Cholesterol-Lowering Therapy: Evaluation of Clinical Trial Evidence

348 Pages·1999·141.771 MB·\348

by  Scott M. Grundy (Editor)

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
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First published in 2000 by Marcel Dekker, Inc.

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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