an observational study, not a randomized trial; serial EBT evaluation and lipid-lowering agents and doses employed were chosen by the treating physicians based on practice patterns, and not according to criteria set by the inFrom the Beth Israel Medical Center, New York, New York; and Kronos Longevity Research Institute, Phoenix, Arizona. Manuscript received July 2, 2002; revised manuscript received and accepted August 12, 2002. Address for reprints: Harvey S. Hecht, MD, P.O. Box 450, Brookside, New Jersey 07926. E-mail: [email protected].
42
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 1, 2003
0002-9149/03/$–see front matter PII S0002-9149(02)02995-8
TABLE 1 Demographics, Lipid, and EBT Values Atorvastatin (n ⫽ 103) Age (yrs) Men (%) Women (%) BMI (kg/m2) Hypertension (%) Diabetes (%) Family history (%) Smoking (%) Dose (mg) Niacin No. (%) Dose (mg) Scan interval Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Non-HDL cholesterol (mg/dl) Total/HDL cholesterol EBT calcium score EBT volume score EBT percentile
58.3 ⫾ 7.6 79 (77%) 24 (23%) 27.3 ⫾ 4.5 31 (30%) 2 (2%) 61 (59%) 6 (6%) 14.2 ⫾ 8.1 57 (55%) 1890 ⫾ 1171 1.18 ⫾ 0.28 216.5 ⫾ 41.4 137.2 ⫾ 37.3 50.6 ⫾ 16.3 143.9 ⫾ 78.9 165.9 ⫾ 39.3 4.6 ⫾ 1.3 469.1 ⫾ 483.0 377.5 ⫾ 385.7 80.1 ⫾ 16.0
Simvastatin (n ⫽ 46)
p Value
59.2 ⫾ 9.0 41 (89%) 5 (11%) 27.5 ⫾ 4.6 12 (26%) 4 (9%) 28 (61%) 2 (4%) 23.7 ⫾ 11.8
NS NS NS NS NS NS NS NS
24 (52%) 1875 ⫾ 899 1.24 ⫾ 0.33 199.7 ⫾ 33.3 121.2 ⫾ 32.6 48.7 ⫾ 12.7 163.0 ⫾ 148.5 150.9 ⫾ 31.4 4.3 ⫾ 1.1 388.3 ⫾ 468.9 306.9 ⫾ 361.3 73.4 ⫾ 16.1
NS NS NS ⬍0.05 ⬍0.05 NS NS ⬍0.05 NS NS NS ⬍0.05
BMI ⫽ body mass index.
burden prematurity shown to be powerfully related to prognosis,3 was derived from the University of Illinois asymptomatic patient database. The pre- and posttreatment EBT studies were evaluated side-by-side for comparability of analysis by an experienced observer (HSH). Changes in coronary calcium and calcium volume scores were calculated on an absolute basis and as a percent change per year. To avoid skewing the data by large percent changes in a few individual patients with low scores, the percent changes per year for the treated and untreated groups were calculated by dividing the mean annualized changes by the mean baseline values for the groups as a whole, rather than by the mean of the percent change per year for each individual patient. Laboratory values: Fasting total cholesterol (TC) and triglycerides were determined using enzymatic methods on samples drawn on the same day as the EBT procedure. High-density lipoprotein (HDL) cholesterol was measured after precipitation of apolipoprotein B particles. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from TC. Treatment: HMG-CoA reductase inhibitors were used to lower LDL cholesterol, and niacin derivatives to increase HDL cholesterol and lower triglycerides. The choice of atorvastatin or simvastatin was based upon physician or patient preference, as well as insurance and cost considerations. Aspirin, appropriate diet, weight loss, and exercise were recommended for all patients, as well as tobacco cessation, and tight control of diabetes and hypertension. Statistical analysis. All statistical analyses were performed using STATVIEW v.4.1 (SAS Institute, Cary, North Carolina). Chi-square analysis with Fisher’s
exact test was employed for differences in distribution of qualitative variables between groups and analysis of variance with Fisher’s least significance difference tests to detect significance of difference between atorvastatin- and simvastatin-treated patients. Repeated measures analysis of variance with a 2-way model was employed to detect both the significance of differences from visit 1 to visit 2 and the effect of atorvastatin versus simvastatin on lipid and EBT values. The level of significance was set at p ⬍0.05 (2-tailed).
