P E R S B E R I C H T
LIPITOR® beschermt patiënten
met Acuut Coronair Syndroom (ACS)
beter tegen overlijden en ernstige cardiovasculaire complicaties dan pravastatine.
New Orleans / Capelle aan den IJssel, 14 maart 2004 - Atorvastatine (merknaam Lipitor) geeft ten opzichte van pravastatine een vermindering van 16% op sterfte en herhaald optreden van cardiovasculaire complicaties (zoals myocard infarct, dotteren en angina pectoris). Dit blijkt uit het Pravastatin or Atorvastatin Evaluation and Infection Therapy onderzoek (PROVE IT) dat vorige week is gepresenteerd op het American College of Cardiology in New Orleans en gelijktijdig on-line in the New England Journal of Medicine is gepubliceerd.
In het PROVE IT-onderzoek werden 4162 patiënten met ACS (ACS is een verzamelnaam voor onstabiele angina pectoris en hartinfarct) willekeurig over twee groepen van gelijke omvang verdeeld en gedurende een periode van gemiddeld 24 maanden met 40 mg pravastatine of 80 mg atorvastatine behandeld.
De atorvastatine-patiënten bereikten een waarde van het LDL-cholesterol (het 'slechte' cholesterol) van 1,60 mmol/l, terwijl de pravastatine-patiënten een LDL-waarde van 2,46 mmol/l bereikten.
Na een follow-up van 2 jaar bleek bij deze ACS patiënten dat hun kans op overlijden en cardiovasculaire complicaties door hoge dosering atorvastatine met 16% verder verlaagd was ten opzichte van behandeling met pravastatine.
Verder bleek de intensieve behandeling met atorvastatine te resulteren in minder sterfte (28%), minder dotterbehandelingen en bypass operaties (14%) en minder instabiele angina pectoris (29%) dan pravastatine. Het klinisch voordeel van behandeling met atorvastatine versus pravastatine werd al na 30 dagen zichtbaar. Beide behandelingen werden goed verdragen.
"De data geven aan dat deze patiëntenpopulatie baat heeft bij het krachtig verlagen van het LDL cholesterol tot onder de huidige streefwaarden," aldus Dr. Christopher Cannon, de hoofdonderzoeker van deze studie.
Dokter Steven Nissen van Cleveland Clinic Foundation in Ohio zei "dat de resultaten des te verrassender zijn, omdat de studie zorgvuldig was opgezet om juist geen verschil aan te tonen tussen beide behandelingen". De studie werd mede door Bristol-Myers Squibb, de producent van pravastatine, financieel ondersteund. Daarnaast zegt hij "Ik denk dat dit een atorvastatine effect is en niet een klasse effect". Dr. Nissen was de hoofdonderzoeker van de Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) studie die "dezelfde medicijnen en doseringen" heeft onderzocht. Deze studie liet zien dat intensieve behandeling met atorvastatine, in tegenstelling tot behandeling met pravastatine, de progressie van atherosclerose stopt.
In het begeleidende editorial in NEJM schreef dr E.J. Topol dat de resultaten een grote verrassing zijn. Ondermeer omdat de superioriteit van atorvastatine al binnen een maand na start van de therapie zichtbaar werd, 'zullen de resultaten van de REVERSAL en PROVE-IT trials bij elkaar, het veld behoorlijk door elkaar schudden', stelt Topol.
Atorvastatine is de meest voorgeschreven cholesterolverlager ter wereld met meer dan 69 miljoen patiëntjaren ervaring. Sinds de introductie van het middel in 1997 is de veiligheid en werkzaamheid van atorvastatine wereldwijd onderbouwd door de uitkomsten van een uitgebreid onderzoekprogramma, het 'Atorvastatin Landmark Program', met tot nu toe ruim 400 afgesloten en nog lopende klinische onderzoeken met in totaal ruim 80.000 patiënten. In Nederland wordt atorvastatine onder de merknaam Lipitor® door Pfizer bv op de markt gebracht.
Pfizer ontdekt, ontwikkelt, produceert en verkoopt toonaangevende, op recept verkrijgbare geneesmiddelen voor mens en dier, en vele bekende consumentenproducten.
# # # # #
Meer informatie voor de redactie:
Contact voor de redactie:
Joep Rijnierse, Corporate Affairs, Pfizer bv, telefoon 010-40 64 237 / 06-51 60 28 58 Marc Hinfelaar , Hinfelaar PR Consultancy, telefoon 035-54 31 535 / 06-55 74 65 23
Bronnen:
1. Cannon CP et al. for the Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction 22 Investigators. Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. NEJM 2004;350
2. Nissen SE et al. Effect of Intensive Compared with Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis - A randomized Controlled Trial. JAMA, March 3, 2004 - Vol. 291 No 9 p 1071 - 80.
Reprints van deze artikelen en van de begeleidende editorials die hierover in beide tijdschriften zijn verschenen, zijn op te vragen bij bovenstaande contactpersonen.
|Postbus 37 - 2900 AA Capelle aan den | |IJssel | |Rivium Westlaan 142 - 2909 LD Capelle| |aan den IJssel | |Telefoon +31 (0)10 406 42 00 - Fax +31| |(0)10 406 42 99 | |Fortis Bank 64 00 62 768 - | |Handelsregister Rotterdam 34087728 | | | |Pfizer bv | | | |Contact voor de redactie: | |Joep Rijnierse, Corporate Affairs | |Pfizer bv, | |telefoon 06-51 60 28 58 |===
| | |Verkorte productinformatie Lipitor® (juni 2002) | | | |Samenstelling: Lipitor® 10, Lipitor® 20 en Lipitor® 40 filmomhulde| |tabletten bevatten respectievelijk 10, 20 en 40 mg atorvastatine. | |Indicaties: Adjuvans bij dieet ter verlaging van verhoogd totaal | |cholesterol, LDL-cholesterol, apolipoproteïne B en triglyceriden | |bij patiënten met primaire hypercholesterolemie waaronder | |familiaire hypercholesterolemie (heterozygote variant) of | |gecombineerde hyperlipidemie (overeenkomend met types IIa en IIb | |van de Fredrickson classificatie), als de reactie op dieet en | |andere maatregelen niet voldoende is. Lipitor is ook geïndiceerd | |voor de verlaging van totaal-C en LDL-C bij patiënten met | |homozygote familiaire hypercholesterolemie, als adjuvans bij | |andere lipiden-verlagende behandelingen (zoals LDL-aferese) of | |indien dergelijke behandelingen niet beschikbaar zijn. | |Contra-indicaties: Overgevoeligheid voor één van de bestanddelen | |van dit middel, een actieve leveraandoening of een onverklaarde en| |aanhoudende verhoging van de serumtransaminasen groter dan 3 maal | |de bovengrens van de normaalwaarden, myopathie, zwangerschap, | |lactatie en vrouwen in de vruchtbare leeftijd die geen adequate | |anticonceptieve maatregelen treffen. Waarschuwingen en voorzorgen:| |Vóór instelling van en periodiek tijdens de behandeling dienen | |leverenzymbepalingen te worden uitgevoerd. Indien stijgingen van | |de serumtransaminasen tot waarden groter dan 3 maal de bovengrens | |van de normaalwaarden aanhouden, wordt aanbevolen de dosering van | |Lipitor te verlagen of de behandeling te staken. Terughoudendheid | |is geboden bij alcoholabusus en/of een (geschiedenis van) | |leverziekte. In geval van verdenking op myopathie dient CPK te | |worden bepaald. Indien aanzienlijke verhogingen van CPK aanhouden,| |wordt aanbevolen de dosering te verlagen of de behandeling te | |staken. Interacties: De kans op myalgie, myositis en myopathie, | |zich voortzettend in rhabdomyolyse, gedurende behandeling met | |HMG-CoA-reductase-remmers neemt toe indien gelijktijdig middelen | |zoals ciclosporine, fibraten, macrolide antibiotica, | |azol-antimycotica, nefazodon, nicotinezuur of HIV-proteaseremmers | |worden gebruikt. Men dient bijzonder voorzichtig te zijn en de | |voordelen en nadelen van combinatie-behandeling met deze middelen | |zorgvuldig af te wegen. Het gebruiken van atorvastatine en | |gelijktijdige inname van grote hoeveelheden grapefruitsap wordt | |niet aangeraden. Patiënten die digoxine gebruiken dienen goed | |gecontroleerd te worden. Men dient met verhoogde concentraties van| |norethisteron en ethinyloestradiol rekening te houden bij | |gelijktijdig gebruik van atorvastatine en deze stoffen bevattende | |orale anticonceptiva. Patiënten die met warfarine behandeld worden| |dienen nauwkeurig gecontroleerd te worden indien Lipitor aan hun | |behandeling wordt toegevoegd. Bijwerkingen: De meest frequente | |bijwerkingen (voorbijgaand van aard) zijn gastrointestinaal: | |obstipatie, flatulentie, dyspepsie, buikpijn.Verder zijn | |waargenomen: misselijkheid, anorexia, braken, thrombocytopenie, | |allergische reacties, anafylaxe, alopecia, hyperglycemie, | |hypoglycemie, pancreatitis, slapeloosheid, amnesie, hoofdpijn, | |duizeligheid, paresthesie, perifere neuropathie, hepatitis, | |cholestatische icterus, huiduitslag, pruritus, urticaria, | |angioneurotisch oedeem, bulleuze dermatitis (waaronder erythema | |multiforme, Stevens-Johnson syndroom en toxische epidermale | |necrolyse), myalgie, arthralgie, myopathie, myositis, | |rhabdomyolyse, impotentie, asthenie, pijn op de borst, rugpijn, | |perifeer oedeem, malaise, gewichtstoename. Net als met andere | |HMG-CoA-reductaseremmers zijn verhoogde serumtransaminasen en | |verhoogde CPK spiegels gerapporteerd. Dosering: Eénmaal daags 10 | |tot 80 mg. De maximale dosering bedraagt 80 mg éénmaal daags. De | |tabletten kunnen op elk moment van de dag worden ingenomen, met of| |zonder voedsel. Afleveringsstatus: UR. Vergoeding en prijzen: | |Lipitor® wordt volledig vergoed binnen het GVS. Voor prijzen zie | |Z-Index taxe. Voor medische informatie over dit product belt u met| |0800-MEDINFO (6334636). Voor volledige productinformatie is de IB | |tekst op aanvraag beschikbaar bij de registratiehouder: Pfizer bv,| |Postbus 37, 2900 AA Capelle a/d IJssel. |
---- -- EDITORIALS Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.
High-Intensity Statin Treatment
for Coronary Heart Disease
Frank M. Sacks, MD The success of statin therapy used at initial or moderate doses leads to an important next step to evaluate whether a N THIS ISSUE OF THE JOURNAL, NISSEN AND COLLEAGUES1 higher dose is better. The results of the REVERSAL trial1 reportthefindingsoftheReversalofAtherosclerosiswith extend similar findings in carotid atherosclerosis to coro- Aggressive Lipid Lowering (REVERSAL) study, a clini- nary atherosclerosis. In one trial, carotid artery intima- cal trial comparing the effects of 2 statins, pravastatin media thickness increased more with 40 mg of simvastatin (40-mgdose)andatorvastatin(80-mgdose).TheREVERSAL
I than with 80 mg of atorvastatin; the difference became evi- study is a first in 2 respects. First, it showed that a statin dent at 1 year and was highly statistically significant by 2 regimen using the most efficacious drug (atorvastatin) and years.14 A subsequent trial reported similar results--a bor- dose available for lowering low-density lipoprotein choles- derline significant difference between atorvastatin and terol(LDL-C)whenthetrialbeganimprovedcoronaryath- pravastatin at 1 year.15 Thus, there is a consistency devel- erosclerosismorethanpravastatin,whichrepresentedastatin oping that maximal statin therapy produces a superior regimenthathadbeenfullyestablishedtosafelyreducecar- result on measurements of atherosclerosis in clinically diovascular disease and mortality.2-6 Second, the advantage important sites. ofatorvastatinwasdemonstratedusinganintravascularul- A potential limitation of REVERSAL is the loss of par- trasound examination of the coronary arteries, a technique ticipantstofollow-up.Twenty-threepercentofthetotalpar- that quantifies plaque by visualizing the coronary arterial ticipants randomized were lost to follow-up, which is simi- intima. While this study is an important achievement, it is lar to some trials that used coronary arteriography for the equallyimportanttodeterminewhatitaddstocurrentknowl- outcome,16,17 althoughothershadlowerratesofbetween9% edge of lipid therapy in atherosclerotic cardiovascular dis- and 10%.18,19 Although the primary analysis of REVERSAL ease and how it should affect clinical practice. included just the participants who completed the treat- All told, nearly 70000 patients have participated in large ment and had intravascular ultrasound at the end, the au- placebo-controlled clinical trials of statins of at least 3 years thors also presented the results with all randomized pa- in duration. The study populations have been diverse, in- tients, using baseline data when outcome data could not be cludingthosewithoutclinicalevidenceofcoronaryarterydis- obtained, as recommended.20 The results of the 2 ap- easeandthosewithvariouspresentationsofcoronaryartery proaches are consistent with each other, strengthening the diseasepriortostatintreatment.Riskreductionhasbeensimi- conclusionthatwhencomparedwitha40-mgdoseofprava- lar (range, 20%-30%) across most of these trials in mortality statin,an80-mgdoseofatorvastatinfavorablyaffectedcoro- andinvirtuallyeveryatheroscleroticcardiovasculareventthat nary atherosclerosis. has been evaluated. All of the statins that have been studied Why should a complete analysis of randomized patients, inthesetrials,namelypravastatin(40-mgdose),2-6 simvasta- as presented by Nissen et al, be so important? The random- tin (20- to 40-mg dose),7-8 lovastatin (40-mg dose),9 fluvas- izedcontrolledtrialisasimpleandelegantsolutiontoprob- tatin (80-mg dose),10 and atorvastatin (10-mg dose),11 have lemsinherentinuncontrolledtrialsandinobservationalstud- produced risk reduction in serious coronary vascular end iesofpopulations.Randomizationcreatesacontrolgroupthat points. Although there is some variation between the trials atthestartofthestudyisidenticaltotheexperimentalgroup. in the results of the population subgroups, considering the This, and complete ascertainment of outcome in all patients results across all trials, it now seems true that statins pro- ensure that selection bias and other confounding factors do duce similar relative risk reduction across a wide variety of notaffecttheresults.Whentherearesubstantiallossestofol- patienttypesandclinicalpresentations.Therefore,healthben- low-up, the accuracy of the result can be biased because the efit(ie,absoluteriskreduction),isprincipallydependenton the underlying level of risk. This is explicitly recognized by Author Affiliation: Harvard School of Public Health and Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. national guidelines for lipid treatment.12,13 Financial Disclosure: Dr Sacks is a consultant for the following companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Fournier, Kos, Kowa, Lilly, Pfizer, Re- liant and Sankyo. See also p 1071. Corresponding Author: Frank M. Sacks, MD, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 (fsacks@hsph.harvard.edu). 1132 JAMA, March 3, 2004--Vol 291, No. 9 (Reprinted) ©2004 American Medical Association. All rights reserved.
