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Prostanoids for intermittent claudication

  1. Lindsay Robertson1,*,
  2. Alina Andras2

Editorial Group: Cochrane Vascular Group

Published Online: 30 APR 2013

Assessed as up-to-date: 22 JAN 2013

DOI: 10.1002/14651858.CD000986.pub3


How to Cite

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

Author Information

  1. 1

    The University of Edinburgh, Centre for Population Health Sciences, The Medical School, Edinburgh, UK

  2. 2

    Freeman Hospital, Department of Vascular Surgery, Newcastle upon Tyne, UK

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

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 30 APR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Belch 1997

MethodsStudy design: randomised, double blind, placebo-controlled study.

Randomisation method: randomised code generated from random-number lists.

Dropouts: none.

No. of groups: 4 treatment groups; placebo versus 3 different dosages of AS-013.

For this analysis, placebo group and the group with the highest (= clinically most effective) dosage of the study drug were compared.


ParticipantsCountry: United Kingdom.

Setting: 7 centres.

No: 43 outpatients.

Age: treatment 72 years; control 69 years.

Sex: treatment 18 male, 4 female; control 16 male, 5 female.

Inclusion criteria: PAOD stage IIb; ABI 0.8; maximum WD 30 to 300 m.

Exclusion criteria: WD difference > 30% between 2 tests.


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

Control: placebo/10 ml NaCl/10 min iv.

Duration: 20 injections in 4 weeks.

Follow up: 4 weeks.


OutcomesTreadmill test (10% slope, 2 km/h):
- PFWD (m)
- MWD (m)
ABPI
Quality of life (questionnaire)
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Treatment was assigned in a randomised code generated from random-number lists"

Comment: Adequate description of allocation sequence generation. Low risk of selection bias.

Allocation concealment (selection bias)High riskQuote: "Random-number lists"

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

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

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

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

Other biasHigh riskInclusion and exclusion criteria not explicitly stated and study design unclear. High risk of bias.

Blume 1986

MethodsStudy design: stated randomised, (no details given), double blind, placebo-controlled study. PGE1 versus placebo.

Dropouts: treatment 14; control 11 during follow up.


ParticipantsCountry: Germany

No: 50 participants.

Age: treatment 66 years; control 70 years.

Sex: treatment 13 male, 12 female; control 13 male, 12 female.

Inclusion criteria: PAOD stage IIb for > 6 months, pain-free WD 40 to100 m.

Exclusion criteria: WD difference > 20% between two tests within 2 weeks.


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

Control: placebo/100 ml NaCl/90 min ia.

Duration: 15 infusions in 3 weeks.

Follow up: 2 weeks.


OutcomesTreadmill test (5% slope, 3 km/h):
- PFWD (m)
- MWD (m)
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomized"

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

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

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes
High risk25 patients were randomised to PGE1 and 25 to a placebo but after 2 weeks only 11 PGE1 and 14 placebo patients completed the follow up treadmill test. High risk of attrition bias.

Selective reporting (reporting bias)High riskResults of doppler studies, plethysmography and laboratory tests are not presented therefore the study is at high risk of reporting bias.

Other biasUnclear riskInsufficient evidence to permit judgement on level of bias.

Böger 1998

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


ParticipantsCountry: Germany.

No: 39 patients with intermittent claudication.
L-arginine 13; PGE1 13; control 13.

Mean age: L-arginine 70.1 years; PGE1 66.1 years; control 66.8 years.

Inclusion criteria: PAOD IIb.

Exclusion criteria: rest-pain, systemic inflammation, renal or liver disease, indication for surgery or angioplasty, concomitant diseases that are associated with reduced WD (arthroses, arthritis, diseases of spinal column, venous diseases, cardiopulmonary insufficiency, neurologic diseases), or seriously impaired cerebral function.

Exclusion criteria: pain-free WD > 20% on two occasions between 4 weeks.

Patients continued their regular walking training.


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

Control no treatment.

Supervised walking training, for 3 weeks for all patients.


OutcomesTreadmill test (12% slope, 3 km/h)
- PFWD (m)
- MWD (m)
ABPI
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned to one of three treatment groups"

Comment: Method of sequence generation not stated. Insufficient information to permit judgement of low or high risk of selection bias.

