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Atherosclerosis 181 (2005) 17

Review

Complementary therapies for peripheral arterial disease:


Systematic review
Max H. Pittler , Edzard Ernst
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, UK
Received 8 July 2004; received in revised form 10 January 2005; accepted 15 February 2005
Available online 31 March 2005

Abstract
While peripheral arterial disease (PAD) affects a considerable proportion of patients in the primary care setting, there is a high level of use of
complementary treatment options. The aim was to assess the effectiveness of any type of complementary therapy for peripheral arterial disease.
A systematic review was performed. Literature searches were conducted on Medline, Embase, Amed, and the Cochrane Library until December
2004. Hand-searches of medical journals and bibliographies were conducted. There were no restrictions regarding the language of publication.
The screening of studies, selection, data extraction, the assessment of methodologic quality and validation were performed independently by
the two reviewers. Data from randomized controlled trials, and systematic reviews and meta-analyses, which based their findings on the results
of randomized controlled trials were included. Seven systematic reviews and meta-analyses and three additional randomized controlled trials
met the inclusion criteria and were reviewed. The evidence relates to acupuncture, biofeedback, chelation therapy, CO2 -applications and the
dietary supplements Allium sativum (garlic), Ginkgo biloba (ginkgo), omega-3 fatty acids, padma 28 and Vitamin E. Most studies included
only patients with peripheral arterial disease in Fontaine stage II (intermittent claudication). The reviewed RCTs, systematic reviews and
meta-analyses which based their findings on the results of RCTs suggest that G. biloba is effective compared with placebo for patients with
intermittent claudication. Evidence also suggests that padma 28 is effective for intermittent claudication, although more data are required to
confirm these findings. For all other complementary treatment options there is no evidence beyond reasonable doubt to suggest effectiveness
for patients with peripheral arterial disease.
2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Peripheral arterial disease; Intermittent claudication; Systematic review; Complementary medicine; Alternative medicine

Contents
1.
2.
3.

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Biofeedback . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Chelation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. CO2 -applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5. Dietary supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.1. Allium sativum (garlic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.2. Ginkgo biloba (ginkgo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.3. Omega-3 fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +44 1392 424872; fax: +44 1392 427562.
E-mail address: M.H.Pittler@exeter.ac.uk (M.H. Pittler).

0021-9150/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2005.02.021

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M.H. Pittler, E. Ernst / Atherosclerosis 181 (2005) 17

3.5.4. Padma 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.5. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Background
Peripheral arterial disease (PAD) affects a considerable
proportion of the general population and is a prevalent condition in the primary care setting [13]. PAD is a potential
threat to functional independence particularly in the elderly
and is associated with hospitalisation, surgery, and death
[4,5]. Treatment is usually conservative [6] and largely consists of regular physical exercise such as walking to nearmaximal pain and pharmacological interventions [710]. In
parallel, the level of use of complementary treatment options
is high among the general population and patient populations
[e.g., 1114]. Prevalence data for the UK indicate that about
2028% use complementary therapies annually and in the
US, the 1-year prevalence currently amounts to about 42%
[1517]. The majority of the data suggest that herbal dietary
supplements are among the most popular treatment options
[11,14], which is supported by the findings of market analyses [1820]. The US Food and Drug Administration also
notes that the rapid growth of this industry will continue into
the near future [21]. Thus, our aim was to assess whether any
type of complementary therapy is effective for treating PAD.

2. Methods
Systematic literature searches were conducted to identify
all RCTs and systematic reviews and meta-analyses of RCTs
of any type of complementary therapy for treating PAD. Data
sources were Medline, Embase, Amed and The Cochrane Library. The search terms used were alternative medicine, complementary medicine, dietary supplements, herbal medicine,
phytotherapy, homeopathy, homoeopathy, acupuncture, osteopathy, chiropractic, peripheral arterial disease, peripheral arterial occlusive disease, intermittent claudication and
derivatives of these. Each database was searched from its inception to December 2004. To identify additional published
or unpublished studies, we conducted hand-searches in conference proceedings (FACTFocus on Alternative and Complementary Therapies 19962004), our own files and relevant medical journals (Phytomedicine 19942004, Alternative and Complementary Therapies 19952004, Erfahrungsheilkunde 19962004, Forschende Komplementarmedizin
Klassische Naturheilkunde 19942004). The bibliographies
of all located papers were searched for further information. There were no restrictions regarding the language of
publication.
To be included, trials were required to state that they were
randomized and were assessing patients with PAD. System-

5
5
5
6

atic reviews and meta-analyses providing the most recently


updated assessment of the evidence were included if their
findings were based on the results of RCTs. Systematic reviews and meta-analyses, which did not report on separate
analyses for RCTs were excluded. Also, studies assessing
surrogate parameters and assessing effects on risk factors of
PAD were excluded. Methodologic quality was evaluated using the Jadad scale [22]. All studies were selected and data
were extracted in a systematic manner (Tables 1 and 2). The
screening and selection of studies, data extraction, the assessment of methodologic quality and validation were performed
independently by the two reviewers. Disagreements during
this process were largely due to reading errors and were resolved through discussion.

