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Comparison of Atorvastatin 80 mg/day Versus Simvastatin 20 to 40mg/day on Frequency of Cardiovascular Events Late (Five Years)After Acute Myocardial Infarction (from the Incremental Decreasein End Points Through Aggressive Lipid Lowering [IDEAL] Trial)

Terje R. Pedersen, MD, PhDa,*, Nilo B. Cater, MDg, Ole Faergeman, MD, DMScb,John J.P. Kastelein, MD, PhDc, Anders G. Olsson, MD, PhDd, Matti J. Tikkanen, MD, PhDf,

Ingar Holme, PhDa, Mogens Lytken Larsen, MD, DMScb, Christina Lindahl, MDe, andMichael Szarek, PhDg

Previous studies have demonstrated that benefits of intensive statin therapy comparedto standard statin therapy begin shortly after an acute event and are continued up to2 years of follow-up. However, whether efficacy and safety of intensive statin therapyin patients with a recent cardiac event are maintained in longer-term follow-up has notbeen evaluated. We conducted a post hoc analysis of a subgroup of 999 patients whohad a first acute myocardial infarction (MI) <2 months before randomization in aprospective, open-label, blinded end-point evaluation trial of 8,888 patients with ahistory of MI that compared intensive statin therapy (atorvastatin 80 mg) to standardstatin therapy (simvastatin 20 to 40 mg) over approximately 5 years of follow-up. Weanalyzed the same composite end point used in the Pravastatin or Atorvastatin Eval-uation and Infection Therapy (PROVE IT) trial (death, MI, hospitalization for unstableangina, revascularization, and stroke). Rates of the composite end point were 44.7% (n� 226) in the simvastatin group and 37.9% (n � 187) in the atorvastatin group (hazardratio 0.82, 95% confidence interval 0.67 to 0.99, p � 0.04). Although statistical powerwas smaller than that of the PROVE IT trial, the relative risk decrease observed at 5years is consistent with that in the 2-year follow-up in PROVE IT. The 2 treatmentregimens were well tolerated. In conclusion, our analysis provides support for thestrategy of placing patients with recent MI on intensive statin therapy and maintainingthe high dose over the long term, beyond 2 years. © 2010 Elsevier Inc. All rights

reserved. (Am J Cardiol 2010;106:354 –359)

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Recent guidelines1,2 have advocated early initiation of in-ensive lipid lowering in patients with acute coronary syn-romes based on results from randomized clinical trials,3–5 buthe short-term benefits of this strategy are still under debate andong-term data are scarce.6,7 The Incremental Decrease innd Points through Aggressive Lipid Lowering (IDEAL)

rial was a prospective, randomized, open-label, blindednd-point trial that compared the effect on outcome ofherapy with atorvastatin 80 mg to that of simvastatin 20 to0 mg in 8,888 patients with a history of acute myocardialnfarction (MI) over a follow-up period of about 5 years.8

aCenter for Preventive Medicine, Oslo University Hospital, and Uni-ersity of Oslo, Norway; bDepartment of Medicine–Cardiology A, Århusniversity Hospital, Århus, Denmark; cAcademic Hospital Amsterdam,msterdam, The Netherlands; dDepartment of Internal Medicine, Univer-

ity Hospital, Linköping, Sweden; ePfizer Sweden, Täby, Sweden; fMedi-al Clinic, Helsinki University Hospital and Folkhälsan Research Center,elsinki, Finland; and gPfizer, Inc., New York, New York. Manuscript

eceived December 22, 2009; revised manuscript received and acceptedarch 15, 2010.

The IDEAL study was funded by Pfizer, Inc., New York, New York.*Corresponding author: fax: �47-22-60-19-00.

tE-mail address: t.r.pedersen@medisin.uio.no (T.R. Pedersen).

