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Clin Evid (Online). 2011; 2011: 0211.
Published online Jan 11, 2011.
PMCID: PMC3275103
Peripheral arterial disease
Kevin Cassar
Kevin Cassar, Aberdeen Royal Infirmary, Aberdeen, UK;
KC declares that he has no competing interests.
Introduction
Up to 20% of adults aged over 55 years have detectable peripheral arterial disease of the legs, but this may cause symptoms of intermittent claudication in only a small proportion of affected people. The main risk factors are smoking and diabetes mellitus, but other risk factors for cardiovascular disease are also associated with peripheral arterial disease.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for people with chronic peripheral arterial disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010. Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review. We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 70 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antiplatelet agents, bypass surgery, cilostazol, exercise, pentoxifylline, percutaneous transluminal angioplasty (PTA), prostaglandins, smoking cessation, and statins.
Up to 20% of adults aged over 55 years have detectable peripheral arterial disease of the legs, but this may cause symptoms of intermittent claudication in only a small proportion of affected people.
  • The main risk factors are smoking and diabetes mellitus, but other risk factors for CVD are also associated with peripheral arterial disease.
  • Overall mortality after the diagnosis of peripheral arterial disease is about 30% after 5 years and 70% after 15 years.
Antiplatelet agents reduce major cardiovascular events, arterial occlusion, and revascularisation compared with placebo, with the overall balance of benefits and harms supporting treatment of people with peripheral arterial disease.
Regular exercise increases maximal walking distance compared with no exercise.
  • Stopping smoking and taking vitamin E may also increase walking distance when combined with exercise.
Statins have been shown to reduce cardiovascular events in large trials including people with PVD, and they may increase walking distance and time to claudication compared with placebo.
  • Cilostazol may improve walking distance compared with placebo.
  • Cilostazol may reduce the incidence of cerebrovascular events compared with placebo but may be no more effective at reducing cardiac events.
  • Cilostazol may be more effective than pentoxifylline at improving claudication distance.
  • We don't know whether pentoxifylline improves symptoms compared with placebo, and it may be less effective than cilostazol.
Percutaneous transluminal angioplasty (PTA) may improve walking distance compared with no intervention, but the benefit may not last beyond 6 months. Adding a stent to PTA may confer additional benefit over PTA alone.
Bypass surgery may improve arterial patency at 12 months compared with PTA, but there seems to be no long-term benefit. Bypass surgery may be associated with improved survival in severe limb ischaemia in the longer term (3–7 years) compared with angioplasty.
Prostaglandins may improve amputation-free survival in critical ischaemia at 6 months when surgical revascularisation is not an option.
  • Prostaglandins may not be of benefit in intermittent claudication.
  • Prostaglandins are associated with higher rates of adverse effects, including headache, vasodilation, diarrhoea, tachycardia, and vasodilation compared with placebo.
Definition
Peripheral arterial disease arises when there is significant narrowing of arteries distal to the arch of the aorta. Narrowing can arise from atheroma, arteritis, local thrombus formation, or embolisation from the heart, or more central arteries. This review includes treatment options for people with symptoms of reduced blood flow to the leg that are likely to arise from atheroma. These symptoms range from calf pain on exercise (intermittent claudication) to rest pain, skin ulceration, or symptoms of ischaemic necrosis (gangrene) in people with critical limb ischaemia.
Incidence/ Prevalence
Peripheral arterial disease is more common in people aged over 50 years than in younger people, and is more common in men than in women. The prevalence of peripheral arterial disease of the legs (assessed by non-invasive tests) is about 14% to 17% in men and 11% to 21% in women over 55 years of age.[1] [2] The overall annual incidence of intermittent claudication is 4.1 to 12.9 per 1000 men and 3.3 to 8.2 per 1000 women.[3]
Aetiology/ Risk factors
Factors associated with the development of peripheral arterial disease include age, sex, cigarette smoking, diabetes mellitus, hypertension, hyperlipidaemia, obesity, and physical inactivity. The strongest associations are with smoking (RR 2.0–4.0) and diabetes mellitus (RR 2.0–3.0).[4]
Prognosis
The symptoms of intermittent claudication can resolve spontaneously, remain stable over many years, or progress rapidly to critical limb ischaemia. About 15% of people with intermittent claudication eventually develop critical limb ischaemia, which endangers the viability of the limb. The annual incidence of critical limb ischaemia in Denmark and Italy in 1990 was 0.25 to 0.45 per 1000 people.[5] [6] CHD is the major cause of death in people with peripheral arterial disease of the legs. Over 5 years, about 20% of people with intermittent claudication have a non-fatal cardiovascular event (MI or stroke).[7] The mortality rate of people with peripheral arterial disease is two to three times higher than that of age- and sex-matched controls. Overall mortality after the diagnosis of peripheral arterial disease is about 30% after 5 years and 70% after 15 years.[7]
Aims of intervention
To reduce intermittent claudication; symptoms of critical limb ischaemia (arterial leg ulcers, rest pain); and general complications (MI and stroke), and improve quality of life, while minimising adverse effects of interventions.
Outcomes
Mortality (all cause and cardiovascular); Cardiovascular events; Claudication distance/time measures (initial claudication distance, absolute claudication distance, pain-free or maximal walking time, etc); Post-intervention patency (e.g., arterial occlusion, arterial reocclusion, restenosis, patency, reintervention rates, ulcer healing, and limb amputation); Physiological measures (ankle brachial index); Generic/disease-specific quality of life; and Adverse effects.
Methods
Clinical Evidence search and appraisal May 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2010, Embase 1980 to May 2010, and The Cochrane Database of Systematic Reviews May 2010 (online) 1966 to date of issue. When editing this review we used The Cochrane Database of Systematic Reviews 2010, issue 3. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language. RCTs had to contain 20 or more individuals, of whom 80% or more were followed up. RCTs had to be at least single blinded where blinding was possible. We excluded all studies described as "open", "open label", or not blinded, unless blinding was impossible. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table
Table
GRADE Evaluation of interventions for Peripheral arterial disease.
Glossary
Absolute claudication distance Also known as the total walking distance. The maximum distance a person can walk before stopping.
Ankle brachial index The ankle brachial index (ABI) is calculated by dividing the blood pressure recorded at the ankle by the blood pressure recorded in the arm. The ABI value is calculated both at rest and after exercise to determine the severity of peripheral arterial disease. A normal ABI value at rest is 1.0. A decrease in the ABI after exercise or a resting ABI below 0.9 indicates that peripheral arterial disease is present.
Critical limb ischaemia Results in a breakdown of the skin (ulceration or gangrene) or pain in the foot at rest. Critical limb ischaemia corresponds to the Fontaine classification III and IV.
Fontaine classification I: asymptomatic; II: intermittent claudication; II-a: pain-free, claudication walking more than 200 metres; II-b: pain-free, claudication walking less than 200 metres; III: rest/nocturnal pain; IV: necrosis/gangrene.
Initial claudication distance The distance a person can walk before the onset of claudication symptoms.
Intermittent claudication Pain, stiffness, or weakness in the leg that develops on walking, intensifies with continued walking until further walking is impossible, and is relieved by rest.
Low-quality evidenceFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidenceFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidenceAny estimate of effect is very uncertain.

Notes
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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Antiplatelet agents
Summary
Antiplatelet agents reduce major cardiovascular events, arterial occlusion, and revascularisation compared with placebo, but increase the risk of serious haemorrhage.
The balance of benefits and harms is in favour of treatment for most people with symptomatic peripheral arterial disease, because as a group they are at much greater risk of cardiovascular events.
Benefits and harms
Antiplatelet agents versus placebo or control:
We found 9 systematic reviews (search dates 1999,[8] 1997,[9] [10] 1990,[11] 1998,[12] 2004,[13] 2008,[14] 2008,[15] 2009[16]). The systematic reviews all identified many of the same RCTs; however, they used different inclusion/exclusion criteria and performed different meta-analyses, and so we report on them all; although the third systematic review[10] described the results presented in the second review [9]and so we include the data only once and reference both papers. One systematic review looked at only aspirin versus placebo.[15]
Mortality
Antiplatelet agents compared with placebo/control Aspirin may be no more effective than placebo at reducing all-cause mortality or cardiovascular mortality (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[15]
Systematic review
3019 people with peripheral arterial disease
9 RCTs in this analysis
All-cause mortality up to 6.7 years
114/1516 (7.5%) with aspirin (100 to 1500 mg/day)
118/1503 (7.9%) with placebo or control

RR 0.96
95% CI 0.75 to 1.22
P = 0.74
Results should be interpreted with caution; over one third of people in the analysis had diabetes
Not significant
[15]
Systematic review
3019 people with peripheral arterial disease
9 RCTs in this analysis
Cardiovascular mortality up to 6.7 years
55/1516 (3.6%) with aspirin (100 to 1500 mg/day)
49/1503 (3.3%) with placebo or control

RR 1.15
95% CI 0.78 to 1.68
P = 0.48
Results should be interpreted with caution; over one third of people in the analysis had diabetes
Not significant
No data from the following reference on this outcome.[10] [8] [9] [11] [12] [13] [14] [16]
Cardiovascular events
Antiplatelet agents compared with placebo/control Antiplatelet agents as a class may be more effective at reducing major cardiovascular events (non-fatal MI, non-fatal stroke, or vascular death). Aspirin may be more effective than placebo at reducing non-fatal stroke but may be no more effective at reducing MI (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Vascular events
[8]
Systematic review
6036 people with intermittent claudication
24 RCTs in this analysis
Proportion of people with a vascular event (non-fatal MI, non-fatal stroke, or vascular death)
202/3100 (7%) with antiplatelet agents
238/2936 (8%) with placebo

OR 0.78
95% CI 0.63 to 0.96
Small effect sizeAntiplatelet agents
[9]
Systematic review
9214 people with peripheral arterial disease
42 RCTs in this analysis
Proportion of people with a serious vascular event
280/4844 (6%) with antiplatelet agents
347/4862 (7%) with control (not further defined)

P <0.004
Effect size not calculatedAntiplatelet agents
[15]
Systematic review
3019 people with peripheral arterial disease
9 RCTs in this analysis
Proportion of people with a vascular event (non-fatal MI, non-fatal stroke, or vascular death) up to 6.7 years
125/1516 (8%) with aspirin (100 to 1500 mg/day)
144/1503 (10%) with placebo or control

RR 0.75
95% CI 0.48 to 1.18
P = 0.21
Results should be interpreted with caution; over one third of people in the analysis had diabetes
Not significant
[15]
Systematic review
3019 people with peripheral arterial disease
9 RCTs in this analysis
Proportion of people with MI up to 6.7 years
59/1516 (3.9%) with aspirin (100 to 1500 mg/day)
67/1503 (4.4%) with placebo or control

RR 0.88
95% CI 0.36 to 2.14
P = 0.78
Results should be interpreted with caution; over one third of people in the analysis had diabetes
Not significant
[15]
Systematic review
3019 people with peripheral arterial disease
9 RCTs in this analysis
Proportion of people with non-fatal stroke up to 6.7 years
32/1516 (2%) with aspirin (100 to 1500 mg/day)
51/1503 (3%) with placebo or control

RR 0.64
95% CI 0.42 to 0.99
P = 0.04
Results should be interpreted with caution; over one third of people in the analysis had diabetes
Small effect sizeAspirin (100 to 1500 mg/day)
No data from the following reference on this outcome.[10] [11] [12] [13] [14] [16]
Claudication distance/time
Antiplatelet agents compared with placebo/control Antiplatelet agents (including ticlopidine, cloricromen, mesoglycan, indobufen, and defibrotide) may be more effective at increasing maximum walking distance at 5 to 12 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum/pain-free walking distance
[16]
Systematic review
1077 people with moderate intermittent claudication and ankle brachial index <0.9
5 RCTs in this analysis
Maximum walking distance 5 to 12 months
with antiplatelet agents
with placebo
Absolute results not reported

WMD 59 metres
95% CI 36.92 m to 81.28 m
Effect size not calculatedAntiplatelet agents
No data from the following reference on this outcome.[8] [9] [10] [11] [12] [13] [14] [15]
Post-intervention patency
Antiplatelet agents compared with placebo/control Antiplatelet agents seem to be more effective at reducing the risk of arterial occlusion (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Arterial occlusion
[12]
Systematic review
2810 people
Data from 1 RCT
Arterial occlusion or revascularisation procedures 3 months
with aspirin
with placebo
Absolute results not reported

OR 0.46
95% CI 0.27 to 0.77
Moderate effect sizeAntiplatelet agents (aspirin)
[13]
Systematic review
356 people undergoing peripheral endovascular intervention
2 RCTs in this analysis
Rates of restenosis or reocclusion 6 months
with low-dose aspirin plus dipyridamole
with placebo
Absolute results not reported

OR 0.69
95% CI 0.44 to 1.10
Not significant
[14]
Systematic review
966 people
6 RCTs in this analysis
Proportion of people with arterial occlusion of either venous or artificial peripheral bypass grafts 12 months
114/501 (23%) with antiplatelet agents (aspirin or aspirin plus dipyridamole)
156/465 (34%) with placebo

OR 0.59
95% CI 0.45 to 0.79
Small effect sizeAntiplatelet agents (aspirin or aspirin plus dipyridamole)
[14]
Systematic review
222 people
4 RCTs in this analysis
Subgroup analysis
Proportion of people with arterial occlusion of artificial peripheral bypass grafts 12 months
21/115 (18%) with antiplatelet agents (aspirin or aspirin plus dipyridamole)
57/107 (53%) with placebo

OR 0.22
95% CI 0.12 to 0.38
Moderate effect sizeAntiplatelet agents (aspirin or aspirin plus dipyridamole)
[14]
Systematic review
642 people
2 RCTs in this analysis
Subgroup analysis
Proportion of people with arterial occlusion of venous peripheral bypass grafts 12 months
71/335 (21%) with antiplatelet agents (aspirin or aspirin plus dipyridamole)
86/307 (28%) with placebo

OR 0.68
95% CI 0.48 to 0.99
Result is of borderline significance
Small effect sizeAntiplatelet agents (aspirin or aspirin plus dipyridamole)
[11]
Systematic review
3226 people with intermittent claudication, or having bypass surgery of the leg, or peripheral artery angioplasty
14 RCTs in this analysis
Arterial occlusion 19 months
with antiplatelet agents
with placebo or no additional treatment
Absolute results not reported

