Coronary artery disease

ORIGINAL ARTICLE

High-dose atorvastatin is superior to moderate-dose

simvastatin in preventing peripheral arterial disease
Robert M Stoekenbroek,1 S Matthijs Boekholdt,2 Rana Fayyad,3 Rachel Laskey,3
Matti J Tikkanen,4 Terje R Pedersen,5 G Kees Hovingh,1 On behalf of the Incremental
Decrease in End Points Through Aggressive Lipid Lowering Study Group
1

Department of Vascular
Medicine, Academic Medical
Center, Amsterdam, the
Netherlands
2
Department of Cardiology,
Academic Medical Center,
Amsterdam, The Netherlands
3
Pzer Inc., New York,
New York, USA
4
Division of Cardiology,
Department of Medicine,
Helsinki University Central
Hospital, Helsinki and the
Folkhlsan Research Center,
Helsinki, Finland
5
University of Oslo and Centre
of Preventive Medicine, Oslo
University Hospital, Ullevl,
Oslo, Norway
Correspondence to
Robert M Stoekenbroek,
Department of Vascular
Medicine, Academic Medical
Center, Meibergdreef 9,
PO box 22660, 1100 DD,
Amsterdam 1105 AZ,
the Netherlands;
r.m.stoekenbroek@amc.uva.nl
Received 30 September 2014
Revised 11 November 2014
Accepted 5 December 2014

ABSTRACT
Objectives To study whether high-dose versus usualdose statin treatment reduces the incidence of peripheral
artery disease (PAD) and what is the effect of high-dose
statin treatment on cardiovascular disease (CVD)
outcome in patients with PAD.
Methods and results In the Incremental Decrease in
End Points Through Aggressive Lipid Lowering trial,
8888 post-myocardial infarction patients were
randomised to high-dose or usual-dose statin therapy
(atorvastatin 80 mg/day vs simvastatin 2040 mg/day).
We investigated the effect of high-dose versus usualdose statins on the pre-specied outcome PAD
incidence, and additionally performed a posthoc analysis
of the efcacy of high-dose statins in reducing CVD risk
among patients with PAD. During a median follow-up of
4.8 years, 94 patients (2.2%) receiving atorvastatin and
135 patients (3.2%) receiving simvastatin developed
PAD (HR=0.70, 95% CI 0.53 to 0.91; p=0.007). The
risk of major coronary events was almost twofold higher
in patients with PAD at baseline, but was no longer
signicant after adjusting for the adverse cardiovascular
risk prole. In PAD patients, major coronary events
occurred in fewer patients in the atorvastatin group
(14.4%) than in the simvastatin group (20.1%), but the
difference did not reach statistical signicance.
(HR=0.68, 95% CI 0.41 to 1.11; p=0.13). Atorvastatin
treatment signicantly reduced overall cardiovascular
( p=0.046) and coronary events ( p=0.004), and coronary
revascularisation ( p=0.007) in these patients.
Conclusions High-dose statin therapy with atorvastatin
signicantly reduced the incidence of PAD compared
with usual-dose statin therapy with simvastatin. Patients
with a history of PAD at baseline were at higher risk of
future coronary events and this risk was reduced by
high-dose atorvastatin treatment.
Trial registration number NCT00159835 (URL:
http://clinicaltrials.gov/show/NCT00159835).

INTRODUCTION

To cite: Stoekenbroek RM,

Boekholdt SM, Fayyad R,
et al. Heart Published Online
First: [ please include Day
Month Year] doi:10.1136/
heartjnl-2014-306906

Coronary artery disease (CAD) and peripheral

arterial disease (PAD) share the same underlying
pathophysiology and risk factors, which is exemplied by the fact that PAD is a powerful predictor
for myocardial infarction (MI).1 2
Large prospective epidemiological studies have
consistently shown that plasma levels of low-density
lipoprotein cholesterol (LDL-C) are associated with
clinical manifestations of atherosclerosis.3 4 Statins
are effective in reducing the risk of CAD, and as a

consequence, are recommended as the rst-choice

lipid-lowering therapy for secondary prevention in
current clinical guidelines.58 Until recently, cardiology and surgery guidelines recommended that the
intensity of lipid-lowering therapy should be titrated
based on a target plasma LDL-C level.6 8 The
recently updated American College of Cardiology/
American Heart Association (ACC/AHA) guideline,
recognising the fact that high-intensity lipid-lowering
therapy provides greater risk reduction than usualdose therapy, now recommends that patients with
clinical atherosclerotic cardiovascular disease (CVD),
including patients with PAD, should be initially
treated with high-intensity lipid-lowering therapy
without the need to monitor LDL-C levels.7 It is,
however, largely unknown whether patients with
PAD do benet in terms of cardiovascular (CV) mortality and morbidity from high-intensity statin treatment compared with usual-dose statin therapy.
Moreover, the efcacy of high-dose statins in reducing the incidence of PAD in patients with CAD
remains to be established.
The Incremental Decrease in End Points
Through Aggressive Lipid Lowering (IDEAL) trial
primarily tested the hypothesis that intensive lowering of LDL-C levels with high-dose atorvastatin
80 mg would prevent recurrent coronary events
more efciently than usual-dose simvastatin
2040 mg among patients with a history of MI.9 In
the current report of the IDEAL trial, we present
(1) the effect of high-dose versus usual-dose statin
therapy on the pre-specied outcome PAD incidence and (2) the results of an exploratory, posthoc
analysis on the impact of baseline PAD on clinical
outcomes and benets of high-dose versus usualdose statin therapy.

