Perlowski, Alice

Tobis, Jonathan M

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UCLAUCLA Previously Published WorksTitleAtheroma Volume by Intravascular Ultrasound as a Surrogate for Clinical End Points⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the A...Permalinkhttps://escholarship.org/uc/item/4kc5s0b8JournalJournal of the American College of Cardiology, 53(13)ISSN0735-1097AuthorsTobis, Jonathan MPerlowski, AlicePublication Date2009-03-01DOI10.1016/j.jacc.2008.11.049Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, availalbe at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaAbUfJLLsmupgmtlphtspecbb(mwbpaacmpptpiep(smamwmrsbtpofio“tdeTpnSr(bwchddC(mfaeeaIso*vADJournal of the American College of Cardiology Vol. 53, No. 13, 2009© 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2008.11.049EDITORIAL COMMENTtheroma Volumey Intravascularltrasound as a Surrogateor Clinical End Points*onathan M. Tobis, MD, Alice Perlowski, MDos Angeles, Californiaarge-scale clinical studies have proven that primary andecondary prevention are effective methods in reducingyocardial infarction, stroke, and overall mortality. Annresolved issue is the optimal levels of lipids and bloodressure to achieve these goals (1,2). National treatmentuidelines have progressively lowered thresholds for treat-ent initiation and target levels (3,4). Although the recentrend has been that “lower is better,” the ideal targets forow-density lipoprotein cholesterol (LDL-C) and bloodressure, and the interaction between these 2 parameters,ave not been clearly defined.See page 1110In this issue of the Journal, Chhatriwalla et al. (5) attempto clarify the relationship between levels of LDL-C andystolic blood pressure and their effects on coronary plaquerogression. The study incorporated 3,437 patients withstablished coronary artery disease who were enrolled in 7linical trials that were stratified into 4 groups according tolood pressure and LDL-C levels. Changes in atheromaurden were monitored by serial intravascular ultrasoundIVUS), which was performed at baseline and at 18 to 24onths with the use of standard parameters. The subgroupith very low LDL-C (70 mg/dl) and normal systoliclood pressure (SBP) (120 mm Hg) displayed the leastrogression in percent atheroma volume (PAV) and totaltheroma volume (TAV) (p  0.001 for trend). This grouplso displayed more frequent plaque regression (p  0.01)ompared with other subgroups. In patients with SBP 120m Hg, very low LDL-C was still associated with lessrogression of PAV, whereas in the group with LDL-CEditorials published in the Journal of the American College of Cardiology reflect theiews of the authors and do not necessarily represent the views of JACC or themerican College of Cardiology.cFrom the David Geffen School of Medicine at UCLA, Los Angeles, California.r. Tobis is on the Speakers’ Bureau for Boston Scientific.70 mg/dl, normal SBP was not associated with lessrogression of PAV or TAV. These observations suggesthat lipid lowering may have a larger impact on plaquerogression compared with blood pressure lowering, whichs consistent with previous findings (6).This study complements the recent SANDS (Stop Ath-rosclerosis in Native Diabetics Study) trial (7), where 499atients with type 2 diabetes were randomized to aggressivegoal LDL-C 70 mg/dl, SBP 115 mm Hg) versustandard (goal LDL-C 100 mg/dl, SBP 130 mm Hg)edical therapy and were evaluated by common carotidrtery intimal medial thickness during the course of 36onths. Mean levels (95% confidence interval) for LDL-Cere 72 and 104 mg/dl, and SBP levels were 117 and 129m Hg in aggressive versus standard groups, respectively.Compared with baseline, mean intimal medial thicknessegressed in the aggressive group and progressed in thetandard group (–0.012 mm vs. 0.038 mm; p  0.001). It isecoming increasingly clear from animal and human datahat a combination of aggressive lipid-lowering and bloodressure control may be necessary for maximum attenuationf plaque progression (8,9), improvement in endothelialunction (10,11), and reduced plasma level markers ofnflammation of oxidative stress (12).Chhatriwalla et al. (5) provide an interesting commentaryn the need for more aggressive treatment guidelines forpre-hypertension,” that is, blood pressure of 120 to 139/80o 89 mm Hg in patients with established coronary arteryisease. Prehypertension has been associated with increasedvent rates (13) and is under-recognized and undertreated.he lack of large, randomized trials with hard clinical endoints have likely contributed to a delayed acceptance of theeed for pharmacological treatment in these individuals.PRINT (Systolic Blood Pressure Intervention Trial) is aandomized multicenter trial that will compare intensiveSBP 120 mm Hg) versus standard (SBP 140 mm Hg)lood pressure control in patients older than 55 years of ageith an SBP 130 mm Hg and at least 1 other cardiovas-ular disease (CVD) risk factor. The study will focus onigh-risk patients, such as those with clinical cardiovascularisease (not including stroke), patients with stage 3 kidneyisease, and patients without clinical CVD who have otherVD risk factors such as low high-density lipoproteinHDL). Primary composite end points will include CVDortality, nonfatal myocardial infarction, stroke, and heartailure. The results of this highly anticipated trial may haveprofound influence on how prehypertension is prioritized.Chhatriwalla et al. (5) use IVUS measurements