design and baseline characteristics of the incremental decrease in end points through aggressive...
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Design and Baseline Characteristics ofthe Incremental Decrease in End Points
Through Aggressive LipidLowering Study
Terje R. Pedersen, MD, Ole Faergeman, MD, John J.P. Kastelein, MD,Anders G. Olsson, MD, Matti J. Tikkanen, MD, Ingar Holme, PhD,
Mogens Lytken Larsen, MD, Fredrik S. Bendiksen, MD, Christina Lindahl, MD, andGary Palmer, MD, on behalf of the Incremental Decrease in End Points Through
Aggressive Lipid Lowering Study Group
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he Incremental Decrease in End Points through Aggres-ive Lipid Lowering (IDEAL) study is an investigator-nitiated trial designed to determine whether additionallinical benefit might be gained through a strategy thatecreases levels of low-density lipoprotein cholesterol
evels better than those currently achieved with estab-ished statin therapy in patients who have coronaryeart disease. IDEAL is a multicenter prospective, ran-omized, open-label, blinded, end point classificationtudy. Patients who had myocardial infarction were ran-omized to prescription treatment with 80 mg/day oftorvastatin or 20 mg/day of simvastatin (the dose was
ncreased to 40 mg/day at week 24 in those patientshose plasma total cholesterol remained >5.0 mmol/L,r 190 mg/dl, or whose low-density lipoprotein choles-erol remained >3.0 mmol/L, or 115 mg/dl). The pri-ary clinical outcome variable is the time to initial oc-
urrence of a major coronary event, which is defined as
hwtbtmTgactpcpemrOcttolhorway. E-mail: [email protected].
20 ©2004 by Excerpta Medica, Inc. All rights reserved.The American Journal of Cardiology Vol. 94 September 15, 2004
onfatal acute myocardial infarction, coronary death, oresuscitated cardiac arrest. The study is designed toave a power of 90% to detect a relative decrease of0% in the atorvastatin-group compared with the simv-statin-group in the number of major events caused byoronary heart disease over �5.5 years. The 8,888andomized patients had the following characteristics:ean age 61.7 � 9.5 years, 19.1% women (mean age4.0 � 9.5 years), baseline total cholesterol 5.1 � 1.0mol/L (197 mg/dl), low-density lipoprotein cholesterol.2 � 0.9 mmol/L (124 mg/dl), and high-density li-oprotein cholesterol 1.2 � 0.3 mmol/L (46 mg/dl).rug treatment before randomization consisted of sta-
ins in 77% of patients, aspirin in 78.9%, � blockers in5.1%, and angiotensin-converting enzyme inhibitors in0%. �2004 by Excerpta Medica, Inc.
(Am J Cardiol 2004;94:720–724)
reater percent decreases in levels of low-densitylipoprotein cholesterol (LDL) than those
chieved in the Scandinavian Simvastatin Survivaltudy (4S)1 might yield greater benefit in patients whoave coronary heart disease. The Heart Protectiontudy has provided evidence that treatment with 40g of simvastatin produces a similar relative de-
reased risk in patients with LDL cholesterol levelselow currently recommended target levels comparedith the risk observed among patients presenting with
rom the Center for Preventive Medicine, Ullevål University Hospital,slo, Norway; the Department of Medicine-Cardiology A, Århus Uni-
ersity Hospital, Århus, Denmark; the Academic Hospital Amsterdam,msterdam, The Netherlands; the Department of Internal Medicine,niversity Hospital, Linköping, Sweden; the Medical Clinic, Helsinkiniversity Hospital, Helsinki, Finland; the Hamar, Lysaker, Norway;fizer Sweden, Täby, Sweden; and Pfizer Inc., New York, New York.his study was supported by Pfizer Inc., New York, New York.anuscript received January 15, 2004; revised manuscript received
nd accepted June 7, 2004.Address for reprints: Terje R. Pedersen, MD, Center for Preventive
edicine, Building K, Ullevål University Hospital, N-0407 Oslo,
igher LDL cholesterol concentrations.2 These dataere attributed to a mean difference in LDL choles-
erol levels of �0.9 to 1.0 mmol/L (35 to 39 mg/dl)etween the treated and control groups. In contrast,he 4S achieved a mean difference of 1.7 mmol/L (66g/dl) between the statin-treated and control groups.he Incremental Decrease in End Points through Ag-ressive Lipid Lowering (IDEAL) study intends tochieve an additional interventional decrease in LDLholesterol of 0.6 to 0.7 mmol/L (23 to 27 mg/dl) byherapy with 80 mg of atorvastatin and therefore com-ares the effect of a mean decrease of �55% in LDLholesterol concentrations with a 35% decrease com-ared with levels before statin therapy. The beneficialffects of a 35% decrease in LDL cholesterol with 10g/day of atorvastatin on clinical end points was
ecently proved in the Anglo-Scandinavian Cardiacutcomes Trial Lipid-Lowering Arm.3 The more re-
ent Pravastatin or Atorvastatin Evaluation and Infec-ion Therapy-Thrombolysis in Myocardial Infarc-ion-22 (PROVE IT-TIMI 22) trial showed that 80 mgf atorvastatin provides greater protection than theess potent 40 mg of pravastatin in patients who havead a recent acute coronary syndrome.4
0002-9149/04/$–see front matterdoi:10.1016/j.amjcard.2004.06.003
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ETHODSStudy aim: The primary objective of the IDEAL
tudy is to investigate whether an incremental de-rease in the risk of coronary heart disease can bechieved by a greater decrease in LDL cholesterol inatients who use secondary prevention than that at-ained with a treatment strategy representing the cur-ent best clinical practice as established in the 4S. Theime to occurrence of a major coronary event will beompared in 2 groups of patients: 1 that achieves anverage decrease of �55% and 1 that achieves anverage decrease of �35% in LDL cholesterol.