METHODS
The design of the IDEAL trial has been previously
described.10 Briey, the IDEAL trial was a prospective, randomised, open-label, blinded outcome assessment trial comparing atorvastatin 80 mg/day
(n=4439) with simvastatin 2040 mg/day (n=4449)
among men and women 80 years of age and with
a history of a conrmed MI with a follow-up of
5 years. The IDEAL trial was conducted in 190
centres in Norway, Sweden, Finland, Denmark,
Iceland and the Netherlands. Patients had to qualify
for statin therapy according to national guidelines at
the time of recruitment. Patients treated with statins
prior to enrolment were eligible if they were using a

Coronary artery disease

dose no higher than an equivalent of simvastatin 20 mg/day.
Patients were considered to have PAD or other morbidities at
baseline if a clinical diagnosis had been documented in the
patient records. Written informed consent was obtained before
study procedures, and the study was approved by appropriate
ethical review boards in all countries and was conducted in compliance with the declaration of Helsinki. After dietary counselling, eligible patients were randomised to receive either
atorvastatin 80 mg/day or simvastatin 20 mg/day. No drug-free
period was required and previous statin therapy was discontinued
without a run-in or wash-out period. Study medication was provided by prescription, except in Finland, where it was dispensed
at the expense of the sponsor. Patients were followed up at the
recruiting centres after 12 and 24 weeks and every 6 months
thereafter. The dose of simvastatin could be increased to 40 mg/
day in case plasma total cholesterol level was >190 mg/dL
(5.0 mmol/L) at 24 weeks. Conversely, the dose of atorvastatin
could be decreased to 40 mg/day in case of adverse events. All
lipid and lipoprotein levels were measured at a central laboratory
from blood samples after fasting.

Denition of end points

For patients without PAD at baseline, the prespecied outcome
incident PAD was dened as a new clinical diagnosis necessitating diagnostic procedures and/or interventions, as assessed by
the investigator and a blinded end point committee. For patients
with PAD at baseline, incident PAD was dened as recurrent
PAD necessitating hospitalisation. In the exploratory posthoc
analysis of the impact of baseline PAD on clinical outcomes and
benets of high-dose versus usual-dose statins, the primary
outcome measure was the rate of major coronary events
(dened as coronary death, hospitalisation for non-fatal MI or
cardiac arrest with resuscitation). The prespecied secondary
composite end points were (1) major CV events (coronary
death, hospitalisation for non-fatal MI, cardiac arrest with resuscitation or stroke), (2) any coronary heart event (coronary
death, hospitalisation for non-fatal MI, cardiac arrest with resuscitation, coronary revascularisation procedure or unstable
angina requiring hospitalisation) and (3) any CV event (any of
the former, plus hospitalisation for congestive heart failure, and
new clinical diagnosis of PAD (for patients without PAD at baseline) or hospitalisation for PAD (for patients with PAD at baseline)). In addition, all-cause mortality and the individual
components of the composite end points were prespecied as
secondary outcomes.

Statistical analysis
Baseline characteristics were compared by two-sample t tests for
continuous variables and by Fishers exact test for categorical
variables. The effect of treatment on the risk of incident PAD
was quantied using a univariate Cox proportional hazards
model. The independent effect of PAD at baseline on the risk of
subsequent CV outcomes was determined using a multivariate
Cox proportional hazard model, while adjusting for the baseline
characteristics that were signicantly different in patients with
and without PAD. In addition, the interaction of treatment arm
by history of PAD was computed from the univariate Cox
model to evaluate the consistency of treatment effect for the
subgroups with and without a history of PAD. Treatment efcacy in terms of LDL-C reductions were analysed using an analysis of covariance model with treatment and baseline LDL-C in
the model. For interaction testing, treatment, baseline LDL-C
and the interaction term were included in the model. Risk estimates are reported as HRs and corresponding 95% CIs. A p
2

value <0.05 was considered statistically signicant, except for

interaction tests, where a signicance level of 0.1 was used. The
p values for the posthoc analysis are provided as descriptive
p values. Analyses were performed using SAS software.

