Review
Advanced Wound Care Therapies for Nonhealing Diabetic, Venous, and
Arterial Ulcers
A Systematic Review
Nancy Greer, PhD; Neal A. Foman, MD, MS; Roderick MacDonald, MS; James Dorrian, MD; Patrick Fitzgerald, MPH; Indulis Rutks, BS;
and Timothy J. Wilt, MD, MPH
Background: Nonhealing ulcers affect patient quality of life and
impose a substantial financial burden on the health care system.
Purpose: To systematically evaluate benefits and harms of ad-
vanced wound care therapies for nonhealing diabetic, venous, and
arterial ulcers.
Data Sources: MEDLINE (1995 to June 2013), the Cochrane Li-
brary, and reference lists.
Study Selection: English-language randomized trials reporting ulcer
healing or time to complete healing in adults with nonhealing ulcers
treated with advanced therapies.
Data Extraction: Study characteristics, outcomes, adverse events,
study quality, and strength of evidence were extracted by trained
researchers and confirmed by the principal investigator.
Data Synthesis: For diabetic ulcers, 35 trials (9 therapies)
met eligibility criteria. There was moderate-strength evidence for
improved healing with a biological skin equivalent (relative risk
[RR], 1.58 [95% CI, 1.20 to 2.08]) and negative pressure wound
therapy (RR, 1.49 [CI, 1.11 to 2.01]) compared with standard care
and low-strength evidence for platelet-derived growth factors and
silver cream compared with standard care. For venous ulcers, 20
N onhealing ulcers (those that are unresponsive to initial
therapy or persist despite appropriate care) affect pa-
tient quality of life and productivity and represent a sub-
stantial financial burden on the health care system (1–3).
More than 6 million persons in the United States are af-
fected, and this number is expected to increase as the pop-
ulation ages and more people develop diabetes (1). Identi-
fying ulcer cause is an important factor in determining
appropriate wound care interventions (4). Nonhealing
ulcers are typically categorized as diabetic, venous, or
arterial.
Standard treatment for ulcers may include debride-
ment of necrotic tissue, revascularization surgery, infection
control, mechanical offloading, management of blood glu-
cose, foot care education, mechanical compression, or limb
elevation (4 – 6). If ulcers do not adequately heal with stan-
dard treatment, “advanced wound care therapies” (thera-
pies used when standard treatments have failed) are con-
See also:
Web-Only
Supplement
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Annals of Internal Medicine
trials (9 therapies) met eligibility criteria. There was moderate-
strength evidence for improved healing with keratinocyte therapy
(RR, 1.57 [CI, 1.16 to 2.11]) compared with standard care and
low-strength evidence for biological dressing and a biological skin
equivalent compared with standard care. One small trial of arterial
ulcers reported improved healing with a biological skin equivalent
compared with standard care. Overall, strength of evidence was
low for ulcer healing and low or insufficient for time to complete
healing.
Limitations: Only studies of products approved by the U.S. Food
and Drug Administration were reviewed. Studies were predomi-
nantly of fair or poor quality. Few trials compared 2 advanced
therapies.
Conclusion: Compared with standard care, some advanced wound
care therapies may improve the proportion of ulcers healed and
reduce time to healing, although evidence is limited.
Primary Funding Source: Department of Veterans Affairs, Veterans
Health Administration, Office of Research and Development, Qual-
ity Enhancement Research Initiative.
Ann Intern Med. 2013;159:532-542. www.annals.org
For author affiliations, see end of text.
sidered. Although a large and growing array of advanced
therapies exists, their efficacy, comparative effectiveness,
and harms are not well-established. The purpose of this
review was to systematically evaluate randomized, con-
trolled trials of the efficacy and harms of advanced wound
care therapies compared with either usual care or another
advanced therapy for lower-extremity, nonhealing, dia-
betic, venous, and arterial ulcers in adult patients.
This report is part of a Department of Veterans Affairs
Evidence-based Synthesis Program review, which is avail-
able at www.hsrd.research.va.gov/publications/esp/wound
-care.cfm.
METHODS
Data Sources and Searches
We searched MEDLINE (Ovid interface) for random-
ized, controlled trials published from 1995 through June
2013 (see the search strategy in Appendix Table 1, avail-
able at www.annals.org). We limited the search to English-
language studies involving adults aged 18 years or older.
We obtained additional references from a search of the
Cochrane Library, existing systematic reviews, and refer-
ence lists of pertinent studies.
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 Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers
Study Selection
Investigators and research associates reviewed abstracts
identified from the literature search for relevance. We in-
cluded randomized, controlled studies of adults with non-
healing diabetic, venous, or arterial ulcers receiving treat-
ment with an advanced wound care therapy of interest as
identified by an expert advisory panel. We included studies
that compared these therapies with standard wound care as
well as with other advanced therapies and reported either