RRR 37%
P <0.00001
Effect size not calculatedAntiplatelet agents
[12]
Systematic review
1302 people
2 RCTs in this analysis
Arterial occlusion or revascularisation procedures up to 7 years
with ticlopidine
with placebo
Absolute results not reported

OR 0.62
95% CI 0.41 to 0.93
Small effect sizeAntiplatelet agents (ticlopidine)
No data from the following reference on this outcome.[8] [9] [10] [15] [16]
Physiological measures
No data from the following reference on this outcome.[8] [9] [10] [11] [12] [13] [14] [15] [16]
Quality of life
No data from the following reference on this outcome.[8] [9] [10] [11] [12] [13] [14] [15] [16]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Bleeding
[8]
Systematic review
8449 people with claudication undergoing surgery or percutaneous transluminal angioplasty (PTA)
36 RCTs in this analysis
Proportion of people with major bleeding
47/4349 (1.1%) with antiplatelet agents
33/4100 (0.8%) with placebo

OR 1.40
95% CI 0.90 to 2.20
The number of events was likely to have been too low to detect a clinically important increase in major bleeding
Not significant
[9]
Systematic review
94,326 people (number of RCTs in analysis not reported) Proportion of people with a major extracranial bleed
535/47,158 (1.1%) with antiplatelet agents
333/47,168 (0.7%) with control (not further defined)

OR 1.6
95% CI 1.4 to 1.8
The review pooled results for all identified RCTs (also including coronary and other conditions) rather than for people with peripheral arterial disease alone
Small effect sizePlacebo
[11]
Systematic review
6425 people (number of RCTs in analysis not reported) Proportion of people with a non-fatal "major" bleed
70/3214 (2%) with antiplatelet agents
29/3201 (1%) with control

P = 0.002
The review pooled results for all identified RCTs (also including coronary and other conditions) rather than for people with peripheral arterial disease alone
Effect size not calculatedPlacebo
[11]
Systematic review
3999 people (number of RCTs in analysis not reported) Proportion of people requiring re-operation, or with haematoma or infection caused by bleed
109/1997 (6%) with antiplatelet agents
72/2002 (4%) with control

P = 0.02
The review pooled results for all identified RCTs (also including coronary and other conditions) rather than for people with peripheral arterial disease alone
Effect size not calculatedPlacebo
[11]
Systematic review
6529 people (number of RCTs in analysis not reported) Proportion of people with fatal bleed
5/3267 (0.15%) with antiplatelet agents
1/3262 (0.03%) with control

P = 0.06
Result was of borderline significance
The review pooled results for all identified RCTs (also including coronary and other conditions) rather than for people with peripheral arterial disease alone
Not significant
[13]
Systematic review
Number of people in RCT not reported
Data from 1 RCT
Bleeding at the puncture site after endovascular treatment
with antiplatelet agents
with placebo

OR 1.52
95% CI 0.47 to 4.96
Not significant
[14]
Systematic review
598 people
2 RCTs in this analysis
Proportion of people with major bleeding
19/318 (6%) with antiplatelet agents
9/280 (3%) with placebo

OR 1.88
95% CI 0.85 to 4.16
P = 0.12
Not significant
[15]
Systematic review
3019 people with peripheral arterial disease
9 RCTs in this analysis
Occurrence of major bleeding
42/1516 (3%) with aspirin (100 to 1500 mg/day)
37/1503 (2%) with placebo or control

P = 0.86
RR 1.04
95% CI 0.66 to 1.62
Results should be interpreted with caution; over one third of people in the analysis had diabetes.
Not significant
Adverse effects (general)
[10]
Systematic review
Number of people and RCTs in analysis not reported Adverse effects (general)
with ticlopidine
with control
Absolute results not reported

Significance not reported for any outcome
Results for the control group were not reported
[14]
Systematic review
966 people
6 RCTs in this analysis
Proportion of people with an adverse effect
58/501 (12%) with antiplatelet agents
36/465 (7%) with placebo

OR 1.55
95% CI 1.00 to 2.41
P = 0.052
Result was of borderline significance
Not significant
[14]
Systematic review
966 people
6 RCTs in this analysis
Proportion of people with GI adverse effects
54/501 (11%) with antiplatelet agents
36/465 (7%) with placebo

OR 1.44
95% CI 0.92 to 2.24
P = 0.11
Not significant
No data from the following reference on this outcome.[12] [16]
Antiplatelet agents other than aspirin (alone or in combination with aspirin) versus aspirin alone:
We found one systematic review (search date 1999)[8] and one subsequent RCT.[17]
Cardiovascular events
Antiplatelet agents other than aspirin (alone or in combination with aspirin) compared with aspirin alone Antiplatelet agents (other than aspirin alone) may be more effective at reducing the risk of cardiovascular events (including vascular death, cardiovascular mortality, and MI) in people with intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Vascular events
[8]
Systematic review
6928 people with peripheral arterial disease
5 RCTs in this analysis
Proportion of people with a vascular event (non-fatal MI, non-fatal stroke, or vascular death)
227/3461 (7%) with antiplatelet agents other than aspirin
292/3467 (8%) with aspirin

OR 0.76
95% CI 0.64 to 0.91
Small effect sizeAntiplatelet agents other than aspirin
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people who had an MI 26 months
36/1545 (2%) with clopidogrel plus aspirin
57/1551 (4%) with placebo plus aspirin

OR 0.63
95% CI 0.42 to 0.96
P = 0.03
Small effect sizeClopidogrel plus aspirin
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people with a cardiovascular event (cardiovascular death, MI, or stroke) 26 months
117/1545 (8%) with clopidogrel plus aspirin
138/1551 (9%) with placebo plus aspirin

HR 0.85
95% CI 0.66 to 1.08
P = 0.18
Not significant
Mortality
No data from the following reference on this outcome.[8] [17]
Claudication distance/time
No data from the following reference on this outcome.[8] [17]
Post-intervention patency
No data from the following reference on this outcome.[8] [17]
Physiological measures
No data from the following reference on this outcome.[8] [17]
Quality of life
No data from the following reference on this outcome.[8] [17]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Bleeding
[8]
Systematic review
7028 people with peripheral arterial disease
5 RCTs in this analysis
Proportion of people with a major bleed
50/3561 (1%) with antiplatelet agents other than aspirin
68/3467 (2%) with aspirin

OR 0.73
95% CI 0.51 to 1.06
The number of events was likely to have been too low to detect a clinically important increase in major bleeding
Not significant
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people with minor bleeding 26 months
531/1545 (34%) with clopidogrel plus aspirin
323/1551 (21%) with placebo plus aspirin

HR 1.99
95% CI 1.69 to 2.34
P <0.001
Small effect sizePlacebo plus aspirin
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people with a fatal bleed 26 months
7/1545 (0.5%) with clopidogrel plus aspirin
6/1551 (0.4%) with placebo plus aspirin

HR 1.17
95% CI 0.39 to 3.49
P = 0.776
Not significant
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people with a primary intracranial haemorrhage 26 months
3/1545 (0.2%) with clopidogrel plus aspirin
6/1551 (0.4%) with placebo plus aspirin

HR 0.50
95% CI 0.12 to 2.01
P = 0.507
Not significant
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people with severe bleeding 26 months
26/1545 (1.7%) with clopidogrel plus aspirin
27/1551 (1.7%) with placebo plus aspirin

HR 0.97
95% CI 0.56 to 1.66
P = 0.90
Not significant
[17]
RCT
3096 people with symptomatic or asymptomatic peripheral arterial disease Proportion of people with moderate bleeding 26 months
38/1545 (3%) with clopidogrel plus aspirin
29/1551 (2%) with placebo plus aspirin

HR 1.32
95% CI 0.81 to 2.16
P = 0.26
Not significant
Further information on studies
None.
Comment
Clinical guide:
Across a wide range of people, antiplatelet agents have been found to cause a clinically meaningful increase the risk of major haemorrhage. Peripheral arterial disease increases the risk of cardiovascular events; for most people, the risk of bleeding is outweighed by the benefits of regular antiplatelet use.
Substantive changes
Antiplatelet agents Two new systematic reviews added comparing antiplatelet agents versus placebo.[15] [16]The first review found no significant difference between aspirin and placebo in cardiovascular events (non-fatal MI, non-fatal stroke, and cardiovascular death), all-cause mortality, or the occurrence of major bleeding. [15] The second review found that antiplatelet agents (ticlopidine, cloricromen, mesoglycan, indobufen, and defibrotide) increased maximal walking distance compared with placebo.[16]Categorisation unchanged (Beneficial).

Summary
Regular exercise increases maximal walking distance compared with no exercise.
Stopping smoking and taking vitamin E may also increase walking distance when combined with exercise.
Benefits and harms
Exercise versus usual care/placebo:
We found three systematic reviews (search date 1996,[18] 2006,[19] and 2008[20]) comparing exercise versus control treatments (placebo tablets or instructions "to continue with normal lifestyle"). We found one additional RCT,[21] and two subsequent RCTs.[22] [23] The systematic reviews identified many of the same RCTs; however, they applied different inclusion criteria and performed different meta-analyses, so we report all three here.
Claudication distance/time
Regular exercise compared with usual care/placebo Regular exercise (including supervised treadmill exercise, an arm crank exercise programme, or undefined exercise) may be more effective at improving measures of walking distance and time in people with chronic stable claudication. We don't know whether resistance training is more effective than control at improving walking distance (assessed by a 6-minute walk test) at 6 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum/pain-free walking distance
[18]
Systematic review
94 people with chronic, stable intermittent claudication
4 RCTs in this analysis
Mean increase in initial claudication distance 3 to 12 months
with exercise programmes
with usual care or placebo
Absolute results not reported

Common difference of the mean (not further defined) 139 metres
95% CI 31 m to 247 m
Effect size not calculatedExercise
[19]
Systematic review
409 people
8 RCTs in this analysis
Increase in pain-free walking distance
with supervised exercise therapy
with usual care
Absolute results not reported

WMD 81.29 m
95% CI 35.45 m to 127.14 m
P = 0.0005
Effect size not calculatedExercise
[23]
RCT
57 men with stable intermittent claudication Change in pain-free walking distance 12 weeks
From 147 m to 225 m with 12-week supervised arm-crank exercise programme
From 177 m to 192 m with control group

P = 0.03
Effect size not calculatedArm-crank exercise programme
[20]
Systematic review
322 people
6 RCTs in this analysis
Mean increase in pain-free walking distance
with exercise
with usual care or placebo
Absolute results not reported

Mean difference 82.19 m
95% CI 71.73 m to 92.65 m
Effect size not calculatedExercise
[18]
Systematic review
115 people
5 RCTs in this analysis
Mean increase in absolute claudication distance 3 to 12 months
with exercise programmes
with usual care or placebo
Absolute results not reported

Common difference of the mean (not further defined) 179 m
95% CI 60 m to 298 m
Effect size not calculatedExercise
[19]
Systematic review
499 people
9 RCTs in this analysis
Increase in maximum walking distance
with supervised exercise therapy
with usual care
Absolute results not reported

WMD 155.79 m
95% CI 80.84 m to 230.74 m
P <0.0001
Effect size not calculatedExercise
[20]
Systematic review
391 people
6 RCTs in this analysis
Mean increase in maximal walking distance
with exercise
with usual care or placebo
Absolute results not reported

Mean difference 113.2 m
95% CI 94.96 m to 131.43 m
Effect size not calculatedExercise
[23]
RCT
57 men with stable intermittent claudication Change in maximum walking distance 12 weeks
From 496 m to 661 m with 12-week supervised arm-crank exercise programme
From 600 m to 626 m with control group

P = 0.01
Effect size not calculatedArm-crank exercise programme
[22]
RCT
3-armed trial
156 people Increase in walking distance (assessed by a 6-minute walk test; change from baseline) 6 months
+20.9 m with supervised treadmill exercise (3 times/week)
–15.0 m with control

Difference 35.9 m
95% CI 15.3 m to 56.5 m
P <0.001 for treadmill v control
Effect size not calculatedExercise
[22]
RCT
3-armed trial
156 people Increase in walking distance (assessed by a 6-minute walk test; change from baseline) 6 months
–2.6 m with resistance training (3 times/week)
–15.0 m with control

Difference +12.4 m
95% CI –8.42 m to +33.3 m
P = 0.24 for resistance training v control
Not significant
Walking time
[20]
Systematic review
255 people
7 RCTs in this analysis
Mean change in walking time
136 minutes with exercise
119 minutes with usual care or placebo

WMD 5.12 minutes
95% CI 4.51 minutes to 5.72 minutes
Effect size not calculatedExercise
[21]
RCT
4-armed trial
52 people with intermittent claudication Increase in walking duration from baseline 6 months
From 804 seconds to 2020 seconds with pole-striding exercise plus placebo
From 612 seconds to 623 seconds with placebo

P value not reported for pole-striding v placebo
Physiological measures
Regular exercise compared with usual care/placebo Regular exercise for 12 weeks to 2 years may be no more effective at improving ankle brachial index (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ankle brachial index
[20]
Systematic review
228 people
7 RCTs in this analysis
Ankle brachial index
with exercise
with usual care or placebo
Absolute results not reported

Mean difference –0.01
95% CI –0.05 to +0.04
Not significant
[23]
RCT
57 men with stable intermittent claudication Resting ankle brachial index 12 weeks
0.71 with 12-week supervised arm-crank exercise programme
0.69 with control group

P = 0.12
Not significant
No data from the following reference on this outcome.[18] [19] [21] [22]
Quality of life
Exercise compared with usual care/placebo We don't know whether exercise (supervised treadmill or resistance training) is more effective at improving quality of life (assessed by the short form-36 [SF-36] or the Walking Impairment Questionnaires) at 6 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[22]
RCT
3-armed trial
156 people Change in SF-36 physical functioning score 6 months
with supervised treadmill exercise (3 times/week)
with control
Absolute results not reported

Difference between groups: 7.50
95% CI 0 to 15.0
P = 0.02 for treadmill v control
Effect size not calculatedTreadmill exercise
[22]
RCT
3-armed trial
156 people Change in SF-36 physical functioning score 6 months
with resistance training (3 times/week)
with control
Absolute results not reported