RESULTS
Baseline characteristics
Most baseline characteristics were similar in atorvastatin-treated
and simvastatin-treated patients with (n=374) and without
(n=8514) PAD at baseline (table 1). All patients were
Caucasian, 81% were men and the average age was 62 years.
One-third had a history of hypertension and 12% had a history
of diabetes. Mean age and systolic blood pressure were signicantly higher in patients with PAD at baseline compared with
those without PAD, and these patients more often had a history
of smoking or diabetes. In patients with PAD at baseline, the
proportion of current smokers was somewhat higher among
those treated with atorvastatin.

Effect of treatment on the risk of PAD

During the study, incident PAD occurred in 94 patients (2.2%)
receiving atorvastatin and 135 patients (3.2%) receiving simvastatin (HR=0.70 95% CI 0.53 to 0.91; p=0.007) (gure 1).

Effect of history of PAD at baseline on risk of cardiovascular

end points
At baseline, 374 (4.2%) patients had a history of PAD. The risk
of major coronary events was almost twofold higher in patients
with PAD at baseline compared with patients without PAD at
baseline (table 2). However, after adjusting for baseline characteristics that were signicantly associated with a history of PAD
(table 1), such as higher age and systolic blood pressure and
history of diabetes, the association between baseline PAD and risk
of CV outcomes was no longer statistically signicant.

History of PAD at baseline and treatment efcacy

Of the total of 374 patients with PAD at baseline, 180 patients
(4.1%) were randomised to atorvastatin and 194 patients
(4.4%) to simvastatin treatment. The rate of major coronary
events during the study was non-signicantly lower in the atorvastatin group (14.4%) compared with the simvastatin group
(20.1%) (HR=0.68, 95% CI 0.41 to 1.11; p=0.13). A signicant treatment effect for atorvastatin was seen for reduction of
overall CV ( p=0.046) and coronary events ( p=0.004) and coronary revascularisation (p=0.007) in these patients (gure 2).
Patients with PAD receiving atorvastatin achieved signicantly
larger LDL-C reductions than those receiving simvastatin (mean
LDL-C change from baseline 39.3 mg/dL (95% CI 43.7 to
34.9) and 22.3 mg/dL (95% CI 26.6 to 18.1), respectively; p<0.001).
Among participants without a history of PAD, treatment with
atorvastatin resulted in a non-signicant reduction in major coronary events (HR=0.91, 95% CI 0.79 to 1.04; p=0.16), and signicantly reduced the risk of major CV events (HR=0.88, 95% CI
0.78 to 1.00; p=0.046), any coronary event (HR=0.86, 95% CI
0.78 to 0.94; p=0.001), any CV event (HR=0.85, 95% CI 0.78
to 0.92; p<0.001), non-fatal MI (HR=0.84, 95% CI 0.71 to
1.00; p=0.046), coronary revascularisation (HR=0.79, 95% CI
0.70 to 0.88; p<0.001) and PAD (HR=0.70, 95% CI 0.53 to
0.91; p=0.007), compared with simvastatin treatment. Also in
patients without PAD at baseline, atorvastatin treatment was associated with an incremental reduction in LDL-C, compared with
simvastatin (mean LDL-C reduction 38.3 mg/dL (95% CI 39.2
Stoekenbroek RM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2014-306906

Coronary artery disease

Table 1 Patient characteristics
PAD at baseline

Age, mean (SD), y

Female sex
Blood pressures (mm Hg)
Systolic
Diastolic
Body mass index (kg/m2)
Cardiovascular history
History of cerebrovascular disease
History of peripheral arterial disease
History of congestive heart failure
Risk factors
Current smoking
History of smoking
Systemic hypertension
History of diabetes
Pretrial statin use
Lipids (mg/dL)
Total cholesterol
LDL-C
HDL-C
Triglycerides
Apolipoprotein A1 (g/L)
Apolipoprotein B (g/L)
Concomitant therapy
Aspirin
-Blockers
Calcium antagonists
ACE inhibitors/ARBs

No PAD at baseline

Simvastatin
(N=194)

Atorvastatin
(N=180)

65.8 (8.5)
43 (22.2)

64.8 (8.4)
38 (21.1)

142.0 (20.3)
79.9 (9.6)
26.9 (3.5)

141.6 (21.7)
79.3 (10.6)
26.8 (3.9)

Simvastatin
(N=4255)

Atorvastatin
(N=4259)

0.24
0.80

61.4 (9.4)
809 (19.0)

0.85
0.55
0.70

p Value

p Value

p Value (PAD at baselineno

PAD at baseline)

61.7 (9.5)
811 (19.0)

0.16
0.97

<0.001
0.21

136.8 (19.8)
80.7 (10.2)
27.3 (3.8)

136.5 (20.1)
80.2 (10.2)
27.3 (3.9)

0.54
0.031
0.64

<0.001
0.14
0.02

307 (7.2)
0 (0)
232 (5.5)