002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2010.03.033

nrollment into IDEAL was not limited with regard toiming after acute MI and most patients were enrolled sev-ral months or years after their MI. For the present analysise focused on the 999 patients randomized within 2 months

fter an acute MI, a period when they were still in thenstable phase after an acute coronary syndrome. To facil-tate placing the data into the context of recent trials oftatins for acute coronary syndromes, the present evaluationocused on analyzing the composite end point that was useds the primary end point of the Pravastatin or Atorvastatinvaluation and Infection Therapy (PROVE IT) trial.5

ethods

The design and principal findings of the trial have beenublished previously.8,9 In brief, IDEAL was a multicenterrial of men and women �80 years of age who had a historyf confirmed MI. The trial was conducted at 190 centers inordic countries and in The Netherlands. The study was

pproved by institutional review committees, and all sub-ects gave informed consent. Patients were screened andnrolled from hospitals during hospitalization for an acuteI and outpatient clinics during follow-up visits for hospi-

alization for recent MI or for long-term management of

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355Coronary Artery Disease/Statin Therapy After Myocardial Infarction

table coronary heart disease. The latter setting providedost patients screened and enrolled in the trial. There were

,689 patients screened, most of whom were already receiv-ng statin therapy. They qualified for randomization unlesshey were already receiving a dose higher than the equiva-ent of simvastatin 20 mg/day. Of patients screened, 8,888ere randomized to treatment with atorvastatin 80 mg/dayr simvastatin 20 mg/day. There were no run-in or wash-outeriods.

Randomization was done through a central interactiveoice-response system with allocation balanced by center.atients randomized in Finland (506 patients in overall trial)eceived study drugs from clinical centers at no cost. Pa-ients in other countries were given prescriptions for the

Figure 1. Schema of patient screening, ra

tatin, which they filled at designated pharmacies. To reflect t

eimbursement rules for statin therapy in the other countries,atients in Norway and Sweden paid part of the medicationost, whereas patients in Denmark and The Netherlandsere reimbursed for medication cost. To equalize cost ofedication, the sponsor paid the difference in cost between

imvastatin and atorvastatin by arrangements made with theovernmental agency in each country.

The trial used a study design that was a prospective,andomized, open-label, blinded end-point evaluation.10

atients were followed by designated study coordinatorsnd investigators at clinical centers after 12 and 24 weeksnd every 6 months thereafter. Blood samples were col-ected at each visit for measurement of lipids and otheromponents for safety assessment. Patients on simvasta-

ation, and follow-up. AMI � acute MI.

in could be titrated to 40 mg/day if their plasma total

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holesterol at the 24-week visit was �190 mg/dl (5.0mol/L) on advice from the central laboratory. Except

or such cases, lipid levels were not reported to studyersonnel during the study.

End-point reports from investigators were first screenedy an independent center (Inveresk, Raleigh, North Caro-ina) for blinding of treatment allocation. All end-pointvents were then adjudicated by an independent end-pointlassification committee that was thus blinded to treatmentllocation. The primary end point was time to first occur-ence of a major coronary event, defined as coronary death,onfirmed nonfatal acute MI, or cardiac arrest with resus-itation.

For the present post hoc analysis, we only included datarom the subgroup of patients who were randomized �2onths after an acute MI. A composite end point that was

dentical to the primary end point of PROVE IT was eval-ated using primary data during 5 years of follow-up. TheROVE IT composite end point consisted of time to occur-ence of all-cause death or a cardiovascular event (a com-

able 1aseline characteristics of patients

haracteristics Simvastatin(n � 506)

Atorvastatin(n � 493)

ge (years), mean � SD 59.8 � 9.6 60.6 � 9.7en 395 (78.1%) 376 (76.3%)urrent smoker 88 (17.4%) 81 (16.4%)ypertension 159 (31.4%) 153 (31.0%)iabetes mellitus 58 (11.5%) 55 (11.2%)revious myocardial infarction 506 (100%) 493 (100%)�1 previous myocardial infarction 85 (16.8%) 77 (15.6%)revious coronary artery bypass

grafting25 (4.9%) 25 (5.1%)

revious percutaneous coronaryintervention

96 (19.0%) 97 (19.7%)

erebrovascular disease 27 (5.3%) 32 (6.5%)eripheral vascular disease 17 (3.4%) 19 (3.9%)ongestive heart failure 24 (4.7%) 31 (6.3%)rerandomization statin therapySimvastatin 206 (40.7%) 219 (44.4%)Atorvastatin 65 (12.9%) 55 (11.2%)Pravastatin 40 (7.9%) 31 (6.3%)Other statins 8 (1.6%) 4 (0.8%)oncomitant therapyAspirin 424 (83.8%) 416 (84.4%)Warfarin or dicoumarol 26 (5.1%) 32 (6.5%)� blockers 446 (88.1%) 437 (88.6%)Calcium antagonists 53 (10.5%) 84 (17.0%)Angiotensin-converting enzyme

inhibitors177 (35.0%) 165 (33.5%)

