Cochrane Database of Systematic Reviews

Prostanoids for intermittent claudication (Review)

Robertson L, Andras A

Robertson L, Andras A.
Prostanoids for intermittent claudication.
Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD000986.
DOI: 10.1002/14651858.CD000986.pub3.

www.cochranelibrary.com

Prostanoids for intermittent claudication (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Analysis 1.1. Comparison 1 PGE1 versus placebo, Outcome 1 Mean change in pain-free walking distance (%). . . 52
Analysis 1.2. Comparison 1 PGE1 versus placebo, Outcome 2 Final pain-free walking distance (meters). . . . . . 53
Analysis 1.3. Comparison 1 PGE1 versus placebo, Outcome 3 Mean change in maximal walking distance (%). . . 54
Analysis 1.4. Comparison 1 PGE1 versus placebo, Outcome 4 Final maximal walking distance (meters). . . . . . 55
Analysis 2.1. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 1 Mean change in pain-free walking distance
(%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Analysis 2.2. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 2 Final pain-free walking distance (meters). 57
Analysis 2.3. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 3 Mean change in maximal walking distance
(%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Analysis 2.4. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 4 Final maximal walking distance (meters). . 59
Analysis 2.5. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 5 Ankle brachial index. . . . . . . . 59
Analysis 2.6. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 6 Adverse events. . . . . . . . . . . 60
Analysis 3.1. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 1 Mean change in pain-free
walking distance (%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Analysis 3.2. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 2 Final pain-free walking distance
(meters). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 3.3. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 3 Mean change in maximal
walking distance (%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 3.4. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 4 Final maximal walking distance
(meters). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 4.1. Comparison 4 PGE1 versus naftidrofuryl, Outcome 1 Mean change in pain-free walking distance (%). 62
Analysis 4.2. Comparison 4 PGE1 versus naftidrofuryl, Outcome 2 Final pain-free walking distance (meters). . . . 63
Analysis 4.3. Comparison 4 PGE1 versus naftidrofuryl, Outcome 3 Ankle brachial index left side. . . . . . . . 63
Analysis 4.4. Comparison 4 PGE1 versus naftidrofuryl, Outcome 4 Ankle brachial index right side. . . . . . . 64
Analysis 4.5. Comparison 4 PGE1 versus naftidrofuryl, Outcome 5 Adverse events. . . . . . . . . . . . . 64
Analysis 5.1. Comparison 5 PGE1 versus L-arginine, Outcome 1 Mean change in pain-free walking distance (%). . 65
Analysis 5.2. Comparison 5 PGE1 versus L-arginine, Outcome 2 Final pain-free walking distance (meters). . . . . 65
Analysis 5.3. Comparison 5 PGE1 versus L-arginine, Outcome 3 Mean change in maximal walking distance (%). . 66
Analysis 5.4. Comparison 5 PGE1 versus L-arginine, Outcome 4 Final maximal walking distance (meters). . . . . 66
Analysis 5.5. Comparison 5 PGE1 versus L-arginine, Outcome 5 Ankle brachial index. . . . . . . . . . . . 67
Analysis 6.1. Comparison 6 PGI2 versus placebo, Outcome 1 Mean change in pain-free walking distance (%). . . 67
Analysis 6.2. Comparison 6 PGI2 versus placebo, Outcome 2 Final pain-free walking distance (meters). . . . . . 68
Analysis 6.3. Comparison 6 PGI2 versus placebo, Outcome 3 Mean change in maximum walking distance (%). . . 69
Analysis 6.4. Comparison 6 PGI2 versus placebo, Outcome 4 Final maximal walking distance (meters). . . . . . 70
Analysis 6.5. Comparison 6 PGI2 versus placebo, Outcome 5 Adverse events. . . . . . . . . . . . . . . 71
Analysis 7.1. Comparison 7 PGI2 versus pentoxifylline (Ptx), Outcome 1 Death. . . . . . . . . . . . . . 71
Prostanoids for intermittent claudication (Review) i
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 7.2. Comparison 7 PGI2 versus pentoxifylline (Ptx), Outcome 2 Revascularisation. . . . . . . . . . 72
Analysis 8.1. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 1 Mean change in pain-free walking
distance (%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Analysis 8.2. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 2 Final pain-free walking distance
(meters). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Analysis 8.3. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 3 Mean change in maximal walking
distance (%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Analysis 8.4. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 4 Final maximal walking distance
(meters). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Analysis 8.5. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 5 Ankle brachial index. . . . . 74
Analysis 8.6. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 6 Venous-occlusion plethysmography -
at rest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Analysis 8.7. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 7 Venous-occlusion plethysmography -
reactive hyperaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 85
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Prostanoids for intermittent claudication (Review) ii

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Prostanoids for intermittent claudication

Lindsay Robertson1 , Alina Andras2

1 Centre for Population Health Sciences, The Medical School, The University of Edinburgh, Edinburgh, UK. 2 Department of Vascular
Surgery, Freeman Hospital, Newcastle upon Tyne, UK

Contact address: Lindsay Robertson, Centre for Population Health Sciences, The Medical School, The University of Edinburgh, Teviot
Place, Edinburgh, EH8 9AG, UK. Lindsay.Robertson@ed.ac.uk.

Editorial group: Cochrane Vascular Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 4, 2013.
Review content assessed as up-to-date: 22 January 2013.

Citation: Robertson L, Andras A. Prostanoids for intermittent claudication. Cochrane Database of Systematic Reviews 2013, Issue 4.
Art. No.: CD000986. DOI: 10.1002/14651858.CD000986.pub3.

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Peripheral arterial disease (PAD) is a common cause of morbidity in the general population. While numerous studies have established
the efficacy of prostanoids in PAD stages III and IV, the question of the role of prostanoids as an alternative or additive treatment in
patients suffering from intermittent claudication (PAD II) has not yet been clearly answered. This is an update of a Cochrane Review
first published in 2004.
Objectives
To determine the effects of prostanoids in patients with intermittent claudication (IC) Fontaine stage II.
Search methods
For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register
(last searched January 2013) and CENTRAL (2012, Issue 12). Clinical trials databases were searched for details of ongoing or
unpublished studies. In addition, reference lists of relevant articles were checked.
Selection criteria
Randomised clinical trials of prostanoids versus placebo or alternative (’control’) treatment in people with intermittent claudication
were considered for inclusion.
Data collection and analysis
Two authors independently assessed trial quality and extracted data. Primary outcomes included pain-free walking distance (PFWD)
and maximum walking distance (MWD), presented as mean change in walking distance during the course of the trial (% improvement)
and as final walking distance (that is walking distance, in metres, after treatment) for the prostanoid and control groups.
Main results
Eighteen trials with a total of 2773 patients were included (16 in the original review and a further two in this update). As the majority of
trials did not report standard deviations for the primary PFWD and MWD outcomes, it was often not possible to test for the statistical
significance of any improvements in walking distance between groups. The quality of individual trials was variable and usually unclear
due to insufficient reporting information. Comparison between trials was hampered by the use of different treadmill testing protocols,
Prostanoids for intermittent claudication (Review) 1
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
including different walking speeds and gradients. Such limitations in the data and the trial heterogeneity meant it was not possible to
meaningfully pool results by meta-analysis.

Four trials compared prostaglandin E1 (PGE1) with placebo; individual trials showed significant increases in walking distances with
administration of PGE1 and in several trials the walking capacity remained increased after termination of treatment. Compared with
pentoxifylline, PGE1 was associated with a higher final PFWD and MWD but these results were based on final walking distances rather
than changes in walking distance from baseline. When PGE1 was compared with other treatments including laevadosin, naftidrofuryl
and L-arginine, improvements in walking distances over time were observed for both PGE1 and the alternative treatment, but it was
not possible from the data available to analyse statistically whether or not one treatment was more effective than the other.

Six studies compared various preparations of prostacyclins (PGI2) with placebo. In one study using three different dosages of iloprost,
PFWD and MWD appeared to increase in a dose-dependent manner; iloprost was associated with headache, pain, nausea and diarrhoea,
leading to a higher rate of treatment withdrawal. Of three studies using beraprost sodium, one showed an improvement in PFWD and
MWD compared with placebo while two showed no significant benefit. Beraprost sodium was associated with an increased incidence
of drug-related adverse events. Of two studies on taprostene, the results of one in particular must be interpreted with caution due to
an imbalance in walking capacity at baseline.

Comprehensive, high quality data on outcomes such as quality of life, ankle brachial index, venous occlusion plethysmography and
haemorrheological parameters were lacking.

Authors’ conclusions

Whilst results from some individual studies suggested a beneficial effect of PGE1, the quality of these studies and of the overall evidence
available is insufficient to determine whether or not patients with intermittent claudication derive clinically meaningful benefit from
the administration of prostanoids. Further well-conducted randomised, double blinded trials with a sufficient number of participants
to provide statistical power are required to answer this question.

PLAIN LANGUAGE SUMMARY

Prostanoids for intermittent claudication

Intermittent claudication (IC) is a symptom of lower limb ischaemia that results from peripheral arterial disease (PAD). It is evident
as muscle pain (ache, cramp, numbness or sense of fatigue) in the leg muscles that occurs during exercise and is relieved by a short
period of rest. Prostaglandin E1 (PGE1) and prostacyclin (PGI2), also known as prostanoids, are vasoactive drugs used in PAD to
reduce arterial insufficiency. The aim of this review was to evaluate the effects of prostanoids in patients with IC. We identified 18
randomised studies with a total of 2773 participants, of which four studies compared the effects of PGE1 versus placebo. Overall, there
was insufficient high quality evidence to suggest that PGE1 improves walking distances in people with IC. There was also a lack of
evidence to determine if PGE1 was more effective than laevadosin, naftidrofuryl or L-arginine. Evidence on the efficacy of prostacyclin
was inconclusive. Results suggest that, compared with PGE1, prostacyclin may be associated with an increased occurrence of side effects
including headache, diarrhoea and facial flushing.

BACKGROUND is the primary symptom of lower limb ischaemia. IC is usually

caused by haemodynamically significant lesions of the aortoiliac,
femoropopliteal or infrapopliteal vessels. IC is a clinical diagnosis
given for muscle pain (ache, cramp, numbness or sense of fatigue)
Description of the condition in the leg muscles, which occurs during exercise and is relieved
Peripheral arterial disease (PAD) is an important cause of morbid- by a short period of rest. Functional independence is threatened
ity in the general population, and intermittent claudication (IC) in people with IC due to limitations on mobility. A survey by
Prostanoids for intermittent claudication (Review) 2
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The Scottish Vascular Audit Group reported that claudicants had
a significantly impaired quality of life in all respects, from general
health, pain, vitality and social parameters to mental and emo-
tional wellbeing (Pell 1995). IC may progress to critical limb is-
chaemia (CLI), causing constant and intractable pain preventing
sleep and is often associated with ulceration and gangrene of the
foot. Ultimately, IC can lead to limb loss, surgical revascularisa-
tion, cardiovascular disease and even death (Dormandy 1999). Re-
cent figures published in the Scottish Health Survey showed that
the prevalence of symptomatic disease increases with age, affecting
approximately 1.7% of people aged 16 to 54 years up to 7.4% in
those aged > 75 years (The Scottish Health Survey 2010). Over
a 16-year period from 1991 to 2007, there were 41,953 new ad-
missions for PAD in Scottish hospitals (Inglis 2012). Results of
follow-up studies of patients with IC have demonstrated that ap-
proximately 20% will experience a worsening of symptoms during
two to seven years of follow up (Leng 1993). Of those that progress
to CLI, approximately 50% of patients die within five years of pre-
senting with symptoms (Davis 2005). The cost of treating CLI in
the UK has been estimated at over £200 million per annum (Beard
2000). The five-year cumulative incidence of amputation is low
(about 1%). However, IC is a marker of generalised atheroscle-
rosis and therefore an indicator associated with increased risk of
premature death (Dormandy 1999).
Description of the intervention
Most patients with stable IC are managed conservatively (Coffman
1991; Ernst 1993). There are two main objectives of therapy: a) to
retard the rate of progression of atherosclerosis, and b) to dimin-
ish the arterial insufficiency and thereby to treat the symptoms.
Reduction of risk factors for progression of disease is the mainstay
of the conservative medical management. Antithrombotic therapy
with antiplatelet agents, especially aspirin, can lower the incidence
of associated cardiovascular events (ATC 2002).
Since the majority of patients with IC are not at high risk of limb
loss, the primary therapeutic goal is to improve exercise perfor-
mance and the functional status of the patients. Exercise training
has been demonstrated to be a very effective therapy to improve
claudication-limiting physical activity in patients with PAD (Leng
2000). However, there are data that suggest that, due to restric-
tions in training ability or poor compliance, only 30% of all pa-
tients with IC benefit from physical training (de la Haye 1992).
Therefore, as an alternative or additive treatment, pharmacologic
measures with so called vasoactive drugs may be applied.
Compared with exercise training, the place of vasoactive drugs
such as prostaglandins, pentoxifylline, naftidrofuryl, cilostazol or
buflomedil in the management of patients suffering from IC is less
clear. Analysis of numerous publications on the efficacy of these
vasoactive substances has shown that in the majority of studies,
methodological errors and inaccuracies with regard to patient se-
lection, investigative methods and statistical evaluation were evi-
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
dent (De Backer 2000; Heidrich 1992). However, a few studies
have been published indicating a favourable effect of these drugs
on the microcirculation or haemorrheological parameters (Hiatt
2001; Van den Brande 1998).
Prostaglandin E1 (PGE1) and prostacyclin (PGI2) have been used
for the treatment of PAD for more than two decades. PGE1 is
rapidly inactivated during passage through the lungs and therefore
has to be given either intra-arterially or in large intravenous doses
(Belch 1997). While intra-arterial application was recommended
initially, intravenous infusions of PGE1 are nowadays preferred.
PGI2 is a very potent but chemically unstable and short-lived
compound and thus has limited clinical use. Therefore more stable
analogues such as iloprost, beraprost, taprostene or ciprostene,
with similar pharmacodynamic profiles, have been developed.
How the intervention might work
The direct vasodilatory properties and subsequent changes in
blood flow and antiplatelet activity are generally regarded as the
most important effects of PGE1 and other prostanoids (Matsuo
1998; Scheffler 1991). However, many other pharmacological ef-
fects have been described that seem to be responsible for clinical
efficacy (Grant 1992). The demonstrated effects of prostanoids
include inhibition of neutrophilic activation and release of toxic
oxygen radicals from activated leukocytes (white blood cells); re-
duction of adhesion of monocytes and macrophages; antiprolifera-
tive activity on vascular smooth muscle cells; reduction of extracel-
lular matrix formation; an inhibitory action on platelet function;
increase in fibrinolytic activity; influence on lipid metabolism; re-
duction of vascular cholesterol content; improvement of oxygen
and glucose metabolism; and an influence on rheological param-
eters by increased erythrocyte (red blood cell) deformability.
Why it is important to do this review
After early enthusiasm for preliminary clinical findings, a more
critical opinion concerning the clinical value of PGE1 and PGI2
has developed. There is now convincing evidence that PGE1 and
iloprost, administered by intermittent daily intravenous infusions,
are effective in patients with CLI (Verstraete 1994), and they are
therefore recommended in such patients (Dormandy 2000). While
the use of prostanoids in the management of severe symptomatic
peripheral ischaemia (a condition for which no alternative drug
therapy exists) can be recommended, it is still unknown whether
patients with IC might benefit from this treatment. This is an
update of a Cochrane Review first published in 2004.
OBJECTIVES
3
To determine the efficacy of prostanoids (PGE1, PGI2 and ana-
logues such as iloprost, beraprost, taprostene, ciprostene) in im-
proving walking distance and other objective and subjective out-
comes in patients with IC Fontaine stage II.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised clinical trials that consider the effects of prostanoids
for the treatment of patients with IC Fontaine stage II. Controlled
prospective trials with parallel groups formed without randomisa-
tion were excluded.
Types of participants
Patients with IC (Fontaine stage II). There were no restrictions for
age or gender.
Types of interventions
Treatment with PGE1, PGI2 and analogues administered by any
route, over any time period, compared with placebo or any alter-
native (’control’) treatment.
Types of outcome measures
Primary outcomes
• Pain-free walking distance (PFWD) or the initial
claudication distance (ICD), which is the distance walked on a
treadmill before the onset of pain
• Maximum walking distance (MWD) or the absolute
claudication distance (ACD), which is the maximum or absolute
distance walked on a treadmill
• Drug side effects
For trials which reported walking time, we converted this to walk-
ing distance in metres using the reported walking gradient and
speed. We planned to convert data obtained using graded treadmill
tests into data comparable with the data obtained using a constant
load treadmill test where this was possible.
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Secondary outcomes
• Quality of life
• Ankle brachial index (ABI), also known as ankle brachial
pressure index
• Venous-occlusion plethysmography
• Haemorrheological parameters
• Necessity of vascular surgery
• Occurrence of amputation
• Mortality
• Cardiovascular events
Search methods for identification of studies
We did not apply any language restrictions on publications, or any
restrictions regarding publications status.
Electronic searches
For this update, the Cochrane Peripheral Vascular Diseases Group
Trials Search Co-ordinator (TSC) searched the Specialised Regis-
ter (last searched January 2013) and the Cochrane Central Regis-
ter of Controlled Trials (CENTRAL) (2012, Issue 12), part of The
Cochrane Library (www.thecochranelibrary.com). See Appendix
1 for details of the search strategy used to search CENTRAL.
The Specialised Register is maintained by the TSC and is con-
structed from weekly electronic searches of MEDLINE, EM-
BASE, CINAHL, and AMED, and through handsearching rele-
vant journals. The full list of the databases, journals and confer-
ence proceedings which have been searched, as well as the search
strategies used, are described in the Specialised Register section of
the Cochrane Peripheral Vascular Diseases Group module in The
Cochrane Library (www.thecochranelibrary.com).
Ongoing studies and unpublished studies
The following trials databases were searched (February 2013) by
AA using the terms ’intermittent claudication’ for details of ongo-
ing and unpublished trials:
• World Health Organization International Clinical Trials
Registry Platform (http://apps.who.int/trialsearch/);
• ClinicalTrials.gov (http://clinicaltrials.gov/);
• Current Controlled Trials (http://www.controlled-
trials.com/).
Searching other resources
We searched the reference lists of articles retrieved by electronic
searches for additional citations. We contacted trialists for further
information in cases where there were missing data or doubts about
whether to include trials in the review.
4
Data collection and analysis
Selection of studies
For this update, two review authors (AA and LR) used the selec-
tion criteria to identify trials for inclusion. Disagreements were
resolved by discussion. We obtained full versions of articles that
potentially met the inclusion criteria based on the title or abstract
and assessed these independently against the inclusion criteria.
The reason for each study’s exclusion is presented in the ’Charac-
teristics of excluded studies’ table.
Data extraction and management
Both review authors (AA and LR) independently extracted the
data for the new studies considered using the standard checklist
developed by the Cochrane Peripheral Vascular Diseases Group.
The following outcome data were sought (if assessed in the indi-
vidual studies): PFWD and MWD on a standard treadmill; drug
side effects; ABI; venous-occlusion plethysmography; haemorrhe-
ological parameters; necessity of vascular surgery; occurrence of
amputation; death; cardiovascular events. Authors of publications
were contacted for additional details. Data were entered into Re-
view Manager (RevMan), the systematic review software from The
Cochrane Collaboration (RevMan 2011).
Assessment of risk of bias in included studies
Two review authors (AA, LR) independently assessed the risk of
bias using the criteria outlined in the Cochrane Handbook for Sys-
tematic Reviews of Interventions (Higgins 2011). The risk of bias
tool provides a strict protocol to assess allocation (selection bias),
blinding (performance bias and detection bias), incomplete out-
come data (attrition bias), selective reporting (reporting bias) and
other potential sources of bias. For each of the six domains, we
assessed the risk of bias as ’low risk’, ’high risk’ or ’unclear risk’ of
bias, with unclear risk of bias indicating that there was insufficient
information available to permit an assessment of either low or high
risk of bias. Disagreements were resolved by discussion between
the two review authors.
Measures of treatment effect
We planned to pool the data on the PFWD and the MWD from
each trial to arrive at an overall estimate of the effectiveness of
the pharmacological interventions. We aimed to calculate the per-
centage change in the walking distance during the course of the
trial and then, where possible, calculate the mean difference in the
prostanoid group compared with the control group. For continu-
ous outcomes such as PFWD and MWD, statistical analysis was
presented as mean difference (MD) with 95% confidence interval
(CI). For dichotomous outcomes, we used odds ratios (OR) with
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
95% CI. However, few studies presented the standard deviations
(SD) of the walking distances and therefore it was seldom possible
to analyse the mean difference in change in walking distance from
baseline to follow up between the treatment and control groups.
Therefore the final walking distance, that is the walking distance
at the end of treatment (in metres), was also presented and pooled,
where possible. There are obvious limitations in presenting dif-
ferences in final walking distances between treatment and control
groups, the main one being that this does not take into account
any differences in walking distances between the two groups at
baseline, that is before treatment. Furthermore, the relationship
between treadmill speed and walking distance is not linear but is
also influenced by the gradient of the treadmill. Individual stud-
ies used a range of speeds and gradients for treadmill testing; and
while these measures were converted into final walking distances
in metres, it could be argued that the walking distance on a gradi-
ent of 7 ° would be different to the walking distance on a gradient
of 10 °. Converting these results into a standard measure of final
walking distance in metres is likely to result in significant hetero-
geneity when pooling the studies. Nevertheless, it was decided to
use all available data in order to make the analysis as complete as
possible.
Unit of analysis issues
The unit of randomisation was the individual participant in all
included studies. All of the trials involved repeat observations on
participants at different points in time, ranging from one week
to one year, and thus were prone to unit of analysis errors. Data
on PFWD, MWD and all other outcomes were presented for all
times reported in the studies and analysed, where possible.
Dealing with missing data
Where necessary, we contacted the authors of included trials to
clarify data and obtain missing data.
Assessment of heterogeneity
All analyses were conducted on an intention-to-treat basis. When
the individual trials did not use intention-to-treat analyses, the
analyses in this review were on the basis of the data (absolute num-
bers) provided in the included trial report. The statistical appro-
priateness of combining the trials was based on tests of hetero-
geneity, which consider whether differences in treatment effect
over individual trials are consistent with natural variation around
a constant effect. We assessed trial heterogeneity using the Chi2
test and I2 statistic, which describes the percentage of the vari-
ability in effect estimates that is due to heterogeneity rather than
sampling error (chance). Where heterogeneity was identified (P <
0.1, or I2 > 50%), we investigated the reason for heterogeneity.
If no apparent reason was found, we conducted a random-effects
5
model meta-analysis to incorporate heterogeneity among trials. In
the absence of heterogeneity we used a fixed-effect model.
Assessment of reporting biases
We planned to assess reporting biases by using funnel plots if more
than 10 studies were included in the meta-analysis.
Data synthesis
Where two or more studies with low methodological and statis-
tical heterogeneity were included, we performed a meta-analysis.
Results for changes in walking distances were stated in percentage
values. For final walking distances, the results were stated in me-
tres. Numeric values were provided as weighted mean differences
(WMD) with the 95% confidence intervals (CI) in parenthesis.
A P value of < 0.05 was considered as significant for analysis of
potential differences between the treatment groups.
Where heterogeneity was identified (P < 0.1, or I2 > 50%), we
investigated the reason for heterogeneity. If no apparent reason
was found, we conducted a random-effects model meta-analysis
to incorporate the heterogeneity among trials. In the absence of
heterogeneity we used a fixed-effect model.
Subgroup analysis and investigation of heterogeneity
We anticipated that the trials would not be homogeneous. There-
fore we planned to do a subgroup analysis of the included trials
according to variables such as duration, dose and route of admin-
istration.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of studies awaiting classification
Results of the search
For this update 20 studies were retrieved from the search of the
Specialised Register. Five additional studies were found from the
search of CENTRAL which were not in the Specialised Regis-
ter. All 25 studies were screened by title and abstract. Two stud-
ies (Creager 2008; Milio 2006) were deemed relevant and in-
cluded in the update. From the updated search, 14 studies were
excluded (Acciavatti 2001; Anon 2011; Barradas 1989; Bieron
1993; Diehm 1990; Esato 1995a; Esato 1995b; Fitscha 1985;
Goya 2003; Ishitobi 1991; Linhart 1998; Okadome-Kenchiro
1992; Sakaguchi-Shukichi 1990; Wang 2009). Three studies were
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
deemed not relevant as the treatment or outcome did not meet
the scope of the review. One study (Valerio 2012) is ongoing and
awaiting publication. One study (Nakagawa 1998) is awaiting
translation before it can be determined if it is relevant for inclusion
in the review. Four studies (Blume 1986; Creutzig 1988; Diehm
1989; Lièvre 2000) were duplicate publications of studies already
included in the original review.
Included studies
Of the 18 included studies (16 in the original review and two
from the update), 13 (Belch 1997; Blume 1986; Böger 1998;
Creager 2008; Creutzig 1988; Diehm 1989; Diehm 1997; Hepp
1996; Lièvre 1996; Lièvre 2000; Mangiafico 2000; Mohler 2003;
Scheffler 1994) excluded all participants with changes in walking
distances exceeding more than 20% to 25% from baseline during
a wash-out phase of about one to four weeks in which no study
drugs were administered. The most frequent, additional exclusion
criteria for trial entry were: pregnancy, congestive heart failure, de-
compensated renal failure, haemodynamically relevant aortic and
pelvic arterial occlusion, respiratory disorders, myocardial infarc-
tion within the previous six months, insulin-dependent diabetes
mellitus, indication for revascularisation procedures, severe un-
controlled hypertension (diastolic blood pressure > 120 mmHg),
orthopaedic and neurological diseases that impaired walking per-
formance, thrombocytosis (increase in the numbers of circulating
platelets) with count > 400,000/ml, and second and third degree
atrioventricular block.
Four studies compared PGE1 with placebo (Belch 1997; Blume
1986; Diehm 1989; Mangiafico 2000), four studies compared
PGE1 with pentoxifylline (Hepp 1996; Luk’Janov 1995; Milio
2006; Scheffler 1994), one study compared PGE1 with laevadosin
(Creutzig 1988), one study compared PGE1 with naftidrofuryl
(Diehm 1989), one study compared PGE1 with L-arginine (Böger
1998), six studies compared PGI2 with placebo (Creager 2008;
Lièvre 1996; Lièvre 2000; Mohler 2003; Virgolini 1989; Virgolini
1990), one study compared PGI2 with pentoxifylline (Creager
2008) and one study compared PGI2 with hydroxy-ethyl starch
(Müller-Bühl 1987).
Sixteen studies measured walking distances in metres (Belch
1997; Blume 1986; Böger 1998; Creager 2008; Creutzig 1988;
Diehm 1989; Diehm 1997; Hepp 1996; Lièvre 1996; Lièvre
2000; Luk’Janov 1995; Mangiafico 2000; Milio 2006; Mohler
2003; Müller-Bühl 1987; Scheffler 1994). Of the 16 studies, 15
used a constant load test with gradients ranging between 3.2 °
(Lièvre 1996), 5 ° (Blume 1986; Creutzig 1988; Hepp 1996;
Luk’Janov 1995; Mangiafico 2000; Scheffler 1994), 7 ° (Milio
2006), 10 ° (Belch 1997; Diehm 1989; Lièvre 2000; Mohler 2003;
Müller-Bühl 1987) and 12 ° (Böger 1998; Diehm 1997) and
speeds ranging between 2 km/h (Belch 1997), 3 km/h (Blume
1986; Böger 1998; Creutzig 1988; Diehm 1997; Hepp 1996;
Lièvre 2000; Luk’Janov 1995; Mangiafico 2000; Milio 2006;
6
Mohler 2003; Müller-Bühl 1987; Scheffler 1994), 3.2 km/h
(Lièvre 1996) and 3.5 km/h (Diehm 1989). One study used a
graded test with a starting incline of 0 ° which was increased by 2 °
every 2 minutes, with a walking speed of 3.2 km/h (Creager 2008).
Two studies measured walking distances in seconds (Virgolini
1989; Virgolini 1990) on a slope of 7.5 º and at a speed of 1.5 mph.
The walking times in these studies were converted into walking
metres using the gradient and walking speed reported by the study
authors.
Three studies (Blume 1986; Milio 2006; Müller-Bühl 1987) pro-
vided no information about the intake of antiplatelet or va-
soactive drugs during the trial. In the studies by Belch (Belch
1997), Creager (Creager 2008), Mohler (Mohler 2003) and Man-
giafico (Mangiafico 2000) the participants continued a previ-
ously indicated therapy with antiplatelet drugs. The participants
in the remaining 11 studies were not treated by any vasoactive
or antiplatelet drug during the study. Only eight studies (Böger
1998; Creutzig 1988; Diehm 1989; Hepp 1996; Lièvre 1996;
Mangiafico 2000; Mohler 2003; Scheffler 1994) provided detailed
information about concomitant vascular exercise. In the study by
Scheffler 1994 all three groups received intensive physical training
in addition to treatment with either PGE1 or pentoxifylline.
Prostanoids were administered by intra-arterial or intravenous in-
fusion, or orally.
For further details of the characteristics of the included studies see
Characteristics of included studies.
Excluded studies
Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
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In total, 20 studies (six from the original review and 14 from
the update) were excluded because they did not meet the in-
clusion criteria. See Characteristics of excluded studies for de-
tails of the reasons for exclusion. In brief, seven trials were
not randomised controlled trials (Barradas 1989; Bieron 1993;
Diehm 1990; Ishitobi 1991; Rudofsky 1987; Rudofsky 1988;
Sakaguchi-Shukichi 1990). Two of those trials (Rudofsky 1987;
Rudofsky 1988) were included in the original review but we ex-
cluded them for this update as we believe that they were not ran-
domised controlled trials. Four studies (Acciavatti 2001; Anon
2011; Linhart 1998; Okadome-Kenchiro 1992) had no placebo
or control group, two studies (Hay 1987; Waller 1986) admin-
istered different drug dosages to patients limiting comparability,
one study (Ylitalo 1990) had no subgroup analysis despite three
of the participants having rest pain, one study (Fitscha 1985) had
incomplete data, while a further study (Wilkinson 1988) did not
present any data. Two studies were excluded as all patients had CLI
(Esato 1995a; Esato 1995b) while a further study (Goya 2003)
was excluded as patients had arteriosclerotic changes in the carotid
artery. Finally, one study (Wang 2009) was excluded as not all pa-
tients had IC and the outcomes measured were not relevant for
the review.
Risk of bias in included studies
The quality of the included trials was variable. See Figure 1 and
Figure 2 for a graphical presentation of the risk of bias. Insufficient
information was the main reason for the ’unclear’ rating for most
trials.
7
 Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