290 (6.8)
0 (0)
275 (6.5)

0.46

<0.001

0.050

0.22

31 (16.0)
194 (100.0)
11 (5.7)

27 (15.0)
180 (100.0)
17 (9.4)

0.79

41 (21.1)
170 (87.6)
73 (37.6)
35 (18.0)
152 (78.4)

62
160
74
34
139

(34.4)
(88.9)
(41.1)
(18.9)
(77.2)

0.01
0.71
0.49
0.83
0.79

902
3391
1394
502
3298

(21.2)
(79.7)
(32.8)
(11.8)
(77.5)

830 (19.5)
3309 (77.7)
1383 (32.5)
498 (11.7)
3240 (76.1)

0.05
0.011
0.78
0.88
0.12

0.001
<0.001
0.007
<0.001
0.65

200.0 (45.5)
126.3 (39.6)
44.2 (12.5)
152.9 (73.7)
1.4 (0.24)
1.2 (0.37)

201.7
125.6
45.6
154.7
1.4
1.2

(44.6)
(39.1)
(10.4)
(75.5)
(0.21)
(0.38)

0.73
0.88
0.24
0.82
0.05
1.00

195.7 (38.7)
121.1 (34.6)
46.2 (12.2)
146.3 (75.1)
1.4 (0.23)
1.2 (0.32)

196.6 (39.2)
121.4 (34.3)
46.0 (11.9)
151.0 (81.8)
1.4 (0.22)
1.2 (0.32)

0.32
0.77
0.38
0.006
0.82
0.64

0.025
0.012
0.054
0.22
0.32
0.005

137 (70.6)
141 (72.7)
49 (25.3)
84 (43.3)

132
132
54
71

(73.3)
(73.3)
(30.0)
(39.4)

0.56
0.89
0.31
0.45

3409
3140
791
1540

3371 (79.2)
3245 (76.2)
828 (19.4)
1476 (34.7)

0.27
0.01
0.32
0.14

<0.001
0.38
<0.001
0.017

0.17

(80.1)
(73.8)
(18.6)
(36.2)

ARB, angiotensin receptor blocker; MI, myocardial infarction; PAD, peripheral arterial disease; y, years.

to 37.5) and 19.7 (95% CI 20.5 to 18.8), respectively;

p<0.001).
Atorvastatin signicantly reduced the incidence of any coronary heart event and coronary revascularisation in both patients
with and without PAD at baseline. Compared with patients

without PAD at baseline, the incremental benet of atorvastatin

appeared to be larger for patients with previous PAD. However,
the only outcomes for which the interaction terms reached the
prespecied level of signicance were any coronary heart event
and coronary revascularisation ( p for interaction=0.042 and
0.090, respectively) (table 3). The incremental LDL-C reduction
observed among patients treated with atorvastatin compared
with simvastatin did not signicantly differ between patients
with or without PAD at baseline ( p for interaction=0.209).

DISCUSSION

Figure 1 Effect of treatment on risk of PAD. HRs and 95% CI of HRs

are calculated by Cox proportional hazard analysis including treatment
as the major predictor. *Incident PAD in patients without PAD at
baseline is dened as a new clinical diagnosis necessitating diagnostic
procedures and/or interventions. Incident PAD in patients with PAD at
baseline is dened as recurrent PAD necessitating hospitalisation. PAD,
peripheral arterial disease.
Stoekenbroek RM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2014-306906

In this report of the IDEAL trial, we show that treatment with

high-dose atorvastatin signicantly reduced the incidence of
PAD compared with usual-dose simvastatin. Furthermore, atorvastatin resulted in a signicant reduction in the risk of any coronary or CV event and coronary revascularisation compared
with simvastatin in patients with PAD. This observation is particularly important in light of the observed higher risk of subsequent CV events in patients with PAD as compared with those
without previous PAD, which could be attributed to an adverse
CV risk prole (eg, higher age, systolic blood pressure and
history of diabetes).
The benet of statin therapy in patients with a high risk for
CVD, including patients with PAD, is well established.
However, to the best of our knowledge, this is the rst analysis
to assess the incremental benet of high-dose atorvastatin compared with usual-dose simvastatin in patients with PAD.
3

Coronary artery disease

Table 2

Effect of history of PAD at baseline on risk of cardiovascular end points

Event rate, n/N (%)

End Point

With history of
PAD at baseline
(N=374)

Without history of
PAD at baseline
(N=8514)

Primary end point: Major coronary events

65 (17.4)

809 (9.5)

Major cardiovascular events

88 (23.5)

1053 (12.4)

Any coronary heart disease

118 (31.6)

1839 (21.6)

Any cardiovascular disease

181 (48.4)

2365 (27.8)

Non-fatal MI

40 (10.7)

548 (6.4)

Stroke

26 (7.0)

299 (3.5)

Revascularisation

68 (18.2)

