Comparative effectiveness of advanced wound dressings for patients with chronic venous leg ulcers: A systematic review M. Frances Valle, DNP, MS1; Nisa M. Maruthur, MD, MHS2,3; Lisa M. Wilson, ScM4; Mahmoud Malas, MD, MHS5; Umair Qazi, MPH5; Elisabeth Haberl, BA4; Eric B. Bass, MD, MPH2,4,6; Jonathan Zenilman, MD, PhD3,7; Gerald Lazarus, MD8 1. 2. 5. 7. 8. 3. 4. 6.

School of Nursing, University of Maryland, Department of Medicine, Department of Surgery, Division of Infectious Diseases, Department of Dermatology, Johns Hopkins University School of Medicine, Department of Epidemiology, Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, and Department of Health Systems and Outcomes, Johns Hopkins University School of Nursing, Baltimore, Maryland

Reprint requests: Dr. M. Frances Valle, University of Maryland School of Nursing, 655 W. Lombard St, Suite 375-D, Baltimore, MD 21201, United States. Tel: 410-706-6836; Fax: 410-706-0344; Email: [email protected] Manuscript received: August 2, 2013 Accepted in final form: October 10, 2013 DOI:10.1111/wrr.12151

ABSTRACT The purpose of this study was to systematically review the literature on the benefits and harms of advanced wound dressings on wound healing, mortality, quality of life, pain, condition of the wound bed, and adverse events for patients with chronic venous leg ulcers as compared with treatment with compression alone. We searched for primary studies in the databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature® from January 1980 through July 2012. Each study title, abstract, and full article was evaluated by two independent reviewers. Thirty-seven studies met our specific search criteria, although most evidence was of low or insufficient quality. Cellular dressings, collagen, and some antimicrobial dressings may improve healing rates of chronic venous leg ulcers vs. compression alone or other dressings. Limited data were available on other outcomes. The poor quality of the literature limits conclusions and necessitates future, well-conducted studies to evaluate the effectiveness of advanced wound dressings on chronic venous ulcers.

Venous leg ulcers are the most commonly diagnosed ulcer of the lower extremity, occurring in approximately 500,000 people in the United States annually.1 While about 1% of the population experiences a chronic venous ulcer (CVU), the prevalence in the population over the age of 65 is as high as 4%.2 CVUs are associated with a decrease in quality of life (QOL) related to pain, loss of function, and reduced mobility, which can result in social isolation.3 The overall cost of treating chronic venous disease in the United States is approximately three billion dollars per year, not accounting for the loss of approximately two million working days.3 Venous ulceration is the culmination of vessel damage, edema, and inflammation that occurs as a result of venous hypertension.4 While surgical intervention for venous ulceration may decrease recurrence rates, it does not appear to affect overall healing rates.5 Conservative medical management, including adequate compression therapy (at least two layers with an elastic component), and debridement, on the other hand, heal approximately 40% to 60% of venous ulcerations.6 Research over the past 50 years supports the premise that a moist wound environment is essential for wound healing, leading to the advent of advanced wound dressings (AWDs).7 Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

These dressings regulate moisture at the wound surface, facilitating autolytic debridement while protecting periwound tissues and minimizing pain before, during, and after dressing changes. Additionally, many biologic dressings contribute connective tissue components, such as collagen, and growth factors that are presumed to facilitate healing.8 Finally, dressings impregnated with silver and other antimicrobial elements may help control infection.9,10 Currently, there are a plethora of costly AWDs available to clinicians. In addition to an understanding of the wound healing process, the wound dressing components, and an ability to recognize the continually changing needs of the chronic wound, the selection of appropriate dressings requires evidence on the performance of these AWDs. Therefore, we

AHRQ AWD CVU MTC-2G QOL RCT

Agency for Healthcare Research and Quality Advanced wound dressing Chronic venous ulcer Mimosa tenuiflora cortex extract Quality of life Randomized controlled trials

193

Advanced wound dressings systematic review

performed a systematic review of the comparative effectiveness of AWDs on wound healing, mortality, pain, QOL, condition of the wound bed, and adverse events for patients with chronic CVUs as compared with compression alone.

METHODS The Johns Hopkins University Evidence-Based Practice Center performed a systematic review of the comparative effectiveness of the benefits and harms of the current medical and surgical therapies for the treatment of chronic venous leg ulcers under a contract from The Agency for Healthcare Research and Quality (AHRQ). The protocol and full evidence report, including the detailed methods for the review and data on the comparative effectiveness of AWDs, antibiotics, and vascular surgery in the treatment of CVUs are available at www.effectivehealthcare.ahrq.gov/reports/final .cfm.11 This paper presents our findings on the comparative effectiveness of AWDs in treating CVUs. Data sources and search strategy

We searched the databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature® from January 1980 through December 31, 2012. The MEDLINE search strategy was based on an analysis of medical subject headings (MeSH) accessed via PubMed as well as relevant text from articles previously identified. We hand-searched reference lists from included articles and relevant review articles. We included non-English language articles. We submitted requests to wound dressing and pharmaceutical manufacturers to identify additional published or unpublished studies. Materials provided by 3M, Akorn, Inc., Baxter Healthcare, ConvaTec, Inc., Fagron, Healthpoint Biotherapeutics, and Systagenix were reviewed. We also searched for ongoing clinical trials via ClinicalTrials.gov. We downloaded the search results, imported them into ProCite version 5 (ISI ResearchSoft, Carlsbad, CA) and removed duplicates. We used Distiller SR (Evidence Partners, Ottawa, Ontario, Canada) to track the search results. Study selection