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

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)Low riskData is presented on all pre-specified outcomes. Study is at low risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Creager 2008

MethodsStudy design: prospective, double blind, randomised, placebo-controlled, parallel group study.


ParticipantsCountry: USA

Setting: 32 centres

No: 430. Iloprost 260, pentoxifylline 86, placebo 84

Sex: 349 (81.2% male), 81 (18.8%) female. Iloprost 213 male 47 female, pentoxifylline 67 male 19 female, placebo 69 male 15 female

Mean age: 67 years

Inclusion criteria: Participants aged ≥ 40 years with stable claudication for ≥ 3 months prior to entry, despite standard care including cardiovascular risk factor modification and exercise training, absolute claudication distance between 50-800 metres on baseline eligibility exercise, ABI ≤ 0.90 in symptomatic leg, > 20% fall in ABI within 1 minute following cessation of exercise. In patients with non-compressible vessels (ABI > 1.0), toe-brachial index (TBI) at rest < 0.70. ACD measured by exercise treadmill on two to three occasions at an interval of 7-14 days had to be within 20% of the ACD measured at the previous exercise test.

Exclusion criteria: Ischemic rest pain, ulcers, gangrene (Fontaine Stage III or IV), evidence of non-atherosclerotic PAD, peripheral neuropathy that impaired walking ability, revascularization procedure for PAD within preceding 3 months, sympathectomy within 6 months, type I diabetes mellitus, myocardial infarction or major cardiac surgery within 3 months, unstable angina, heart failure, receiving standard or low molecular weight heparin, warfarin in combination with aspirin, or any drug specific for the treatment of intermittent claudication.


InterventionsTreatment 1: Iloprost 50 mcg, 100 mcg or 150 mcg twice daily

Treatment 2: Pentoxifylline 400 mg three times daily.

Control: Placebo


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

- Change in ACD between baseline and 6 months

- Change in initial claudication distance (ICD) between baseline and 6 months

Quality of life

Death at 6 months

Revascularisation at 6 months

Major amputation at 6 months


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomised"

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

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Number and size of capsules administered were similar within all treatment groups to ensure blinding of participants but it is unclear if the study personnel were also blind to the treatment regimen. Unclear risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

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

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

Other biasHigh riskThe study was sponsored by a drug company and is therefore deemed to be at high risk of bias.

Creutzig 1988

MethodsStudy design: stated randomised, (no details given), double-blind, parallel study. PGE1 versus laevadosin.

Dropouts: 5 dropouts in both groups during follow-up.


ParticipantsCountry: Germany.

No: 40 randomised patients.

Age: treatment 64 years; control 69.5 years.

Sex: treatment 12 male, 8 female; control 15 male, 5 female.

Inclusion criteria: PAOD stage II, stable over 6 months, maximal WD 30 to 200 m.

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


InterventionsTreatment: PGE1 5 µg/50 ml NaCl/50 min ia.

Control: Laevadosin (energy rich phosphates) 10 ml/50 ml NaCl/50 min ia.

Duration: 36 infusions in 21 days.

Follow up: 9 months.


OutcomesTreadmill test (5% incline, 3 km/h):
- PFWD (m)
- MWD (m)
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomized"

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

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)High riskNot all pre-specified outcomes are reported so the study is at high risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Diehm 1989

MethodsStudy design: stated randomised, (no details given), double blind, parallel study. PGE1 versus naftidrofuryl.

Drop outs: 1 in the experimental group during follow up.


ParticipantsCountry: Germany.

No: 48 randomised.

Age: treatment 58 years; control 65 years.

Sex: treatment 19 male, 5 female; control 20 male, 4 female.

Inclusion criteria: PAOD stage IIb, symptoms for > 1 year, pain-free WD following 6 months of supervised physical training < 250 m.

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


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

Control: Naftidrofuryl 600 mg/250 ml NaCl/2h once daily iv.

Duration: 3 weeks.

Follow up: 3 months.