1254 (14.7)

All-cause mortality

55 (14.7)

685 (8.0)

Cardiovascular mortality

37 (9.9)

404 (4.7)

Non-cardiovascular mortality

18 (4.8)

281 (3.3)

Coronary death

28 (7.5)

325 (3.8)

Congestive heart failure

16 (4.3)

206 (2.4)

Cerebrovascular events

29 (7.8)

397 (4.7)

Hospitalisation for angina

32 (8.6)

354 (4.2)

Transient ischaemic attack

5 (1.3)

126 (1.5)

Unadjusted and adjusted* HRs

(95% CI), p values
1.92
1.03
2.03
1.00
1.56
1.08
2.05
1.02
1.74
1.07
2.09
1.04
1.28
1.11
1.91
1.04
2.17
1.04
1.53
1.07
2.04
1.05
1.85
1.07
1.75
1.03
2.16
1.09
0.94
1.06

(1.49 to
(0.92 to
(1.63 to
(0.89 to
(1.29 to
(0.95 to
(1.76 to
(0.88 to
(1.26 to
(0.95 to
(1.40 to
(0.93 to
(1.01 to
(0.99 to
(1.45 to
(0.92 to
(1.55 to
(0.93 to
(0.95 to
(0.96 to
(1.39 to
(0.94 to
(1.11 to
(0.96 to
(1.20 to
(0.92 to
(1.50 to
(0.98 to
(0.39 to
(0.95 to

2.47),
1.16),
2.52),
1.13),
1.88),
1.23),
2.38),
1.18),
2.40),
1.19),
3.12),
1.16),
1.64),
1.25),
2.51),
1.16),
3.04),
1.16),
2.46),
1.19),
3.00),
1.17),
3.07),
1.19),
2.55),
1.15),
3.10),
1.22),
2.30),
1.18),

<0.001
0.582
<0.001
1.000
<0.001
0.246
<0.001
0.793
0.001
0.274
<0.001
0.485
0.044
0.071
<0.001
0.544
<0.001
0.481
0.083
0.227
<0.001
0.361
0.018
0.251
0.003
0.578
<0.001
0.113
0.894
0.282

*Adjusted for baseline characteristics that were significantly different in patients with and without PAD (table 1).
MI, myocardial infarction; PAD, peripheral arterial disease.

Prevention of PAD in high-risk patients

In previous placebo-controlled trials, such as the Heart
Protection Study (HPS) and the Scandinavian Simvastatin
Survival Study (4S), it was shown that moderate-dose simvastatin was effective in the prevention of symptomatic PAD in
patients with CAD and patients at risk for CVD.11 12 Our
results extend this nding and show superior efcacy of more
aggressive LDL-C lowering by means of high-dose atorvastatin
compared with usual-dose simvastatin. Specically, 4S showed a
38% decline in the relative risk of new or worsening intermittent claudication in patients with coronary heart disease at a
follow-up of 5 years.12 Our results indicate an additional 30%
relative risk reduction of PAD in atorvastatin-treated patients
with a history of MI. HPS showed a 16% decline in the relative
risk of a rst peripheral arterial event, dened as any noncoronary revascularisation, aneurysm repair, major amputation
or PAD death.11 It should be noted that the study population
enrolled in the HPS was different from the patients enrolled in
the IDEAL: HPS also included patients at risk for, but without
prior CVD.
Results from the Treating to New Targets (TNT) trial did not
indicate that intensive lipid control using atorvastatin 80 mg
resulted in a signicant reduction of PAD incidence compared
with atorvastatin 10 mg in patients with established CAD.
LDL-C differences between both treatment arms were larger in
TNT than in the IDEAL trial. Therefore, the discrepancy
4

cannot be explained by differences in achieved lipid control.

Several other factors should be considered when interpreting
the different results. First, in IDEAL, patients were randomised
to atorvastatin or simvastatin, whereas all patients in TNT
received atorvastatin in different dosages. Hence, it could be
speculated that the decrease in PAD incidence observed in the
current study is at least partially attributable to a benecial
effect of atorvastatin as opposed to simvastatin, irrespective of
the achieved level of LDL-C. In addition, differences in baseline
characteristics may have contributed to the discrepant ndings.
For example, only 58% of participants of TNT had a previous
MI, whereas all patients in IDEAL had a previous MI.
Moreover, participants of the TNT trial had a mean baseline
LDL-C of 98 mg/dL, compared with 121 mg/dL in IDEAL.
Although we were able to show an incremental effect of highdose atorvastatin over usual-dose simvastatin with regard to the
incidence of PAD, we did not investigate the clinical relevance
of this nding in terms of severity of symptoms. It has been
shown in several randomised and non-randomised studies that
the maximum and pain-free walking distance are increased in
statin-treated
patients
compared
with
placebo-treated
patients.1315