Difference between groups: 7.50
95% CI 0 to 15.0
P = 0.04 for resistance training v control
Effect size not calculatedResistance training
[22]
RCT
3-armed trial
156 people Change in Walking Impairment Questionnaire distance score 6 months
with supervised treadmill exercise (3 times/week)
with control
Absolute results not reported

Difference between groups: 10.7
95% CI 1.56 to 19.9
P = 0.02 for treadmill v control
Effect size not calculatedExercise
[22]
RCT
3-armed trial
156 people Change in Walking Impairment Questionnaire distance score 6 months
with resistance training (3 times/week)
with control
Absolute results not reported

Difference between groups: 6.92
95% CI 1.07 to 12.8
P = 0.03 for resistance training v control
Effect size not calculatedResistance training
[22]
RCT
3-armed trial
156 people Change in stair-climbing score 6 months
with supervised treadmill exercise (3 times/week)
with control
Absolute results not reported

Difference between groups: 8.33
95% CI 0 to 16.7
P = 0.06 for treadmill v control
Not significant
[22]
RCT
3-armed trial
156 people Change in stair-climbing score 6 months
with resistance training (3 times/week)
with control
Absolute results not reported

Difference between groups: 10.4
95% CI 0 to 20.8
P = 0.02 for resistance training v control
Effect size not calculatedResistance training
[22]
RCT
3-armed trial
156 people Change in speed score 6 months
with supervised treadmill exercise (3 times/week)
with control
Absolute results not reported

Difference between groups: +3.80
95% CI –4.35 to +12.0
P = 0.39 for treadmill v control
Not significant
[22]
RCT
3-armed trial
156 people Change in speed score 6 months
with resistance training (3 times/week)
with control
Absolute results not reported

Difference between groups: +1.63
95% CI –5.43 to +8.70
P = 0.55 for resistance training v control
Not significant
No data from the following reference on this outcome.[18] [19] [20] [21] [23]
Mortality
No data from the following reference on this outcome.[18] [19] [20] [21] [22] [23]
Cardiovascular events
No data from the following reference on this outcome.[18] [19] [20] [21] [22] [23]
Post-intervention patency
No data from the following reference on this outcome.[18] [19] [20] [21] [22] [23]
Adverse effects
No data from the following reference on this outcome.[18] [19] [20] [21] [22] [23]
Exercise as part of a multicomponent intervention versus usual care or placebo:
We found two RCTs.[21] [24]
Claudication distance/time
Exercise as part of a multicomponent intervention compared with usual care/placebo Regular exercise plus vitamin E may be more effective at increasing walking duration at 6 months. A "stop smoking and keep walking" intervention may be more effective at increasing the maximal walking distance at 12 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum walking distance
[24]
RCT
882 men with early PVD identified by population screening Increase in self-reported maximal walking distance (assessed using the Edinburgh Claudication Questionnaire; change from baseline) 12 months
23% with "stop smoking and keep walking" intervention package
15% with usual care

P = 0.008
Effect size not calculatedExercise (as part of a multicomponent intervention)
Walking time
[21]
RCT
4-armed trial
52 people with intermittent claudication Increase in walking duration on a constant work-rate treadmill test (change from baseline) 6 months
From 486 seconds to 1886 seconds with pole-striding exercise plus vitamin E
From 612 seconds to 623 seconds with placebo

Significance not assessed
Claudication grade
[24]
RCT
882 men with early PVD identified by population screening Intermittent claudication grade (assessed using the Edinburgh Claudication Questionnaire) 12 months
with "stop smoking and keep walking" intervention package
with usual care
Absolute results not reported

P = 0.26
Not significant
Mortality
No data from the following reference on this outcome.[21] [24]
Cardiovascular events
No data from the following reference on this outcome.[21] [24]
Post-intervention patency
No data from the following reference on this outcome.[21] [24]
Physiological measures
No data from the following reference on this outcome.[21] [24]
Quality of life
No data from the following reference on this outcome.[21] [24]
Adverse effects
No data from the following reference on this outcome.[21] [24]
Different types of exercise versus each other:
We found three RCTs.[25] [26] [27]
Claudication distance/time
Different types of exercise compared with each other We don't know whether upper-limb exercises are more effective than lower-limb exercises at improving claudication distance and maximum walking distance. Cycling three times a week for 6 weeks may be less effective than walking exercise at increasing maximum walking time and pain-free walking time in people with intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Claudication distance
[25]
RCT
3-armed trial
67 people with moderate to severe intermittent claudication Improvement in initial claudication distance from baseline 6 weeks
122% with arm exercises
93% with leg exercises
Absolute results reported graphically

Reported as not significant for arm v leg exercises
P value not reported
Not significant
[25]
RCT
3-armed trial
67 people with moderate to severe intermittent claudication Improvement in absolute claudication distance from baseline 6 weeks
147% with arm exercises
150% with leg exercises
Absolute results reported graphically

Reported as not significant for arm v leg exercises
P value not reported
Not significant
[26]
RCT
3-armed trial
94 people Improvement in claudication distance 24 weeks
51% with upper-limb exercises (twice weekly)
57% with lower-limb exercises (twice weekly)
Absolute numbers not reported

Significance not assessed
[26]
RCT
3-armed trial
94 people Improvement in maximal walking distance 24 weeks
29% with upper-limb exercises (twice weekly)
31% with lower-limb exercises (twice weekly)
Absolute numbers not reported

Significance not assessed
Maximum/pain free walking time
[27]
RCT
3-armed trial
42 people Increase in maximum walking time 24 weeks
+240 seconds with treadmill training
+48 seconds with cycle training

Significance not assessed
[27]
RCT
3-armed trial
42 people Change in pain-free walking time 24 weeks
+195 seconds with treadmill training
–8 seconds with cycle training

Significance not assessed
Mortality
No data from the following reference on this outcome.[25] [26] [27]
Cardiovascular events
No data from the following reference on this outcome.[25] [26] [27]
Post-intervention patency
No data from the following reference on this outcome.[25] [26] [27]
Physiological measures
No data from the following reference on this outcome.[25] [26] [27]
Quality of life
No data from the following reference on this outcome.[25] [26] [27]
Adverse effects
No data from the following reference on this outcome.[25] [26] [27]
Further information on studies
The general practitioners of the people received a letter plus educational material (including information about the effects of stopping smoking, nicotine replacement products, and peripheral arterial disease) and a recommendation to refer the person to community physiotherapy. The community physiotherapist received details about likely referrals. Physiotherapists provided a community-based mobility programme for senior citizens, consisting of supervised or home-based exercise sessions, and advice to walk for at least 30 minutes per day.
The RCTs in the systematic reviews had low withdrawal rates, but it is unclear whether those assessing the outcomes were blind to the group allocation. Concealment of the allocation to participants was not possible.
Comment
We found one further systematic review (search date 1993; 21 observational studies or RCTs of exercise; 564 people with peripheral arterial disease).[28] It calculated effects based on the differences in claudication distance before and after exercise treatment, but made no allowance for any spontaneous improvement that might have occurred in the participants. It reported large increases with exercise in the initial claudication distance (126–351 m) and in the absolute claudication distance (325–723 m), but these estimates were based on observational data. The benefit from arm exercise may be caused by generally improved cardiovascular function rather than local changes in the peripheral circulation.
Substantive changes
Exercise One RCT added, which found that a 12-week supervised arm crank exercise programme improved pain-free and maximal walking distances in men with stable intermittent claudication when compared with no exercise.[23] The RCT found no significant difference between exercise and control in resting ankle brachial index.[23] Categorisation unchanged (Beneficial).

Bypass surgery
Summary
Bypass surgery may improve arterial patency at 12 months compared with PTA, but there seems to be no long-term benefit. Bypass surgery may be associated with improved survival in severe limb ischaemia in the longer term (3–7 years) compared with angioplasty.
The risk of serious postoperative complications and mortality may be greater after bypass surgery compared with PTA.
Benefits and harms
Bypass surgery versus percutaneous transluminal angioplasty (PTA):
We found one systematic review (search date 2007; 4 RCTs; 873 people with intermittent claudication or critical limb ischaemia) comparing bypass surgery versus PTA.[29] The review did not pool data for all outcomes because of differences in symptoms of included participants and follow-up time between RCTs. We also found long-term follow-up of one RCT (452 people with severe limb ischaemia) identified by the review.[30]
Mortality
Bypass surgery compared with percutaneous transluminal angioplasty (PTA) We don't know how bypass surgery and PTA compare at reducing mortality at 30 days or 2 years, but bypass surgery may be more effective at reducing mortality in the longer term (3–7 years) (low quality-evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
All-cause mortality
[29]
Systematic review
452 people
Data from 1 RCT
Mortality within 30 days
11/197 (6%) with bypass surgery
7/237 (3%) with percutaneous transluminal angioplasty (PTA)

OR 1.93
95% CI 0.75 to 4.99
Not significant
[29]
Systematic review
54 people
Data from 1 RCT
Mortality within 30 days
0/24 (0%) with bypass surgery
0/30 (0%) with PTA
[29]
Systematic review
102 people
Data from 1 RCT
Mortality within 30 days
0/49 (0%) with bypass surgery
0/53 (0%) with PTA
[30]
RCT
452 people with severe limb ischaemia due to infrainguinal disease All-cause mortality 2 years
70/228 (31%) with bypass surgery
61/224 (27%) with PTA

P = 0.85
Not significant
[30]
RCT
452 people with severe limb ischaemia due to infrainguinal disease All-cause mortality 3 to 7 years (from 2 years after randomisation to trial end point)
49/228 (21%) with bypass surgery
70/224 (31%) with PTA

P = 0.01
Effect size not calculatedBypass surgery
Post-intervention patency
Bypass surgery compared with percutaneous transluminal angioplasty (PTA) Bypass surgery may be more effective at improving primary arterial patency at 12 months, but we don't know whether it is more effective after 4 years. We don't know whether bypass surgery is more effective at decreasing amputation rates at 1 and 4 years in people with critical limb ischaemia or intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Primary patency
[29]
Systematic review
355 people
2 RCTs in this analysis
Proportion of people with improved primary patency 12 months
137/178 (77%) with bypass surgery
119/177 (67%) with percutaneous transluminal angioplasty (PTA)

OR 1.6
95% CI 1.0 to 2.6
P = 0.04
Small effect sizeBypass surgery
[29]
Systematic review
263 people
Data from 1 RCT
Proportion of people with improved primary patency median of 4 years of follow-up
with bypass surgery
with PTA
Absolute results not reported

P = 0.14
Not significant
Progression to amputation
[29]
Systematic review
41 people with intermittent claudication
Data from 1 RCT
Progression to amputation 1 year
0/18 (0%) with bypass surgery
1/23 (4%) with PTA

OR 0.17
95% CI 0 to 8.73
Not significant
[29]
Systematic review
513 people with critical limb ischaemia
2 RCTs in this analysis
Progression to amputation 1 year
74/257 (29%) with bypass surgery
56/256 (22%) with PTA

OR 1.45
95% CI 0.97 to 2.15
Not significant
[29]
Systematic review
191 people with intermittent claudication
Data from 1 RCT
Progression to amputation median follow-up of 49 months
8/94 (8.5%) with bypass surgery
9/97 (9.3%) with PTA

OR 0.91
95% CI 0.34 to 2.46
Not significant
[29]
Systematic review
525 people with critical limb ischaemia
2 RCTs in this analysis
Progression to amputation median follow-up of 49 months
102/265 (38%) with bypass surgery
102/259 (39%) with PTA

OR 0.97
95% CI 0.69 to 1.39
Not significant
Cardiovascular events
No data from the following reference on this outcome.[29] [30]
Claudication distance/time
No data from the following reference on this outcome.[29] [30]
Physiological measures
No data from the following reference on this outcome.[29] [30]
Quality of life
No data from the following reference on this outcome.[29] [30]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[29]
Systematic review
472 people with critical limb ischaemia
2 RCTs in this analysis
Proportion of people with an operative complication
122/226 (54%) with bypass surgery
72/246 (29%) with percutaneous transluminal angioplasty (PTA)

OR 2.85
95% CI 1.97 to 4.12
Moderate effect sizePTA
[29]
Systematic review
41 people with intermittent claudication
Data from 1 RCT
Proportion of people with an operative complication
1/18 (6%) with bypass surgery
3/23 (13%) with PTA

OR 0.44
95% CI 0.06 to 3.40
Not significant
[29]
Systematic review
263 people
Data from 1 RCT
Procedure-related deaths
3/133 (2%) with bypass surgery
0/130 (0%) with PTA

Significance not assessed
[29]
Systematic review
452 people
Data from 1 RCT
Length of hospital stay
46.1 days with bypass surgery
36.4 days with PTA

P <0.0001
Effect size not calculatedPTA
Bypass surgery versus percutaneous transluminal angioplasty (PTA) plus stent placement:
We found one RCT comparing long-term outcomes of surgery versus PTA plus stent placement.[31]
Post-intervention patency
Bypass surgery compared with percutaneous transluminal angioplasty (PTA) plus stent placement We don't know whether bypass surgery is more effective at improving primary patency rates at 6 to 24 months in people with superficial femoral artery occlusive disease (low quality-evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Primary patency
[31]
RCT
86 people (100 limbs) with superficial femoral artery occlusive disease Rate of primary patency 6 months
84% with femoral to above-knee popliteal artery bypass with synthetic graft
81% with percutaneous transluminal angioplasty (PTA) plus stent placement
Absolute numbers not reported

P = 0.72
P value reported for overall difference between groups (includes all time points)
Not significant
[31]
RCT
86 people (100 limbs) with superficial femoral artery occlusive disease Rate of primary patency 12 months
83% with femoral to above-knee popliteal artery bypass with synthetic graft
72% with PTA plus stent placement
Absolute numbers not reported

P = 0.72
P value reported for overall difference between groups (includes all time points)
Not significant
[31]
RCT
86 people (100 limbs) with superficial femoral artery occlusive disease Rate of primary patency 24 months
76% with femoral to above-knee popliteal artery bypass with synthetic graft
64% with PTA plus stent placement
Absolute numbers not reported

P = 0.72
P value reported for overall difference between groups (includes all time points)
Not significant
Mortality
No data from the following reference on this outcome.[31]
Cardiovascular events
No data from the following reference on this outcome.[31]
Claudication distance/time
No data from the following reference on this outcome.[31]
Physiological measures
No data from the following reference on this outcome.[31]
Quality of life
No data from the following reference on this outcome.[31]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[31]
RCT
86 people (100 limbs) with superficial femoral artery occlusive disease Proportion of people with an early complication
3/46 (7%) with femoral to above-knee popliteal artery bypass with synthetic graft
4/40 (10%) with percutaneous transluminal angioplasty (PTA) plus stent placement

Significance not assessed
Further information on studies
None.
Comment
Clinical guide:
Although the consensus is that bypass surgery is the most effective treatment for people with debilitating symptomatic peripheral arterial disease, we found inadequate evidence from RCTs reporting long-term clinical outcomes to confirm this view.
Substantive changes
Bypass surgery Long-term follow-up of one RCT [30] identified by an already reported review[29] added. The RCT found no significant difference in all-cause mortality at 2 years between bypass surgery and percutaneous transluminal angioplasty (PTA), although beyond 2 years up to the trial end point (maximum 7 years' follow-up), it found bypass surgery improved survival compared with PTA. Categorisation unchanged (Likely to be beneficial).