percentage of ulcers healed at study completion or time to
complete ulcer healing.
Data Extraction and Quality Assessment
Study, patient, ulcer, and treatment characteristics;
outcomes; and adverse events were extracted from the full
text of eligible articles by a trained research associate and
verified by a second research associate. The principal inves-
tigator confirmed key characteristic and outcome data. Our
primary outcome of interest was the percentage of ulcers
healed at study completion. Additional outcomes of inter-
est included time to complete ulcer healing, patient global
assessment, and return to daily activities. We also assessed
pain, ulcer infection, amputation, revascularization sur-
gery, ulcer recurrence, time to ulcer recurrence, hospital-
ization, all-cause mortality, adverse events, and adverse re-
actions to treatment.
The quality of individual studies was rated as good,
fair, or poor using a modification of the Cochrane ap-
proach to determining risk of bias (7), which involved eval-
uation of established criteria for randomized, controlled
trials: allocation concealment, blinding, analysis approach,
and description of withdrawals. We attempted to minimize
publication bias through a comprehensive literature search,
hand-searching of reference lists, and input from content
experts. Funnel plots were not possible because of the small
number of trials for each intervention and outcome.
Data Synthesis and Analysis
Results are summarized according to ulcer cause (arte-
rial, venous, or diabetic) as defined by study authors.
When feasible, data were analyzed in Review Manager,
version 5.1 (The Nordic Cochrane Centre, Copenhagen,
Denmark). Random-effects models were used to generate
pooled estimates of relative risks (RRs) with 95% CIs for
outcomes from studies of equivalent therapies used to treat
similar ulcer types. We evaluated statistical heterogeneity
using a chi-square test and the I2 statistic (with cutoffs of
25.0%, 50.0%, and 75.0% for low, moderate, and sub-
stantial heterogeneity, respectively) (8). We calculated ab-
solute risk differences (ARDs) with 95% CIs for the
primary outcome of ulcers healed. All other data are nar-
ratively summarized. Strength of evidence was determined
for the percentage of ulcers healed and time to complete
ulcer healing. We rated the overall strength of the evidence
as high, moderate, low, or insufficient (9). Rating of study
quality and strength of evidence was done by a research
associate and verified by the principal investigator.
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Review
Role of the Funding Source
The funding source (Department of Veterans Affairs,
Veterans Health Administration, Office of Research and
Development, Quality Enhancement Research Initiative)
assigned the topic and reviewed the key questions but was
not involved in data collection or analysis or manuscript
preparation or submission.
RESULTS
We screened 1322 titles and abstracts, excluded 1135,
and performed a detailed review of the remaining 187 ar-
ticles. From these, 59 articles representing 56 randomized,
controlled trials (35 involving patients with diabetic ulcers,
20 involving those with venous ulcers, and 1 involving
those with arterial ulcers) were eligible for inclusion (Ap-
pendix Figure 1, available at www.annals.org). Most stud-
ies compared advanced wound care therapies with standard
care or placebo. Direct comparison of one advanced ther-
apy with another was done in 10 studies (29%) of diabetic
ulcers and 4 studies (20%) of venous ulcers.
Diabetic Ulcers
We identified 35 eligible trials of 9 advanced wound
care therapies for diabetic ulcers (10 – 45). Appendix Table
2 (available at www.annals.org) summarizes baseline pa-
tient and wound characteristics. Enrollees were generally
middle-aged, and most were white men. Sample size
ranged from 9 to 382, and treatment duration ranged from
4 to 20 weeks.
Mean ulcer size ranged from 1.9 to 41.5 cm2, al-
though it was greater than 10 cm2 in only 6 of 30 studies
that reported ulcer size. Mean ulcer duration ranged from
2 to 94 weeks. Complete study characteristics, including
the risk-of-bias assessment, are presented in Table 1 of the
Supplement (available at www.annals.org).
The ulcer was described as a “foot” ulcer in 26 trials
(11–13, 15–21, 23, 25, 31– 43, 45), a “lower-extremity”
ulcer in 7 trials (10, 24, 26 –30, 44), and a “diabetic” ulcer
in 2 trials (14, 22). The ulcer type was further described as
neuropathic in 11 trials (10, 17, 19, 20, 24 –26, 28, 29,
31, 33, 36), ischemic in 1 trial (44), neuroischemic in 1
trial (23), and mixed in 3 trials (34, 35, 38). Of the re-
maining trials, 16 had inclusion or exclusion criteria re-
lated to circulation or severe arterial disease (11–17, 21,
27, 30, 32, 37, 39, 41, 43, 45) and 3 did not specify
criteria related to circulation (22, 40, 42).
Findings for our primary outcome of interest—
proportion of healed ulcers at study conclusion—are pre-
sented in Figure 1 and Table 1. In Figure 1, results are
depicted according to the sample size of the individual
studies and whether results significantly (P ⬍ 0.05) favored
the listed advanced wound therapy versus standard care or
another advanced wound care product. Table 1 provides
ARDs and RRs with 95% CIs.
15 October 2013 Annals of Internal Medicine Volume 159 • Number 8 533
 Review Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers

Figure 1. Healed diabetic ulcers.

Versus Standard Care

Advanced Therapy Total Advanced No Difference Strength of

Patients Therapy Between Groups Evidence
Randomly Superior
Assigned, n

Collagen 489 Low

BSE (Dermagraft*) 576 Low
BSE (Apligraf†) 359 Moderate
PDGF 813 Low
PRP 72 Low
Silver cream 66 Low
NPWT 341 Moderate
HBOT 240 Low
Ozone–oxygen therapy 61 Low

Versus Another Advanced Therapy

Advanced Therapy Total Patients No Difference Strength of

Randomly Between Groups Evidence
Assigned, n

Biological dressing 124 ‡ § Low

BSE (Dermagraft) 26 ‡ Low
BSE (Apligraf) 28 Low
PDGF 211 § Low
PRP 24 Low
Silver cream 40 || Low
Silver dressing 134 Low
HBOT 86 ¶ Low

<50 randomly assigned 50–100 randomly assigned >100 randomly assigned

Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Figure 2 and Appendix Figure 2 [available at
www.annals.org]). BSE ⫽ biological skin equivalent; HBOT ⫽ hyperbaric oxygen therapy; NPWT ⫽ negative pressure wound therapy; PDGF ⫽
platelet-derived growth factor; PRP ⫽ platelet-rich plasma.
* Shire Regenerative Medicine, San Diego, California.
† Organogenesis, Canton, Massachusetts.
‡ Compared biological dressing with BSE (Dermagraft) and found no significant difference (15).
§ Compared biological dressing with PDGF and found no significant difference (14).
储 A second study of silver cream did not report the proportion of healed ulcers (36).
¶ Found extracorporeal shock wave therapy to be more effective than HBOT (40).

Ulcers Healed: Advanced Wound Care Versus Standard Care
Overall, the strength of evidence favoring advanced
therapies over standard care was low for 7 therapies and
moderate for 2 therapies (Figure 1 and Appendix Table 3,
available at www.annals.org). Study design (for example,
duration of intervention and time of final outcome assess-
ment) and clinical heterogeneity (for example, ulcer size,
duration, and location and comorbid conditions) pre-
cluded meta-analyses of results in many situations.
We were able to combine results from trials comparing
3 advanced therapies with standard care (Figure 1; Table
534 15 October 2013 Annals of Internal Medicine Volume 159 • Number 8
1; and Appendix Figure 2, available at www.annals.org).
Although effect sizes were similar for all 3 therapies, the
findings were statistically significant for only 2. We found
moderate-strength evidence for improved healing with the
biological skin equivalent Apligraf (Organogenesis, Can-
ton, Massachusetts) (2 fair-quality trials; ARD, 21% [95%
CI, 9% to 32%]; RR, 1.58 [CI, 1.20 to 2.08]; I2 ⫽ 0%)
(19, 20) and low-strength evidence for improved healing
with platelet-derived growth factors (2 good-quality and 5
fair-quality trials; ARD, 21% [CI, 14% to 29%]; RR, 1.45
[CI, 1.03 to 2.05]; I2 ⫽ 85%) (23–30). The rating of low
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 Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers Review