Prevention of additional CVD in patients with PAD

PAD is a clinical manifestation of systemic atherosclerosis and a
well-known predictor of CV morbidity and mortality.1 In the
Stoekenbroek RM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2014-306906

Coronary artery disease

Figure 2 Effect of treatment on risk
of cardiovascular end points in
subjects with a history of PAD at
baseline. CHF, congestive heart failure;
CV, cardiovascular; MI, myocardial
infarction; PAD, peripheral arterial
disease; TIA, transient ischaemic
attack. Major coronary event (MCE) is
dened as coronary death,
hospitalisation for non-fatal MI or
cardiac arrest with resuscitation. Major
cardiovascular event refers to MCE plus
stroke. Any coronary event indicates
MCE, coronary revascularisation or
unstable angina requiring
hospitalisation. Any cardiovascular
event refers to any of the former, plus
hospitalisation for congestive heart
failure and new clinical diagnosis of
PAD or hospitalisation for PAD. HRs,
95% CI of HRs p values are calculated
by Cox proportional hazard analysis
including treatment as the major factor
in the model.
IDEAL trial population of patients with previous MI, a recurrent major coronary event occurred in 9.5% of patients without
PAD at baseline, whereas 17.4% of patients with PAD at baseline suffered from a major coronary event during the study,
clearly demonstrating that patients with CVD and PAD are at
sharply increased risk of a second coronary event. The increased
CV risk in these patients could be explained by the higher
prevalence of CV risk factors, such as a history of diabetes and
smoking. Although this observation underlines the importance
of intensive secondary preventive therapy in patients with PAD,
a recent cohort study demonstrated that patients with PAD

often receive less aggressive statin therapy compared with

patients with CAD, which was associated with suboptimal lipid
control.16
In HPS, the prevalence of major vascular events and revascularisations was reduced by 22% in patients with PAD who were
randomised to simvastatin, compared with placebo.11 The
results of our study indicate that high-dose atorvastatin, in addition to reducing the occurrence of PAD in high-risk patients,
may provide patients with PAD with incremental benet in the
prevention of other CVD events. In addition to the observed
signicant decline in any coronary or CV event or coronary

Table 3 Effect of treatment on risk of cardiovascular end points in subjects with and without a history of PAD at baseline
Event rate, n/N (%)
With PAD at baseline

Without PAD at baseline

End point

Simvastatin
(N=194)

Atorvastatin
(N=180)

Simvastatin
(N=4255)

Atorvastatin
(N=4259)

p Value*

Primary endpoint: Major coronary events

Major cardiovascular events
Any coronary heart disease
Any cardiovascular disease
Non-fatal MI
Stroke
Revascularisation
PAD
All-cause mortality
Cardiovascular mortality
Non-cardiovascular mortality
Coronary death
Congestive heart failure
Cerebrovascular events
Hospitalisation for angina
Transient ischaemic attack

39 (20.1)
51 (26.3)
74 (38.1)
104 (53.6)
24 (12.4)
14 (7.2)
45 (23.2)
32 (16.5)
32 (16.5)
23 (11.9)
9 (4.6)
17 (8.8)
10 (5.2)
16 (8.2)
19 (9.8)
2 (1.0)

26 (14.4)
37 (20.6)
44 (24.4)
77 (42.8)
16 (8.9)
12 (6.7)
23 (12.8)
33 (18.3)
23 (12.8)
14 (7.8)
9 (5.0)
11 (6.1)
6 (3.3)
13 (7.2)
13 (7.2)
3 (1.7)

424
557
985
1266
297
160
698
135
342
195
147
161
113
207
189
62

385 (9.0)
496 (11.6)
854 (20.1)
1099 (25.8)
251 (5.9)
139 (3.3)
556 (13.1)
94 (2.2)
343 (8.1)
209 (4.9)
134 (3.1)
164 (3.9)
93 (2.2)
190 (4.5)
165 (3.9)
64 (1.5)

0.2669
0.4140
0.0421
0.3360
0.5142
0.9230
0.0901
N/A
0.3045
0.1403
0.7853
0.3110
0.6187
0.8556
0.6071
0.6412

(10.0)
(13.1)
(23.1)
(29.8)
(7.0)
(3.8)
(16.4)
(3.2)
(8.0)
(4.6)
(3.5)
(3.8)
(2.7)
(4.9)
(4.4)
(1.5)

The p values are based on the Walds test from the treatment-by-history of PAD at baseline interaction term including a Cox model with treatment and history of PAD at baseline as the
two major factors.
*The p values represent the interaction term of treatment efficacy and a history of PAD at baseline.
A significant interaction of treatment effect by history of PAD was observed for any coronary events and coronary revascularisation, but not for the other outcomes.
Recurrent PAD (ie, among patients with PAD at baseline) is defined as hospitalisation for PAD.
MI, myocardial infarction; PAD, peripheral arterial disease.