Statins (HMG-CoA reductase inhibitors)
Summary
Statins have been shown to reduce cardiovascular events in large trials including people with PVD, and they may increase walking distance and time to claudication compared with placebo.
Benefits and harms
Statins versus placebo:
We found one systematic review (search date 2009; 3 RCTs, 380 people)[16]and three additional RCTs (reported in 4 publications) comparing statins versus placebo.[32] [33] [34] [35]The review[16] did not pool data for statins as a class but reported the effects of atorvastatin versus placebo from one RCT[36] that it identified and pooled data for simvastatin from two RCTs it identified.
Mortality
Statins compared with placebo We don't know whether statins as a class are more effective at reducing all-cause or cardiovascular mortality (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
All-cause mortality
[32] [33]
RCT
20,536 people with CHD, other occlusive arterial disease, or diabetes mellitus; 6748 people with peripheral arterial disease and 2701 people with peripheral arterial disease but without diagnosed CHD Rate of all-cause mortality
1328/10,269 (13%) with simvastatin 40 mg daily
1507/10,267 (15%) with placebo

P = 0.0003
Effect size not calculatedSimvastatin 40 mg daily
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
All-cause mortality
1/120 (0.8%) with atorvastatin 80 mg daily
1/114 (0.9%) with placebo

Significance not assessed
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
All-cause mortality
4/120 (3%) with atorvastatin 10 mg daily
1/114 (1%) with placebo

Significance not assessed
[34]
RCT
10,305 people with hypertension; 514 (5%) with peripheral arterial disease Rate of all-cause mortality median follow-up of 3.3 years
185/5168 (3.6%) with atorvastatin 10 mg daily
212/5137 (4.1%) with placebo

HR 0.87
95% CI 0.71 to 1.06
Not significant
Cardiovascular mortality
[32] [33]
RCT
20,536 people with CHD, other occlusive arterial disease, or diabetes mellitus; 6748 people with peripheral arterial disease and 2701 people with peripheral arterial disease but without diagnosed CHD Rate of cardiovascular mortality
587/10,269 (6%) with simvastatin 40 mg daily
707/10,267 (7%) with placebo

P = 0.0005
Effect size not calculatedSimvastatin 40 mg daily
[34]
RCT
10,305 people with hypertension; 514 (5%) with peripheral arterial disease Rate of cardiovascular mortality median follow-up of 3.3 years
74/5168 (1.4%) with atorvastatin 10 mg daily
82/5137 (1.6%) with placebo

HR 0.90
95% CI 0.66 to 1.23
Not significant
No data from the following reference on this outcome.[35]
Cardiovascular events
Statins compared with placebo Statins (simvastatin, atorvastatin, and pravastatin) may be more effective at reducing major cardiovascular events and composite outcomes that include fatal cardiovascular events in people with peripheral arterial disease (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Vascular event
[32] [33]
RCT
6748 people with peripheral arterial disease
Subgroup analysis
Proportion of people with a first major vascular event (major coronary event, stroke, and revascularisation)
895 (26%) with simvastatin 40 mg daily
1101 (33%) with placebo
Absolute numbers not reported

Absolute reduction of 63 per 1000
P <0.001
Effect size not calculatedSimvastatin 40 mg daily
[32] [33]
RCT
2701 people with peripheral arterial disease but without diagnosed CHD
Subgroup analysis
Proportion of people with a first major vascular event (major coronary event, stroke, and revascularisation)
327/1325 (25%) with simvastatin 40 mg daily
420/1376 (31%) with placebo

P <0.0001
Effect size not calculatedSimvastatin 40 mg daily
[35]
RCT
5804 people; aged 70 to 82 years; 513 (9%) with intermittent claudication or previous peripheral arterial surgery Proportion of people with a non-fatal MI, fatal or non-fatal stroke, or coronary death mean follow-up of 3.2 years
408/2891 (14%) with pravastatin 40 mg daily
473/2913 (16%) with placebo

HR 0.85
95% CI 0.74 to 0.97
Small effect sizePravastatin 40 mg daily
[34]
RCT
10,305 people with hypertension; 514 (5%) with peripheral arterial disease Proportion of people with a cardiovascular event (non-fatal MI and fatal CHD) median follow-up of 3.3 years
389/5168 (8%) with atorvastatin 10 mg daily
486/5137 (9%) with placebo

HR 0.79
95% CI 0.69 to 0.90
Small effect sizeAtorvastatin 10 mg daily
[34]
RCT
10,305 people with hypertension; 514 (5%) with peripheral arterial disease Proportion of people with a coronary event median follow-up of 3.3 years
178/5168 (3%) with atorvastatin 10 mg daily
247/5137 (5%) with placebo

HR 0.71
95% CI 0.59 to 0.86
Small effect sizeAtorvastatin 10 mg daily
[34]
RCT
10,305 people with hypertension; 514 (5%) with peripheral arterial disease Proportion of people with a fatal or non-fatal stroke median follow-up of 3.3 years
89/5168 (1.7%) with atorvastatin 10 mg daily
121/5137 (2.4%) with placebo

HR 0.73
95% CI 0.56 to 0.96
Small effect sizeAtorvastatin 10 mg daily
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Proportion of people with a cardiovascular event (MI and stroke)
3/120 (2.5%) with atorvastatin 80 mg daily
3/114 (2.6%) with placebo

Significance not assessed
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Proportion of people with a cardiovascular event (MI and stroke)
5/120 (4%) with atorvastatin 10 mg daily
3/114 (3%) with placebo

Significance not assessed
Claudication distance/time
Statins compared with placebo Statins may be more effective at increasing maximum walking distance or pain-free walking time (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum/pain free walking time
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Mean improvement in pain-free walking time (change from baseline) 12 months
74 seconds with atorvastatin 10 mg daily
39 seconds with placebo

P = 0.13
Not significant
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Mean improvement in pain-free walking time (change from baseline) 12 months
81 seconds with atorvastatin 80 mg daily
39 seconds with placebo

P = 0.025 for atorvastatin 80 mg daily versus placebo
Effect size not calculatedAtorvastatin 80 mg)
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Mean improvement in maximal walking time (change from baseline) 12 months
90 seconds with atorvastatin 10 mg daily
50 seconds with placebo

P = 0.37
Not significant
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Mean improvement in maximal walking time (change from baseline) 12 months
90 seconds with atorvastatin 80 mg daily
50 seconds with placebo

P = 0.37
Not significant
Maximum/pain-free walking distance
[16]
Systematic review
146 people with moderate intermittent claudication and ankle brachial index <0.9
2 RCTs in this analysis
Maximum walking distance 6 to 12 months
with simvastatin
with placebo
Absolute results not reported

WMD 104.14 metres
95% CI 61.51 m to 146.77 m
Results should be interpreted with caution; significant statistical heterogeneity between RCTs (P <0.001; no explanation of heterogeneity suggested)
Effect size not calculatedSimvastatin
No data from the following reference on this outcome.[32] [33] [34] [35]
Physiological measures
Atorvastatin compared with placebo We don't know whether atorvastatin is more effective than placebo at improving ankle brachial index after exercise at 12 months in people with peripheral arterial disease and intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ankle brachial index
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Improvement in ankle brachial index after exercise (change from baseline) 12 months
From 0.62 to 0.64 with atorvastatin 80 mg daily
From 0.62 to 0.64 with atorvastatin 10 mg daily
From 0.59 to 0.63 with placebo

P = 0.57 across all groups
Significance of between group differences not assessed
No data from the following reference on this outcome.[32] [33] [34] [35]
Quality of life
Atorvastatin compared with placebo Atorvastatin seems no more effective at improving quality-of-life scores (assessed by the Walking Impairment Questionnaire and short form-36 [SF-36] questionnaire) in people with peripheral arterial disease and intermittent claudication (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Quality of life assessed using the Walking Impairment Questionnaire
with atorvastatin 80 mg daily
with placebo
Absolute results not reported

Reported as not significant
No further data reported
Not significant
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Quality of life assessed using the Walking Impairment Questionnaire
with atorvastatin 10 mg daily
with placebo
Absolute results not reported

Reported as not significant
No further data reported
Not significant
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Quality of life assessed using the short form-36 (SF-36) questionnaire
with atorvastatin 80 mg daily
with placebo
Absolute results not reported

Reported as not significant
No further data reported
Not significant
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Quality of life assessed using the SF-36 Questionnaire
with atorvastatin 10 mg daily
with placebo
Absolute results not reported

Reported as not significant
No further data reported
Not significant
No data from the following reference on this outcome.[32] [33] [34] [35]
Post-intervention patency
No data from the following reference on this outcome.[16] [32] [33] [34] [35] [36]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[34]
RCT
10,305 people with hypertension; 514 (5%) with peripheral arterial disease Proportion of people with a serious adverse effect
with atorvastatin 10 mg daily
with placebo
Absolute results not reported

Significance not assessed
[32] [33]
RCT
20,536 people with CHD, other occlusive arterial disease, or diabetes mellitus; 6748 people with peripheral arterial disease and 2701 people with peripheral arterial disease but without diagnosed CHD Proportion of people discontinuing treatment because of adverse effects
4.8% with simvastatin 40 mg daily
5.1% with placebo
Absolute numbers not reported

Significance not assessed
[36]
RCT
3-armed trial
354 people with peripheral arterial disease and intermittent claudication
In review [16]
Proportion of people discontinuing study drug due to adverse events 12 months
3/120 (3%) with atorvastatin 80 mg daily
7/120 (6%) with atorvastatin 10 mg daily
2/114 (2%) with placebo

Significance not assessed
[32] [33]
RCT
20,536 people with CHD, other occlusive arterial disease, or diabetes mellitus; 6748 people with peripheral arterial disease and 2701 people with peripheral arterial disease but without diagnosed CHD Proportion of people with a new primary cancer
814/10,269 (7.9%) with simvastatin 40 mg daily
803/10,267 (7.8%) with placebo

RR 1.0
95% CI 0.91 to 1.11
Not significant
[35]
RCT
5804 people; aged 70 to 82 years; 513 (9%) with intermittent claudication or previous peripheral arterial surgery Proportion of people with a new cancer
245/2891 (9%) with pravastatin 40 mg daily
199/2913 (7%) with placebo

HR 1.25
95% CI 1.04 to 1.51
Small effect sizePlacebo
[32] [33]
RCT
20,536 people with CHD, other occlusive arterial disease, or diabetes mellitus; 6748 people with peripheral arterial disease and 2701 people with peripheral arterial disease but without diagnosed CHD Proportion of people with muscular pain and weakness
32.9% with simvastatin 40 mg daily
33.2% with placebo
Absolute numbers not reported

Reported as not significant
P value not reported
Not significant
[35]
RCT
5804 people; aged 70 to 82 years; 513 (9%) with intermittent claudication or previous peripheral arterial surgery Proportion of people with myalgia
36/2891 (1.2%) with pravastatin 40 mg daily
32/2913 (1.1%) with placebo

Significance not assessed
Further information on studies
The RCT found that in all people, simvastatin significantly reduced non-fatal or fatal stroke, and coronary or non-coronary revascularisation compared with placebo at 5 years (20,536 people: non-fatal or fatal stroke: 444/10,269 [4%] with simvastatin v 585/10,267 [6%] with placebo; P <0.0001; coronary or non-coronary revascularisation: 939/10,269 [9%] with simvastatin v 1205/10,267 [12%] with placebo; P <0.0001).
Comment
Clinical guide:
In most of the RCTs we identified evaluating statins, people with peripheral arterial disease formed only a small proportion of the total number of people randomised. However, similar benefits were observed in this subgroup, suggesting that the results of the RCTs may be generalisable to people with peripheral arterial disease. [32] [33] [34] [35]
High doses of atorvastatin have been associated with an increased risk of haemorrhagic stroke in people with recent haemorrhagic stroke or lacunar infarct. In these people, commencing high-dose atorvastatin (80 mg) should be carefully considered as the balance of risks and benefits is uncertain.[37] [38]
Substantive changes
Statins (HMG-CoA reductase inhibitors) One new systematic review [16]added comparing statins versus placebo. The review found that statins increased maximal walking distance compared with placebo. Categorisation unchanged (Likely to be beneficial).