OutcomesTreadmill test (10% incline, 3.5 km/h):
- PFWD (m)
- MWD (m)
ABPI
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised"

Comment: Authors describe the trial as randomised but method of randomisation not stated. Insufficient information to permit judgement of low or high risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)Low riskData is presented on all pre-specified outcomes. Low risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Diehm 1997

MethodsStudy design: stated randomised (no details given), double blind, placebo-controlled, parallel study. PGE1 vs. placebo.

Dropouts: 5 during treatment.


ParticipantsCountry: Germany, 16 centres.

No: 208 outpatients randomised, 208 evaluated.

Age: 62 years.

Sex: treatment 75 male, 31 female; control 80 male, 22 female.

Inclusion criteria: PAOD stage II for > 6 months, stable for > 3 months, maximum WD 50 to 200 m.

Exclusion criteria: WD difference > 25% between 2 treadmill tests within 2 weeks.


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

Control: placebo/100 ml NaCl/2 hours iv.

Duration: 20 infusions in 4 weeks, followed by 8 infusions over the next 4 weeks.

Follow up: 3 months.


OutcomesTreadmill test (12% slope, 3 km/h):
- PFWD (m)
- MWD (m)
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised"

Comment: Authors describe the trial as randomised but method of randomisation not stated. Insufficient information to permit judgement on risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes
High risk42/213 protocol violations which were unexplained. High risk of attrition bias.

Selective reporting (reporting bias)Low riskData are presented on all pre-specified outcomes. Low risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Hepp 1996

MethodsStudy design: Randomised, single blind study. PGE1 versus pentoxifylline (Ptx).

Dropouts: none during treatment period.


ParticipantsCountry: Germany, 8 centres.

No:195 participants (treated as inpatients).

Age: 65 years (range 39 to 84).

Sex: treatment 71 male, 25 female; control 71 male, 26 female.

Inclusion criteria: PAOD stage IIb, stable for > 6 months, pain-free WD > 50 m, maximum WD < 200 m.

Exclusion criteria: difference in pain-free WD > 20% between 2 tests within 7days.


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

Control: Ptx 200 mg/250 ml NaCl x 2 hours iv. twice daily.

Duration: 4 weeks.

Follow up: 1 year.


OutcomesTreadmill test (5% grade, 3 km/h):
- PFWD (m)
- MWD (m)
ABPI


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The two patient groups formed by randomisation

Comment: Authors describe the trial as randomised but method of sequence generation not stated. Insufficient information to permit judgement of low or high risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)Low riskData are presented on all pre-specified outcomes. Low risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Lièvre 1996

MethodsStudy design: randomised, double blind, placebo versus 3 different BPS groups (40 µg is used for analysis).

Randomisation method: telematic system (Minitel).

Dropouts: 15.


ParticipantsCountry: France.

No: 83 participants. Treatment 42; control 41.

Age: treatment 62 ± 10 years; control 61 ± 11 years.

Inclusion criteria: Fontaine II for at least 6 months, stable for 3 months, pain-free WD 50 to 300 m.

Exclusion criteria: PAOD III+IV, recent acute ischaemia, undergoing physiotherapy during the trial or operation in the next 6 months, evidence of non-atheromatous peripheral occlusion, IDDM, diabetes with clinical neuropathy, SBP > 180 mmHg, DBP > 110 mmHg, recent MI or stroke, WD difference between 3 tests between 6 weeks.

All other vasodilator or anti ischaemic drugs stopped.


InterventionsTreatment: BSP 2 tablets BSP+one tablet placebo 3 x daily po for 12 weeks.

Control: 3 tablets placebo 3 x daily.

Advice on diet, smoking, regular exercise given.


OutcomesTreadmill test (3.2% grade, 3.2 km/h)
- PFWD (m)
- MWD (m)
-ABPI


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned by telematic system"

Comment: Adequate description of random sequence generation is provided. Low risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)Low riskData are presented on all pre-specified outcomes. Low risk of reporting bias.

Other biasUnclear riskSignificantly higher rate of previous myocardial infarction in placebo group compared to the treatment group which could potentially bias the study.

Lièvre 2000

MethodsStudy design: randomised, double blind, multicenter, placebo-controlled study. BPS versus placebo.

Randomisation method: computer network (Minitel).


ParticipantsCountry: France, multicentre (66).