Prostanoids for intermittent claudication (Review) 8

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation
For random sequence generation, only four of the 18 included
studies (Belch 1997; Lièvre 1996; Lièvre 2000; Milio 2006) ad-
equately described the methods used, with random number lists
used in two studies (Belch 1997; Milio 2006) and random com-
puter generators used in the other two (Lièvre 1996; Lièvre 2000).
The remaining 14 studies (Blume 1986; Böger 1998; Creager
2008; Creutzig 1988; Diehm 1989; Diehm 1997; Hepp 1996;
Luk’Janov 1995; Mangiafico 2000; Mohler 2003; Müller-Bühl
1987; Scheffler 1994; Virgolini 1989; Virgolini 1990) did not
state the method used to generate the allocation sequence and thus
there was insufficient information to permit a judgment of low
or high risk of selection bias. In terms of concealing the alloca-
tion sequence, only one study (Milio 2006) used sealed envelopes
and was therefore at low risk of selection bias. One study (Belch
1997) was deemed to be at high risk due to the fact that it used
a random number list, which, according to the Cochrane criteria
for assessing risk of bias (Higgins 2011), can introduce selection
bias. The remaining 16 studies (Blume 1986; Böger 1998; Creager
2008; Creutzig 1988; Diehm 1989; Diehm 1997; Hepp 1996;
Lièvre 1996; Lièvre 2000; Luk’Janov 1995; Mangiafico 2000;
Mohler 2003; Müller-Bühl 1987; Scheffler 1994; Virgolini 1989;
Virgolini 1990) did not provide adequate descriptions of methods
used to conceal allocation and therefore a judgment on the risk of
selection bias could not be made.
Blinding
Although some studies (Belch 1997; Creager 2008; Creutzig 1988;
Diehm 1989; Diehm 1997; Hepp 1996; Lièvre 1996; Lièvre 2000;
Luk’Janov 1995; Mangiafico 2000; Mohler 2003; Virgolini 1989;
Virgolini 1990) were reported as ’double blind’, authors did not
provide any more information on how blinding of study partici-
pants and personnel was maintained throughout the study. As it
could not be guaranteed that blinding was ensured and unbro-
ken, these studies were deemed to be at unclear risk of perfor-
mance bias. Five studies (Blume 1986; Böger 1998; Milio 2006;
Müller-Bühl 1987; Scheffler 1994) were deemed to be at high risk
of performance bias. In Blume 1986, PGE1 was administered as
an intra-arterial infusion over 90 minutes while the placebo was
an injection, and therefore blinding of the study participants or
personnel was impossible. Böger 1998 blinded two of the three
treatment groups. Milio 2006 and Müller-Bühl 1987 both con-
ducted single blinded trials with only the participants blinded to
the treatment. Finally, in the study by Scheffler 1994, one of the
’treatment’ groups received no treatment. None of the 18 included
studies provided any information on the blinding of outcome as-
sessors and therefore judgements on the risk of detection bias could
not be made.
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Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Incomplete outcome data
Seven studies (Belch 1997; Böger 1998; Diehm 1989; Lièvre 2000;
Mangiafico 2000; Müller-Bühl 1987; Scheffler 1994) accounted
for all data and were deemed to be at low risk of attrition bias. Six
studies (Blume 1986; Creager 2008; Creutzig 1988; Diehm 1997;
Hepp 1996; Virgolini 1990) were deemed to be at high risk due
to large losses to follow up with inadequate explanations. For the
remaining five studies (Lièvre 1996; Luk’Janov 1995; Milio 2006;
Mohler 2003; Virgolini 1989) there was insufficient information
to permit a judgement on risk of attrition bias.
Selective reporting
Seven studies (Böger 1998; Diehm 1989; Diehm 1997; Hepp
1996; Lièvre 1996; Lièvre 2000; Müller-Bühl 1987) reported data
on all pre-specified outcomes and were therefore at low risk of
reporting bias. Seven studies (Belch 1997; Blume 1986; Creager
2008; Creutzig 1988; Mangiafico 2000; Scheffler 1994; Virgolini
1990) did not present data on all pre-specified outcomes and were
deemed to be at high risk of reporting bias. The remaining four
studies (Luk’Janov 1995; Milio 2006; Mohler 2003; Virgolini
1989) did not provide sufficient information to permit a judge-
ment on the level of reporting bias.
Other potential sources of bias
Only one study (Müller-Bühl 1987) appeared to be free from
other sources of bias. The remaining studies were either at high
risk of bias (Belch 1997; Creager 2008) because of unclear study
design and missing inclusion and exclusion criteria (Belch 1997)
and sponsorship from a pharmaceutical company (Creager 2008)
or at unclear risk of bias (Blume 1986; Böger 1998; Creutzig
1988; Diehm 1989; Diehm 1997; Hepp 1996; Lièvre 1996; Lièvre
2000; Luk’Janov 1995; Mangiafico 2000; Milio 2006; Mohler
2003; Scheffler 1994; Virgolini 1989; Virgolini 1990) because of
insufficient information to permit judgement of low or high risk
of bias.
Effects of interventions
PGE1 versus placebo (Comparison 1)
Walking distances
Three studies (Blume 1986; Diehm 1997; Mangiafico 2000), with
a total of 300 participants (152 PGE1 group and 148 placebo
group), analysed the effects of PGE1 versus placebo. Only one
study (Blume 1986) with 50 participants (25 PGE1 group and 25
9
placebo group) investigated the effects of intra-arterial (ia) infu-
sions on PFWD and MWD. After three weeks of treatment, the
mean PFWD improved by 109% (59 m) in PGE1 patients com-
pared to 35% (19 m) in placebo patients, while the mean MWD
improved by 74% (72 m) and 18% (17 m) in the two treatment
groups respectively. Based on final walking distances, the PFWD
improved by 40 m (95% CI 13.42 to 66.58 m, P = 0.003) and
MWD by 56 m (95% CI 20.45 to 91.55 m, P = 0.002) in patients
treated with intra-arterial PGE1 compared to a placebo.
The two remaining studies (Diehm 1997; Mangiafico 2000) mea-
sured the effects of intravenous (iv) infusions. Both studies mea-
sured the PFWD and MWD after four weeks of treatment and
individual results showed significant improvements in patients
treated with PGE1. Diehm 1997 examined 208 patients (106
PGE1 and 102 placebo) and estimated that after four weeks of
treatment PGE1 improved the PFWD by 75% compared to 43%
with the placebo, while MWD improved by 65% with PGE1
compared to 42% with the placebo. Standard deviations around
the mean differences were not presented and therefore significance
levels could not be assessed. Based on final walking distances and
compared to a placebo, PGE1 improved PFWD and MWD by
17.2 m (95% CI 16.68 to 17.72 m) and 21.1 m (95% CI 20.62 to
21.58 m), respectively. The study by Mangiafico 2000 was much
smaller with only 42 patients (21 in each group) and, after four
weeks of treatment, the PFWD improved by 87.5% compared to
4% in the placebo group, and MWD improved by 90% compared
to 1% in the placebo group. Significance levels could not be as-
sessed as standard deviations around the differences were not pre-
sented in this publication. Based on final walking distances, PGE1
was associated with an increase in PFWD of 51 m (95% CI 35.12
to 66.88 m) while the MWD was 112 m (95% CI 80.67 to 143.33
m) compared to placebo. However, results based on final walking
distances must be interpreted with caution as they do not take
into account the change from baseline. In this study (Mangiafico
2000), baseline walking distances were not comparable between
the treatment groups: the PFWD was 9 m less and the MWD was
12 m less in PGE1 patients compared to the placebo controls. In
this study, reporting final walking distances alone led to an under-
reporting on the improvement in PFWD and MWD with PGE1.
The two studies could not be combined in a meta-analysis as they
were deemed too heterogeneous (I2 = 97%).
The study by Diehm 1997 also administered treatment for eight
weeks and measured walking distances at this time point. After
an initial treatment period of four weeks with PGE1 or placebo
administered five days a week, an interval treatment period of
four weeks was applied where treatment was reduced to bi-weekly.
After this four-week interval, and eight weeks after treatment first
commenced, the mean PFWD in PGE1 patients improved by
100% from baseline compared to 60% in the placebo group. Using
final walking distance to estimate improvement, the PFWD was
increased by 22.30 m (95% CI 21.74 to 22.86 m) with PGE1
(P < 0.001). At the same time point, MWD improved by 88%
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
compared to 61% in the PGE1 and placebo groups respectively.
Compared with placebo, PGE1 led to an improvement of 25.8 m
(95% CI 25.27 to 26.33 m) in MWD (P < 0.001). The study by
Mangiafico 2000 also measured walking distance at eight weeks
although treatment was administered for only four weeks. This
study was not included in a meta-analysis as the study authors did
not report the PFWD and MWD at eight weeks in the placebo
group. Attempts were made to retrieve this information from the
author but we were unsuccessful. Mean PFWD increased by 57%
(41 m) while the mean MWD improved by 64% (89 m) from
baseline in the PGE1 group. Data on walking distances at eight
weeks in the placebo group were not presented.
A further study (Belch 1997) analysed the PGE1 prodrug AS-
013 (59 participants) versus placebo (21 participants) but it could
not be included in our analysis because the data were reported in
medians rather than means. Those who received PGE1 were split
into three groups according to dosing schedule: 2 µg five days a
week (n = 19), 5 µg two days a week (n = 18) and 5 µg five days
a week (n = 22). The authors only reported walking distances for
the highest dose group. At four weeks, there was no significant
difference in the median improvement of PFWD between the
PGE1 group (20 m, interquartile range (IQR) 33 m) and the
placebo group (9 m, IQR 18 m) (P > 0.05). However, the study
authors reported a significant difference between the PGE1 group
(28 m, IQR 81 m) and the placebo group (4 m, IQR 20 m) (P
< 0.05) in the improvement of the MWD. At eight weeks, the
median PFWD increased by 20.9 m (IQR 43 m) in PGE1 patients
but did not improve in placebo patients (0 m, IQR 29 m) (P <
0.01) while the median MWD improved by 35 m (IQR 68 m) but
decreased by 11.2 m (IQR 35 m) in the PGE1 and placebo groups
respectively (P < 0.01). However, PFWD and MWD at baseline
were not comparable between the placebo and PGE1 patients and
thus the results should be interpreted with caution.
Table 1; Table 2
Quality of life
Quality of life was measured in two studies. Mangiafico 2000
used two methods, the walking impairment questionnaire (WIQ)
which specifically assesses changes in walking capacity in response
to treatment of IC and the RAND 36-Item health Survey, which
is a generic tool designed to measure health-related quality of life.
After four weeks of treatment, analysis of the WIQ demonstrated
significant improvements in the walking impairment, distance,
speed and stair climbing scores (all P < 0.001) while the RAND
survey showed improvements in physical function (P < 0.001)
and bodily pain scores (P < 0.01). At the end of the eight-week
treatment-free follow up, all WIQ and RAND scores were still
increased compared with baseline (P < 0.01). Belch 1997 used an
8-point questionnaire to determine quality of life and concluded
that, overall, patients given a placebo deteriorated by a score of
64 points while those administered the PGE1 prodrug AS-013
10
improved by a score of 22 to 73 points, with the most marked
difference being observed in physical functioning and leisure ac-
tivities.
Ankle brachial index (ABI)
ABI was an outcome in four studies (Belch 1997; Blume 1986;
Diehm 1997; Mangiafico 2000). No study presented data but all
study authors stated that there were no significant differences in
ABI between the PGE1 and placebo groups throughout the course
of the studies.
Venous occlusion plethysmography
Blume 1986 performed venous occlusion plethysmography and,
although data were not reported, the study authors stated that
there were no significant changes during or after therapy.
Haemorrheological parameters
The study by Blume 1986 reported that the haemorrheological
parameters including haematocrit, erthrocyte aggregation and de-
formability) were normal at the start of the study and did not
change significantly in either the PGE1 or placebo group.
Adverse events
Adverse events were reported in four studies (Belch 1997; Blume
1986; Diehm 1997; Mangiafico 2000). In one study (Blume
1986), treatment was stopped due to side effects (pain, swelling,
flushing) in 1/25 placebo patients and 4/25 PGE1 patients. In
another trial (Belch 1997), 2/59 PGE1 patients experienced se-
vere treatment-related events (atrial fibrillation and hypotension).
Flu-like symptoms occurred in 7/80 patients (5/59 PGE1, 2/21
placebo), dyspepsia in 3/59 PGE1 patients and mild injection site
reactions occurred in 6/59 PGE1 patients (Belch 1997). Two stud-
ies (Diehm 1997; Mangiafico 2000) reported no serious drug-re-
lated adverse events. The rate of less severe events (skin reddening,
pain at infusion site, dizziness and nausea) was 12.8% in the 106
PGE1 patients and 7.7% in the 102 placebo patients respectively
(Diehm 1997) while skin reddening occurred in 9.5% of PGE1
patients (Mangiafico 2000). It was not possible to pool the ad-
verse events (AEs) data into a meta-analysis because they differed
in severity. Blume 1986 only reported serious AEs that resulted
in treatment discontinuation, while Diehm 1997 and Mangiafico
2000 did not present the number of patients.
PGE1 versus pentoxifylline (Comparison 2)
Walking distances
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Four studies (Hepp 1996; Luk’Janov 1995; Milio 2006; Scheffler
1994) analysed iv PGE1 versus iv pentoxifylline. Although the
mean difference in walking distance could be calculated for each
study, the SDs for the mean differences were not reported and
therefore the studies could not be pooled in a meta-analysis. Hepp
1996 conducted a study on 195 patients (97 PGE1, 98 pentoxi-
fylline). Results showed that administration of PGE1 and pentox-
ifylline significantly increased the PFWD by 218% (83 m to 264
m) and 124% (84 m to 188 m), respectively, and the MWD by
164% (130 m to 343 m) and 146% (131 m to 322 m), respec-
tively. Luk’Janov 1995 measured the PFWD only and reported
a significant improvement in PFWD of 119% (89 m to 195 m)
in the PGE1 group (n = 42) and 91% (78 m to 149 m) in the
pentoxifylline group (n = 40). It was not clear at what time point
this was measured and this could not be clarified by the study
authors. Meanwhile Milio 2006 showed that, after four weeks of
treatment, PFWD increased with both PGE1 (396%) and pen-
toxifylline (113%), while MWD improved by 260% in 63 PGE1
patients and 118% in 60 pentoxifylline-treated patients. Based
on final walking distances and compared to pentoxifylline, PGE1
was associated with an improvement in PFWD of 212 m (95%
CI 130 to 294 m) while MWD increased by 192 m (95% CI 95
to 289 m). The study by Scheffler 1994 comprised 45 patients,
15 received PGE1, 15 pentoxifylline, and 15 underwent physical
exercise alone. Four weeks after treatment, the mean PFWD had
increased by 119% in the exercise group (72 m to 158 m), 105%
in the pentoxifylline group (75 m to 154 m) and 604% in the
PGE1 group (81 m to 570 m). Compared to pentoxifylline, PGE1
was associated with an increase in PFWD of 416 m (95% CI 27.7
to 804.3 m). Mean MWD also increased by 99% (131 m to 261
m), 119% (160 m to 350 m) and 371% (158 m to 744 m ) in
the physical exercise, pentoxifylline and PGE1 groups respectively.
Final MWD was improved by 393 m (95% CI -32.5 to 818.5 m)
in favour of PGE1. Forty-four patients were followed up for one
year and a reduction in PFWD was observed, with the extent of
deterioration differing by treatment. In both the exercise and pen-
toxifylline groups, the symptomatic walking distance remained at
just 30% above pretreatment distance while the PGE1 patients
still showed a 149% increase in PFWD.
Two studies (Milio 2006; Scheffler 1994) that reported SDs for
final walking distances were combined in a meta-analysis as low
heterogeneity was determined (I2 = 2% and 0% for PFWD and
MWD respectively). Combining these two studies (77 PGE1 and
75 pentoxifylline patients) and based on final walking distances,
PGE1 was associated with a significant improvement in PFWD
(221 m, 95% CI 141 to 300 m, P < 0.001) and MWD (202 m,
95% CI 107 to 297 m, P < 0.001).
Table 3; Table 4
Ankle brachial index (ABI)
ABI was measured in two studies (Hepp 1996; Luk’Janov 1995).
11
In one study (Hepp 1996), the ABI increased significantly af-
ter four weeks of treatment with both PGE1 (0.47 (SD 0.21) to
0.53 (SD 0.21); mean difference (MD) 0.06, +12.8%, P < 0.001)
and pentoxifylline (0.53 (SD 0.21) to 0.60 (SD 0.20); MD 0.07,
+13.2%, P < 0.001). ABI measurements at final follow up showed
a very slight significant improvement in favour of pentoxifylline
(MD -0.07, 95% CI -0.13 to -0.01). Luk’Janov 1995 reported
that at 12 months the ankle arm pressure index increased from
0.66 (SD 0.17) to 0.74 (SD 0.5) and from 0.66 (SD 0.26) to 0.69
(SD 0.26) in the PGE1 and pentoxifylline groups respectively.
Venous occlusion plethysmography
One study (Milio 2006) measured plethysmographic parameters.
At the end of treatment maximal post-ischaemic flow (PF) was sig-
nificantly higher in the PGE1 group (16.21) than in the pentox-
ifylline group (13.47) while minimal vascular resistance (MVR)
was significantly lower in the PGE1 patients compared to pentox-
ifylline-treated patients (16.93 versus 18.24 respectively). There
were no significant differences in muscular flow at rest (MR) nor
basal vascular resistance (BVR) between the two groups. Scheffler
1994 reported that plasma viscosity and erthrocyte aggregation
decreased in the PGE1 group but not to a statistically significant
level (P = NS).
Adverse events
Three studies (Hepp 1996; Milio 2006; Scheffler 1994) measured
adverse events. In the study by Hepp 1996, the rate of adverse
events four weeks after treatment was similar between PGE1 (5%)
and pentoxifylline (7%) patients (OR 0.71, 95% CI 0.22 to 2.31),
and remained so at 12-months follow up (OR 0.32, 95% CI 0.06
to 1.64). Of the adverse events which occurred during the year after
treatment, there were two in the PGE1 group (one embolism and
one stroke) and six in the pentoxifylline group (two amputations,
two bypass operations, one fracture, and one arterial occlusion).
Scheffler 1994 reported no serious side effects but reported that
side effects including flushing (n = 6), reddening of the vein (n =
4) and diarrhoea (n = 1) occurred. It was not possible to determine
which treatment group these side effects occurred in and attempts
to clarify this query with the author were unsuccessful. Milio
2006 reported no side effects, while Luk’Janov 1995 provided no
information about side effects during treatment with prostanoids.
PGE1 versus laevadosin (Comparison 3)
Walking distances
Creutzig 1988 compared the effects of PGE1 ia (20 participants)
with laevadosin ia (20 participants). After three weeks of treat-
ment, the mean PFWD increased significantly in both treatment
groups: from 60 m to 198 m (230%) in PGE1 patients and from
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
69 m to 170 m (146%) in the laevadosin group. Improvements
in mean MWD were 239% (90 m to 305 m) and 156% (107 m
to 274m) in the PGE1 and laevadosin groups respectively. Signifi-
cance levels of these results could not be assessed because standard
deviations (SD) were not stated in this publication. Follow up was
completed at 4, 12 and 36 weeks after treatment discontinuation.
With the exception of MWD in PGE1 patients, the PFWD in
both treatment groups and MWD in laevadosin patients remained
elevated at all time points.
Adverse events
Adverse events occurred in 2/20 PGE1 patients (one nausea and
one sweating) and 3/20 laevadosin patients (one nausea, one vom-
iting, and one thoracic oppression).
PGE1 versus naftidrofuryl (Comparison 4)
Walking distances
One study (Diehm 1989) analysed the effects of PGE1 iv (24 par-
ticipants) versus naftidrofuryl iv (24 participants). Standard devi-