Two investigators reviewed titles, abstracts, and full text articles independently. A title was advanced to abstract review if either reviewer included it. Abstracts and full text articles were excluded if both reviewers agreed that the abstract or article met an exclusion criterion. Any differences among reviewers at the abstract or article review levels were resolved by adjudication. We were primarily interested in comparing AWDs with standard compression therapy in patients with CVUs, as they are the least medically confounding type of leg ulcer. We included studies of AWDs that evaluated wound healing (time to complete wound healing, wound healing rates, proportion of total ulcers healed, and wound recurrence), mortality, QOL, pain, condition of the wound bed, functional status, or adverse events (maceration, infection, and contact dermatitis). We defined time to complete wound healing as the amount of 194

Valle et al.

time needed for the ulcer to heal completely, wound healing rates as the relative change in ulcer area over time, and the proportion of ulcers healed as the percentage of ulcers in the study that healed completely. We included studies of any AWD, including those with debridement activity, antimicrobial activity, and enhanced absorptive/barrier properties, and biological dressings with or without viable human cells. Studies were included if AWDs were concurrently compared with compression therapy or with another intervention plus compression therapy. Based on prior evidence on the effectiveness of compression, we only included studies in which subjects in both the experimental and control groups received at least two layers of compression or in which compression was described either qualitatively or quantitatively (>20 mmHg).6 We only included studies in which subjects had an active chronic ulcer (ulcer duration at least 6 weeks with no decrease in size) accompanied by evidence of earlier stages of venous disease such as varicose veins, edema, hemosiderin pigmentation, or venous eczema. We excluded studies without at least 4 weeks of follow-up and those without quantitative results on outcomes of interest. We excluded studies of (1) arterial ulcers, pressure ulcers, postsurgical ulcers, and neuropathic ulcers, including those related to diabetic neuropathy; (2) venous ulcers complicated by coexisting sickle cell disease, thrombophilia, collagenvascular diseases, or inflammatory bowel disease; and (3) ulcers with active infection or those occurring in atypical locations (such as the soles, toes, or mid-calf). Studies of both venous ulcers and nonvenous ulcers were included only if results for the subgroup with CVUs were provided. Lastly, we excluded studies that used intermittent pneumatic compression as a comparison group.

Data abstraction, quality, and applicability assessments

Our team of 10 clinicians and methodological experts created and piloted standardized forms for data extraction. Each article was reviewed for data abstraction by two study investigators who were paired to have clinical and methodological expertise. The second investigator confirmed the accuracy and completeness of data abstraction by the first investigator. We did not mask investigators to article authors, affiliations, or journal of publication. Reviewers extracted data into a DistillerSR database on general study characteristics, study participants, interventions, types of comparisons, outcome measures, definitions, and the results of each outcome, including measures of variability. We also collected information on subgroups of interest, defined by age, comorbidity, or study setting. Two reviewers independently assessed study quality (reporting, internal validity, statistical power, and conflicts of interest) using the Downs and Black quality assessment tool.12 We supplemented this tool with additional questions based on the Methods Guide for Effectiveness and Comparative Effectiveness Reviews.13,14 We also evaluated the degree to which the study population (age, duration of ulcer, comorbidity), interventions (treatment, co-interventions, duration of treatment), outcomes, and settings (nursing home, wound care center, primary care, hospital/inpatient) were typical for those with CVUs receiving treatment. Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

Valle et al.

Data analysis and synthesis

We performed a qualitative synthesis of the included studies and calculated risk differences and relative risks for the outcomes of proportion of ulcers healed and wound recurrence when possible. We did not conduct quantitative synthesis with meta-analyses because of the heterogeneity and paucity of studies. We also described relevant subgroup analyses qualitatively.

Advanced wound dressings systematic review

Electronic Databases PubMed (5,689) EMBASE® (9,695) Cochrane (827) CINAHL (1,355) Hand Searching 8 Retrieved 17,566 Duplicates 6,890

Grading of the evidence

Two or more reviewers graded the strength of the evidence independently for the outcomes of wound healing, time to complete wound closure, proportion of ulcers healed, and wound recurrence. We determined the risk of bias through assessment of internal validity across studies for a given comparison and outcome.12 Randomized controlled trials (RCTs) were considered to be at “low” risk of bias but then could be downgraded based on aspects of internal validity as described in our quality instrument.12 We rated the body of evidence as “consistent” if most studies showed the same direction of effect. In the case of single study within a category, we rated consistency as “not applicable;” this did not downgrade the evidence. We rated the body of evidence as “direct” if most of the studies evaluated wound healing and “indirect” if most studies evaluated only intermediate outcomes such as wound healing rates, pain, and condition of the wound bed. We considered the body of evidence “precise” if the width of the confidence interval for a risk difference was less than or equal to 30%. When we were unable to calculate a risk difference, we used our judgment based on the data available. We used four basic grades to classify the strength of the evidence. “High” grade indicates that the evidence probably reflects the true effect, “moderate” grade indicates moderate confidence that the evidence reflects the true effect, “low” grade indicates low confidence that the evidence reflects the true effect, and “insufficient” grade when the evidence did not allow us to draw a conclusion. Role of funding source

AHRQ reviewed our key questions and the overall work plan prior to project initiation and periodically throughout the project but did not participate in the literature search, data analysis, or interpretation of the results. AHRQ provided copyright assertion for this manuscript.

