- Email: [email protected]
Comparison of effectiveness of statin monotherapy versus statin and niacin combination therapy in primary prevention and effects on calcified plaque burden
Comparison of Effectiveness of Statin Monotherapy Versus Statin and Niacin Combination Therapy in Primary Prevention and Effects on Calcified Plaque Burden Harvey S. Hecht,
MD,
and S. Mitchell Harman,
he combination of a statin and niacin is increasingly being prescribed for treatment of combined T lipid disorders, and has recently been shown to produce a dramatic decrease in clinical events and atherosclerosis progression, measured by quantitative coronary angiography in secondary prevention patients.1 This study was designed to determine whether calcified plaque progression, determined by electron beam tomography (EBT), differs in groups of primary prevention patients treated with statins alone compared with statin and niacin combination therapy. In addition, the correlations between the change in calcified plaque burden and changes in low-density lipoprotein (LDL) particle size and subgroups were evaluated. •••
One hundred sixty-two consecutive asymptomatic patients with EBT evidence for subclinical atherosclerosis, who were treated with a statin alone or in combination with niacin (Niaspan; Kos Pharmaceuticals, Miami, Florida) and underwent repeat EBT evaluation, comprised the patient population. This was an observational study; serial EBT evaluation and lipidlowering agents and doses employed were chosen by the treating physicians based on clinical considerations, and not according to criteria set by the investigators. All patients gave consent for their data to be used in subsequent analyses. No patient had a history of clinical coronary artery disease. Hypertension was defined as the current or recommended use of antihypertensive medications for blood pressure control. Smoking was defined as current tobacco usage, and diabetes was defined as the current or recommended use of diet or medication to decrease blood sugar. Family history of coronary artery disease was defined as established disease in first-degree male relatives ⬍56 years of age or female relatives ⬍66 years of age. Body mass index was calculated as weight (kilograms)/height (meters squared). Lipid measurements were obtained at the time of both EBT evaluations. EBT was performed using an Imatron C-150 scanner (GE/Imatron, South San Francisco, California) and previously described acquisition protocol.2 The coronary artery calcium score was calculated with the Agatston method.3 The calcium volume score, a paFrom the Beth Israel Medical Center, New York, New York; and Kronos Longevity Research Institute, Phoenix, Arizona. Dr. Hecht’s address is: PO Box 450, 9 Woodland Road, Brookside, New Jersey 07926. E-mail: [email protected]. Manuscript received July 22, 2002; revised manuscript received and accepted September 20, 2002.
348
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 February 1, 2003
MD, PhD
TABLE 1 Patient Characteristics Variable
Statin (n ⫽ 78)
Statin ⫹ Niacin (n ⫽ 84)
Men* 56 (72%) 72 (86%) Women* 22 (28%) 12 (14%) Age (yrs) 60 ⫾ 8 58 ⫾ 9 2 26.4 ⫾ 4.6 28.0 ⫾ 4.1 Body mass index (kg/m ) Systemic hypertension (%) 16 (20) 24 (28) Diabetes (%) 1 (1) 3 (4) Family history of coronary 26 (33) 30 (36) disease (%) Smoking (%) 3 (4) 4 (4) Scan interval (yrs) 1.25 ⫾ 0.33 1.18 ⫾ 0.32 Treatment† Atorvastatin 48 (14.8 ⫾ 8.8) 57 (13.7 ⫾ 11.7) Simvastatin 22 (24.1 ⫾ 14.0) 24 (24.2 ⫾ 9.8) Pravastatin 8 (22.5 ⫾ 6.7) 3 (20 ⫾ 0) Niaspan — 84 (1,897 ⫾ 1,112) *p ⫽ 0.03. † Values expressed as number of patients (mg).