3. Results
Seven systematic reviews and meta-analyses and three
additional RCTs, which were not assessed in the reviews
and meta-analyses met all inclusion criteria. The identified evidence relates to acupuncture, biofeedback, chelation
therapy, CO2 -applications and the dietary supplements Allium sativum (garlic), Ginkgo biloba (ginkgo), omega-3 fatty
acids, padma 28 and Vitamin E. All studies except one [23]
included only patients with PAD in Fontaine stage II (intermittent claudication). Data on methodologic quality are
reported in Tables 1 and 2.
3.1. Acupuncture
The literature searches identified one RCT of acupuncture
for treating PAD (Table 2). Patients with unilateral lower and
upper leg amputations due to PAD were included [23]. The
authors suggest significant intergroup differences in favor of
acupuncture (p not reported). Thus, at present little but encouraging data from rigorous clinical trials exists to suggest
that acupuncture is effective for patients with PAD. Independent replication of this trial is needed. Adverse events were
not reported (Table 2).
3.2. Biofeedback
One small (n = 12) RCT tested biofeedback as an adjunctive treatment for patients with intermittent claudication [24].
The treatment consisted of electromyographic feedback and
skin temperature feedback from fingers and toes (Table 2).
Patients also practiced muscle relaxation using a modified Jacobson/Benson technique twice daily for 20 min. There was

Table 1
Systematic reviews and meta-analyses of complementary therapies for peripheral arterial disease
Included trials;
quality (scalea )

Intervention, Fontaine
stage, n (analysed)

Regimen, daily dose

Duration

Control

Main parameter

Main result Mean


difference, (95% CI)

Adverse events
(intervention group)

Villarruz [25]

RCTs; A to C
(Cochrane)b

Chelation therapy, II,


167

20 infusions of 3 g
Na2 EDTA

520 weeks

Placebo

Painfree walking
distance after 20
infusions

16.4 m (32.0 to
0.8)

Brockow [26]

RCTs; 12 (Jadad)
2742 (Maastricht)

CO2 insufflation, II,


(1) 109; (2) 102

1218 insufflations
of 100 to 450 ml CO2

35 weeks

(1) Waiting list;


(2) CO2 baths

Walking distance

Jepson [28]

Double-blind RCTs;
no numerical result
(Cochrane)b
Double-blind RCTs
(not reported)

Dietary supplement
Allium sativum, II, 78

800 mg

12 weeks

Placebo

Painfree walking
distance

(1) Intergroup
difference; (2) No
difference
4 m (35 to 43)

Faintness,
gastrointestinal
symptoms,
proteinuria,
hypocalcemia,
phlebitis, pain
Not reported

Dietary supplement
Ginkgo biloba, II, 619

120160 mg

624 weeks

Placebo

Ratio of painfree walking


distances

Theta 1.2 (1.21.3)

Sommerfield [31]

RCTs; 5 (Jadad)

45 mg to 3 g

4 months to 2
years

Placebo

Painfree walking
distance

17.1 m (51.4 to
17.2)

Melzer [32]

RCTs (not reported)

Dietary supplement
omega-3 fatty acids,
II, 74
Dietary supplement
Padma 28, IIb, 333

1.52.3 g

4 months

Placebo

Maximum walking
distance

81.3 m (65.597.1)c

Kleijnen [33]

Double-blind RCTs;
37 (Kleijnen)

Dietary supplement
Vitamin E, II, 154

300900 mg

810 months

Placebo

Various exercise
performance measures

Not enough evidence


to determine
effectiveness

Horsch [30]

Severe side effects


were not observed
Abdominal
complaints, nausea,
tachycardia,
headache, apoplexy,
pruritus, face-, hand
swelling, high blood
pressure
Gastrointestinal upset

Exanthema,
dermatosis (1.4%),
worsening of
symptoms (1.4%);
four serious adverse
events, none of which
were drug related (one
death, three cases of
neoplasms)
No study reported
any serious side
effect

M.H. Pittler, E. Ernst / Atherosclerosis 181 (2005) 17

First author
[reference]

Jadad scale, Kleijnen scale, Maastricht scale award a maximum of 5, 10, and 100 points, respectively.
It is reported, that neither the method of randomization nor the concealment of allocation were described; no intention-to-treat analysis; inclusion, exclusion criteria were adequately reported; number of
drop-outs described.
c Based on orally presented data.
b

Not reported

Not reported

Not reported.
p < 0.001 compared to
baseline
Not reported.
p < 0.001 compared to
baseline
Jadad scale awards a maximum of five points.