RESULTS Study selection and characteristics

We included 37 studies (38 publications) enrolling a total of 3,990 patients (Figure 1).15–52 Thirty-six of 37 studies were RCTs, one was a nonrandomized trial, and another was a retrospective cohort study. All studies were of short duration with the length of follow-up ranging from 4 weeks to 1 year (median of 12 weeks). Twenty-four of 38 studies were conducted in Europe, while 5 were exclusive to the United States. Two took place in the United States and Canada, one took place in the United States, Canada, and the United Kingdom, Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

Title Review 10,676 Excluded 6,974

Reasons for Exclusion at the Abstract Review Level* No original data: 1,480 No separate analysis of chronic venous ulcers: 894 No comparison group of interest: 749 No human subjects: 140 Intermittent compression: 9 Different levels of compression: 58 Other exclusion: 73

Abstract Review 3,702 Excluded 3,099 Article Review 603 Excluded 565 Included Studies 38 evaluated advanced wound dressings

Reasons for Exclusion at the Article Review Level* No original data: 114 No separate analysis of chronic venous ulcers: 137 No intervention of interest: 138 No concurrent comparison: 58 Intermittent compression: 7 Less than two levels of compression: 72 No outcome of interest: 65 Fewer than 4 weeks follow-up: 19 Case series with fewer than 30: 73 No KQ applies: 20 No human subjects: 1 Case series no ulcer healing: 8 Case series no sampling frame: 4 Case series no demographics: 40 Other exclusion: 48 Not advanced wound dressing: 26

Figure 1. Summary of literature search (number of articles). *Total may exceed number in corresponding box, as articles could be excluded for more than one reason at this level. CINAHL, Cumulative Index of Nursing and Allied Health Literature; KQ, key question.

one in Canada and the United Kingdom, and one study each took place in Brazil and Mexico. Most studies recruited patients from outpatient centers although 15 studies did not report on recruitment site. No studies recruited patients from long-term care settings. Thirty-four of 37 studies did not report the number of patients screened. Study population characteristics

Patient profiles of included studies were similar in nature. Median age ranged from 60 to 70 years with the majority of participants being female. Most studies excluded patients with insulin-dependent diabetes. All studies excluded patients with peripheral arterial disease. The most common cause of abnormal venous function as reported by venous ultrasound was venous reflux. However, less than 50% of the studies reported such data. Wound healing (Table 1)

Hydrocolloid dressing Findings from three RCTs that evaluated wound healing over 10–24 weeks suggested that hydrocolloid dressings were not 195

196

Greguric, 199425

Gottrup, 200753

Gottrup, 200824

Gethin, 200923

Gatti, 201122

duration) Franks, 200721

on ulcers >1 year

G2: Hydrocolloid, 55

Non-Adhesive, Coloplast A/S) G1: Impregnated gauze, 55

G2: Foam, with ibuprofen (Biatain-Ibu

Coloplast A/S)

G1: Foam (Biatain Non-adhesive,

Two-layer compression

ankle

circumference at the

Kept a constant

Multilayer

NR

47 days

12 weeks

G2: 3 (5)

G2: 32; p = 0.0001

G1: 21

(mm2/day)

11.2 to 7.9 cm2; p = 0.26 Mean reduction in ulcer area

RD, 2% (CI, −10% to 15%) G1: 0 (0)

7.2 to 3.8 cm2

G2: 34% (p < 0.001) G1: Average area reduction from

G1: 13%

at 4 weeks

Median reduction in wound size

NR

G2: Average area reduction from NR

NR

NR

NR

RR, 1.15 (CI, 0.5 to 2.6)

G2: 9/62 patients (15); p > 0.05

G1: 10/ 60 patients (16)

RR, 1.38 (CI, 1.02 to 1.88)

G2: 24/54 (44%)

G1: 18/54 (33%)

G2: Compression and manuka honey, 54

venom, fatty acids, compression, 13 G1: Compression and hydrogel, 54

RD, −4% (CI, −20% to 10%) G1: 5/11 (45%)

RR, 0.9 (CI, 0.7 to 1.2)

G2: 50/75 patients (67); p > 0.05

NR

G2: 181 days; p < 0.005

G1: 50/81 patients (62)

G1: Closure not attained

NR

G2: 18%; p > 0.05 NR

G1: 20.5%

per week

G2: 71% (4.3); p > 0.05 Percent of original ulcer healed

G2: 34/72 (47); p < 0.005

NR

time, 1.5 (CI, 1.3 to 1.9)

RH of wound closure per unit

G2: 61 (9 to 233)

G1:181 (10 to 232)

Median (range) days

NR

NR

G1: 43% (7.1)

area (SD)

Mean percent decrease in ulcer

Wound healing rates

G1: 9/48 (19)

p = 0.02

G2: 92/146 patients (63);

G1: 63/129 patients (49)

G2: 21/57; p = 0.18

G1: 33/62

G2: 21/28 patients (75); p > 0.05

G1: 22/28 patients (78)

G1: 8.2 (0.4) G2: 7.09 (0.2); p > 0.05

Mean weeks (SE)

G1: 14 ulcers

Time to healing

G2: 11 ulcer, p > 0.05

healed, n/n (%)

Proportion of ulcers

G2: 7/13 (54%)

