Do angiotensin converting enzyme inhibitors improve walking distance
in patients with symptomatic lower limb arterial disease? A systematic
review and meta-analysis of randomised controlled trials
Yousef Shahin*, Fayyaz Mazari, Ian Chetter
Academic Vascular Surgical Unit, University of Hull, Hull, UK
a r t i c l e i n f o
Received 25 October 2010
Received in revised form
7 December 2010
Accepted 15 December 2010
Available online 30 December 2010
Peripheral arterial disease
Renin angiotensin system
Angiotensin converting enzyme inhibitors
Treadmill walking distance
a b s t r a c t
Background: Several studies have reported the clinical effects of long-term treatment with car-
dioprotective medications in patients with lower limb peripheral arterial disease (PAD) in terms of
reducing cardiovascular morbidity and mortality. A number of these studies investigated the clinical
effect of angiotensin converting enzyme inhibitors (ACEIs) on walking distance in this group of patients.
Objective: To review the evidence regarding the effects of ACEIs in patients with symptomatic PAD of the
lower limbs in terms of the effect on maximum and pain-free walking distances and ankle brachial
pressure index (ABPI).
Methods: A systematic literature search of the medical literature from 1966 to 2010 on randomized
placebo-controlled trials which assessed the effect of ACEIs on maximum and/or pain-free walking
distances and/or ABPI in patients with symptomatic lower limbs PAD was performed. Data from included
studies were pooled with use of random-effects model with standard mean differences. Heterogeneity
across studies was assessed with calculation of I2statistic.
Results: From a total of 346 publications identified, 34 articles were selected for full review based on title
and abstract. 4 RCTs comprising 576 patients (334(58%) males, mean age 60.7 years, age range (58e66))
met the inclusion criteria and were systematically reviewed. Of those, 137 (24%) patients suffered from
symptomatic lower limb PAD. Maximum walking distances were pooled successfully from all 4 studies.
After analysing these data, we found significant heterogeneity among the groups and no significant
difference in the pooled treatment effect (standard mean difference ¼ 0.46, 95% CI (?0.99e1.92),
p ¼ 0.53, I2; ¼ 95%). Pain-free walking distances and ankle brachial pressure indices were pooled
successfully from 3 studies and showed an insignificant overall treatment effect (standard mean
difference ¼ 0.97, 95% CI (?0.24e2.18), p ¼ 0.12 and 0.68, 95% CI (?0.70e2.06), p ¼ 0.33, respectively).
Conclusion: The evidence regarding ACE inhibition efficacy on treadmill walking distance in patients with
intermittent claudication is contradicting and lacked properly powered RCTs. However, based on this
study, ACEIs did not improve treadmill walking distance and ABPI in patients with symptomatic lower
limb arterial disease. Further research from properly powered RCTs is needed.
? 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Lower limb peripheral arterial disease (PAD) is a common
of PAD is found in approximately 12% of adults above the age of 50
years.1Of those, almost a third experience pain on walking or inter-
mittent claudication.2PAD is an important marker of cardiovascular
risk and is associated with mortality 3e5 times that of an aged
matched population mainly due to cardiac and cerebrovascular
events. The overall prognosis for the patient with PAD is poor with
a cumulative annual mortality of up to 5%. In claudicants, however,
the prognosis for the limb is more benign with 75% of patients’
symptoms remaining stable/improving with only a small minority
progressing to critical ischaemia. It has been recommended that
patients with PAD should have aggressive secondary prevention and
management of risk factors.3e7
Over the last decade, intensive research has investigated the
potential clinical benefits of angiotensin converting enzyme inhibi-
tors (ACEIs).The reninangiotensinsystem (RAS) playsamajorrole in
cardiovascular disease. ACEIs competitively inhibit the angiotensin
* Corresponding author. Clinical research fellow in vascular surgery, Academic
Vascular Surgery Unit, Vascular Laboratory, Hull Royal Infirmary, Anlaby Road, Hull,
UK. HU3 2JZ. Tel.: þ441482674961; fax: þ441482674765.
E-mail address: email@example.com (Y. Shahin).