rameter of plaque burden that is density independent, was calculated according to the method of Callister et al.4 The calcium percentile, an age and gender corrected index of plaque prematurity, was derived from the University of Illinois asymptomatic patient database. EBT studies done before and after treatment were reviewed side-by-side for comparability of analysis by an experienced observer (HSH), blinded to the treatment effects. 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 percentage changes in a few patients with lower scores, the percent change per year for the treated and untreated groups was calculated by dividing the mean annualized change by the mean baseline values for the groups as a whole, rather than by the mean of the percent change per year for each patient. Fasting plasma lipid and lipoprotein cholesterol concentrations were determined by the methods of the Lipid Research Clinics in all patients.5 In 53 patients treated with niacin, densitometric measurements of LDL subspecies were carried out using custom made, triple gradient (S3), 2% to 16% polyacrylamide gradient gel electrophoresis (S3GGE) of plasma samples (Berkeley HeartLab, Burlingame, California).6 LDL peak particle diameter was measured and LDL subclass distribution was determined in 3 large regions (I, IIa, IIb) and 4 small regions (IIIa, IIIb, IVa, IVb). LDL subclass pattern was classified based on LDL peak particle diameter, number and position of peaks, and 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(02)03168-5
TABLE 2 Electron Beam Tomography (EBT) and Lipid Values Before Treatment Variable 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
Statin 216 134 58 119 158 3.9 449 359 75.8
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
44 41 14 71 43 1.2 698 386 16.2
Statin ⫹ Niacin 205 129 44 170 161 4.9 483 386 80.2
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
35 30 12 121 34 1.1 486 383 16.3
After Treatment p Value NS NS ⬍0.0001 0.004 NS 0.0001 NS NS NS
Statin 163 83 60 95 103 2.9 506 398 76.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
26 23 18 57 25 1.0 824 648 16.2
Statin ⫹ Niacin
p Value
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.007 0.025 NS NS NS NS NS NS NS
149 73 54 109 95 2.9 552 434 80.7
26 19 14 63 25 0.7 563 423 16.2
the effect of statin versus statin ⫹ niacin on lipid and EBT values. The level of significance was set at p Variable Statin Statin ⫹ Niacin p Value ⬍0.05 (2-tailed). Total cholesterol (mg/dl) ⫺22.8 ⫾ 14.5 ⫺26.3 ⫾ 12.8 NS Patient characteristics are listed in LDL cholesterol (mg/dl) ⫺34.2 ⫾ 22.3 ⫺40.9 ⫾ 17.9 NS Table 1. There was a slight preponHDL cholesterol (mg/dl) ⫹ 4.3 ⫾ 22.5 ⫹ 24.9 ⫾ 22.7 ⬍0.0001 Triglycerides (mg/dl) ⫺12.7 ⫾ 38.4 ⫺26.5 ⫾ 40.2 ⬍0.0001 derance of men in the statin ⫹ niacin Non-HDL cholesterol (mg/dl) ⫺32.4 ⫾ 18.2 ⫺39.8 ⫾ 15.5 0.03 group. The distribution of statin Total/HDL cholesterol ⫺24.1 ⫾ 17.1 ⫺39.1 ⫾ 15.2 ⬍0.0001 drugs between atorvastatin, simvaEBT calcium score per year ⫹ 12.2 ⫹ 12.1 NS statin, and pravastatin was similar in EBT volume score per year ⫹ 8.9 ⫹ 12.4 NS the statin monotherapy and combination therapy subsets. The mean niacin dose was 1,897 mg in the combination therapy group. TABLE 4 Low-density Lipoprotein (LDL)–Graded Gel Electrophoresis Values in Patients Treated with Statin ⫹ Niacin Before treatment, high-density lipoprotein (HDL) cholesterol was Before Treatment After Treatment significantly lower, and trigycerides Variable (n ⫽ 53) (n ⫽ 53) % Change* and total/HDL cholesterol were Total cholesterol (mg/dl) 203 ⫾ 38 149 ⫾ 28 ⫺24.9 higher in the statin ⫹ niacin group, LDL cholesterol (mg/dl) 126 ⫾ 33 74 ⫾ 21 ⫺37.9 providing the rationale for the addiHDL cholesterol (mg/dl) 43 ⫾ 10 54 ⫾ 13 ⫹28.9 Triglycerides (mg/dl) 178 ⫾ 91 106 ⫾ 57 ⫺30.5 tion of niacin (Table 2). After treatNon-HDL cholesterol (mg/dl) 160 ⫾ 37 95 ⫾ 28 ⫺38.6 ment, the total, LDL, and HDL choTotal/HDL cholesterol 4.9 ⫾ 1.1 2.9 ⫾ 0.7 ⫺39.7 lesterol levels were lower in the Peak particle size (a) 255 ⫾ 8 264 ⫾ 7 — combination therapy group (Table LDL III a ⫹ b (%) 32 ⫾ 8 23 ⫾ 6 ⫺23.1 EBT calcium score 487 ⫾ 497 567 ⫾ 608 13.9/year 2), accompanied by significant imEBT volume score 391 ⫾ 396 440 ⫾ 455 10.6/year provements in HDL cholesterol, triglycerides, and total/HDL cholesterol *p ⬍0.0001 for all before versus after treatment. (p ⬍0.0001; Table 3). There were no differences between groups in either the pre- or post-treatment EBT calpercent distribution of the LDL regions classified as cium score, volume score, or percentile (Table 2). Moreover, there were no significant differences pattern A (predominately large LDL), pattern B (predominately small LDL), and pattern I (predominately between the statin monotherapy and combination therintermediate size LDL). Because a predominance of apy groups in the annualized rate of progression of small LDL can also be defined as LDL IIIa ⫹ IIIb calcium score (12.2% vs 12.1%) or volume score (8.9% vs 12.4%; Table 3). ⬎20%, this parameter was calculated as well. The lipid and EBT parameters for the patients All statistical analyses were carried out in STATVIEW Version 4.1 (SAS