ations of walking distances were not stated and therefore signif-
icance levels could not be assessed: the PFWD increased in the
PGE1 group from 136 m to 270 m (98.5%) and in the naftidro-
furyl group from 117 m to 230 m (96.6%) after three weeks of
treatment. Three months after treatment was initiated, the mean
PFWD in the PGE1 group increased to 306 m while at the same
follow-up point the mean PFWD fell to 210 m in the naftidro-
furyl group.
Ankle brachial index (ABI)
The study by Diehm 1989 showed no significant difference be-
tween the groups in the ABI of the right leg (P = 0.1) and the ABI
of the left leg (P = 0.9).
Adverse events
The rate of adverse events (vein reddening, pain, headache, change
in blood pressure, diarrhoea, dizziness, nausea, discomfort and
paraesthesia) was 20.8% in the PGE1 group compared to 91.6%
in the naftidrofuryl group (OR 0.02, 95% CI 0 to 0.14) but
treatment was never discontinued.
PGE1 versus L-arginine (Comparison 5)
Walking distances
Böger 1998 investigated the effects of PGE1 versus L-arginine in
26 participants (13 PGE1 and 13 L-arginine). After three weeks
12
of treatment, the mean PFWD improved in the L-arginine group
from 52 m to 147 m (185%) and in the PGE1 group from 52
m to 128 m (147%). Corresponding results for the MWD were
an improvement from 93 m to 216 m (132%) in the L-arginine
group and from 93 m to 199 m (114%) in the PGE1 group. We
could not include the data in our statistical program because SDs
of the changes in walking distances were not reported but the study
authors stated that there was no significant differences between
treatments.
Quality of life
This study also measured claudication-associated pain using a 10-
point scale to estimate intensity. Results showed that both treat-
ments were associated with a significant improvement in pain,
with the improvement most pronounced in the L-arginine group
(P < 0.05).
Ankle brachial index (ABI)
Böger 1998 detected no difference in the ABI between patients
treated with PGE1 and L-arginine.
PGI2 versus placebo (Comparison 6)
Walking distances
Six studies (Creager 2008; Lièvre 1996; Lièvre 2000; Mohler 2003;
Virgolini 1989; Virgolini 1990) measured the efficacy of prosta-
cyclins against a placebo: one (Creager 2008) compared iloprost,
three studies (Lièvre 1996; Lièvre 2000; Mohler 2003) compared
beraprost, and the remaining two studied taprostene (Virgolini
1989; Virgolini 1990). Creager 2008 conducted a study in which
260 patients received three different dosages of iloprost: 50 µg
twice-daily (n = 87), 100 µg twice-daily (n = 86), and 150 µg
twice-daily (n = 87). In contrast, 84 patients were given a placebo.
Data on PFWD and MWD were presented as mean percentage
changes from baseline to follow up. At six months, PFWD im-
proved by 3.3% in the placebo group compared to 7.7%, 8.8%
and 11.2% in the iloprost 50 µg, 100 µg and 150 µg groups respec-
tively, while MWD improved by 3.2%, 7.1%, 13.7% and 25.7%
in the placebo and three iloprost groups respectively. As the mean
walking distances and SDs after treatment were not reported, it
was not possible to perform statistical analyses on the data. Con-
tact was made with the author to obtain the raw data but attempts
were unsuccessful.
Three studies (Lièvre 1996; Lièvre 2000; Mohler 2003) analysed
the effects of beraprost (BPS) versus placebo. All three studies ad-
ministered a 120 µg dose of BPS; Lièvre 1996 administered treat-
ment for 12 weeks, Lièvre 2000 administered treatment for six
months, while the study by Mohler 2003 administered treatment
for one year. Walking distances at 12 weeks were used in order to
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
make the results comparable but data from other time points were
also reported. The studies by Lièvre 2000 and Mohler 2003 could
not be included in a meta-analysis as the study authors only pro-
vided log-transformed values without SDs. Lièvre 1996 reported
baseline PWFD and MWD and presented results as percentage
change from baseline to follow up. As the SDs for the percentage
change were presented, it was possible to conduct statistical anal-
ysis on this study. Results showed that while BPS was associated
with an improvement in PFWD, it was not statistically signifi-
cant (MD 56%, 95% CI -13% to 126%). The same was true for
MWD, which improved by 99% and 61% in the two groups re-
spectively (MD 38%, 95% CI -23% to 99%). These results were
supported by Mohler 2003, who reported that BPS was not more
effective than placebo in the improvement of walking distances at
12, 18 and 24 weeks (all P > 0.05). The study by Lièvre 1996 also
reported change in walking distance in metres but as they did not
present SDs for the final distances it was not possible to include
this study in a meta-analysis based on final walking distance.
The study by Lièvre 1996 also administered doses of 60 µg and
180 µg of BPS daily. BPS administered at a dose of 60 µg improved
PFWD by 129% (SD 210%) compared with placebo (58% (SD
107%)) but the improvement was not statistically significant (MD
76%, 95% CI -0.4% to 142%). The MWD increased by 142%
(SD 318%) and 61% (SD 92%) in the BPS 60 µg and placebo
groups respectively, but again this improvement was not statisti-
cally significant (MD 81%, 95% CI -19% to 181%). At a higher
dose of 180 µg, PFWD was improved by 51% (SD 114%) com-
pared to 58% (SD 107%) with placebo (MD -7%, 95% CI -56%
to 41%) while MWD was improved by 69% (SD 133%) and 61%
(SD 92%) in the BPS 180 µg and placebo groups respectively
(MD 8%, 95% CI -42% to 58%).
In the two studies by Virgolini 1989 and Virgolini 1990, PFWD
and MWD were reported in seconds. For the purpose of this re-
view, the walking times were converted into metres. The study by
Virgolini 1989 evaluated taprostene versus placebo in 30 partic-
ipants (15 taprostene and 15 placebo). Analysis of the data sug-
gested that taprostene was not as effective as a placebo in improv-
ing PFWD (MD -9 m, 95% CI -12 to -6 m) but it is important to
note that the baseline walking distance was higher in the placebo
group. Taprostene was associated with an increase in MWD of 11
m (95% CI 0 to 22 m) but again the baseline MWD was higher in
the placebo group, thus suggesting that the effect of taprostene was
greater than as reported in the analysis. In the study by Virgolini
1990, 54 patients were randomised to PGI2 and 54 were given
a placebo. The baseline PFWD and MWD were comparable be-
tween the two treatment groups. Although walking distances ap-
peared to improved with taprostene, this was not to a statistically
significant degree (PFWD MD 6 m, 95% CI -9 to 22 m; MWD
MD 18 m, 95% CI -11 m to 48 m).
Table 5; Table 6
13
Quality of life
The study by Lièvre 2000 demonstrated a marginally significant
improvement in quality of life in favour of BPS treatment (P =
0.049), with specific items such as ’going out’, ’general condition’,
’relationships with people’ and ’concerns about health’ showing
increased satisfaction. Mohler et al (Mohler 2003) observed no
significant differences in quality of life parameters between oral
prostacyclin and placebo.
Ankle brachial index (ABI)
Lièvre 2000 specified ABI as an outcome. Data were not presented
but the study authors reported that there was no difference in ABI
during the exercise tests between the two treatment groups.
Adverse events
Four of the six studies (Creager 2008; Lièvre 1996; Lièvre 2000;
Mohler 2003) measured adverse events associated with PGI2. In
the study by Creager 2008 one patient in the placebo group died
but there were no major amputations. The rate of revascularisa-
tion was 5.7%, 5.8% and 1.1% in the iloprost 50 µg, 100 µg and
150 µg groups respectively, compared to 6% in the placebo group.
Headache was reported in 44%, 64% and 67% of the iloprost
50 µg, 100 µg and 150 µg groups compared to 16% of placebo-
treated patients. There was no significant difference in the rate
of flushing between the two treatments (5% iloprost versus 4%
placebo). Pain in the extremity, jaw pain, nausea and diarrhoea oc-
curred more frequently in the iloprost group compared to placebo.
Cardiovasular events occurred at a similar rate between the two
groups. The rate of adverse events leading to discontinuation of
the study medications was two to three-fold higher in the iloprost
groups than with placebo (31%, 57% and 53% for 50 µg, 100
µg and 150 µg iloprost groups respectively, compared to 14% in
the placebo group). Mohler 2003 reported five cases of myocar-
dial infarction and four cardiovascular deaths in the placebo group
and one cardiovascular death in the BPS group. No limb ampu-
tation occurred but four BPS and eight placebo patients under-
went limb revascularisation. In the study by Lièvre 1996, the rate
of adverse events did not differ significantly by treatment group:
10 in the placebo group, 17 in the BPS 60 µg group, 13 in the
BPS 120 µg group, and 19 in the BPS 180 µg group (P = 0.113).
The most common adverse events were gastrointestinal disorders,
headache, skin complaints and flushes. Lièvre 2000 reported that
fewer critical cardiovascular events (that is death and myocardial
infarction) occurred in the BPS group (OR 0.28, 95% CI 0.1 to
0.78). Arterial thrombosis of the leg occurred in 8 BPS and 14
placebo patients (OR 0.57, 95% CI 0.23 to 1.38). Drug-related
adverse events occurred at a significantly higher rate in the patients
treated with BPS (OR 2.66, 95% CI 1.40 to 5.03). Side effects
led to discontinuation of the study drug in 18 BPS and 31 placebo
patients respectively.
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
PGI2 versus pentoxifylline (Comparison 7)
Walking distances
Creager 2008 also compared 270 iloprost patients with 86 patients
who received pentoxifylline. At six months, PFWD increased by
24%, 28.9% and 31.2% for the groups treated with twice-daily 50
µg, 100 µg and 150 µg iloprost respectively, compared to 34.3%
in patients treated with pentoxifylline. Furthermore, the MWD
increased by 7.7%, 8.8% and 11.2% for the three iloprost dosage
groups respectively, compared to 13.9% with pentoxifylline. How-
ever, the study authors did not report SDs so it was impossible
to determine if the improvement in PFWD and MWD observed
with pentoxifylline was statistically significant.
Adverse events
One death occurred in the pentoxifylline group (OR 0.11, 95%
CI 0 to 2.71). Revascularisation rates were similar between the
two treatment groups, both when all iloprost doses were combined
(OR 1.86, 95% CI 0.48 to 5.09) and when the three doses were
compared individually (50 µg twice-daily OR 2.56, 95% CI 0.48
to 13.57; 100 µg twice-daily OR 2.59, 95% CI 0.49 to 13.74; 150
µg twice-daily OR 0.49, 95% CI 0.04 to 5.49). No major ampu-
tations occurred in this study. Headache was reported in 44% of
patients receiving iloprost 50 µg twice-daily, in 64% of those re-
ceiving iloprost 100 µg twice-daily and in 67% of those receiving
150 µg twice-daily, compared to 19% of patients treated with pen-
toxifylline. Additionally, while the frequency of flushing was com-
parable between the pentoxifylline (2%) and iloprost 50 µg twice-
daily (5%) groups, it increased in a dose-respondent manner to
23% in patients receiving 100 µg twice-daily and 31% in patients
receiving 150 µg twice-daily iloprost. Furthermore, diarrhoea oc-
curred more often in iloprost-treated patients (13%) than pentox-
ifylline-treated patients (6%). On the other hand, mild dyspepsia
occurred at twice the frequency in patients receiving pentoxifylline
(13%) compared to those receiving 50 to 100 µg iloprost twice-
daily (6%). The occurrence of adverse events led to discontinua-
tion of treatment in 31%, 57% and 53% of the twice-daily 50 µg,
100 µg and 150 µg iloprost groups respectively, compared to 15%
of the pentoxifylline group.
PGI2 versus hydroxy-ethyl starch (HES) (Comparison
8)
Walking distances
One study (Müller-Bühl 1987) compared iv iloprost (11 partici-
pants) versus iv hydroxyl-ethyl starch (HES) (12 participants). At
the end of a two-week treatment period, PFWD improved by 36.5
m (59%) in PGI2 patients compared to 17.9 m (31%) in HES
14
patients while the corresponding improvements in MWD were
50.2 m (49%) and 44.6 m (45%) in the two treatment groups
respectively. The improvements in final PFWD (22 m, 95% CI -
8.9 m to 53.3 m) and final MWD (7.4 m, 95% CI -49.8 m to
64.6 m) were not statistically significant.
Ankle brachial Index (ABI)
The Doppler brachiocrural index did not change significantly in
either treatment group. At baseline the ABI was 0.63 (SD 0.38)
in the iloprost group and rose to 0.77 (SD 0.55) after 10 days of
treatment; while in the HES group, the baseline ABI was 0.55 (SD
0.25) and rose to 0.71 (SD 0.38) after 10 days. The ABI remained
higher than baseline at both two and six weeks after treatment in
both groups.
Venous occlusion plethysmography
A slight increase in calf blood flow was shown by venous occlusion
plethysmography at rest and after tourniquet ischaemia, but this
was not significant.
Haemorrheological parameters
Study authors (Müller-Bühl 1987) reported that the haematocrit
level declined to the lowest mean value of 40.6% at the end of
HES treatment but returned to normal levels during the six-weeks
follow up. The change in haematocrit level in the iloprost group
was less pronounced, with a lowest mean value of 42.3%. In
both groups, neither plasma viscosity nor erythrocyte aggregation
changed significantly. Furthermore, plasma thrombin time and
the thromboelastogram were in the normal range before and after
both iloprost and HES treatment.
Adverse events
Flushing occurred in 82% of iloprost patients at the beginning of
infusion while mild headache and nausea also occurred. However,
none of these events led to the discontinuation of iloprost treat-
ment.
DISCUSSION
We reviewed 18 randomised controlled trials studying the clinical
effectiveness of prostanoids in patients with intermittent claudi-
cation (IC).
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Summary of main results
Results of some individual studies included in this review suggested
that PGE1 improved walking capacity in patients with IC. Five
studies reported that walking capacity even continued to increase
after termination of treatment (Belch 1997; Creutzig 1988; Hepp
1996; Mangiafico 2000; Scheffler 1994). Two studies (Diehm
1989; Scheffler 1994) suggested that PGE1 is beneficial as an ad-
dition to physical training and leads to a greater improvement in
walking distances than with exercise alone. However, the quality
of the studies is variable and the individual results could not be
strengthened by pooled analysis. Therefore, the overall evidence is
insufficient to determine whether or not patients with IC derive
clinically meaningful benefit from administration of PGE1. Data
concerning the effects of beraprost sodium are conflicting with one
study reporting an increase in walking distances while two studies
demonstrated it had no significant effect. Results from individual
trials also suggested that walking distances improved in a dose-
dependent manner with iloprost, a prostacyclin analogue (PGI2).
However iloprost was also associated with an increased incidence
of drug-related adverse events, particularly at higher doses. Pen-
toxifylline may be a useful alternative as it was associated with an
improvement in walking distances, but it did not produce fewer
drug-related side effects than PGI2.
Overall completeness and applicability of
evidence
The search identified studies of the majority of well-known treat-
ments for IC, including prostaglandin, pentoxifylline and PGI2.
However, studies on cilostazol were not identified in the completed
searches.
Three studies provided no information about participants’ charac-
teristics (especially risk factors for the development of atheroscle-
rosis, for example smoking habits, hypertension, dyslipidaemia or
diabetes mellitus) and therefore a potential heterogeneity between
the study groups that may influence the final results could not
be rated (Diehm 1989; Luk’Janov 1995; Müller-Bühl 1987). The
additional effect of vascular training could not be included in our
analysis because only eight studies clearly mentioned this impor-
tant part of therapy, and described a daily, controlled or super-
vised training for all randomised groups (Böger 1998; Creutzig
1988; Diehm 1989; Hepp 1996; Lièvre 1996; Mangiafico 2000;
Mohler 2003; Scheffler 1994). The remaining studies provided
no information concerning the start or continuation of a training
program. It is possible that the lack of this important information
could have influenced our final results. Three studies did not men-
tion whether other vasoactive or antiplatelet drugs were continued
during the study (Blume 1986; Milio 2006; Müller-Bühl 1987).
The possible administration of these drugs could have lead to false
positive results and should therefore should be considered in the
interpretation of this publication.
15
The major problem of our review was the limited comparability of
the included studies, as our analyses revealed a significant hetero-
geneity between the studies. Additionally, different study designs
have to be considered in the interpretation of the included studies
used; the duration of administration and therefore the total dosages
of the study drugs differed significantly between the studies. In ad-
dition, different walking treadmills were used to determine walk-
ing distances, with gradients ranging from 5 ° to 12 ° and walking
speeds ranging from 2 km/h to 3.5 km/h. Due to the difference in
treadmill testing, results were not always comparable. For exam-
ple, it would be expected that a patient walking at a slower speed
or on a lower gradient would be able to walk further than a pa-
tient walking at a faster speed or a higher gradient. Therefore, final
walking distance is not always a true indication of the effectiveness
of treatment but is also influenced by the speed and gradient of
the treadmill. Ideally all studies would use a standardised protocol
to measure walking distances. However this was not the case. To
be as complete as possible, final walking distances were converted
regardless of the treadmill test but the review authors did so know-
ing that this would introduce heterogeneity between individual
studies. Seventeen of the 18 included studies used a constant load
test and one used a graded test (Creager 2008). Authors of this
study did not present final walking distances but rather a percent-
age change from baseline. Without the final walking distance and
standard deviations, it was not possible to convert the results of the
graded test to make them comparable with a constant load test.
However, as this study was not included in a meta-analysis, it had
no effect on the overall result. Most of the studies enrolled only a
small number of participants and therefore their statistical power
appears low, generating a considerable beta-error. Additional sta-
tistical problems occurred in the analysis of 15 studies (Belch 1997;
Blume 1986; Böger 1998; Creager 2008; Creutzig 1988; Diehm
1989; Diehm 1997; Hepp 1996; Lièvre 2000; Luk’Janov 1995;
Mangiafico 2000; Milio 2006; Mohler 2003; Müller-Bühl 1987;
Scheffler 1994) because the standard deviations of the results were
missing and therefore significance levels could not be assessed.
Quality of the evidence
A restriction of this review was that the majority of studies did
not provide enough information to permit a judgement on the
risk of selection, performance, attrition, detection and reporting
biases. Attempts were made to contact authors for more infor-
mation but only one author (Milio 2006) responded with the re-
quired information. The major problem was the lack of informa-
tion about methods of randomisation and blinding, and the num-
ber of withdrawals and dropouts. In addition, several methodolog-
ical errors of the published data were evident. In five studies base-
line values of walking distances were determined by a single mea-
surement (Luk’Janov 1995; Müller-Bühl 1987; Virgolini 1989;
Virgolini 1990). This could have generated false results because