Angiotensin II blockers 22 (4.4%) 27 (5.5%)lood pressure (mm Hg), mean � SDSystolic 134.4 � 20.2 134.9 � 21.5Diastolic 80.2 � 10.9 79.0 � 10.5ody mass index (kg/m2), mean � SD 27.1 � 3.6 27.2 � 3.7atients with lipid values 504 489ipid values (mg/dl), mean � SETotal cholesterol 201 � 2.0 203 � 2.0Low-density lipoprotein cholesterol 128 � 1.8 129 � 1.8High-density lipoprotein cholesterol 44 � 0.5 44 � 0.5Triglycerides 152 � 3.3 160 � 3.7

osite of hospitalization for nonfatal acute MI, hospitaliza- s

ion for unstable angina, coronary revascularization, andtroke). Time to occurrence of first end point after random-zation was examined using Kaplan-Meier hazard rates, androup differences were assessed with log-rank test. Coxroportional hazard models were used to calculate hazardatios (HRs) and 95% confidence interval (CIs). Statisticalnalysis was performed using SAS 8.2 (SAS Institute, Cary,orth Carolina). All analyses are based on an intention-to-

reat principle including all patients. Two-sided p values0.05 were considered statistically significant; corrections

or multiple comparisons were not done.An analysis for adherence was also conducted. Overall

dherence for each subject was defined as total study med-cation exposure as percent total follow-up time for all-ause death. Total study medication exposure was defineds the interval between dates of first and last dose, regard-ess of the number of doses taken during that interval.ategories of adherence were defined as adherence �80%

adherers) and adherence �80% (nonadherers).Statistical analyses were performed by the sponsor’s

tatistician (MS) and independently verified by the steeringommittee’s independent academic statistician (IH) whoad full access to the data. The authors had full access to theata and take responsibility for the integrity of the data. Alluthors have read and agree to the report as written.

esults

From March 1999 to March 2001, 9,689 patients with aonfirmed history of MI were screened for the trial (Figure 1).f these patients, 1,073 (11%) had a screening visit �2onths after hospitalization for an acute MI. Of these pa-

ients 74 were excluded, mostly because they were alreadyeceiving a statin dose higher than simvastatin 20 mg/day orn equipotent dose of another statin. Thus, 999 were ran-omized, 506 to simvastatin and 493 to atorvastatin. Meanime from index MI to randomization was 46 days. Allandomized patients were included in the intention-to-treatnalyses for efficacy and safety. Only 5 subjects (0.5%)ithdrew their consent or were lost to follow-up, but vital

tatus was known for 3 of these subjects (0.3%) at the endf the study.

Baseline characteristics were similar in the 2 treatmentroups (Table 1), except that slightly more patients in thetorvastatin group were receiving calcium antagonists thann the simvastatin group.

At 24 weeks, 117 patients (23.1%) randomized to sim-astatin had their dose titrated to 40 mg/day, whereas 30atients (6.1%) in the atorvastatin group had their doseecreased to 40 mg/day at the discretion of the investigatorho might have related patients’ adverse reports to the highose. After 1 year, 2% of patients on simvastatin hadwitched to a different statin, most often atorvastatin; theorresponding proportion in the atorvastatin group was 5%,ost of whom had switched to simvastatin. At the end of the

rial, 27% of patients being prescribed simvastatin wereaking 40 instead of 20 mg/day, whereas 12% of those beingrescribed atorvastatin were taking 40 instead of 80 mg/day.

At 12 weeks, mean levels of low-density lipoproteinLDL) cholesterol were 104 mg/dl (2.7 mmol/L) in the

imvastatin group and 79 mg/dl (2.0 mmol/L) in the ator-

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357Coronary Artery Disease/Statin Therapy After Myocardial Infarction

astatin group (Figure 2). At 1 year, mean LDL cholesterolevels were 102 mg/dl (2.6 mmol/L) in the simvastatinroup and 81 mg/dl (2.1 mmol/L) in the atorvastatin group,epresenting an absolute difference of 21 (p �0.0001). Overhe course of the trial, mean LDL cholesterol levels were05 mg/dl (2.7 mmol/L) in the simvastatin group and 83g/dl (2.1 mmol/L) in the atorvastatin group. Only small

hanges occurred in high-density lipoprotein cholesterolevels, with minor differences between treatment groups.riglycerides were lowered by 7% in the simvastatin group

o a mean of 145 mg/dl (1.64 mmol/L) during the trial. Inhe atorvastatin group, triglyceride levels were lowered by1% to a mean of 118 mg/dl (1.33 mmol/L).