8 weeks

24 weeks

24 weeks

6 months

20 weeks

12 weeks

10 weeks

time

Follow-up

G2: Fibrin sealant derived from snake

Unna boot

multilayer

G2: Foam (Mepilex)

G1: Fatty acids plus compression, 11

Short stretch or

G1: Foam (Allevyn)

G2: Cellular skin substitute or ECM

(Subgroup analysis

from Falanga, 199819

G1: Compression

G2: Cellular skin substitute or ECM, 146

Unna boot

Unna boot

G2: Compression and hydrogel, 57 G1: Compression, 129

microbial shale, 62

Two-layer

Multilayer

zinc oxide paste

Unna boot gradient and

in both groups

Compression used

G1: Compression and hydrogel and

G2: Hydrocolloid, 28

G2: Hydrocolloid, 35 G1: Compression, 28

United Kingdom, 35

United States, saline/Betadine in

G1: Impregnated gauze; paraffin in

Intervention, n

Falanga, 199920

Falanga, 199819

Beckert, 200617

Backhouse, 198716

Arnold,

199415

Author, year

Table 1. Wound healing for studies evaluating the treatment of chronic venous ulcers

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Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

Limova, 200333

201232

Lammoglia-Ordiales,

Kucharzewski, 200331

200330

Krishnamoorthy,

Holloway, 198929

Harding, 201128

Harding, 200527

Hansson, 199826

Author, year

Table 1. Continued.

healed, n/n (%)

Dressing), 9

G2: Alginate (Sorbsan Topical Wound

G1: Alginate (3 M Tegagen HG), 10

G2: Compression and MTC-2G, 18

G1: Compression and hydrogel, 14

G2: (Bioprocess) Cellulose membrane

G4: Compression only G1: Unna boot

Dermagraft 1pc

G3: Cellular skin substitute or ECM

Dermagraft 4pcs

G2: Cellular skin substitute or ECM

Dermagraft 12 pcs

G1: Cellular skin substitute or ECM

antibacterial dressing, 38

G2: Compression and hydrocolloid

G1: Compression, 37

G2: Compression and silver dressings

dressings, 136

Two-layer compression

Two-layer

compression

Unspecified

Multilayer Profore

Toe-to-knee elastic

6 weeks

8 weeks

11 weeks

12 weeks

NR

G2: 2/9 (22%)

p = 0.0001 G1: 0/10 (0%)

G2: 4/18;

RD, −33% (CI, −58% to −8%) G1: 3/14

RR, 0.5 (CI, 0.3 to 0.9)

G2: 18/27 patients (67); p < 0.05

G1: 9/27 patients (33)

G4: 2/13 (15); p > 0.05

G3: 1/13 (8)

G2: 5/13 (38)

G1: 5/13 (38)

NR

NR

G3: 13/45

G2: 36/95

G1: 13/53

NR

Proportion of ulcers

keratinocyte lysate, 45 G1: Compression and antibacterial 8 weeks

24 weeks

12 weeks

time

Follow-up

p = 0.239 (overall) Class III

Two-layer

Short stretch

in both groups

Compression used

G3: Compression and hydrocolloid

95

G2: Compression and cellular or ECM,

G1: Compression and hydrocolloid, 53

G3: Compression and paraffin gauze, 20

paste, 17

G2: Compression and cadexomer iodine

G1: Compression and Duoderm, 14

Intervention, n

Time to healing

in weeks, 14

G2: Time at complete closure

in weeks, 20

G1: Time at complete closure

NR

p = 0.366 (overall) NR

G3: 97.8 days (4.5)

G2: 148.5 days (5.6)

G1: 152.5 days (7.4)

Mean (SE)

NR

Wound healing rates

G2: 29.6%; p = 0.88

G1: 33.7%

Wound area reduction

p = 0.0720 (vs. G1)

G2: 0.04(0.04)

G1: 0.03(0.01)

as function of baseline circ

baseline) Mean (SE) healing (cm2)/week

G2: 0.17(0.17); p = 0.438 (vs.

baseline)

G1: 0.14(0.43); p = 0.438 (vs.

Mean (SD)

p = 0.0127 (G2 to G1) NR

G3: 50.9 (53.2)

G2: 66.1 (25.4)

G1: 17.9 (51.6)

baseline ulcer area

Mean (SD) percent reduction of

Valle et al. Advanced wound dressings systematic review

197

198

Scurr, 199344

Schulze, 200143

Pessenhofer, 198942

Ormiston, 198340

Ormiston, 198541

Omar, 200439

Nelson, 200738

Mostow, 200537

Moffatt, 199236

Michaels, 200935

Maggio,

201134

Author, year

Table 1. Continued.

G2: 16/26 (61%); p = 0.01

G1: 7/26 (27%)

healed, n/n (%)

Proportion of ulcers

alginate, 10

G2: Compression and Transparent film

G2: 2/10 (20)

G1: 2/10 (20)

6 weeks

G2: 1/37

G1: 3/22 G3: 2/54

Compression stockings

4 weeks

12 weeks

G2: 4/10 (50); p = 0.15

12 weeks G1: 1/8 (12.5)

G2: 20/33 (60)

G2: aOR†, 3.0; p = 0.01 24 weeks G1: 17/27 patients (63)