EDITORIALS
groupsthatwereidenticalatthestartbecomedifferenttoan gressionofatherosclerosis"1 issomewhattroubling.Thispro- unknown extent.20 In this way, a randomized trial takes on vokes an expectation for a dramatic reduction in coronary the limitations of observational studies. Clinical investiga- events when statin therapy is intensified. The likelihood of tors, understandably experiencing frustration that the treat- this is belied by the small difference in atheroma volume ment effect may be diluted by including all randomized pa- between the groups--1%--and by the progression in ath- tients, are at times tempted to present the data of only the eroma in many patients in the intensive group, as noted by patients who completed the study. Trials should have suffi- the authors. A more conservative and perhaps realistic pro- cientsamplesizetomaintainadequatestatisticalpowerwith jectioncanbemadefromtheeffectsofthe2statinsonLDL-C. allrandomizedpatients--essentialtopreservethevalidityof In the Heart Protection Study,8 an approximately 40- the randomized trial, which is the criterion standard for evi- mg/dL (1-mmol/L) reduction in LDL-C corresponded with dence-based medicine. a 25% reduction in coronary event incidence, and this re- The authors defended their selection of 40 mg of prava- lationship also fits the results of most other statin trials.2-11 statin and 80 mg of atorvastatin as a fair test of their hy- In the REVERSAL trial, the difference in LDL-C between pothesis on intensity of statin therapy, and their reasoning thetreatmentgroupswas30mg/dL(0.78mmol/L)(80mg/dL is appropriate. However, the reductions in the pravastatin foratorvastatinvs110mg/dL group in LDL-C of 25% and 5% in C-reactive protein are forpravastatin),projectinga19%additionalrelativeriskre- less than those established by larger trials with high adher- duction from intensive compared with conventional statin enceinwhichLDL-Cwasreducedby32%over5years2 and therapy. C-reactive protein by between 13% and 14% at 6 months21 Couldthis"cholesterol-centric"projectionofclinicalben- and17%and18%at5years.22 InREVERSAL,adherencewas efit of an 80-mg dose of atorvastatin compared with con- not reported, and it is possible that diminished adherence ventionalstatintherapybeamplifiedbynonlipid-mediated could have affected the response in the pravastatin group. effects? Perhaps, but in this projection, a 40-mg/dL (1.04- Researchersstudyingtheeffectsoflipidtherapyhavebe- mmol/L) reduction in LDL-C is accompanied by reduc- moaned the limited information provided by contrast arte- tions in other risk factors including other atherogenic lipo- riography that quantifies only the lumen. Clinical coro- proteins24 andinflammatorymediators.21,22,25,26 Togetherthey narydiseasehasgradualandabruptpresentations.Gradual correspond to the 25% relative reduction in coronary inci- isoftenassociatedwithluminalnarrowingofmorethan75% dence. How much reduction in coronary heart disease dur- and chronic angina and abrupt is associated with less lu- ingstatintherapyisduetoLDL-Cloweringortoothereffects minalnarrowingbutlipid-rich"vulnerable"plaquewithac- isdifficulttodetermine,althoughtheLDL-Ctheorystilldomi- tive inflammation that causes acute coronary syndromes.23 nates, justifiably so because of many levels of strong evi- Intravascular ultrasound can identify morphological char- dence.12 Agoodcasehasbeenmadeforstatinsreducingstroke acteristics of vulnerable plaque, but not of inflammatory byenhancementofnitricoxideproductionandendothelial plaqueactivity,whichrequiresotherinvestigational"activ- function,27 although this mechanism lacks direct proof by ityimaging"techniques.23 Nonetheless,intravascularultra- clinicaltrial.Recently,newimportantdataonthisissuewas sound is an exciting step forward and will probably con- reportedinastatintrialonsymptomaticnonischemicdilated tinue to be refined for use in clinical trials to identify cardiomyopathy.28 Treatment for only 14 weeks with a low potentially vulnerable plaques and quantify changes due to dose of simvastatin (5-10 mg) compared with placebo therapy. New lipid therapies and other antiatherosclerosis improved left ventricular ejection fraction and functional drugscouldbeevaluatedbyintravascularultrasoundforim- class, while lowering substantially several inflammatory proving specifically these most worrisome lesions, and the mediators, tumor necrosis factor , IL-6, and brain natri- results would have immediate clinical meaning especially ureticpeptide,andimprovingendothelialfunction.Itseems if coupled with assessment of plaque inflammation. How- highly unlikely that such rapid clinical improvement in ever, intravascular ultrasound may be limited in use by re- nonischemiccardiomyopathycouldhavebeencausedbythe strictivevesselcharacteristicsorbyahighpercentageofpa- small (16%) reduction in LDL-C. Would these non-LDL- tients who decline intravascular ultrasound or who do not CmediatedeffectstrackproportionatelywithLDL-Creduc- complete follow-up studies. tion with higher statin doses? Relatively equipotent doses The critical remaining question is to what extent the ad- of statins (eg, 10 mg of atorvastatin, 20 mg of simvastatin, ditional improvement in atherosclerosis measurements or 40 mg of pravastatin) have similar effects on C-reactive caused by maximal compared with standard statin therapy protein,26 and there is a dose-related effect.1,25 Thus, non- translates into more clinical benefit, such as prevention of lipid effects of statins probably contribute to the cardiovas- unstable angina, myocardial infarction, or coronary death. cular benefits as a function of intensity of therapy. It is reasonable to expect benefit, although it is difficult to Is this reasoning compelling enough to change clinical predicthowmuchfromtheREVERSALstudyinviewofthe practicewithouttheneedforaclinicaloutcometrial,ashas newness of intravascular ultrasound. The authors' asser- been urged recently?29 The results of the 3 atherosclerosis tionmadeinthearticlethat"intensivetreatmenthaltedpro- studieswithultrasound1,14,15 addsupport.However,apolicy ©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, March 3, 2004--Vol 291, No. 9 1133
EDITORIALS
to use the highest statin doses as standard therapy has im- 11. SeverPS,DahlofB,PoulterNR,etal.Preventionofcoronaryandstrokeevents with atorvastatin in hypertensive pattients who have average or lower-than- plications for cost and potential adverse effects.30 The vast average cholesterol concentrations in the Anglo-Scandinavian Cardiac Outcomes majority of clinical and research experience is with con- Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. ventionalstatindoses,whichhaveprovidedadeservedlyposi- Lancet. 2003;361:1149-1158. 12. National Cholesterol Education Program (NCEP) Expert Panel on Detection, tive view of statin therapy. To put maximal statin therapy, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment Panel III). such as with 80 mg of atorvastatin or 40 mg of rosuva- Third Report of the National Cholesterol Education Program (NCEP) Expert Panel onDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(Adult statin, on the same footing of clinical confidence requires Treatment Panel III) final report. Circulation. 2002;106:3143-3421. resultsfromlargelong-termclinicaltrials.Fortunately,sev- 13. De Backer G, Ambrosioni E, Borch-Johnsen K, et al, for the Third Joint Force ofEuropeanandotherSocietiesonCardiovascularDiseaseandPreventioninClini- erallargetrialscomparingintensivewithconventionalstatin cal Practice. European guidelines on cardiovascular disease and prevention in clini- therapy are near completion and results are expected soon. cal practice. Atherosclerosis. 2003;171:145-155. Until the results of these studies are available, it is pru- 14. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus con- ventional lipid lowering on atherosclerosis progression in familial hypercholester- denttotreatanyhigh-riskpatient,asdefinedbynationalguide- olemia (ASAP): a prospective, randomized, double-blind trial. Lancet. 2001;357: lines,12,13 with a statin at an intensity appropriate to achieve 577-581. 15. Taylor AJ, Kent SM, Flaherty PJ, et al. ARBITER: Arterial Biology for the In- therecommendedgoalsforLDL-C.Inaddition,withthisfo- vestigation of the Treatment Effects of Reducing Cholesterol: a randomized trial cusonLDL-Creduction,cliniciansmustnotlosesightofthe comparingtheeffectsofatorvastatinandpravastatinoncarotidintimamedialthick- ness. Circulation. 2002;106:2055-2060. needtomanageotherestablishedcardiovasculardiseaserisk 16. Pitt B, Mancini GB, Ellis SG, et al. Pravastatin limitation of atherosclerosis in factors including hypertension and atherogenic dyslipid- the coronary arteries (PLAC I): reduction in atherosclerosis progression and clini- cal events. J Am Coll Cardiol. 1995;26:1133-1139. emia,manifestedbylowlevelsofhigh-densitylipoproteincho- 17. Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary lesterol and high levels of triglycerides.12 At least as impor- atherosclerosis in patients wth mild to moderate cholesterol evalation (Lipopro- tant,thisconcentrationondrugtreatmentshouldnotdeflect tein and Coronary Atherosclerosis Study ). Am J Cardiol. 1997;80:278- 286.
attention from diet and lifestyle interventions that have the 18. TheMAASStudyGroup.Effectofsimvastatinoncoronaryatheroma:themul- potential even with moderate improvements to reduce car- ticentre anti-atheroma study (MAAS). Lancet. 1994;344:633-638. 19. Waters D, Higginson L, Gladstone P, et al. Effects of monotherapy with an diovascular disease incidence by between 75% and 80%.31 HMG CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atheroscle- rosis Intervention Trial. Circulation. 1994;89:959-968. REFERENCES 20. Ware JH. Interpreting incomplete data in studies of diet and weight loss.
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8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study diac function and symptons in patients with idiopathic dilated cardiomyopathy. of cholesterol lowering with simvastatin in 20,356 high-risk individuals: a ran- Circulation. 2003;108:839-843. domised placebo-controlled trial. Lancet. 2002;360:7-22. 29. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ.
9. DownsJR,ClearfieldM,WeisS,etal,fortheAFCAPS/TexCAPSResearchGroup. 2002;324:1570-1576. Primary prevention of acute coronary events with lovastatin in men and women 30. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al, for the American College with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279: ofCardiology,AmericanHeartAssociation,andtheNationalHeart,LungandBlood
1615-1622. Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am
10. Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of car- Coll Cardiol. 2002;40:567-572. diac events following successful percutaneous coronary intervention: a random- 31. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart ized controlled trial. JAMA. 2002;287:3215-3222. disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.
1134 JAMA, March 3, 2004--Vol 291, No. 9 (Reprinted) ©2004 American Medical Association. All rights reserved.
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The new england journal of medicine
original article Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Daniel J. Rader, M.D., Jean L. Rouleau, M.D., Rene Belder, M.D., Steven V. Joyal, M.D., Karen A. Hill, B.A., Marc A. Pfeffer, M.D., Ph.D., and Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 Investigators* abstract background
Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the From the Thrombolysis in Myocardial In- optimal level of low-density lipoprotein (LDL) cholesterol is unclear. farction (TIMI) Study Group, Cardiovas- cular Division, Department of Medicine, Brigham and Women's Hospital and Har- methods vard Medical School, Boston (C.P.C., E.B., We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome C.H.M., M.A.P.); the University of Penn- sylvania, Philadelphia (D.J.R.); the Univer- within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) sity of Montreal, Montreal (J.L.R.); Bristol- with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a com- Myers Squibb, Princeton, N.J. (R.B., S.V.J.); posite of death from any cause, myocardial infarction, documented unstable angina re- and the Nottingham Clinical Research Group, Nottingham, United Kingdom quiring rehospitalization, revascularization (performed at least 30 days after randomiza- (K.A.H., A.M.S.). Address reprint requests tion), and stroke. The study was designed to establish the noninferiority of pravastatin to Dr. Cannon at the TIMI Study Group, as compared with atorvastatin with respect to the time to an end-point event. Follow-up Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, lasted 18 to 36 months (mean, 24). MA 02115, or at cpcannon@partners.org. results *The investigators and research coordina- tors who participated in the Pravastatin The median LDL cholesterol level achieved during treatment was 95 mg per deciliter or Atorvastatin Evaluation and Infection (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter TherapyThrombolysis in Myocardial In- (1.60 mmol per liter) in the high-dose atorvastatin group (P 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. conclusions
Among patients who have recently had an acute coronary syndrome, an intensive lipid- lowering statin regimen provides greater protection against death or major cardiovas- cular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially be- low current target levels. n engl j med 350;15 www.nejm.org april 8, 2004 1-cannon Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine s
everal large, randomized, con- dex acute coronary syndrome had to have a total trolled trials have documented that cholester- cholesterol level of 200 mg per deciliter (5.18 mmol ol-lowering therapy with 3-hydroxy-3-meth- per liter ) or less at the time of screening in the local ylglutaryl coenzyme A reductase inhibitors (statins) hospital. reduces the risk of death or cardiovascular events Patients were ineligible for the study if they had across a wide range of cholesterol levels whether or a coexisting condition that shortened expected sur- not patients have a history of coronary artery dis- vival to less than two years, were receiving therapy ease.1-7 The doses of statins used in these trials re- with any statin at a dose of 80 mg per day at the duced low-density lipoprotein (LDL) cholesterol time of their index event or lipid-lowering therapy levels by 25 to 35 percent, and current guidelines with fibric acid derivatives or niacin that could not recommend a target LDL cholesterol level of less be discontinued before randomization, had received than 100 mg per deciliter (2.59 mmol per liter) for drugs that are strong inhibitors of cytochrome P-450 patients with established coronary artery disease or 3A4 within the month before randomization or were diabetes.8,9 It is not clear whether lowering lipid lev- likely to require such treatment during the study els further would increase the clinical benefit. Ac- period (because atorvastatin is metabolized by this cordingly, the Pravastatin or Atorvastatin Evaluation pathway), had undergone percutaneous coronary and Infection TherapyThrombolysis in Myocardial intervention within the previous six months (other Infarction 22 (PROVE ITTIMI 22) trial was de- than for the qualifying event) or coronary-artery by- signed to compare the standard degree of LDL cho- pass surgery within the previous two months or were lesterol lowering to approximately 100 mg per deci- scheduled to undergo bypass surgery in response to liter with the use of 40 mg of pravastatin daily2,3 with the index event, had factors that might prolong the more intensive LDL cholesterol lowering to approx- QT interval, had obstructive hepatobiliary disease or imately 70 mg per deciliter (1.81 mmol per liter) other serious hepatic disease, had an unexplained with the use of 80 mg of atorvastatin daily10 as a elevation in the creatine kinase level that was more mean of preventing death or major cardiovascular than three times the upper limit of normal and that events in patients with an acute coronary syndrome. was not related to myocardial infarction, or had a creatinine level of more than 2.0 mg per deciliter methods (176.8 µmol per liter). patient population study protocol Between November 15, 2000, and December 22, The protocol specified that patients were to receive