Institute, Cary, North Caro- treated with niacin who underwent LDL-graded gel lina). Chi-square analysis with Fisher’s exact proba- electrophoresis are listed in Table 4. The niacin dose bility test was employed for differences in distribution was 1,464 ⫾ 1,239 mg and the statin distribution was of qualitative variables between groups, and analysis similar to that in the total population. All lipid paramof variance with Fisher’s least significance difference eters improved significantly, 64% of the patients with tests to detect the significance of differences between small, dense LDL pattern B (n ⫽ 34) or pattern I (n ⫽ patients treated with statin and those treated with 13) were converted to pattern A, and the calcium score statin ⫹ niacin. Repeated measures analysis of vari- and volume increased by 13.9% and 10.6%, respecance with a 2-way model was employed to detect the tively. However, there was no correlation between significance of differences from visit 1 to visit 2 and either the change in particle size or LDL III a ⫹ b, and TABLE 3 Percent Change After Treatment
BRIEF REPORTS
349
FIGURE 1. Correlation of changes in EBT plaque burden and changes in LDL subgroup parameters. (Top) Peak particle size, Y ⴝ 82.1 to 2.2 X, r ⴝ 0.134, p ⴝ 0.28; (Bottom) LDL III a ⴙ b, Y ⴝ 70.4 ⴙ 0.68 X, r ⴝ 0.46, p ⴝ 0.71.
the change in calcium score (Figure 1) or volume score in individual patients. •••
In any given patient, the relative contributions of specific lipid disorders to the disease process cannot be ascertained. Similarly, the relative contribution to decreasing atherosclerosis progression of decreasing LDL cholesterol, triglycerides, or LDL III a ⫹ b, or of increasing HDL cholesterol or LDL particle size, cannot be determined. This report demonstrates that statin monotherapy to lower LDL cholesterol in the setting of normal HDL cholesterol and triglycerides, and combination therapy with a statin and niacin directed toward improvement of HDL cholesterol, triglycerides, and LDL particle size as well, were associated with similar calcified plaque progression after 1.2 years of treatment. There was no correlation between changes in calcified plaque burden and changes in LDL particle size or subgroup distribution. 350 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 91
Combination therapy was prescribed in the setting of more severe lipid abnormalities, characterized by significantly lower HDL cholesterol, higher triglycerides, higher total/HDL cholesterol, and excess of small, dense LDL than was noted in the statin monotherapy group. HDL, triglyceride, and total/HDL cholesterol values were similar in the 2 groups after treatment, despite the very different values before treatment. Compared with statin monotherapy, combination therapy produced lower total and LDL cholesterol, and a higher percentage improvement in HDL cholesterol, triglycerides, total/HDL cholesterol, and non-HDL cholesterol. Despite the significantly less favorable pretreatment plasma lipids in the combination therapy group, which might have been expected to result in more accelerated plaque formation, the addition of niacin to statin therapy resulted in plaque progression rates similar to those in the statin monotherapy group— lending further support to the concept of combination therapy. Whether or not similar results would have been obtained with statin monotherapy in the 2 groups is unknown and requires further investigation in a randomized trial; although the HDL-Atherosclerosis Treatment Study1 (HATS) supports the concept of dramatically better clinical outcomes from the combination of a statin and niacin than has previously been achieved with a statin alone. The similar calcified plaque progression rates in the 2 groups, with significantly different pre- and post-treatment lipid values and treatment regimens, suggest that pleiotropic effects of the medications, independent of their alteration of plasma lipid values,7 may be contributory. Further support to this concept is lent by the similar plaque progression noted in patients on atorvastatin compared with simvastatin,8 and similar decreases in clinical events by simvastatin in the Heart Protection Study, irrespective of the LDL cholesterol levels before or after treatment.9 In summary, EBT-determined calcified plaque progression was similar in response to statin and niacin combination therapy and statin monotherapy despite the less favorable baseline lipid profile, characterized by significantly lower baseline HDL cholesterol and higher triglycerides in the combination therapy group. This finding lends further support to the concept of combination therapy. 1. Brown BG, Zhao X, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583–1592. 2. Hecht HS, Superko HR, Smith LK, McGolgan BP. Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment. Am J Cardiol 2001;87:406 –412. 3. 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;15:827–828. 4. 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. 5. Lipid and lipoprotein analysis. In: Lipid Research Clinics Manual of Laboratory Operations, vol. I. Washington, DC: US Government Printing Office; 1974. HEW publication NIH 75– 628.