54 G1: Compression and Alginate foam, 10

compression

Short-stretch

Unna boot

bandage

Crepe and cotton crepe

Four-layer

Four-layer

G3: Specialty absorptive hydropolymer,

G2: Alginate plus swabs, 37

G1: Alginate plus film, 22

G2: Unna boot and foam, 24

G1: Unna boot, 17

30

G2: Compression and cadexomer iodine,

polyfax, 30

G1: Compression and Gentian violet and

replacement, Dermagraft, 10

G2: Human fibroblast-derived dermal

G1: Compression only, 8

G2: Hydrocolloid, 33

G1: Knitted viscose, 27

Debridement

G2: Composite acellular or ECM

G2: 34/62 (55); p = 0.02

G1:20/68 (34)

6 months

Multilayer

30 G1: Standard compression therapy

69.1); p = 0.673 12 weeks G1: 7/30 patients (23)

G2: 62/104 (59.6; CI, 50.2 to

66.3)

12 weeks G1: 59/104 (56.7; CI, 47.2 to

70 days

time

Follow-up

G2: 13/30 patients (43)

Four-layer

Multilayer

Multilayer

in both groups

Compression used

G2: Hydrocolloid (Comfeel, Coloplast),

antibacterial dressings, 104 G1: Nonadherent, 30

G2: Compression and Silver containing

dressings, 104

G1: Compression and matched

G2: Alginate (Vulnamin®), 26

G1: Alginate, 26

Intervention, n

G2: 99; p > 0.05

G1: 127

Median days

p = 0.077

G2: RR, 2.25 (CI, 0.88 to 5.75);

G1: Reference

Time to healing

G2: −65.6%

G1: +78.3%

(mm2)

Area reduction from baseline

p = 0.0001

G2: 0.89

G1: 0.46

p = 0.001 Change per week (cm2)

G2: 0.82 cm2 per week;

G1: 0.15 cm2 per week

Ulcer area rate of healing

NR

NR

cm2; p < 0.05

G2: 13.95 (4.5) cm2 to 3.04 (0.8)

(3.8) cm2

G1: 15.14 (4.7) cm2 to 10.96

Mean (SD) ulcer area

Wound healing rates

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Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

G1: Betadine and contact layer, 62

G2: Hydrocolloid, 20

G1: Alginates, 20

Intervention, n

G1: Betadine and contact layer, 39

Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

G2:Foam (Allevyn)

G1: Foam (Cutinova foam)

(Xelmat), 42

G2: Compression + amelogenin proteins

G1: Compression, 41

G2: Alginate

G1: Amelogenin proteins (Xelmat)

substitute or ECM, 116

stocking

Jobst®UlcerCare

High compression

High compression

p = 0.0106

G2: 44/116 patients (38);

healed per day

G2: 9/20 (45%); p = 0.258 Median area (cm2) of ulcer

G1: 14/20 (70%)

≥40% decrease in area

G2: 8/20 (40%)

G1: 2/20 (10%)

G1: 5.6 G2: 6.5

Mean weeks

p < 0.0001

G2: 176 (114 to 184);

G1: >201 (201 to ∞)

Median (CI) days

Median area (cm2) of ulcer

interaction, p = 0.37 See above

G2: −33.1% (49.7); p = 0.06 NR

G1: −11.1% (46.6)

ulcer area

G2: 25.6% Mean (SD) percent change in

G1: 33.8%

ulcer area

Median percent reduction in

G2: 0.184; p = 0.09

G1: 0.017

healed per day

G2: 0.056; p = 0.40

Treatment and ulcer area

RR, 1.6 (CI, 0.75 to 3.4) RD, 30% (CI, −13% to 72%)

Wound healing rates ≥40% increase in area

healing, 1.16 (CI, 0.77 to 1.77) G1: 0.062

G2: 4/8 patients (50); p > 0.05

16 weeks G1: 8/10 patients (80)

12 weeks

12 weeks No difference

182 days

G1: 24/109 patients (22)

G2: Contact layer + cellular skin

Short stretch

G1: 3/23 (13)

G2:12/35 patients (34); p = 0.02

G1:4/39 patients (10)

G2: 3/24 (13)

6 weeks

Time to healing

G1: Reference

NR

G2: 38/64 patients (59); p = 0.27 G2: RR† for time to complete

G1: 43/62 patients (69)

G2: 2 (10)

G1: 6 (30)

healed, n/n (%)

Proportion of ulcers

24 G1: Contact layer, 109

Short-stretch

4 months

4 months

6 weeks

time

Follow-up

G2: Compression and cellular or ECM,

G1: Compression and hydrocolloid, 23

linear, graduated

Two-layer compression,

linear, graduated

Two-layer compression,

compression stocking

Graduated elastic

in both groups

Compression used

aOR, adjusted odds ratio; CI, confidence interval; ECM, extracellular matrix; MTC, Mimosa tenuiflora cortex extract; NR, not reported; RD, risk difference; RH, relative hazard; RR, relative risk; SD, standard deviation; SE, standard error.

Weiss, 199651

Vowden, 200750

Vowden, 200649

Vanscheidt, 200748

Teepe, 199347

size of >4 cm

Among those with initial ulcer G2: Hydrocolloid, 35

Smith, 199246

size of 2–4 cm

Among those with initial ulcer G2: Hydrocolloid, 64

Smith, 199246

Scurr, 199445

Author, year

Table 1. Continued.

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Advanced wound dressings systematic review

more effective than compression systems alone (low strength of evidence).16,36,38 Healing rates and time to complete healing favored the hydrocolloid dressings, but results were not statistically significant. Evidence on the comparative effectiveness of hydrocolloids relative to other AWDs was insufficient because of low quality of studies.15,25,45,46 We found no studies comparing different types of hydrocolloid dressings to each other.