Study eligibility: Men and women �80 years oldho had been hospitalized or had a history of aefinite myocardial infarction and who qualified fortatin therapy according to guidelines at the time ofecruitment were eligible for study entry. Major ex-lusion criteria were a known hypersensitivity to anytatin; active liver disease or hepatic dysfunction de-ned as a level of alanine aminotransferase or aspar-
ate aminotransferase �2 times the upper limit oformal; women who were pregnant or breast-feeding;ephrotic syndrome; uncontrolled diabetes mellitus;ncontrolled hypothyroidism; plasma triglycerides6.8 mmol/L (600 mg/dl); congestive heart failure
New York Heart Association classification IIIb orV); hemodynamically important valvular disease;astrointestinal disease that might limit drug absorp-ion or partial ileal bypass; other significant abnormal-ties that in the investigator’s opinion could compro-
ise the patient’s safety or successful participation inhe study; and treatment with medications, such asther lipid-lowering drugs or any immunosuppressivegent that could compromise the patient’s safety orbscure the efficacy or safety comparisons. Patientslready titrated to a dose of statin more than thequivalent of 20 mg/day of simvastatin were alsoxcluded.
Study design, treatment, and patient management:DEAL is a multicenter, randomized, open-label studyith stratified randomization carried out in blocks by
enter and with blinded end point classification (theo-called PROBE design5). After dietary counseling,ll patients fulfilling the eligibility criteria were ran-omized to treatment with 80 mg/day of atorvastatinr 20 mg/day of simvastatin. No drug-free period wasequired. Study medication was provided by prescrip-ion in all countries except Finland, where it wasispensed at the clinical centers at the expense of theponsor. In Norway and Sweden, patients paid part ofhe cost of medication; in Denmark and The Nether-ands, all costs were reimbursed. These proceduresorresponded to reimbursement rules for statin ther-py in the respective countries. The difference in costetween simvastatin and atorvastatin was equalized byhe sponsor through agreements with governmentalgencies in these countries.
The study protocol allowed the dose of simvastatino be increased to 40 mg/day at week 24 in thoseatients whose plasma total cholesterol remained5.0 mmol/L (190 mg/dl). All patients were followed
p 12 and 24 weeks after randomization and will be n
CORONARY ART
ollowed every 6 months thereafter until the predeter-ined number of primary end points for the study is
bserved. This is estimated to occur after a medianuration of 5.5 years. Follow-up visits occur in theutpatient clinic of the recruiting hospital or a special-st center to monitor compliance and adverse eventsnd study end points.