Contents lists available at ScienceDirect
International Journal of Surgery
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1743-9191/$ e see front matter ? 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
International Journal of Surgery 9 (2011) 209e213
converting enzyme which is a non specific enzyme involved in the
metabolism of many small peptides. This includes the conversion of
angiotensin I, an inactive octapeptide, into angiotensin II. Inhibition
of the angiotensin converting enzyme will reduce the levels of
angiotensin II and increase the levels of bradykinin; the latter
stimulates the synthesis of nitric oxide (NO) which plays a vital role
in vasodilatation and inhibition of vascular hypertrophy.8ACEIs also
promote an elastogenic profile in the extracellular matrix of the
arterial wall by increasingelastin and decreasing the levels of matrix
metalloproteinases.9These effects of ACEIs improve vascular endo-
thelial function in PAD patients.
Long termACE inhibitionin PADpatients with noevidence of left
ventricular dysfunction or heart failure is supported by level-1
mortality and health economic analyses of cost effectiveness.10e14
However, perhaps due to the relatively high incidence of side
effects and concerns regarding deterioration in renal function in
universally accepted into the arsenal of secondary prevention
measures in PAD patients. It is conceivable that increased ACEIs
prescribing in this patient group may occur if there was clear
evidence of associated improvement in disease specific symptoms.
This study aims to review the evidence supporting ACEIs use in
patients with symptomatic PAD in terms of effect on maximum
walking distance as a primary outcome measure and pain-free
walking distance and/or ABPI as secondary outcome measures.
2.1. Search strategy
A systematic search of literature was performed in the medical databases: MED-
LINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL). In addi-
identify articles missed by the electronic searches. The keywords ‘angiotensin con-
verting enzyme inhibitors,’ OR ‘angiotensin converting enzyme inhibitors,’ OR ‘ACE
inhibitors,’ AND ‘peripheral arterial disease,’ OR ‘peripheral arterial occlusive disease,’
OR ‘intermittent claudication,’ were used along with their synonyms. Limits: English
language, involving humans and randomised controlled trials were applied.
2.2. Inclusion criteria
Studies were eligible to be included in our review if they were: 1. Randomised
controlled trials which compared any kind of ACEIs with placebo or no treatment 2.
Included patients with symptomatic peripheral arterial disease of the lower limbs
(intermittent claudication) as either the study population or a subgroup 3. Used
maximum and/or pain-free walking distances and/or ABPI as outcome measures 4.
1966 until present. A summary of these studies can be found in Table 1. We excluded
studies which compared ACEIs combined with any other drug with placebo.
2.3. Quality and data extraction
Quality was assessed using the Jadad five-point scale for randomised trials.15The
characteristics (total number of patients, number of patients with symptomatic PAD,
age, and sex), ACEI type and dose, duration of treatment, follow up period and
outcome. Two independent reviewers (YS and FM) extracted and checked thestudies
included. Disagreements between the reviewers were resolved by consensus.
Authors of one of the selected studies2have been contacted successfully to
obtain unpublished data in order to complete a meta-analysis. In studies where
mean maximum and/or pain-free walking times were reported,2,17they were con-
verted to distances using the treadmill speeds reported in those studies.
2.4. Statistical analysis
For both treatment groups in the included studies2,16e18standard mean differ-
ences and 95% confidence intervals were calculated based on means and standard
deviations extractedfrom individualstudies. One study16reportedmeanand standard
error. We converted standard error to standard deviation by using a standard for-
tested with use of both the chi square test (significant if p < 0.1) and the I2test (with
substantial heterogeneity defined as values > 50%). As studies showed significant
heterogeneity, a random-effects model was used to calculate the pooled effect sizes.
Review Manager (version 5.0, The Cochrane Collaboration 2008) was used for
3.1. Literature search
The search identified 346 potentially eligible studies of which
312 studies were excluded on title and abstract. Full articles of the
Summary of studies included in the systematic review.