FEBRUARY 1, 2003
6. Krauss RM, Blanche PJ. Detection and quantitation of LDL subfractions. Curr Opin Lipidology 1992;3:377–383. 7. LaRosa JC. Pleiotropic effects of statins and their clinical significance. Am J Cardiol 2001;88:291–293. 8. Hecht HS, Harman SM. Comparison of the effects of atorvastatin versus
simvastatin on subclinical atherosclerosis in primary prevention as determined by electron beam tomography. Am J Cardiol 2003;91:42–45. 9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.
Comparison of Left Atrial Volume Assessed by Magnetic Endocardial Catheter Mapping Versus Transthoracic Echocardiography Vickas V. Patel, MD, PhD, Jian-Fang Ren, MD, Maren E. Jeffery, MD, Theodore J. Plappert, CVT, Martin G. St. John Sutton, MBBS, and Francis E. Marchlinski, MD ncreased left atrial (LA) size and volume have been shown to predict a higher risk of recurrent atrial Ifibrillation (AF) and atrial arrhythmias. Methods 1–3
for delineating LA size and volume are of significant clinical importance. The most common technique used for determining LA size in clinical practice is 2-dimensional guided M-mode echocardiography.4 Although LA size determined by M-mode echocardiography is most commonly used in clinical practice, it has recently been shown that this technique is the least accurate for determining LA volume.5 Two-dimensional transthoracic echocardiography has been established as a reliable technique by which to determine LA volume that correlates closely with volume estimated by cine computed tomography6,7 and cine magnetic resonance imaging.8 Magnetic electroanatomic mapping (MEAM) creates an anatomic shell of the endocardial surface of the chamber being mapped, and we have previously shown that this technique can be used to determine LA dimension with the same accuracy as 2-dimensional guided M-mode echocardiography.9 MEAM uses the current generated by a location sensor at the tip of the mapping catheter to identify the catheter tip at the intersection of 3 lowstrength magnetic fields.10 When the roving catheter is moved in 3-dimensional space, its location relative to a reference placed on the patient’s back is continuously monitored with a resolution of ⬍1 mm.11 We hypothesized that the high spatial resolution of MEAM would be able to obtain precise LA volume measurements that were similar to those obtained by 2-dimensional transthoracic echocardiography. An additional method for determining LA volume may prove valuable in those patients with AF who underwent LA mapping and ablation. Creating a 3-dimensional shell of the left atrium using this system has From the Sections of Cardiac Electrophysiology and Cardiac Imaging, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Dr. Marchlinski’s address is: Hospital of the University of Pennsylvania, 3400 Spruce Street, Ninth Floor Founders Pavilion, Philadelphia, Pennsylvania 19104. E-mail: francis. [email protected]. Manuscript received June 27, 2002; revised manuscript received and accepted September 26, 2002. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 February 1, 2003
been reported to facilitate ablation of focal triggers for paroxysmal AF.12 The purpose of our study was to establish the accuracy of LA volume measurements by MEAM against LA volume measured by 2-dimensional transthoracic echocardiography using the disk method. •••
The study group included 57 consecutive patients (46 men) with symptomatic drug-refractory AF who were referred for AF ablation between March 2000 and September 2001. The mean age of the study group was 50 ⫾ 12 years (range 21 to 74). The history of symptomatic AF ranged from 3 to 360 months (mean 51), 52 patients had paroxysmal AF, and 5 patients had persistent AF (⬎3 months). The median number of failed antiarrhythmic drugs was 4 (range 1 to 7). Left ventricular ejection fraction was normal in 52 patients and mildly depressed (range 40% to 50%) in 5 patients. Echocardiograms were obtained for all patients during the same hospitalization as when the mapping and ablation procedure was performed. The time between the 2 procedures ranged from 0 to 3 days with a median of 2 days. MEAM was performed using a 7Fr deflectable catheter (CARTO; Webster Biosense Inc., Diamond Bar, California). The