Antimicrobial dressings vs. other types of dressings We found moderate strength of evidence on the effects of the antimicrobial-containing dressings with cadexomer iodine, silver, and Mimosa tenuiflora extract relative to nonantimicrobial-containing dressings.26,32,35 Cadexomer iodine caused a modest, but significantly greater, mean ulcer area reduction compared with hydrocolloid and paraffin gauze over 12 weeks in one RCT.26 Silver-impregnated dressings did not significantly change healing rates when compared with nonsilver dressings, and Mimosa tenuiflora cortex extract plus hydrogel showed no significant difference in mean wound area reduction compared with hydrogel over 8 weeks.32,35 Lastly, low strength of evidence was generated from one trial with Manuka honey compared with a nonantimicrobial dressing.23 In a single RCT of 108 ulcers, those treated with Manuka honey achieved a greater median reduction in wound size at 4 weeks as compared with hydrogel; however, the mean reduction in wound size was not considered significant.23 Evidence on antimicrobial dressings compared with compression and other antimicrobial dressings was insufficient.17,28,29,40,41,52

Collagen dressings Low strength of evidence was generated from one US multicenter trial examining the effects of small intestinal freezedried pig submucosa (Oasis Wound Matrix) on CVUs.37 Oasis healed a greater proportion of ulcers over 6 months than compression alone.37 There was no significant difference in wound recurrence rates between the two groups.37

Cellular dressings Three trials (four publications) evaluated Apligraf, an allogeneic cultured human skin equivalent, and Dermagraft, a cryo-preserved human fibroblast-derived dermal substitute.19,20,30,39 Over 12 weeks, Apligraf achieved significantly improved median time to complete wound closure, median time to 75% wound closure, and was more effective than compression in healing ulcers greater than 1,000 mm2, deeper ulcers, and on ulcers older than 6 months (moderate strength of evidence).19 In a subgroup analysis of 120 ulcers older than 1 year that had failed conservative therapy, the Apligraf group healed a significantly greater proportion of ulcers and achieved complete wound closure significantly faster over 6 months than compression alone (moderate strength of evidence).20 There was no difference in ulcer recurrence rates between groups in the original study or the subgroup analysis.19,20 We were unable to draw any 200

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meaningful conclusions on the effect of Dermagraft on CVUs because of an insufficient strength of evidence generated from the trials.30,39 Lastly, autologous keratinocytes in a fibrin sealant healed a significantly greater proportion of ulcers and achieved a shorter median time to complete wound closure over 26 weeks when compared with compression on ulcers following a 4-week run-in period of optimal conservative care.48 We did not identify any studies that assessed wound healing rates for composite dressings, specialty absorptive dressings, contact layer dressings, hydrogel dressings, impregnated gauzes, or dressings with debriding agents. Of the RCTs evaluating transparent films, alginates, collagen, acellular human skin equivalents, and antimicrobials vs. compression; hydrocolloids, transparent films, alginates, and cellular skin equivalents vs. other types of dressings; and head-to-head comparisons of different types of alginates, foams, and antimicrobial dressing, we did not find sufficient evidence from which we were able to draw meaningful conclusions. Generally, this was due to high risk of bias, including publication bias, inconsistent results, selective outcome reporting, and/or imprecise estimates. Mortality

Eleven studies reported on mortality rates.19,21,27,28,30,35–37,40,46,48 Mortality rates were less than 5% across these studies, and there was no significant difference between intervention groups.19,21,27,28,30,35–37,40,46,48 Adverse events

Wound infection was defined differently among the selected studies (Appendix S1). Six of the 10 studies reporting on infection did not provide a definition precluding meaningful conclusions. Trials that met our criteria compared wound infection rates of hydrocolloid dressings with compression or with an antiseptic/antimicrobial plus compression; foam dressings with and without ibuprofen; acellular and cellular human skin equivalents with compression; an antimicrobial dressing with paraffin gauze plus compression; and spray cell therapy with a foam dressing and found no differences in infection rates across intervention arms.8,16,19,24–27,30,37,46,52 Contact dermatitis was reported in two studies, which found no difference.21,38 No study evaluated maceration. Other outcomes (Appendix S2)

General study and measurement heterogeneity limited our ability to draw conclusions about the effect of AWDs on QOL (n = 4),15,24,25,35 pain (n = 12),15,17,25,26,29,33,40,43–46,50 and wound bed condition (n = 10).17,26,30,32,33,39,40,43,45,49 Risk of bias and applicability of evidence

Most studies were at moderate to high risk of bias because of flaws in study design (Table 2). Randomization and allocation methods were frequently unclear. Studies did not attempt to mask outcome assessors or did not report on masking at all. Losses to follow-up tended to be substantial or unreported, and studies did not account for this in analyses. Definitions of Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

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Table 2. Summary of the comparative benefits of advanced wound dressings in terms of wound healing

Comparison (number of included studies)*

Strength of evidence†

Hydrocolloids vs. compression (3)

Low

Hydrocolloids vs. other dressings (4) Transparent films vs. compression (1) Transparent films vs. other dressings (1) Alginate dressings vs. compression (1) Alginate dressings vs. alginate dressings (2) Alginate dressings vs. other dressings (1) Foam dressings vs. foam dressings (3) Collagen vs. compression (1)

Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Low

Acellular human skin equivalent dressings vs. compression (3) Cellular (cryo-preserved human fibroblast-derived dermal substitute) vs. compression (2) Cellular (allogeneic bilayered cultured human skin equivalent) vs. compression (1)

Insufficient

Conclusions Hydrocolloid dressings were not more effective than compression therapy alone in terms of the proportion of chronic venous ulcers healed. The results from the three studies addressing this comparison were imprecise and subject to some bias. We are unable to draw a conclusion. We are unable to draw a conclusion. We are unable to draw a conclusion. We are unable to draw a conclusion. We are unable to draw a conclusion. We are unable to draw a conclusion. We are unable to draw a conclusion. Collagen dressings healed a greater proportion of ulcers than compression alone. This conclusion is based on a single study with imprecise estimates. We are unable to draw a conclusion.