Ref. NoFirst authorYearTypeJadad
Total No. of
16Roberts et al1987RCT4/523Captopril50 mg/day6 months
(1 month treatment)
No effect on pain free and
maximum walking distances
No effect on leg blood flow & adverse
effect on walking time on a treadmill
No effect on pain free and maximum
Improved pain free and maximum
17Spence et al1993RCT4/523Cilazapril2.5 mg/day
18 Overlack et al1994RCT4/5490
(54 with clinical PAD)
Perindopril4 mg/day6 weeks
2 Ahimastos et al2006RCT5/5Ramipril10 mg/day24 weeks
34 studies selected for full text
screening and detailed review
4 full text studies met the inclusion
criteria and were included in the
No comparison of ACE inhibitors with
No maximum or pain-free walking
distances or ABPI as endpoints (2)
Not in English language (2)
No data for PAD patients (2)
No inclusion of PAD patients (2)
Duplicate publication (5)
Not a randomised controlled trial (1)
Treatment period <1 month (1)
346 citations in total identified and
screened (title, abstract, keywords)
Fig. 1. Study flow diagram of systematic review and exclusion criteria.
Y. Shahin et al. / International Journal of Surgery 9 (2011) 209e213
remaining 34 studies were collected and evaluated. 4 studies met
our inclusion criteria and were included in the systematic review.
Study flow diagram and exclusion criteria are presented in Fig. (1).
3.2. Patient’s characteristics
Studies included a total of 576 patients. There were 334 (58%)
males and 242 (42%) females, with a mean age of 60.7 years, age
range (58e66). 137 (24%) patients had symptomatic peripheral
arterial disease of the lower limbs (intermittent claudication).
3.3. Description of included studies
A double blind, placebo- controlled, crossover trial of antihy-
pertensive treatment in 23 patients with hypertension and
peripheral arterial disease, failed to demonstrate any statistically
significant benefit of captopril 25 mg twice daily over placebo in
terms of pain free and maximum walking distances (149 ? 71.5 m
vs.145 ? 89.4 m and 228 ? 143 mvs. 226 ?151.9 m, respectively).16
Captopril preserved lower limb arterial circulation possibly by
maintaining the collateral blood supply which could be attributed
to the lack of angiotensin II vasoconstriction effect caused by ACE
inhibition and reduced breakdown of bradykinin.
Indeed, a placebo controlled, crossover, RCT of ACE inhibition
with cilazapril (2.5 mg/day) for 8 weeks in 23 claudicants demon-
strated a deleterious effect on treadmill walking time.17Mean
maximum treadmill walking time was longer in the placebo group
8.04 ? 6.39 min (431 ? 343 m) than the cilazapril group
6.05 ? 5.01 min (325 ? 269 m), p < 0.009. ABPI was higher, but
statistically insignificant, after treatment in the placebo group than
the cilazapril group (0.69 ? 0.12 vs. 0.66 ? 0.15), p > 0.05.
A multicentre, double blind, RCT of 54 patients with essential
hypertension and claudication (Fontaine IIb) randomised to peri-
ndopril 4 mg o.d (n ¼ 26) or matching placebo (n ¼ 28) for 6 weeks
in pain-free walking distance in favour of the perindopril group
patients in the placebo group walked a significantly longer distance
the authors. There was no difference in the ABPI in both groups after
treatment (0.75 ? 0.05).
Finally, a further double blind trial randomised 40 intermittent
claudicants with superficial femoral artery disease to either ram-
ipril 10 mg once dailyor matched placebo for 24 weeks (20 patients
per group) and found ramipril in comparison to placebo to be
associated with statistically significant improvements in pain- free
walking time, 381 ? 124 s (339 ? 110 m) in the ramipril group vs.
161 ? 29 s (143 ? 26 m) in the placebo group, p < 0.001. This was
also the case for maximum treadmill walking time, 687 ? 181 s
(611 ?161 m) in the ramipril group vs. 234 ? 31.4 s (208 ? 28 m) in
the placebo group, p < 0.001, ankle brachial pressure indices at rest
and post exercise and Walking Impairment Questionnaire scores2
The changes in ABPI with ramipril (0.73 ? 0.09 in the ramipril
group vs. 0.50 ? 0.10 in the placebo group, p < 0.001) were found to
be due to a reduction in brachial systolic blood pressure at rest and
both a reduction in brachial systolic blood pressure and an increase
in ankle pressure post exercise.