2001, 4162 patients were enrolled at 349 sites in standard medical and interventional treatment for eight countries (see the Appendix). The protocol acute coronary syndromes, including aspirin at a was approved by the relevant institutional review dose of 75 to 325 mg daily, with or without clopid- boards, and written informed consent was obtained ogrel or warfarin. Patients were not permitted to be from all patients. As described previously,11 men treated with any lipid-modifying therapy other than and women who were at least 18 years old were el- the study drug. Eligible patients were randomly as- igible for inclusion if they had been hospitalized signed in a 1:1 ratio to receive 40 mg of pravastatin for an acute coronary syndrome -- either acute my- or 80 mg of atorvastatin daily in a double-blind, dou- ocardial infarction (with or without electrocardio- ble-dummy fashion. In addition, patients were also graphic evidence of ST-segment elevation) or high- randomly assigned to receive with the use of a two- risk unstable angina -- in the preceding 10 days. by-two factorial design a 10-day course of gatiflox- Patients had to be in stable condition and were to acin or placebo every month during the trial. The re- be enrolled after a percutaneous revascularization sults of the antibiotic component of the trial are not procedure if one was planned. Finally, patients had reported here. to have a total cholesterol level of 240 mg per deci- Patients were seen for follow-up visits and re- liter (6.21 mmol per liter) or less, measured at the ceived dietary counseling8 at 30 days, at 4 months, local hospital within the first 24 hours after the onset and every 4 months thereafter until their final visit in of the acute coronary syndrome or up to six months August or September 2003. Patients who discontin- earlier if no sample had been obtained during the ued the study drug during the trial were followed by first 24 hours. Patients who were receiving long- means of telephone calls. Blood samples were ob- term lipid-lowering therapy at the time of their in- tained at randomization, at 30 days, at 4, 8, 12, and cannon-2 n engl j med 350;15 www.nejm.org april 8, 2004 Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
intensive vs. moderate lipid lowering with statins
16 months, and at the final visit for the measure- statistical analysis ment of lipids and other components that were part Although the trial was designed as a time-to-event of the safety assessment. Measurements were made study, the definition of noninferiority was arrived at at the core laboratories listed in the Appendix. LDL through a consideration of two-year event rates. For cholesterol levels were monitored, and the protocol the comparison of pravastatin with atorvastatin, we specified that the dose of pravastatin was to increase defined the prespecified boundary for noninferior- to 80 mg in a blinded fashion if the LDL cholesterol ity as an upper limit of the one-sided 95 percent con- level exceeded 125 mg per deciliter (3.23 mmol per fidence interval of the relative risk at two years of less liter) on two consecutive visits and the patient had than 1.17 (corresponding to a hazard ratio through- been taking study medication and had returned for out follow-up of 1.198). Assuming a two-year event the required study visits. The dose of either study rate of 22 percent in the atorvastatin group and that drug could be halved in the event of abnormal liver- the two treatments had equivalent efficacy, we de- function results, elevations in creatine kinase levels, termined that enrollment of 2000 patients per group or myalgias. would give the study a statistical power of 87 per- Patients were followed for 18 to 36 months, with cent and that this power would be preserved if fol- an average follow-up of 24 months. The trial con- low-up continued until 925 end-point events had tinued until 925 events had been reported to the co- occurred.14 A central randomization system was ordinating center, after which time all patients were used that involved a permuted-block design in requested to return for a final study visit. Eight pa- which assignment was stratified according to cen- tients (0.2 percent) were lost to follow-up. ter. Three interim assessments of efficacy and safety were carried out by the data and safety monitoring end points board. Rules for stopping the study early in the event The primary efficacy outcome measure was the time that the superiority of either treatment was estab- from randomization until the first occurrence of a lished were not prespecified. component of the primary end point: death from All efficacy analyses are based on the intention- any cause, myocardial infarction, documented un- to-treat principle. Estimates of the hazard ratios and stable angina requiring rehospitalization, revascu- associated 95 percent confidence intervals compar- larization with either percutaneous coronary inter- ing pravastatin with atorvastatin were obtained with vention or coronary-artery bypass grafting (if these the use of the Cox proportional-hazards model, with procedures were performed at least 30 days after randomized treatment as the covariate and stratifi- randomization), and stroke. Myocardial infarction cation according to the receipt of gatifloxacin or was defined by the presence of symptoms suggestive placebo. (Using the two-by-two factorial design, of ischemia or infarction, with either electrocardio- we conducted a preliminary test for interaction and graphic evidence (new Q waves in two or more leads) found none. For the primary end point, the interac- or cardiac-marker evidence of infarction, according tion P value was 0.90 and the hazard ratios compar- to the standard TIMI and American College of Car- ing pravastatin with atorvastatin were almost iden- diology definition.12,13 Unstable angina was de- tical for the gatifloxacin and placebo groups.) When fined as ischemic discomfort at rest for at least 10 it was determined that noninferiority was not dem- minutes prompting rehospitalization, combined onstrated, the subsequent assessment of superiority with one of the following: ST-segment or T-wave was carried out with the use of two-sided confidence changes, cardiac-marker elevations that were above intervals. The investigators designed the trial and the upper limit of normal but did not meet the cri- had free and complete access to the data. Data co- teria for myocardial infarction, or a second episode ordination was performed by the Nottingham Clin- of ischemic chest discomfort lasting more than ical Research Group (see the Appendix). Investi-
10 minutes and that was distinct from the episode gators at TIMI, the sponsor, and members of the that had prompted hospitalization. Secondary end Nottingham Clinical Research Group performed points were the risk of death from coronary heart data analysis jointly. disease, nonfatal myocardial infarction, or revascu- larization (if it was performed at least 30 days after results randomization), the risk of death from coronary
heart disease or nonfatal myocardial infarction, and The two groups of patients were well matched with the risk of the individual components of the primary regard to base-line characteristics, with the excep- end point. tion of a history of peripheral arterial disease, which n engl j med 350;15 www.nejm.org april 8, 2004 3-cannon Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine was more common in the pravastatin group than tion without electrocardiographic evidence of ST- the atorvastatin group (P=0.03) (Table 1). Their av- segment elevation in approximately one third, and erage age was 58 years, and 22 percent were women. myocardial infarction with ST-segment elevation Before their index event, 18 percent of patients had in one third. Sixty-nine percent of patients under- had a myocardial infarction, 11 percent had previ- went percutaneous coronary intervention for the ously undergone coronary-artery bypass surgery, treatment of their index acute coronary syndrome and 18 percent had diabetes mellitus. The index before randomization. One quarter of the patients event was high-risk unstable angina in approxi- were taking statin drugs at the time of the index mately one third of the patients, myocardial infarc- event. Concomitant medications were administered Table 1. Base-Line Characteristics of the Patients.*
40 mg of Pravastatin 80 mg of Atorvastatin Characteristic (N=2063) (N=2099) Age -- yr 58.3±11.3 58.1±11.2 Male sex -- no. (%) 1617 (78.4) 1634 (77.8) White race -- no. (%) 1865 (90.4) 1911 (91.0) Diabetes mellitus -- no. (%) 361 (17.5) 373 (17.8) Hypertension -- no. (%) 1014 (49.2) 1077 (51.3) Current smoker -- no. (%) 766 (37.1) 763 (36.4) Prior myocardial infarction -- no. (%) 395 (19.1) 374 (17.8) Percutaneous coronary intervention -- no. (%) Before index event 320 (15.5) 322 (15.3) For treatment of index event 1426 (69.1) 1442 (68.7) Coronary bypass surgery before index event -- no. (%) 221 (10.7) 233 (11.1) Peripheral arterial disease -- no. (%) 136 (6.6) 105 (5.0) Prior statin therapy -- no. (%) 514 (24.9) 535 (25.5) Index event -- no. (%)
Unstable angina 614 (29.8) 604 (28.8) MI without ST-segment elevation 757 (36.7) 747 (35.6) MI with ST-segment elevation 690 (33.4) 748 (35.6) Lipid values
Total cholesterol
No. of patients 1981 2014 Median -- mg/dl 180 181 Interquartile range -- mg/dl 158202 160205 LDL cholesterol
No. of patients 1973 2003 Median -- mg/dl 106 106 Interquartile range -- mg/dl 87127 89128 HDL cholesterol
No. of patients 1981 2014 Median -- mg/dl 39 38 Interquartile range -- mg/dl 3346 3246 Triglycerides
No. of patients 1984 2016 Median -- mg/dl 154 158 Interquartile range -- mg/dl 115207 119214
* Plusminus values are means ±SD. None of the differences between groups were significant with the exception of a his- tory of peripheral arterial disease (P=0.03). Two patients did not have information regarding the electrocardiographic type of acute coronary syndrome, and one patient had missing information regarding prior statin use. HDL denotes high-density lipoprotein, and LDL low-density lipoprotein. To convert values for cholesterol to millimoles per liter, multi- ply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129. cannon-4 n engl j med 350;15 www.nejm.org april 8, 2004 Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
intensive vs. moderate lipid lowering with statins to patients during the treatment period as follows: aspirin to 93 percent, warfarin to 8 percent, clo- 120 pidogrel or ticlodipine to 72 percent initially and 40 mg of pravastatin
100
20 percent at one year, beta-blockers to 85 per- cent, angiotensin-convertingenzyme inhibitors to 80
69 percent, and angiotensin-receptor blockers to 60
14 percent. 80 mg of atorvastatin At the time of randomization, a median of seven 40 days after the onset of the index event, the median LDL Cholesterol (mg/dl) 20 LDL cholesterol levels were 106 mg per deciliter
(2.74 mmol per liter) before treatment in each group 0 (Fig. 1). The LDL cholesterol levels achieved during Base line 30 Days 4 Mo 8 Mo 16 Mo Final follow-up were 95 mg per deciliter (2.46 mmol per Time of Visit liter; interquartile range, 79 to 113 mg per deciliter No. of Patients Pravastatin 1973 1844 1761 1647 1445 1883 ) in the pravastatin Atorvastatin 2003 1856 1758 1645 1461 1910 group and 62 mg per deciliter (1.60 mmol per liter; interquartile range, 50 to 79 mg per deciliter [1.29 Figure 1. Median Low-Density Lipoprotein (LDL) Cholesterol Levels during to 2.04 mmol per liter]) in the atorvastatin group the Study. (P3). The risk of the secondary end point of death due a 7 percent reduction among patients with a base- to coronary heart disease, myocardial infarction, or line LDL cholesterol below 125 mg per deciliter revascularization was similarly reduced by 14 per- (P for interaction=0.02). n engl j med 350;15 www.nejm.org april 8, 2004 5-cannon Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine cardiovascular events, intensive therapy with high- 30 dose atorvastatin resulted in a median LDL choles- 25 terol level of 62 mg per deciliter, as compared with a level of 95 mg per deciliter for standard-dose prav- 40 mg of pravastatin 20 80 mg of atorvastatin astatin. Among patients who had recently been hos- 15 pitalized for an acute coronary syndrome, the more intensive regimen resulted in a lower risk of death Event (%) 10 from any cause or major cardiac events than did a 5 more moderate degree of lipid lowering with the use P=0.005
Death or Major Cardiovascular of a standard dose of a statin. Although prior place- 0 bo-controlled studies have shown that a standard- 0 3 6 9 12 15 18 21 24 27 30
dose statin is beneficial,1-7 we demonstrated that Months of Follow-up more intensive lipid lowering significantly increased No. at Risk
Pravastatin 2063 1688 1536 1423 810 138 this clinical benefit. Atorvastatin 2099 1736 1591 1485 842 133 Although the exact mechanism of the benefit cannot be established solely on the basis of our re- Figure 2. KaplanMeier Estimates of the Incidence of the Primary End Point sults, the extent of the benefit afforded by the 80-mg of Death from Any Cause or a Major Cardiovascular Event. dose of atorvastatin is in keeping with what would Intensive lipid lowering with the 80-mg dose of atorvastatin, as compared be expected on the basis of the greater degree of lip- with moderate lipid lowering with the 40-mg dose of pravastatin, reduced id lowering produced by this regimen. In the Heart the hazard ratio for death or a major cardiovascular event by 16 percent. Protection study, statin treatment resulted in an LDL cholesterol level that was 40 mg per deciliter (1.03 mmol per liter) lower than the value in the placebo tolerability and safety group and that was accompanied by a 25 percent re- The rates of discontinuation of treatment because duction in cardiovascular events. In our study, the of an adverse event or the patient's preference or for LDL cholesterol level was 33 mg per deciliter (0.85 other reasons were 21.4 percent in the pravastatin mmol per liter) lower in the atorvastatin group than group and 22.8 percent in the atorvastatin group at in the pravastatin group. This difference should one year (P=0.30) and 33.0 percent and 30.4 per- translate into a 20 percent reduction in clinical cent, respectively, at two years (P=0.11). During events, which is very similar to the 16 percent re- treatment, the dose of pravastatin was increased to duction we observed and suggests that much of the 80 mg in 8 percent of patients, and the dose was benefit is attributable to the difference in the degree halved among 1.4 percent of the patients in the prav- of LDL cholesterol lowering. However, we cannot astatin group and 1.9 percent of those in the atorva- exclude the possibility that the difference in clinical statin group (P=0.20), owing to side effects or liver- outcomes may be due in part to nonlipid-related function abnormalities. The percentages of patients pleiotropic effects, which may differ between the who had elevations in alanine aminotransferase lev- two the statins we used.15 Future trials involving dif- els that were more than three times the upper limit ferent doses of a single statin should help address of normal were 1.1 percent in the pravastatin group this possibility. and 3.3 percent in the atorvastatin group (P 2.7 percent of pravastatin-treated patients, as com- reduction in the need for revascularization. The re- pared with 3.3 percent of atorvastatin-treated pa- duction in the rate of death from any cause was of tients (P=0.23). There were no cases of rhabdomy- borderline significance (28 percent, P=0.07), sug- olysis in either group. gesting that more aggressive lipid lowering is im- portant not only to reduce the risk of recurrent is- discussion chemia, but possibly also to decrease the risk of fatal events. In this comparison of two statin regimens of differ- The reduction in clinical events with the more ent lipid-lowering intensities for the prevention of intensive lipid-lowering therapy was apparent as cannon-6 n engl j med 350;15 www.nejm.org april 8, 2004 Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
intensive vs. moderate lipid lowering with statins
Event Rates Censoring Time Hazard Ratio (95% CI) Risk Reduction Atorvastatin Pravastatin percent 30 Days 17 1.9 2.2 90 Days 18 6.3 7.7 180 Days 14 12.2 14.1 End of follow-up 16 22.4 26.3 0.50 0.75 1.00 1.25 1.50
High-Dose Standard-Dose Atorvastatin Better Pravastatin Better Figure 3. Hazard Ratio for the the Primary End Point of Death from Any Cause or a Major Cardiovascular Event at 30, 90, and 180 Days and at the End of Follow-up in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group.
Event rates are KaplanMeier estimates censored at the time points indicated with the use of the average duration of fol- low-up (two years). CI denotes confidence interval. 2-Yr Event Rates End Point Hazard Ratio (95% CI) Risk Reduction Atorvastatin Pravastatin percent Death from any cause 28 2.2 3.2 Death from CHD 30 1.1 1.4 Death from other causes 27 1.2 1.8 MI 13 6.6 7.4
Death or MI 18 8.3 10.0 Death from CHD or MI 16 7.2 8.3 Revascularization 14 16.3 18.8 MI, revascularization, or death 14 19.7 22.3 from CHD
Unstable angina requiring 29 3.8 5.1 hospitalization
Stroke ¡9 1.0 1.0 0.50 1.00 1.50
High-Dose Standard-Dose Atorvastatin Better Pravastatin Better Figure 4. Estimates of the Hazard Ratio for the Secondary End Points and the Individual Components of the Primary End Point in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group. CI denotes confidence interval, CHD coronary heart disease, and MI myocardial infarction. Revascularization was per- formed at least 30 days after randomization.