No: 422 patients. Treatment 209; control: 213.

Mean age: 62.9 years.

Sex: treatment 177 male, 32 female; control 179 male, 34 female.

Inclusion criteria: PAD > 6 months, stable for 3 months, PFWD of 50 to 300 m. PFWD change of < 25% between 2 run-in treadmill exercise tests

Exclusion criteria: Ischaemic rest pain, ulceration or gangrene, antiplatelet therapy, no MI or stroke in the last 3 months, severe angina pectoris, IDDM.

74 premature treatment discontinuations.


InterventionsTreatment: 40 µg BSP.

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


OutcomesTreadmill test (10% grade, 3 km/h):
- PFWD (m)
- MWD (m)
Quality of life


NotesAntiocoagulants and vasodilators were not allowed during the trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned through a computer network (Minitel)"

Comment: Adequate description of random sequence generation is provided. Low risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: 'Every potential critical cardiovascular event was evaluated blindly by 3 experienced cardiologists"

Comment: Investigators measuring CV events were blinded to treatment but it is unclear if investigators performing the treadmill tests were blinded to treatment. Insufficient information to permit judgement on risk of detection bias.

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

Selective reporting (reporting bias)Low riskData are presented on all pre-specified outcomes. Low risk of reporting bias.

Other biasUnclear riskSignificant differences between treatment groups with regards to number of patients on lifestyle modification preparations, presence of popliteal/anterior tibial pulse and physical activity levels at baseline. Imbalances likely to bias study results.

Luk'Janov 1995

MethodsStudy design: randomised, double blind study. PGE1 versus Ptx.


ParticipantsCountry: Russia.

No: treatment (PGE1) 42 patients; control (Ptx) 40 patients.

Mean age: 60.4 ± 6.8 years.


InterventionsTreatment: 40 mg PGE1.

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


OutcomesTreadmill test (5% grade, 3 km/h)
- PFWD (m)
ABPI


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomised"

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

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of attrition bias.

Selective reporting (reporting bias)Unclear riskComment: Insufficient information to permit judgement of low or high risk of reporting bias.

Other biasUnclear riskComment: Insufficient information to permit judgement of low or high risk of bias.

Mangiafico 2000

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


ParticipantsCountry: Italy.

No: 42 untrained outpatients.
Treatment 21; control 21.

Sex: 37 male, 5 female.

Mean age: 64 ± 8 years.

Inclusion criteria: PAOD, WD 50 to 200 m.

Exclusion criteria: WD change > 20% 2 weeks before study, congestive heart failure, renal failure, respiratory insufficiency, effort angina, unstable angina, uncontrolled arrhythmias, recent MI, transient Ischaemic attack or stroke, recent DVT, substance abuse.

Cardioactive and antiplatelet drugs allowed. Vasoactive and rheologic drugs for PAOD stopped.


InterventionsTreatment: 60 µg PGE1 iv.

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


OutcomesTreadmill test (5% slope, 3 km/h)
- PFWD (m)
- MWD (m)
ABPI
Walking impairment questionnaire


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomised"

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

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

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

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

Other biasUnclear riskInsuffificient information to permit judgement on risk of other bias.

Milio 2006

MethodsStudy design: Randomised, controlled, single blind study


ParticipantsCountry: Italy

No: 123 patients. Treatment 63, control 60

Mean age: Treatment 55 ± 14 years, control 53 ± 16 years

Sex: Treatment 44 male, 19 female. Control 42 male, 18 female

Inclusion criteria: Presence of PAD at the 2nd B stage Fontaine's classification for ≥ 6 months and the existence of steno-obliterating lesions of the iliac-femoral axis demonstrated with echocolour Doppler examination or angiographic procedure.

Exclusion criteria: Patients with heart failure, respiratory insufficiency, recent myocardial infarction, arrhythmias, recent episodes of cerebral ischaemia, renal insufficiency, pregnancy and patients with diseases that could not permit normal de-ambulation.


InterventionsTreatment: 60 ug/d PGE1 iv injection

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


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

- PFWD (m)

- MWD (m)

Rest flow, peak flow, time to reach peak flow, basal and minimal vascular resistance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomised in two groups, with an allocation sequence obtained using a random-number table (sealed envelopes)"

Comment: Adequate description of sequence generation. Low risk of selection bias.

