Cholesterol-Lowering Therapy: Evaluation of Clinical Trial Evidence PDF
Preview Cholesterol-Lowering Therapy: Evaluation of Clinical Trial Evidence
Cholesterol-Lowering Therapy Evaluation of Clinical Trial Evidence Cholesterol-Lovvering Therapy Evaluation of Clinical Trial Evidence edited by Scott M. Grundy University ofTexas Southwestern Medical Centerat Dallas Dallas, Texas informa healthcare NewYork London [amit][D:/3B2Templates/#_Informa_Template/Sample_for_CR/6x9/6x9_CP.3d] [13/4/010/21:27:11][2–3] First published in 2000 by Marcel Dekker, Inc. This edition published in 2011 by Informa Healthcare, Telephone House, 69-77 Paul Street, LondonEC2A4LQ,UK. SimultaneouslypublishedintheUSAbyInformaHealthcare,52VanderbiltAvenue,7thFloor, NewYork,NY10017,USA. 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This book contains information from reputable sources and although reasonable efforts have beenmadetopublishaccurateinformation,thepublishermakesnowarranties(eitherexpressor implied) as to the accuracy or fitness for a particular purpose of the information or advice containedherein.Thepublisherwishestomakeitclearthatanyviewsoropinionsexpressedin thisbookbyindividualauthorsorcontributorsaretheirpersonalviewsandopinionsanddonot necessarilyreflecttheviews/opinionsofthepublisher.Anyinformationorguidancecontained inthisbookisintendedforusesolelybymedicalprofessionalsstrictlyasasupplementtothe medical professional’s own judgement, knowledge of the patient’s medical history, relevant manufacturer’sinstructionsandtheappropriatebestpracticeguidelines.Becauseoftherapid advancesinmedicalscience,anyinformationoradviceondosages,procedures,ordiagnoses shouldbeindependentlyverified.Thisbookdoesnotindicatewhetheraparticulartreatmentis appropriateorsuitableforaparticularindividual.Ultimatelyitisthesoleresponsibilityofthe medical professionalto makehis or her own professional judgements,so as appropriately to adviseandtreatpatients.Savefordeathorpersonalinjurycausedbythepublisher’snegligence and to the fullest extent otherwise permitted by law, neither the publisher nor any person engaged or employed by the publisher shall be responsible or liable for any loss, injury or damagecausedtoanypersonorpropertyarisinginanywayfromtheuseofthisbook. ACIPrecordforthisbookisavailablefromtheBritishLibrary. LibraryofCongressCataloging-in-PublicationDataavailableonapplication ISBN-13:9780824782160 Ordersmaybesentto:InformaHealthcare,SheepenPlace,Colchester,EssexCO33LP,UK Telephone:+44(0)2070175540 Email:[email protected] Website:http://informahealthcarebooks.com/ Forcorporatesalespleasecontact:[email protected] Forforeignrightspleasecontact:[email protected] Forreprintpermissionspleasecontact:[email protected] Foreword That arteries can "degenerate into bones" has been known since the latter part ofthe sixteenth century (Gabriel Fallopius, 1575). However, only since the be ginning ofthe twentieth century has cholesterol achieved a central position in basic and clinical research to understand the "ossificationprocess" ofthe arter ies, whichbythen was known as atherosclerosis. Studiesofthe metabolismand role ofthe blood lipoproteins intensified greatly in the second halfofthis cen tury, largelybecausetheassociationbetweenatherosclerosisandcoronaryheart disease became irrefutable. Agreatdealofthe workdoneinthe 1960sand 1970scameto ahead with Brown and Goldstein's fundamental discovery ofthe LDL receptors and ofthe mechanismofcellularuptakeandtransportofLDLinthecell. Forthis,theywere awarded the Nobel Prize in Physiology orMedicine in 1985. This extraordinary discovery, and others that followed, led to a surge of optimism that perhaps soon we would conquer coronary heart disease and halt its epidemic. This hope was articulated ina 1996editorial in Science by Brown andGoldstein(1)titled"HeartAttacks: GonewiththeCentury?"Init,theywrote: Exploitationofrecentbreakthroughsonproofofthecholesterolhypothesis, discoveryofeffective drugs, and betterdefinition ofgenetic susceptibility facctors may well end coronary disease as amajor public health problem early in the nextcentury. Asthis volumeappearsontheeveofthe nextcentury, wemustask: "Have we fulfilled the prediction of Brown and Goldstein?" Unfortunately, for the United States the answer is no, although we have made significantprogress, as attestedtobyacontinuousdeclineinthecoronaryheartdiseasedeathrate. Else where, beyond our borders, the problems has worsened. The World Health Or ganization predicts that in 2020ischemic heartdisease will rankfirst onthe list ofglobaldiseaseburdens. Howcanthisbethecase,whendiscovery ofeffective iii iv Foreword drugs and better definition of genetic susceptibility factors have certainly occurred? Indeed, in the last few years we have witnessed the publication of superbstudiesdemonstratingthe effectivenessofthe statinsin primaryandsec ondary