Percutaneous transluminal angioplasty (PTA)
Summary
Percutaneous transluminal angioplasty (PTA) may improve walking distance compared with no intervention, but the benefit may not last beyond 6 months.
Adding a stent to PTA may confer additional benefit over PTA alone.
Benefits and harms
Percutaneous transluminal angioplasty (PTA) versus no percutaneous intervention:
We found one systematic review (search date 2006; 2 RCTs; 98 people)[39] and one subsequent RCT.[40] The review[39] did not pool the results of the RCTs identified and so we report data from the individual RCTs.[41] [42]
Claudication distance/time
Percutaneous transluminal angioplasty (PTA) compared with no percutaneous intervention PTA may be more effective at improving walking distance after 6 months, but not after 2 or more years, compared with no angioplasty or with exercise alone in people with mild to moderate intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Claudication distance
[42]
RCT
36 people
In review [39]
Increase in mean claudication distance 6 months
with Percutaneous transluminal angioplasty (PTA)
with exercise programme
Absolute results reported graphically

No direct statistical comparison between groups
No significant difference with PTA compared with baseline
P <0.01 with exercise programme compared with baseline
[42]
RCT
36 people
In review [39]
Increase in mean maximum walking distance 6 months
with PTA
with exercise programme
Absolute results reported graphically

No direct statistical comparison between groups
No significant difference with PTA compared with baseline
P <0.01 with exercise programme compared with baseline
[41]
RCT
62 people with mild to moderate intermittent claudication
In review [39]
Median initial claudication distance 6 months
667 metres with PTA
172 m with no PTA

P <0.05
Effect size not calculatedPTA
[41]
RCT
62 people with mild to moderate intermittent claudication
In review [39]
Median initial claudication distance 2 years
383 m with PTA
333 m with no PTA

P = 0.578
Not significant
[40]
RCT
56 people with disabling intermittent claudication Pain-free walking distance 24 months
174.9 m with PTA plus optimal medical treatment
435 m with optimal medical treatment alone

P = 0.0001
Effect size not calculatedOptimal medical treatment alone
[40]
RCT
56 people with disabling intermittent claudication Maximum walking distance 24 months
319.5 m with PTA plus optimal medical treatment
539.2 m with optimal medical treatment alone

P = 0.0009
Effect size not calculatedOptimal medical treatment alone
Quality of life
Percutaneous transluminal angioplasty (PTA) compared with no PTA We don't know whether PTA is more effective at improving quality of life (assessed by the Nottingham Health Profile or short form-36 [SF-36] questionnaire) at 3 to 24 months (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[41]
RCT
62 people with mild to moderate intermittent claudication
In review [39]
Quality of life assessed using the Nottingham Health Profile 2 years
with percutaneous transluminal angioplasty (PTA)
with no PTA
Absolute results not reported

P >0.05
Not significant
[40]
RCT
56 people with disabling intermittent claudication Change in physical functioning component of short form-36 (SF-36) questionnaire 3 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

P = 0.0003
Effect size not calculatedPTA plus optimal medical treatment
[40]
RCT
56 people with disabling intermittent claudication Change in bodily pain component of SF-36 questionnaire 3 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

P <0.014
Effect size not calculatedPTA plus optimal medical treatment
[40]
RCT
56 people with disabling intermittent claudication Change in health transition component of SF-36 questionnaire 3 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

P <0.0001
Effect size not calculatedPTA plus optimal medical treatment
[40]
RCT
56 people with disabling intermittent claudication Change in pain during activity component of claudication scale questionnaire 3 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

P = 0.0014
Effect size not calculatedPTA plus optimal medical treatment
[40]
RCT
56 people with disabling intermittent claudication Change in severity of pain component of claudication scale questionnaire 3 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

P = 0.001
Effect size not calculatedPTA plus optimal medical treatment
[40]
RCT
56 people with disabling intermittent claudication Various components of SF-36 and claudication scale questionnaires 3 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

Difference between groups in listed domains reported as not significant
P values not reported
Not significant
[40]
RCT
56 people with disabling intermittent claudication Change in physical functioning component of SF-36 questionnaire 24 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

P <0.0098
Effect size not calculatedPTA plus optimal medical treatment
[40]
RCT
56 people with disabling intermittent claudication Various components of SF-36 and claudication scale questionnaires 24 months
with PTA plus optimal medical treatment
with optimal medical treatment alone
Absolute results not reported

Difference between groups in listed domains reported as not significant
P values not reported
No data from the following reference on this outcome.[42]
Mortality
No data from the following reference on this outcome.[41] [42] [40]
Cardiovascular events
No data from the following reference on this outcome.[39] [40] [41] [42]
Post-intervention patency
No data from the following reference on this outcome.[39] [40] [41] [42]
Physiological measures
No data from the following reference on this outcome.[39] [40] [41] [42]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[39]
Systematic review
Adverse effects
with percutaneous transluminal angioplasty (PTA)
with no PTA
Absolute results not reported
No data from the following reference on this outcome.[40]
Percutaneous transluminal angioplasty (PTA) plus stent versus PTA alone:
We found two systematic reviews (search date 2008, 7 RCTs, 519 people, 614 limbs;[43]and search date 2009, 8 RCTs, 968 people[44]). The second review includes three of the RCTs reported in the first review but as it reports on different outcomes we include both reviews here. The second review also includes two of the RCTs we report separately in the PTA plus routine stent versus PTA plus selective stent comparison[45] [46] [47]). It is unclear in either of the reviews [43] [44] whether they included any additional RCTs that randomised people to PTA plus routine stent versus PTA plus selective stent.
Claudication distance/time
Percutaneous transluminal angioplasty (PTA) plus stent compared with PTA alone PTA plus stent may be more effective at increasing mean treadmill walking distance at 6 and 12 months but we don't know whether it is more effective at 24 months (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum/pain-free walking distance
[44]
Systematic review
104 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
Data from 1 RCT
Mean treadmill walking distance 6 months
271 m with percutaneous transluminal angioplasty (PTA) plus stent
183 m with PTA alone
Review commented that the type of antiplatelet medication varied between the included RCTs; clopidogrel was given in one large RCT

Mean difference 88.00 metres
95% CI 74.54 m to 101.46 m
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Effect size not calculatedPTA plus stent
[44]
Systematic review
240 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
2 RCTs in this analysis
Mean treadmill walking distance 12 months
with PTA plus stent
with PTA alone
Absolute results not reported

Mean difference 62.52 m
95% CI 48.36 m to 76.68 m
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial.
Results should be interpreted with caution because of statistical heterogeneity (P <0.00001) as one large RCT in the analysis reported much higher results for walking distance in the PTA plus stent group than did the other RCTs
Effect size not calculatedPTA plus stent
[44]
Systematic review
98 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
2 RCTs in this analysis
Mean treadmill walking distance 24 months
180 m with PTA plus stent
163 m with PTA alone

Mean difference +17.00 m
95% CI –123.23 m to +157.23 m
P = 0.81
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
No data from the following reference on this outcome.[43]
Post-intervention patency
Percutaneous transluminal angioplasty (PTA) plus stent compared with PTA alone PTA plus stent may be more effective at increasing patency rates at 6 months but we don't know whether it is more effective at improving patency at 12 to 24 months (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Patency
[43]
Systematic review
230 people (304 limbs)
4 RCTs in this analysis
Patency rate 6 months
106/128 limbs (83%) with percutaneous transluminal angioplasty (PTA) plus stenting
122/176 limbs (69%) with PTA alone

OR (PTA v PTA plus stent) 0.47
95% CI 0.27 to 0.84
P <0.05
Moderate effect sizePTA plus stenting
[44]
Systematic review
325 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
4 RCTs in this analysis
Patency on duplex USS 6 months
127/158 (80%) with PTA plus stent
118/167 (71%) with PTA alone

OR 1.71
95% CI 1.03 to 2.85
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Small effect sizePTA plus stent
[44]
Systematic review
261 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
3 RCTs in this analysis
Patency on angiography 6 months
113/141 (80%) with PTA plus stent
84/120 (70%) with PTA alone

OR 2.06
95% CI 1.15 to 3.72
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Moderate effect sizePTA plus stent
[43]
Systematic review
468 people (519 limbs)
6 RCTs in this analysis
Patency rate 12 months
164/249 limbs (66%) with PTA plus stenting
190/270 limbs (70%) with PTA alone

OR (PTA v PTA plus stent) 1.27
95% CI 0.87 to 1.86
Not significant
[43]
Systematic review
374 people (417 limbs)
4 RCTs in this analysis
Patency rate 24 months
113/201 limbs (56%) with PTA plus stenting
131/216 limbs (61%) with PTA alone

OR (PTA v PTA plus stent) 1.22
95% CI 0.81 to 1.82
Not significant
[44]
Systematic review
520 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
6 RCTs in this analysis
Patency on duplex USS 12 months
178/254 (70%) with PTA plus stent
167/266 (63%) with PTA alone

OR 1.41
95% CI 0.97 to 2.04
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
[44]
Systematic review
384 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
5 RCTs in this analysis
Patency on angiography 12 months
134/205 (65%) with PTA plus stent
109/179 (61%) with PTA alone

OR 1.31
95% CI 0.84 to 2.03
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
[44]
Systematic review
192 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
3 RCTs in this analysis
Patency on duplex USS 24 months
57/91 (63%) with PTA plus stent
48/101 (48%) with PTA alone

OR 1.78
95% CI 0.98 to 3.24
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
[44]
Systematic review
74 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
2 RCTs in this analysis
Patency on angiography 24 months
15/30 (50%) with PTA plus stent
26/44 (59%) with PTA alone

OR 0.70
95% CI 0.28 to 1.76
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
Physiological measures
Percutaneous transluminal angioplasty (PTA) plus stent compared with PTA alone PTA plus stent may be more effective than PTA alone at improving ankle brachial index at 6 and 12 months but maybe no more effective at 24 months (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ankle brachial pressure index
[44]
Systematic review
104 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
Data from 1 RCT
Mean improvement in ankle brachial index 6 months
0.25 with percutaneous transluminal angioplasty (PTA) plus stent
0.18 with PTA alone

Mean difference 0.07
95% CI 0.04 to 0.10
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Effect size not calculatedPTA plus stent
[44]
Systematic review
291 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
3 RCTs in this analysis
Mean improvement in ankle brachial index 12 months
with PTA plus stent
with PTA alone
Absolute results not reported

Mean difference 0.07
95% CI 0.05 to 0.09
Results should be interpreted with caution because of statistical heterogeneity as one large RCT in the analysis reported much higher results for ankle brachial index in the PTA plus stent group than the other RCTs
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Effect size not calculatedPTA plus stent
[44]
Systematic review
98 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
Data from 1 RCT
Mean improvement in ankle brachial index 24 months
0.26 with PTA plus stent
0.23 with PTA alone
Review commented that the type of antiplatelet medication varied between the included RCTs; clopidogrel was given in one large RCT

Mean difference +0.03
95% CI –0.04 to +0.10
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
No data from the following reference on this outcome.[43]
Quality of life
Percutaneous transluminal angioplasty (PTA) plus stent compared with PTA alone We don't know whether PTA plus stent is more effective than PTA alone at improving quality of life scores at 6 or 12 months (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[44]
Systematic review
208 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
Data from 1 RCT
Improvement in quality of life score 6 months
with percutaneous transluminal angioplasty (PTA) plus stent
with PTA alone
Absolute results not reported
Review commented that the type of antiplatelet medication varied between the included RCTs; clopidogrel was given in one large RCT

Mean difference –1.13
95% CI –5.03 to +2.77
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
[44]
Systematic review
208 people with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion
Data from 1 RCT
Improvement in quality of life score 12 months
with PTA plus stent
with PTA alone
Absolute results not reported

Mean difference +0.96
95% CI –2.62 to +4.53
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
Not significant
No data from the following reference on this outcome.[43]
Mortality
No data from the following reference on this outcome.[43] [44]
Cardiovascular events
No data from the following reference on this outcome.[43] [44]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[44]
Systematic review
People with intermittent claudication or critical limb ischaemia and superficial femoral artery stenosis or occlusion Intervention complication rates
with percutaneous transluminal angioplasty (PTA) plus stent
with PTA alone
Absolute results not reported
Five RCTs reported intervention complication rates of between 4.0% and 7.8%. The review did not report pooled data for this outcome.
Review commented that the type of antiplatelet medication varied between the included RCTs; clopidogrel was given in one large RCT

RCTs reported no significant difference in complication rates between groups; no pooled data reported
Results should be interpreted with caution as it was unclear in some of the RCTs how many people in the PTA alone arm went on to have "bailout" (secondary) stenting and whether or not they were subsequently included in the PTA plus stent arm for analysis, or excluded from the trial
No data from the following reference on this outcome.[43]
Percutaneous transluminal angioplasty (PTA) plus routine stent versus PTA plus selective stent:
We found 4 RCTs (reported in 5 publications) in which people were randomised to PTA plus routine stent or PTA plus selective stent, which we report here.[45] [46] [47] [48] [49]One of the systematic reviews [44]reported in the PTA plus stent versus PTA alone comparison included two of the RCTs that we also report here in its meta-analysis. [45] [46] [47]
Claudication distance/time
Percutaneous transluminal angioplasty (PTA) plus routine stent compared with PTA plus selective stent PTA plus routine stent may be more effective at improving walking distance at 6 and 12 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Walking distance
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Patient-reported average maximum walking distance 6 months
800 metres with percutaneous transluminal angioplasty (PTA) plus routine stenting (nitinol self-expanding stents)
600 m with PTA with optional secondary stenting

Intention-to-treat analysis
P = 0.002
Effect size not calculatedPTA plus routine stenting
[46]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [47]
Walking distance 12 months
387 m with PTA plus routine stenting (primary nitinol self-expanding stents)
267 m with balloon angioplasty with optional secondary stenting

P = 0.04
Effect size not calculatedPTA plus routine stenting
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Patient-reported average maximum walking distance 12 months
800 m with PTA plus routine stenting (nitinol self-expanding stents)
550  with PTA with optional secondary stenting

Intention-to-treat analysis
P = 0.042
Effect size not calculatedPTA plus routine stenting
No data from the following reference on this outcome.[45] [48]
Post-intervention patency
Percutaneous transluminal angioplasty (PTA) plus routine stent compared with PTA plus selective stent PTA plus routine stenting may be more effective at reducing reintervention rates or rates of restenosis at 3, 6, and 12 months (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Re-intervention / restenosis
[48]
RCT
279 people with intermittent claudication and iliac artery stenosis Proportion of people requiring reintervention
10/143 (7%) with percutaneous transluminal angioplasty (PTA) plus routine stenting
6/136 (4%) with PTA plus selective stenting

ARR +3%
95% CI –3% to +8%
Not significant
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Proportion of people with >50% restenosis according to duplex ultrasound 3 months
1/34 (3%) with PTA plus routine stenting (nitinol self-expanding stents)
7/37 (19%) with PTA with optional secondary stenting

P = 0.033
Effect size not calculatedPTA plus routine stenting
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Proportion of people with >50% restenosis 6 months
7/32 (22%) with PTA plus routine stenting (nitinol self-expanding stents)
20/36 (56%) with PTA with optional secondary stenting

Intention-to-treat analysis
P = 0.005
Effect size not calculatedPTA plus routine stenting
[45]
RCT
227 people with severe claudication or limb-threatening stenosis of the superficial femoral artery Proportion of people who died or had >50% restenosis 1 year
30/89 (34%) with PTA plus routine stenting
29/86 (33%) with PTA plus selective stenting