Insufficient We are unable to draw a conclusion. Moderate

The allogeneic bilayered cultured HSE healed a greater proportion of ulcers and provided as much as three times more rapid healing of chronic venous ulcers than compression alone, especially for ulcers that had failed therapy and were present for over 1 year. Cellular (autologous keratinocytes in a fibrin Low Autologous keratinocytes in fibrin sealant healed a greater sealant) vs. compressions (1) proportion of ulcers and achieved a shorter median time to complete wound closure vs. compression. This conclusion is based on a single study that is subject to some bias. Antimicrobial dressings vs. compression (2) Insufficient We are unable to draw a conclusion. Antimicrobial dressings vs. antimicrobial dressings Insufficient We are unable to draw a conclusion. (2) Antimicrobial containing dressings vs. other Moderate There was modest improvement with a cadexomer iodine types of dressings (3) dressing in wound healing rates and wound area reduction as compared with nonantimicrobial dressings in another single RCT. Silver dressings did not significantly improve wound healing as compared with nonsilver dressings. Antimicrobial containing dressings vs. other Low Manuka honey achieved a greater median reduction in wound types of dressings (1) size but did not significantly affect a mean reduction in wound size compared with a nonantimicrobial dressing in one trial. *The strength of evidence for all comparisons not listed here were graded as insufficient because we did not find any studies addressing them or because we were unable to draw a conclusion from the evidence. † We defined the strength of evidence as follows: High = High confidence that the evidence reflects the true effect. Further research is unlikely to change our confidence in the estimate of the effect. Moderate = Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of the effect and may change the estimate. Low = Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of the effect and is likely to change the estimate. Insufficient = Evidence is unavailable or does not permit a conclusion. HSE, human skin equivalent; RCT, randomized controlled trial.

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outcome measures and adverse events were unclear or lacking completely. Small sample sizes limited statistical power. Lastly, studies often did not report prespecified analyses raising the concern for selective reporting of results. Study populations were generally representative of the population of patients with CVUs in that they consisted mostly of elderly patients, a minority being men, with ulcer durations of greater than 12 months. However, it was often unclear as to how the study population represented screened population and if the care they received was similar to that received by other patients with CVUs. Additionally, the treatment period of most of the studies was 4 months or less, making it difficult to draw conclusions about the longer term effects of AWDs on chronic CVUs.

DISCUSSION Despite the overabundance of AWDs on the market today for CVU healing, we found limited evidence on their comparative effectiveness and safety in this comprehensive systematic review. Of the thousands of citations that we reviewed, just 38 met our criteria. Five of these studies generated moderate levels of evidence from which we were able draw conclusions on CVU healing. However, the poor quality of study design and the heterogeneity among studies limited our ability to draw meaningful conclusions related to QOL, pain, condition of the wound bed, and most adverse events. Improved healing rates were observed in trials that evaluated the allogeneic bilayered cultured human skin equivalent, Apligraf®.19,20 This dressing healed a greater proportion of ulcers and provided as much as three times more rapid healing of CVUs than compression alone, especially for recalcitrant ulcers that were present for over 1 year. However, no added benefit was seen in recurrence rates, supporting the evidence of the benefit of lifelong compression therapy for patients with venous ulcers.19,20 Additional studies are needed to validate these results. While the antimicrobial dressing of cadexomer iodine provided a significant advantage in wound healing rates in one trial, silver-impregnated dressings and Manuka honey did not significantly affect healing rates of CVUs.26,35 Clearly, more studies are needed to further explore the role of antimicrobial dressings in the management of CVUs. Hydrocolloid dressings do not appear more effective than compression alone in healing the chronic venous leg ulcers.16,36,38 However, all hydrocolloids are not exactly the same, and the lack of standardization in water vapor transmission rates among hydrocolloid dressings could potentially affect wound healing. The low strength of evidence on hydrocolloids indicates that we cannot rule out the possibility of a benefit, but better studies would be needed to show a benefit. Lastly, during our refined search, we found promising research related to spray cell therapy containing growtharrested neonatal keratinocytes and fibroblasts that healed a significantly greater proportion of ulcers and achieved a significantly shorter median time to healing and a greater percent of wound area reduction.4 Wound recurrence rates are not available from this study. This trial was not included in the original review as it is currently in a phase III trial and the product was not available to clinicians. 202

