Scolaris Content Display Scolaris Content Display

استفاده از سولودکساید (sulodexide) در درمان زخم‌‌های وریدی پا

Appendices

Appendix 1. CENTRAL search strategy

CENTRAL search strategy

#1 MeSH descriptor Leg Ulcer explode all trees
#2 ((varicose NEXT ulcer*) or (venous NEXT ulcer*) or (leg NEXT ulcer*) or (stasis NEXT ulcer*) or (crural NEXT ulcer*) or "ulcus cruris" or "ulcer cruris"):ti,ab,kw
#3 (#1 OR #2)
#4 MeSH descriptor Glycosaminoglycans explode all trees
#5 (sulodexide or mucopolysaccharide* or glycosaminoglycan* or vessel or aterina or luzone or (glucuronyl* NEAR/1 sulfate) or 3‐glucosaminoglycan or KRX‐101):ti,ab,kw
#6 (#4 OR #5)
#7 (#3 AND #6)

Appendix 2. Ovid MEDLINE search strategy

Ovid MEDLINE search strategy

#1 exp Leg Ulcer/
#2 (varicose ulcer* or venous ulcer* or leg ulcer* or stasis ulcer* or crural ulcer* or ulcus cruris or ulcer cruris).tw.
#3 or/1‐2
#4 exp Glycosaminoglycans/
#5 (sulodexide or mucopolysaccharide* or glycosaminoglycan* or vessel or aterina or luzone or (glucuronyl* adj1 sulfate) or 3‐glucosaminoglycan or KRX‐101).tw.
#6 or/4‐5
#7 3 and 6
#8 randomized controlled trial.pt.
#9 controlled clinical trial.pt.
#10 randomi?ed.ab.
#11 placebo.ab.
#12 clinical trials as topic.sh.
#13 randomly.ab.
#14 trial.ti.
#15 or/8‐14
#16 exp animals/ not humans.sh.
#17 15 not 16
#18 7 and 17

Appendix 3. Ovid EMBASE search strategy

Ovid EMBASE search strategy

#1 exp Leg Ulcer/
#2 (varicose ulcer* or venous ulcer* or leg ulcer* or stasis ulcer* or crural ulcer* or ulcus cruris or ulcer cruris).tw.
#3 or/1‐2
#4 exp Glycosaminoglycans/
#5 (sulodexide or mucopolysaccharide* or glycosaminoglycan* or vessel or aterina or luzone or (glucuronyl* adj1 sulfate) or 3‐glucosaminoglycan or KRX‐101).tw.
#6 or/4‐5
#7 3 and 6
#8 Randomized controlled trials/
#9 Single‐Blind Method/
#10 Double‐Blind Method/
#11 Crossover Procedure/
#12 (random$ or factorial$ or crossover$ or cross over$ or cross‐over$ or placebo$ or assign$ or allocat$ or volunteer$).ti,ab.
#13 (doubl$ adj blind$).ti,ab.
#14 (singl$ adj blind$).ti,ab.
#15 or/8‐14
#16 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
#17 human/ or human cell/
#18 and/16‐17
#19 16 not 18
#20 15 not 19
#21 7 and 20

Appendix 4. EBSCO CINAHL search strategy

EBSCO CINAHL search strategy

S1 (MH "Leg Ulcer+")
S2 TI ( varicose ulcer* or venous ulcer* or leg ulcer* or stasis ulcer* or crural ulcer* or ulcus cruris or ulcer cruris) OR AB (varicose ulcer* or venous ulcer* or leg ulcer* or stasis ulcer* or crural ulcer* or ulcus cruris or ulcer cruris)
S3 S1 OR S2
S4 (MH "Glycosaminoglycans+")
S5 TI (sulodexide or mucopolysaccharide* or glycosaminoglycan* or vessel or aterina or luzone or glucuronyl* N1 sulfate or 3‐glucosaminoglycan or KRX‐101)
S6 S4 OR S5
S7 S3 AND S6
S8 MH "Clinical Trials+"
S9 PT Clinical trial
S10 TI clinic* N1 trial* or AB clinic* N1 trial*
S11 TI (singl* or doubl* or trebl* or tripl*) and TI ( blind* or mask*)
S12 AB (singl* or doubl* or trebl* or tripl*) and AB ( blind* or mask*)
S13 TI randomi?ed control* trial* or AB randomi?ed control* trial*
S14 MH "Random Assignment"
S15 TI random* allocat* or AB random* allocat*
S16 MH "Placebos"
S17 TI placebo* or AB placebo*
S18 MH "Quantitative Studies"
S19 S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18
S20 S7 AND S19