P = 0.9
Not significant
[46]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [47]
Proportion of people with restenosis 12 months
18/49 (37%) with PTA plus routine stenting (primary nitinol self-expanding stents)
33/52 (63%) with balloon angioplasty with optional secondary stenting

P = 0.01
Effect size not calculatedPTA plus routine stenting
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Proportion of people with >50% restenosis according to duplex ultrasound 12 months
11/32 (34%) with PTA plus routine stenting (nitinol self-expanding stents)
22/36 (61%) with PTA with optional secondary stenting

Intention-to-treat analysis
P = 0.028
Effect size not calculatedPTA plus routine stenting
Physiological measures
Percutaneous transluminal angioplasty (PTA) plus routine stent compared with PTA plus selective stent We don't know how PTA plus routine stenting and PTA plus selective stenting compare at improving ankle brachial index at 6 and 12 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ankle brachial index
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Ankle brachial index 6 months
1.20 with percutaneous transluminal angioplasty (PTA) plus routine stenting (nitinol self-expanding stents)
1.06 with PTA with optional secondary stenting

Intention-to-treat analysis
P = 0.84
Not significant
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Ankle brachial index 12 months
0.93 with PTA plus routine stenting (nitinol self-expanding stents)
0.89 with PTA with optional secondary stenting

Intention-to-treat analysis
P = 0.40
Not significant
No data from the following reference on this outcome.[48] [45] [46] [47]
Quality of life
Percutaneous transluminal angioplasty (PTA) plus routine stent compared with PTA plus selective stent We don't know whether routine use of stents as part of PTA or selective use of stents is more effective at improving quality of life at 3 to 12 months (assessed using the RAND-36 questionnaire or the short form-36 [SF-36] questionnaire) (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[48]
RCT
279 people with intermittent claudication and iliac artery stenosis Improvement in quality of life (assessed using the RAND-36 questionnaire) 3 months
with percutaneous transluminal angioplasty (PTA) plus routine stenting
with PTA plus selective stenting
Absolute results not reported

Reported as not significant
P value not reported
Not significant
[47]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [46]
Physical component of the short form-36 (SF-36) quality-of-life questionnaire 6 months
33 with PTA plus routine stenting (primary nitinol self-expanding stents)
37 with balloon angioplasty with optional secondary stenting

P = 0.8
Not significant
[47]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [46]
Mental component of the SF-36 quality-of-life questionnaire 6 months
53 with PTA plus routine stenting (primary nitinol self-expanding stents)
50 with balloon angioplasty with optional secondary stenting

P = 0.5
Not significant
[47]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [46]
Physical component of the SF-36 quality-of-life questionnaire 12 months
35 with PTA plus routine stenting (primary nitinol self-expanding stents)
37 with balloon angioplasty with optional secondary stenting

P = 0.9
Not significant
[47]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [46]
Mental component of the SF-36 quality-of-life questionnaire 12 months
54 with PTA plus routine stenting (primary nitinol self-expanding stents)
51 with balloon angioplasty with optional secondary stenting

P = 0.1
Not significant
No data from the following reference on this outcome.[45] [49]
Mortality
No data from the following reference on this outcome.[45] [46] [47] [48] [49]
Cardiovascular events
No data from the following reference on this outcome.[45] [46] [47] [48] [49]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[48]
RCT
279 people with intermittent claudication and iliac artery stenosis Proportion of people with complications
6/143 (4%) with percutaneous transluminal angioplasty (PTA) plus routine stenting
10/136 (7%) with PTA plus selective stenting

95% CI (for difference between groups) –2% to +9%
Not significant
[49]
RCT
73 people with severe intermittent claudication, chronic critical limb ischaemia or ischaemic ulcers, and superficial femoral artery stenosis or occlusion Post-intervention complications
with PTA plus routine stenting (nitinol self-expanding stents)
with PTA with optional secondary stenting
Absolute results not reported
[45]
RCT
227 people with severe claudication or limb-threatening stenosis of the superficial femoral artery Risk of local vascular events 1 year
with PTA plus routine stenting
with PTA plus selective stenting
Absolute results not reported

P = 0.017
Effect size not calculatedPTA plus selective stenting
[46]
RCT
104 people with severe claudication caused by stenosis or occlusion of the superficial femoral artery
Further report of reference [47]
Adverse effects (any) 12 months
with PTA plus routine stenting (primary nitinol self-expanding stents)
with balloon angioplasty with optional secondary stenting
Absolute results not reported
Percutaneous transluminal angioplasty (PTA) alone versus PTA plus statins:
We found one RCT.[50]
Post-intervention patency
Percutaneous transluminal angioplasty (PTA) alone compared with PTA plus statin Adding a statin to PTA may be no more effective than PTA alone at reducing restenosis rates and limb amputation at 12 months (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Restenosis
[50]
RCT
37 people taking aspirin 250 mg/day with critical ischaemia or severe claudication; Fontaine classification class IIb or II Proportion of people with restenosis 12 months
4/18 (22%) with percutaneous transluminal angioplasty (PTA) plus lovastatin 20 mg daily
8/19 (42%) with PTA alone

Reported as not significant
P value not reported
The RCT is likely to have been underpowered to detect a small but clinically important difference between the two groups
Not significant
Amputation
[50]
RCT
37 people taking aspirin 250 mg/day with critical ischaemia or severe claudication; Fontaine classification class IIb or II Proportion of people with amputation of a limb 12 months
4/18 (11%) with percutaneous transluminal angioplasty (PTA) plus lovastatin 20 mg daily
4/19 (21%) with PTA alone

Reported as not significant
P value not reported
The RCT is likely to have been underpowered to detect a small but clinically important difference between the two groups
Not significant
Mortality
No data from the following reference on this outcome.[50]
Cardiovascular events
No data from the following reference on this outcome.[50]
Claudication distance/time
No data from the following reference on this outcome.[50]
Physiological measures
No data from the following reference on this outcome.[50]
Quality of life
No data from the following reference on this outcome.[50]
Adverse effects
No data from the following reference on this outcome.[50]
Percutaneous transluminal angioplasty (PTA) versus bypass surgery:
See option on bypass surgery.
Further information on studies
Optimal medical treatment involved patient education regarding exercise, nutrition, and smoking cessation, and medication including antiplatelet agents, lipid-lowering agents, anti-hypertensives, and anti-diabetic agents, when indicated.
Comment
Clinical guide:
Further large RCTs are warranted in the future to fully assess newer stents. The small number of large RCTs and their small sample sizes and methodological weaknesses suggest that further RCTs are needed in order to reliably establish clinical effects of newer stents.
This limited evidence suggests transient benefit from angioplasty compared with no angioplasty. The longer term effects of angioplasty or stent placement on symptoms, bypass surgery, and amputation remain unclear, and the available RCTs are likely to have been too small to detect clinically important effects of stent placement. The long-term patency of femoro-popliteal angioplasties is poor, and we found conflicting evidence as to whether the addition of stents confers any additional benefit.[46] [51] [52] [53]
Prospective cohort studies have found that complications of PTA include puncture site major bleeding (3.4%), pseudo-aneurysms (0.5%), limb loss (0.2%), renal failure secondary to intravenous contrast (0.2%), cardiac complications such as MI (0.2%), and death (0.2%).[54] [55]
Substantive changes
Percutaneous transluminal angioplasty (PTA) One systematic review [44] and one RCT[49]added comparing PTA plus stenting versus PTA alone. The review found improved patency rates on duplex ultrasound scans and angiography with PTA plus stenting at 6 months compared with PTA alone but no significant difference at 1 or 2 years. It also found that PTA plus stenting increased walking distance at 6 and 12 months but not at 24 months. The review found no significant difference between groups in ankle brachial index, quality of life, and adverse effects. The RCT [49]compared PTA plus routine stenting versus PTA plus selective stenting. It found that PTA plus routine stenting reduced restenosis at 3, 6, and 12 months and increased patient-reported maximum walking distance at 6 and 12 months. Categorisation unchanged (Likely to be beneficial).

Smoking cessation
Summary
Stopping smoking may increase walking distance when combined with exercise.
We found no clinically important results from RCTs about the effects of advice to stop smoking in people with peripheral arterial disease.
Benefits and harms
Advice to stop smoking versus no advice:
We found no RCTs. We found one systematic review (search date 1996; 4 observational studies; 866 people) of advice to stop cigarette smoking versus no advice (see comment).[18]
Further information on studies
None.
Comment
Clinical guide:
RCTs of advice to stop smoking are considered unethical. The consensus is that stopping smoking improves symptoms in people with intermittent claudication. One observational study included in the systematic review found no significant increase in absolute claudication distance after stopping smoking (+46.7 m, 95% CI –19.3 m to +112.7 m). The second and third studies identified by the review found conflicting results about the risk of deteriorating from moderate to severe claudication in people who successfully stopped smoking compared with current smokers. The second study found that significantly more smokers deteriorated from Fontaine stage II to III compared with people who had stopped smoking (26/304 [9%] smokers v 0/39 [0%] non-smokers; ARR 8.6%, 95% CI 5.4% to 11.7%). However, the third study found no difference in deterioration in ankle brachial index at 1 year between smokers and people who had stopped smoking (data not reported). There was also no significant difference in the number of failed revascularisation procedures between smokers and non-smokers (P = 0.07).[18] The fourth study provided no numerical results. Overall, the review found no good evidence to confirm or refute the consensus that advice to stop smoking improves symptoms in people with intermittent claudication.
Substantive changes
No new evidence

Cilostazol
Summary
Cilostazol may improve walking distance compared with placebo.
Cilostazol may reduce the incidence of cerebrovascular events compared with placebo but may be no more effective at reducing cardiac events.
Cilostazol may be more effective than pentoxifylline at improving claudication distance.
Adverse effects of cilostazol are common, and include headache, diarrhoea, and palpitations.
Benefits and harms
Cilostazol versus placebo:
We found two systematic reviews (search date 2008, 7 RCTs, 1579 people with peripheral arterial disease;[56] and search date 2007, 12 RCTs, 5674 people[57]) and one subsequent RCT (80 people).[58] The first review did not pool results for claudication distance or ankle brachial index for different doses of cilostazol, and so we have reported these separately by dose. The second review [57]identified all the RCTs identified by the first review[56] but reported on different outcomes and so we include both here.
Cardiovascular events
Cilostazol compared with placebo Cilostazol seems to be more effective at reducing all vascular events and cerebrovascular events, but seems no more effective than placebo at reducing cardiac events (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Cardiovascular events
[57]
Systematic review
5674 people with coronary stenting, cerebrovascular disease, or peripheral arterial disease; 3782 people (67%) with peripheral arterial disease
12 RCTs in this analysis
Occurrence of all cardiovascular events 12 to 144 weeks
289/3038 (10%) with cilostazol
328/2636 (12%) with placebo

RR 0.86
95% CI 0.74 to 0.99
P = 0.038
Small effect sizeCilostazol
[57]
Systematic review
5674 people with coronary stenting, cerebrovascular disease, or peripheral arterial disease; 3782 people (67%) with peripheral arterial disease
12 RCTs in this analysis
Occurrence of cerebrovascular events 12 to 144 weeks
67/3038 (2%) with cilostazol
111/2636 (4%) with placebo

RR 0.58
95% CI 0.43 to 0.78
P <0.001
Small effect sizeCilostazol
[57]
Systematic review
5674 people with coronary stenting, cerebrovascular disease, or peripheral arterial disease; 3782 people (67%) with peripheral arterial disease
12 RCTs in this analysis
Occurrence of cardiac events 12 to 144 weeks
222/3038 (7%) with cilostazol
217/2636 (8%) with placebo

RR 0.99
95% CI 0.83 to 1.17
P = 0.908
Not significant
No data from the following reference on this outcome.[56] [58]
Claudication distance/time
Cilostazol compared with placebo Cilostazol 100 mg twice daily may be more effective at improving initial and absolute claudication distance measures at 6 weeks and 12 to 24 weeks, but we don't know whether cilostazol 50 mg twice daily or 150 mg twice daily is more effective (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Claudication distance
[58]
RCT
80 people with stable intermittent claudication Mean initial claudication distance 6 weeks
105.5 metres with cilostazol 100 mg twice daily
67.5 m with placebo

P = 0.02
Methods of randomisation not reported
Effect size not calculatedCilostazol 100 mg twice daily
[58]
RCT
80 people with stable intermittent claudication Mean absolute claudication distance 6 weeks
193.1 m with cilostazol 100 mg twice daily
168.5 m with placebo

P = 0.04
Methods of randomisation not reported
Effect size not calculatedCilostazol 100 mg twice daily
[56]
Systematic review
104 people
Data from 1 RCT
Mean change in initial claudication distance from baseline 12 weeks
50.1 m with cilostazol 150 mg twice daily
34.4 m with placebo

WMD +15.7 m
95% CI –9.6 m to +41 m
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Not significant
[56]
Systematic review
104 people
Data from 1 RCT
Mean change in absolute claudication distance from baseline 12 weeks
89.9 m with cilostazol 150 mg twice daily
38 m with placebo

WMD +51.8 m
95% CI –13.9 m to +118 m
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Not significant
[56]
Systematic review
475 people
2 RCTs in this analysis
Improvement in initial claudication distance 12 to 24 weeks
with cilostazol 50 mg twice daily
with placebo
Absolute results not reported

WMD +41.3 m
95% CI –7.1 m to +89.7 m
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Not significant
[56]
Systematic review
1326 people
6 RCTs in this analysis
Improvement in initial claudication distance 12 to 24 weeks
with cilostazol 100 mg twice daily
with placebo
Absolute results not reported

WMD 31.3 m
95% CI 21.3 m to 40.9 m
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 100 mg twice daily
[56]
Systematic review
497 people
2 RCTs in this analysis
Improvement in absolute claudication distance 12 to 24 weeks
with cilostazol 50 mg twice daily
with placebo
Absolute results not reported

WMD 31.9 m, 95% CI 12.4 m to 51.5 m
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 50 mg twice daily
[56]
Systematic review
1579 people
7 RCTs in this analysis
Improvement in absolute claudication distance 12 to 24 weeks
with cilostazol 100 mg twice daily
with placebo
Absolute results not reported