early as 30 days after the start of therapy. This rapid enrolled them immediately after their condition had time frame is similar to that reported with statin stabilized. Three quarters of the patients were treat- treatment in the placebo-controlled Myocardial ed with an early invasive strategy, and the majority Ischemia Reduction with Aggressive Cholesterol were treated with multiple medications for second- Lowering (MIRACL) trial16 and in prior observation- ary prevention, including antiplatelet therapy, beta- al studies.17,18 We studied patients who had been blockers, and angiotensin-convertingenzyme in- hospitalized for an acute coronary syndrome and hibitors (and a statin as part of the trial design). n engl j med 350;15 www.nejm.org april 8, 2004 7-cannon Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
2-Yr Event Rates Base-Line Characteristic No. of Patients (%) Hazard Ratio Atorvastatin Pravastatin percent Sex
Male 3251 (78) 23.0 26.2 Female 911 (22) 20.3 27.0 Age
65 yr 1230 (30) 28.1 29.5 Yes 734 (18) 28.8 34.6 No 3428 (82) 21.0 24.6 Prior smoking
Yes 3077 (74) 22.8 26.5 No 1085 (26) 21.3 25.9 Prior statin therapy
Yes 1049 (25) 27.5 28.9 No 3112 (75) 20.6 25.5 Index event
Unstable angina 1218 (29) 26.5 31.4 MI without ST-segment elevation 1504 (36) 19.0 24.1 MI with ST-segment elevation 1438 (35) 22.6 24.2 LDL cholesterol
125 mg/dl 1091 (27) 20.1 28.2 40 mg/dl 1776 (44) 21.7 26.7
High-Dose Standard-Dose Atorvastatin Better Pravastatin Better Figure 5. Two-Year Event Rates and Estimates of the Hazard Ratio for the Primary End Point in the High-Dose Atorvastat- in Group, as Compared with the Standard-Dose Pravastatin Group, According to Base-Line Characteristics. A test for interaction was significant only for a base-line low-density lipoprotein (LDL) value of at least 125 mg per deci- liter, as compared with a value of less than 125 mg per deciliter (P=0.02). LDL cholesterol was measured at base line in a total of 3976 patients, and high-density lipoprotein (HDL) cholesterol was measured in 3995. Two patients did not have information regarding the electrocardiographic type of acute coronary syndrome, and one patient had missing in- formation regarding prior statin use. MI denotes myocardial infarction. Nonetheless, early and continued separation of the dromes, who have a culprit lesion and frequently event curves was observed in the more intensive multiple additional vulnerable plaques as well,19,20 lipid-lowering group. This early reduction in event can derive particular benefit from early and intensive rates in patients with acute coronary syndromes lipid lowering with statins. The current guidelines contrasts with the lag of approximately one to two of the American College of Cardiology and Ameri- years in prior studies of statins in patients with can Heart Association recommend instituting lipid- chronic atherosclerosis.1-6 These data suggest that lowering therapy at the time of hospital discharge this population of patients with acute coronary syn- in patients with acute coronary syndromes, on the cannon-8 n engl j med 350;15 www.nejm.org april 8, 2004 Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
intensive vs. moderate lipid lowering with statins theory that it will improve patients' compliance with It is important to note that our safety and effica- the use of statins for long-term secondary preven- cy results were obtained in a carefully selected and tion.21 Our data are evidence that such therapy will monitored study population (for example, we ex- also provide protection against early recurrent car- cluded patients who were concomitantly receiving diovascular events. strong inhibitors of cytochrome P-450 3A4, be- After the early separation of the clinical-event cause this is integral to the route of metabolism of curves, we also observed a continued benefit of ator- atorvastatin). Although both drugs were generally vastatin therapy throughout the follow-up period of well tolerated, there were significantly more liver- two and one-half years (Fig. 2). It cannot be deter- related side effects with high-dose atorvastatin than mined from this study whether this longer-term with standard-dose pravastatin. Patients in clinical benefit was due to ongoing intensive lipid-lowering practice generally have more coexisting conditions therapy or was the result of an early benefit in stabi- than did our patients, and they may not tolerate a lizing vulnerable plaques with the early and inten- high-dose statin regimen as well as our patients did. sive treatment after the acute event. It also cannot be Thus, clinicians must take these factors into account determined whether other differences between the when applying the results of our trial in clinical two statins used explain the observed clinical bene- practice. fit. Nonetheless, our findings suggest that patients The National Cholesterol Education Program with acute coronary syndromes who receive early and European guidelines currently recommend that and intensive lipid-lowering therapy continue to de- the goal of treatment in patients with established rive benefit in the chronic phase of atherosclerosis coronary artery disease should be an LDL choles- when high-dose statin therapy is maintained. terol level of less than 100 mg per deciliter.8,9 Al- Our finding of a continued benefit of intensive though our data provide support for the use of this lipid-lowering therapy during the follow-up phase approach, given the substantially lower LDL choles- is consistent with studies showing that such an ap- terol levels achieved in the group given 80 mg of proach results in a slower rate of progression of ath- atorvastatin daily (median, 62 mg per deciliter), our erosclerosis in patients with stable coronary artery results suggest that after an acute coronary syn- disease22 or in those who undergo coronary-artery drome, the target LDL cholesterol level may be low- bypass grafting,23 as well as in greater reductions in er than that recommended in the current guidelines. carotid intimalmedial thickening.24-26 Although Supported by Bristol-Myers Squibb and Sankyo. Drs. Rader and Pfeffer report having received consulting fees and our study documented a benefit for up to an aver- lecture fees from Bristol-Myers Squibb. Drs. Joyal and Belder are age of two years of follow-up, several large, ongoing employees of Bristol-Myers Squibb and have equity in the company. trials involving patients with stable atherosclerosis Dr. Rouleau reports having received consulting fees and lecture fees will determine the five-year outcomes of intensive from Novartis. as compared with moderate lipid lowering.27
a p p e n d i x The following investigators and research coordinators participated in the study (the complete list of investigators and coordinators is avail- able at http://www.timi.org): Operations Committee -- E. Braunwald (Study Chair), C. Cannon (Principal Investigator), T. Grayston, B. Muh- lestein, D. Rader, J. Rouleau, and members of the Data Coordinating Center and Sponsor indicated with an asterisk; Steering Committee -- Members of the Operations Committee and R. Byington, A. Castaigne, H. Darius, G. DeFerrari, B. Gersh, D. Gilbert, S. Grundy, G. Jackson, R. Knopp, I. Meredith, E. Ofili, M. Pfeffer, F. Sacks, P. Shah, S. Smith, A. Tonkin, J. Velasco; TIMI Study Group -- C. McCabe (Project Direc- tor),* S. McHale (Project Manager); Sponsor (Bristol-Myers Squibb, Princeton, N.J., and Wallingford, Conn.) -- R. Belder,* J. Breen,* G. Cu- cinotta, S. Joyal,* C.-S. Lin, K. Natarajan,* S. Nichols; Data Coordinating Center (Nottingham Clinical Research Group, Nottingham, United Kingdom) -- A. Skene,* K. Hill; Clinical Events Committee -- M. Pfeffer (Chairman), R. Guertin-Mercier; J. Potzka, R. Messing; Physician Re- viewers -- E. Ascher, P. Finn, R. Giugliano, J. Kirdar, D. Lee, A. Mirza, T. Rocco; Biomarker Core Laboratory (Brigham and Women's Hospital, Boston) -- D. Morrow, P. Ridker, E. Danielson, G. Borkowski; Chlamydia/Serology Core Laboratory (John Hopkins University, Baltimore) -- T. Quinn; C. Gaydos, B. Wood; Electrocardiographic Core Laboratory (eResearch Technology, Philadelphia) -- J. Morganroth; Special Lipid Core Lab- oratory (University of Pennsylvania, Philadelphia) -- D. Rader, M. Wolfe; Chemistry Core Laboratory (LabCorp, Raritan, N.J.); Data and Safety Monitoring Board -- A. Gotto (Chair), J. Bartlett, D. DeMets, J. Banas, T. Pearson; Clinical Centers Enrolling the Most Patients (in order of enrollment) -- Huntsville Hospital, Huntsville, Ala.: W. Haught and K. Griffin; Fremantle Hospital, Fremantle, Wash.: R. Hendriks and D. Greenwell; Detar Hospital, Victoria, Tex.: H. Chandna and D. Holly; St. Francis Hospital, Tulsa, Okla.: J. Cassidy and N. Ritchie; Advanced Health In- stitute, Galax, Va.: J. Puma and E. Jones; Michigan Heart, Ypsilanti: J. Bengtson and C. Carulli; North Mississippi Medical Center, Tupelo: B. Bertolet and M. Jones; Wilford Hall Medical Center, Lackland Air Force Base, Lackland, Tex.: R. Krasuski and U. Ward; Queen Elizabeth Hospital, Woodville, Saskatchewan, Canada: J. Horowitz and R. Prideaux; Moses H. Cone Hospital, Greensboro, N.C.: T. Kelly and K. Cochran; Deaconess Medical Center, Spokane Wash.: D. Hollenbaugh and J. Mansfield; Louisiana Cardiology Associates, Baton Rouge: J. McLachlan and A. Yoches; New Mexico Heart Institute, Albuquerque: R. Orchard and S. Justice; River Cities Cardiology, Jeffersonville, Ind.: D. Denny and B. Vanvactor; Laval Hospital, Quebec, Canada: P. Bogaty and L. Boyer; Altru Health System Research Center, Grand Forks, n engl j med 350;15 www.nejm.org april 8, 2004 9-cannon Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine N.D.: A. Ahmed and D. Vold; Iowa Heart Center, Des Moines: W. Wickmeyer and N. Coffman; MetroHealth Medical Center, Cleveland: R. Finkelhor and M. Dettmer; Scarborough Cardiology Research, Scarborough, Ont., Canada: A. Ricci, and B. Bozek; Moses Cone Hospital, Greensboro, N.C.: T. Stuckey and S. Milks; Lake Forest Hospital, Bannockburn, Ill.: J. Alexander and K. Anderson; Centre Hospitalier Uni- versitaire, Fleurimont, Que., Canada: S. LePage and L. Larrivee; Butterworth Hospital, Grand Rapids, Mich.: R. McNamara and B. Van Over; Centre Hospitalier Regional de Lanaudière, Quebec, Canada: S. Kouz and M. Roy; Craigavaon Area Hospital, Portadown, County Armagh, United Kingdom: A. Moriarty and D. McEneaney. r e f e r e n c e s
1. Scandinavian Simvastatin Survival Study National Cholesterol Education Program 20. Goldstein JA, Demetriou D, Grines CL, Group. Randomised trial of cholesterol low- treatment goals. Am J Cardiol 1997;80:347- Pica M, Shoukfeh M, O'Neill WW. Multiple ering in 4 444 patients with coronary heart 8. complex coronary plaques in patients with disease: the Scandinavian Simvastatin Sur- 11. Cannon CP, McCabe CH, Belder R, acute myocardial infarction. N Engl J Med vival Study (4S). Lancet 1994;344:1383-9. Breen J, Braunwald E. Design of the Prava- 2000;343:915-22.
2. Sacks RM, Pfeffer MA, Moye LA, et al. statin or Atorvastatin Evaluation and Infec- 21. Braunwald E, Antman EM, Beasley JW, The effect of pravastatin on coronary events tion Therapy (PROVE IT)-TIMI 22 trial. Am J et al. ACC/AHA guideline update for the after myocardial infarction in patients with Cardiol 2002;89:860-1. management of patients with unstable average cholesterol levels. N Engl J Med 12. Cannon CP, McCabe CH, Wilcox RG, et angina and non-ST-segment elevation myo-
1996;335:1001-9. al. Oral glycoprotein IIb/IIIa inhibition with cardial infarction -- 2002: summary article:
3. The Long-Term Intervention with Prava- orbofiban in patients with unstable coro- a report of the American College of Cardiol- statin in Ischaemic Disease (LIPID) Study nary syndromes (OPUS-TIMI 16) trial. Cir- ogy/American Heart Association Task Force Group. Prevention of cardiovascular events culation 2000;102:149-56. on Practice Guidelines (Committee on the and death with pravastatin in patients with 13. Cannon CP, Battler A, Brindis RG, et al. Management of Patients with Unstable coronary heart disease and a broad range of American College of Cardiology key data Angina). Circulation 2002;106:1893-900. initial cholesterol levels. N Engl J Med 1998; elements and definitions for measuring the 22. Nissen SE, Tuzcu EM, Schoenhagen P,
339:1349-57. clinical management and outcomes of et al. Effect of intensive compared with mod-
4. Heart Protection Study Collaborative patients with acute coronary syndromes: a erate lipid-lowering therapy on progression Group. MRC/BHF Heart Protection Study of report of the American College of Cardiol- of coronary atherosclerosis. JAMA 2004; cholesterol lowering with simvastatin in 20 ogy Task Force on Clinical Data Standards 291:1071-80.
536 high-risk individuals: a randomised pla- (Acute Coronary Syndromes Writing Com- 23. Campeau L, Hunninghake DB, Knat- cebo-controlled trial. Lancet 2002;360:7-22. mittee). J Am Coll Cardiol 2001;38:2114-30. terud GL, et al. Aggressive cholesterol low-
5. Shepard J, Cobbe SM, Ford I, et al. Pre- 14. Lachin JM, Foulkes MA. Evaluation of ering delays saphenous vein graft athero- vention of coronary heart disease with prav- sample size and power for analyses of sur- sclerosis in women, the elderly, and patients astatin in men with hypercholesterolemia. vival with allowance for nonuniform patient with associated risk factors: NHLBI post N Engl J Med 1995;333:1301-7. entry, losses to follow-up, noncompliance, coronary artery bypass graft clinical trial.