of ath-roma volume as a surrogate end point in place of clinicalvents. As distinguished from angiography, which provides2-dimensional longitudinal image of the artery lumen,VUS uses high-frequency soundwaves to reveal the athero-clerotic plaque deposited within the arterial wall. The usef IVUS provides low-resolution, cross-sectional images oforonary arteries and is useful because it produces an imageifAtUamaaa6uplattmIm6i(aslsslpocattptietTstembtcpuorccdronwotbcbosblarmcmtIotctbhepmdTwdboRU1ER1117JACC Vol. 53, No. 13, 2009 Tobis and PerlowskiMarch 31, 2009:1116–8 Atheroma Volume by IVUSn a living person, usually attainable only with histologyrom autopsy specimens.In the REVERSAL (Reversal of Atherosclerosis Withggressive Lipid Lowering) (14) and ASTROID (A Studyo Evaluate the Effect of Rosuvastatin on Intravascularltrasound-Derived Coronary Atheroma Burden) (15) tri-ls, authors used IVUS to demonstrate that aggressive lipidanagement was associated with slower plaque progressionnd even plaque regression in patients with known coronaryrtery disease (CAD). In REVERSAL, 80 mg/day oftorvastatin was compared with 40 mg/day of pravastatin in54 patients with angiographically established CAD whonderwent IVUS at baseline and at 18 months. For therimary end point of percent change in TAV, a significantlyower rate of progression from baseline was observed in thetorvastatin group (–0.4%) as compared with the pravasta-in group (2.7%, p  0.02). The ASTROID trial evaluatedhe effect of maximally intensive statin therapy with 40g/day of rosuvastatin in 349 patients with CAD. TheVUS measurements performed at baseline and at 24onths demonstrated a reduction of total plaque volume by.8% (–14.7  25.7 mm3) (p  0.001). The medicationntervention trials published by this IVUS core laboratory16–19) are a product of a monumental amount of effortnd 10 years of development and have contributed impres-ively to our knowledge and understanding of pharmaco-ogical therapies for atherosclerosis.We must exercise caution, however, when interpretingtudies that use atheroma burden measured by IVUS as aurrogate end point. The acceptance of this parameter isargely based on evidence that luminal narrowing (20) orlaque progression (21) on IVUS in the left main artery atne specific cross section has been associated with futureoronary events in patients with CAD and in the leftnterior descending artery in patients undergoing heartransplant (22). However, the interpretation of trials withhe use of IVUS as a surrogate end point must be placed intoerspective: IVUS, although a robust clinical and researchool, is subject to certain limitations.In the aforementioned clinical studies, atheroma volumes obtained by taking the sum of the differences betweenxternal elastic membrane (EEM) cross-sectional area andhe luminal cross-sectional area for all available images.AV is then obtained by first calculating the mean cross-ectional atheroma area for each pullback study. This area ishen indexed by multiplying by the average length of thentire population of IVUS exams. To our knowledge, thisethod of calculating TAV, although logical, has nevereen directly correlated with clinical event rates even withinhese clinical trials because they were not powered forlinical events. Additionally, there are several sources ofotential error when acquiring these data from intravascularltrasound.Any obstruction or distortion of the border of the EEMr lumen can contribute to measurement error and decreaseeproducibility. For example, significant artifacts can bereated by regions of heavy calcification, causing one diffi-ultly in defining the EEM border. Nonuniform rotationalistortion, a phenomenon created by variations in catheterotation speeds; transducer ring down, a result of acousticscillations resulting in high frequency signals that obscureear field imaging; and geometric distortion, which occurshen the ultrasound beam interrogates a plane that is notrthogonal to vessel walls, can obscure an operator’s abilityo define the true luminal and EEM borders.Additionally, variations in pullback speeds between theaseline and follow-up measurements can interfere with thealculation of total atheroma volumes. These limitations cane corrected mathematically when there is a known lengthf artery, for example, if one is evaluating intimal hyperpla-ia within coronary stents. The pullback length from theaseline and follow-up IVUS can be indexed to the knownength of the stent. It is less certain that we can do thisccurately when calculating atheroma volume from 2 sepa-ate studies where the average difference in pullback lengthay be 10% between anatomic landmarks. The scientificommunity could be reassured of the accuracy of thisethod by having an independent IVUS Core Lab repeathe analysis of these data.Although we may use plaque progression/regression onVUS to deduce that we are producing positive results forur patients, the true determination of the impact of ourherapy depends on clinical and mortality end points, whichan only be obtained from large-scale randomized clinicalrials. It must be recognized that a direct relationshipetween atheroma progression and regression on IVUS andard clinical events has never been clearly defined. Forxample, it is possible that a greater clinical effect isroduced by altering plaque composition from lipid-rich toore fibrotic tissue, thus stabilizing the atheroma, indepen-ent of any change in lumen area or plaque volume.herefore, until clinical outcomes are shown to correspondith predictions based on the IVUS surrogates, conclusionserived from these trials should be considered inferential, toe used as guides for future trials focused on clinicalutcome measures.eprint requests and correspondence: Dr. Jonathan M. Tobis,CLA Medical Center, Medicine, B-976 Factor Building CHS,0833 LeConte Avenue, Los Angeles, California 90095-3075.