Ahimastos et al.2used strict inclusion criteria which limited the
applicability of the results to non diabetic patients with infrain-
guinal arterial disease.
3.4. Outcome measures reporting
All four studiesevaluatedmaximum walkingdistance/
time.2,16e18Three studies evaluated pain free walking distance/
3.5. ACEIs effect on maximum treadmill walking distance
Maximum walking distances/times were pooled successfully
from four studies.2,16e18After analysing these data, we found
significant heterogeneity among the groups and no significant
difference in the pooledtreatment
difference ¼ 0.46, 95% CI (?0.99e1.92), p ¼ 0.53, I2¼ 95%) (Fig. 2).
3.6. ACEIs effect on pain-free treadmill walking distance
Pain free walking distance/time could be pooled from three
Fig. 2. Forest plot illustrating pooled maximum treadmill walking distance. CI: confidence interval, SD: standard deviation, IV: inverse variance.
Fig. 3. Forest plot illustrating pooled pain-free treadmill walking distance. CI: confidence interval, SD: standard deviation, IV: inverse variance.
Y. Shahin et al. / International Journal of Surgery 9 (2011) 209e213
and no significant differences in the pooled treatment effect (stan-
dardmeandifference ¼ 0.97,95%CI(?0.24e2.18),p ¼ 0.12,I2¼ 90%)
3.7. ACEIs effect on ABPI
Ankle Brachial Pressure Indices were also pooled from three
studies2,17,18and analysis of data showed significant heterogeneity
and no significant differences in the pooled treatment effect
(standard mean difference ¼ 0.68, 95% CI (?0.70e2.06), p ¼ 0.33,
I2p2; ¼ 93%) (Fig. 4).
3.8. Side effects and withdrawals due to treatment with ACEIs
In Overlack et al,18out of 253 patients randomised to receive
perindopril, 4(1.5%) patients suffered from cough. 8 (3.2%) patients
in the perindopril group withdrew, of those, 1 patient withdrew
due to cough. Other studies did not report any side effects and/or
withdrawals due to treatment with ACEIs.
the impact of ACE inhibition on treadmill walking distances in
patients with PAD; as 3 out of 4 studies reported negative results;
however, these studies were not properly powered and two of them
were crossovertrials.16,17Crossovertrialsare not likely to be suitable
for evaluating disease progression and severity because treatment
effects are not fully reversible after each treatment. Moreover, the
variation in findings may reflect variability in patient subgroups,
disease distribution, and dose/duration of treatment. Long term
(>24 weeks) treatment of non diabetic patients with isolated
infrainguinal disease would seem to infer maximal benefit.
Further data from properly powered randomised controlled
trials is required to analyse the effectiveness of ACEIs for symptom
relief, generic and disease specific quality of life and perhaps the
vascular endothelium in patients with intermittent claudication.
4.1. Study strengths and limitations
The strengths of this meta-analysis include a comprehensive
literature search which included only randomised controlled trials,
duplicate data extraction and duplicate assessment of quality of
evidence using the Jadad 5-point scale for randomised trials.15
Moreover, authors of unpublished data were contacted to clarify
areas of concern and to provide unreported data which consisted of
unreported means and standard deviations in one study.2We
successfully managed to obtain unreported data from the author,
which made it possible to do a meta-analysis.
However, this meta-analysis had some limitations, including the
high heterogeneity among the included studies and the small
number of studies which have been found in the literature.
Therefore, results from this meta-analysis should be interpreted
Conflict of interest/funding
The authors declare that there are no conflict of interests and no
sources of funding for this work.
YS searched the literature, reviewed the articles, extracted and
analyzed data and prepared the manuscript.
IC reviewed the included studies and revised the final
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Fig. 4. Forest plot illustrating pooled Ankle Brachial Pressure Index. CI: confidence interval, SD: standard deviation, IV: inverse variance.
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