Sulodexide for treating venous leg ulcers

Bin Wu; Jing Lu; Ming Yang; Ting Xu

doi:10.1002/14651858.CD010694.pub2

Sulodexida para el tratamiento de la úlcera venosa de la pierna

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References

Referencias de los estudios incluidos en esta revisión

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excluded studies
additional references

Coccheri S, Scondotto G, Agnelli G, Aloisi D, Palazzini E, Zamboni V, et al. Randomised, double blind, multicentre, placebo controlled study of sulodexide in the treatment of venous leg ulcers. Thrombosis and Haemostasis 2002;87(6):947‐52.

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Referencias de los estudios excluidos de esta revisión

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included studies
additional references

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Serra R, Gallelli L, Conti A, De Caridi G, Massara M, Spinelli F, et al. The effects of sulodexide on both clinical and molecular parameters in patients with mixed arterial and venous ulcers of lower limbs. Drug Design, Development and Therapy 2014;8:519‐27.

Referencias adicionales

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excluded studies

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Fu X, Sheng Z, Cherry GW, Li Q. Epidemiological study of chronic dermal ulcers in China. Wound Repair and Regeneration 1998;6(1):21‐7.

González‐Consuegra RV, Verdú J. Quality of life in people with venous leg ulcers: an integrative review. Journal of Advanced Nursing 2011;67(5):926‐44.

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Higgins JPT, Altman DG, Sterne JAC, on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group. Chapter 8: Assessing risk of bias in included studies. In Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

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Lasierra‐Cirujeda J, Coronel P, Aza M, Gimeno M. Use of sulodexide in patients with peripheral vascular disease. Journal of Blood Medicine 2010;1:105‐15.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies

Coccheri 2002

Methods	RCT Parallel design Location: Italy 31 centres Carried out from July 1998 until August 2000
Participants	235 people with leg ulcers due to CVI with a diameter greater than 2 cm. CVI was assessed by ultrasound (echo‐color‐Doppler) demonstration of valvular incompetence, or reflux in the superficial veins or post‐thrombotic changes and or reflux in the deep veins, or both Age (sulodexide/control): 63.18 ± 10.40 / 64.18 ± 9.94 years Gender (sulodexide/control): 68/59 females, 53/55 males Ulcer size ≦ 10 cm² (sulodexide/control): 104/92 ulcers; > 10 cm²: 35/35 ulcers. Ulcer duration ≦ 12 months (sulodexide/control): 96/85 ulcers; > 12 months: 42/44 ulcers.
Interventions	Intervention: sulodexide + local treatment Control: placebo + local treatment Administration: sulodexide: 600 LSU intramuscular injection, once daily for 20 days; then 500 LSU orally, twice daily for 70 days Local treatment: wound care and compression therapy. Quote: "Wound care included the following steps as appropriate: mechanical cleansing of ulcer; detersion and removal of debris; local application of proteolytic enzymes (collagenases or proteases), or autolysis with hydrogel; antisepsis; dressing of the wound. High compression bandages were applied according to the local condition and the patient's compliance. The allowed materials for compression therapy were stretch elastic bandages, adhesive bandages, self adherent bandages, zinc oxide bandages, 4‐layer bandages."
Outcomes	Proportion of ulcers completely healed (reported at 60 days and 90 days) Absolute ulcer size (reported at 0 days, 20 days, 60 days and 90 days) Adverse events (reported at 90 days) Fibrinogen levels (reported at 90 days)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind; placebo controlled. Quote: "Patients received local treatment and were blindly allocated to sulodexide or matching placebo."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "At end of study ulcer tracings were sent in a random order to a blind, independent, off‐site assessor who calculated the total ulcerated area (in cm²) with a standardised computer system."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis. A total of 31 (25.8%) patients in sulodexide group and 24 (21.8%) in the control withdrawn during treatment, the reasons were as follow: lost to follow up (9 vs. 6), protocol violation (1 vs. 2), non compliance (0 vs. 1), informed consent withdrawn (3 vs. 1), adverse events (7 vs. 7), ulcer recovered (6 vs. 5) and other reasons (5 vs. 2).
Selective reporting (reporting bias)	Low risk	Protocol could not be reviewed, however all outcomes in the 'Methods' were reported in the 'Results' section
Other bias	Low risk	Sample size was calculated