Open, parallel; 1
Hartmann [27]

Fresh water 30 min immersion,


five times weekly

Open, parallel; 2
Greenspan [24]

(Median)
6568, II

Biofeedback

CO2 water

4 weeks

24/24

Maximal walking
time (inclination 10 ,
speed 3.6 km/h)
Painfree walking
distance (flat ground,
speed 120 steps/min)
12/12
8 weeks

Significant (p not
reported)
Perfusion at lower
extremity
50/32
4 weeks
Open, parallel; 2

58, II

Control
Treatment

Eyb [23]

3.5.2. Ginkgo biloba (ginkgo)


The effectiveness of G. biloba extract for treating patients
with intermittent claudication was assessed in a meta-analysis
of double-blind, placebo-controlled RCTs [30]. Trials using
the standardized extract EGb 761 and measuring pain-free
walking distance were included. Nine studies, which assessed

Patients mean
age (year),
Fontaine stage

3.5.1. Allium sativum (garlic)


A Cochrane review [28] of A. sativum extract for treating intermittent claudication identified one RCT [29]. This
trial was double-blind and placebo-controlled and included
78 patients who were treated for 12 weeks. In addition to A.
sativum extract, all patients received physical therapy twice
weekly. The Cochrane reviewers report that based on their
data analysis, there is no statistically significant difference
between the groups.

Design; quality
scorea

3.5. Dietary supplements

Table 2
Randomized clinical trials of complementary therapies for peripheral arterial disease

Subcutaneous CO2 insufflations are being used as a treatment modality in naturopathy almost exclusively in Europe.
A systematic review [26] identified three RCTs, which assessed patients with intermittent claudication. The data from
one trial suggested significant intergroup differences for
painfree walking distance compared with patients on a waiting list, while two others reported mixed results compared
with waiting list controls and patients receiving CO2 -baths
(p not reported). Another small RCT (n = 24) assessed the effects of immersion in CO2 -containing water [27]. It reports an
increase in painfree walking distance after immersion of the
lower extremities for 30 min five times weekly for 4 weeks
compared with baseline.

Regimen, daily dose

3.4. CO2 -applications

Waiting list 20 min at point N 8


(frequency not
reported)
Waiting list 1 h training sessions;
three times weekly

Duration Randomized/
analyzed

Main parameter

Chelation therapy uses oral and intravenous administration of EDTA, usually in combination with vitamins and
trace elements to treat a variety of conditions including PAD.
A Cochrane review identified five RCTs [25] (Table 1). All
studies were performed double-blind and compared EDTA
chelation with isotonic NaCl solution or distilled water. There
were no significant intergroup differences in favor of chelation therapy. For painfree walking distance after 20 infusions,
there was a significant effect in favor of control (weighted
mean difference 16.4 m, 95% CI 32.0 to 0.8). The review concluded that there is not enough evidence to determine
the effectiveness or otherwise of chelation therapy. Adverse
events included faintness, hypocalcemia, proteinuria and gastrointestinal symptoms.

Acupuncture

3.3. Chelation therapy

67, IIIV

Intergroup differences Adverse events


(intervention group)

no mention of intergroup differences. Compared with baseline, maximal walking time assessed on a treadmill at an
inclination of 10 and a speed of 3.6 km/h increased significantly (p < 0.001).

Not reported

M.H. Pittler, E. Ernst / Atherosclerosis 181 (2005) 17

First author
[reference]

M.H. Pittler, E. Ernst / Atherosclerosis 181 (2005) 17

a total of 619 patients were included. The results indicate a


significant effect in favor of G. biloba (Table 1). A sensitivity
analysis of a homogenous sample in terms of design, treatment duration, inclusion and exclusion criteria and methods
of measurement confirms these findings. According to these
data G. biloba extract seems more effective than placebo for
patients with intermittent claudication.
3.5.3. Omega-3 fatty acids
Fish oils from, for instance, salmon or mackerel contain omega-3 fatty acids. A Cochrane review [31] included
four placebo-controlled RCTs. The two trials, which assessed walking distances suggested no significant changes
for painfree and maximal walking distance. It was concluded
that, although omega-3 fatty acids may have some beneficial
effects, there is no evidence of improved clinical outcomes
in patients with intermittent claudication.
3.5.4. Padma 28
Padma 28 is an herbal mixture including 22 different ingredients. Data from five double-blind RCTs measuring maximal walking distance are available [32]. Based on these data,
meta-analytical pooling suggests a difference of the change
of about 81 m over placebo (Table 1). Overall therefore, the
available evidence suggests that this herbal mixture is an
option for patients with intermittent claudication. However,
more data from rigorous clinical trials are required to confirm
these findings.
3.5.5. Vitamin E
A Cochrane review assessed the evidence for Vitamin E
and identified three double-blind RCTs [33]. The reviewers
report that the trials were small and generally of poor quality.
The authors concluded that there is insufficient evidence to
determine whether Vitamin E is effective for treating patients
with intermittent claudication. The meta-analysis of two trials reporting similar dosage and duration of treatment, which
however, included one trial that was not randomized, suggested a relative risk of 0.6 (95% CI 0.31.2) for patients
subjective evaluation of the treatment.

