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Progression of Coronary Artery Calcification: Not Down-and-Out

Progression of Coronary Artery Calcification: Not Down-and-Out In the December 14, 2009, issue, McCullough et al1 presented a systematic review of randomized trials that used coronary artery calcification (CAC) progression as the primary end point. Despite the noninclusion of 2 eligible randomized placebo-controlled trials,2,3 we agree with their assertion that CAC progression has not been consistently reduced in any therapeutic randomized trial to date. The field of CAC progression has been hampered by the issue of variability between scans and a lack of consensus on how progression is best measured. Interscan variability increases as levels of baseline CAC increase. Thus, progression by change in mean annualized CAC (as used in this analysis) may be underestimated in subjects with high baseline CAC scores and overestimated in subjects with low baseline CAC scores. This fact helps explain the counterintuitive findings of Figure 3 in the article by McCullough et al,1 where baseline CAC score is inversely related to progression, and may solve the catastrophic inference from Figure 3 that a zero baseline CAC score (which has been repeatedly shown to represent a low risk for progression) is associated with the highest annualized weighted mean increase in CAC. Hokanson et al4 have found that the square root transformation of the calcium volume score provides a stable estimate of interscan variability across the range of baseline CAC scores. This allows investigation of CAC progression that is less biased by baseline CAC score. Technical issues aside, the heterogeneity of the treatment and control arms of these trials, as well as the populations under study, limits the applicability of the findings. For example, statins have been shown to promote microcalcification, which may lead to CAC progression even when total atherosclerosis is reduced.5 Also, the abnormal calcium homeostasis associated with chronic kidney disease causes calcification of both the intima and media and should be distinguished from the isolated intimal calcification seen in atherosclerosis. Blood pressure has been consistently shown to be strongly associated with CAC progression, and we believe that the findings of INSIGHT (International Nifedipine Study: Intervention as Goal for Hypertension Therapy) are diluted by inclusion in the heterogeneous review by McCullough et al.1 In INSIGHT, nifedipine was associated with a 13% mean annualized CAC progression as opposed to 25% with coamilozide (P = .02).6 Unfortunately, on-treatment blood pressure control was not reported in this trial. We look forward to seeing the results of future blood pressure and CAC progression trials before agreeing with the authors' conclusion that CAC “may not be a suitable surrogate target for treatment trials in patients with cardiovascular or renal disease.”1(p2069) Correspondence: Dr McEvoy, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Blalock 524C, 600 N Wolfe St, Baltimore, MD 21287 (jmcevoy1@jhmi.edu). References 1. McCullough PAChinnaiyan KM Annual progression of coronary calcification in trials of preventive therapies: a systematic review. Arch Intern Med 2009;169 (22) 2064- 2070PubMedGoogle ScholarCrossref 2. Terry JGCarr JJKouba EO et al. Effect of simvastatin (80 mg) on coronary and abdominal aortic arterial calcium (from the coronary artery calcification treatment with zocor [CATZ] study). Am J Cardiol 2007;99 (12) 1714- 1717PubMedGoogle ScholarCrossref 3. Budoff MJAhmadi NGul KM et al. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med 2009;49 (2-3) 101- 107PubMedGoogle ScholarCrossref 4. Hokanson JEMacKenzie TKinney G et al. Evaluating changes in coronary artery calcium: an analytic method that accounts for interscan variability. AJR Am J Roentgenol 2004;182 (5) 1327- 1332PubMedGoogle ScholarCrossref 5. Wu BElmariah SKaplan FSCheng GMohler ER III Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol 2005;25 (3) 592- 597PubMedGoogle ScholarCrossref 6. Motro MShemesh J Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics. Hypertension 2001;37 (6) 1410- 1413PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Progression of Coronary Artery Calcification: Not Down-and-Out

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Publisher
American Medical Association
Copyright
Copyright © 2010 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2010.60
Publisher site
See Article on Publisher Site

Abstract

In the December 14, 2009, issue, McCullough et al1 presented a systematic review of randomized trials that used coronary artery calcification (CAC) progression as the primary end point. Despite the noninclusion of 2 eligible randomized placebo-controlled trials,2,3 we agree with their assertion that CAC progression has not been consistently reduced in any therapeutic randomized trial to date. The field of CAC progression has been hampered by the issue of variability between scans and a lack of consensus on how progression is best measured. Interscan variability increases as levels of baseline CAC increase. Thus, progression by change in mean annualized CAC (as used in this analysis) may be underestimated in subjects with high baseline CAC scores and overestimated in subjects with low baseline CAC scores. This fact helps explain the counterintuitive findings of Figure 3 in the article by McCullough et al,1 where baseline CAC score is inversely related to progression, and may solve the catastrophic inference from Figure 3 that a zero baseline CAC score (which has been repeatedly shown to represent a low risk for progression) is associated with the highest annualized weighted mean increase in CAC. Hokanson et al4 have found that the square root transformation of the calcium volume score provides a stable estimate of interscan variability across the range of baseline CAC scores. This allows investigation of CAC progression that is less biased by baseline CAC score. Technical issues aside, the heterogeneity of the treatment and control arms of these trials, as well as the populations under study, limits the applicability of the findings. For example, statins have been shown to promote microcalcification, which may lead to CAC progression even when total atherosclerosis is reduced.5 Also, the abnormal calcium homeostasis associated with chronic kidney disease causes calcification of both the intima and media and should be distinguished from the isolated intimal calcification seen in atherosclerosis. Blood pressure has been consistently shown to be strongly associated with CAC progression, and we believe that the findings of INSIGHT (International Nifedipine Study: Intervention as Goal for Hypertension Therapy) are diluted by inclusion in the heterogeneous review by McCullough et al.1 In INSIGHT, nifedipine was associated with a 13% mean annualized CAC progression as opposed to 25% with coamilozide (P = .02).6 Unfortunately, on-treatment blood pressure control was not reported in this trial. We look forward to seeing the results of future blood pressure and CAC progression trials before agreeing with the authors' conclusion that CAC “may not be a suitable surrogate target for treatment trials in patients with cardiovascular or renal disease.”1(p2069) Correspondence: Dr McEvoy, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Blalock 524C, 600 N Wolfe St, Baltimore, MD 21287 (jmcevoy1@jhmi.edu). References 1. McCullough PAChinnaiyan KM Annual progression of coronary calcification in trials of preventive therapies: a systematic review. Arch Intern Med 2009;169 (22) 2064- 2070PubMedGoogle ScholarCrossref 2. Terry JGCarr JJKouba EO et al. Effect of simvastatin (80 mg) on coronary and abdominal aortic arterial calcium (from the coronary artery calcification treatment with zocor [CATZ] study). Am J Cardiol 2007;99 (12) 1714- 1717PubMedGoogle ScholarCrossref 3. Budoff MJAhmadi NGul KM et al. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med 2009;49 (2-3) 101- 107PubMedGoogle ScholarCrossref 4. Hokanson JEMacKenzie TKinney G et al. Evaluating changes in coronary artery calcium: an analytic method that accounts for interscan variability. AJR Am J Roentgenol 2004;182 (5) 1327- 1332PubMedGoogle ScholarCrossref 5. Wu BElmariah SKaplan FSCheng GMohler ER III Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol 2005;25 (3) 592- 597PubMedGoogle ScholarCrossref 6. Motro MShemesh J Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics. Hypertension 2001;37 (6) 1410- 1413PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Apr 26, 2010

Keywords: coronary artery calcium

References