Allocation concealment (selection bias)Low riskQuote: "Sealed envelopes"

Comment: Adequate concealment of allocation. Low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote: "Single-blind"

Comment: Due to the nature of the treatment, the study personnel were not blinded and therefore the study was at high risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement on risk of detection bias.

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

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

Other biasUnclear riskInsufficient information to permit judgement on risk of other bias.

Mohler 2003

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


ParticipantsCountry: USA.

No: treatment 385; control 377.

Age: between 40 to 80 years; stable IC for longer than 6 months; rest ABI ≤ 0.90 with a 10 mmHg decrease in ankle pressure 1 min after completion on the exercise treadmill test; PFWD on a standardised treadmill test ≥ 164 feet (50 m) but ≤ 984 feet (300 m) at the screening visit; PFWD variability < 25% between tests performed during the run-in phase.

Exclusion criteria: critical limb ischaemia; underwent coronary artery or peripheral artery angioplasty or surgical limb arterial bypass within the last three months; were anticipated to require surgical or percutaneous revascularization within six months of randomisation; or were currently participating in a supervised exercise regimen; suffered a stroke or myocardial infarction or deep-vein thrombosis within the last three months; nonatherosclerotic PAD (e.g., thromboangiitis obliterans); a known abdominal aortic aneurysm 4.5 cm; unstable angina pectoris within the last three months; heart failure; severe, uncontrolled hypertension; anaemia or any clinically significant bleeding episode within the last year; an abnormal platelet count; type I diabetes mellitus; morbid obesity; severe renal insufficiency; severe hepatic insufficiency; any disorder that would affect the interpretation
of treadmill test results; and any other lifethreatening disease or any psychiatric condition that would impair either informed consent or compliance with the study protocol; use of cilostazol, pentoxifylline, or HeartBar (L-arginine) within one month prior to the screening treadmill test; current use of warfarin, heparin, or thrombolytic therapy; or any disease state that could potentially decrease gastrointestinal absorption of the study medication.

Patients using aspirin, clopidogrel, or ticlopidine were not excluded from the study.


InterventionsTreatment: oral 40 µg BPS.

Control: placebo.

Duration: over one year.


OutcomesTreadmill test (10% slope, 3 km/h )
- PFWD (m)
- MWD (m)
- ABPI
- QOL


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned"

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

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double-blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)Unclear riskNumber of patients at follow up is significantly less than at baseline. High risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Müller-Bühl 1987

MethodsStudy design: stated randomised (no details given), single-blind, placebo-controlled study. Iloprost versus placebo (hydroxy-ethyl starch).

Dropouts: none.


ParticipantsCountry: Germany.

No: 24 outpatients.

Age: 47 to 71 years.

Sex: male.

Inclusion criteria: PAOD stage IIb, stable > 3 months.


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

Control: hydroxy-ethyl starch 200/0.5 500 ml iv.

Duration: 10 infusions in 2 weeks.

Follow up: 1 month.


OutcomesTreadmill test (10% slope, 3 km/h):
- PFWD (m)
- MWD (m)
ABPI
venous occlusion plethysmography:
- during rest (ml/100ml x min)
- reactive hyperaemia (ml/100ml x min)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned"

Comment: Authors describe the trial as randomised but method of randomisation not stated. Insufficient information to permit judgement on risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote: "Patient-blinded trial"

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

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

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

Other biasLow riskComment: Study appears to be free from other sources of bias

Scheffler 1994

MethodsStudy design: stated randomised, (no details given), open study with 3 treatment arms: intensive physical training alone vs. intensive training + PGE1 iv. versus intensive training + Ptx iv.

Dropouts: none.


ParticipantsCountry: Germany.

No: 44 randomised (3 groups).

Age: 60 ± 9 years.

Sex: 33 male, 11 female.

Inclusion criteria: PAOD stage IIb, stable for > 6 months, maximal WD 50 to 200 m.

Exclusion criteria: WD differences > 20% between 3 treadmill tests during 2 weeks.