WMD 49.7 m, 95% CI 24.2 m to 75.2 m
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 100 mg twice daily
[58]
RCT
80 people with stable intermittent claudication Mean initial claudication distance 24 weeks
82.7 m with cilostazol 100 mg twice daily
85.0 m with placebo

P = 0.98
Methods of randomisation not reported
Not significant
[58]
RCT
80 people with stable intermittent claudication Mean absolute claudication distance 24 weeks
286.1 m with cilostazol 100 mg twice daily
227.1 m with placebo

P = 0.22
Methods of randomisation not reported
Not significant
No data from the following reference on this outcome.[57]
Physiological measures
Cilostazol compared with placebo Cilostazol 100 mg twice daily may be more effective at improving ankle brachial index at 12 to 24 weeks (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ankle brachial index
[56]
Systematic review
859 people
3 RCTs in this analysis
Improvement in ankle brachial index 12 to 24 weeks
with cilostazol 100 mg twice daily
with placebo
Absolute results not reported

WMD 0.06
95% CI 0.03 to 0.09
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 100 mg twice daily
[58]
RCT
80 people with stable intermittent claudication Median ankle brachial index (left lower limb) 24 weeks
0.82 with cilostazol 100 mg twice daily
0.73 with placebo

P = 0.17
Methods of randomisation not reported
Not significant
[58]
RCT
80 people with stable intermittent claudication Median ankle brachial index (right lower limb) 24 weeks
0.80 with cilostazol 100 mg twice daily
0.80 with placebo

P = 0.45
Methods of randomisation not reported
Not significant
No data from the following reference on this outcome.[57]
Quality of life
Cilostazol compared with placebo We don't know whether cilostazol is more effective at improving quality of life (assessed using the short form-36 [SF-36], VascuQol, and the Walking Impairment Questionnaires) at 12 to 24 weeks (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Quality of life
[56]
Systematic review
1149 people
3 RCTs in this analysis
Improvement in physical function component of the short form-36 (SF-36) questionnaire
with cilostazol 50 mg and 100 mg twice daily
with placebo
Absolute results not reported

P = 0.002
No further details reported
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 50 mg and 100 mg twice daily
[56]
Systematic review
1149 people
3 RCTs in this analysis
Improvement in bodily pain component of the SF-36 questionnaire
with cilostazol 50 mg and 100 mg twice daily
with placebo
Absolute results not reported

P <0.05
No further details reported
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 50 mg and 100 mg twice daily
[56]
Systematic review
1149 people
3 RCTs in this analysis
Improvement in mental health component of the SF-36 questionnaire
with cilostazol 50 mg and 100 mg twice daily
with placebo
Absolute results not reported

Reported as not significant
P value not reported
No further details reported
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Not significant
[58]
RCT
80 people with stable intermittent claudication Mean percentage total improvement from baseline (assessed by the SF-36 questionnaire) 24 weeks
1.8% with cilostazol 100 mg twice daily
1.4% with placebo
Absolute numbers not reported

P = 0.50
Not significant
[58]
RCT
80 people with stable intermittent claudication Mean percentage total improvement from baseline (assessed by the VascuQol questionnaire) 24 weeks
5.5% with cilostazol 100 mg twice daily
3.0% with placebo
Absolute numbers not reported

P = 0.78
Not significant
[56]
Systematic review
755 people
2 RCTs in this analysis
Improvement in people's perception of walking speed (assessed by Walking Impairment Questionnaire)
with cilostazol 50 mg and 100 mg twice daily
with placebo
Absolute results not reported

P <0.05
No further details reported
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedCilostazol 50 mg and 100 mg twice daily
[58]
RCT
80 people with stable intermittent claudication Speed component score of the Walking Impairment Questionnaire 24 weeks
39% with cilostazol 100 mg twice daily
38% with placebo
Absolute numbers not reported

P = 0.88
Not significant
[58]
RCT
80 people with stable intermittent claudication Distance component score of the Walking Impairment Questionnaire 24 weeks
38% with cilostazol 100 mg twice daily
37% with placebo
Absolute numbers not reported

P = 0.41
Not significant
No data from the following reference on this outcome.[57]
Mortality
No data from the following reference on this outcome.[56] [57] [58]
Post-intervention patency
No data from the following reference on this outcome.[56] [57] [58]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[56]
Systematic review
Number of people and RCTs assessed not clear Adverse effects including headache, diarrhoea, peripheral oedema, rhinitis, and infection
with cilostazol 50 mg and 100 mg twice daily
with placebo
Absolute results not reported

P <0.05
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Effect size not calculatedPlacebo
[59]
RCT
3-armed trial
698 people
In review [56]
Proportion of people withdrawing because of adverse effects
39/227 (17%) with cilostazol 100 mg twice daily
24/239 (10%) with placebo

RR (cilostazol v placebo) 1.71
95% CI 1.06 to 2.75
NNH 14
95% CI 8 to 111
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
Small effect sizePlacebo
[60]
RCT
3-armed trial
394 people
In review [56]
Proportion of people withdrawing because of adverse effects
23% with cilostazol 100 mg twice daily
12% with cilostazol 50 mg twice daily
10% with placebo
Absolute numbers not reported

Significance not assessed
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
[60]
RCT
3-armed trial
394 people
In review [56]
Proportion of people withdrawing because of headache
4.5% with cilostazol 100 mg twice daily
0% with placebo
Absolute numbers not reported

Significance not assessed
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
[60]
RCT
3-armed trial
394 people
In review [56]
Proportion of people withdrawing because of cardiovascular events
12/133 (9%) with cilostazol 100 mg twice daily
5/129 (4%) with placebo

Significance not assessed
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
[61]
RCT
81 people
In review [56]
Proportion of people reporting a GI adverse effect
44% with cilostazol 100 mg twice daily
15% with placebo
Absolute numbers not reported

Significance not assessed
The RCTs included in the review had some weaknesses in their methods that may limit the applicability of the results (see further information on studies for more details)
[58]
RCT
80 people with stable intermittent claudication Number of medication-related adverse effects 24 weeks
36 with cilostazol 100 mg twice daily
7 with placebo

Significance not assessed
[58]
RCT
80 people with stable intermittent claudication Proportion of people withdrawing from study 24 weeks
6/39 (15%) with cilostazol 100 mg twice daily
3/41 (7%) with placebo

Significance not assessed
[57]
Systematic review
5674 people with coronary stenting, cerebrovascular disease, or peripheral arterial disease; 3782 people (67%) with peripheral arterial disease
12 RCTs in this analysis
Occurrence of serious bleeding 12 to 144 weeks
46/3038 (1.5%) with cilostazol
45/2636 (1.7%) with placebo

RR 1.00
95% CI 0.66 to 1.51
P = 0.996
Not significant
Cilostazol versus pentoxifylline:
See option on pentoxifylline.
Further information on studies
None of the RCTs evaluated cilostazol beyond 24 weeks. In addition, some of the RCTs had high withdrawal rates after randomisation (up to 29%). In most of the RCTs, withdrawals were more common with cilostazol than with placebo. To allow for these problems, the authors performed intention-to-treat analyses using "last available observation carried forward". However, the analyses did not include people with no observations to carry forward, and the effect of the difference in withdrawals between the groups was not explored adequately. If people with worsening claudication were more likely to withdraw, then the observed differences might have been artefactual.
Comment
The review did not describe the outcomes of cardiovascular morbidity and mortality from the included trials. However, it commented on a separate review of the same RCTs comparing cilostazol versus placebo, which included a summary of adverse effects and cardiovascular events from these trials. It found a similar incidence of cardiovascular events (incidence of MI: 1.0% with cilostazol v 0.8% with placebo; incidence of stroke: 0.5% with cilostazol v 0.5% with placebo; statistical assessment not reported). It also found a similar incidence of total cardiovascular morbidity and all-cause mortality (6.5% with cilostazol 100 mg twice daily v 6.3% with cilostazol 50 mg twice daily v 7.7% with placebo; statistical assessment not reported; absolute numbers not reported).[56]
Cilostazol is a phosphodiesterase inhibitor; RCTs have found that other phosphodiesterase inhibitors (milrinone, vesnarinone) are associated with increased mortality in people with heart failure. However, results aggregated from other studies have not found an excess of cardiovascular events with cilostazol.[64]
Substantive changes
Cilostazol One systematic review [57] and one RCT[58]added both comparing cilostazol versus placebo. The review found cilostazol reduced all vascular and cerebrovascular events compared with placebo; however, it found no significant difference in cardiac events or serious bleeding episodes.[57] The RCT found cilostazol improved claudication distances at 6 weeks, although there was no significant difference at 24 weeks.[58] The RCT also found no significant difference between groups in ankle brachial index or quality-of-life scores at 24 weeks and reported more people withdrawing and reporting medication-related adverse effects at 24 weeks in the cilostazol group; however, the overall significance was not reported. Categorisation unchanged (Likely to be beneficial).

Prostaglandins
Summary
Prostaglandins may improve amputation-free survival in critical ischaemia at 6 months when surgical revascularisation is not an option.
Prostaglandins are unlikely to be of benefit in intermittent claudication.
Prostaglandins are associated with higher rates of adverse effects, including headache, vasodilation, diarrhoea, tachycardia, and vasodilation compared with placebo.
Benefits and harms
Prostaglandins versus placebo:
We found three systematic reviews,[65] [66] [67] and one additional RCT.[68] The first review (search date 2004; 5 RCTs, 300 people) reported on prostanoids for treating patients with intermittent claudication.[65]The second review (search date 2004; 3 RCTs, 254 people) reported on prostaglandin E1 (PGE1) for treating severe peripheral arterial occlusive disease (stage III and IV),[66]and the third review (search date 2010; 6 RCTs, 946 people)[67] reported on prostanoids for treating patients with critical limb ischaemia, without chance of rescue or reconstructive intervention and included two of the RCTs also reported in the second review,[66]but we report both here as they use the RCTs for different comparisons.
Mortality
Prostaglandins compared with placebo We don't know whether lipo-ecraprost is more or less effective than placebo at reducing mortality in people with critical limb ischaemia (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
All-cause mortality
[68]
RCT
322 people with critical limb ischaemia undergoing endovascular or surgical revascularisation Mortality rate 6 months
13/141 (9%) with lipo-ecraprost (intravenously for 8 weeks)
19/143 (13%) with placebo

P = 0.28
Significantly fewer people in the lipo-ecraprost group adhered to study medication compared with people in the placebo group (see further information on studies for absolute numbers)
Not significant
No data from the following reference on this outcome.[65] [66] [67]
Claudication distance/time
Prostaglandins compared with placebo We don't know whether prostaglandins are more effective at increasing pain-free and maximal walking distances in people with intermittent claudication (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum/pain-free walking distance
[65]
Systematic review
100 people with intermittent claudication (peripheral arterial occlusive disease [PAOD] stage IIb) for > 6 months
2 RCTs in this analysis
Pain-free walking distance
with intra-arterial prostaglandin E1 (PGE1)
with placebo
Absolute results not reported

Mean difference 95.7 metres
95% CI 76.35 m to 115.05 m
P <0.00001
See further information on studies for details of methodological issues that may affect the results
Effect size not calculatedIntra-arterial PGE1
[65]
Systematic review
300 people with intermittent claudication
3 RCTs in this analysis
Pain-free walking distance
with intravenous PGE1
with placebo
Absolute results not reported

Mean difference 22.34 m
95% CI 21.78 m to 22.90 m
P <0.00001
Results should be interpreted with caution as significant statistical heterogeneity and meta-analysis dominated by one large RCT (208 people), which was heavily weighted in the analysis. See further information on studies for further details
Effect size not calculatedIntravenous PGE1
[65]
Systematic review
43 people with intermittent claudication (PAOD stage IIb)
Data from 1 RCT
Median improvement of pain-free walking distance
20 m with prostaglandin E1 prodrug (AS-013 )
9 m with placebo

P >0.05
Not significant
[65]
Systematic review
100 people with intermittent claudication (PAOD stage IIb) for >6 months
2 RCTs in this analysis
Maximal walking distance
with intra-arterial PGE1
with placebo
Absolute results not reported

Mean difference 126.92 m
95% CI 99.10 m to 154.73 m
P <0.00001
See further information on studies for details of methodological issues that may affect the results
Effect size not calculatedIntra-arterial PGE1
[65]
Systematic review
300 people with intermittent claudication
3 RCTs in this analysis
Maximal walking distance
with intravenous PGE1
with placebo
Absolute results not reported

Mean difference 25.82 m
95% CI 25.29 m to 26.35 m
P <0.00001
Results should be interpreted with caution as significant statistical heterogeneity and meta-analysis dominated by one large RCT (208 people), which was heavily weighted in the analysis. See further information on studies for further details
Effect size not calculatedIntravenous PGE1
[65]
Systematic review
43 people with intermittent claudication (PAOD stage IIb)
Data from 1 RCT
Median improvement of maximal walking distance
28 m with prostaglandin E1 prodrug (AS-013)
4 m with placebo

P <0.05
Effect size not calculatedProstaglandin E1 prodrug (AS-013)
No data from the following reference on this outcome.[66] [68] [67]
Post-intervention patency
Compared with placebo We do not know whether prostaglandins are more effective than placebo at improving ulcer healing, reducing amputations, increasing rest pain relief, or reducing analgesic consumption in people with severe peripheral arterial disease or critical limb ischaemia (very low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ulcer healing/pain reduction
[67]
Systematic review
30 people with critical limb ischaemia presenting with rest pain, ischaemic ulceration, or both, and without chance of rescue or reconstructive intervention
Data from 1 RCT
Ulcer healing
0/9 (0%) with intravenous infusion of prostaglandin E1 (PGE1)
3/10 (30%) with placebo

RR 0.16
95% CI 0.01 to 2.68
Review suggests that results should be interpreted with caution as the RCT had unclear methods
Not significant
[66]
Systematic review
254 people with severe peripheral arterial disease (stage III or IV), not eligible for arterial reconstruction
3 RCTs in this analysis
Response for ulcer healing and/or pain reduction 6 months
48% with PGE1
25% with placebo
Absolute numbers not reported

P = 0.0294
Effect size not calculatedPGE1
[67]
Systematic review
85 people with type II diabetes and foot ulcers due to an arterial occlusive disease (critical limb ischaemia), without chance of rescue or reconstructive intervention
Data from 1 RCT
Ulcer healing
6/36 (17%) with intravenous PGE1
2/37 (5%) with placebo