the remaining studies observed variations of walking distances in
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
several participants of more than 20% between two measurements
(performed in the pre-treatment period) and excluded these pa-
tients from participation in the study (Belch 1997; Blume 1986;
Böger 1998; Creager 2008; Creutzig 1988; Diehm 1989; Diehm
1997; Hepp 1996; Lièvre 1996; Lièvre 2000; Mangiafico 2000;
Mohler 2003; Scheffler 1994).
Potential biases in the review process
In this systematic review we identified all the randomised con-
trolled trials (RCTs) that compared prostanoids to a placebo or
control treatment. Open or cohort studies were not included be-
cause prostanoids are a well studied drug over a long period of time,
and there is a significant number of RCTs available. We believe
our search for RCTs has been inclusive and it is unlikely that our
standardised methods of study selection and data extraction could
have introduced bias. Due to the heterogeneity of the included
studies, lack of standard deviations reported in the publications
and the variable presentation of the outcomes by the trialists, we
did not pool all the available data. This is likely to have resulted
in the conclusion of this review being less robust.
Two studies (Virgolini 1989; Virgolini 1990) presented walking
distances in seconds. In order to make these results comparable
with other studies, we converted the walking times in seconds to
walking distances in metres using the gradient and speed reported
by the authors. While this may have introduced some bias into
the review, we considered that not including the data would have
introduced even more bias.
Due to the lack of data presented in studies, it was not possible to
account for background exercise and treadmill testing. Variations
in exercise levels prior to participating in the study may have in-
troduced bias into the results. However as authors of the studies
did not clarify this, there was no way to assess the level of bias.
In most cases we presented final walking distances instead of the
percentage change in walking distance because of a lack of standard
deviations reported in the original publications. There are obvious
limitations in presenting final walking distances, the main one be-
ing that the final value does not take into account the change from
baseline. Furthermore, variations in treadmill testing meant that
walking distances were not always comparable between individual
studies, and this is likely to result in significant heterogeneity when
pooling the studies. Nevertheless it was decided to use all available
data in order to make the analysis as complete as possible.
Agreements and disagreements with other
studies or reviews
To date, no systematic review has examined the effect of
prostanoids on intermittent claudication (IC). Three systematic
reviews (Ernst 1994; Frampton 1995; Salhiyyah 2012) have mea-
sured the effectiveness of pentoxifylline on improving walking dis-
16
tance in IC. A greater improvement in PFWD and TWD has been
shown for pentoxifylline-treated patients compared with placebo.
However, the studies were poor quality and the large degree of
heterogeneity between them resulted in the reviews concluding
that the overall clinical effect of pentoxifylline was unclear. One
review (Ruffolo 2010) measured the effectiveness of prostanoids
in treating critical limb ischaemia (CLI) and, while there were
some positive results regarding rest pain relief, ulcer healing and
amputations, the reviewers determined that there was no conclu-
sive evidence on the long-term effectiveness and safety of different
prostanoids in patients with CLI.
AUTHORS’ CONCLUSIONS
Implications for practice
Due to many methodological errors, lack of data, and variations
in the protocols for treadmill testing between individual studies,
there is insufficient high quality evidence to suggest that PGE1
produces any clinical benefit on walking distance in patients with
IC.
Implications for research
Further well-conducted randomised double blinded trials that
include a sufficient number of participants to provide statisti-
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References to studies included in this review
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cal power should be performed to overcome methodological er-
rors evident in the published literature. Standardised, supervised
vascular training performed by a control group during study
and follow-up phases should be compared with the administra-
tion of prostanoids. Studies investigating the additional effects of
prostanoids during exercise should only compare groups which
perform the same training program in order to provide clear
data. Concomitant vasoactive therapy should not be administered.
Study drug dosage and the administration regime should follow
manufacturers’ recommendations and standardised treadmill tests
should determine walking distances. To analyse long-term effects
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a follow up of at least one year. The following outcome parameters
should be considered: (1) pain-free and maximal walking distance
by standardised treadmill test; (2) ABI; (3) occurrence of ampu-
tation and vascular surgery; (4) drug side effects; and (5) quality
of life. A cost-effectiveness analysis would also be informative.
ACKNOWLEDGEMENTS
We would like to thank Markus Reiter, Robert Bucek, Andreas
Stumpflen and Erich Minar for their work on the earlier ver-
sion of this review. The review authors would like to thank the
Cochrane Peripheral Vascular Disease Review Group, especially
Marlene Stewart and Karen Welch for their invaluable support
and advice.
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Diehm C, Stammler F, Hubsch MC, Eckstein HH.
Intravenous prostaglandin E1 infusions in peripheral arterial
(AVK) Stadium III - A placebo-controlled study. Zeitschrift
fur Kardiologie 1987;76 Suppl 1:101.
Weiss T, Wilhelm C, Hübsch-Müller C, Hsu E, Diehm C.
Does infusion therapy in trained patients with intermittent
claudication have advantages? [Bringt eine Infusionstherapie
bei austrainierten Patienten mit Claudicatio intermittens
Vorteile?]. Vasa - Supplementum 1990;30:142–5.
Diehm 1997 {published data only}
Diehm C, Balzer K, Bisler H, Bulling B, Camci M, Creutzig
A, et al. Efficacy of a new prostaglandin E1 regimen in
outpatients with severe intermittent claudication: results of
a multicenter placebo-controlled double-blind trial. Journal
of Vascular Surgery 1997;25(3):537–44.
Hepp 1996 {published data only}
∗
Hepp W, von Bary S, Corovic D, Diehm C, Mühe E,
Rudofsky G, et al. Clinical efficacy of iv prostaglandin
E1 and iv pentoxifylline in patients with arterial occlusive
disease of Fontaine stage IIb: A multicenter, randomized
comparative study. International Journal of Angiology 1996;
5(1):32–7.
Hepp W, von Bary S, Corovic D, Diehm C, Mühe E,
Rudofsky G, et al. Intravenous prostaglandin E1 versus
pentoxifylline: a randomized controlled study in patients
with intermittent claudication. International Angiology
1995;14 Suppl 1:280.
Hepp W, von Bary S, Corovic D, Diehm C, Mühe E,
Rudofsky G, et al. Randomized study comparing the
clinical effectiveness of intravenous prostaglandin E1 and
intravenous pentoxifylline in patients with Fontaine stage
IIb arterial occlusive disease [Randomisierte Studie zum
Vergleich der klinischen Wirksamkeit von i.v. Prostaglandin
E1 und i.v. Pentoxifyllin bei Patienten mit arterieller
Verschlußkrankheit im Stadium IIb nach Fontaine.]. VASA
- supplementum 1991;33:348–9.
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lièvre 1996 {published data only}
Labs KH, Nehler MR, Roessner M, Jaeger KA, Hiatt WR.
Reliability of treadmill testing in peripheral arterial disease:
a comparison of a constant load with a graded load treadmill
protocol. Vascular Medicine 1999;4(4):239–46.
∗
Lievre M, Azoulay S, Lion L, Morand S, Girre JP, Boissel
JP. A dose-effect study of beraprost sodium in intermittent
claudication. Journal of Cardiovascular Pharmacology 1996;
27(6):788–93.
Lièvre 2000 {published data only}
Lievre M, Morand S, Lion L, Boissel JP. Effects of beraprost
sodium in intermittent claudication: results of BERCI-
2, a randomized study, placebo-controlled, double-blind.
Fundamentals in Clinical Pharmacology 1997;11:182.
∗
Lièvre M, Morand S, Besse B, Fiessinger JN, Boissel
JP, (BERCI) Research Group. Oral beraprost sodium, a
prostaglandin I(2) analogue, for intermittent claudication:
a double blind, randomized, multicenter controlled trial.
Circulation 2000;102(4):426–31.
Luk’Janov 1995 {published data only}
∗
Luk’Janov Y. Hemorheologic and hemodynamic changes
after treatments with PGE versus pentoxifyllin (PF) in
patients with peripheral arterial disease (PAD). International
Angiology 1995;14 Suppl 1:372.
Mangiafico 2000 {published data only}
Mangiafico RA, Messina R, Attina T, Dell’Arte S, Giuliano
L, Malatino LS. Impact of a 4-week treatment with
prostaglandin E1 on health-related quality of life of patients
with intermittent claudication. Angiology 2000;51(6):
441–9.
Milio 2006 {published data only}
Milio G, Coppola G, Novo S. The effects of prostaglandin
E1 in patients with intermittent claudication. Cardiovascular
and Haematological Disorders Drug Targets 2006;6(2):71–6.
Mohler 2003 {published data only}
Mohler ER 3rd, Hiatt WR, Olin JW, Wade M, Jeffs
R, Hirsch AT. Treatment of intermittent claudication
with beraprost sodium, an orally active prostaglandin I2
analogue: a double-blinded, randomized, controlled trial.
Journal of the American College of Cardiology 2003;41(10):
1679–86.
Müller-Bühl 1987 {published data only}
Müller-Bühl U, Diehm C, Krais T, Zimmermann R, Mörl
H, Eckstein HH. Clinical effects of intravenous iloprost in
patients with intermittent claudication. European Journal of
Clinical Pharmacology 1987;33(2):127–31.
Scheffler 1994 {published data only}
Scheffler P, de la Hamette D, Gross J, Mueller H, Schieffer
H. Intensive vascular training in stage IIb of peripheral
arterial occlusive disease. The additive effect of intravenous
prostaglandin E1 or intravenous pentoxifylline during
training. Circulation 1994;90(2):818–22.
Virgolini 1989 {published data only}
Virgolini I, Fitscha P, O’Grady J, Barth H, Sinzinger H.
Effects of taprostene, a chemically stable prostacyclin
analogue in patients with ischaemic peripheral vascular
18
 disease: a placebo controlled double-blind trial.
Prostaglandins Leukotrienes and Essential Fatty Acids 1989;38
(1):31–5.
Virgolini 1990 {published data only}
Virgolini I, Fitscha P, Linet OI, O’Grady J, Sinzinger H.
A double blind placebo controlled trial of intravenous
prostacyclin (PGI2) in 108 patients with ischaemic
peripheral vascular disease. Prostaglandins 1990;39(6):
657–64.
References to studies excluded from this review
Acciavatti 2001 {published data only}
Acciavatti A, Pasine FL, Capecchi PL, Messa GL, Lazzerini
PE, De Giorgi L, et al. Effects of alprostadil on blood
rheology and nucleoside metabolism in patients affected
with lower limb chronic ischaemia. Clinical Hemorheology
and Microcirculation 2001;24(1):49–57.
Anon 2011 {published data only}
NCT0126392. Prostaglandin E1 in outpatients with
intermittent claudication. http://clinicaltrials.gov/ct2/
show/NCT01263925?term=NCT01263925&rank=1
2011.
Barradas 1989 {published data only}
Barradas MA, Fonseca VA, Mikhailidis DP, Dandona P.
The effect of iloprost infusion on platelet function in
patients with peripheral vascular disease. Journal of Drug
Development 1989;2(3):147–53.
Bieron 1993 {published data only}
Bieron K, Grodzinska L, Kostka-Trabka E, Gryglewski RJ.
Prostacyclin and molsidomine synergise in their fibrinolytic
and anti-platelet actions in patients with peripheral arterial
disease. Wiener Klinische Wochenschrift 1993;105(1):7–11.
Diehm 1990 {published data only}
Diehm C, Wilhelm C, Weiss T, Schomig A, Kubler
W. Effects of an intravenous infusion treatment with
prostaglandin PGE1 and naftidrofuryl in trained patients
with claudicatio intermittens. Zeitschrift fur Kardiologie
1990;79 Suppl 1:89.
Esato 1995a {published data only}
Esato K, Yasuda K, Abe T, Hoshino S, Ishimaru S, Hori G,
et al. Clinical study of TTC-909 (Prostacyclin derivative,
Clinprost Incorporated in Lipid Microspheres) in patients
with peripheral arterial occlusive disease: Establishment
of optimal dose in multi-center double-blind comparative
study. Rinsho Iyaku 1995;11(10):2083–110.
Esato K, Yasuda K, Abe T, Hoshino S, Ishimaru S, Hori G,
et al. Clinical study of TTC-909 (Prostacyclin derivative,
Clinprost Incorporated in Lipid Microspheres) in patients
with peripheral arterial occlusive disease: Establishment
of optimal dose in multi-center double-blind comparative
study. Rinsho Iyaku 1997;13(21):5595–622.
Esato 1995b {published data only}
Esato K, Yasuda K, Abe T, Hoshino S, Ishimaru S, Hori G,
et al. [Studies on the clinical efficacy and safety of TTC-
909 in the treatment of peripheral arterial occlusive disease:
a multi-center double-blind comparison with Alprostadil
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Incorporated in Lipid Microspheres]. Rinsho Iyaku 1995;11
(10):2111–41.
Fitscha 1985 {published data only}
Fitscha P, Sinzinger H. Clinical effects of iloprost, a
stable prostacyclin analogue in patients with peripheral
vascular disease. In: Maurer PC, Becker HM, Heidrich H,
Hoffmann G, Kriessmann A, Muller-Wiefel H, Pratorius
C editor(s). What is New in Angiology? Trends and
Controversies. Munich, West Germany: W Zuchschwerdt,
1986:537–8.
Fitscha P, Sinzinger H, Tiso B. Prostaglandin E1 in
peripheral occlusive disease. Zeitschrift fur Kardiologie 1985;
74 Suppl 5:105.
Fitscha P, Tiso B, Sinzinger H. Iloprost in peripheral
vascular disease - platelet function and clinical outcome.
Progress in Clinical and Biological Research 1987;242:463–8.
Sinzinger H, Fitscha P. The effect of Iloprost on haemostasis
in peripheral arterial occlusive disease [Einfluß von
Iloprost auf die Hämostase bei peripherer arterieller
Verschlußkrankheit (PVK)]. Vasa - Supplementum 1987;20:
253–5.
Sinzinger H, Fitscha P, Popovic R, Krais T. Clinical and
platelet effects of ZK 36374 (Iloprost) - A stable prostacyclin
analogue - in peripheral vascular disease. Thrombosis and
Haemostasis 1985;54(1):294, Abstract 1747.
Goya 2003 {published data only}
Goya K, Otsuki M, Xu X, Kasayama S. Effects of the
prostaglandin I2 analogue, beraprost sodium, on vascular
cells and circulating vascular cell adhesion molecule-1 level
in patients with type 2 diabetes mellitus. Metabolism:
Clinical and Experimental 2003;52(2):192–8.
Hay 1987 {published data only}
Hay CR, Waller PC, Carter C, Cameron HA, Parnell L,
Ramsey LE, et al. Lack of effect of a 24-hour infusion of
iloprost in intermittent claudication. Thrombosis Research
1987;46(2):317–24.
Ishitobi 1991 {published data only}
Ishitobi K, et al. Therapeutic efficacy of iloprost, a
prostacyclin analogue for chronic arterial occlusion: a
double-blind comparative study with PGE1. Rinsho to
Kenkyu 1991;68:1836–50.
Linhart 1998 {published data only}
Linhart J. Prostaglandin therapy of peripheral occlusive
arterial disease. Sbornik Lekarsky 1998;99(4):355–62.
Okadome-Kenchiro 1992 {published data only}
Okadome-Kenchiro, et al. Efficacy of lipo PGE1 in
combination with an oral anti-platelet agent in chronic
arterial obstruction: A multicenter comparative study.
Rinsho to Kenkyu 1992;69:3655–62.
Rudofsky 1987 {published data only}
Rudofsky G. Intra-arterial infusion treatment with
prostaglandin E1 in patients with intermittent claudication
[Intraarterialle Infusionsbehandlung mit Prostaglandin
19
 E1 bei Patienten mit Claudicatio intermittens]. Wiener
Klinische Wochenschrift 1988;100(14):484–8.
Rudofsky G, Altenhoff B, Meyer P, Lohmann A. Intra-
arterial perfusion with prostaglandin E1 in patients with
intermittent claudication. VASA - Supplementum 1987;17:
47–51.
Rudofsky 1988 {published data only}
Rudofsky G. Intravenous infusion therapy using
prostaglandin E1 in patients with peripheral arterial occlusive
disease Stage 11b [Intravenöse PGE1–Infusionsbehandlung
bei Patienten mit arterieller Verschlußkrankheit im Stadium
IIb]. In: Heidrich H, Böhme H, Rogatti W editor
(s). Prostaglandin E1 - Wirkungen und therapeutische
Wirksamkeit. Berlin: Springer - Verlag, 1988:103–11.
Sakaguchi-Shukichi 1990 {published data only}
Sakaguchi-Shukichi, et al. Evaluation of the efficacy of
beraprost sodium (PGI2 analogue) in chronic arterial
occlusion: a double-blind comparative study with
ticlopidine hydrochloride. Rinsho to Kenkyu 1990;67:
575–84.
Waller 1986 {published data only}
Waller PC, Hay CRM, Cameron HA, Carter C, Parnell
L, Greaves M, et al. Placebo controlled trial of iloprost
in patients with stable intermittent claudication. British
Journal of Clinical Pharmacology 1986;21:562P–3P.
Wang 2009 {published data only}
Wang X, Chen S, Yu F, Li H. Effect of prostaglandin E1
and traditional Chinese medicine on limb atherosclerosis
obliterns. Practical Pharmacy and Clinical Remedies 2009;
12(6):399–400.
Wilkinson 1988 {published data only}
Wilkinson D, Parkin A, Kester RC. Does iloprost benefit
the patient with claudication? Results of a double-blind
placebo-controlled trial. British Journal of Surgery 1989;76
(12):1330–1.
Wilkinson D, Parkin A, Kester RC. Does iloprost benefit
the patient with claudication? Results of a double-blind
placebo-controlled trial. Journal of Cardiovascular Surgery
1988;29:72.
Ylitalo 1990 {published data only}
Ylitalo P, Kaukinen S, Reinikainen P, Salenius JP, Vapaatalo
H. A randomized, double-blind, crossover comparison
of iloprost with dextran in patients with peripheral
arterial occlusive disease. International Journal of Clinical
Pharmacology, Therapy and Toxicology 1990;28(5):197–204.
References to studies awaiting assessment
Nakagawa 1998 {published data only}
Nakagawa T, Sanke T, Anaguchi R, Konami T, Useda K,
Bessho H, et al. The prophylactic effect of beraprost on
development of atherosclerosis in non-insulin dependent
diabetes mellitus patients. Journal of the Japan Diabetes
Society 1998;41(11):989–94.
References to ongoing studies
Prostanoids for intermittent claudication (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Valerio 2012 {published data only}
Valerio A, Gussoni G, Anastasio L, Mazzuca S, Bitti G,
Cardinale A, et al. Effect of Iloprost on pain-free walking
distance and clinical outcomes in patients with IIb-stage
peripheral artery disease non-eligible for surgery. The
FADOI - 2bPILOT study. Italian Journal of Medicine 2012;
6:143.
Valerio A, Gussoni G, Fontanella A, Anastasio L, Bitti
G, DiSalvo M, et al. Clinical improvement in patients
treated with iloprost at iib-stage peripheral arterial disease.
The multicenter randomized fadoi-2bpilot study. Blood
Transfusion 2012;10:s49–50.
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Beard 2000
Beard J. ABC of arterial and venous disease: critical limb
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Coffman 1991
Coffman JD. Intermittent claudication -- be conservative.
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Davis 2005
Davis M. Critical limb ischemia, ulcers and gangrene. The
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De Backer 2000
De Backer TL, Vander Stichele RH, Bogaert MG.
Buflomedil for intermittent claudication. Cochrane
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Ernst E. Pentoxifylline for intermittent claudication. A
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Grant 1992
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Pell 1995
Pell JP. Impact of intermittent claudication on quality of
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of Vascular and Endovascular Surgery 1995;9(4):469–72.
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Van den Brande P, Maurel A. A placebo-controlled study
of the effects of intravenous Buflomedil on foot skin
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Reiter 2003
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∗
Indicates the major publication for the study
21
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Belch 1997