Baseline serum lipid and lipoprotein levels wereeasured from fasting blood samples taken 7 to 14
ays before randomization. Lipid profiles were deter-ined at weeks 12 and 24 and 1 year and will beeasured every 12 months thereafter and at the final
isit. Liver enzymes (specifically aspartate amino-ransferase and alanine aminotransferase), creatinehosphokinase, and other laboratory measurementsere determined at randomization and at weeks 12
nd 24 and will be determined every 12 months there-fter and at the final visit. All laboratory proceduresnd lipoprotein determinations are conducted at a cen-ral laboratory. Results of lipid and lipoprotein deter-inations will not be revealed to investigators or other
tudy personnel during the study with exception ofritical values of total and/or LDL cholesterol valuest week 24, when titration of the simvastatin dose wasllowed (as previously mentioned). Patient hospitalecords are marked with labels telling the staff not toeasure such values. General physical examinations
nd electrocardiograms are carried out annually.Study management: The study was initiated by the
nvestigators and is scientifically led by a steeringommittee consisting of independent researchers andnvestigators and 3 members employed by the spon-or. This committee has the full responsibility for thetudy protocol and publications from the study. Theommittee is granted full access to all data at studyompletion through a contract with the sponsor. Thetudy is monitored by employees of the sponsor whoollect all case report forms after review and submithem to a contract research organization (COVANCE,rinceton, New Jersey) that enters the data into aatabase. Data are then reviewed for errors and incon-istencies through a comprehensive system of algo-ithms, and queries are sent to investigators for clari-cations. The contract research organization isesponsible for preparing interim analysis reports forhe data safety and monitoring board. These reportsre not shared with the sponsor or any other personneln the trial.
Study outcomes: The primary clinical outcome vari-ble is the time to first occurrence of a major coronaryvent, which is defined as nonfatal acute myocardialnfarction according to criteria of the Joint Europeanociety of Cardiology/American College of Cardiol-gy, coronary death, or resuscitated cardiac arrest.econdary outcomes are the occurrence of any pri-ary event, any coronary artery revascularization pro-
edure, or hospitalization for unstable angina; hospi-alization with a primary diagnosis of congestive heartailure; any cerebrovascular event; peripheral arterialisease; any cardiovascular event; and all-cause mor-ality rate. Because all end points except death and
ew diagnosis of peripheral artery disease requireERY DISEASE/DESIGN AND BASELINE DATA IDEAL STUDY 721
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ospitalization, the potential for biased reporting bynvestigators is being minimized by study monitorsho review patient records at regular intervals to
earch for potential end points. An end point commit-ee blindly and individually reviews all primary andecondary end points to confirm that the data supporthe end point designation. Any differences betweenommittee members are adjudicated at regular meet-ngs. To ensure blinding by this committee, all endoint reports accompanied by narratives or copies ofospital records are first sent to an independent centeror masking.
Data safety monitoring board: An independentafety data monitoring board, not otherwise involvedn the conduct of the trial, will monitor aggregated endoint summaries and medically serious adverse eventsn an ongoing basis. The primary responsibility of thisoard is the safety of trial participants. The board willonvene every 6 months to review the status of thetudy and has the power to make recommendations toalt the trial, continue the trial beyond the plannedize or duration, or change trial procedures.
Sample size calculation: The trial originally plannedecruitment of 7,600 patients based on experiencerom the 4S, in which the mean LDL cholesterol ataseline was �4.87 � 0.65 mmol/L. In contrast to theS, in which patients were randomized on average �3ears after their first myocardial infarction or firstiagnosis of angina pectoris, the plan was to random-ze patients participating in the IDEAL study within 6eeks of a myocardial infarction. Because of compe-
ition with other ongoing trials in this population, mostatients had been recruited several months or yearsfter the initial myocardial infarction. As a conse-uence, most patients were on lipid-lowering therapy,nd the profile of the first patients recruited made itore likely that the sample size calculations should be
ased on those of the Cholesterol and Recurrentvents (CARE) study.6 In that study, the mean base-
ine LDL cholesterol level was 3.6 mmol/L (139 mg/l). It is expected that 20 to 40 mg/day of simvastatinill decrease LDL cholesterol levels by 35% and that0 mg/day of atorvastatin will decrease LDL choles-erol levels by 55% compared with nontreatment lev-ls. This difference in turn is expected to decrease theumber of 5-year recurrent coronary events by 20% inhe atorvastatin group compared with the simvastatinroup. These figures reflect the decreases achieved inong-term statin trials after taking into account medi-ation switch-over, decreased compliance, and num-er of dropouts. Therefore, assuming a 10% recurrentvent rate for 20 to 40 mg/day of simvastatin (basedn experience from the 40-mg pravastatin group in theARE trial) and a 7.9% recurrent event rate for 80g/day of atorvastatin, it was determined that 7,764
atients would provide 90% power to detect a 21%ecrease in recurrent coronary events over 5 yearsetween treatment groups when using a 2-tailed test� � 0.05) based on the log-rank test. After adjustingor interim observations at 50% and 75% informationimes (percent primary end points) using O’Brien-
leming boundaries, the trial randomized 8,888 pa- t22 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 94
ients with a target of 774 patients with primaryvents.