Niglio 1991

Methods	RCT Parallel design Location: Italy Single centre
Participants	20 patients with ulcers caused by lower limb venous insufficiency Age: 48.3 ± 5.2 years Gender: 14 females, 6 males
Interventions	Intervention: sulodexide + local treatment Control: local treatment Administration: sulodexide: 500 LSU orally, once daily in the morning Local treatment: wound care and compression therapy
Outcomes	Time to complete ulcer healing Adverse events
Notes	Abstract only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described in the abstract section
Allocation concealment (selection bias)	Unclear risk	Not described in the abstract section
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blind design
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blind design
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not described in the abstract section
Selective reporting (reporting bias)	Unclear risk	Cannot be judged from the abstract
Other bias	Unclear risk	Cannot be judged from the abstract

Scondotto 1999

Methods	RCT Parallel design Location: Italy Single centre
Participants	94 patients suffering from venous leg ulcers, secondary to post‐thrombotic syndrome or due to primary phlebopathology. Diagnosis was confirmed by venous echo Doppler Age (sulodexide/control): 72 ± 10 / 72 ± 10 years Gender (sulodexide/control): 37/25 females, 15/17 males Ulcer duration ≦ 6 months (sulodexide/control): 35/27 participants; 7 months to 12 months: 12/10 participants; > 12 months: 5/5 participants Depth of ulcer (sulodexide/control): epidermal ulcer: 17/24 participants; dermal ulcer: 30/15 participants; subcutaneous ulcer: 5/3 participants
Interventions	Intervention: sulodexide + local treatment Control: local treatment Administration: sulodexide 600 LSU intramuscular injection, once daily for 30 days; then 250 LSU orally, twice a day for 30 days Local treatment: wound care and compression therapy. Quote: "cleansing by washing with physiological solution and the application of elastic compression with short extensibility removable bandages."
Outcomes	Proportion of ulcers completely healed (reported at 60 days) Time to complete ulcer healing (mean ± SD)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By a randomisation list
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blind design
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blind design
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing participants or outcome data
Selective reporting (reporting bias)	Low risk	Protocol could not be reviewed, however all outcomes in the 'Methods' were reported in the 'Results' section
Other bias	Low risk	No other source of bias identified

Zou 2007

Methods	RCT Parallel design Location: China Single centre Carried out from May 2005 until March 2006
Participants	114 patients with venous leg ulcers, diagnosis was confirmed by colour Doppler, along with symptoms, Perthe test and Trendelinburg test Age (sulodexide/control): 61.1 ± 6.0 / 60.1 ± 5.7 years Gender (sulodexide/control): 34/25 females, 27/28 males Ulcer size ≦ 10 cm² (sulodexide/control): 48/41 patients; > 10 cm²: 13/12 patients Ulcer duration ≦ 12 months (sulodexide/control): 44/41 patients; > 12 months: 17/12 patients
Interventions	Intervention: sulodexide + local treatment Control: local treatment Administration: sulodexide 600 LSU intramuscular injection, once daily until ulcer healing or maximum 30 days Local treatment: wound care and compression therapy. Wound care consisted of ulcer surface cleansed; necrotic tissues cleansed, removed, disinfected and dressed by gauze with salt solution wetted. The allowed materials for compression therapy were stretch elastic bandages and stretch socks, and compression therapy was dependent on ulcer condition and patients' will.
Outcomes	Proportion of ulcers completely healed (reported at 30 days) Absolute ulcer size (reported at 30 days) Adverse events (reported at 30 days)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random sequence was generated by random number table
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blind design
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blind design
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing participants or outcome data
Selective reporting (reporting bias)	Low risk	Protocol could not be reviewed, however all outcomes in the 'Methods' were reported in the 'Results' section
Other bias	Low risk	No other source of bias identified