Methods Study design: randomised, double blind, placebo-controlled study

Randomisation method: randomised code generated from random-number lists
Dropouts: none.
No. of groups: 4 treatment groups; placebo versus 3 different dosages of AS-013
For this analysis, placebo group and the group with the highest (= clinically most effective)
dosage of the study drug were compared

Participants Country: United Kingdom.

Setting: 7 centres.
No: 43 outpatients.
Age: treatment 72 years; control 69 years.
Sex: treatment 18 male, 4 female; control 16 male, 5 female.
Inclusion criteria: PAOD stage IIb; ABI 0.8; maximum WD 30 to 300 m
Exclusion criteria: WD difference > 30% between 2 tests.

Interventions Treatment: AS-013 5 µg/10 ml NaCl/10 min iv.

Control: placebo/10 ml NaCl/10 min iv.
Duration: 20 injections in 4 weeks.
Follow up: 4 weeks.

Outcomes Treadmill test (10% slope, 2 km/h):

- PFWD (m)
- MWD (m)
ABPI
Quality of life (questionnaire)
Side effects

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Treatment was assigned in a ran-
bias) domised code generated from random-
number lists”
Comment: Adequate description of alloca-
tion sequence generation. Low risk of se-
lection bias

Allocation concealment (selection bias) High risk Quote: “Random-number lists”

Comment: High risk of selection bias.
Cochrane checklist specifies that a list of
random numbers is associated with a high

Prostanoids for intermittent claudication (Review) 22

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Belch 1997 (Continued)

risk of selection bias

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Comment: No information on whether the
bias) outcome assessors were blinded to the treat-
All outcomes ment. Cannot permit judgement of low or
high risk of detection bias

Incomplete outcome data (attrition bias) Low risk All study participants are accounted for.
All outcomes Low risk of attrition bias

Selective reporting (reporting bias) High risk Study outcomes not clearly specified. High
risk of reporting bias

Other bias High risk Inclusion and exclusion criteria not explic-
itly stated and study design unclear. High
risk of bias

Blume 1986

Methods Study design: stated randomised, (no details given), double blind, placebo-controlled
study. PGE1 versus placebo
Dropouts: treatment 14; control 11 during follow up.

Participants Country: Germany

No: 50 participants.
Age: treatment 66 years; control 70 years.
Sex: treatment 13 male, 12 female; control 13 male, 12 female
Inclusion criteria: PAOD stage IIb for > 6 months, pain-free WD 40 to100 m
Exclusion criteria: WD difference > 20% between two tests within 2 weeks

Interventions Treatment: PGE1 10-20 µg/100 ml NaCl/90 min ia.

Control: placebo/100 ml NaCl/90 min ia.
Duration: 15 infusions in 3 weeks.
Follow up: 2 weeks.

Outcomes Treadmill test (5% slope, 3 km/h):

- PFWD (m)
- MWD (m)
Side effects

Notes

Risk of bias

Prostanoids for intermittent claudication (Review) 23

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Blume 1986 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Randomized”

bias) Comment: Trial described as randomised
but authors do not state how the random
allocation sequence was generated. Insuffi-
cient information to permit judgement of
low or high risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel High risk Treatment was intra-arterial infusion over
(performance bias) 90 minutes while placebo was an injec-
All outcomes tion. Impossible to blind treatment thus
the study was at high risk of bias of perfor-
mance bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
High risk 25 patients were randomised to PGE1 and
25 to a placebo but after 2 weeks only 11
PGE1 and 14 placebo patients completed
the follow up treadmill test. High risk of
attrition bias

Selective reporting (reporting bias) High risk Results of doppler studies, plethysmogra-
phy and laboratory tests are not presented
therefore the study is at high risk of report-
ing bias

Other bias Unclear risk Insufficient evidence to permit judgement

on level of bias.

Böger 1998

Methods Study design: randomised, double blind study. PGE1 vs. L-arginine vs. control group
without any treatment

Participants Country: Germany.

No: 39 patients with intermittent claudication.
L-arginine 13; PGE1 13; control 13.
Mean age: L-arginine 70.1 years; PGE1 66.1 years; control 66.8 years
Inclusion criteria: PAOD IIb.

Prostanoids for intermittent claudication (Review) 24

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Böger 1998 (Continued)

Exclusion criteria: rest-pain, systemic inflammation, renal or liver disease, indication

for surgery or angioplasty, concomitant diseases that are associated with reduced WD
(arthroses, arthritis, diseases of spinal column, venous diseases, cardiopulmonary insuf-
ficiency, neurologic diseases), or seriously impaired cerebral function
Exclusion criteria: pain-free WD > 20% on two occasions between 4 weeks
Patients continued their regular walking training.

Interventions Treatment: iv. L-arginine 2x8 g/day; iv. 2 x 40 µg PGE1/day.

Control no treatment.
Supervised walking training, for 3 weeks for all patients.

Outcomes Treadmill test (12% slope, 3 km/h)

- PFWD (m)
- MWD (m)
ABPI
Side effects

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomly assigned
bias) to one of three treatment groups”
Comment: Method of sequence generation
not stated. Insufficient information to per-
mit judgement of low or high risk of selec-
tion bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel High risk Blinding of two of the three treatment
(performance bias) groups was achieved but the third group re-
All outcomes ceived no treatment. Therefore the study is
at high risk of performance bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias) Low risk All data accounted for so study is at low risk
All outcomes of attrition bias

Selective reporting (reporting bias) Low risk Data is presented on all pre-specified out-
comes. Study is at low risk of reporting bias

Prostanoids for intermittent claudication (Review) 25

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Böger 1998 (Continued)

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Creager 2008

Methods Study design: prospective, double blind, randomised, placebo-controlled, parallel group
study

Participants Country: USA

Setting: 32 centres
No: 430. Iloprost 260, pentoxifylline 86, placebo 84
Sex: 349 (81.2% male), 81 (18.8%) female. Iloprost 213 male 47 female, pentoxifylline
67 male 19 female, placebo 69 male 15 female
Mean age: 67 years
Inclusion criteria: Participants aged ≥ 40 years with stable claudication for ≥ 3 months
prior to entry, despite standard care including cardiovascular risk factor modification
and exercise training, absolute claudication distance between 50-800 metres on baseline
eligibility exercise, ABI ≤ 0.90 in symptomatic leg, > 20% fall in ABI within 1 minute
following cessation of exercise. In patients with non-compressible vessels (ABI > 1.0),
toe-brachial index (TBI) at rest < 0.70. ACD measured by exercise treadmill on two to
three occasions at an interval of 7-14 days had to be within 20% of the ACD measured
at the previous exercise test
Exclusion criteria: Ischemic rest pain, ulcers, gangrene (Fontaine Stage III or IV), evi-
dence of non-atherosclerotic PAD, peripheral neuropathy that impaired walking ability,
revascularization procedure for PAD within preceding 3 months, sympathectomy within
6 months, type I diabetes mellitus, myocardial infarction or major cardiac surgery within
3 months, unstable angina, heart failure, receiving standard or low molecular weight
heparin, warfarin in combination with aspirin, or any drug specific for the treatment of
intermittent claudication

Interventions Treatment 1: Iloprost 50 mcg, 100 mcg or 150 mcg twice daily
Treatment 2: Pentoxifylline 400 mg three times daily.
Control: Placebo

Outcomes Treadmill test (3.2 km/hr at grade 0% increased by 2% every 2 minutes)

- Change in ACD between baseline and 6 months
- Change in initial claudication distance (ICD) between baseline and 6 months
Quality of life
Death at 6 months
Revascularisation at 6 months
Major amputation at 6 months

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Prostanoids for intermittent claudication (Review) 26

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Creager 2008 (Continued)

Random sequence generation (selection Unclear risk Quote: “Randomised”

bias) Comment: Trial described as randomised
but authors do not state how the random
allocation sequence was generated. Insuffi-
cient information to permit judgement of
low or high risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Number and size of capsules
All outcomes administered were similar within all treat-
ment groups to ensure blinding of partici-
pants but it is unclear if the study personnel
were also blind to the treatment regimen.
Unclear risk of performance bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias) High risk There was a huge loss to follow up (only
All outcomes 50% completed the 6 month follow up) in
this study and therefore there is a high risk
of attrition bias

Selective reporting (reporting bias) High risk Quality of life was a pre-specified outcome
but authors did not present data on this.
High risk of reporting bias

Other bias High risk The study was sponsored by a drug com-
pany and is therefore deemed to be at high
risk of bias

Creutzig 1988

Methods Study design: stated randomised, (no details given), double-blind, parallel study. PGE1
versus laevadosin
Dropouts: 5 dropouts in both groups during follow-up.

Participants Country: Germany.

No: 40 randomised patients.
Age: treatment 64 years; control 69.5 years.
Sex: treatment 12 male, 8 female; control 15 male, 5 female.
Inclusion criteria: PAOD stage II, stable over 6 months, maximal WD 30 to 200 m

Prostanoids for intermittent claudication (Review) 27

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Creutzig 1988 (Continued)

Exclusion criteria: WD difference > 20% between 2 treadmill tests during 4 weeks

Interventions Treatment: PGE1 5 µg/50 ml NaCl/50 min ia.

Control: Laevadosin (energy rich phosphates) 10 ml/50 ml NaCl/50 min ia
Duration: 36 infusions in 21 days.
Follow up: 9 months.

Outcomes Treadmill test (5% incline, 3 km/h):

- PFWD (m)
- MWD (m)
Side effects

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Randomized”

bias) Comment: Trial described as randomised
but authors do not state how the random
allocation sequence was generated. Insuffi-
cient information to permit judgement of
low or high risk of selection bias

Allocation concealment (selection bias) Unclear risk Method of allocation concealment not
stated. Insufficient information to permit
judgement of low or high risk of selection
bias

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
High risk Only 75% in each treatment group at-
tended follow up examination and the rea-
sons for withdrawals or drop outs are not
stated. Study deemed to be at high risk of
attrition bias

Selective reporting (reporting bias) High risk Not all pre-specified outcomes are reported
so the study is at high risk of reporting bias

Prostanoids for intermittent claudication (Review) 28

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Creutzig 1988 (Continued)

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Diehm 1989

Methods Study design: stated randomised, (no details given), double blind, parallel study. PGE1
versus naftidrofuryl
Drop outs: 1 in the experimental group during follow up.

Participants Country: Germany.

No: 48 randomised.
Age: treatment 58 years; control 65 years.
Sex: treatment 19 male, 5 female; control 20 male, 4 female.
Inclusion criteria: PAOD stage IIb, symptoms for > 1 year, pain-free WD following 6
months of supervised physical training < 250 m
Exclusion criteria: WD difference > 20% between 2 treadmill tests during 2 weeks

Interventions Treatment: PGE1 60 µg/250 ml NaCl/2h once daily iv.

Control: Naftidrofuryl 600 mg/250 ml NaCl/2h once daily iv.
Duration: 3 weeks.
Follow up: 3 months.

Outcomes Treadmill test (10% incline, 3.5 km/h):

- PFWD (m)
- MWD (m)
ABPI
Side effects

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomised”
bias) Comment: Authors describe the trial as
randomised but method of randomisation
not stated. Insufficient information to per-
mit judgement of low or high risk of selec-
tion bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Prostanoids for intermittent claudication (Review) 29

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Diehm 1989 (Continued)

Blinding of participants and personnel Unclear risk Insufficient information to permit judge-
(performance bias) ment of low or high risk of performance
All outcomes bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias) Low risk All data accounted for. Low risk of attrition
All outcomes bias.

Selective reporting (reporting bias) Low risk Data is presented on all pre-specified out-
comes. Low risk of reporting bias

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Diehm 1997

Methods Study design: stated randomised (no details given), double blind, placebo-controlled,
parallel study. PGE1 vs. placebo
Dropouts: 5 during treatment.

Participants Country: Germany, 16 centres.

No: 208 outpatients randomised, 208 evaluated.
Age: 62 years.
Sex: treatment 75 male, 31 female; control 80 male, 22 female
Inclusion criteria: PAOD stage II for > 6 months, stable for > 3 months, maximum WD
50 to 200 m
Exclusion criteria: WD difference > 25% between 2 treadmill tests within 2 weeks

Interventions Treatment: PGE1 60 µg/100 ml NaCl/2 hours iv.

Control: placebo/100 ml NaCl/2 hours iv.
Duration: 20 infusions in 4 weeks, followed by 8 infusions over the next 4 weeks
Follow up: 3 months.

Outcomes Treadmill test (12% slope, 3 km/h):

- PFWD (m)
- MWD (m)
Side effects

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Prostanoids for intermittent claudication (Review) 30

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Diehm 1997 (Continued)

Random sequence generation (selection Unclear risk Quote: “Patients were randomised”
bias) Comment: Authors describe the trial as
randomised but method of randomisation
not stated. Insufficient information to per-
mit judgement on risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of on risk of selection
bias

Blinding of participants and personnel Unclear risk Insufficient information to permit judge-
(performance bias) ment of low or high risk of performance
All outcomes bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias) High risk 42/213 protocol violations which were un-
All outcomes explained. High risk of attrition bias

Selective reporting (reporting bias) Low risk Data are presented on all pre-specified out-
comes. Low risk of reporting bias

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Hepp 1996

Methods Study design: Randomised, single blind study. PGE1 versus pentoxifylline (Ptx)
Dropouts: none during treatment period.

Participants Country: Germany, 8 centres.

No:195 participants (treated as inpatients).
Age: 65 years (range 39 to 84).
Sex: treatment 71 male, 25 female; control 71 male, 26 female
Inclusion criteria: PAOD stage IIb, stable for > 6 months, pain-free WD > 50 m, maxi-
mum WD < 200 m
Exclusion criteria: difference in pain-free WD > 20% between 2 tests within 7days

Interventions Treatment: PGE1 40 µg/250 ml NaCl x 2 hours iv. twice daily.

Control: Ptx 200 mg/250 ml NaCl x 2 hours iv. twice daily.
Duration: 4 weeks.
Follow up: 1 year.