Interim analyses: Interim analyses for IDEAL wille performed when �50% and �75% of primaryvents have occurred, and they will include assess-ent of recruitment, subject characteristics, primary
fficacy and safety variables, all-cause mortality rates,nd adverse events. Early discontinuation of the trials a complex decision involving a number of factorsside from the simple comparison of 1 statistic with 1ritical value. A recommendation to modify or termi-ate the trial would not be based solely on the crossingf a group-sequential boundary.
Baseline data: RECRUITMENT: Enrollment into theDEAL study was carried out at 190 centers in Nor-ay, Sweden, Finland, Denmark, Iceland, and Theetherlands. The first patient was recruited on March1, 1999 and the final patient was randomized onarch 29, 2001. Of the 9,689 patients screened, 8,888ere randomized to open-label prescription treatmentith 80 mg/day of atorvastatin or 20 mg/day of sim-astatin. At the 6-month follow-up, the simvastatinose was increased to 40 mg in 20.3% of patients.
BASELINE CHARACTERISTICS: Selected baseline char-cteristics of randomized patients are listed in Table 1.ost patients were randomized �6 months after theiryocardial infarction. Accordingly, 77% were receiv-
ng statin therapy at the time of randomization. Serumoncentrations at baseline of different lipid parame-ers, glucose, and glycosylated hemoglobin are pre-ented in Table 2. Because patients already titrated toarger doses of statin were excluded and most random-zed patients were on statin therapy, the mean baselineDL cholesterol concentration was only 3.2 mmol/L
122 mg/dl).
ISCUSSIONPost hoc analysis of the 4S data demonstrated a
irect relation between the degree to which LDL cho-esterol was decreased and the risk of future clinicalvents.7 Therefore, in the IDEAL study, we are using0 mg of atorvastatin to determine whether moreggressive lipid lowering would improve the progno-is in patients who have coronary heart disease com-ared with a strategy that reflects the current bestlinical practice resulting from the 4S.
Treatment in the present study is administered inn open-label manner. The validity of the PROBEesign is well documented in published reports, and aignificant bias that affects the end points of the trial isighly unlikely.5 Patients were assigned to treatmenty central randomization, thus effectively eliminatinghe potential for biased assignment.
Clearly, the treatment groups in the IDEAL studyiffer from each other in 2 respects, drug type andntensity of therapy. Although our primary objective isot to compare 2 lipid-lowering agents, atorvastatinnd simvastatin, it is evident that, irrespective of therial results, we will be faced with �1 explanation forny differences in outcome that might occur. For thiseason, IDEAL has been closely linked to the Treating
8
o New Targets (TNT) study. In contrast to theSEPTEMBER 15, 2004
CORONARY ART
IDEAL study, TNT will evaluate thedifference in incidence of end pointsat 2 different absolute levels of treat-ment of LDL cholesterol among pa-tients who have coronary heart dis-ease. In that study, patients are beingtreated with 2 different doses of ator-vastatin, 10 mg and 80 mg. The firstgroup is expected to reach a meanLDL cholesterol level of �2.6mmol/L (100 mg/dl), and the secondgroup is expected to reach of level of2.0 mmol/L (75 mg/dl). The closecollaboration between IDEAL andTNT means that together these stud-ies will provide insight into the im-portance of the percentage by whichcholesterol is decreased and the ab-solute level of LDL cholesterol thatcan be achieved for the prevention ofcardiovascular events.
Acknowledgment: We are indebtedto the departments of health and thenational health insurance institutions inNorway and Sweden, the NationalMedicines Agency, Copenhagen, Den-mark, and the national societies ofpharmacies in these countries and inIceland for their cooperation in orga-nizing the reimbursement and studydrug delivery systems for the trial.
APPENDIXSteering Committee: Terje R. Pedersen, MD
(chair); Ole Faegeman, MD; Ingar Holme, PhD; AndersG. Olsson, MD; Matti Tikkanen, MD; John J.P. Kaste-lein, MD; Mogens Lytken Larsen, MD; Christina Lin-dahl, MD; Gary Palmer, MD; Fredrik S. Bendiksen,MD; Sverre Maehlum, MD.
Data Safety and Monitoring Board: Desmond G.Julian, MD (chair); Hans Wedel, PhD; Knut Rasmus-sen, MD; Christie Ballantyne, MD.
End-Point Committee: Kristian Thygensen, MD(chair); Bengt W. Johansson, MD; Per Lund-Johansen,MD.