6. Downs JR, Clearfield M, Weis S, et al. and stratification. Biometrics 1986;42:507- Circulation 1999;99:3241-7. Primary prevention of acute coronary events 19. 24. Taylor AJ, Kent SM, Flaherty PJ, Coyle with lovastatin in men and women with aver- 15. Bonetti PO, Lerman LO, Napoli C, Ler- LC, Markwood TT, Vernalis MN. ARBITER: age cholesterol levels: results of AFCAPS/ man A. Statin effects beyond lipid lowering Arterial Biology for the Investigation of the TexCAPS: Air Force/Texas Coronary Athero- -- are they clinically relevant? Eur Heart J Treatment Effects of Reducing Cholesterol: sclerosis Prevention Study. JAMA 1998;279: 2003;24:225-48. a randomized trial comparing the effects of
1615-22. 16. Schwartz GG, Olsson AG, Ezekowitz atorvastatin and pravastatin on carotid
7. Shepherd J, Blauw GJ, Murphy MB, et al. MD, et al. Effects of atorvastatin on early intima medial thickness. Circulation 2002; Pravastatin in elderly individuals at risk of recurrent ischemic events in acute coronary 106:2055-60. vascular disease (PROSPER): a randomised syndromes: the MIRACL study: a random- 25. Kent SM, Coyle LC, Flaherty PJ, Mark- controlled trial. Lancet 2002;360:1623-30. ized controlled trial. JAMA 2001;285:1711- wood TT, Taylor AJ. Marked low-density lipo-
8. Expert Panel on Detection, Evaluation, 8. protein cholesterol reduction below current and Treatment of High Blood Cholesterol in 17. Stenestrand U, Wallentin L. Early statin National Cholesterol Education Program tar- Adults. Executive summary of the Third treatment following acute myocardial infarc- gets provides the greatest reduction in carotid Report of the National Cholesterol Educa- tion and 1-year survival. JAMA 2001;285: atherosclerosis. Clin Cardiol 2004;27:17-21. tion Program (NCEP) Expert Panel on Detec- 430-6. 26. Smilde TJ, van Wissen S, Wollersheim tion, Evaluation, and Treatment of High 18. Aronow HD, Topol EJ, Roe MT, et al. H, Trip MD, Kastelein JJ, Stalenhoef AF. Blood Cholesterol in Adults (Adult Treat- Effect of lipid-lowering therapy on early mor- Effect of aggressive versus conventional lipid ment Panel III). JAMA 2001;285:2486-97. tality after acute coronary syndromes: an lowering on atherosclerosis progression in
9. De Backer G, Ambrosioni E, Borch- observational study. Lancet 2001;357:1063- familial hypercholesterolaemia (ASAP): a Johnsen K, et al. European guidelines on car- 8. prospective, randomised, double-blind trial. diovascular disease and prevention in clinical 19. Asakura M, Ueda Y, Yamaguchi O, et al. Lancet 2001;357:577-81. practice. Atherosclerosis 2003;171:145-55. Extensive development of vulnerable plaques 27. LaRosa JC. New and emerging data
10. Davidson MH, Nawrocki JW, Weiss SR, as a pan-coronary process in patients with from clinical trials of statins. Curr Athero- et al. Effectiveness of atorvastatin for reduc- myocardial infarction: an angioscopic study. scler Rep 2004;6:12-9. ing low-density lipoprotein cholesterol to J Am Coll Cardiol 2001;37:1284-8. Copyright © 2004 Massachusetts Medical Society. cannon-10 n engl j med 350;15 www.nejm.org april 8, 2004 Downloaded from www.nejm.org at PFIZER INC on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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The new england journal of medicine
editorial
Intensive Statin Therapy -- A Sea Change in Cardiovascular Prevention Eric J. Topol, M.D. In the management of atherosclerotic vascular dis- effects in a wide range of diseases, including multi- ease, statin drugs have already surpassed all other ple sclerosis, neurodegenerative disorders such as classes of medicines in reducing the incidence of the Alzheimer's disease, and nonischemic cardiomyop- major adverse outcomes of death, heart attack, and athy, in the prevention of bone fractures, and even in stroke. A decade ago, their effectiveness was first the reduction in the incidence of some types of can- demonstrated by the results of the Scandinavian cer. More evidence is needed to prove the benefit of Simvastatin Survival Study (4S), a trial that provid- statins for these varied conditions, but the diverse ed definitive evidence of the benefit of simvastatin, effects of these drugs do not appear simply to be re- as compared with placebo, in improving survival.1 lated to cholesterol lowering. For the most part, a By 1996, statins were dubbed "miracle drugs," and generalized antiinflammatory action has been in- their underuse was duly noted.2 Prominent scien- voked as an explanation. tists in the field even speculated that heart attacks Virtually everything we understood about the ef- might be "gone with the century."3 For the most fects of statins on atherosclerotic coronary disease part, it was believed that the benefit of statins was had come from placebo-controlled trials until two due to the lowering of low-density lipoprotein (LDL) new head-to-head randomized trials were complet- cholesterol levels. ed. In the mechanistic Reversing Atherosclerosis In 2002, the Heart Protection Study not only con- with Aggressive Lipid Lowering (REVERSAL) trial,6 firmed the benefit of statins but raised new ques- Nissen and colleagues compared atorvastatin with tions. This study, the largest trial of a statin, showed pravastatin to determine whether the extent of pro- that an overall 25 percent reduction in the incidence gression of atherosclerotic coronary disease could of coronary events was associated with a reduction be differentiated between the two drugs with the use of 40 mg per deciliter (1.03 mmol per liter) in the of intravascular ultrasonography. During 18 months LDL cholesterol level.4 Equally important, patients of study-drug treatment, in a total of 502 patients with a "normal" base-line LDL cholesterol level -- with stable coronary disease who could be evaluat- that is, below 100 mg per deciliter (2.59 mmol per ed, atorvastatin was superior to pravastatin in terms liter) -- according to the currently accepted Nation- of limiting the progression of atheroma. LDL cho- al Cholesterol Education Program guidelines for lesterol levels were lowered substantially more with therapy,5 received just as much benefit as those with atorvastatin, but careful analysis showed that "LDL- high LDL cholesterol levels. This surprising finding cholesterol reduction alone did not explain all of raised the question of whether the benefits of statins the differences in efficacy."6 Even though this trial were fully attributable to their effects on LDL cho- was not designed to detect differences in clinical lesterol. outcomes, it attracted considerable attention be- The "pleiotropic" actions of statins -- the term cause of the implication that more intensive lipid- refers to their several distinct and seemingly unre- lowering therapy was the preferred approach.7-9 lated effects, apart from lowering LDL cholesterol In this issue of the Journal, Cannon and associ- levels -- have also been suggested by their salutary ates report on the Pravastatin or Atorvastatin Evalu- n engl j med 350;15 www.nejm.org april 8, 2004 1-topol Downloaded from www.nejm.org on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
ation and Infection Therapy (PROVE-IT) trial, a end after a certain number of events had occurred), comparison of the effects on clinical outcomes of it was felt that the short duration of follow-up, the exactly the same daily doses of atorvastatin (80 mg) use of "soft" end points (those that do not cause ir- and pravastatin (40 mg) as used in REVERSAL.10 In revocable damage) in the composite measure, and
4162 patients with acute coronary syndromes who the relatively small number of patients would make were followed for a mean of 24 months, atorvastat- it impossible to discern differences between the ef- in was superior to pravastatin, resulting in a 16 per- fects of the two statins. In contrast, three other large cent lower risk of the primary end point, a compos- trials comparing different statins or different doses ite of major cardiovascular events.10 The benefit of of the same statin, with study populations rang- atorvastatin was evident very early, even in the first ing from 8888 to 12,000 patients and with five-
30 days of therapy, and was consistent among all year planned follow-up, are currently under way. subgroups. Mortality from all causes was reduced Taken together, the REVERSAL and PROVE-IT by 28 percent, and every other individual outcome trials herald a shake-up in the field. Previously, it was favored the use of atorvastatin -- with the exception considered optimal to lower the LDL cholesterol of stroke, for which there was little difference be- level to less than 100 mg per deciliter.4 That axiom tween the groups. has now come under serious question, because we This result is a major surprise, for several rea- know that atherosclerotic progression and clinical sons. First, the trial was designed to demonstrate outcomes will be ameliorated by much more aggres- the noninferiority of pravastatin, as compared with sive use of statins. Indeed, the 80-mg dose of ator- aforvastatin, and not its superiority. Second, the vastatin is the most intensive LDL-lowering regimen beneficial effect appeared extremely rapidly, where- for which data on clinical outcomes are available. as in the placebo-controlled trials, such as 4S1 and Unfortunately, we do not know the precise mecha- the Heart Protection Study,4 there was a lag of ap- nism of action responsible for atorvastatin's supe- proximately 18 months before the event curves sep- riority. The drug is lipophilic, whereas pravastatin arated. Third, although PROVE-IT was an event- is water-soluble, but this is just one feature of each driven trial (that is, it was prospectively designed to drug's profile. Analysis is further complicated by the fact that lowering LDL cholesterol results in other antiinflammatory effects, such as reductions in the Table 1. Key Findings in Two New Trials of Statin Drugs.* levels of high-sensitivity C-reactive protein (CRP) and soluble CD40 ligand. However, there is a lack of Variable REVERSAL PROVE-IT correlation between LDL cholesterol and inflamma- Clinical indication for therapy Stable coronary Acute coronary tory markers. disease syndromes Even in these two trials, the results with respect Length of follow-up (mo) 18 24 to inflammatory markers are disparate. The patients LDL cholesterol 150 106 in the REVERSAL trial, who had stable coronary dis- Base-line (mg/dl) ease, had a markedly different degree of reduction in Atorvastatin group (mg/dl) 79 62 the CRP level with the two drugs, but in PROVE-IT, Percent decrease 46 42 in which patients with acute ischemic heart disease Pravastatin group (mg/dl) 110 95 made up the study population, there was relatively little difference in the degree of reduction in CRP Percent decrease 26 10 (Table 1). Clearly, more investigation is needed to High-sensitivity CRP
disentangle the independent and interdependent ef- Base-line (mg/liter) 2.9 12.3 fects of statins on LDL cholesterol levels and the pro- Atorvastatin group (mg/liter) 1.8 1.3 cess of arterial inflammation. Percent decrease 36 89 The implications of this turning point -- that is, Pravastatin group (mg/liter) 2.9 2.1 of the new era of intensive statin therapy -- are pro- Percent decrease 5 83 found. Even today, only a fraction of the patients who should be treated with a statin are actually re-
* REVERSAL denotes Reversing Atherosclerosis with Aggressive Lipid Lowering ceiving such therapy.10 It is estimated on the basis trial, PROVE-IT Pravastatin or Atorvastatin Evaluation and Infection Therapy trial, LDL low-density lipoprotein, and CRP C-reactive protein. of the criteria in current national guidelines that 36 To convert values for cholesterol to millimoles per liter, multiply by 0.02586. million people in the United States should be taking One fourth of the patients were taking a statin drug at the time of enrollment. a statin, but only 11 million are currently being treat- topol-2 n engl j med 350;15 www.nejm.org april 8, 2004 Downloaded from www.nejm.org on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
editorial
ed.11 Worldwide, the discrepancy is even more stag- or biologic markers of inflammation, is likely to re- gering; more than 200 million people meet the cri- sult in even greater steps toward actualizing the full teria for treatment, but fewer than 25 million take benefit of this remarkable class of medicines. statins. One of the most important reasons for this degree of undertreatment is cost, and more aggres- From the Cleveland Clinic Lerner College of Medicine, and the De- partment of Cardiovascular Medicine, Cleveland Clinic Founda- sive use of statins may exacerbate the problem. The tion -- both in Cleveland. recommended starting dose of atorvastatin is 10 mg Address reprint requests to Dr. Topol at the Cleveland Clinic per day; the cost at this dosage in Cleveland pharma- Foundation, 9500 Euclid Ave., Desk F25, Cleveland, OH 44105, cies is $900 per year. The 80-mg dose costs $1,400 or at topole@ccf.org. per year. The statin drugs already account for the 1. Scandinavian Simvastatin Survival Study Group. Randomized largest prescription drug expenditure in the United trial of cholesterol lowering in 4 444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet States, at $12.5 billion per year.12 Treatment based 1994;344:1383-9. on the new data could cause the costs associated 2. Roberts WC. The underused miracle drugs: the statin drugs are with statin therapy to skyrocket even further. to atherosclerosis what penicillin was to infectious disease. Am J Cardiol 1996;78:377-8. In addition to the likely changes in practice, the 3. Brown MS, Goldstein JL. Heart attacks: gone with the century. lessons of the new findings for clinical investigation Science 1996;272:629. are many. The combination of a clinical-outcomes 4. Heart Protection Study Collaboration Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 trial (PROVE-IT) and an imaging study (REVERSAL), high-risk individuals: a randomised placebo-controlled trial. Lancet in which identical doses of the two drugs were used, 2002;360:7-22. yields a compelling validation of intravascular ul- 5. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol trasonography as a surrogate measure of the clini- in Adults (Adult Treatment Panel III). Third report of the National cal benefits of antiatherosclerotic agents. This Cholesterol Education Program (NCEP) Expert Panel on Detection, approach was presaged by comparative studies of Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002;106: statins in which B-mode ultrasonography was used 3143-421. to measure carotid-artery intimalmedial thickness. 6. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive Furthermore, these two studies strongly reinforce compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA the need to engage in more head-to-head trials of 2004;291:1071-80. drugs within the same class, despite the recent as- 7. Winslow R. Study signals how low to go on cholesterol. Wall sertion by a senior Food and Drug Administration Street Journal. November 13, 2003:D1.
8. Kolata G. Study of two cholesterol drugs finds one halts heart official that "there is almost never a difference be- disease. New York Times. November 13, 2003:A1. tween active treatments."13 We have long suffered 9. Head-to-head drug combat. New York Times. November 16, from ignorance as a result of not having compara- 2003(Section 4):12.
10. Cannon CP, Braunwald E, McCabe CH, et al. Comparison of tive data for similar agents, and it is well worth the intensive and moderate lipid lowering with statins following acute resources and effort to illuminate such therapeutic coronary syndrome. N Engl J Med 2004;350. choices. 11. Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total cho- lesterol concentrations and awareness, treatment, and control of There will soon be a sea change in the prevention hypercholesterolemia among US adults: findings from the National and management of atherosclerotic vascular dis- Health and Nutrition Examination Survey, 1999 to 2000. Circulation ease. The proportional reduction in major clinical 2003;107:2185-9.
12. Wilde Mathews A, Landers P. An FDA shift could transform outcomes that results from aggressive statin thera- market for statins: agency will consider allowing over-the-counter py is of the same order of magnitude as that seen sales of cholesterol medicine. Wall Street Journal. November 12, when statins were compared with placebo in con- 2003:A1.