4. Discussion
The reviewed data from RCTs, systematic reviews and
meta-analyses, suggest that G. biloba extract is effective compared with placebo for patients with intermittent claudication
(PAD Fontaine stage II). Evidence also suggests that padma
28 is effective, yet more data are required to confirm these
findings. For all other complementary treatment options there
is no evidence beyond reasonable doubt to suggest their effectiveness beyond placebo for patients with PAD. The sample
sizes of the single trials presented in Table 2 are small and
independent replication is required.
For G. biloba, this conclusion is corroborated by an earlier
meta-analysis [34]. In this study, the difference of the change

of painfree walking distance was 34 m (95% CI 2643) in


favor of G. biloba compared with placebo. Sensitivity analyses of trials using similar methodology and of those scoring
highest for methodological quality corroborate the main result. A walking speed of less than 3 km/h on flat ground
in contrast to the speed and inclination in most trials using
ergometers may further increase painfree walking distance.
Other pharmacological interventions for intermittent claudication, which are approved by the FDA include pentoxifylline
and cilostazol [9,35,36]. An early meta-analysis of RCTs testing pentoxifylline suggests a mean difference in the increase
of painfree walking distance of 57% compared with placebo
[37]. In another meta-analysis, this difference was 21 m for
painfree walking distance and 44 m for maximal walking distance [38]. A double-blind RCT suggested a similar increase
in painfree and maximal walking distance for pentoxifylline
and G. biloba extract [39]. Cilostazol also seems efficacious
when compared with placebo [40,41]. However, the increase
of painfree walking distance with regular physical exercise
is substantially larger than for oral treatments. It has been reported to range between 88 and 190% from baseline [42,43].
A meta-analysis suggested a significant average increase of
painfree walking distance of 139 m in favor of exercise training compared with placebo or no intervention [38]. One disadvantage of exercise therapy for intermittent claudication
lies, of course, in the notoriously poor compliance with such
programs.
The notion that G. biloba is effective for intermittent claudication is supported by its pharmacological actions. The
main active principles are bilobalide and ginkgolides [44].
The latter, in particular ginkgolide B, inhibits platelet activating factor [45]. Other actions include a decrease in eythrocyte
aggregation and blood viscosity as well as anti-ischemic effects through the increase of trancutaneous partial pressure
of oxygen [e.g., 46]. In vitro experiments suggest that the
vasorelaxing effects of G. biloba extract are related to the
release of nitric oxide which, in turn, may be influenced by
the free radical-scavenging activity of the extract [44]. The
relative importance of these actions for the clinical effects of
G. biloba is, however, uncertain at present.
We aimed to identify all RCTs, and all systematic reviews
and meta-analyses based on RCTs of any type of complementary therapy for treating PAD. The potential incompleteness of the citation tracking is one of the limitations of this
systematic review and indeed systematic reviews in general.
Although strong efforts were made to locate and retrieve all
trials on the subject, it is conceivable that some were not uncovered. Restrictions of literature searches relating to the language of publications and databases are problematic. For this
review we searched databases with a focus on the European
and American literature and one that specializes in complementary medicine. There were no restrictions in terms of publication language. We are therefore confident that our search
strategy minimized bias. The appraisal of the evidence involved a degree of judgement and is another potential source
of bias. However, for individual RCTs we used a standard

M.H. Pittler, E. Ernst / Atherosclerosis 181 (2005) 17

scale [22] to assess important criteria of methodologic quality (Table 2). This scale was also used in two of seven systematic reviews and meta-analyses (Table 1). The methodologic
quality of the evidence was combined in an informal process
with the type of evidence (e.g., RCT, meta-analysis) and the
volume of evidence to produce an indication of weight. This
process of appraising the clinical evidence was performed independently by the two reviewers, which further minimized
bias.
In conclusion, the available data from RCTs, and systematic reviews and meta-analyses which based their findings
on the results of RCTs suggest that G. biloba is effective
compared with placebo for patients with intermittent claudication. Evidence also suggests that padma 28 is effective
for intermittent claudication, although more data are required
to confirm these findings. For all other complementary treatment options there is no evidence beyond reasonable doubt
to suggest effectiveness for patients with PAD.
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