prevention ofcoronary heartdisease. This is acomplex question that has no single answer, but at least one as pect ofthis situation is well recognized: statins are not prescribed as much as they should be. This then raises another question: Why are physicians not pre scribing these medications? Thisvolumeis notananswertothatquestion, butitisintendedtoprovide busy physicians with the information they need to make the bestpossibiledeci sions for theirpatients. Forthe first time, we bring togetherinone placethe ra tionale and results ofall the majorclinical trials initiated to assess the efficacy ofthe newestand bestcholesterol-lowering agents. The editor, Scott Grundy, has a worldwide reputation as an expert in the cholesterol-lowering field. The chapters, each describing a different study, are written by the researchers who designed andcoordinatedthe trials. Somuch in formation is given to practicing physicians nowadays that it often makes their jobmoredifficult. This authoritative compendiumcan make iteasier and, in so doing, will greatly benefitpatients. Heartattacks may notbegone with the cen tury, buttheysooncouldbeifthey arepreventedandtreatedappropriately. This bookwill help. Claude Lenfant, M.D. Director, National Heart, Lung andBloodInstitute National Institutes ofHealth REFERENCE 1. Brown,MS,Goldstein,JL. Heartattacks: gonewiththecentury?[editorial]. Science 1996;272(5262):629. Preface Clinical trials of cholesterol-lowering therapy constitute a triumph of modern medicine. No question has been more contentious than that ofthe relationship between serum cholesterol and coronary heart disease (CHD). In contrast, the medical community readily accepted the importance of cigarette smoking and highblood pressure as risk factors. Partofthis acceptance grew outofthe mul tipledangersofsmokingandhypertension. Cigarettesmokingcauseschroniclung diseaseandlungcanceras wellas CHD.Hypertensionleadstostrokeandchronic renal failure as well as to CHD. The dangers of high serum cholesterol, how ever, arelimitedtothedevelopmentofatheroscleroticdisease, particularlyCHD. Furthermore, the database that defines the impact ofhigh serum cholesterol on CHD risk was acquired more slowly than that for the otherrisk factors. Slowly but surely, nonetheless, a broad base ofevidence has emerged that links an el evation ofserum cholesterol levels to developmentCHD. The driving force for this evidence was the "cholesterol hypothesis." This is a two-part hypothesis postulating that a rising serum cholesterol level enhances the risk of CHD, whereas afalling level reduces the risk. Thefirst line ofsupportfor the hypothesis that an elevated serumcholes terolcausesatherosclerosiscamefrom studiesinlaboratoryanimals. Forexample, the feeding of excess cholesterol to rabbits produced marked hypercholester olemia and caused deposition ofcholesterol in arteries. This deposition closely resembledhumanatherosclerosis. Sincethoseearly studiesalmost lOOyearsago, agreat many investigations have been carried out in animals. This research ex tendedto awidevarietyofanimals, recentlyincludinggeneticallymodifiedani mals. Taken in aggregate, this body ofresearch provides a strong base of sup port for the concept that elevated serum cholesterol-particularly when the cholesterol is carried in low-density lipoproteins (LDLs) and remnant lipopro teins-is highly atherogenic. Theseearly studies inlaboratory animals were the foundation ofthe"cholesterolhypothesis," andavastnumberofpublicationsin animal research strongly supports this hypothesis. v vi Preface Thesecond lineofsupportfor the cholesterol hypothesis comes from epi demiological investigations. Prospectiveand cross-sectional studieshaveexam ined the correlation between serum cholesterol levels and incidence (or preva lence) ofCHD. Notable examples include the Seven Countries Study and the FraminghamHeartStudy,butthereare many others. Onthewhole thesestudies reveal apositivecorrelationbetweenserumcholesterollevelsandriskfor CHD. Such investigations have the advantage ofcomparing the influence ofhigh se rum cholesterol to the othermajor risk factors for CHD. Three important conclusions emerge from these investigations. First, in countries in which serum cholesterol levels are very low, rates ofCHD are also low, even in the presence ofotherrisk factors. This confirmsthefinding in ani mal studies thatcholesterol-rich lipoproteins are the primary atherogenic factor among all the known risk factors. The secondconclusion is thatmultivariate analysisofepidemiological in vestigations indicates that elevated serum cholesterol in high-risk populations accountsfor approximatelyone-thirdofallCHD.Indeed, aftercorrectingthedata for a factor called regression-dilution bias, prospective studies reveal that the dangers ofserumcholesterolareevengreaterthansuggestedbyearlieranalyses. Finally, multiple