13. Harris G. 2 Cancer drugs, no comparative data. New York trolled trials. Intensive therapy with statins, moni- Times. February 26, 2004:C1. tored by means of measurements of LDL cholesterol Copyright © 2004 Massachusetts Medical Society. n engl j med 350;15 www.nejm.org april 8, 2004 3-topol Downloaded from www.nejm.org on March 08, 2004. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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Effect of Intensive Compared With Moderate
Lipid-Lowering Therapy on Progression
of Coronary Atherosclerosis
A Randomized Controlled Trial
Steven E. Nissen, MD Context Statin drugs reduce both atherogenic lipoproteins and cardiovascular mor- E. Murat Tuzcu, MD bidity and mortality. However, the optimal strategy and target level for lipid reduction remain uncertain. Paul Schoenhagen, MD
Objective To compare the effect of regimens designed to produce intensive lipid low- B. Greg Brown, MD ering or moderate lipid lowering on coronary artery atheroma burden and progression. Peter Ganz, MD Design, Setting, and Patients Double-blind, randomized active control multi- Robert A. Vogel, MD center trial (Reversal of Atherosclerosis with Aggressive Lipid Lowering ) performed at 34 community and tertiary care centers in the United States comparing Tim Crowe, BS the effects of 2 different statins administered for 18 months. Intravascular ultrasound Gail Howard, MS was used to measure progression of atherosclerosis. Between June 1999 and Septem- ber 2001, 654 patients were randomized and received study drug; 502 had evaluable Christopher J. Cooper, MD intravascular ultrasound examinations at baseline and after 18 months of treatment. Bruce Brodie, MD Interventions Patients were randomly assigned to receive a moderate lipid- Cindy L. Grines, MD loweringregimenconsistingof40mgofpravastatinoranintensivelipid-loweringregi- Anthony N. DeMaria, MD men consisting of 80 mg of atorvastatin. Main Outcome Measures The primary efficacy parameter was the percentage for the REVERSAL Investigators change in atheroma volume (follow-up minus baseline). N A SERIES OF PIVOTAL CLINICAL Results Baseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL [3.89 trials,statindrugshavebeenshown mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L) in the to reduce both atherogenic lipo- pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin group (P .001). proteins and cardiovascular mor- C-reactiveproteindecreased5.2%withpravastatinand36.4%withatorvastatin(P .001). bidityandmortality.1-5 However,theop-
I The primary end point (percentage change in atheroma volume) showed a significantly lower progression rate in the atorvastatin (intensive) group (P=.02). Similar differences timal approach to lipid reduction with between groups were observed for secondary efficacy parameters, including change in statinsinpatientswithestablishedcoro- totalatheromavolume(P=.02),changeinpercentageatheromavolume(P .001),and naryarterydisease(CAD)remainsun- change in atheroma volume in the most severely diseased 10-mm vessel subsegment certain. Although the efficacy of the (P .01). For the primary end point, progression of coronary atherosclerosis occurred in various statins in reducing athero- the pravastatin group (2.7%; 95% confidence interval , 0.2% to 4.7%; P=.001) geniclipoproteinsandvascularinflam- comparedwithbaseline.Progressiondidnotoccurintheatorvastatingroup(-0.4%;CI mation varies significantly,6 the im- -2.4% to 1.5%; P=.98) compared with baseline. pact of these differences on clinical Conclusions For patients with coronary heart disease, intensive lipid-lowering treat- outcomeisunknown.Becausethelarge ment with atorvastatin reduced progression of coronary atherosclerosis compared with trials assessing morbidity and mortal- pravastatin. Compared with baseline values, patients treated with atorvastatin had no ity were placebo controlled, they pro- change in atheroma burden, whereas patients treated with pravastatin showed progres- sion of coronary atherosclerosis. These differences may be related to the greater reduc- videlimitedinsightintodifferencesbe- tioninatherogeniclipoproteinsandC-reactiveproteininpatientstreatedwithatorvastatin. tween alternative strategies and target
JAMA. 2004;291:1071-1080 www.jama.com levels for lipid reduction. Accord-
ingly, there is little scientific basis for
Corresponding Author: Steven E. Nissen, MD, De- Author Affiliations, Financial Disclosures, and a List partmentofCardiovascularMedicine,ClevelandClinic For editorial comment see p 1132. of the REVERSAL Investigators are listed at the end Foundation, 9500 Euclid Ave, Cleveland, OH 44195 of this article. (nissens@ccf.org). ©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, March 3, 2004--Vol 291, No. 9 1071
INTENSIVE VS MODERATE LIPID LOWERING
recommending treatment to reduce 40-mg dose of pravastatin was se- (Ultracross,BostonScientificScimedInc, low-density lipoprotein cholesterol lected because it was the highest ap- MapleGrove,Minn)wasadvancedinto (LDL-C) levels below the current rec- proved dose at the time of study initia- thetargetvesselandthetransducerwas ommended guidelines.7,8 tion and was one of the best-studied positioned distal to a side branch (dis- We compared the effects of 2 statin regimens in secondary prevention of tal fiduciary site). A motor drive pro- regimens by using intravascular ultra- coronary events.2,4 In addition, prava- gressivelywithdrewthetransducerata sound. One of the regimens was de- statin carried a label approved by the speedof0.5mm/s.Duringpullback,im- signed to produce a moderate reduc- Food and Drug Administration for re- ages were obtained at 30 frames/s and tion in LDL-C level and the other was duction in atherosclerotic progression recordedonvideotape.Theintravascu- designedtoproduceanintensive(maxi- based on prior angiographic trials.9,10 larultrasoundexaminationwasscreened mal)reductioninLDL-Clevel.Intravas- Because a baseline LDL-C level of ap- forimagequalityinacorelaboratoryat cular ultrasound provides detailed proximately150mg/dL(3.89mmol/L) theClevelandClinicFoundation.Only images of the vessel wall with a high- was anticipated, the regimen of 40 mg patients meeting prespecified image frequency (30 MHz), miniaturized, ul- of pravastatin was expected to lower quality requirements were eligible for trasound transducer. Using a motor- LDL-C to approximately 100 mg/dL randomization. ized pullback device, cross-sectional (2.59mmol/L).Adoseof80mgofator- The patients were examined during imagesaregeneratedthroughouttheves- vastatin was selected as the more in- scheduled clinic visits every 3 months. sel length, enabling precise quantifica- tensiveagentbecausethisdosewasca- A central laboratory performed all bio- tion of atherosclerotic disease burden. pableofproducingthelargestreduction chemical determinations (Medical This study, the Reversal of Atheroscle- inatherogeniclipoproteinsofanyavail- Research Laboratory, Highland rosis with Aggressive Lipid Lowering able therapy. Heights, Ky). (REVERSAL)trial,measuredtherateof After an 18-month treatment period, disease progression in patients treated Randomization and actively participating patients under- with 2 different statins over an 18- Allocation Concealment wentrepeatcardiaccatheterizationand month treatment period. Lipid-lowering medications were dis- intravascular ultrasound examination. continued for at least 4 weeks. After a Theoperatorplacedtheintravascularul- METHODS 2-week placebo run-in period, pa- trasound catheter in the vessel origi- The institutional review boards of all tientswererandomizedtoreceiveeither nallyinterrogatedandpositioneditdis- participating centers approved the 80mgofatorvastatin(2 40mg)daily tal to the original fiduciary site. A REVERSAL protocol and all patients and a pravastatin placebo or 40 mg of motorized pullback was repeated un- providedwritteninformedconsent.The pravastatin (1 40 mg) daily and 2 der conditions identical to the baseline protocol specified enrollment of pa- atorvastatin placebos (FIGURE 1). The study. (See VIDEO at http://jama.com tients aged 30 to 75 years who re- patients and all study personnel were /cgi/content/full/291/9/1071/DC1.) quiredcoronaryangiographyforaclini- blinded to treatment assignment and calindicationanddemonstratedatleast lipid measurements. The intravascu- Intravascular Ultrasound
1 obstruction with angiographic lumi- lar ultrasound reading was performed Core Laboratory Analysis naldiameternarrowingof20%ormore. bypersonnelwhowereblindedtotreat- Videotapes containing the intravascu- The"targetvessel"forintravascularul- ment assignment. The randomization lar ultrasound pullbacks were ana- trasound interrogation must not have code was generated using a permuted lyzed in a blinded fashion by the core undergoneangioplastyorhavealumi- block size of 4 (stratified by site) by a laboratoryaspreviouslyreported.11 The nal narrowing of more than 50% consultingstatisticiannototherwisein- operatorselectedadistalfiduciarysite, throughout a "target segment" with a volved in the trial. No other restric- usually a branch site, as the beginning minimum length of 30 mm. Lipid cri- tions were used in the randomization point for analysis. Subsequently, ev- teria required an LDL-C level between procedure. ery 60th image was analyzed, generat-
125 mg/dL (3.24 mmol/L) and 210 ing a series of cross-sections spaced mg/dL (5.44 mmol/L) after a 4- to 10- Catheterization and exactly 1.0-mm apart. The final cross- week washout period. Intravascular Ultrasound section analyzed was obtained at a Following diagnostic angiography, in- proximal fiduciary site. Selection of Regimens travascularultrasoundexaminationwas Thestudydesignsoughttocomparethe performedinboththelongestandleast Intravascular Ultrasound effects on coronary disease progres- angulated target vessel meeting inclu- Measurements sionoftreatmentregimensdesignedto sioncriteria.Afteradministrationofbe- Intravascular ultrasound measure- produce an intensive lipid-lowering tween 100 and 300 µg of intracoronary ments were performed in accordance effect or a moderate lipid-lowering nitroglycerin, a 30 MHz, 2.6 F (0.87 withthestandardsoftheAmericanCol- effect. For the moderate regimen, a mm) intravascular ultrasound catheter legeofCardiologyandtheEuropeanSo-
1072 JAMA, March 3, 2004--Vol 291, No. 9 (Reprinted) ©2004 American Medical Association. All rights reserved.
INTENSIVE VS MODERATE LIPID LOWERING
ciety of Cardiology.12 Using the Na- ouscross-sectionswiththegreatestand median (with 95% confidence intervals tionalInstitutesofHealthImage(version least atheroma volume. ), and SDs. For the efficacy analy-
1.62, National Institutes of Health pub- sescomparingtreatmentarms,ananaly- licdomainsoftware,Bethesda,Md),the Statistical Methods sisofcovariancemodelappliedtorank- operatorperformedacalibrationbymea- In the protocol, the assumptions used transformed data was used. For suring1-mmgridmarksencodedinthe for power calculations required a comparisons within treatment groups image. Manual planimetry was used to sample size of 200 patients per treat- from baseline to follow-up, a Wilcoxon tracetheleadingedgesoftheluminaland mentgrouptoprovide90%power(as- signed rank test was performed. Analy- external elastic membrane (EEM) bor- suming a SD of 23%) to detect a 7.4% sisofvariancewasusedtoanalyzelipid ders. The accuracy and reproducibility differenceintheprimaryendpointwith parameters and log-transformed C- of this method has been previously re- a 5% type I error rate for a 2-sided test. reactive protein (CRP) data. The rela- ported.13 In addition, intraobserver and Withananticipateddropoutrateofap- tionship between reduction in LDL-C interobserver variability were deter- proximately35%,enrollmentof300pa- levelandchangeinatheromavolumewas minedforasubsetofpatientsinthistrial. tients per treatment group (total 600 assessed using linear regression analy- A total of 48 individually paired (base- randomized patients) was specified to sis.AnalyseswereperformedusingSAS lineandfollow-up)patientdatasetswere provide an adequate number of evalu- statisticalsoftware(version8.12,SASIn- randomlychosenforevaluationby6in- able patients. stitute Inc, Cary, NC). travascular ultrasound reviewers. Each Demographic and laboratory charac- RESULTS reviewer reanalyzed 3 of his/her origi- teristicsaresummarizedforallrandom- Patient Population nal intravascular ultrasound tapes--a ized patients completing the trial. The total of 18 paired reviews for the analy- analysisofsafetywasperformedinallpa- Between June 1999 and September sis of intrareviewer variability. Each of tients who received at least 1 dose of 2001,2163patientswerescreened,657 the6reviewersalsoreanalyzedoneofthe drug. Categorical variables are de- were randomized, and 654 received other 5 reviewer's original intravascu- scribed using frequencies, while con- studydrugat34centers.Atotalof502 larultrasoundtapes--atotalof30paired tinuous variables are reported as mean, patientshadevaluableintravascularul- reviews for the analysis of interre-
viewer variability. Figure 1. Disposition of Patients The primary end point (percentage
change in total atheroma volume) was 2163 Patients Screened computed as:
1506 Excluded TAV (month 18)- (baseline) 1330 Did Not Meet Inclusion Criteria or Met
100 Exclusion Criteria TAV (baseline) 176 Did Not Meet Criteria After Placebo Run-in where TAV is total atheroma volume.
Total atheroma volume was calculated 657 Randomized as the sum of the differences between
EEM and lumen areas across all evalu- 329 Assigned to Receive Moderate Lipid Lowering 328 Assigned to Receive Intensive Lipid Lowering able slices: total atheroma volume= With 40 mg of Pravastatin With 80 mg of Atorvastatin
2 Did Not Receive Study Drug 1 Did Not Receive Study Drug (EEMCSA-LUMENCSA), where EEMCSA
=external elastic membrane cross-
sectional area and LUMENCSA=luminal 78 Did Not Complete End Point Assessment 74 Did Not Complete End Point Assessment
13 Final Intravascular Ultrasound Not Obtained 14 Final Intravascular Ultrasound Not Obtained cross-sectional area. A secondary effi- 17 Final Intravascular Ultrasound Not Analyzable 8 Final Intravascular Ultrasound Not Analyzable cacy parameter, change in percentage 4 Had Adverse Events 11 Had Adverse Events
1 Abdominal Pain atheroma volume (PAV) was calcu- 2 Abdominal Pain
1 Muscular Pain 5 Muscular Pain lated as PAV=PAV (month 18) - PAV 1 Colon Cancer 1 Itching (baseline).PAVwascalculatedusingthe 44 Withdrew Consent Before Final Intravascular 1 Headache Ultrasound 1 Hepatitis B following formula: 1 Elevated Liver Enzymes
1 Increased Low-Density Liproprotein (EEMCSA - LUMENCSA) Cholesterol PAV = 100 41 Withdrew Consent Before Final Intravascular (EEMCSA) Ultrasound Other prespecified secondary efficacy 249 Included in Primary Analysis 253 Included in Primary Analysis measures included the nominal change 327 Included in Safety Analysis 327 Included in Safety Analysis inatheromavolumeforthe10contigu-
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INTENSIVE VS MODERATE LIPID LOWERING
trasound examinations at both base- lyzable due to artifacts or pullbacks mmol/L) in the intensive (atorvas- line and 18-month follow-up (249 in shorter than the prespecified mini- tatin)groupand110mg/dL(26)(2.85 the pravastatin group and 253 in the mum length of 30 mm. The distribu- mmol/L)inthemoderate(prava- atorvastatin group). Of the 155 pa- tion of these patients in the 2 study statin)group(P .001).Significantdif- tientswhowerenotincludedinthein- groupsissummarizedinFigure1.Base- ferences in the reduction in CRP were travascularultrasoundanalysis:3never linedemographicandlaboratorychar- also observed: 36.4% in the atorvas- received either study drug; 85 with- acteristics are summarized in TABLE 1. tatin group vs 5.2% in the pravastatin drew before a final intravascular ultra- group (P .001). soundcouldbeobtained;15werewith- Laboratory Results drawn for an adverse event; 27 did not TABLE 2 summarizes laboratory val- Efficacy Analyses have a final intravascular ultrasound; ues at trial completion for the 2 treat- PrimaryEfficacy.TABLE3illustratesthe and 25 had an intravascular ultra- ment cohorts. The mean (SD) LDL-C resultsforthepercentagechangeinath- sound examination that was not ana- level was 79 (30) mg/dL (2.05 eromavolume,whichistheprimaryef- ficacyparameter.Comparingthe2regi- Table 1. Baseline Demographic and Laboratory Characteristics mens, the progression rate was Type of Lipid-Lowering Regimen significantly lower in the atorvastatin Moderate; 40 mg Intensive; 80 mg group (P=.02). The change in ath- of Pravastatin of Atorvastatin eromavolumewaspositiveintheprava- Characteristic (n = 249) (n = 253) P Value statingroup(2.7%;95%CI,0.24-4.67), Mean (SD) Age, y 56.6 (9.2) 55.8 (9.8) .37 indicating net progression (P=.001 Weight, kg 91.4 (17.6) 90.9 (19.3) .75 compared with baseline). In the ator- Body mass index* 30.5 (5.6) 30.5 (6.5) .96 vastatin group, the change was nega- Cholesterol, mg/dL tive (-0.4%; 95% CI, -2.35 to 1.49), Total 232.6 (34.1) 231.8 (34.2) .80 showingnodiseaseprogression(P=.98 Low-density lipoprotein 150.2 (25.9) 150.2 (27.9) .99 compared with baseline). High-density lipoprotein 42.9 (11.4) 42.3 (9.9) .51 Secondary Efficacy. Table 3 also il- Triglycerides, mg/dL 197.7 (105.6) 197.2 (95.7) .96 lustratestheresultsforprespecifiedsec- Apolipoprotein B 100, mg/dL 153.0 (22.5) 152.4 (24.3) .79 ondaryefficacyanalyses.Significantdif- C-reactive protein, mg/L 3.0 (2.9) 2.8 (3.0) .46 ferences favoring intensive lipid No. (%) lowering were observed for the nomi- Men (n = 362) 182 (73) 180 (71) .69 nal change in total atheroma volume White (n = 444) 217 (87) 227 (90) .54 (P=.02). Larger differences were ob- Smoking status served for change in PAV (P .001). Current smoker (n = 132) 66 (27) 66 (26) .97 Progressionwasobservedintheprava- Past or nonsmoker (n = 370) 183 (74) 187 (74) .97 statin-treated group (P .001 for both History of hypertension (n = 344) 173 (70) 171 (68) .70 endpointscomparedwithbaseline)and Prior statin use (n = 144) 81 (32) 63 (25) .06 no progression occurred in the ator- History of diabetes mellitus (n = 95) 45 (18) 50 (20) .65 vastatin group (Table 3). Metabolic syndrome (n = 203) 98 (39) 105 (42) .65 Forthe10-mmsubsegmentwiththe SI conversion factors: To convert cholesterol to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113. *Calculated as weight in kilograms divided by the square of the height in meters. greatest disease burden on intravascu- Table 2. Final Laboratory Results (n = 502)
Type of Lipid-Lowering Regimen Moderate; 40 mg of Pravastatin (n = 249) Intensive; 80 mg of Atorvastatin (n = 253) Characteristic Final Mean (SD) Change From Baseline, % Final Mean (SD) Change From Baseline (%) P Value* Cholesterol, mg/dL
Total 187.5 (32.2) -18.4 151.3 (38.9) -34.1 .001 Low-density lipoprotein 110.4 (25.8) -25.2 78.9 (30.2) -46.3 .001 High-density lipoprotein 44.6 (11.3) 5.6 43.1 (11.3) 2.9 .06 Triglycerides, mg/dL 165.8 (92.1) -6.8 148.4 (94.9) -20.0 .001 Apolipoprotein B 100, mg/dL 118.1 (24.0) -22.0 91.8 (27.9) -39.1 .001 C-reactive protein, mg/L 2.9 (3.0) -5.2 1.8 (3.7) -36.4 .001 SI conversion factors: To convert cholesterol to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113. *Analysis of variance was used to analyze lipid parameters and log-transformed C-reactive protein data.