Prostanoids for intermittent claudication (Review) 31

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hepp 1996 (Continued)

Outcomes Treadmill test (5% grade, 3 km/h):

- PFWD (m)
- MWD (m)
ABPI

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: ”The two patient groups formed by
bias) randomisation
Comment: Authors describe the trial as
randomised but method of sequence gen-
eration not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of on risk of selection
bias

Blinding of participants and personnel Unclear risk Insufficient information to permit judge-
(performance bias) ment of low or high risk of performance
All outcomes bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
High risk Only 31/97 PGE1 patients and 30/98 pen-
toxifylline patients completed a 12-month
follow up. Study deemed to be at high risk
of attrition bias due to large number of
withdrawals and losses to follow up

Selective reporting (reporting bias) Low risk Data are presented on all pre-specified out-
comes. Low risk of reporting bias

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Prostanoids for intermittent claudication (Review) 32

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lièvre 1996

Methods Study design: randomised, double blind, placebo versus 3 different BPS groups (40 µg
is used for analysis)
Randomisation method: telematic system (Minitel).
Dropouts: 15.

Participants Country: France.

No: 83 participants. Treatment 42; control 41.
Age: treatment 62 ± 10 years; control 61 ± 11 years.
Inclusion criteria: Fontaine II for at least 6 months, stable for 3 months, pain-free WD
50 to 300 m
Exclusion criteria: PAOD III+IV, recent acute ischaemia, undergoing physiotherapy dur-
ing the trial or operation in the next 6 months, evidence of non-atheromatous peripheral
occlusion, IDDM, diabetes with clinical neuropathy, SBP > 180 mmHg, DBP > 110
mmHg, recent MI or stroke, WD difference between 3 tests between 6 weeks
All other vasodilator or anti ischaemic drugs stopped.

Interventions Treatment: BSP 2 tablets BSP+one tablet placebo 3 x daily po for 12 weeks
Control: 3 tablets placebo 3 x daily.
Advice on diet, smoking, regular exercise given.

Outcomes Treadmill test (3.2% grade, 3.2 km/h)

- PFWD (m)
- MWD (m)
-ABPI

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomly assigned
bias) by telematic system”
Comment: Adequate description of ran-
dom sequence generation is provided. Low
risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of on risk of selection
bias

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Prostanoids for intermittent claudication (Review) 33

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lièvre 1996 (Continued)

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment of low or high risk of detection bias
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Data on number of dropouts and with-
drawals presented but cannot determine if
this was due to adverse events or withdrawal
of consent in the treatment groups. Insuffi-
cient information to permit judgement on
risk of attrition bias

Selective reporting (reporting bias) Low risk Data are presented on all pre-specified out-
comes. Low risk of reporting bias

Other bias Unclear risk Significantly higher rate of previous my-

ocardial infarction in placebo group com-
pared to the treatment group which could
potentially bias the study

Lièvre 2000

Methods Study design: randomised, double blind, multicenter, placebo-controlled study. BPS
versus placebo
Randomisation method: computer network (Minitel).

Participants Country: France, multicentre (66).

No: 422 patients. Treatment 209; control: 213.
Mean age: 62.9 years.
Sex: treatment 177 male, 32 female; control 179 male, 34 female
Inclusion criteria: PAD > 6 months, stable for 3 months, PFWD of 50 to 300 m. PFWD
change of < 25% between 2 run-in treadmill exercise tests
Exclusion criteria: Ischaemic rest pain, ulceration or gangrene, antiplatelet therapy, no
MI or stroke in the last 3 months, severe angina pectoris, IDDM
74 premature treatment discontinuations.

Interventions Treatment: 40 µg BSP.

Control: Placebo.
Both groups po TID for 6 months.

Outcomes Treadmill test (10% grade, 3 km/h):

- PFWD (m)
- MWD (m)
Quality of life

Notes Antiocoagulants and vasodilators were not allowed during the trial

Risk of bias

Prostanoids for intermittent claudication (Review) 34

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lièvre 2000 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: ”Patients were randomly assigned
bias) through a computer network (Minitel)“
Comment: Adequate description of ran-
dom sequence generation is provided. Low
risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of on risk of selection
bias

Blinding of participants and personnel Unclear risk Quote: ”Double blind“

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Quote: ’Every potential critical cardiovas-
bias) cular event was evaluated blindly by 3 ex-
All outcomes perienced cardiologists”
Comment: Investigators measuring CV
events were blinded to treatment but it
is unclear if investigators performing the
treadmill tests were blinded to treatment.
Insufficient information to permit judge-
ment on risk of detection bias

Incomplete outcome data (attrition bias) Low risk All data accounted for. Low risk of attrition
All outcomes bias.

Selective reporting (reporting bias) Low risk Data are presented on all pre-specified out-
comes. Low risk of reporting bias

Other bias Unclear risk Significant differences between treatment

groups with regards to number of pa-
tients on lifestyle modification prepara-
tions, presence of popliteal/anterior tibial
pulse and physical activity levels at baseline.
Imbalances likely to bias study results

Prostanoids for intermittent claudication (Review) 35

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Luk’Janov 1995

Methods Study design: randomised, double blind study. PGE1 versus Ptx

Participants Country: Russia.

No: treatment (PGE1) 42 patients; control (Ptx) 40 patients.
Mean age: 60.4 ± 6.8 years.

Interventions Treatment: 40 mg PGE1.

Control: 200 mg Ptx.
Both groups 3 h intravenous infusion twice daily for 12 months

Outcomes Treadmill test (5% grade, 3 km/h)

- PFWD (m)
ABPI

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Randomised”

bias) Comment: Trial described as randomised
but authors do not state how the allocation
sequence was generated. Insufficient infor-
mation to permit judgement of low or high
risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Methods to conceal allocation
sequence are not stated. Insufficient infor-
mation to permit judgement of low or high
risk of selection bias

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) Unclear risk Comment: Insufficient information to per-
All outcomes mit judgement of low or high risk of attri-
tion bias

Selective reporting (reporting bias) Unclear risk Comment: Insufficient information to per-
mit judgement of low or high risk of re-
porting bias

Prostanoids for intermittent claudication (Review) 36

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Luk’Janov 1995 (Continued)

Other bias Unclear risk Comment: Insufficient information to per-

mit judgement of low or high risk of bias

Mangiafico 2000

Methods Study design: randomised, double blind, placebo-controlled study. PGE1 versus placebo

Participants Country: Italy.

No: 42 untrained outpatients.
Treatment 21; control 21.
Sex: 37 male, 5 female.
Mean age: 64 ± 8 years.
Inclusion criteria: PAOD, WD 50 to 200 m.
Exclusion criteria: WD change > 20% 2 weeks before study, congestive heart failure,
renal failure, respiratory insufficiency, effort angina, unstable angina, uncontrolled ar-
rhythmias, recent MI, transient Ischaemic attack or stroke, recent DVT, substance abuse
Cardioactive and antiplatelet drugs allowed. Vasoactive and rheologic drugs for PAOD
stopped

Interventions Treatment: 60 µg PGE1 iv.

Control: placebo (250 ml saline) iv. OD over 4 weeks.

Outcomes Treadmill test (5% slope, 3 km/h)

- PFWD (m)
- MWD (m)
ABPI
Walking impairment questionnaire

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomised”
bias) Comment: Trial was described as ran-
domised but authors do not state how the
allocation sequence was generated. Insuffi-
cient information to permit judgement of
low or high risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of on risk of selection
bias

Prostanoids for intermittent claudication (Review) 37

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mangiafico 2000 (Continued)

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) Low risk Comment: All data accounted for. Low risk
All outcomes of attrition bias.

Selective reporting (reporting bias) High risk Study design. ABPI listed as pre-specified
outcome but data is not presented. High
risk of reporting bias

Other bias Unclear risk Insuffificient information to permit judge-

ment on risk of other bias

Milio 2006

Methods Study design: Randomised, controlled, single blind study

Participants Country: Italy

No: 123 patients. Treatment 63, control 60
Mean age: Treatment 55 ± 14 years, control 53 ± 16 years
Sex: Treatment 44 male, 19 female. Control 42 male, 18 female
Inclusion criteria: Presence of PAD at the 2nd B stage Fontaine’s classification for ≥ 6
months and the existence of steno-obliterating lesions of the iliac-femoral axis demon-
strated with echocolour Doppler examination or angiographic procedure
Exclusion criteria: Patients with heart failure, respiratory insufficiency, recent myocar-
dial infarction, arrhythmias, recent episodes of cerebral ischaemia, renal insufficiency,
pregnancy and patients with diseases that could not permit normal de-ambulation

Interventions Treatment: 60 ug/d PGE1 iv injection

Control: 200 mg pentoxifylline + 200 mg/d buflomedil over 2 hours in 250 ml saline
or glucose solution, administered for 4 weeks

Outcomes Treadmill test (gradient of 7%, 3 km/h )

- PFWD (m)
- MWD (m)
Rest flow, peak flow, time to reach peak flow, basal and minimal vascular resistance

Notes

Risk of bias

Prostanoids for intermittent claudication (Review) 38

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Milio 2006 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomised in
bias) two groups, with an allocation sequence
obtained using a random-number table
(sealed envelopes)”
Comment: Adequate description of se-
quence generation. Low risk of selection
bias

Allocation concealment (selection bias) Low risk Quote: “Sealed envelopes”

Comment: Adequate concealment of allo-
cation. Low risk of selection bias

Blinding of participants and personnel High risk Quote: “Single-blind”

(performance bias) Comment: Due to the nature of the treat-
All outcomes ment, the study personnel were not blinded
and therefore the study was at high risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Insufficient information to permit judge-
bias) ment on risk of detection bias
All outcomes

Incomplete outcome data (attrition bias) Unclear risk Insufficient information to determine if all
All outcomes participants were followed up for 28 days.
Unclear risk of attrition bias

Selective reporting (reporting bias) Unclear risk Unit of measurement for walking distance
is not provided and the authors have not
responded to queries to clarify this. Unclear
risk of reporting bias

Other bias Unclear risk Insufficient information to permit judge-

ment on risk of other bias

Mohler 2003

Methods Study design: randomised, double blind placebo-controlled study. BPS versus placebo

Participants Country: USA.

No: treatment 385; control 377.
Age: between 40 to 80 years; stable IC for longer than 6 months; rest ABI ≤ 0.90 with
a 10 mmHg decrease in ankle pressure 1 min after completion on the exercise treadmill
test; PFWD on a standardised treadmill test ≥ 164 feet (50 m) but ≤ 984 feet (300 m)
at the screening visit; PFWD variability < 25% between tests performed during the run-
in phase
Exclusion criteria: critical limb ischaemia; underwent coronary artery or peripheral artery

Prostanoids for intermittent claudication (Review) 39

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mohler 2003 (Continued)

angioplasty or surgical limb arterial bypass within the last three months; were antici-
pated to require surgical or percutaneous revascularization within six months of ran-
domisation; or were currently participating in a supervised exercise regimen; suffered a
stroke or myocardial infarction or deep-vein thrombosis within the last three months;
nonatherosclerotic PAD (e.g., thromboangiitis obliterans); a known abdominal aortic
aneurysm 4.5 cm; unstable angina pectoris within the last three months; heart failure;
severe, uncontrolled hypertension; anaemia or any clinically significant bleeding episode
within the last year; an abnormal platelet count; type I diabetes mellitus; morbid obesity;
severe renal insufficiency; severe hepatic insufficiency; any disorder that would affect the
interpretation
of treadmill test results; and any other lifethreatening disease or any psychiatric condition
that would impair either informed consent or compliance with the study protocol; use
of cilostazol, pentoxifylline, or HeartBar (L-arginine) within one month prior to the
screening treadmill test; current use of warfarin, heparin, or thrombolytic therapy; or
any disease state that could potentially decrease gastrointestinal absorption of the study
medication
Patients using aspirin, clopidogrel, or ticlopidine were not excluded from the study

Interventions Treatment: oral 40 µg BPS.

Control: placebo.
Duration: over one year.

Outcomes Treadmill test (10% slope, 3 km/h )

- PFWD (m)
- MWD (m)
- ABPI
- QOL

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomly assigned”
bias) Comment: Trial was described as ran-
domised but authors do not state how the
allocation sequence was generated. Insuffi-
cient information to permit judgement of
low or high risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of on risk of selection
bias

Blinding of participants and personnel Unclear risk Quote: “Double-blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-

Prostanoids for intermittent claudication (Review) 40

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mohler 2003 (Continued)

formation to permit judgement on risk of

performance bias

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) Unclear risk Patients lost to follow up are not accounted
All outcomes for. High risk of attrition bias

Selective reporting (reporting bias) Unclear risk Number of patients at follow up is signif-
icantly less than at baseline. High risk of
reporting bias

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Müller-Bühl 1987

Methods Study design: stated randomised (no details given), single-blind, placebo-controlled
study. Iloprost versus placebo (hydroxy-ethyl starch)
Dropouts: none.

Participants Country: Germany.

No: 24 outpatients.
Age: 47 to 71 years.
Sex: male.
Inclusion criteria: PAOD stage IIb, stable > 3 months.

Interventions Treatment: Iloprost 2 ng/kg/ min over 5 hours iv.

Control: hydroxy-ethyl starch 200/0.5 500 ml iv.
Duration: 10 infusions in 2 weeks.
Follow up: 1 month.

Outcomes Treadmill test (10% slope, 3 km/h):

- PFWD (m)
- MWD (m)
ABPI
venous occlusion plethysmography:
- during rest (ml/100ml x min)
- reactive hyperaemia (ml/100ml x min)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Prostanoids for intermittent claudication (Review) 41

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Müller-Bühl 1987 (Continued)

Random sequence generation (selection Unclear risk Quote: “Patients were randomly assigned”
bias) Comment: Authors describe the trial as
randomised but method of randomisation
not stated. Insufficient information to per-
mit judgement on risk of selection bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel High risk Quote: “Patient-blinded trial”

(performance bias) Comment: Only the patients were blinded
All outcomes to treatment therefore the study is at high
risk of performance bias

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) Low risk Comment: All data accounted for. Low risk
All outcomes of attrition bias.

Selective reporting (reporting bias) Low risk Comment: Data on all pre-specified study
outcomes are presented. Low risk of report-
ing bias

Other bias Low risk Comment: Study appears to be free from

other sources of bias

Scheffler 1994

Methods Study design: stated randomised, (no details given), open study with 3 treatment arms:
intensive physical training alone vs. intensive training + PGE1 iv. versus intensive training
+ Ptx iv
Dropouts: none.

Participants Country: Germany.

No: 44 randomised (3 groups).
Age: 60 ± 9 years.
Sex: 33 male, 11 female.
Inclusion criteria: PAOD stage IIb, stable for > 6 months, maximal WD 50 to 200 m
Exclusion criteria: WD differences > 20% between 3 treadmill tests during 2 weeks

Interventions Treatment: PGE1 40 µg/250 ml NaCl twice daily iv. plus intensive physical training
Control 1: Ptx 200 mg/250ml NaCl twice daily iv. plus intensive physical training
Control 2: intensive physical training alone without pharmacological treatment
Duration: 4 weeks.

Prostanoids for intermittent claudication (Review) 42

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Scheffler 1994 (Continued)

Follow up: 1 year

Outcomes Treadmill test (5% incline, 3 km/h):

- PFWD (m)
- MWD (m)
Side effects

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Randomly allocated to the three
bias) treatment groups”
Comment: Insufficient information to per-
mit judgement of low or high risk of selec-
tion bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel High risk One of the three groups did not receive any
(performance bias) drug intervention and thus both partici-
All outcomes pants and personnel would be aware of the
treatment. High risk of performance bias

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) Low risk Comment: All data accounted for. Low risk
All outcomes of attrition bias.

Selective reporting (reporting bias) High risk The three treatment groups were not simi-
lar. High risk of reporting bias

Other bias Unclear risk Insufficient information to permit judge-

ment of low or high risk of bias

Prostanoids for intermittent claudication (Review) 43

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Virgolini 1989

Methods Study design: randomised, double blind, placebo-controlled study. Taprostene versus
placebo

Participants Country: Austria.

No: 30 patients with PAOD II. Treatment 15; control 15.
Sex: 15 male, 15 female.
Age: treatment 57 years; control 60 years.
Exclusion criteria: > 70 years, diabetes, peripheral neuropathy, angina pectoris, MI less
than one year prior admission, no antiplatelet drugs

Interventions Treatment: taprostene 25 ng/kg/min iv.

Control: placebo iv. for 6 hours on 5 consecutive days.

Outcomes Treadmill test (7.5° elevation, 1.5 miles/hour)

- walking times (s)

Notes Walking times in seconds were translated in WD (m)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomly allocated”
bias) Comment: Method of sequence generation
not stated. Insufficient information to per-
mit judgement of low or high risk of selec-
tion bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel Unclear risk Quote: “Double-blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) Unclear risk Comment: Authors did not state number
All outcomes of patients at follow up. Insufficient infor-
mation to permit judgement of low or high
risk of attrition bias

Prostanoids for intermittent claudication (Review) 44

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Virgolini 1989 (Continued)

Selective reporting (reporting bias) Unclear risk Comment: Authors do not specify primary
outcomes. Insufficient information to per-
mit judgement of low or high risk of re-
porting bias

Other bias Unclear risk Study design vague and outcomes were not
clearly specified. Unclear risk of bias

Virgolini 1990

Methods Study design: randomised, double blind, placebo-controlled study. Prostacyclin (PGI2)
versus placebo

Participants Country: Austria.

No: 108 patients with PAOD II. Treatment 54; control 54.
Exclusion criteria: patient did not reach an absolute claudication time on treadmill within
8 minutes, recent cardiovascular events or aspirin-like drugs, 2 weeks run-in period

Interventions Intravenous administration 8 hours/day over 5 consecutive days 6 ng/kg/min PGI2 or

placebo (NaCl)

Outcomes Treadmill test: (7.5° elevation, 1.5 miles/hour)

walking time (s)

Notes Walking times in seconds were translated in WD (m)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomly allocated”
bias) Comment: Method of sequence generation
not stated. Insufficient information to per-
mit judgement of low or high risk of selec-
tion bias

Allocation concealment (selection bias) Unclear risk Comment: Method of allocation conceal-
ment not stated. Insufficient information
to permit judgement of low or high risk of
selection bias

Blinding of participants and personnel Unclear risk Quote: “Double blind”

(performance bias) Comment: Authors state that trial was dou-
All outcomes ble blind but do not provide enough in-
formation to permit judgement on risk of
performance bias

Prostanoids for intermittent claudication (Review) 45

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Virgolini 1990 (Continued)

Blinding of outcome assessment (detection Unclear risk Comment: Insufficient information to per-
bias) mit judgement of low or high risk of detec-
All outcomes tion bias

Incomplete outcome data (attrition bias) High risk Dropouts not accounted for. High risk of
All outcomes attrition bias.

Selective reporting (reporting bias) High risk Authors only report results for participants
who had a positive response to treatment.
High risk of reporting bias

Other bias Unclear risk Not enough information to assess risk of

other bias.