catheter was placed in the left atrium using the standard Brockenbrough transseptal technique.13 All aspects of the left atrium were mapped in detail during sinus rhythm under the guidance of fluoroscopy and MEAM with sample points acquired during atrial diastole. If the patient was not in sinus rhythm they were either cardioverted, or the map was constructed after the successful ablation of all AF triggers. A mean of 126 ⫾ 37 individual points were acquired (range 78 to 224) with attention to defining the mitral valve annulus, LA appendage, and each of the pulmonary veins in every patient. We were able to define these structures for all patients in the study, including the right lower pulmonary vein, and construction of the LA map took a mean of 28 ⫾ 10 minutes (range 14 to 48). The LA volume was computed by MEAM using the built-in volume computation function of the Biosense system (Figure 1). 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(02)03169-7
351
MD,
and S. Mitchell Harman,
he combination of a statin and niacin is increasingly being prescribed for treatment of combined T lipid disorders, and has recently been shown to produce a dramatic decrease in clinical events and atherosclerosis progression, measured by quantitative coronary angiography in secondary prevention patients.1 This study was designed to determine whether calcified plaque progression, determined by electron beam tomography (EBT), differs in groups of primary prevention patients treated with statins alone compared with statin and niacin combination therapy. In addition, the correlations between the change in calcified plaque burden and changes in low-density lipoprotein (LDL) particle size and subgroups were evaluated. •••
One hundred sixty-two consecutive asymptomatic patients with EBT evidence for subclinical atherosclerosis, who were treated with a statin alone or in combination with niacin (Niaspan; Kos Pharmaceuticals, Miami, Florida) and underwent repeat EBT evaluation, comprised the patient population. This was an observational study; serial EBT evaluation and lipidlowering agents and doses employed were chosen by the treating physicians based on clinical considerations, and not according to criteria set by the investigators. All patients gave consent for their data to be used in subsequent analyses. No patient had a history of clinical coronary artery disease. Hypertension was defined as the current or recommended use of antihypertensive medications for blood pressure control. Smoking was defined as current tobacco usage, and diabetes was defined as the current or recommended use of diet or medication to decrease blood sugar. Family history of coronary artery disease was defined as established disease in first-degree male relatives ⬍56 years of age or female relatives ⬍66 years of age. Body mass index was calculated as weight (kilograms)/height (meters squared). Lipid measurements were obtained at the time of both EBT evaluations. EBT was performed using an Imatron C-150 scanner (GE/Imatron, South San Francisco, California) and previously described acquisition protocol.2 The coronary artery calcium score was calculated with the Agatston method.3 The calcium volume score, a paFrom the Beth Israel Medical Center, New York, New York; and Kronos Longevity Research Institute, Phoenix, Arizona. Dr. Hecht’s address is: PO Box 450, 9 Woodland Road, Brookside, New Jersey 07926. E-mail: [email protected]. Manuscript received July 22, 2002; revised manuscript received and accepted September 20, 2002.
348
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 February 1, 2003
MD, PhD
TABLE 1 Patient Characteristics Variable
Statin (n ⫽ 78)
Statin ⫹ Niacin (n ⫽ 84)
Men* 56 (72%) 72 (86%) Women* 22 (28%) 12 (14%) Age (yrs) 60 ⫾ 8 58 ⫾ 9 2 26.4 ⫾ 4.6 28.0 ⫾ 4.1 Body mass index (kg/m ) Systemic hypertension (%) 16 (20) 24 (28) Diabetes (%) 1 (1) 3 (4) Family history of coronary 26 (33) 30 (36) disease (%) Smoking (%) 3 (4) 4 (4) Scan interval (yrs) 1.25 ⫾ 0.33 1.18 ⫾ 0.32 Treatment† Atorvastatin 48 (14.8 ⫾ 8.8) 57 (13.7 ⫾ 11.7) Simvastatin 22 (24.1 ⫾ 14.0) 24 (24.2 ⫾ 9.8) Pravastatin 8 (22.5 ⫾ 6.7) 3 (20 ⫾ 0) Niaspan — 84 (1,897 ⫾ 1,112) *p ⫽ 0.03. † Values expressed as number of patients (mg).