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INTENSIVE VS MODERATE LIPID LOWERING
lar ultrasound, differences between ). In the atorvas- (P .01) and no progression in the treatments were also significant tatin group, 246 (97%) of 253 patients atorvastatin group (P=.93) compared (P .01). There was net regression in achieved the guideline LDL-C level of with baseline (Table 4). both groups (P .001 compared with less than 100 mg/dL (2.59 mmol/L) Sensitivity Analysis. Because inva- baseline in the atorvastatin group and (mean level, 67.7 mg/dL sive regression-progression trials re- P=.05 compared with baseline in the ). When the 2 quire patients to consent to a repeat pravastatin group). No differences be- treatment regimens were compared, catheterization for research purposes, tween treatment groups were ob- there was a strong trend toward a all such trials have experienced a sig- servedforthe10-mmsubsegmentwith lower progression rate in the atorvas- nificantdropoutrateduringthecourse the least disease burden (P=.20). tatin group (P=.07). In the subgroup of the study. In REVERSAL, 78 prava- Prespecified Subgroups. TABLE 4 il- attaining low LDL-C levels, there was statin-treated patients and 74 atorvas- lustratestheresultsfortheprimaryend progression in the pravastatin group tatinpatientsdidnotcompletethetrial point (percentage change in atheroma
volume) for 22 prespecified subgroups Table 3. Change in Atheroma Volume, Change in Percentage of Atheroma Volume, and and 1 subgroup defined post-hoc. The Atheroma Volume in 10-mm Subsegment With the Greatest Disease Severity results were similar for patients with P Value baselineLDL-Clevelsaboveorbelowthe Pravastatin Atorvastatin Between mean. Compared with baseline, ab- (n = 249) (n = 253) Groups* Atheroma Volume, mm3 senceofprogressionwasevidentinthe Baseline intensivelipid-loweringgroup(atorvas- Mean (SD) 194.5 (114.8) 184.4 (115.7) tatin) for all 22 subgroups, whereas 15 Median (IQR) 168.6 (117.4 to 246.2) 161.9 (111.0 to 228.2) .20 of these subgroups showed statistically Follow-up significant progression in the moder- Mean (SD) 199.6 (112.3) 183.9 (108.8) ate lipid-lowering group (pravastatin). Median (IQR) 180.0 (125.5 to 255.3) 160.9 (107.4 to 240.3) .05 ObserverVariability.Forthe18pa- Nominal change Mean (SD) 5.1 (31.4) -0.4 (31.8) tients included in the analysis for in- Median (95% CI) 4.4 (0.1 to 6.0) -0.9 (-3.5 to 1.6) .02 traobservervariability,therewereatotal P value compared with baseline .01 .72 of 1177 images analyzed. The mean Percentage change, % (SD) differences were negligible for Mean (SD) 5.4 (20.1) 4.1 (29.6) bothEEM(-0.16mm2 )and Median (95% CI) 2.7 (0.2 to 4.7) -0.4 (-2.4 to 1.5) .02§ lumen areas (-0.02 mm2 ). P value compared with baseline .001 .98 Linearregressionanalysisshowedclose Percent Atheroma Volume, % correlationsbetweentheoriginalanaly- Baseline sis and reanalysis (r=0.99 for EEM; Mean (SD) 39.5 (10.77) 38.4 (11.27) r=0.98 for lumen areas). Of the 30 pa- Median (IQR) 40.0 (32.5 to 46.3) 38.2 (31.7 to 45.8) .18 tients included in the analysis for in- Follow-up Mean (SD) 41.4 (10.0) 39.0 (10.8) terobservervariability,therewereatotal Median (IQR) 41.8 (35.0 to 47.7) 38.7 (31.6 to 45.7) .004 of 2151 images. The mean (SD) differ- Nominal change ences were negligible for both EEM Mean (SD) 1.9 (4.9) 0.6 (5.1) (-0.07 mm2) and lumen areas Median (95% CI) 1.6 (1.2 to 2.2) 0.2 (-0.3 to 0.5) .001 (-0.07 mm2).Regressionanaly- P value compared with baseline .001 .18 sis showed close correlations between Atheroma Volume in 10-mm Vessel Subsegment With Greatest Disease Severity, mm3 the original analysis and subsequent Baseline analyses (r=0.99 for EEM; r=0.98 for Mean (SD) 72.7 (29.0) 71.2 (29.8) lumen areas). Median (IQR) 69.4 (50.9 to 91.9) 67.2 (50.4 to 90.6) .54 Exploratory Analyses. We also Follow-up Mean (SD) 71.0 (28.7) 67.0 (27.9) compared the progression rates in the Median (IQR) 67.5 (49.3 to 91.9) 63.4 (47.2 to 83.7) .16
2 treatment groups for patients attain- Nominal change ing the guideline LDL-C level of less Mean (SD) -1.7 (12.4) -4.2 (12.8) than 100 mg/dL (2.59 mmol/L) in Median (95% CI) -1.2 (-2.63 to 0.20) -4.2 (-5.2 to -2.9) .01 post-hoc analysis. In the pravastatin P value compared with baseline .049 .001 group, 161 (65%) of 249 patients Abbreviations: CI, confidence interval; IQR, interquartile range. reached the guideline LDL-C level of *Based on an analysis of covariance model applied to rank-transformed data. Prespecified secondary efficacy parameter. less than 100 mg/dL (2.59 mmol/L) Wilcoxon signed rank test for comparisons with baseline within groups. §Prespecified primary efficacy parameter. (mean level, 87.5 mg/dL
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, March 3, 2004--Vol 291, No. 9 1075
INTENSIVE VS MODERATE LIPID LOWERING
(and 3 patients never received either tients. A second approach imputed all parisonwithbaselinecannotbereadily study drug). To examine the possibil- 155 noncompleters as showing no interpreted. However, using both im- ity that these patients might have al- change from baseline in atheroma vol- putation methods, the primary effi- teredtheoutcome,weperformed2sen- ume. For the imputed data, the mean cacy analysis and both major second- sitivity analyses in which all 155 andmedianvalues,SDs,andinterquar- ary efficacy analyses (between-group patientswhodidnotcompletethetrial tile ranges are shown in TABLE 5. Be- comparisons) retained statistical sig- were imputed as showing no benefit cause the imputed values are close to nificance. fromthemoreintensiveregimen.Inone the central tendency for both treat- TABLE 6 shows the adverse events of these analyses, all noncompleters in ment groups, the median values in andclinicalendpointsencounteredin both treatment groups were assigned Table 5 are identical for the 2 treat- the trial. Both regimens were well tol- themedianchangeobservedforallpa- ment groups and the P values for com- erated. The number of clinical events inthis18-monthtrialwastoosmallfor Table 4. Median Percentage Change in Atheroma Volume in Prespecified Subgroups any meaningful analysis of morbidity Pravastatin Atorvastatin and mortality. (n = 249) (n = 253) COMMENT
Median % Median % Change in Change in P Value Although statin drugs are among the Atheroma P Atheroma P Between best-studied contemporary cardiovas- Prespecified Subgroup Volume Value* Volume Value* Groups Age, y cular therapies, the optimal approach Median (n = 231) 4.8 .001 -1.5 .67 .01 tocholesterolreductioninpatientswith Median (n = 271) -0.2 .31 0.5 .64 .75 established CAD remains controver- Sex sial. Current US and European guide- Male (n = 362) 2.3 .05 0.7 .72 .30 lines emphasize reducing LDL-C level Female (n = 140) 3.9 .004 -2.3 .67 .03 to less than 100 mg/dL (2.59 Race
White (n = 444) 3.1 .001 -0.8 .99 .03 mmol/L).7,8 Theguidelinesassumethat Nonwhite (n = 58) -1.4 .60 0.5 .81 .92 different strategies for lipid lowering Smoking status will provide similar benefits as long as Current smoker (n = 132) 0.4 .63 0.8 .88 .66 patients attain the recommended Past or nonsmoker (n = 370) 3.2 .006 -1.2 .96 .04 LDL-Ctargetlevel.Becausemajorstatin Body mass index trialstypicallyhaveusedauniformdose
30 (n = 234) 3.2 .008 -2.5 .59 .04 ofasinglestatininallpatients,nocom-
30 (n = 268) 1.9 .06 1.5 .58 .34 parative data exist to suggest a greater History of diabetes mellitus
Present (n = 95) 3.2 .03 0.7 .54 .35 clinicalbenefitformoreaggressivetar- Absent (n = 407) 2.5 .01 -0.8 .78 .06 gets or alternative agents. We ap- History of hypertension proached this knowledge gap by per- Present (n = 344) 4.6 .001 -0.3 .86 .03 forming the first active-control statin Absent (n = 158) 1.7 .63 -1.6 .75 .86 trial of CAD progression. The metabolic syndrome In the current trial, patients with Present (n = 203) 2.1 .10 -1.2 .76 .19 moderate cholesterol elevations re- Absent (n = 299) 3.2 .005 0.2 .73 .11 ceived 18 months of intensive therapy History of statin use
Present (n = 144) 5.1 .003 -4.0 .91 .06 with80mgofatorvastatinandshowed Absent (n = 358) 0.7 .06 0.3 .88 .26 significantly reduced progression of Cholesterol, mg/dL coronary atherosclerosis in compari- Low-density lipoprotein son with patients who received a more Mean (n = 221) 2.7 .04 1.9 .24 .66 moderate regimen consisting of 40 mg Mean (n = 281) 2.8 .01 -2.3 .26 .02 ofpravastatin.Fortheprimaryandsec- Patients reaching NCEP guideline 1.9 .01 -0.9 .93 .07 level ( 100 m/dL)§ ondary efficacy measures, lower pro- High-density lipoprotein gression rates were observed in the in- Mean (n = 206) 4.4 .006 -1.5 .97 .07 tensively treated patients (P=.02 to Mean (n = 296) 1.7 .05 0.1 .92 .24 P .001). Numerically similar results Abbreviation: NCEP, National Cholesterol Education Program. were observed in prespecified sub- SI conversion factor: To convert cholesterol to mmol/L, multiply by 0.0259. *Wilcoxon signed rank test for comparisons with baseline within groups. groups (Table 4). Overall, these find- Based on an analysis of covariance model applied to rank-transformed data. Calculated as weight in kilograms divided by the square of the height in meters. ings provide strong evidence that in- §Post-hoc analysis (not prespecified). Of 249 patients receiving pravastatin, 167 achieved NCEP guideline level; and of tensive treatment using the maximum
253 patients receiving atorvastatin, 246 achieved NCEP guideline level. approved dose of atorvastatin reduces
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INTENSIVE VS MODERATE LIPID LOWERING
progression of atherosclerosis com- Table 5. Sensitivity Analyses Imputing Results for Patients Not Completing Trial pared with a more moderate regimen
P Value consisting of 40 mg of pravastatin. Pravastatin Atorvastatin Between Thesefindingshavepotentialimpli- (n = 329) (n = 328) Groups* cationsfortreatmentguidelinesforpa- Median Imputation Method tients with dyslipidemia and estab- Nominal change in atheroma volume, mm3 Mean (SD) 4.2 (27.4) 0 (27.9) lishedCAD.Currentrecommendations
Median (95% CI) 1.38 (-2.4 to 5.2) 1.38 (-2.3 to 5.1) .04 are based on the principle of a recom-
P value compared with baseline .001 .001 mended threshold for optimal benefit Percentage change in atheroma volume, % (establishedasalevelofLDL-Cof 100 Mean (SD) 4.3 (17.6) 3.4 (26.0) mg/dL ) for second- Median (95% CI) 0.9 (-2.6 to 4.4) 0.9 (-1.5 to 3.3) .04 aryprevention.Thecurrentstudysug- P value compared with baseline .001 .001 geststhatoptimalbenefitsareachieved Change in percentage atheroma volume, % using a more intensive regimen (ator- Mean (SD) 1.7 (4.3) 0.7 (4.5) vastatin) designed to achieve LDL-C Median (95% CI) 0.9 (0.3 to 1.5) 0.9 (0.3 to 1.5) .01 levels well below current guidelines. P value compared with baseline .001 .001 Differences between the 2 treatment Zero Change Imputation Method regimenswereevidentforpatientswith Nominal change in atheroma volume, mm3 Mean (SD) 3.8 (27.4) -0.3 (27.9) baselineLDL-Candhigh-densitylipo-
Median (95% CI) 0 (-3.8 to 3.8) 0 (-3.8 to 3.8) .05 proteincholesterollevelsaboveandbe-
P value compared with baseline .13 .80 low the mean (Table 4). Thus, pa-
Percentage change in atheroma volume, % tientswithentryLDL-Clevelsbelowthe Mean (SD) 4.1 (17.7) 3.2 (26.0) mean actually showed similar benefit Median (95% CI) 0 (-3.6 to 3.6) 0 (-2.5 to 2.5) .05 when they received the more inten- P value compared with baseline .13 .80 sive (atorvastatin) regimen (P=.02; Change in percentage atheroma volume, % Table4).Thisfindingisconsistentwith Mean (SD) 1.4 (4.3) 0.5 (4.5) other recent clinical trials, such as the Median (95% CI) 0 (-0.6 to 0.6) 0 (-0.6 to 0.6) .01 HeartProtectionStudy,whichdemon- P value compared with baseline .001 .71 strated a further risk reduction when Abbreviation: CI, confidence interval. *Based on an analysis of covariance model applied to rank-transformed data. simvastatin was administered to pa- Wilcoxon signed rank test for comparison with baseline within groups. tientswithbaselineLDL-Clevelsabove
andbelow100mg/dL(2.59mmol/L).5
Although the current study does not Table 6. Adverse Events, Drug Discontinuations, and Clinical End Points (Safety Population) provide sufficient evidence to modify No. (%) of Patients guidelines,severalongoingtrialsareex-
Pravastatin Atorvastatin amining clinical outcomes following
Major adverse event more intensive compared with less in- (n = 327) (n = 327) tensive treatment. Death 1 (0.3) 1 (0.3) The REVERSAL trial suggests sev- Myocardial infarction 7 (2.1) 4 (1.2) eral potential mechanisms for the Stroke 1 (0.3) 1 (0.3) greaterbenefitobservedwithaninten- (n = 316) (n = 311) Alanine aminotransferase 3* 5 (1.6) 7 (2.3) sive treatment regimen. Most athero-
Aspartate aminotransferase 3* 2 (0.6) 2 (0.6) genic lipoproteins were reduced to a
Creatine phosphokinase 10* 0 0 greater extent in the intensive treat-
(n = 327) (n = 327) ment group (atorvastatin), including Drug discontinuation 22 (6.7) 21 (6.4) levels of LDL-C, total cholesterol, and Musculoskeletal complaint 12 (3.4) 9 (2.8) triglycerides. However, factors other Abdominal complaint§ 5 (1.5) 3 (0.9) than greater LDL-Creducing efficacy Cancer 2 (0.6) 0 may also have influenced the results, Chest pain 2 (0.6) 0 including the differential effect of the Increased aspartate or alanine aminotransferase 3 0 4 (1.2)
2 treatment regimens on inflamma- Other 1 (0.6) 5 (1.5) tion.The36.4%reductioninCRPinthe *Multiplied by the upper limit of normal. atorvastatin group compared with the Regardless of whether the patient dropped out of the study. Muscle pain or weakness, joint pain, or elevated creatinine phosphokinase ( 10 times the upper limit of normal). 5.2%reductioninthepravastatingroup §Abdominal pain, cramping, or diarrhea. Flulike symptoms, hot flashes, itching, headaches, or hepatitis B. was larger than expected and signifi-
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, March 3, 2004--Vol 291, No. 9 1077
INTENSIVE VS MODERATE LIPID LOWERING
Figure 2. Comparison of Percentage of Low-Density Lipoprotein Cholesterol Reduction and Change in Atheroma Volume Both Treatment Groups (N = 502) Pravastatin Group (n = 249) Atorvastatin Group (n = 253)
3 20
15
olume, mm 10
5
oma V
0
5
10
Change in Ather 15
80 70 60 50 40 30 20 10 0 10 20 80 70 60 50 40 30 20 10 0 10 20 80 70 60 50 40 30 20 10 0 10 20
% Change in Low-Density Lipoprotein Cholesterol % Change in Low-Density Lipoprotein Cholesterol % Change in Low-Density Lipoprotein Cholesterol The solid line indicates the relationship between mean change in low-density lipoprotein cholesterol and change in atheroma volume from linear regression analysis. The dashed lines indicate the upper and lower 95% confidence limits for the mean values. cant(P .001).Furtheranalysiswillbe level reductions alone did not explain tion in angiographic stenosis severity, required to elucidate the relationship all of the differences in efficacy. Al- mostpriortrialshaveshownonlyslow- betweentheextentofreductioninCRP though the 2 regression lines are par- ingoftheprogressionofthediseasebut orotherinflammatorymarkersandthe allel, the progression rate at any level neither regression nor an absence of effect on the progression of coronary of LDL-C reduction was lower with progression.9-10,14-16 However, these atherosclerosis. atorvastatin compared with pravasta- studies used typical starting doses of In addition to unpaired compari- tin. The lower progression rate in the statinsandthereforedidnotexplorethe sonsbetweenthe2treatmentgroups,the atorvastatingroupwasequivalenttoan potential of more intensive therapy to studyprespecifiedpairedanalysiswithin additional20%(30mg/dL[0.78mmol/ delay or prevent progression. The cur- groups to determine whether progres- L]) reduction in LDL-C level. These rent study had several important ad- sion or regression had occurred from data strongly suggest that other fac- vantages over earlier studies. The ac- baseline to follow-up. Absence of mea- torsplayedanimportantroleintheim- tivelytestedagent,atorvastatin(80mg surable progression in the intensively proved outcome in the group treated dose), is a more potent lipid-lowering treated cohort was evident for the pri- with atorvastatin. The most likely ex- agent and produced both a reduction mary end point, 3 prespecified second- planationisthelargerreductioninCRP in LDL-C level approaching 50% and aryendpoints,and22prospectivelyde- and other atherogenic lipoproteins, large reductions in CRP. The method finedsubgroups(Tables3and4).These such as triglycerides, in the atorvas- (intravascular ultrasound) for assess- subgroups included men and women, tatin group. Supporting this observa- ing atherosclerosis is also relatively individualswithorwithoutdiabetes,and tion, progression occurred even in the novel, allowing measurement of ath- individuals with or without hyperten- patients in whom pravastatin lowered eromaburden,notmerelyluminalnar- sion. In contrast, patients treated with LDL-C level below the recommended rowing.11,17,18 Interestingly,2otherstud- a more moderate regimen of 40 mg of goal of 100 mg/dL (2.59 mmol/L) ies using an ultrasound method for pravastatinshowedsignificantprogres- (mean , 88 mg/dL [2.27 imaging the vessel wall (measurement sion (P=.01 to P .001 compared with {0.25} mmol/L]; Table 4). Impor- ofcarotidintimalmedialthickness)also baseline) for all 4 prespecified efficacy tantly,thelowerprogressionrateinthe showed reduced progression with in- parameters (Table 3) and 15 of 22 sub- more intensive atorvastatin treatment tensive treatment using 80 mg of ator- groups (Table 4). group was achieved with a safety and vastatin.19,20 Aninverserelationshipbetweenper- tolerability profile similar to the more Becausedifferentdosesofthe2stat- centage reduction in LDL-C level and moderatepravastatinregimen(Table6). ins were used, the potential impact of atherosclerosisprogression(changein Thisisthefirstlargerandomizedtrial using a higher dose of pravastatin on atheroma volume) for both drugs was todirectlycomparetherateofCADpro- thetrialresultsmustbeconsidered.At apparent from linear regression analy- gressionforpatientstreatedwith2dif- the time of study initiation, the high- sis (FIGURE 2). Expressed as percent- ferent statins. All prior coronary re- estdoseofpravastatinapprovedbythe age change, each 10% reduction in gression-progressiontrialswereplacebo FoodandDrugAdministrationwas40 LDL-C level (15 mg/dL [0.39 mmol/ controlled and had a longer duration mg.An80-mgdosewasapprovedmid- L])yieldedapproximatelya1%reduc- (2-3 years). Although a recent single way through the trial. However, we tion in the change in atheroma vol- center study using a combination of deemeditundesirabletoalterthedose umeafter18months.However,LDL-C simvastatin and niacin showed reduc- of either study drug during an ongo-