ABPI = ankle brachial pressure index

BSP = beraprost sodium
DVT = deep vein thrombosis
IDDM = insulin dependant diabetes mellitus
ia = intra-arterial
iv = intravenous
g = gram
h = hour
m = metre
MI = myocardial infarction
MWD = maximum walking distance
NaCl = sodium chloride
ng = nanogram
OD = once daily
PAOD = peripheral arterial occlusive disease
PFWD = pain-free walking distance
PGE1 = prostaglandin E1
PGI2 = prostacyclin
po = per oral
Ptx = pentoxifylline
QOL = quality of life
TID = three times daily
vs. = versus
WD = walking distance

Prostanoids for intermittent claudication (Review) 46

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Acciavatti 2001 Long-term versus short-term treatment, no placebo or control

Anon 2011 Daily versus twice weekly treatment, no placebo or control

Barradas 1989 Not RCT

Bieron 1993 Not RCT

Diehm 1990 Not RCT

Esato 1995a Patients have critical limb ischaemia

Esato 1995b Patients have critical limb ischaemia

Fitscha 1985 Excluded because of the inconclusive data given

Goya 2003 Patients have arteriosclerotic changes in the carotid artery

Hay 1987 Excluded because the administered dosages differed between the patients

Ishitobi 1991 Not RCT

Linhart 1998 No placebo or control, short-term versus long-term treatment

Okadome-Kenchiro 1992 No placebo or control

Rudofsky 1987 Not a randomised controlled trial. Attempts were made to contact the author to clarify but there was no
response

Rudofsky 1988 Not a randomised controlled trial. Attempts were made to contact the author to clarify but there was no
response

Sakaguchi-Shukichi 1990 Not a randomised controlled trial

Waller 1986 Excluded because the administered dosages differed between the patients

Wang 2009 Excluded because not all patients have intermittent claudication and it is impossible to extract data on
those that did. Also, the study outcomes were not relevant for this review

Wilkinson 1988 Excluded since no data were published

Ylitalo 1990 Three patients had rest pain and no subgroup analysis was done

Prostanoids for intermittent claudication (Review) 47

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of studies awaiting assessment [ordered by study ID]

Nakagawa 1998

Methods Awaiting translation

Participants

Interventions

Outcomes

Notes

Characteristics of ongoing studies [ordered by study ID]

Valerio 2012

Trial name or title FADOI-2b Pilot Study

Methods Multicentre randomised trial

Participants 100 patients with stage IIb PAD with a PFWD < 100 m, who were unable to undergo revascularisation

Interventions Standard therapy versus standard therapy plus iloprost for 1 year. Iloprost administered for 10 days every 3
months as a continuous iv infusion of 0.5 - 2.0 ng/kg/min for 6 h/day

Outcomes PFWD, major cardiovascular events, death, adverse reaction

Starting date

Contact information Antonella Valerio (antonella.valerio@fadoi.org)

Notes Based on personal communication with the study author, the two study abstracts will be published as one
full paper. The article has been submitted and is awaiting an outcome regarding publication

Prostanoids for intermittent claudication (Review) 48

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. PGE1 versus placebo

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free 3 508 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
walking distance (%)
1.1 Intra-arterial, 3 weeks 1 50 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Intravenous, 4 weeks 2 250 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.3 Intravenous, 8 weeks 1 208 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Final pain-free walking distance 3 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
2.1 Intra-arterial, 3 weeks 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Intravenous, 4 weeks 2 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.3 Intravenous, 8 weeks 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Mean change in maximal 3 508 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
walking distance (%)
3.1 Intra-arterial, 3 weeks 1 50 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Intravenous, 4 weeks 2 250 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.3 Intravenous, 8 weeks 1 208 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4 Final maximal walking distance 3 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
4.1 Intra-arterial, 3 weeks 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Intravenous, 4 weeks 2 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.3 Intravenous, 8 weeks 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 2. PGE1 versus pentoxifylline (Ptx)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free 4 429 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
walking distance (%)
2 Final pain-free walking distance 4 429 Mean Difference (IV, Fixed, 95% CI) 220.62 [140.80,
(meters) 300.44]
3 Mean change in maximal 3 348 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
walking distance (%)
4 Final maximal walking distance 3 347 Mean Difference (IV, Fixed, 95% CI) 201.93 [107.33,
(meters) 296.54]
5 Ankle brachial index 2 240 Mean Difference (IV, Fixed, 95% CI) -0.06 [-0.12, 0.00]
6 Adverse events 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
6.1 4 weeks 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.2 12 months 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Prostanoids for intermittent claudication (Review) 49

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 3. PGE1 versus laevadosin (energy rich phosphates)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
walking distance (%)
2 Final pain-free walking distance 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
3 Mean change in maximal 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
walking distance (%)
4 Final maximal walking distance 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)

Comparison 4. PGE1 versus naftidrofuryl

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free
walking distance (%)
2 Final pain-free walking distance
(meters)
3 Ankle brachial index left side
4 Ankle brachial index right side
5 Adverse events
1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 5. PGE1 versus L-arginine

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
walking distance (%)
2 Final pain-free walking distance 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
3 Mean change in maximal 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
walking distance (%)
4 Final maximal walking distance 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
5 Ankle brachial index 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

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Comparison 6. PGI2 versus placebo

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free
walking distance (%)
2 Final pain-free walking distance
(meters)
3 Mean change in maximum
walking distance (%)
4 Final maximal walking distance
(meters)
5 Adverse events
5.1 Critical cardiovascular
events
5.2 Arterial thrombosis
5.3 Drug-related adverse
events
6 1575 Mean Difference (IV, Fixed, 95% CI) 56.00 [-13.85, 125.
85]
5 1402 Mean Difference (IV, Random, 95% CI) -3.66 [-18.77, 11.
46]
6 1575 Mean Difference (IV, Fixed, 95% CI) 38.0 [-23.83, 99.83]
5 1328 Mean Difference (IV, Fixed, 95% CI) 12.36 [1.84, 22.87]
1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 7. PGI2 versus pentoxifylline (Ptx)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Death
2 Revascularisation
2.1 50 µg iloprost
2.2 100 µg iloprost
2.3 150 µg iloprost
1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 8. Iloprost versus hydroxy-ethyl starch (HES)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in pain-free 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
walking distance (%)
2 Final pain-free walking distance 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
3 Mean change in maximal 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
walking distance (%)
4 Final maximal walking distance 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
(meters)
5 Ankle brachial index 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
Prostanoids for intermittent claudication (Review) 51
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
6 Venous-occlusion 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
plethysmography - at rest
7 Venous-occlusion 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
plethysmography - reactive
hyperaemia

Analysis 1.1. Comparison 1 PGE1 versus placebo, Outcome 1 Mean change in pain-free walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 1 PGE1 versus placebo

Outcome: 1 Mean change in pain-free walking distance (%)

Std. Std.
Mean Mean
Study or subgroup PGE1 Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Intra-arterial, 3 weeks
Blume 1986 (1) 25 109 (0) 25 35 (0) Not estimable

Subtotal (95% CI) 25 25 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
2 Intravenous, 4 weeks
Diehm 1997 (2) 106 75 (0) 102 43 (0) Not estimable

Mangiafico 2000 (3) 21 88 (0) 21 4 (0) Not estimable

Subtotal (95% CI) 127 123 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
3 Intravenous, 8 weeks
Diehm 1997 (4) 106 100 (0) 102 60 (0) Not estimable

Subtotal (95% CI) 106 102 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 258 250 Not estimable
Heterogeneity: not applicable
Test for overall effect: not applicable
Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

-1000 -500 0 500 1000

Placebo PGE1

Prostanoids for intermittent claudication (Review) 52

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 (1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

(4) SD = 0 reflects missing standard deviations

Analysis 1.2. Comparison 1 PGE1 versus placebo, Outcome 2 Final pain-free walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 1 PGE1 versus placebo

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup PGE1 Placebo Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Intra-arterial, 3 weeks
Blume 1986 25 113 (54) 25 73 (41) 40.00 [ 13.42, 66.58 ]

2 Intravenous, 4 weeks
Diehm 1997 106 112.7 (1.8) 102 95.5 (2) 17.20 [ 16.68, 17.72 ]

Mangiafico 2000 21 135 (33) 21 84 (17) 51.00 [ 35.12, 66.88 ]

3 Intravenous, 8 weeks
Diehm 1997 106 128.9 (2) 102 106.6 (2.1) 22.30 [ 21.74, 22.86 ]

-100 -50 0 50 100

Placebo PGE1

Prostanoids for intermittent claudication (Review) 53

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.3. Comparison 1 PGE1 versus placebo, Outcome 3 Mean change in maximal walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 1 PGE1 versus placebo

Outcome: 3 Mean change in maximal walking distance (%)

Mean Mean
Study or subgroup PGE1 Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Intra-arterial, 3 weeks
Blume 1986 (1) 25 74 (0) 25 18 (0) Not estimable

Subtotal (95% CI) 25 25 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
2 Intravenous, 4 weeks
Diehm 1997 (2) 106 65 (0) 102 42 (0) Not estimable

Mangiafico 2000 (3) 21 90 (0) 21 1 (0) Not estimable

Subtotal (95% CI) 127 123 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
3 Intravenous, 8 weeks
Diehm 1997 (4) 106 87.5 (0) 102 60.7 (0) Not estimable

Subtotal (95% CI) 106 102 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 258 250 Not estimable
Heterogeneity: not applicable
Test for overall effect: not applicable
Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

-1000 -500 0 500 1000

Placebo PGE1

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

(4) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 54

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.4. Comparison 1 PGE1 versus placebo, Outcome 4 Final maximal walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 1 PGE1 versus placebo

Outcome: 4 Final maximal walking distance (meters)

Mean Mean
Study or subgroup PGE1 Placebo Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Intra-arterial, 3 weeks
Blume 1986 25 170 (75) 25 114 (51) 56.00 [ 20.45, 91.55 ]

2 Intravenous, 4 weeks
Diehm 1997 106 163 (1.8) 102 141.9 (1.7) 21.10 [ 20.62, 21.58 ]

Mangiafico 2000 21 266 (62) 21 154 (39) 112.00 [ 80.67, 143.33 ]

3 Intravenous, 8 weeks
Diehm 1997 106 186.3 (2) 102 160.5 (1.9) 25.80 [ 25.27, 26.33 ]

-100 -50 0 50 100

Placebo PGE1

Prostanoids for intermittent claudication (Review) 55

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.1. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 1 Mean change in pain-free walking
distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 2 PGE1 versus pentoxifylline (Ptx)

Outcome: 1 Mean change in pain-free walking distance (%)

Mean Mean
Study or subgroup PGE1 Pentoxifylline Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Hepp 1996 (1) 97 218 (0) 98 124 (0) Not estimable

Luk’Janov 1995 (2) 42 119 (0) 40 91 (0) Not estimable

Milio 2006 (3) 63 396 (0) 60 113 (0) Not estimable

Scheffler 1994 (4) 14 604 (0) 15 105 (0) Not estimable

Total (95% CI) 216 213 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
Test for subgroup differences: Not applicable

-1000 -500 0 500 1000

Favours Ptx Favours PGE1

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

(4) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 56

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.2. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 2 Final pain-free walking distance
(meters).

Review: Prostanoids for intermittent claudication

Comparison: 2 PGE1 versus pentoxifylline (Ptx)

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup PGE1 Pentoxifylline Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Hepp 1996 (1) 97 264 (0) 98 188 (0) Not estimable

Luk’Janov 1995 (2) 42 195 (0) 40 149 (0) Not estimable

Milio 2006 63 387 (274) 60 175 (180) 95.8 % 212.00 [ 130.44, 293.56 ]

Scheffler 1994 14 570 (727) 15 154 (150) 4.2 % 416.00 [ 27.69, 804.31 ]

Total (95% CI) 216 213 100.0 % 220.62 [ 140.80, 300.44 ]

Heterogeneity: Chi2 = 1.02, df = 1 (P = 0.31); I2 =2%
Test for overall effect: Z = 5.42 (P < 0.00001)
Test for subgroup differences: Not applicable

-500 -250 0 250 500

Favours Ptx Favours PGE1

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 57

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.3. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 3 Mean change in maximal walking
distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 2 PGE1 versus pentoxifylline (Ptx)

Outcome: 3 Mean change in maximal walking distance (%)

Mean Mean
Study or subgroup PGE1 Pentoxifylline Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Hepp 1996 (1) 97 164 (0) 98 146 (0) Not estimable

Milio 2006 (2) 63 260 (0) 60 118 (0) Not estimable

Scheffler 1994 (3) 15 371 (0) 15 119 (0) Not estimable

Total (95% CI) 175 173 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
Test for subgroup differences: Not applicable

-1000 -500 0 500 1000

Favours Ptx Favours PGE1

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 58

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.4. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 4 Final maximal walking distance
(meters).

Review: Prostanoids for intermittent claudication

Comparison: 2 PGE1 versus pentoxifylline (Ptx)

Outcome: 4 Final maximal walking distance (meters)

Mean Mean
Study or subgroup PGE1 Pentoxifylline Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Hepp 1996 (1) 97 343 (0) 98 322 (0) Not estimable

Milio 2006 63 515 (285) 60 323 (264) 95.1 % 192.00 [ 94.97, 289.03 ]

Scheffler 1994 14 744 (697) 15 351 (432) 4.9 % 393.00 [ -32.55, 818.55 ]

Total (95% CI) 174 173 100.0 % 201.93 [ 107.33, 296.54 ]

Heterogeneity: Chi2 = 0.81, df = 1 (P = 0.37); I2 =0.0%
Test for overall effect: Z = 4.18 (P = 0.000029)
Test for subgroup differences: Not applicable

-500 -250 0 250 500

Favours Ptx Favours PGE1

(1) SD = 0 reflects missing standard deviations

Analysis 2.5. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 5 Ankle brachial index.

Review: Prostanoids for intermittent claudication

Comparison: 2 PGE1 versus pentoxifylline (Ptx)

Outcome: 5 Ankle brachial index

Mean Mean
Study or subgroup PGE1 Pentoxifylline Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Hepp 1996 81 0.53 (0.21) 77 0.6 (0.2) 87.8 % -0.07 [ -0.13, -0.01 ]

Luk’Janov 1995 42 0.74 (0.5) 40 0.69 (0.26) 12.2 % 0.05 [ -0.12, 0.22 ]

Total (95% CI) 123 117 100.0 % -0.06 [ -0.12, 0.00 ]

Heterogeneity: Chi2 = 1.65, df = 1 (P = 0.20); I2 =40%
Test for overall effect: Z = 1.81 (P = 0.070)
Test for subgroup differences: Not applicable

-0.5 -0.25 0 0.25 0.5

Favours Ptx Favours PGE1

Prostanoids for intermittent claudication (Review) 59

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 Analysis 2.6. Comparison 2 PGE1 versus pentoxifylline (Ptx), Outcome 6 Adverse events.

Review: Prostanoids for intermittent claudication

Comparison: 2 PGE1 versus pentoxifylline (Ptx)

Outcome: 6 Adverse events

Study or subgroup PGE1 Pentoxifylline Odds Ratio Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 4 weeks
Hepp 1996 5/97 7/98 0.71 [ 0.22, 2.31 ]

2 12 months
Hepp 1996 2/97 6/98 0.32 [ 0.06, 1.64 ]

0.01 0.1 1 10 100

Favours PGE1 Favours Ptx

Analysis 3.1. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 1 Mean change in
pain-free walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 3 PGE1 versus laevadosin (energy rich phosphates)

Outcome: 1 Mean change in pain-free walking distance (%)

Mean Mean
Study or subgroup PGE1 Laevadosin Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Creutzig 1988 (1) 20 230 (0) 20 146 (0) Not estimable

-10 -5 0 5 10
Favours Laevadosin Favours PGE1

Prostanoids for intermittent claudication (Review) 60

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 (1) SD = 0 reflects missing standard deviations

Analysis 3.2. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 2 Final pain-free
walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 3 PGE1 versus laevadosin (energy rich phosphates)

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup PGE1 Laevadosin Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Creutzig 1988 (1) 20 198 (0) 20 170 (0) Not estimable

-100 -50 0 50 100

Favours Laevadosin Favours PGE1

(1) SD = 0 reflects missing standard deviations

Analysis 3.3. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 3 Mean change in
maximal walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 3 PGE1 versus laevadosin (energy rich phosphates)

Outcome: 3 Mean change in maximal walking distance (%)

Mean Mean
Study or subgroup PGE1 Laevadosin Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Creutzig 1988 (1) 20 239 (0) 20 156 (0) Not estimable

-10 -5 0 5 10
Favours Laevadosin Favours PGE1

Prostanoids for intermittent claudication (Review) 61

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 (1) SD = 0 reflects missing standard deviations

Analysis 3.4. Comparison 3 PGE1 versus laevadosin (energy rich phosphates), Outcome 4 Final maximal
walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 3 PGE1 versus laevadosin (energy rich phosphates)

Outcome: 4 Final maximal walking distance (meters)

Mean Mean
Study or subgroup PGE1 Laevadosin Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Creutzig 1988 (1) 20 305 (0) 20 274 (0) Not estimable

-100 -50 0 50 100

Favours Laevadosin Favours PGE1

(1) SD = 0 reflects missing standard deviations

Analysis 4.1. Comparison 4 PGE1 versus naftidrofuryl, Outcome 1 Mean change in pain-free walking
distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 4 PGE1 versus naftidrofuryl

Outcome: 1 Mean change in pain-free walking distance (%)

Mean Mean
Study or subgroup PGE1 Naftidrofuryl Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Diehm 1989 (1) 24 98.5 (0) 24 96.6 (0) Not estimable

-10 -5 0 5 10
Favours Naftidrofuryl Favours PGE1

Prostanoids for intermittent claudication (Review) 62

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 (1) SD = 0 reflects missing standard deviations

Analysis 4.2. Comparison 4 PGE1 versus naftidrofuryl, Outcome 2 Final pain-free walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 4 PGE1 versus naftidrofuryl

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup PGE1 Naftidrofuryl Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Diehm 1989 (1) 24 270 (0) 24 230 (0) Not estimable

-100 -50 0 50 100

Favours Naftidrofuryl Favours PGE1

(1) SD = 0 reflects missing standard deviations

Analysis 4.3. Comparison 4 PGE1 versus naftidrofuryl, Outcome 3 Ankle brachial index left side.

Review: Prostanoids for intermittent claudication

Comparison: 4 PGE1 versus naftidrofuryl

Outcome: 3 Ankle brachial index left side

Mean Mean
Study or subgroup PGE1 Naftidrofuryl Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Diehm 1989 23 0.75 (0.18) 24 0.76 (0.27) -0.01 [ -0.14, 0.12 ]

-1 -0.5 0 0.5 1
Favours Naftidrofuryl Favours PGE1

Prostanoids for intermittent claudication (Review) 63

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 Analysis 4.4. Comparison 4 PGE1 versus naftidrofuryl, Outcome 4 Ankle brachial index right side.

Review: Prostanoids for intermittent claudication

Comparison: 4 PGE1 versus naftidrofuryl

Outcome: 4 Ankle brachial index right side

Mean Mean
Study or subgroup PGE1 Naftidrofuryl Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Diehm 1989 23 0.79 (0.23) 24 0.68 (0.24) 0.11 [ -0.02, 0.24 ]

-1 -0.5 0 0.5 1
Favours Naftidrofuryl Favours PGE1

Analysis 4.5. Comparison 4 PGE1 versus naftidrofuryl, Outcome 5 Adverse events.

Review: Prostanoids for intermittent claudication

Comparison: 4 PGE1 versus naftidrofuryl

Outcome: 5 Adverse events

Study or subgroup PGE1 Naftidrofuryl Odds Ratio Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Diehm 1989 5/24 22/24 0.02 [ 0.00, 0.14 ]

0.005 0.1 1 10 200

Favours PGE1 Favours Naftidrofuryl

Prostanoids for intermittent claudication (Review) 64

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 5.1. Comparison 5 PGE1 versus L-arginine, Outcome 1 Mean change in pain-free walking distance
(%).

Review: Prostanoids for intermittent claudication

Comparison: 5 PGE1 versus L-arginine

Outcome: 1 Mean change in pain-free walking distance (%)

Mean Mean
Study or subgroup PGE1 L-arginine Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Böger 1998 (1) 13 147 (0) 13 185 (0) Not estimable

-10 -5 0 5 10
Favours L-arginine Favours PGE1

(1) SD = 0 reflects missing standard deviations

Analysis 5.2. Comparison 5 PGE1 versus L-arginine, Outcome 2 Final pain-free walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 5 PGE1 versus L-arginine

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup PGE1 L-arginine Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Böger 1998 (1) 13 128 (0) 13 147 (0) Not estimable

-100 -50 0 50 100

Favours L-arginine Favours PGE1

(1) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 65

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 Analysis 5.3. Comparison 5 PGE1 versus L-arginine, Outcome 3 Mean change in maximal walking distance
(%).

Review: Prostanoids for intermittent claudication

Comparison: 5 PGE1 versus L-arginine

Outcome: 3 Mean change in maximal walking distance (%)

Mean Mean
Study or subgroup PGE1 L-arginine Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Böger 1998 (1) 13 114 (0) 13 132 (0) Not estimable

-100 -50 0 50 100

Favours L-arginine Favours PGE1

(1) SD = 0 reflects missing standard deviations

Analysis 5.4. Comparison 5 PGE1 versus L-arginine, Outcome 4 Final maximal walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 5 PGE1 versus L-arginine

Outcome: 4 Final maximal walking distance (meters)

Mean Mean
Study or subgroup PGE1 L-arginine Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Böger 1998 (1) 13 199 (0) 13 216 (0) Not estimable

-100 -50 0 50 100

Favours L-arginine Favours PGE1

(1) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 66

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 Analysis 5.5. Comparison 5 PGE1 versus L-arginine, Outcome 5 Ankle brachial index.

