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A major controversyin cardiologytoday iswhether loweringthe level oflow-density lipoprotein cholesterol(LDL-C) to substantiallybelow 100mg/dL-the current NationalCholesterol EducationProgram goal for patientswith existing coronaryheart disease1-willfurther reduce the incidenceof cardiovascularmorbidity and mortality.
A major controversyin cardiologytoday iswhether loweringthe level oflow-density lipoprotein cholesterol(LDL-C) to substantiallybelow 100mg/dL--the current NationalCholesterol EducationProgram goal for patientswith existing coronaryheart disease1--willfurther reduce the incidenceof cardiovascularmorbidity and mortality.Although an analysisof the Cholesterol and RecurrentEvents (CARE) trialsuggested that lowering theLDL-C level to less than 124mg/dL produced no furtherdecrease in coronaryevents,2 several studieshave demonstrated reducedprogression, and even regression,of atherosclerosiswhen the LDL-C level waslowered to less than 100mg/dL with intensive statintreatment.3-5 Moreover, theHeart Protection Studyshowed that similar loweringof LDL-C levels leads toa decreased incidence ofcardiovascular events.6The effects of intensivecholesterol reduction continue to be investigated.Here I discuss the resultsof the ReversingAtherosclerosis With AggressiveLipid Lowering(REVERSAL) study7--which were presented atthe 2003 scientific sessionsof the American Heart Association--as well as otherrecent and ongoing trials.In addition, I report on anintriguing study that examinedthe effect of a recombinantvariant of apolipoproteinA-I on plaque regression(Box).
REVERSAL: ANINTENSIVE STATINTREATMENT TRIALStudy design. TheREVERSAL study was adouble-blind, randomized,active-controlled, multicenterstudy that included 502patients aged 35 to 78 yearswho had symptomatic coronaryartery disease (CAD)and moderate hyperlipidemia(mean baseline LDLC,150 mg/dL). All patientshad documented CAD (withat least 20% stenosis) andreceived either intensivelipid-lowering therapy withatorvastatin, 80 mg, or moderatetherapy with pravastatin,40 mg, for 18 months.Atherosclerotic burden(atheroma volume) wasmeasured at baseline and atstudy end by intravascularultrasound (IVUS).Results. Atheromavolume increased slightlywith pravastatin (+2.7%),but not with atorvastatin(-0.4%), which loweredLDL-C to a mean level of79 mg/dL, compared with110 mg/dL for pravastatin (P 7. The atorvastatin-treated group also had amore pronounced reductionin the inflammatorymarker C-reactive protein:36% versus 5% of the patientstreated with pravastatin(P 7The investigators speculatedthat a greater antiinflammatoryeffect withmore intensive lowering ofLDL-C might be a factor inthe different results observedwith the two statins.The clinical benefits of intensivelowering of LDL-Cin patients with elevated Creactiveprotein levels arecurrently being investigatedin the Justification for theUse of Statins in PrimaryPrevention: An InterventionTrial Evaluating Rosuvastatin(JUPITER).8The REVERSAL trialresults provide further surrogateend point data thatshow lower LDL-C levelsare beneficial, at least interms of atherosclerosis progression.In addition, theyadd to the growing evidencethat patients with CAD mayneed more intensive lipidlowering than current guidelinesrecommend.A few caveats. However,the study investigatorsnoted 2 main caveats in interpretingtheir data. First,the REVERSAL trial wasnot designed to measuredifferences in clinicalevents. Second, althoughthe primary end point--percent change in atheromavolume as measured byIVUS--was significantly differentwith intensive comparedwith moderate lipidloweringtherapy, atheroma volume is a surrogate endpoint and, at fractions ofmillimeters, the absolutedifferences are small.Therefore, additional confirmatorystudies are required,including trials withclinical end points.