1078 JAMA, March 3, 2004--Vol 291, No. 9 (Reprinted) ©2004 American Medical Association. All rights reserved.
INTENSIVE VS MODERATE LIPID LOWERING
ing clinical trial. Furthermore, the re- REVERSAL trial, substantial regres- ings must be confirmed in large out- ductioninLDL-Clevelofallstatins,in- sion in atherosclerotic disease burden comestudiescomparingmorbidityand cluding pravastatin, increases only wasobserved(FIGURE 3).Theseobser- mortality using alternative lipid- moderately with an increased dose.21 vations confirm the potential of anti- lowering regimens. Several studies are ThelabelingapprovedbytheFoodand atherosclerotictherapiestoreversethe under way comparing the effect of in- Drug Administration indicates only a disease process. However, it also must tensive with moderate lipid-lowering
3% greater mean LDL-C reduction us- be emphasized that many patients in regimens on clinical events. These re- ing80mgofpravastatincomparedwith both groups had significant progres- sults will not be available for several the 40-mg dose. A meta-analysis of sion despite statin treatment. years. statintrialscalculatedonlya4%greater Thecurrentstudyhaslimitations.In- Despite these limitations, we be- effect with 80 mg of pravastatin.21 Ac- travascular ultrasound is a relatively lievethefollowingconclusionsarewar- cordingly, we think it is unlikely that newmodalityforassessmentofathero- ranted. For secondary prevention, in- theuseoftherecentlyapproved80-mg sclerotic disease burden. Accordingly, tensive treatment with 80 mg of doseofpravastatinwouldhavesignifi- theclinicalimplicationsofevidenceof atorvastatin in patients with moderate cantly affected study results. drug benefit derived from intravascu- cholesterolelevationsreducedprogres- The importance of the progression lar ultrasound remain uncertain. We sion of coronary atherosclerosis com- rateofatherosclerosisasaclinicaltrial also recognize that the major adverse pared with a more moderate lipid- endpointalsorequiresadditionalcom- clinical outcomes of death and myo- lowering regimen consisting of 40 mg ment. It is statistically challenging to cardial infarction are the most impor- of pravastatin. Compared with base- performactivelycontrolledstatintrials tant end points for secondary preven- line, intensive treatment halted pro- using morbidity and mortality end tion trials. There were too few events gression of atherosclerosis, whereas pointsbecausethedifferencesinevent foranymeaningfulanalysisbecause502 moderate therapy was associated with rates are likely to be small. Such stud- patients were followed up for only 18 significantdiseaseprogression.Thein- ies require enrollment of approxi- months(Table6).Therefore,ourfind- tensive regimen produced greater re- mately 10000 patients for 5 to 6 years
of follow-up. The current study de-
sign enabled comparison of 2 active Figure 3. Intravascular Ultrasound Images at Baseline and Follow-up drugs with a sample size of about 500
patients and a duration of only 18 A Determination of Atheroma Area months. However, to accept this re- Landmarks EEM Area Lumen Area Atheroma Area sult as clinically meaningful, evidence
of a relationship between progression
rate and clinical outcome is impor-
tant.Sucharelationshiphasbeendem- Vein onstrated in prior angiographic trials Side Branch withahighrateofadverseclinicalout-
comes in patients with more rapid dis-
B Change in Atheroma Area From Baseline to Follow-up ease progression.22,23 In these studies,
smalldifferencesinprogressionrateof Baseline Follow-up atherosclerosiswereassociatedwithsig-
nificant differences in clinical out- Lumen Area Lumen Area
7.7 mm2 9.8 mm2 come.
Webelievethatthecurrentstudyhas
importantimplicationsforunderstand-
ing the natural history of CAD. Previ-
ously,coronaryatherosclerosishasbeen
perceived as a progressive disease pro-
cess in which most therapies are de-
signedtoslowtheinexorableadvance- EEM Area Atheroma Area EEM Area Atheroma Area 17.1 mm2 7.4 mm2 ment of the disease. The present study 20.7 mm2 13.0 mm2 suggestsanimpendingparadigmshift,
in which intensive lipid-modulating A, Atheroma area is calculated by subtracting the lumen area from the area of the external elastic membrane strategies can be used to stop and po- (EEM). B, Patient randomized to 80 mg of atorvastatin. There is substantial reduction in atheroma area (from tentiallyreversetheatheroscleroticdis- 13.0 to 7.4 mm2). A lesser increase in lumen area is noted (from 7.7 to 9.8 mm2). See video at http://jama.com/cgi/content/full/291/9/1071/DC1. ease process. In some patients in the
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, March 3, 2004--Vol 291, No. 9 1079
INTENSIVE VS MODERATE LIPID LOWERING
ductions in atherogenic lipoproteins the integrity of the data and the accuracy of the data monary Associates (John Corbelli, MD); New York: analysis. Mount Sinai Hospital (Samin Sharma, MD). North and CRP, which likely explain the im- Studyconceptanddesign:Nissen,Tuzcu,Ganz,Vogel. Carolina:ChapelHill:UniversityofNorthCarolina(Sid- proved outcome. A more intensive Acquisition of data: Nissen, Tuzcu, Schoenhagen, ney C. Smith, MD); Greensboro: LeBauer Cardiovas- lipid-loweringtherapyisrequiredthan Vogel, Howard, Cooper, Brodie, Grines, DeMaria. cular Research Foundation (Bruce Brodie, MD); Analysis and interpretation of data: Nissen, Tuzcu, Greenville: East Carolina University (Michael Miller, is currently recommended by national Schoenhagen, Brown, Ganz, Vogel, Crowe, Grines, MD); Winston-Salem: Wake Forest University (Mi- and international guidelines to obtain DeMaria. chael A. Kutcher, MD). Ohio: Cleveland: Cleveland Drafting of the manuscript: Nissen, Tuzcu, Ganz, Clinic Foundation (E. Murat Tuzcu, MD); University maximal reduction in the progression Cooper, DeMaria. Hospitals of Cleveland (Ravi Nair, MD); Columbus: of coronary atherosclerosis. Critical revision of the manuscript for important in- Ohio State University Medical Center (Raymond Ma- tellectualcontent:Nissen,Tuzcu,Schoenhagen,Brown, gorien, MD); Elyria: North Ohio Heart Care (Charles Ganz,Vogel,Crowe,Howard,Brodie,Grines,DeMaria. O'Shaughnessy,MD);Toledo:MedicalCollegeofOhio Author Affiliations: Departments of Cardiovascular Statistical expertise: Nissen, Brown, Ganz. (Christopher Cooper, MD). Oklahoma Heart Insti- Medicine (Drs Nissen, Tuzcu, Schoenhagen, and Mr Obtained funding: Nissen, Tuzcu. tute, Tulsa (Wayne N. Leimbach, MD). Pennsylva- Crowe) and Diagnostic Radiology (Dr Schoenhagen), Administrative,technical,ormaterialsupport:Nissen, nia:HeartCareGroupPC,Allentown(J.PatrickKleave- Cleveland Clinic Lerner School of Medicine, Cleve- Tuzcu, Ganz, Vogel, Crowe, Howard. land,MD).RhodeIsland:MiriamHospital,Providence land, Ohio; Department of Medicine, University of Supervision:Nissen,Tuzcu,Schoenhagen,Ganz,Vogel, (Paul Gordon, MD); Rhode Island Hospital, Provi- Washington,Seattle(DrBrown);DepartmentofMedi- Cooper, Brodie, Grines. dence(BarrySharaf,MD).UniversityofTexas,SanAn- cine, Brigham and Women's Hospital, Boston, Mass REVERSAL Investigators: University of Arkansas for tonio (Steven R. Bailey, MD). University of Washing- (Dr Ganz); Department of Medicine, University of Medical Sciences, Little Rock (Luis Garza, MD). Cali- ton Medical Center, Seattle (David Linker, MD). Maryland,Baltimore(DrVogel);PfizerInc,NewYork, fornia: Los Angeles: Cedars-Sinai Medical Center Funding/Support: This study was funded by Pfizer. NY (Ms Howard); Department of Medicine, Medical (James Forrester, MD); UCLA Medical Center for Role of the Sponsor: The sponsor, Pfizer, participated College of Ohio, Toledo (Dr Cooper); LeBauer Car- HealthSciences(JonathonTobis,MD);SanDiego:Uni- indiscussionsregardingstudydesignandprotocolde- diovascularResearchFoundation,Greensboro,NC(Dr versity of California (Anthony DeMaria, MD). Uni- velopment and provided logistical support during the Brodie); Cardiac Catheterization Laboratory, Division versity of Colorado Health Sciences Center, Boulder trial.Monitoringofthestudywasperformedbyacon- ofCardiacDiseases,WilliamBeaumontHospital,Royal (Jeb Burchenal, MD). University of Florida, Gaines- tract research organization, Covalent, under contract Oak, Mich (Dr Grines); and Department of Medi- ville (Richard Kerensky, MD). Cardiology of Georgia, with the sponsor, and maintained the trial database. cine,UniversityofCalifornia,SanDiego(DrDeMaria). PCPiedmontHospital,Atlanta(CharlesWickliffe,MD). The intravascular ultrasound end points were pre- Financial Disclosures: Dr Nissen has received re- Illinois: Blue Island: Heart Care Center (Robert S. Iaf- pared by the Cleveland Clinic Cardiovascular Coordi- search support from AstraZeneca, Merck-Schering faldano, MD); Chicago: University of Chicago (John nating Center. Statistical analysis was performed by Plough,EsperionTherapeutics,Takeda,Pfizer,andSan- Lopez, MD). Kentucky: University of Louisville (Mas- AverionInc,undercontractwiththesponsor.Themanu- kyo. Dr Tuzcu has received research support from soud Leesar, MD). Maine: Androscoggin Cardiology script was prepared by the corresponding author and Pfizer, AstraZeneca, Merck, and Novartis. Dr Grines Research, Auburn (Robert Weiss, MD). Massacchus- modifiedafterconsultationwiththeotherauthors.The has received research support from Berlex, setts: New England Medical Center, Boston (Jeffrey sponsor was permitted to review the manuscript and GlaxoSmithKline,Pfizer,Aventis,Guidant,Lilly,Scimed, Kuvin, MD). Michigan: Kalamazoo: Heart Institute at suggestchanges,butthefinaldecisiononcontentwas Johnson & Johnson, Otsuka, Esperion, and Inner- Borgess (Timothy A. Fischell, MD); Royal Oak: Wil- exclusively retained by the authors. cool. Dr Ganz has received research support from liamBeaumontHospital(CindyL.Grines,MD);StClair RelatedInformation: Onlinevideoavailableathttp:// AstraZeneca, Merck, and Pfizer. Mr Crowe owns Shores: Eastlake Cardiovascular Associates PC (Rob- jama.com/cgi/content/full/291/9/1071/DC1. Pfizer stock. Dr Vogel has received research support ert Mansfield Cleary Jr, MD). Missouri: Kramer & Acknowledgment: We acknowledge the contribu- from Pfizer. CrouseCardiologyPC,KansasCity(PaulKramer,MD). tions made by Brian Lyman, PhD, Kim Caswell, RN, Author Contributions: DrNissenhadfullaccesstoall NewYork:Albany:CapitalCardiologyAssociates(Au- Penny Sambroak, BS, Halit Silbershatz, PhD, Gary of the data in the study and takes responsibility for gustin DeLago, MD); Buffalo: Cardiology and Pul- Palmer, MD, Lee Golden, MD, and John Tsai, MD. REFERENCES
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