1. Scandinavian Simvastatin Survival Study Group. Ran-domised trial of cholesterol lowering in 4444 patients withcoronary heart disease: the Scandinavian Simvastatin Sur-vival Study (4S). Lancet 1994;344:1383–1389.2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering withsimvastatin in 20 536 high-risk individuals: a randomisedplacebo-controlled trial. Lancet 2002;360:7–22.3. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G,Caulfield M, Collins R, Kjeldsen SE, Kristinsson A,Mcinnes GT, et al. Prevention of coronary and strokeevents with atorvastatin in hypertensive patients who haveaverage or lower-than-average cholesterol concentrations,in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre ran-domized controlled trial. Lancet 2003;361:1149–1158.4. Cannon CP, Braunwald E, McCabe CH, Rader DJ,Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA,Skene AM. Comparison of intensive and moderate lipidlowering with statins after acute coronary syndromes.N Engl J Med 2004;350:1495–1504.5. Hansson L, Hedner T, Dahlöf B. Prospective Ran-domized Open Blinded End-point (PROBE) study. Anovel design for intervention trials. Blood Press 1992;1:113–119.
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Hemoglobin
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mmol/L
5.1 � 1.01.2 � 0.33.2 � 0.91.7 � 0.9
————
6.0 � 1.7
TABLE 1 Baseline Characteristics of Patients (n � 8,888)
Mean � SD
Men (age) 61.2 � 9.4 7,187 (80Women (age) 64.0 � 9.5 1,701 (19Age (yrs) 61.7 � 9.5
�40 87 (1.40–44 263 (3.45–49 601 (6.50–54 1,193 (1355–59 1,448 (1660–64 1,537 (1765–69 1,654 (1870–74 1,318 (14�75 785 (8.
Caucasian 8,816 (99Noncaucasian 72 (0.No. of previous myocardial infarctions 1.2 � 0.5Yrs since last myocardial infarction 3.9 � 4.9Coronary angioplasty only 1,764 (19Coronary bypass only 1,477 (16Angioplasty and bypass 289 (3.Current smoker 1,832 (20Ex-smoker 5,197 (58Systemic hypertension history 2,857 (32Diabetes mellitus 1,057 (11Body mass index �30 kg/m2 1,826 (20Cerebrovascular disease 650 (7.Peripheral vascular disease 355 (4.Congestive heart failure 1,169 (13Concomitatant treatment
Aspirin 7,017 (78Other antiplatelet drugs 151 (1.Anticoagulants 1,022 (11� Blockers 6,677 (75Calcium antagonists 1,723 (19ACE inhibitors 2,668 (30Angiotensin II receptor blockers 526 (5.Digitalis 280 (3.Spironolactone 182 (2.Other diuretics 1,662 (18Nitrates 3,361 (37Hormone replacement therapy 185 (10Simvastatin 4,537 (51Atorvastatin 1,025 (11Pravastatin 872 (9.Fluvastatin 253 (2.Lovastatin 107 (1.Cerivastatin 52 (0.Nonstatin drugs 48 (0.
Systolic blood pressure (mm Hg) 136.9 � 20.1Diastolic blood pressure (mm Hg) 80.4 � 10.2Weight (kg) 82.5 � 13.8
ACE � angiotensin-converting enzyme.
TABLE 2 Fasting Serum Levels of Lipids, Glucose, and Glycosylated
Concentration (mean
mg/dl
Total cholesterol 196 � 39.3HDL cholesterol 46 � 12.0LDL cholesterol 122 � 34.7Triglycerides 149 � 78.5Total/HDL ratio 4.5 � 1.4Apolipoprotein A-1 (g/L) 1.4 � 0.2Apolipoprotein B (g/L) 1.2 � 0.3Hemoglobin A1c (%) 5.0 � 0.9Glucose 107.3 � 29.9
HDL � high-density lipoprotein.
ERY DISEASE/DESIGN AND BASELINE DATA IDEAL STUDY 723
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. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,rown L, Warnica JW, Arnold JMO, Wun C, et al. The effect of pravastatin onoronary events after myocardial infarction in patients with average cholesterolevels. N Engl J Med 1996;335:1001–1009.. Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K,
ilhelmsen L, Haghfelt T, Thorgeirsson G, Pyörälä K, et al. Lipoprotein changes c24 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 94
nd reduction in the incidence of major coronary heart disease events in thecandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453–1460.. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C.reating to New Targets (TNT) study: does lowering low-density lipoproteinholesterol levels below currently recommended guidelines yield incremental
linical benefit? Am J Cardiol 2004;93:154–158.SEPTEMBER 15, 2004