InterventionsTreatment: PGE1 40 µg/250 ml NaCl twice daily iv. plus intensive physical training.

Control 1: Ptx 200 mg/250ml NaCl twice daily iv. plus intensive physical training.

Control 2: intensive physical training alone without pharmacological treatment.

Duration: 4 weeks.

Follow up: 1 year


OutcomesTreadmill test (5% incline, 3 km/h):
- PFWD (m)
- MWD (m)
Side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomly allocated to the three treatment groups"

Comment: Insufficient information to permit judgement of low or high risk of selection bias.

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

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

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)High riskThe three treatment groups were not similar. High risk of reporting bias.

Other biasUnclear riskInsufficient information to permit judgement of low or high risk of bias.

Virgolini 1989

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


ParticipantsCountry: Austria.

No: 30 patients with PAOD II. Treatment 15; control 15.

Sex: 15 male, 15 female.

Age: treatment 57 years; control 60 years.

Exclusion criteria: > 70 years, diabetes, peripheral neuropathy, angina pectoris, MI less than one year prior admission, no antiplatelet drugs.


InterventionsTreatment: taprostene 25 ng/kg/min iv.

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


OutcomesTreadmill test (7.5° elevation, 1.5 miles/hour)
- walking times (s)


NotesWalking times in seconds were translated in WD (m)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly allocated"

Comment: Method of sequence generation not stated. Insufficient information to permit judgement of low or high risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double-blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

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

Selective reporting (reporting bias)Unclear riskComment: Authors do not specify primary outcomes. Insufficient information to permit judgement of low or high risk of reporting bias.

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

Virgolini 1990

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


ParticipantsCountry: Austria.

No: 108 patients with PAOD II. Treatment 54; control 54.

Exclusion criteria: patient did not reach an absolute claudication time on treadmill within 8 minutes, recent cardiovascular events or aspirin-like drugs, 2 weeks run-in period.


InterventionsIntravenous administration 8 hours/day over 5 consecutive days 6 ng/kg/min PGI2 or placebo (NaCl).


OutcomesTreadmill test: (7.5° elevation, 1.5 miles/hour)
walking time (s)


NotesWalking times in seconds were translated in WD (m)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly allocated"

Comment: Method of sequence generation not stated. Insufficient information to permit judgement of low or high risk of selection bias.

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

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "Double blind"

Comment: Authors state that trial was double blind but do not provide enough information to permit judgement on risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: Insufficient information to permit judgement of low or high risk of detection bias.

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

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

Other biasUnclear riskNot enough information to assess risk of other bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

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

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

Barradas 1989Not RCT

Bieron 1993Not RCT

Diehm 1990Not RCT

Esato 1995aPatients have critical limb ischaemia

Esato 1995bPatients have critical limb ischaemia

Fitscha 1985Excluded because of the inconclusive data given

Goya 2003Patients have arteriosclerotic changes in the carotid artery

Hay 1987Excluded because the administered dosages differed between the patients

Ishitobi 1991Not RCT

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

Okadome-Kenchiro 1992No placebo or control

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

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

Sakaguchi-Shukichi 1990Not a randomised controlled trial

Waller 1986Excluded because the administered dosages differed between the patients

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

Wilkinson 1988Excluded since no data were published

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

 
Characteristics of studies awaiting assessment [ordered by study ID]
Nakagawa 1998

MethodsAwaiting translation

Participants

Interventions

Outcomes

Notes

 
Characteristics of ongoing studies [ordered by study ID]
Valerio 2012

Trial name or titleFADOI-2b Pilot Study

MethodsMulticentre randomised trial

Participants100 patients with stage IIb PAD with a PFWD < 100 m, who were unable to undergo revascularisation

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

OutcomesPFWD, major cardiovascular events, death, adverse reaction

Starting date

Contact informationAntonella Valerio (antonella.valerio@fadoi.org)

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

 
Comparison 1. PGE1 versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)3508Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.1 Intra-arterial, 3 weeks
150Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Intravenous, 4 weeks
2250Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Intravenous, 8 weeks
1208Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