RESULTS
Demographics (Table 1): There were no differences in risk factor distribution between the 2 groups. Men predominated and a family history of premature CAD was frequently noted (⬃60%). Hypertension was considerably more common than smoking or diabetes. The atorvastatin dose was lower than that of simvastatin, reflecting their difference in potency. Similar percentages of patients were on niacin, in almost identical doses. The interscan interval was 1.2 years for atorvastatin and simvastatin patients. Lipid and EBT values (Table 1): Before treatment, TC, LDL cholesterol, and non-HDL cholesterol were significantly higher in the atorvastatin group. There were no differences in HDL cholesterol, triglycerides, and TC/HDL ratio. EBT calcium score and volume score were similar. EBT percentile was high in both groups, reflecting the severity of the underlying subclinical atherosclerosis, but was significantly higher in the atorvastatin cohort. After treatment (Table 2), there were no differences in any of the lipid parameters. There were no differences in calcium score or volume between groups after treatment. Percent change in lipid and EBT parameters: The 2 cohorts achieved equally dramatic improvement in all lipid parameters (Table 2). There were no significant differences in the mean annualized rates of progression for either calcium score (10.8% vs 7.5%) or volume score (8.5% vs 7.8%) (Table 3). Validation of EBT for tracking progression: Validation of EBT to track changes in plaque burden is provided in Figure 1, which demonstrates the highly significant correlation between serial scans, performed 1.2 ⫾ 0.3 years apart, in 182 treated patients, of both the calcium score (r ⫽ 0.982, p ⬍0.0001) and volume (r ⫽ 0.981, p ⬍0.0001). This extraordinarily strong fit demonstrates the consistency of the method and its potential for evaluating disease progression.
DISCUSSION This study demonstrates that aggressive treatment with atorvastatin and simvastatin is associated with similar outcomes as measured by calcified plaque
PREVENTIVE CARDIOLOGY/EBT EVALUATION OF ATORVASTATIN VS SIMVASTATIN
43
TABLE 2 Change in Lipid Values Atorvastatin
Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Non-HDL cholesterol (mg/dl) TC/HDL cholesterol
†
Simvastatin ‡
Pre*
Post
%Change
Pre*
Post
% Change
216.5 137.2 50.6 143.9 165.9 4.6
156.0 79.1 57.0 100.1 99.0 2.9
⫺26.2 ⫺39.8 ⫹15.6 ⫺22.1 ⫺38.3 ⫺34.1
199.7 121.2 48.7 163.3 150.9 4.3
153.7 75.7 54.9 114.8 98.8 3.0
⫺22.2 ⫺34.7 ⫹14.9 ⫺18.8 ⫺34.3 ⫺29.8
*Pre versus post: all p ⬍0.0001. † Atorvastatin post versus simvastatin post: all p ⫽ NS ‡ Atorvastatin percent change versus simvastatin percent change: all p ⫽ NS.
TABLE 3 Annualized Change in EBT Values Atorvastatin
Calcium score Volume score
Simvastatin
Pre*
Post†
% Change/Yr‡
Pre*
Post
% Change/Yr
469.1 377.5
528.9 415.3
⫹10.8 ⫹8.5
388.3 306.9
424.6 336.6
⫹7.5 ⫹7.8
*Pre versus post: all p ⬍0.0001. † Atorvastatin post versus simvastatin post: all p ⫽ NS. ‡ Atorvastatin percent change per year versus simvastatin percent change per year: all p ⫽ NS.
progression in a primary prevention population. This suggests that, in doses producing similar improvements in lipid profiles, they manifest a class effect with respect to progression of subclinical atherosclerosis, rather than a property unique to a particular drug. Comparison with prior studies: The present study represents the largest series of statin-treated patients evaluated by serial EBT scans, and is the only study with detailed lipid analyses. The reported annualized rate of progression in untreated patients has ranged from 24% to 52%.4 – 6 Maher et al4 reported a 24% annual increase in 35 patients, of whom only 15 had a baseline calcium score ⬎20. Callister et al5 reported a 52%/year progression of calcium volume in 44 untreated asymptomatic patients, 25% in 40 statintreated patients whose LDL cholesterol remained ⬎120 mg/dl, and a 7% decrease associated with achieved LDL cholesterol ⬍120 mg/day in 65 subjects. Budoff et al6 reported a 39% annual progression of calcium score in 81 untreated asymptomatic patients irrespective of risk factors, and 15% progression in 62 statin-treated subjects. Importantly, calcium progression appears to be associated with a worse prognosis. In a follow-up of 225 subjects, there was a relative risk for a cardiac event of 13.4 in those patients whose calcium score progressed ⬎10% versus ⬍10%/year.6 In a second study of 269 subjects, 91% of cardiac events (20 of 22) were associated with progression (41 ⫾ 10% increase in calcium volume) and almost 50% were in patients who progressed despite achieving an LDL cholesterol of ⬍120 mg/dl.7 Calcified plaque may increase as the result of new plaque formation with subsequent calcification, which would appear more ominous, or by calcification of previously existing plaque. The poorer 44 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FIGURE 1. Correlation of EBT plaque burden measured 1.2 ⴞ 0.3 years apart in 182 treated patients. Top panel, calcium score: Y ⴝ ⴚ6.6 ⴙ 1.15 X, r ⴝ 0.982, p <0.0001. Bottom panel, volume score: Y ⴝ ⴚ6.1 ⴙ 1.1 X, r ⴝ 0.98, p <0.0001.