RCT: Randomized Controlled Trial
CVI: Chronic Venous Insufficiency
LSU: Lipasemic Units

Characteristics of excluded studies [ordered by study ID]

Jump to:

included studies

Study	Reason for exclusion
Andreozzi 2012	Review
Colletta 2003	Not controlled trial, no use of sulodexide as a study intervention
Dereure 2012	RCT, parallel design, no use of sulodexide as a study intervention
Incandela 2001	RCT, cross over design, no use of sulodexide as a study intervention
Krasinski 2010	Review
Kucharzewski 2003	Quasi‐RCT. Quote: "Group I included patients with odd numbers, group II included patients with even numbers. The numbers were determined by the surgeon."
Meaume 2008	RCT, parallel design, no use of sulodexide as a study intervention
Serra 2014	RCT, parallel design, not previously defined patients, with mixed arterial and venous ulcers of lower limbs

Data and analyses

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Comparison 1. Sulodexide + local treatment vs. local treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of ulcers completely healed (overall) Show forest plot	3	438	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [1.30, 2.12]
Open in figure viewer Analysis 1.1 Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 1 Proportion of ulcers completely healed (overall).
2 Proportion of ulcers completely healed (sensitivity analysis) Show forest plot	3	438	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.27, 1.83]
Open in figure viewer Analysis 1.2 Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 2 Proportion of ulcers completely healed (sensitivity analysis).
3 Proportion of ulcers completely healed at 30 days Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 3 Proportion of ulcers completely healed at 30 days.
4 Proportion of ulcers completely healed at 60 days Show forest plot	2	324	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [1.20, 2.28]
Open in figure viewer Analysis 1.4 Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 4 Proportion of ulcers completely healed at 60 days.
5 Proportion of ulcers completely healed at 90 days Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 5 Proportion of ulcers completely healed at 90 days.
6 Adverse effects Show forest plot	2	344	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [0.48, 4.34]
Open in figure viewer Analysis 1.6 Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 6 Adverse effects.

Figure 1

PRISMA flow diagram of literature screening

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 1 Proportion of ulcers completely healed (overall).

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Analysis 1.2

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 2 Proportion of ulcers completely healed (sensitivity analysis).

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Analysis 1.3

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 3 Proportion of ulcers completely healed at 30 days.

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Analysis 1.4

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 4 Proportion of ulcers completely healed at 60 days.

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Analysis 1.5

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 5 Proportion of ulcers completely healed at 90 days.

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Analysis 1.6

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 6 Adverse effects.

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Summary of findings for the main comparison. Sulodexide + local treatment compared to local treatment for treating venous leg ulcers