rameter of plaque burden that is density independent, was calculated according to the method of Callister et al.4 The calcium percentile, an age and gender corrected index of plaque prematurity, was derived from the University of Illinois asymptomatic patient database. EBT studies done before and after treatment were reviewed side-by-side for comparability of analysis by an experienced observer (HSH), blinded to the treatment effects. 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 percentage changes in a few patients with lower scores, the percent change per year for the treated and untreated groups was calculated by dividing the mean annualized change by the mean baseline values for the groups as a whole, rather than by the mean of the percent change per year for each patient. Fasting plasma lipid and lipoprotein cholesterol concentrations were determined by the methods of the Lipid Research Clinics in all patients.5 In 53 patients treated with niacin, densitometric measurements of LDL subspecies were carried out using custom made, triple gradient (S3), 2% to 16% polyacrylamide gradient gel electrophoresis (S3GGE) of plasma samples (Berkeley HeartLab, Burlingame, California).6 LDL peak particle diameter was measured and LDL subclass distribution was determined in 3 large regions (I, IIa, IIb) and 4 small regions (IIIa, IIIb, IVa, IVb). LDL subclass pattern was classified based on LDL peak particle diameter, number and position of peaks, and 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(02)03168-5
TABLE 2 Electron Beam Tomography (EBT) and Lipid Values Before Treatment Variable 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
Statin 216 134 58 119 158 3.9 449 359 75.8
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
44 41 14 71 43 1.2 698 386 16.2
Statin ⫹ Niacin 205 129 44 170 161 4.9 483 386 80.2
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
35 30 12 121 34 1.1 486 383 16.3
After Treatment p Value NS NS ⬍0.0001 0.004 NS 0.0001 NS NS NS
Statin 163 83 60 95 103 2.9 506 398 76.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
26 23 18 57 25 1.0 824 648 16.2
Statin ⫹ Niacin
p Value
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.007 0.025 NS NS NS NS NS NS NS
149 73 54 109 95 2.9 552 434 80.7
26 19 14 63 25 0.7 563 423 16.2
the effect of statin versus statin ⫹ niacin on lipid and EBT values. The level of significance was set at p Variable Statin Statin ⫹ Niacin p Value ⬍0.05 (2-tailed). Total cholesterol (mg/dl) ⫺22.8 ⫾ 14.5 ⫺26.3 ⫾ 12.8 NS Patient characteristics are listed in LDL cholesterol (mg/dl) ⫺34.2 ⫾ 22.3 ⫺40.9 ⫾ 17.9 NS Table 1. There was a slight preponHDL cholesterol (mg/dl) ⫹ 4.3 ⫾ 22.5 ⫹ 24.9 ⫾ 22.7 ⬍0.0001 Triglycerides (mg/dl) ⫺12.7 ⫾ 38.4 ⫺26.5 ⫾ 40.2 ⬍0.0001 derance of men in the statin ⫹ niacin Non-HDL cholesterol (mg/dl) ⫺32.4 ⫾ 18.2 ⫺39.8 ⫾ 15.5 0.03 group. The distribution of statin Total/HDL cholesterol ⫺24.1 ⫾ 17.1 ⫺39.1 ⫾ 15.2 ⬍0.0001 drugs between atorvastatin, simvaEBT calcium score per year ⫹ 12.2 ⫹ 12.1 NS statin, and pravastatin was similar in EBT volume score per year ⫹ 8.9 ⫹ 12.4 NS the statin monotherapy and combination therapy subsets. The mean niacin dose was 1,897 mg in the combination therapy group. TABLE 4 Low-density Lipoprotein (LDL)–Graded Gel Electrophoresis Values in Patients Treated with Statin ⫹ Niacin Before treatment, high-density lipoprotein (HDL) cholesterol was Before Treatment After Treatment significantly lower, and trigycerides Variable (n ⫽ 53) (n ⫽ 53) % Change* and total/HDL cholesterol were Total cholesterol (mg/dl) 203 ⫾ 38 149 ⫾ 28 ⫺24.9 higher in the statin ⫹ niacin group, LDL cholesterol (mg/dl) 126 ⫾ 33 74 ⫾ 21 ⫺37.9 providing the rationale for the addiHDL cholesterol (mg/dl) 43 ⫾ 10 54 ⫾ 13 ⫹28.9 Triglycerides (mg/dl) 178 ⫾ 91 106 ⫾ 57 ⫺30.5 tion of niacin (Table 2). After treatNon-HDL cholesterol (mg/dl) 160 ⫾ 37 95 ⫾ 28 ⫺38.6 ment, the total, LDL, and HDL choTotal/HDL cholesterol 4.9 ⫾ 1.1 2.9 ⫾ 0.7 ⫺39.7 lesterol levels were lower in the Peak particle size (a) 255 ⫾ 8 264 ⫾ 7 — combination therapy group (Table LDL III a ⫹ b (%) 32 ⫾ 8 23 ⫾ 6 ⫺23.1 EBT calcium score 487 ⫾ 497 567 ⫾ 608 13.9/year 2), accompanied by significant imEBT volume score 391 ⫾ 396 440 ⫾ 455 10.6/year provements in HDL cholesterol, triglycerides, and total/HDL cholesterol *p ⬍0.0001 for all before versus after treatment. (p ⬍0.0001; Table 3). There were no differences between groups in either the pre- or post-treatment EBT calpercent distribution of the LDL regions classified as cium score, volume score, or percentile (Table 2). Moreover, there were no significant differences pattern A (predominately large LDL), pattern B (predominately small LDL), and pattern I (predominately between the statin monotherapy and combination therintermediate size LDL). Because a predominance of apy groups in the annualized rate of progression of small LDL can also be defined as LDL IIIa ⫹ IIIb calcium score (12.2% vs 12.1%) or volume score (8.9% vs 12.4%; Table 3). ⬎20%, this parameter was calculated as well. The lipid and EBT parameters for the patients All statistical analyses were carried out in STATVIEW Version 4.1 (SAS Institute, Cary, North Caro- treated