prognosis associated with calcified plaque progression6,7 suggests the former mechanism. Our results differ from the mean 7% decrease in volume score JANUARY 1, 2003
reported by Callister et al5 in patients who achieved a LDL cholesterol of ⬍120 mg/dl (100 ⫾ 17 mg/L), but who had a considerably higher baseline volume score (980 ⫾ 1,611). No other studies, with or without treatment, have reported a mean decrease in calcium or volume scores. The present results are closer to the 15% increase in calcium score reported by Budoff et al,6 in statin-treated patients with baseline calcium scores similar to the present study (mean calcium score 392). Lipid values were not reported in that study. The slightly different percent change analysis in the present study may contribute to differences from other studies. Aggressive lipid treatment: Statins were employed to decrease LDL cholesterol and niacin was used to increase HDL cholesterol and lower triglyceride levels. National Cholesterol Education Program Adult Treatment Panel III secondary prevention treatment goals8 were achieved in 90% of this asymptomatic, primary prevention population with high calcified plaque burdens. This aggressive treatment approach is justified by the high annual event rates (4%/year), equal to or greater than patients with established CAD, in patients with high calcium scores and percentiles.3 Further support is lent by studies demonstrating a relative risk of 8 for scores ⬎270, after adjusting for all risk factors,9 and odds ratios from 14.3 to 20.2 for scores ranging from ⬎80 to ⬎600, which are 3 to 7 times greater than that for the National Cholesterol Education Progam risk factors.10 Calcium percentile has been recommended as a replacement for age in the Framingham risk score11 and is being increasingly recommended for risk assessment.12,13 Atorvastatin versus simvastatin: The validity of this study is dependent on the comparability of the 2 groups, which were not prospectively randomized. Table 1 demonstrates their remarkable similarity. Significantly higher TC, LDL cholesterol and non- HDL cholesterol were noted in the atorvastatin group (Table 2), probably reflecting preferential use of the more potent agent in patients with higher values. However, the differences, although significant, were not large. There were no differences in calcium or volume scores. The calcium percentile was slightly, but significantly, higher in the atorvastatin group, but both represent very large, premature plaque burdens. The post-treatment lipid values and the percent change in lipid values speak strongly for the comparability of therapy (Table 2); there were no differences in any of the post-treatment lipid parameters between the 2 groups, and the percent change in EBT parameters was similar (Table 3). Because combination therapy was used in approximately 50% of both groups, the relative effects on plaque burden of the HMG-CoA reductase inhibitors and niacin cannot be differentiated. The presence of data supporting the impact of the HMG-CoA reductase inhibitors on EBT plaque burden progression6,7
and the lack of data for niacin does not at all discount the possibility that niacin is effective, especially in view of the documented effects of niacin on angiographic regression.14 Although we have demonstrated similar plaque progression in patients on a statin alone compared with statin and niacin combination therapy (unpublished data), the combination therapy group had a much higher incidence of combined metabolic disorders related to HDL cholesterol and triglycerides, and might have had more progression without the addition of niacin. In the present study, the dosages and percentages of patients on niacin were virtually identical, and there were no differences in either the pre- or post-treatment HDL cholesterol and triglyceride levels between the 2 groups. It is, therefore, reasonable to assign either the presence or absence of a difference in plaque progression to either a unique or “class effect” of atorvastatin or simvastatin. The similar plaque progression supports the “class effect” hypothesis, but does not differentiate between LDL cholesterol lowering and pleiotropic components.15,16 1. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–823. 2. Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electronbeam CT volumetric method. Radiology 1998;208:807–814. 3. Raggi P, Callister TQ, Cooil B, He Z, Lippolis NJ, Russo DJ, Zelinger A, Mahmarian JJ. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron beam computed tomography. Circulation 2000; 101:850 –855. 4. Maher JE, Bielak LF, Raz JA, Sheedy PF, Schwartz RS, Peyser PA. Progression of coronary artery calcification: a pilot study. Mayo Clin Proc 1999;74:347– 355. 5. Callister T, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998;339:1972–1978. 6. Budoff MJ, Lane KL, Bakhsheshi H, Mao S, Grassmann BO, Friedman BC, Brundage BH. Rates of progression of coronary calcium by electron beam tomography. Am J Cardiol 2000;86:8 –11. 7. Budoff MJ, Raggi P. Coronary artery disease progression assessed by electron beam computed tomography. Am J Cardiol 2001;88(suppl):51E–55E. 8. Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 9. Wong ND, Hsu JC, Detrano RC, Diamond G, Eisenberg H, Gardin JM. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol 2000;86:495–498. 10. Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:1253–1260. 11. Grundy SM. Coronary plaque as a replacement for age as a risk factor in global risk assessment. Am J Cardiol 2001;88(suppl):8E–11E. 12. Hecht HS, Rodgers GP, Rumberger JA, Achenbach S, Agatston AA, Berman DS, Brown BG, Budoff MJ, Callister TQ, Castelli WP, et al. Practice guidelines for electron beam tomography: a report of the Society of Atherosclerosis Imaging. Am J Cardiol 2000;86:705–706. 13. Greenland P, Smith SC, Grundy SM. Improving coronary heart disease assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–1867. 14. Brown BG, Zhao X, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993;87:1781–1791. 15. LaRosa JC. Pleiotropic effects of statins and their clinical significance. Am J Cardiol 2001;88:291–293. 16. Faggiotto A, Paoletti R. Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins? Curr Atheroscler Rep 2000;2:20 –25.
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