Stoekenbroek RM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2014-306906

Coronary artery disease

revascularisation, we observed a non-signicant reduction in
major coronary events in patients with PAD (26/180 in the atorvastatin group and 39/194 in the simvastatin group).

Strengths and limitations

To our knowledge, this is the rst report of the effect of highintensity and moderate-intensity statin treatment on the incidence of PAD in high-risk patients. In addition, the incremental
benet of high-intensity lipid lowering on CVD outcomes has
not been previously investigated in patients with PAD. The
major limitation of our study is that the results of tests to quantify the extent of PAD were not registered according to a prespecied protocol, despite the fact that incident PAD was a
predened outcome measure of the IDEAL trial. However, a
blinded end point committee conrmed the appropriateness of
the designation of all end points, including PAD, based on
detailed narratives and hospital records. Moreover, obtaining
objective test results, such as an anklebrachial index, is
common practice in all participating countries and embedded in
local treatment guidelines. Also, the risk of selective reporting
by investigators was minimised by regular reviews of the patient
records by study monitors. Although the risk of inadequate and
heterogeneous adjudication of incident PAD is therefore at least
partially addressed by the design of the trial, this does not
necessarily hold for the posthoc analysis presented in this
report. In addition, considering the limited sample size and
exploratory nature of the posthoc analysis, no correction for
multiplicity was performed and further studies are needed to
conrm the results.

Mechanisms of action
Statins are known to reduce CV morbidity and mortality by
their capacity to lower circulating levels of LDL-C. The
lipid-lowering effects of statins may account for a large proportion of the effects of statins on the prevention of PAD. This has
been demonstrated in the Program on the Surgical Control of
the Hyperlipidemias trial, where 838 patients with previous MI
were randomised to either ileal bypass or no intervention.17
During over 10 years of follow up, patients treated with ileal
bypass were less likely to develop PAD (RR 0.653, 95% CI
0.469 to 0.908; p=0.011), an effect that should be considered
to be mainly driven by the LDL-C-lowering effect.
In addition to their effects on circulating lipid levels, recent
studies have indicated that part of the benecial effects of statins
in the prevention of CVD may be explained by benecial effects
on endothelial function, inammation and coagulation.18

Future perspectives
Based on the results derived from large intervention studies
such as 4S and HPS, international guidelines recommend
lipid-lowering therapy in patients with PAD.68 19 In most
guidelines, the LDL-C goal is below 100 or 70 mg/dL, depending on the CV risk. Simvastatin is commonly prescribed as a
rst choice of therapy. Patients treated with atorvastatin reached
an LDL-C level of 70 mg/dL in 50% of cases, whereas only
10%15% of patients treated with simvastatin 20 or 40 mg/day
attained this target, while there was no difference in serious
adverse events. Thus, in patients with previous MI, mean
LDL-C levels were closer to treatment goals when treated with
atorvastatin compared with simvastatin. The lower the better
was found to hold true: incremental benet in terms of CVD
event prevention was seen in patients achieving an LDL-C level
of 70 mg/dL compared with those with an LDL-C level of
100 mg/dL.20
6

In patients with PAD, atorvastatin treatment resulted in an

incremental benet in terms of CVD event reduction compared
with simvastatin. These ndings, combined with our observation
of a superior effectiveness of atorvastatin compared with simvastatin with regard to the prevention of PAD in patients with previous MI, support the recommendation of the recent ACC/AHA
guideline of initial aggressive lipid lowering in patients with
PAD or previous MI.

Key messages
What is already known on this subject?
Several studies have demonstrated incremental benet of
high-dose versus usual-dose statin therapy in the secondary
prevention of cardiovascular disease (CVD). However, the
efcacy of this approach in reducing the incidence of peripheral
arterial disease (PAD), as well as the effects on CVD risk among
patients with established PAD, is currently unknown.
What might this study add?
Our study is the rst to demonstrate the efcacy of high-dose
versus usual-dose statins in reducing the incidence of PAD in
patients with previous myocardial infarction. In addition, our
ndings indicate that high-intensity statin treatment provides
patients with PAD with incremental benet in terms of the
prevention of future coronary and cardiovascular events.
How might this impact on clinical practice?
These ndings provide support for the recommendation in the
recently updated ACC/AHA guideline that high-risk patients,
including patients with PAD, should be initially treated with
high-intensity statin therapy.