ONGOING TRIALSMore information onthe value of intensive lipidloweringtherapy is anticipatedfrom several studiesunder way. The Treating toNew Targets (TNT) trialis following 10,003 patientswith CAD who are receiving10 or 80 mg/d ofatorvastatin to achieve anLDL-C level of 100 or 75mg/dL, respectively. Thistrial is expected to provideevidence about whether aggressivelowering of LDL-Cto well below 100 mg/dLwill result in additional reductionsin cardiovascularrisk.9 Results are expectedin 2005.A Study to Evaluatethe Effect of Rosuvastatinon Intravascular Ultrasound-Derived CoronaryAtheroma Burden(ASTEROID) is the firsttrial to use both IVUS andquantitative coronary angiographyto evaluate theeffects of intensive LDLloweringtherapy with rosuvastatin,40 mg, on coronaryartery atheroma in patientswith known CAD.10About 60 centers worldwideare following approximately450 patients for 2years. The primary endpoint of this open-labelstudy is the percent changein atheroma volume in a 30-to 80-mm segment of an IVUS-targeted coronaryartery. Secondary endpoints include changesin total plaque volumeand percent changein the minimal luminal diameterwithin all measuredsegments. Study results areeagerly awaited, becauserosuvastatin, the neweststatin to be approved bythe FDA, has demonstratedsuperior LDL-lowering efficacy.11 Results will be availablein 2006.A recent study by vonBirgelen and associates12has found a positive linearrelationship between theLDL-C level and changes inplaque size, with no plaqueprogression occurringbelow an LDL-C thresholdof 75 mg/dL. After thesepreliminary study datahave been verified in futurelarger trials with clinicalend points, a goal of lessthan 75 mg/dL may becomethe revised recommendationof cholesterolguidelines and the newstandard of care.
. The Expert Panel. Third Report ofthe National Cholesterol EducationProgram (NCEP) Expert Panel on Detection,Evaluation, and Treatment ofHigh Blood Cholesterol in Adults(Adult Treatment Panel III). Final report.Circulation. 2002;106:3143-3421.Also available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
. Sacks FM, Pfeffer MA, MoyÃ© LA,et al. The effect of pravastatin oncoronary events after myocardial infarctionin patients with average cholesterollevels. Cholesterol and RecurrentEvents Trial investigators. N EnglJ Med. 1996;335:1001-1009.
. Blankenhorn DH, Azen SP,Kramsch DM, et al. Coronary angiographicchanges with lovastatin therapy.The Monitored AtherosclerosisRegression Study (MARS). Ann InternMed. 1993;119:969-976.
. The Post Coronary Artery BypassGraft Trial Investigators. The effect ofaggressive lowering of low-density lipoprotein cholesterol levels and low--dose anticoagulation on obstructivechanges in saphenous-vein coronary--artery bypass grafts. N Engl J Med.1997;336:153-162.
. Taylor AJ, Kent SM, Flaherty PJ,et al. ARBITER: Arterial Biology forthe Investigation of the Treatment Effectsof Reducing Cholesterol: a randomizedtrial comparing the effects ofatorvastatin and pravastatin on carotidintima medial thickness. Circulation.2002;106:2055-2060.
. Heart Protection Study CollaborativeGroup. MRC/BHF Heart ProtectionStudy of cholesterol loweringwith simvastatin in 20,536 high-risk individuals:a randomised placebo-controlledtrial. Lancet. 2002;360:7-22.
. Nissen SE, for the REVERSAL Investigators.Comparison of intensiveversus moderate lipid lowering on theprogression of coronary atherosclerosismeasured by intravascular ultrasound:a randomized controlled trial[abstract]. Circulation. 2003. Availableat: http://circ.ahajournals.org/cgi/reprint/108/21/2723.pdf. AccessedJanuary 5, 2004.
. Ridker PM, JUPITER StudyGroup. Rosuvastatin in the primaryprevention of cardiovascular diseaseamong patients with low levels of lowdensitylipoprotein cholesterol and elevatedhigh-sensitivity C-reactive protein:rationale and design of theJUPITER trial. Circulation. 2003;108:2292-2297.
. Waters DD, Guyton JR, HerringtonDM, et al. Treating to New Targets(TNT) study: does lowering low-densitylipoprotein cholesterol levelsbelow currently recommended guidelinesyield incremental clinical benefit?Am J Cardiol. 2004;93:154-158.
. Nissen S. Design and methodologyof A Study To evaluate the Effectof Rosuvastatin On Intravascular ultrasound-Derived coronary atheromaburden: the ASTEROID study. AtherosclerSuppl. 2003;4:27.
. Davidson M, Ma P, Stein EA, etal. Comparison of effects on low-densitylipoprotein cholesterol and highdensitylipoprotein cholesterol withrosuvastatin versus atorvastatin in patientswith type IIa and IIb hypercholesterolemia.Am J Cardiol. 2002;89:268-275.
. von Birgelen C, Hartmann M,Mintz GS, et al. Relation between progressionand regression of atheroscleroticleft main coronary artery diseaseand serum cholesterol levels as assessedwith serial long-term (> or = 12months) follow-up intravascular ultrasound.Circulation. 2003;108:2757-2762.
. Nissen SE, Tsunoda T, TuzcuEM, et al. Effect of recombinant ApoAIMilano on coronary atherosclerosisin patients with acute coronary syndromes:a randomized controlled trial.JAMA. 2003;290:2292-2300.