with niacin who underwent LDL-graded gel lina). Chi-square analysis with Fisher’s exact proba- electrophoresis are listed in Table 4. The niacin dose bility test was employed for differences in distribution was 1,464 ⫾ 1,239 mg and the statin distribution was of qualitative variables between groups, and analysis similar to that in the total population. All lipid paramof variance with Fisher’s least significance difference eters improved significantly, 64% of the patients with tests to detect the significance of differences between small, dense LDL pattern B (n ⫽ 34) or pattern I (n ⫽ patients treated with statin and those treated with 13) were converted to pattern A, and the calcium score statin ⫹ niacin. Repeated measures analysis of vari- and volume increased by 13.9% and 10.6%, respecance with a 2-way model was employed to detect the tively. However, there was no correlation between significance of differences from visit 1 to visit 2 and either the change in particle size or LDL III a ⫹ b, and TABLE 3 Percent Change After Treatment
BRIEF REPORTS
349
FIGURE 1. Correlation of changes in EBT plaque burden and changes in LDL subgroup parameters. (Top) Peak particle size, Y ⴝ 82.1 to 2.2 X, r ⴝ 0.134, p ⴝ 0.28; (Bottom) LDL III a ⴙ b, Y ⴝ 70.4 ⴙ 0.68 X, r ⴝ 0.46, p ⴝ 0.71.
the change in calcium score (Figure 1) or volume score in individual patients. •••
In any given patient, the relative contributions of specific lipid disorders to the disease process cannot be ascertained. Similarly, the relative contribution to decreasing atherosclerosis progression of decreasing LDL cholesterol, triglycerides, or LDL III a ⫹ b, or of increasing HDL cholesterol or LDL particle size, cannot be determined. This report demonstrates that statin monotherapy to lower LDL cholesterol in the setting of normal HDL cholesterol and triglycerides, and combination therapy with a statin and niacin directed toward improvement of HDL cholesterol, triglycerides, and LDL particle size as well, were associated with similar calcified plaque progression after 1.2 years of treatment. There was no correlation between changes in calcified plaque burden and changes in LDL particle size or subgroup distribution. 350 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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Combination therapy was prescribed in the setting of more severe lipid abnormalities, characterized by significantly lower HDL cholesterol, higher triglycerides, higher total/HDL cholesterol, and excess of small, dense LDL than was noted in the statin monotherapy group. HDL, triglyceride, and total/HDL cholesterol values were similar in the 2 groups after treatment, despite the very different values before treatment. Compared with statin monotherapy, combination therapy produced lower total and LDL cholesterol, and a higher percentage improvement in HDL cholesterol, triglycerides, total/HDL cholesterol, and non-HDL cholesterol. Despite the significantly less favorable pretreatment plasma lipids in the combination therapy group, which might have been expected to result in more accelerated plaque formation, the addition of niacin to statin therapy resulted in plaque progression rates similar to those in the statin monotherapy group— lending further support to the concept of combination therapy. Whether or not similar results would have been obtained with statin monotherapy in the 2 groups is unknown and requires further investigation in a randomized trial; although the HDL-Atherosclerosis Treatment Study1 (HATS) supports the concept of dramatically better clinical outcomes from the combination of a statin and niacin than has previously been achieved with a statin alone. The similar calcified plaque progression rates in the 2 groups, with significantly different pre- and post-treatment lipid values and treatment regimens, suggest that pleiotropic effects of the medications, independent of their alteration of plasma lipid values,7 may be contributory. Further support to this concept is lent by the similar plaque progression noted in patients on atorvastatin compared with simvastatin,8 and similar decreases in clinical events by simvastatin in the Heart Protection Study, irrespective of the LDL cholesterol levels before or after treatment.9 In summary, EBT-determined calcified plaque progression was similar in response to statin and niacin combination therapy and statin monotherapy despite the less favorable baseline lipid profile, characterized by significantly lower baseline HDL cholesterol and higher triglycerides in the combination therapy group. This finding lends further support to the concept of combination therapy. 1. Brown BG, Zhao X, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583–1592. 2. Hecht HS, Superko HR, Smith LK, McGolgan BP. Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment. Am J Cardiol 2001;87:406 –412. 3. 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;15:827–828. 4. 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. 5. Lipid and lipoprotein analysis. In: Lipid Research Clinics Manual of Laboratory Operations, vol. I. Washington, DC: US Government Printing Office; 1974. HEW publication NIH 75– 628.