Contributors RMS, SMB and GKH analysed and interpreted the research data and
drafted the manuscript. RF analysed the data and critical revision of the manuscript.
RL, MJT and TRP worked for the conception, design, interpretation and critical
revision of the manuscript. All authors have approved the nal version of the
manuscript and agree to be accountable for all aspects of the work.
Funding The IDEAL trial was sponsored by Pzer.
Competing interests RL and RF are employees of Pzer. MT received speaking
and consultancy fees from Pzer, Amgen and Aegerion, is a recipient of grants from
Amgen and Pzer, declares stock ownership in the Orion Company and is the
chairman of the committee creating and updating the Finnish National Guidelines
for Dyslipidemia. TRP received research grants, advisory board and speaker honoraria
from Pzer, MSD and Amgen, and speaker honoraria from AstraZeneca and Roche.
GKH received lecture fees from Pzer, Sano, Amgen, Roche and Genzyme, and is a
recipient of a Veni grant ( project number 91612122) from the Netherlands
Organisation for Scientic Research.
Ethics approval Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES
1

2
3

Ankle Brachial Index Collaboration. Anklebrachial index combined with

Framingham risk score to predict cardiovascular events and mortality:
a meta-analysis. JAMA 2008;300:197208.
Hussein AA, Uno K, Wolski K, et al. Peripheral arterial disease and progression
of coronary atherosclerosis. J Am Coll Cardiol 2011;57:12205.
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age,
sex, and blood pressure: a meta-analysis of individual data from 61 prospective
studies with 55,000 vascular deaths. Lancet 2007;370:182939.
Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of
vascular disease. JAMA 2009;302:19932000.

Stoekenbroek RM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2014-306906

Coronary artery disease

5

10

11

12

Cholesterol Treatment Trialists (CTT) Collaboration. Efcacy and safety of more

intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000
participants in 26 randomised trials. Lancet 2010;376:167081.
Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular
disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of
the European Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice (constituted by representatives of nine societies and
by invited experts). Eur Heart J 2012;33:1635701.
Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the
treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults:
a report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889934.
Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the
Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg
2007;33(Suppl 1):S175.
Pedersen TR, Faergeman O, Kastelein JJ, et al.; Incremental Decrease in End Points
Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs
usual-dose simvastatin for secondary prevention after myocardial infarction: the
IDEAL study: a randomized controlled trial. JAMA 2005;294:243745.
Pedersen TR, Faergeman O, Kastelein JJ, et al.; Incremental Decrease in End Points
Through Aggressive Lipid Lowering Study Group. Design and baseline characteristics
of the Incremental Decrease in End Points through Aggressive Lipid Lowering study.
Am J Cardiol 2004;94:7204.
Heart Protection Study Collaborative Group. Randomized trial of the effects of
cholesterol-lowering with simvastatin on peripheral vascular and other major
vascular outcomes in 20,536 people with peripheral arterial disease and other
high-risk conditions. J Vasc Surg 2007;45:64554.
Pedersen TR, Kjekshus J, Pyrl K, et al. Effect of simvastatin on ischemic signs
and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol
1998;81:3335.

Stoekenbroek RM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2014-306906

13

14

15

16

17

18

19

20

Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance

and symptoms of intermittent claudication in hypercholesterolemic patients with
peripheral vascular disease. Am J Med 2003;114:35964.
Aronow WS, Nayak D, Woodworth S, et al. Effect of simvastatin versus placebo on
treadmill exercise time until the onset of intermittent claudication in older patients
with peripheral arterial disease at six months and at one year after treatment. Am J
Cardiol 2003;92:71112.
McDermott MM, Guralnik JM, Greenland P, et al. Statin use and leg functioning in
patients with and without lower-extremity peripheral arterial disease. Circulation
2003;107:75761.
Sharma S, Thapa R, Jeevanantham V, et al. Comparison of lipid management in
patients with coronary versus peripheral arterial disease. Am J Cardiol
2014;113:13205.
Buchwald H, Campos CT, Boen JR, et al. Disease-free intervals after partial ileal
bypass in patients with coronary heart disease and hypercholesterolemia: report
from the Program on the Surgical Control of the Hyperlipidemias (POSCH). J Am
Coll Cardiol 1995;26:3517.
Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function,
vascular inammation, immunomodulation and thrombogenesis. Atherosclerosis
2009;203:32530.
Tendera M, Aboyans V, Bartelink ML, et al.; ESC Committee for Practice Guidelines.
ESC Guidelines on the diagnosis and treatment of peripheral artery diseases:
document covering atherosclerotic disease of extracranial carotid and vertebral,
mesenteric, renal, upper and lower extremity arteries: the Task Force on the
Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of
Cardiology (ESC). Eur Heart J 2011;32:2851906.
Olsson AG, Lindahl C, Holme I, et al.; Incremental Decrease in End Points Through
Aggressive Lipid Lowering Study Group. LDL cholesterol goals and cardiovascular
risk during statin treatment: the IDEAL study. Eur J Cardiovasc Prev Rehabil
2011;18:2629.

High-dose atorvastatin is superior to

moderate-dose simvastatin in preventing
peripheral arterial disease
Robert M Stoekenbroek, S Matthijs Boekholdt, Rana Fayyad, Rachel
Laskey, Matti J Tikkanen, Terje R Pedersen and G Kees Hovingh
Heart published online January 16, 2015

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