Sulodexide + local treatment compared to local treatment for treating venous leg ulcers
Patient or population: patients with venous leg ulcers Settings: Italy and China Intervention: Sulodexide + local treatment Comparison: local treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	local treatment	Sulodexide + local treatment
Proportion of ulcers completely healed (overall) Follow‐up: 30 to 90 days	298 per 1000	494 per 1000 (387 to 631)	RR 1.66 (1.3 to 2.12)	438 (3 studies)	⊕⊕⊝⊝ low¹
Proportion of ulcers completely healed at 30 days Follow‐up: mean 30 days	189 per 1000	360 per 1000 (189 to 691)	RR 1.91 (1 to 3.66)	114 (1 study)	⊕⊝⊝⊝ very low²
Proportion of ulcers completely healed at 60 days Follow‐up: mean 60 days	250 per 1000	412 per 1000 (300 to 570)	RR 1.65 (1.2 to 2.28)	324 (2 studies)	⊕⊕⊝⊝ low¹
Proportion of ulcers completely healed at 90 days Follow‐up: mean 90 days	327 per 1000	524 per 1000 (383 to 720)	RR 1.6 (1.17 to 2.2)	230 (1 study)	⊕⊕⊝⊝ low³
Time to complete ulcer healing	Available data were limited and not analysed
Change in absolute ulcer size	Available data were limited and not analysed
Ulcer recurrence	Not reported
Adverse effects Follow‐up: 30 to 90 days	31 per 1000	44 per 1000 (15 to 133)	RR 1.44 (0.48 to 4.34)	344 (2 studies)	⊕⊝⊝⊝ very low⁴
Health‐related quality of life	Not reported
Direct costs	Not reported
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Downgraded two levels for risk of bias (risk of selection bias due to lack of allocation concealment; risk of performance bias due to lack of blinding of participants, personnel and outcome assessors). ² Downgraded two levels for risk of bias (risk of selection bias due to lack of allocation concealment; risk of performance bias due to lack of blinding of participants, personnel and outcome assessors) and one level for imprecision (single study with very wide confidence intervals). ³ Downgraded one level for risk of bias (lack of allocation concealment) and one level for imprecision (single study with very wide confidence intervals). ⁴ Downgraded two levels for risk of bias (risk of selection bias due to lack of allocation concealment; risk of performance bias due to lack of blinding of participants, personnel and outcome assessors) and one level for imprecision (wide confidence intervals).

Summary of findings for the main comparison. Sulodexide + local treatment compared to local treatment for treating venous leg ulcers

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Comparison 1. Sulodexide + local treatment vs. local treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of ulcers completely healed (overall) Show forest plot	3	438	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [1.30, 2.12]

2 Proportion of ulcers completely healed (sensitivity analysis) Show forest plot	3	438	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.27, 1.83]

3 Proportion of ulcers completely healed at 30 days Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4 Proportion of ulcers completely healed at 60 days Show forest plot	2	324	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [1.20, 2.28]

5 Proportion of ulcers completely healed at 90 days Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6 Adverse effects Show forest plot	2	344	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [0.48, 4.34]

Comparison 1. Sulodexide + local treatment vs. local treatment

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References

Referencias de los estudios incluidos en esta revisión

Coccheri 2002 {published data only}

Niglio 1991 {published data only}

Scondotto 1999 {published data only}

Zou 2007 {published data only}

Referencias de los estudios excluidos de esta revisión

Andreozzi 2012 {published data only}

Colletta 2003 {published data only}

Dereure 2012 {published data only}

Incandela 2001 {published data only}

Krasinski 2010 {published data only}

Kucharzewski 2003 {published data only}

Meaume 2008 {published data only}

Serra 2014 {published data only}

Referencias adicionales

Andreozzi 2014

Augustin 1997

Baker 1991

Beebe‐Dimmer 2005

Bosanquet 1992

Browse 1982

Ciszewicz 2009

Coon 1973

Cosmi 2003

De Araujo 2003

de Oliveira Carvalho 2016

Deeks 2011

EndNote 2014 [Computer program]

Erickson 1995

Franks 1995

Fu 1998

González‐Consuegra 2011

GRADEpro GDT 2015 [Computer program]

Hareendran 2005

Herberger 2011

Herdman 2011

Higgins 2003

Higgins 2011

Jull 2012

Karoń 2007

Lasierra‐Cirujeda 2010

Lefebvre 2011

Liberati 2009

Mayer 1994

McCulloch 2001

Nelson 2011

Nelzen 1994

NHS CRD 1997

O'Meara 2012

Olde Engberink 2015

Pascarella 2005

RevMan 2014 [Computer program]

Scallon 2013

Schünemann 2011

SIGN 2015

Simon 2004

Sterne 2011

Valencia 2001

Velasco 2011

Ware 2000

White 2005

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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