Appendix 5. Chinese Biomedical Literature Database (CBM) search strategy

Chinese Biomedical Literature Database (CBM) search strategy

#1 静脉曲张溃疡/全部树/全部副主题词 [主题词]

#2 (ulcer or 溃疡) [缺省]

#3 #1 or #2

#4 (sulodexide or 舒洛地特 or 伟素) [缺省]

#5 #3 and #4

Appendix 6. China National Knowledge Infrastructure Database (CNKI) search strategy

China National Knowledge Infrastructure Database (CNKI) search strategy

#1 (ulcer or 溃疡) [主题]

#2 (sulodexide or 舒洛地特 or 伟素) [主题]

#3 #1 and #2

Appendix 7. Wan Fang Database search strategy

Wan Fang Database search strategy

#1 (ulcer or 溃疡) [题名或关键词]

#2 (sulodexide or 舒洛地特 or 伟素) [题名或关键词]

#3 #1 and #2

Appendix 8. VIP Database search strategy

VIP Database search strategy

#1 (ulcer or 溃疡) [题名或关键词]

#2 (sulodexide or 舒洛地特 or 伟素) [题名或关键词]

#3 #1 and #2

Appendix 9. Criteria for judging risk of bias

1. Was the allocation sequence randomly generated?

Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear

Insufficient information about the sequence generation process provided to permit a judgement of low or high risk of bias.

2. Was the treatment allocation adequately concealed?

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based and pharmacy‐controlled randomisation); sequentially‐numbered drug containers of identical appearance; sequentially‐numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: use of an open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. envelopes were unsealed, non‐opaque, or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear

Insufficient information to permit judgement of low risk or high risk to be made. This is usually the case if the method of concealment is not described, or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

3. Blinding ‐ was knowledge of the allocated interventions adequately prevented during the study?

Low risk of bias

Any one of the following:

  • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.

  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.

High risk of bias

Any one of the following:

  • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, and the non‐blinding of others likely to introduce bias.

Unclear

Either of the following:

  • Insufficient information available to permit judgement of low risk or high risk.

  • The study did not address this outcome.

4. Were incomplete outcome data adequately addressed?

Low risk of bias

Any one of the following:

  • No missing outcome data.

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is not enough to have a clinically relevant impact on the intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes is not enough to have a clinically relevant impact on observed effect size.

  • Missing data have been imputed using appropriate methods.

High risk of bias

Any one of the following:

  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size.

  • 'As‐treated' analysis done with substantial departure of the intervention received from that assigned at randomisation.

  • Potentially inappropriate application of simple imputation.

Unclear

Either of the following:

  • Insufficient reporting of attrition/exclusions to permit judgement of low risk or high risk (e.g. number randomised not stated, no reasons for missing data provided).

  • The study did not address this outcome.

5. Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias

Either of the following:

  • The study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

  • The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).

High risk of bias

Any one of the following:

  • Not all of the study's pre‐specified primary outcomes have been reported.

  • One or more, primary outcome is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified.

  • One or more, reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

  • One or more, outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear

Insufficient information to permit judgement of low risk or high risk. It is likely that the majority of studies will fall into this category.

6. Other sources of potential bias

Low risk of bias

The study appears to be free of other sources of bias.

High risk of bias

There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used;

  • has been claimed to have been fraudulent;

  • had some other problem.

Unclear

There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists;

  • insufficient rationale or evidence that an identified problem will introduce bias.

PRISMA flow diagram of literature screening
Figuras y tablas -
Figure 1

PRISMA flow diagram of literature screening

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

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

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 1 Proportion of ulcers completely healed (overall).
Figuras y tablas -
Analysis 1.1

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

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 2 Proportion of ulcers completely healed (sensitivity analysis).
Figuras y tablas -
Analysis 1.2

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

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 3 Proportion of ulcers completely healed at 30 days.
Figuras y tablas -
Analysis 1.3

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

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 4 Proportion of ulcers completely healed at 60 days.
Figuras y tablas -
Analysis 1.4

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

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 5 Proportion of ulcers completely healed at 90 days.
Figuras y tablas -
Analysis 1.5

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

Comparison 1 Sulodexide + local treatment vs. local treatment, Outcome 6 Adverse effects.
Figuras y tablas -
Analysis 1.6

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

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).

Figuras y tablas -
Summary of findings for the main comparison. Sulodexide + local treatment compared to local treatment for treating venous leg ulcers
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]

Figuras y tablas -
Comparison 1. Sulodexide + local treatment vs. local treatment