prospective studies demonstrate that serum cholesterol concentrations are positively correlated with CHD risk over a broad range of cholesterollevels,fromverylow tohigh.Theseprospectivestudiesprovideuseful information about the optimal level of serum cholesterol. Earlier and smaller prospective studies suggested that the optimal level of serum cholesterol is a concentrationanywherebelow200mg/dL. Laterinvestigations,however, reveal that up to one-quarter of major coronary events occur in persons whose total cholesterolconcentrationsare intherangeof150to200mgldL; incontrast, CHD events arelessfrequent whencholesterollevels are~150 mg/dL. Thesefindings strongly imply that the optimal level ofserum total cholesterol is ~150 mg/dL. Indeed, populationsin whichmeanlevels oftotalcholesterol arebelow 150mg/ dL have a very low prevalence ofCHD. Athirdlineofsupportforthe"cholesterol hypothesis"comesfrom genetic disorders oflipoproteinmetabolism.Foremostamongthesedisordersaregenetic forms ofelevatedserumcholesterol (namely,familialhypercholesterolemia)and familial defectiveapolipoproteinB-lOO. When thesedisorders arepresent,coro nary atherosclerosis develops rapidly, leading to early onset ofCHD. Genetic forms ofhypercholesterolemiacan produceprematureCHDeveninthe absence ofotherrisk factors. Theoccurrence ofprematureCHD in persons with genetic hypercholesterolemiaprovides the strongestevidencethatahigh level ofserum cholesterol is a directcause ofatherosclerosis in humans. Thus, the past century leaves an enormous body of evidence that higher serum cholesterol levels promote the development of CHD. This evidence de rivesfrom animal studies, epidemiologicalinvestigations, and geneticdisorders Preface vii oflipoprotein metabolism; all ofthem support the "cholesterol hypothesis." In spite ofthis support, a critical question remains: Does lowering serum choles terol reduce the risk of CHD? According to most investigators, ultimate proof ofthe"cholesterolhypothesis"depends onthedemonstrationofbenefitinclini caloutcomes from reducing cholesterollevels. Suchproofcan beobtainedonly throughcontrolledclinicaltrials. Thehistoryofcontrolledclinical trials ofcho lesterol-lowering therapy goes back almost 40 years. The first clinical trials of this type were initiated in the 1960s. These clinical trials can be divided into earlierend-pointtrials, angiographic trials, andrecenttrials with HMG-CoAre ductase inhibitors (statins). To introduce this monograph on cholesterol-lower ing trials, these categories are examined briefly. They are considered in more detailinthefirstchapter,andthekeytrialsaredescribedandanalyzedthoroughly in subsequentchapters. Betweenthe late 1960sand 1990, asizablenumberofsmallerclinicaltri als were carried out to determine whether cholesterol-lowering therapy would reduce theriskofCHD. Thesetrials employedeitherdietordrugs to reduce se rum cholesterol levels. The studies have been oftwo types: primary prevention trials (prevention ofnew-onset CHD) and secondary prevention trials (preven tion ofrecurrent coronary morbidity and mortality in patients with established CHD). Most ofthese clinical trials suggested some benefit from lowering cho lesterol. Inseveraltrials, thefavorable resultwas statisticallysignificant; inoth ers, strong nonsignificant trends were recorded. In spite ofthese results, how ever, the evidence from single trials was not robust enough to convince the medical community ofthe benefit ofcholesterol-lowering therapy in high-risk patients. More recently, thesemultiple trials havebeensubjectedto meta-analy siswithmoreencouragingresults. Meta-analysisstrengthenedtheconclusionthat lowering ofserum cholesterol levels reduces risk for CHD. On the otherhand, meta-analysis also raised a disturbing question. Itfailed to show that lowering cholesterol reduces total mortality. Although this failure likely reflected a lack ofstatisticalpowerin the analysis, the possibility couldnotbeexcludedthatre ducingserumcholesterolconcentrations induces sideeffectsthatoffsettheben efit ofreducing serum cholesterol on coronary risk. This latter possibility cre ated a widespread skepticism in the medical community as to the benefit of cholesterol-lowering therapy. A secondary category ofclinical trials includedthose thathave addressed the question ofwhethercholesterol-lowering therapy will slow the progression orpromotetheregressionofcoronaryplaques.Thisquestionwasstudiedbycoro nary angiographic techniques. In mostofthese studies aggressive measures, of tenincludingdrugcombinations,wereemployedto lowercholesterollevels. The resultofthese trials were strikingly consistent. They showedthat loweringcho lesterol levels does indeed retard progression and promote regression ofcoro nary lesions. Onthe otherhand, the observed changes in lesion size were small
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