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Limitations

The major limitations of this systematic review are related to the existing evidence on the comparative effectiveness of AWDs for CVU healing (Appendix S3). We found relatively few studies comparing AWDs to the standard of care (compression). The existing studies were often of low quality because of problems with internal validity further exacerbated by poor reporting. Notable deficiencies included lack of description of randomization and allocation concealment, unclear masking of outcome assessors, limited information on or substantial losses to follow-up, heterogeneity of measurement and reporting on outcomes, and insufficient sample sizes. Another major concern about this literature is conflict of interest and resultant selective reporting and publication bias given that most studies are funded by AWD manufacturers. While we evaluated dressings by categories, we are aware that there may be subtle, proprietary differences between dressings within the same category. This limits our ability to generalize findings to all dressings within a category. Additionally, this review evaluated the effectiveness of AWDs in the treatment of CVUs only, and we cannot generalize our findings to all wound types. Further research is needed to evaluate the effectiveness of AWDs for other wounds. Conclusions

In this systematic review, we provide a thorough qualitative synthesis of the comparative effectiveness of AWDs for CVUs. This review builds on the prior evidence of compression as the standard of care.6 Several strengths of this study deserve mention: The study team was composed of experts in wound care, including physicians and nurses, as well as experts in comparative effectiveness research. We combined this expertise with the use of established, rigorous methods using a prespecified protocol and feel confident that the evidence identified, abstracted, and synthesized is the most accurate and relevant evidence on AWDs for CVU healing. Additionally, this review included detailed assessment of quality of individual studies to facilitate interpretation of the evidence and highlight gaps for future study. The implications of this study are far-reaching. CVUs are a major and growing public health problem causing substantial morbidity at a large cost globally.3 There has been an explosion of the AWD market leading to a bewildering number of choices for clinicians. Unfortunately, the available evidence on AWDs simply does not match up in quantity or quality to the availability of these often expensive AWD products. We demonstrate that a few AWDs may be helpful in improving wound healing, but other important effectiveness and safety outcomes are still understudied for these AWDs. Our findings do not imply that AWDs have no merit in the treatment of the CVU. Rather, they indicate that there is insufficient data to support such claims, and re-evaluation of the standards for conducting research on AWDs for CVUs is imperative.54 We speculate that because many wound dressings are classified as medical devices, the existing evidence is partly a response to the less rigorous standards set forth by the Food and Drug Administration for medical devices.55 We hope that this review provides a call to action for the CVU research community to standardize its research to facilitate more meaningful conclusions in the future. Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society

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ACKNOWLEDGMENTS We would like to thank Dr. Christine Chang, our Task Order Officer at AHRQ, for her guidance and support throughout this project. Source of Funding: This project was funded under Contract No. HHS 290–2006-10061-I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. Conflicts of Interest: None of the authors have any potential conflicts of interest to disclose. REFERENCES 1. Margolis D, Berlin JA, Strom BL. Which venous leg ulcers will heal with limb compression bandages? Am J Med 2001; 109: 15–19.2. 2. Word R. Medical and surgical therapy for advanced chronic venous insufficiency. Surg Clin North Am 2010; 90: 1195–214. 3. Bergan J, Schmid-Schonbein G, Smith P, Nicolaides AN, Boisseau MR, et al. Chronic venous disease. N Engl J Med 2006; 355: 488–98. 4. Kirsner RS, Marston WA, Snyder RJ, Lee TD, Cargill DI, Slade HB. Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicenter, double-blind, randomized, placebo-controlled trial. Lancet 2012; 380: 977–85. 5. Barwell JR, Taylor M, Deacon J, Ghauri AS, Wakely C, Phillips LK, et al. Surgical correction of isolated superficial venous reflux reduces long-term recurrence rate in chronic venous leg ulcers. Eur J Vasc Endovasc Surg 2000; 20: 363–8. 6. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev 2009; (1): CD000265. 7. Winter GD. Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature 1962; 193: 293–4. 8. Limova M. Active wound coverings: bioengineered skin and dermal substitutes. Surg Clin North Am 2010; 90: 1237–55. 9. Shi L, Carson D. Collagenase Santyl ointment: a selective agent for wound debridement. J Wound Ostomy Continence Nurs 2009; 36 (6 Suppl.): 12–16. 10. Vermeulen H, van Hattem J, StormVersloot M, Ubbink DT. Topical silver for treating infected wounds. Cochrane Database of Sys Rev 2007; (1): CD005486. 11. Zenilman J, Valle F, Malas M, Maruthur N, Qazi U, Suh Y, et al. Chronic venous ulcers: a comparative effectiveness review of treatment modalities. Rockville, MD: Agency for Healthcare Research and Quality, 2013. Updated January 2014. 12. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomized and non-randomized studies of health care interventions. J Epidemiol Community Health 1998; 52: 377–84. 13. Agency for Healthcare Research and Quality. Methods guide for effectiveness and comparative effectiveness reviews. Rockville, MD: Agency for Healthcare Research and Quality, 2011. AHRQ Publication no. 10(11)-EHC063-EF. Available at:: http://www.effectivehealthcare.ahrq.gov/methodsguide.cfm (accessed June 11, 2013).

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1. Summary of adverse events among patients with chronic venous ulcers comparing advanced wound dressings. Appendix S2A. Summary of the comparative effectiveness of advanced wound dressings on quality of life among patients with chronic venous ulcers. Appendix S2B. Summary of the comparative effectiveness of advanced wound dressings on pain in patients with chronic venous ulcers. Appendix S2C. Summary of the comparative effectiveness of advanced wound dressings on wound bed condition for patients with chronic venous ulcers. Appendix S3. Study quality evaluations for studies evaluating the treatment of chronic venous ulcers. Wound Rep Reg (2014) 22 193–204 © 2014 by the Wound Healing Society