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6. Krauss RM, Blanche PJ. Detection and quantitation of LDL subfractions. Curr Opin Lipidology 1992;3:377–383. 7. LaRosa JC. Pleiotropic effects of statins and their clinical significance. Am J Cardiol 2001;88:291–293. 8. Hecht HS, Harman SM. Comparison of the effects of atorvastatin versus
simvastatin on subclinical atherosclerosis in primary prevention as determined by electron beam tomography. Am J Cardiol 2003;91:42–45. 9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.
Comparison of Left Atrial Volume Assessed by Magnetic Endocardial Catheter Mapping Versus Transthoracic Echocardiography Vickas V. Patel, MD, PhD, Jian-Fang Ren, MD, Maren E. Jeffery, MD, Theodore J. Plappert, CVT, Martin G. St. John Sutton, MBBS, and Francis E. Marchlinski, MD ncreased left atrial (LA) size and volume have been shown to predict a higher risk of recurrent atrial Ifibrillation (AF) and atrial arrhythmias. Methods 1–3
for delineating LA size and volume are of significant clinical importance. The most common technique used for determining LA size in clinical practice is 2-dimensional guided M-mode echocardiography.4 Although LA size determined by M-mode echocardiography is most commonly used in clinical practice, it has recently been shown that this technique is the least accurate for determining LA volume.5 Two-dimensional transthoracic echocardiography has been established as a reliable technique by which to determine LA volume that correlates closely with volume estimated by cine computed tomography6,7 and cine magnetic resonance imaging.8 Magnetic electroanatomic mapping (MEAM) creates an anatomic shell of the endocardial surface of the chamber being mapped, and we have previously shown that this technique can be used to determine LA dimension with the same accuracy as 2-dimensional guided M-mode echocardiography.9 MEAM uses the current generated by a location sensor at the tip of the mapping catheter to identify the catheter tip at the intersection of 3 lowstrength magnetic fields.10 When the roving catheter is moved in 3-dimensional space, its location relative to a reference placed on the patient’s back is continuously monitored with a resolution of ⬍1 mm.11 We hypothesized that the high spatial resolution of MEAM would be able to obtain precise LA volume measurements that were similar to those obtained by 2-dimensional transthoracic echocardiography. An additional method for determining LA volume may prove valuable in those patients with AF who underwent LA mapping and ablation. Creating a 3-dimensional shell of the left atrium using this system has From the Sections of Cardiac Electrophysiology and Cardiac Imaging, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Dr. Marchlinski’s address is: Hospital of the University of Pennsylvania, 3400 Spruce Street, Ninth Floor Founders Pavilion, Philadelphia, Pennsylvania 19104. E-mail: francis. [email protected]. Manuscript received June 27, 2002; revised manuscript received and accepted September 26, 2002. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 February 1, 2003
been reported to facilitate ablation of focal triggers for paroxysmal AF.12 The purpose of our study was to establish the accuracy of LA volume measurements by MEAM against LA volume measured by 2-dimensional transthoracic echocardiography using the disk method. •••
The study group included 57 consecutive patients (46 men) with symptomatic drug-refractory AF who were referred for AF ablation between March 2000 and September 2001. The mean age of the study group was 50 ⫾ 12 years (range 21 to 74). The history of symptomatic AF ranged from 3 to 360 months (mean 51), 52 patients had paroxysmal AF, and 5 patients had persistent AF (⬎3 months). The median number of failed antiarrhythmic drugs was 4 (range 1 to 7). Left ventricular ejection fraction was normal in 52 patients and mildly depressed (range 40% to 50%) in 5 patients. Echocardiograms were obtained for all patients during the same hospitalization as when the mapping and ablation procedure was performed. The time between the 2 procedures ranged from 0 to 3 days with a median of 2 days. MEAM was performed using a 7Fr deflectable catheter (CARTO; Webster Biosense Inc., Diamond Bar, California). The catheter was placed in the left atrium using the standard Brockenbrough transseptal technique.13 All aspects of the left atrium were mapped in detail during sinus rhythm under the guidance of fluoroscopy and MEAM with sample points acquired during atrial diastole. If the patient was not in sinus rhythm they were either cardioverted, or the map was constructed after the successful ablation of all AF triggers. A mean of 126 ⫾ 37 individual points were acquired (range 78 to 224) with attention to defining the mitral valve annulus, LA appendage, and each of the pulmonary veins in every patient. We were able to define these structures for all patients in the study, including the right lower pulmonary vein, and construction of the LA map took a mean of 28 ⫾ 10 minutes (range 14 to 48). The LA volume was computed by MEAM using the built-in volume computation function of the Biosense system (Figure 1). 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(02)03169-7
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