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

    2.1 Intra-arterial, 3 weeks
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Intravenous, 4 weeks
2Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Intravenous, 8 weeks
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Mean change in maximal walking distance (%)3508Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.1 Intra-arterial, 3 weeks
150Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Intravenous, 4 weeks
2250Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Intravenous, 8 weeks
1208Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Final maximal walking distance (meters)3Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 Intra-arterial, 3 weeks
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Intravenous, 4 weeks
2Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Intravenous, 8 weeks
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. PGE1 versus pentoxifylline (Ptx)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)4429Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Final pain-free walking distance (meters)4429Mean Difference (IV, Fixed, 95% CI)220.62 [140.80, 300.44]

 3 Mean change in maximal walking distance (%)3348Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Final maximal walking distance (meters)3347Mean Difference (IV, Fixed, 95% CI)201.93 [107.33, 296.54]

 5 Ankle brachial index2240Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.12, 0.00]

 6 Adverse events1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    6.1 4 weeks
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 12 months
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. PGE1 versus laevadosin (energy rich phosphates)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

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

 3 Mean change in maximal walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Final maximal walking distance (meters)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Comparison 4. PGE1 versus naftidrofuryl

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

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

 3 Ankle brachial index left side1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Ankle brachial index right side1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Adverse events1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 5. PGE1 versus L-arginine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

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

 3 Mean change in maximal walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Final maximal walking distance (meters)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Ankle brachial index1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Comparison 6. PGI2 versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)61575Mean Difference (IV, Fixed, 95% CI)56.00 [-13.85, 125.85]

 2 Final pain-free walking distance (meters)51402Mean Difference (IV, Random, 95% CI)-3.66 [-18.77, 11.46]

 3 Mean change in maximum walking distance (%)61575Mean Difference (IV, Fixed, 95% CI)38.0 [-23.83, 99.83]

 4 Final maximal walking distance (meters)51328Mean Difference (IV, Fixed, 95% CI)12.36 [1.84, 22.87]

 5 Adverse events1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    5.1 Critical cardiovascular events
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Arterial thrombosis
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.3 Drug-related adverse events
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 7. PGI2 versus pentoxifylline (Ptx)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Revascularisation1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 50 µg iloprost
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 100 µg iloprost
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 150 µg iloprost
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in pain-free walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

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

 3 Mean change in maximal walking distance (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Final maximal walking distance (meters)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Ankle brachial index1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Venous-occlusion plethysmography - at rest1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 Venous-occlusion plethysmography - reactive hyperaemia1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Table 1. PFWD PGE1 versus placebo

StudyDose

(µg)
Duration

(weeks)
PGEPLCPGE0SDPGEESD%ageSD%PLC0SDPLCESD%ageSD%DIFF (%)

Belch 1997 *2, 5 d/wk4192144.816.0not stated

5, 2 d/wk1850.733.5not stated

5, 5 d/wk2245.033.064.5431726

2, 5 d/wk8 a192144.816.0not stated

5, 2 d/wk1850.733.5not stated

5, 5 d/wk2245.033.065.946046

Blume 198610-2032525541311354109541673413574

Diehm 199760410610264.31.6112.71.87566.61.695.52.04332

8 b128.92.0100106.62.16040

Mangiafico 200060421217216135338881178417484

8 a1132657not statednot stated

 PGE = prostaglandin treatment group sample size
PLC = placebo group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGE and placebo
* Study reported PFWD as a median with IQR.
a = treatment was administered for 4 weeks, treadmill tests conducted at 4 weeks and also at 8 weeks (after a 4-week period of no treatment).
b = treatment was administered for 5 days a week for 4 weeks and reduced to 2 days a week for a further 4 weeks, treadmill tests conducted at both 4 and 8 weeks.
 