-mail: jtobis@mednet.ucla.edu.EFERENCES1. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E.Meta-analysis of cardiovascular outcomes trials comparing intensiveversus moderate statin therapy. J Am Coll Cardiol 2006;48:438–45.2. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. ProspectiveStudies Collaboration. Age-specific relevance of usual blood pressureto vascular mortality: a meta-analysis of individual data for one millionadults in 61 prospective studies. Lancet 2002;360:1903–13.3. Executive Summary of the Third Report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection. Evaluation,and Treatment of High Blood Cholesterol in Adults (Adult Treat-ment Panel III). JAMA 2001;285:2486–97.1111111111222K1118 Tobis and Perlowski JACC Vol. 53, No. 13, 2009Atheroma Volume by IVUS March 31, 2009:1116–84. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of theJoint National Committee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure. Hypertension 2003;42:1206–52.5. Chhatriwalla AK, Nicholls SJ, Wang TH, et al. Low levels oflow-density lipoprotein cholesterol and blood pressure and progressionof coronary atherosclerosis. J Am Coll Cardiol 2009;53:1110–5.6. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterollowering and angiotensin-converting enzyme inhibition on coronaryatherosclerosis: The Simvastatin/Enalapril Coronary AtherosclerosisTrial (SCAT). Circulation 2000;102:1748–54.7. Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targetsfor blood pressure and LDL cholesterol on atherosclerosis in diabetes:the SANDS randomized trial. JAMA 2008;299:1678–89.8. Kato M, Sada T, Mizuno M, Kitayama K, Inaba T, Koike H. Effectof combined treatment with an angiotensin II receptor antagonist andan HMG-CoA reductase inhibitor on atherosclerosis in geneticallyhyperlipidemic rabbits. J Cardiovasc Pharmacol 2005;46:556–62.9. Trion A, de Maat M, Jukema W, et al. Anti-atherosclerotic effect ofamlodipine, alone and in combination with atorvastatin, in APOE*3-Leiden/hCRP transgenic mice. J Cardiovasc Pharmacol 2006;47:89–95.0. Ceriello A, Assaloni R, Da Ros R, et al. Effect of atorvastatin andirbesartan, alone and in combination, on postprandial endothelialdysfunction, oxidative stress, and inflammation in type 2 diabeticpatients. Circulation 2005;111:2518–24.1. Koh KK, Quon MJ, Han SH, et al. Vascular and metabolic effects ofcombined therapy with ramipril and simvastatin in patients with type2 diabetes. Hypertension 2005;45:1088–93.2. Koh KK, Quon MJ, Han SH, Ahn JY, Lee Y, Shin EK. Combinedtherapy with ramipril and simvastatin has beneficial additive effects ontissue factor activity and prothrombin fragment 12 in patients withtype 2 diabetes. Atherosclerosis 2007;194:230–7.3. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults acrossthe age spectrum: current outcomes and control in the community.JAMA 2005;294:466–72. y4. Nissen SE. Halting the progression of atherosclerosis with intensivelipid lowering: results from the Reversal of Atherosclerosis WithAggressive Lipid Lowering (REVERSAL) trial. Am J Med 2005;118:22S–7S.5. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statintherapy on regression of coronary atherosclerosis: the ASTEROID trial.JAMA 2006;295:1556–65.6. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-IMilano on coronary atherosclerosis in patients with acute coronarysyndromes: a randomized controlled trial. JAMA 2003;290:2292–300.7. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensiveagents on cardiovascular events in patients with coronary disease andnormal blood pressure: the CAMELOT study: a randomized con-trolled trial. JAMA 2004;292:2217–25.8. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on theprogression of coronary atherosclerosis. N Engl J Med 2007;356:1304–16.9. Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant onprogression of atherosclerosis in patients with abdominal obesity andcoronary artery disease. JAMA 2008;299;1547–60.0. Ricciardi MJ, Meyers S, Choi K, Pang JL, Goodreau L, Davidson CJ.Angiographically silent left main disease detected by intravascularultrasound: a marker for future adverse cardiac events. Am Heart J2003;146:507–12.1. Von Birgelen C, Hartmann M, Mintz GS, et al. Relationship betweencardiovascular risk as predicted by established risk scores versus plaqueprogression as measured by serial intravascular ultrasound in left maincoronary arteries. Circulation 2004;110:1579–85.2. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravas-cular ultrasound validation study among heart transplant recipients:outcomes after five years. J Am Coll Cardiol 2005;45:1532–7.ey Words: coronary artery disease y atherosclerosis y LDL cholesterolhypertension y intravascular ultrasound.

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Atheroma Volume by Intravascular Ultrasound as a Surrogate for Clinical End Points⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

Atheroma volume by intravascular ultrasound as a surrogate for clinical end points.

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