RR 3.08
95% CI 0.67 to 14.28
Review suggests that results should be interpreted with caution as the RCT had unclear methods
Not significant
[67]
Systematic review
69 people under 70 years old with critical limb ischaemia without chance of rescue or reconstructive intervention
2 RCTs in this analysis
Rest pain relief
11/36 (31%) with PGE1
5/33 (15%) with placebo

RR 1.52
95% CI 0.69 to 3.34
Authors advise interpreting results with caution because of unclear methods in the RCTs
Not significant
[67]
Systematic review
58 people under 70 years old with critical limb ischaemia without chance of rescue or reconstructive intervention
2 RCTs in this analysis
Reduction in analgesics consumption
21/33 (64%) with PGE1
10/25 (40%) with placebo

RR 1.58
95% CI 0.92 to 2.72
Authors advise interpreting results with caution because of unclear methods in the RCTs
Not significant
Limb amputation
[67]
Systematic review
85 people with type II diabetes and foot ulcers due to an arterial occlusive disease (critical limb ischaemia), without chance of rescue or reconstructive intervention
Data from 1 RCT
Total amputations
4/36 (11%) with intravenous PGE1
10/37 (27%) with placebo

RR 0.41
95% CI 0.14 to 1.19
Review suggests interpreting results with caution as the RCT had unclear methods
Not significant
[66]
Systematic review
207 people with severe peripheral arterial disease (stage III or IV), not eligible for arterial reconstruction
2 RCTs in this analysis
Proportion of people with major amputation or death 6 months
23/102 (23%) with PGE1
38/105 (36%) with placebo

P = 0.02
Per-protocol analysis
Effect size not calculatedPGE1
[69]
RCT
379 people with critical limb ischaemia who were not candidates for revascularisation
In review [67]
Proportion of people who had a limb amputated 6 months
29/179 (16%) with lipo-ecraprost (a lipid-encapsulated PGE1 prodrug)
23/177 (13%) with placebo

Reported as not significant
P value not reported
Not significant
[68]
RCT
322 people with critical limb ischaemia undergoing endovascular or surgical revascularisation Proportion of people with amputation at or above the level of the ankle 6 months
17/141 (12%) with lipo-ecraprost (intravenously for 8 weeks)
19/143 (13%) with placebo

Reported as not significant
P value not reported
Significantly fewer people in the lipo-ecraprost group adhered to study medication compared with people in the placebo group (see further information on studies for absolute numbers)
Not significant
[67]
Systematic review
30 people with critical limb ischaemia presenting with rest pain, ischaemic ulceration, or both, and without chance of rescue or reconstructive intervention
Data from 1 RCT
Total amputations
7/14 (50%) with intravenous infusion of PGE1
5/16 (31%) with placebo

RR 1.60
95% CI 0.65 to 3.92
Review suggests interpreting results with caution as the RCT had unclear methods
Not significant
No data from the following reference on this outcome.[65]
Cardiovascular events
No data from the following reference on this outcome.[65] [66] [67] [68]
Physiological measures
No data from the following reference on this outcome.[65] [66] [67] [68]
Quality of life
No data from the following reference on this outcome.[65] [66] [67] [68]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[66]
Systematic review
672 people with severe peripheral arterial disease (stage III or IV), not eligible for arterial reconstruction
7 RCTs in this analysis
Rate of adverse effects 6 months
40% with prostaglandin E1 (PGE1)
15% with placebo
Absolute numbers not reported

P value not reported
Analysis included non-placebo-controlled RCTs
See further information on studies for potential methodological limitations in the RCTs identified
[69]
RCT
379 people with critical limb ischaemia who were not candidates for revascularisation
In review [67]
Proportion of people with an adverse effect 6 months
7094 (202 serious) for 189 people with lipo-ecraprost (a lipid-encapsulated PGE1 prodrug)
1594 (235 serious) for 190 people with placebo

P value not reported
[68]
RCT
322 people with critical limb ischaemia undergoing endovascular or surgical revascularisation Adverse effects 6 months
with lipo-ecraprost (intravenously for 8 weeks)
with placebo
Absolute results not reported

Significantly fewer people in the lipo-ecraprost group adhered to study medication compared with people in the placebo group (see further information on studies for absolute numbers)
[67]
Systematic review
69 people under 70 years old with critical limb ischaemia without chance of rescue or reconstructive intervention
2 RCTs in this analysis
Proportion of people reporting adverse events
15/36 (42%) with PGE1
2/33 (6%) with placebo

RR 5.81
95% CI 1.62 to 20.86
Authors advise interpreting results with caution because of unclear methods in the RCTs
Large effect sizePlacebo
[65]
Systematic review
1255 people with intermittent claudication
16 RCTs in this analysis
Adverse events
54/392 (14%) with intra-arterial or intravenous PGE1
54/863 (6%) with placebo
Prostaglandins versus pentoxifylline:
We found one systematic review (search date 2004; 2 RCTs, 277 people) comparing prostaglandin E1 (PGE1) versus pentoxifylline in people with intermittent claudication.[65]
Claudication distance/time
Prostaglandins compared with pentoxifylline Prostaglandin E1 may increase maximal and pain-free walking distances compared with pentoxifylline in people with intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Maximum/pain-free walking distance
[65]
Systematic review
195 people with intermittent claudication
Data from 1 RCT
Mean increase in pain-free walking distance
181 metres with prostaglandin E1 (PGE1)
104 m with pentoxifylline

Reported as significant but no further details given
Effect size not calculatedPGE1
[65]
Systematic review
82 people with intermittent claudication
Data from 1 RCT
Mean increase in pain-free walking distance
106 m with PGE1
71 m with pentoxifylline

Reported as significant but no further details given
Effect size not calculatedPGE1
[65]
Systematic review
195 people with intermittent claudication
Data from 1 RCT
Mean increase in maximal walking distance
213 m with PGE1
191 m with pentoxifylline

Reported as significant but no further details given
Effect size not calculatedPGE1
Physiological measures
Prostaglandins compared with pentoxifylline We don't know how prostaglandin E1 and pentoxifylline compare at improving ankle brachial index in people with intermittent claudication (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Ankle brachial index
[65]
Systematic review
240 people with intermittent claudication
2 RCTs in this analysis
Ankle brachial index
with PGE1
with pentoxifylline
Absolute results not reported

Mean difference –0.05
95% CI –0.11 to +0.02
P = 0.14
Not significant
Mortality
No data from the following reference on this outcome.[65]
Post-intervention patency
No data from the following reference on this outcome.[65]
Cardiovascular events
No data from the following reference on this outcome.[65]
Quality of life
No data from the following reference on this outcome.[65]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[65]
Systematic review
545 people with intermittent claudication Gastrointestinal disorders
6/392 (2%) with intra-arterial or intravenous PGE1
6/153 (4%) with pentoxifylline
Further information on studies
Proportion of people who received at least 35 of the intended 40 treatment doses was significantly less in the lipo-ecraprost group (37/141 [26%] with lipo-ecraprost v 73/143 [51%] with placebo; reported as significant; P value not reported).
The 7 RCTs included in the systematic review were conducted between 1987 and 1992, and therefore did not comply with current guidelines regarding the conducting of clinical trials in peripheral arterial disease. Four of the included studies were not double-blind, placebo-controlled studies, and the end point of ulcer healing and pain relief used in some of these studies is somewhat subjective.
The review included 4 RCTs, all of which were of poor methodological quality and classified as moderate risk of bias. The review's authors suggest that this may be because the studies were done 15 to 30 years ago when current concepts from evidence-based medicine were not so well established.
The review reported significant heterogeneity between the included studies because of variations in study design, including duration of interventions, drug doses, and use of different treadmills for measuring walking distances. The review also reported that many of the RCTs included had poor-quality methods including a lack of data on methods of randomisation and withdrawals, and several of the RCTs used baseline values for walking distance determined from a single measurement. This may have generated false results as other RCTs found variations of >20% between two measurements performed pre-treatment (baseline measurements) and excluded these people.
Comment
Substantive changes
Prostaglandins Two systematic reviews added.[65] [67] The first review [65]found that prostaglandins increased maximal walking distance and pain-free walking distance compared with both placebo and with pentoxifylline in people with intermittent claudication. The second review[67] found no significant difference between prostaglandins and placebo in ulcer healing, amputations, rest pain relief, or reduction in analgesic consumption, although prostaglandins were associated with more adverse effects. Categorisation unchanged (Trade off between benefits and harms).

Pentoxifylline
Summary
We don't know whether pentoxifylline improves symptoms compared with placebo, but it may be less effective than cilostazol.
Benefits and harms
Pentoxifylline versus placebo:
We found two systematic reviews[16] [70] and one additional RCT.[59] The first review (search date 1999; 2 RCTs,192 people) did not perform a meta-analysis and so we report data from the RCTs. The second review (search date 2009; 6 RCTs, 788 people)[16] pooled data and identified one RCT identified by the first review.[70]
Claudication distance/time
Pentoxifylline compared with placebo Pentoxifylline may be more effective than placebo at increasing maximum walking distance but may be no more effective at increasing initial claudication distance (low-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Claudication distance
[70]
Systematic review
40 people with peripheral arterial disease (Fontaine stage II)
Data from 1 RCT
Improvement in mean initial claudication distance
From 144 metres to 364 m with pentoxifylline
From 134 m to 384 m with placebo

Mean difference –30 m
95% CI –138 m to +78 m
Not significant
[70]
Systematic review
40 people with peripheral arterial disease (Fontaine stage II)
Data from 1 RCT
Improvement in mean absolute claudication distance
From 166 m to 504 m with pentoxifylline
From 151 m to 420 m with placebo
Absolute results not reported

Mean difference +69 m
95% CI –44 m to +182 m
Not significant
[59]
RCT
3-armed trial
698 people Proportion of people who had either no change or had deterioration in the claudication distance
72/212 (34%) with pentoxifylline
68/226 (30%) with placebo

RR 1.13
95% CI 0.86 to 1.48
The RCT had a high withdrawal rate after randomisation, which could be a source of bias
Not significant
[16]
Systematic review
788 people with moderate intermittent claudication and ankle brachial index <0.9
6 RCTs in this analysis
Maximum walking distance 3 weeks to 12 months
with pentoxifylline
with placebo
Absolute results not reported

WMD 59.23 m
95% CI 37.46 m to 81.00 m
Effect size not calculatedPentoxifylline
Mortality
No data from the following reference on this outcome.[16] [59] [70]
Cardiovascular events
No data from the following reference on this outcome.[16] [59] [70]
Post-intervention patency
No data from the following reference on this outcome.[16] [59] [70]
Physiological measures
No data from the following reference on this outcome.[16] [59] [70]
Quality of life
No data from the following reference on this outcome.[16] [59] [70]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[59]
RCT
3-armed trial
698 people Proportion of people withdrawing because of adverse effects or concerns about safety
44/232 (19%) with pentoxifylline
24/239 (10%) with placebo

RR 1.89
95% CI 1.19 to 3.00
NNH 12
95% CI 7 to 39
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 38/239 [16%] with placebo)
Small effect sizePlacebo
[59]
RCT
3-armed trial
698 people Proportion of people with sore throat
32/232 (14%) with pentoxifylline
17/239 (7%) with placebo

Between group significance not assessed
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 38/239 [16%] with placebo)
[59]
RCT
3-armed trial
698 people Proportion of people with diarrhoea
18/232 (8%) with pentoxifylline
13/239 (5%) with placebo

Between group significance not assessed
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 38/239 [16%] with placebo)
No data from the following reference on this outcome.[16] [70]
Pentoxifylline versus cilostazol:
We found one systematic review (search date 2009; 1 RCT, 454 people).[16] The review found one RCT [59]comparing pentoxifylline, cilostazol, and placebo.
Claudication distance/time
Pentoxifylline compared with cilostazol Pentoxifylline seems to be less effective at improving initial and absolute claudication distance after 24 weeks (moderate-quality evidence).
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Claudication distance
[59]
RCT
3-armed trial
698 people
In review [16]
Proportion of people who had either no change or had deterioration in claudication distance 24 weeks
72/212 (34%) with pentoxifylline
47/205 (23%) with cilostazol

RR 1.48
95% CI 1.08 to 2.03
ARR 11%
95% CI 2.4% to 20.0%
NNT 9
95% CI 5 to 42
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 61/237 [26%] with cilostazol)
Small effect sizeCilostazol
[59]
RCT
3-armed trial
698 people
In review [16]
Initial claudication distance 24 weeks
202 metres with pentoxifylline
218 m with cilostazol

Mean difference –16 m
P = 0.0001
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 61/237 [26%] with cilostazol)
Effect size not calculatedCilostazol
[59]
RCT
3-armed trial
698 people
In review [16]
Absolute claudication distance 24 weeks
308 m with pentoxifylline
350 m with cilostazol

Mean difference –42 m
P = 0.0005
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 61/237 [26%] with cilostazol)
Effect size not calculatedCilostazol
Mortality
No data from the following reference on this outcome.[16] [59]
Cardiovascular events
No data from the following reference on this outcome.[16] [59]
Post-intervention patency
No data from the following reference on this outcome.[16] [59]
Physiological measures
No data from the following reference on this outcome.[16] [59]
Quality of life
No data from the following reference on this outcome.[16] [59]
Adverse effects
Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[59]
RCT
3-armed trial
698 people
In review [16]
Proportion of people withdrawing because of adverse effects or concerns about safety
44/232 (19%) with pentoxifylline
39/227 (17%) with cilostazol

Significance not assessed
The RCT had a high withdrawal rate after randomisation, which could be a source of bias (60/232 [26%] with pentoxifylline v 38/239 [16%] with placebo)
Pentoxifylline versus prostaglandins:
See option on prostaglandins.
Further information on studies
None.
Comment
No life-threatening adverse effects of pentoxifylline have been reported, although to date RCTs have been too small to assess this reliably.
Substantive changes
Pentoxifylline One systematic review added, which reported on both pentoxifylline versus placebo and pentoxifylline versus cilostazol.[16]. The review found pentoxifylline increased maximal walking distance compared with placebo.[16] For the pentoxifylline versus cilostazol comparison, the review[16] identified only one RCT,[59] which we already report in this Clinical Evidence review. Categorisation unchanged (Unknown effectiveness).
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