Table 2. MWD PGE1 versus placebo

StudyDose

(µg)
Duration

(weeks)
PGEPLCPGE0SDPGEESD%ageSD%PLC0SDPLCESD%ageSD%DIFF (%)

Belch 1997 *2, 5 d/wk4192160.025.6not stated

5, 2 d/wk1868.648.8not stated

5, 5 d/wk2267.168.895.14275.693.080.1636

2, 5 d/wk8 a192160.025.6not stated

5, 2 d/wk1868.648.8not stated

5, 5 d/wk2267.168.8102.15275.693.064.4-1567

Blume 198610-2032525984517075749728114511856

Diehm 199760410610298.81.51631.86599.81.4141.91.74223

8 b186.32.088160.51.96127

Mangiafico 200060421211403026662901523815439189

8a2295564not statednot stated

 PGE = prostaglandin treatment group sample size
PLC = placebo group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGE and placebo
* Study reported MWD as a median with IQR.
a = treatment was administered for 4 weeks, treadmill tests conducted at 4 weeks and also at 8 week (after a 4-week period of no treatment).
b = treatment was administered for 5 days a week for 4 weeks and reduced to 2 days a week for a further 4 weeks, treadmill tests conducted at both 4 and 8 weeks.
 
Table 3. PFWD PGE1 versus pentoxifylline

StudyDose PGE (µg)Dose PTX (mg)Duration (weeks)PGE1PTXPGE0SDPGEESD%ageSD%PTX0SDPTXESD%ageSD%DIFF (%)

Hepp 19968040049798832642188418812494

Luk'Janov 1995404004424089195119781499145

Milio 2006602004636078363872743968241175180113260

Scheffler 1994802004141581235707276047541154150105499

 PGE = prostaglandin treatment group sample size
PTX= pentoxifylline group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PTX0 = pentoxifylline baseline walking distance
PTXE = pentoxifylline end walking distance
DIFF = difference in percentage of improvement of PGE and pentoxifylline
 
Table 4. MWD PGE1 versus pentoxifylline

StudyDose PGE (µg)Dose PTX (mg)Duration (weeks)PGE1PTXPGE0SDPGEESD%ageSD%PTX0SDPTXESD%ageSD%DIFF (%)

Hepp 1996804004979813034316413132214618

Luk'Janov 19954040044240-------------

Milio 200660200463601435551528526014869323264118158

Scheffler 1994802004141515895744697371160133351432119252

 PGE = prostaglandin treatment group sample size
PTX= pentoxifylline group sample size
PGE0 = PGE baseline walking distance
SD = standard deviation
PGEE = PGE end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PTX0 = pentoxifylline baseline walking distance
PTXE = pentoxifylline end walking distance
DIFF = difference in percentage of improvement of PGE and pentoxifylline
 
Table 5. PFWD PGI2 versus placebo

StudyDose

(µg)
Duration

(weeks)
PGI2PLCPGI20SDPGI2ESD%ageSD%PLC0SDPLCESD%ageSD%DIFF (%)

Creager 2008100268784105817.7120883.34.4

20086124968.85.5

300871298811.27.9

Lièvre 19966012424113272254129210131731905810771

120421426927011420456

180391377418651114-7

Lièvre 20001202620921313065280115133712458431

Mohler 200312052385377851011990104154

Virgolini 198925 ng/kg/min1151554.074.352263.664.41418

Virgolini 19906 ng/kg/min1545467.1225.411660.7554.94124

 PGI2 = prostaglandin treatment group sample size
PLC = placebo group sample size
PGI20 = PGI2 baseline walking distance
SD = standard deviation
PGI2E = PGI2 end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGI2 and placebo
 
Table 6. MWD PGI2 versus placebo

StudyDose

(µg)
Duration

(weeks)
PGI2PLCPGI20SDPGI2ESD%ageSD%PLC0SDPLCESD%ageSD%DIFF (%)

Creager 2008100268784105817.1120883.23.9

200861249613.710.5

300871298825.722.5

Lièvre 199660124241203123384142318206145291619281

12042224944289918238

18039207112357691333

Lièvre 200012026209213275229467702712403783931

Mohler 200312052385377164191.416.7170195.7151.7

Virgolini 198925 ng/kg/min11515224.8721.2814213.46.28212

Virgolini 19906 ng/kg/min15454177.5662.8916158.8693.2779

 PGI2 = prostaglandin treatment group sample size
PLC = placebo group sample size
PGI20 = PGI2 baseline walking distance
SD = standard deviation
PGI2E = PGI2 end walking distance
%AGE = percentage improvement of walking distance
SD% = standard deviation of percentage improvement of walking distance
PLC0 = placebo baseline walking distance
PLCE = placebo end walking distance
DIFF = difference in percentage of improvement of PGI2 and placebo