A total of 74 patients (14.6%) in the simvastatin groupad �1 primary end point of the study compared to 479.5%) in the atorvastatin group (HR 0.64, 95% CI 0.45 to.92, p � 0.02; Figure 3).

The most important component of the primary end pointas recurrent nonfatal acute MI occurring in 12.3% (n � 62)

n the simvastatin group and in 6.7% (n � 33) in the atorva-tatin group (HR 0.54%, 95% CI 0.35 to 0.82, p � 0.004).

Rates of the PROVE IT end point were 44.7% (n � 226) inhe simvastatin group and 37.9% (n � 187) in the atorvastatin

Figure 2. Mean LDL choleste

igure 3. Kaplan-Maier estimates of the primary study end point of a majororonary event, a composite of cardiovascular death, nonfatal MI, oresuscitated cardiac arrest. RRR � relative risk decrease.

roup (HR 0.82, 95% CI 0.67 to 0.99, p � 0.04), representing 0

relative risk decrease of 18% in the atorvastatin group (Figure). To compare the magnitude of this relative risk decrease tohat found in the 2-year PROVE IT trial, data at 2 years werelso evaluated (Figure 5). Relative risk decrease for theROVE IT end point in this recent MI cohort at 2 years was4% (HR 0.86, 95% CI 0.69 to 1.06), the magnitude of whichs comparable to the relative risk decrease of 16% (p � 0.005)eported in the PROVE IT trial.

Overall adherence to study treatment in these patientsith recent MI was high, with particularly high adherence

ates in those randomized to simvastatin compared to thoseandomized to atorvastatin. Adherence rates �80% wereeen in 93% of those randomized to simvastatin comparedo 86% in those randomized to atorvastatin. In patients whoere adherent, the rate for the PROVE IT end point was

ignificantly higher in the simvastatin group than in thetorvastatin group (44% vs 36%, respectively, p � 0.021).n those whose adherence rates were �80%, event rates inhe 2 groups were about similar (50% vs 48%, respectively).

The 2 statin regimens were well tolerated. Adversevents resulting in permanent discontinuation of study drugere reported in 23 patients (4.6%) in the simvastatin group

nd in 36 patients (7.3%) in the atorvastatin group (p �

L-C) levels during the study.

igure 4. Kaplan-Meier estimates of the composite end point of death,onfatal MI, hospitalization for unstable angina, and coronary revascular-zation procedures (PROVE IT end point). Abbreviation as in Figure 3.

.09). There were no reports of myopathy in the atorvasta-

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358 The American Journal of Cardiology (www.ajconline.org)

in-treated patients by report from the investigator directlyesponsible for care of the patient or by report of 2 consec-tive measurements of creatine kinase �10 times the upperimit of normal measured in the central laboratory that weressociated with complaints of muscle symptoms. In theimvastatin group, investigators reported 2 cases of myop-thy, 1 of which was reported to be rhabdomyolysis. How-ver, there were no reports of 2 consecutive measurementsf creatine kinase �10 times the upper limit of normaleasured in the central laboratory that were associated withuscle symptoms. Plasma liver enzyme increases to levels3 times the upper limit of normal on 2 consecutive mea-

urements were seen in only a handful of patients. Suchncreases in aspartate aminotransferase were not seen in theimvastatin group and were found in only 2 patients (0.4%)n the atorvastatin group, whereas increases in alanine ami-otransferase were noted in only 1 simvastatin-treated pa-ient (0.2%) and in 5 atorvastatin-treated patients (1.0%).he rate of significant increase in aspartate aminotransfer-se or alanine aminotransferase in the atorvastatin groupas 1% (2 patients had increased alanine aminotransferase

nd aspartate aminotransferase).