Review: Prostanoids for intermittent claudication

Comparison: 5 PGE1 versus L-arginine

Outcome: 5 Ankle brachial index

Mean Mean
Study or subgroup PGE1 L-arginine Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Böger 1998 13 0.5 (0.216) 13 0.48 (0.216) 0.02 [ -0.15, 0.19 ]

-1 -0.5 0 0.5 1
Favours L-arginine Favours PGE1

Analysis 6.1. Comparison 6 PGI2 versus placebo, Outcome 1 Mean change in pain-free walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 6 PGI2 versus placebo

Outcome: 1 Mean change in pain-free walking distance (%)

Mean Mean
Study or subgroup PGI2 Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Creager 2008 (1) 86 8.8 (0) 84 3.3 (0) Not estimable

Li vre 1996 42 114 (204) 41 58 (107) 100.0 % 56.00 [ -13.85, 125.85 ]

Li vre 2000 (2) 209 115 (0) 213 84 (0) Not estimable

Mohler 2003 (3) 385 19 (0) 377 15 (0) Not estimable

Virgolini 1989 (4) 15 22 (0) 15 4 (0) Not estimable

Virgolini 1990 (5) 54 16 (0) 54 12 (0) Not estimable

Total (95% CI) 791 784 100.0 % 56.00 [ -13.85, 125.85 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.57 (P = 0.12)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours Placebo Favours PGI2

Prostanoids for intermittent claudication (Review) 67

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 (1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

(4) SD = 0 reflects missing standard deviations

(5) SD = 0 reflects missing standard deviations

Analysis 6.2. Comparison 6 PGI2 versus placebo, Outcome 2 Final pain-free walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 6 PGI2 versus placebo

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup PGI2 Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Li vre 1996 (1) 41 270 (0) 39 190 (0) Not estimable

Li vre 2000 (2) 209 280 (0) 213 245 (0) Not estimable

Mohler 2003 (3) 385 101 (0) 377 104 (0) Not estimable

Virgolini 1989 15 54.07 (4.35) 15 63.66 (4.41) 62.8 % -9.59 [ -12.72, -6.46 ]

Virgolini 1990 54 67.12 (25.41) 54 60.75 (54.94) 37.2 % 6.37 [ -9.77, 22.51 ]

Total (95% CI) 704 698 100.0 % -3.66 [ -18.77, 11.46 ]

Heterogeneity: Tau2 = 92.16; Chi2 = 3.62, df = 1 (P = 0.06); I2 =72%
Test for overall effect: Z = 0.47 (P = 0.64)
Test for subgroup differences: Not applicable

-50 -25 0 25 50
Favours Placebo Favours PGI2

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 68

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 Analysis 6.3. Comparison 6 PGI2 versus placebo, Outcome 3 Mean change in maximum walking distance
(%).

Review: Prostanoids for intermittent claudication

Comparison: 6 PGI2 versus placebo

Outcome: 3 Mean change in maximum walking distance (%)

Mean Mean
Study or subgroup PGI2 Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Creager 2008 (1) 86 13.7 (0) 84 3.2 (0) Not estimable

Li vre 1996 42 99 (182) 41 61 (92) 100.0 % 38.00 [ -23.83, 99.83 ]

Li vre 2000 (2) 209 70 (0) 213 39 (0) Not estimable

Mohler 2003 (3) 385 16.7 (0) 377 15 (0) Not estimable

Virgolini 1989 (4) 15 14 (0) 15 2 (0) Not estimable

Virgolini 1990 (5) 54 16 (0) 54 7 (0) Not estimable

Total (95% CI) 791 784 100.0 % 38.00 [ -23.83, 99.83 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.20 (P = 0.23)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours Placebo Favours PGI2

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

(4) SD = 0 reflects missing standard deviations

(5) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 69

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 Analysis 6.4. Comparison 6 PGI2 versus placebo, Outcome 4 Final maximal walking distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 6 PGI2 versus placebo

Outcome: 4 Final maximal walking distance (meters)

Mean Mean
Study or subgroup PGI2 Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Li vre 1996 (1) 41 428 (0) 39 291 (0) Not estimable

Li vre 2000 (2) 177 467 (0) 171 378 (0) Not estimable

Mohler 2003 (3) 385 191 (0) 377 196 (0) Not estimable

Virgolini 1989 15 224.87 (21.28) 15 213.4 (6.28) 87.7 % 11.47 [ 0.24, 22.70 ]

Virgolini 1990 54 177.56 (62.89) 54 158.86 (93.27) 12.3 % 18.70 [ -11.30, 48.70 ]

Total (95% CI) 672 656 100.0 % 12.36 [ 1.84, 22.87 ]

Heterogeneity: Chi2 = 0.20, df = 1 (P = 0.66); I2 =0.0%
Test for overall effect: Z = 2.30 (P = 0.021)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours Placebo Favours PGI2

(1) SD = 0 reflects missing standard deviations

(2) SD = 0 reflects missing standard deviations

(3) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 70

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 Analysis 6.5. Comparison 6 PGI2 versus placebo, Outcome 5 Adverse events.

Review: Prostanoids for intermittent claudication

Comparison: 6 PGI2 versus placebo

Outcome: 5 Adverse events

Study or subgroup PGI2 Placebo Odds Ratio Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Critical cardiovascular events

Li vre 2000 5/209 17/213 0.28 [ 0.10, 0.78 ]

2 Arterial thrombosis

Li vre 2000 8/209 14/213 0.57 [ 0.23, 1.38 ]

3 Drug-related adverse events

Li vre 2000 35/209 15/213 2.66 [ 1.40, 5.03 ]

0.01 0.1 1 10 100

Favours PGI2 Favours Placebo

Analysis 7.1. Comparison 7 PGI2 versus pentoxifylline (Ptx), Outcome 1 Death.

Review: Prostanoids for intermittent claudication

Comparison: 7 PGI2 versus pentoxifylline (Ptx)

Outcome: 1 Death

Study or subgroup PGI2 Pentoxifylline Odds Ratio Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Creager 2008 0/260 1/86 0.11 [ 0.00, 2.71 ]

0.005 0.1 1 10 200

Favours PGI2 Favours Ptx

Prostanoids for intermittent claudication (Review) 71

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 Analysis 7.2. Comparison 7 PGI2 versus pentoxifylline (Ptx), Outcome 2 Revascularisation.

Review: Prostanoids for intermittent claudication

Comparison: 7 PGI2 versus pentoxifylline (Ptx)

Outcome: 2 Revascularisation

Study or subgroup PGI2 Pentoxifylline Odds Ratio Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 50 g iloprost
Creager 2008 5/87 2/86 2.56 [ 0.48, 13.57 ]

2 100 g iloprost
Creager 2008 5/86 2/86 2.59 [ 0.49, 13.74 ]

3 150 g iloprost
Creager 2008 1/87 2/86 0.49 [ 0.04, 5.49 ]

0.01 0.1 1 10 100

Favours PGI2 Favours Ptx

Analysis 8.1. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 1 Mean change in pain-
free walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 1 Mean change in pain-free walking distance (%)

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 (1) 11 36.5 (0) 12 17.9 (0) Not estimable

-100 -50 0 50 100

Favours HES Favours Iloprost

(1) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 72

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 Analysis 8.2. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 2 Final pain-free walking
distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 2 Final pain-free walking distance (meters)

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 11 98.1 (44.1) 12 75.9 (30.1) 22.20 [ -8.93, 53.33 ]

-100 -50 0 50 100

Favours HES Favours Iloprost

Analysis 8.3. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 3 Mean change in
maximal walking distance (%).

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 3 Mean change in maximal walking distance (%)

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 (1) 11 50.2 (0) 12 44.6 (0) Not estimable

-100 -50 0 50 100

Favours HES Favours Iloprost

(1) SD = 0 reflects missing standard deviations

Prostanoids for intermittent claudication (Review) 73

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 Analysis 8.4. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 4 Final maximal walking
distance (meters).

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 4 Final maximal walking distance (meters)

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 11 151.8 (82.4) 12 144.4 (53) 7.40 [ -49.79, 64.59 ]

-100 -50 0 50 100

Favours HES Favours Iloprost

Analysis 8.5. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 5 Ankle brachial index.

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 5 Ankle brachial index

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 11 0.77 (0.55) 12 0.71 (0.38) 0.06 [ -0.33, 0.45 ]

-4 -2 0 2 4
Favours HES Favours Iloprost

Prostanoids for intermittent claudication (Review) 74

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 Analysis 8.6. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 6 Venous-occlusion
plethysmography - at rest.

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 6 Venous-occlusion plethysmography - at rest

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 11 6.5 (2.3) 12 4.9 (2.3) 1.60 [ -0.28, 3.48 ]

-10 -5 0 5 10
Favours HES Favours Iloprost

Analysis 8.7. Comparison 8 Iloprost versus hydroxy-ethyl starch (HES), Outcome 7 Venous-occlusion
plethysmography - reactive hyperaemia.

Review: Prostanoids for intermittent claudication

Comparison: 8 Iloprost versus hydroxy-ethyl starch (HES)

Outcome: 7 Venous-occlusion plethysmography - reactive hyperaemia

Mean Mean
Study or subgroup Iloprost Hydroxy-ethyl starch Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Müller-Bühl 1987 11 6.5 (2.5) 12 8.2 (4.3) -1.70 [ -4.55, 1.15 ]

-10 -5 0 5 10
Favours HES Favours Iloprost

Prostanoids for intermittent claudication (Review) 75

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ADDITIONAL TABLES
Table 1. PFWD PGE1 versus placebo

Dose Du- PGE PLC SD SD SD SD %age SD%

Study (µg) ra- PGE0 PGEE %age SD% PLC0 PLCE DIFF
tion (%)

(weeks)

2, 5 4 19 21 44.8 16.0 not

Belch
d/wk stated
1997
* 5, 2 18 50.7 33.5 not
d/wk stated

5, 5 22 45.0 33.0 64.5 43 17 26

d/wk

2, 5 8 a 19 21 44.8 16.0 not

d/wk stated

5, 2 18 50.7 33.5 not

d/wk stated

5, 5 22 45.0 33.0 65.9 46 0 46

d/wk

10- 3 25 25 54 13 113 54 109 54 16 73 41 35 74

Blume
20
1986

60 4 106 102 64.3 1.6 112. 1.8 75 66.6 1.6 95.5 2.0 43 32
Diehm
7
1997
8b 128. 2.0 100 106. 2.1 60 40
9 6

60 4 21 21 72 16 135 33 88 81 17 84 17 4 84
Man-
giafico
8a 113 26 57 not not
2000 stated stated

PGE = prostaglandin treatment group sample size

PLC = placebo group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGE and placebo
* Study reported PFWD as a median with IQR.
Prostanoids for intermittent claudication (Review) 76
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
a
= treatment was administered for 4 weeks, treadmill tests conducted at 4 weeks and also at 8 weeks (after a 4-week period of no
treatment).
b = treatment was administered for 5 days a week for 4 weeks and reduced to 2 days a week for a further 4 weeks, treadmill tests

conducted at both 4 and 8 weeks.

Table 2. MWD PGE1 versus placebo

Dose Du- PGE PLC SD SD SD SD

Study (µg) ra- PGE0 PGEE %age SD% PLC0 PLCE %age SD% DIFF
tion (%)

(weeks)

2, 5 4 19 21 60.0 25.6 not

Belch
d/wk stated
1997
* 5, 2 18 68.6 48.8 not
d/wk stated

5, 5 22 67.1 68.8 95.1 42 75.6 93.0 80.1 6 36

d/wk

2, 5 8 a 19 21 60.0 25.6 not

d/wk stated

5, 2 18 68.6 48.8 not

d/wk stated

5, 5 22 67.1 68.8 102. 52 75.6 93.0 64.4 -15 67

d/wk 1

10- 3 25 25 98 45 170 75 74 97 28 114 51 18 56

Blume
20
1986

60 4 106 102 98.8 1.5 163 1.8 65 99.8 1.4 141. 1.7 42 23
Diehm
9
1997
8b 186. 2.0 88 160. 1.9 61 27
3 5

60 4 21 21 140 30 266 62 90 152 38 154 39 1 89

Man-
giafico 8a 229 55 64 not not
2000 stated stated

PGE = prostaglandin treatment group sample size

PLC = placebo group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
Prostanoids for intermittent claudication (Review) 77
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGE and placebo
* Study reported MWD as a median with IQR.
a = treatment was administered for 4 weeks, treadmill tests conducted at 4 weeks and also at 8 week (after a 4-week period of no

treatment).
b = treatment was administered for 5 days a week for 4 weeks and reduced to 2 days a week for a further 4 weeks, treadmill tests

conducted at both 4 and 8 weeks.

Table 3. PFWD PGE1 versus pentoxifylline

Du- SD SD SD SD
Study Dose Dose ra- PGE1 PTX PGE0 PGEE %age SD% PTX0 PTXE %age SD% DIFF
PGE PTX tion (%)
(µg) (mg) (weeks)

80 400 4 97 98 83 264 218 84 188 124 94

Hepp

1996

40 400 4 42 40 89 195 119 78 149 91 45

Luk’Janov

1995

60 200 4 63 60 78 36 387 274 396 82 41 175 180 113 260

Milio
2006

80 200 4 14 15 81 23 570 727 604 75 41 154 150 105 499

Schef-
fler
1994
PGE = prostaglandin treatment group sample size
PTX= pentoxifylline group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PTX0 = pentoxifylline baseline walking distance
PTXE = pentoxifylline end walking distance
DIFF = difference in percentage of improvement of PGE and pentoxifylline

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Table 4. MWD PGE1 versus pentoxifylline

Du- SD SD SD SD
Study Dose Dose ra- PGE1 PTX PGE0 PGEE %age SD% PTX0 PTXE %age SD% DIFF
PGE PTX tion (%)
(µg) (mg) (weeks)

80 400 4 97 98 130 343 164 131 322 146 18

Hepp

1996

40 400 4 42 40 - - - - - - - - - - - - -
Luk’Janov

1995

60 200 4 63 60 143 55 515 285 260 148 69 323 264 118 158
Milio
2006

80 200 4 14 15 158 95 744 697 371 160 133 351 432 119 252
Schef-
fler
1994
PGE = prostaglandin treatment group sample size
PTX= pentoxifylline group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PTX0 = pentoxifylline baseline walking distance
PTXE = pentoxifylline end walking distance
DIFF = difference in percentage of improvement of PGE and pentoxifylline

Table 5. PFWD PGI2 versus placebo

Dose Du- PLC SD SD SD SD %age SD%

Study (µg) ra- PGI2 PGI20 PGI2E %age SD% PLC0 PLCE DIFF
tion (%)

(weeks)

100 26 87 84 105 81 7.7 120 88 3.3 4.4

Crea-
ger 200 86 124 96 8.8 5.5
2008
300 87 129 88 11.2 7.9

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Table 5. PFWD PGI2 versus placebo (Continued)

60 12 42 41 132 72 254 129 210 131 73 190 58 107 71

Lièvre
1996 120 42 142 69 270 114 204 56

180 39 137 74 186 51 114 -7

120 26 209 213 130 65 280 115 133 71 245 84 31

Lièvre
2000

120 52 385 377 85 101 19 90 104 15 4

Mohler
2003

Vir- 25 1 15 15 54. 4.35 22 63. 4.41 4 18

golini ng/ 07 66
kg/
1989 min

Vir- 6 ng/ 1 54 54 67. 25. 16 60. 54. 12 4

golini kg/ 12 41 75 94
min
1990
PGI2 = prostaglandin treatment group sample size
PLC = placebo group sample size
PGI20 = PGI2 baseline walking distance
SD = standard deviation
PGI2E = PGI2 end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGI2 and placebo

Table 6. MWD PGI2 versus placebo

Dose Du- PLC SD SD SD SD

Study (µg) ra- PGI2 PGI20 PGI2E %age SD% PLC0 PLCE %age SD% DIFF
tion (%)

(weeks)

100 26 87 84 105 81 7.1 120 88 3.2 3.9

Crea-
ger 200 86 124 96 13.7 10.5
2008
300 87 129 88 25.7 22.5

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Table 6. MWD PGI2 versus placebo (Continued)

60 12 42 41 203 123 384 142 318 206 145 291 61 92 81

Lièvre
1996 120 42 224 94 428 99 182 38

180 39 207 112 357 69 133 3

120 26 209 213 275 229 467 70 271 240 378 39 31

Lièvre
2000

120 52 385 377 164 191. 16.7 170 195. 15 1.7

Mohler
4 7
2003

Vir- 25 1 15 15 224. 21. 14 213. 6.28 2 12

golini ng/ 87 28 4
kg/
1989 min

Vir- 6 ng/ 1 54 54 177. 62. 16 158. 93. 7 9

golini kg/ 56 89 86 27
min
1990
PGI2 = prostaglandin treatment group sample size
PLC = placebo group sample size
PGI20 = PGI2 baseline walking distance
SD = standard deviation
PGI2E = PGI2 end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGI2 and placebo

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APPENDICES

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Arteriosclerosis] this term only 890

#2 MeSH descriptor: [Arteriolosclerosis] this term only 0

#3 MeSH descriptor: [Arteriosclerosis Obliterans] this term only 71

#4 MeSH descriptor: [Atherosclerosis] this term only 382

#5 MeSH descriptor: [Arterial Occlusive Diseases] this term only 753

#6 MeSH descriptor: [Intermittent Claudication] this term only 710

#7 MeSH descriptor: [Peripheral Vascular Diseases] explode all 2146

trees

#8 (atherosclero* or arteriosclero* or PVD or PAOD or PAD) 16775

#9 (arter*) near (*occlus* or steno* or obstuct* or lesio* or block* 4842

or obliter*)

#10 (vascular) near (*occlus* or steno* or obstuct* or lesio* or 1368

block* or obliter*)

#11 (vein*) near (*occlus* or steno* or obstuct* or lesio* or block* 706

or obliter*)

#12 (veno*) near (*occlus* or steno* or obstuct* or lesio* or block* 974

or obliter*)

#13 (peripher*) near (*occlus* or steno* or obstuct* or lesio* or 1352

block* or obliter*)

#14 peripheral near/3 dis* 3203

#15 arteriopathic 9

#16 (claudic* or hinken*) 1427

#17 dysvascular* 13

#18 leg near/4 (obstruct* or occlus* or steno* or block* or obliter*) 176

#19 limb near/4 (obstruct* or occlus* or steno* or block* or 227

obliter*)

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(Continued)

#20 (lower near/3 extrem*) near/4 (obstruct* or occlus* or steno* 136

or block* or obliter*)

#21 (aort* or iliac or femoral or popliteal or femoropop* or fem- 320

pop* or crural) near/3 (obstruct* or occlus*)

#22 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or 24780

#11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #
19 or #20 or #21

#23 MeSH descriptor: [Prostaglandins] explode all trees 4448

#24 MeSH descriptor: [Thromboxanes] explode all trees 703

#25 *prosta* 16501

#26 PGE* 1721

#27 PGI* 602

#28 AS-013 or ventavis or TTC-909 12

#29 thrombox* 1467

#30 iloprost:ti,ab,kw (Word variations have been searched) 273

#31 liprostin:ti,ab,kw (Word variations have been searched) 0

#32 alprostadil:ti,ab,kw (Word variations have been searched) 671

#33 taprostene:ti,ab,kw (Word variations have been searched) 12

#34 beraprost*:ti,ab,kw (Word variations have been searched) 48

#35 clinprost:ti,ab,kw (Word variations have been searched) 3

#36 #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or # 18697
31 or #32 or #33 or #34 or #35

#37 #22 and #36 in Trials 927

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WHAT’S NEW
Last assessed as up-to-date: 22 January 2013.

Date Event Description

22 January 2013 New citation required and conclusions have changed New authors have taken over this review. Searches rerun.
Two new studies included, 14 new studies excluded, one
ongoing study awaiting publication, one study awaiting
classification. Risk of bias tables completed for all in-
cluded studies. Conclusions changed

22 January 2013 New search has been performed Searches rerun. Two new studies included, 14 new studies
excluded, one ongoing study awaiting publication, one
study awaiting classification. Conclusions changed

HISTORY
Protocol first published: Issue 1, 1998
Review first published: Issue 1, 2004

Date Event Description

28 October 2008 Amended Converted to new review format.

20 August 2004 Amended Synopsis added to the review. Minor revisions made in accordance with Cochrane Style Guide

CONTRIBUTIONS OF AUTHORS
LR identified potential trials, extracted data, assessed the quality of trials and wrote the text.
AA identified potential trials, extracted data and assessed the quality of trials.

DECLARATIONS OF INTEREST
None known

Prostanoids for intermittent claudication (Review) 84

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SOURCES OF SUPPORT

Internal sources
• No sources of support provided, Not specified.

External sources
• National Institute for Health Research (NIHR), UK.
The authors are supported by a programme grant from the NIHR.
• Chief Scientist Office, Scottish Government Heath Directorates, The Scottish Government, UK.
The PVD Group editorial base is supported by the Chief Scientist Office.
• National Institute for Health Research (NIHR), UK.
The PVD Group editorial base is supported by a programme grant from the NIHR.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In the original review, the overall quality of studies was assessed using the Jadad score. For this update, the quality of all included studies
was assessed using the risk of bias tool from The Cochrane Collaboration.

INDEX TERMS

Medical Subject Headings (MeSH)

Alprostadil [therapeutic use]; Epoprostenol [adverse effects; analogs & derivatives; therapeutic use]; Iloprost [adverse effects; therapeutic
use]; Intermittent Claudication [∗ drug therapy]; Prostaglandins [adverse effects; ∗ therapeutic use]; Randomized Controlled Trials as
Topic

MeSH check words

Humans

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