iscussion

The results of this post hoc analysis demonstrate that thefficacy and safety of atorvastatin 80 mg/day compared withmoderate statin dose in decreasing the risk of clinical

vents previously demonstrated in the 2-year PROVE ITrial are sustained in longer-term follow-up. Although thetatistical power of our analysis was smaller than that of theROVE IT study due to a smaller number of events, weound a statistically significant and sustained difference inavor of the high-dose regimen for the primary trial endoint. Kaplan-Meier curves start to separate from the firstonth of treatment and thus are very similar to results of theROVE IT study. In that study the difference for the pri-ary end point was statistically significant already at

-month follow-up, but the number of randomized patientsas 4 times larger than in our subgroup analysis.We observed continuous widening of the gap between

he Kaplan-Meier curves over the entire 4.8 years durationf the study indicating sustained benefit of the higher dose,ut we did not study in a randomized fashion a strategy toecrease the dose in the stable phase. On average patients inhis subgroup analysis were randomized 46 days after their

Figure 5. HR for PROVE

ndex infarction, which is later than the mean duration of 7 f

ays after the acute event in the PROVE IT study, but theajority (63%) had already been receiving a moderate dose

f statin before randomization. It is therefore not possible toetermine the exact optimal timing of introducing a highose of atorvastatin after an acute coronary event based onesults of this trial.

Event rates in the IDEAL patients with recent MI wereigher than in the PROVE IT patients. Compared to eventates at 2 years in PROVE IT (26% in pravastatin 40 mgroup and 22% in atorvastatin 80 mg group), absolute eventates in IDEAL were 10% higher (36% in simvastatin groupnd 32% in atorvastatin group). In IDEAL all patients hadprevious MI and they were also slightly older than in

ROVE IT. Because the IDEAL study was carried out inorthern Europe, only a small proportion (�25%) of pa-

ients in this subgroup analysis had undergone a revascu-arization procedure immediately after their index infarc-ion. This is in contrast to the PROVE IT study, where 69%f patients enrolled had undergone revascularization to treatheir acute coronary syndrome before randomization. An-ther difference between the PROVE IT study and thisubgroup of the IDEAL study is that baseline LDL choles-erol was lower in the PROVE IT study at 106 mg/dl (2.7mol/L), whereas it was 128 mg/dl (3.3 mmol/L) in

DEAL. Nonetheless, results of the 2 trials were remarkablyimilar.

The continued increasing difference between event rates ofhe 2 treatment arms during the entire study duration of ap-roximately 5 years supports a strategy of continuing the in-ensive lipid-lowering therapy beyond the initial unstable pe-iod after the acute event. Mean serum level of LDLholesterol in the atorvastatin group remained within in theange currently recommended by US and European guidelines.

As in the study as a whole, there were more atorvastatin-reated patients in this subgroup analysis who were taken offreatment because of adverse experiences than in the sim-astatin group, although the difference did not reach statis-ical significance in the recent MI subgroup. The differencen withdrawal between the 2 treatment arms was not largerhan for the remaining patients in the study and the propor-ion showing liver enzyme increases to �3 times the upperimit of normal was small (1%). Thus, early introduction of

high dose of atorvastatin after infarction was well toler-ted. The prospective, randomized, open-label, blinded end-oint design of the IDEAL trial might partly be responsible

point at 2 and 5 years.

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359Coronary Artery Disease/Statin Therapy After Myocardial Infarction

he atorvastatin group. At the time of the conduct of thetudy, clinicians and patients were cautious about high-dosetatin use and the threshold for withdrawal or dose de-reases was probably lower than currently when higheroses is more usual practice. The impact of a higher rate ofithdrawal in the atorvastatin arm of the study than in the

imvastatin arm on the main results have been analyzed forhe entire IDEAL study.11 This analysis found that theifference in adherence between treatment groups may haveed to an underestimation of the treatment effect differential.

Our analysis was performed post hoc and as such ithould on its own be considered as hypothesis-generating.he results, however, agree well with data from other trials,hich strengthens the analysis.

cknowledgment: The authors thank Rana Fayyad, PhD,n employee of Pfizer, Inc., New York, New York, for herssistance with statistical analyses, and Grace E. Johnson,harmD, an employee of Scientific Therapeutics Informa-

ion, Inc., Springfield, New Jersey, who received fundingrom Pfizer, Inc., for providing editorial assistance in pre-aring this report. Assistance with formatting for submis-ion was provided by Paul Lane, PhD, at UBC Scientificolutions, Ltd., Horsham, West Sussex, United Kingdom,nd was funded by Pfizer, Inc.

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