strength of evidence for the platelet-derived growth factor
trials was based on high heterogeneity (inconsistent results)
in trials of predominantly fair quality and concerns about
lack of directness (probable enrollment of a highly selected
population). Low-strength evidence suggested no statisti-
cally significant effect with the biological skin equivalent
Dermagraft (Shire Regenerative Medicine, San Diego, Cal-
ifornia) (3 fair-quality trials; ARD, 10% [CI, 2% to 18%];
RR, 1.49 [CI, 0.96 to 2.32]; I2 ⫽ 43%) (16 –18).
We found moderate-strength evidence of improved
healing with negative pressure wound therapy (1 good-
quality trial; ARD, 14% [CI, 4% to 24%]; RR, 1.49 [CI,
1.11 to 2.01]) (37) and low-strength evidence of improved
healing with silver cream (1 fair-quality trial; ARD, 23%
[CI, 2% to 43%]; RR, 2.45 [CI, 0.98 to 6.09]) (33).
For the remaining therapies, either no difference was
observed between the advanced therapy (platelet-rich
plasma or ozone– oxygen therapy) and standard care or

Table 1. ARDs and RRs for Percentages of Healed Ulcers: Diabetic Ulcer Studies

Study, Year Treatment Control Healed Diabetic Ulcers, n/N (%) ARD* (95% CI), % RR* (95% CI)
(Reference)
Treatment Control
Blume et al, Formulated collagen Standard care 14/31 (45) 5/16 (31) 14 (⫺15 to 43) 1.45 (0.63 to 3.29)
2011 (10) gel
Reyzelman et al, Collagen (Graftskin) Standard care 32/46 (70) 18/39 (46) 23 (3 to 44) 1.51 (1.02 to 2.22)
2009 (13)
Veves et al, Collagen Standard care 51/138 (37) 39/138 (28) 9 (⫺2 to 20) 1.31 (0.93 to 1.84)
2002 (11) (Promogran†)
Donaghue et al, Collagen (Fibracol†) Standard care 24/50 (48) 9/25 (36) 12 (⫺11 to 35) 1.33 (0.73 to 2.42)
1998 (12)
Niezgoda et al, Biological dressing PDGF 18/37 (49) 10/36 (28) 21 (⫺1 to 43) 1.75 (0.94 to 3.26)
2005 (14) (OASIS‡)
Landsman et al, Biological dressing BSE (Dermagraft§) 10/13 (77) 11/13 (85) ⫺8 (⫺38 to 22) 0.91 (0.62 to 1.33)
2008 (15) (OASIS)
Pooled studies BSE (Dermagraft) Standard care 87/251 (35) 62/254 (24) 10 (2 to 18) 1.49 (0.96 to 2.32)
(16–18)
Pooled studies BSE (Apligraf㛳) Standard care 80/145 (55) 46/134 (34) 21 (9 to 32) 1.58 (1.20 to 2.08)
(19–20)
DiDomenico et al, BSE (Apligraf) Theraskin¶ 8/17 (47) 8/12 (67) ⫺20 (⫺55 to 16) 0.71 (0.37 to 1.34)
2011 (21)
Pooled studies PDGF Standard care 189/325 (58) 133/360 (37) 21 (14 to 29) 1.45 (1.03 to 2.05)
(23–30)
Aminian et al, rhPDGF Silver sulfadiazine 4/7 (57) 0/5 (0) 57 (16 to 98) 6.75 (0.44 to 102.80)
2000 (22)
d’Hemecourt et al, PDGF (becaplermin NaCMC 15/34 (44) 25/70 (36) 8 (⫺12 to 29) 1.24 (0.76 to 2.02)
1998 (30) gel)
Saad Setta et al, PRP Platelet-poor plasma 12/12 (100) 9/12 (75) 25 (⫺1 to 51) 1.32 (0.93 to 1.86)
2011 (31)
Driver et al, PRP Placebo gel ITT: 13/40 (33) ITT: 9/32 (28) ITT: 4 (⫺17 to 26) ITT: 1.16 (0.57 to 2.35)
2006 (32) PP: 13/19 (68) PP: 9/21 (43) PP: 26 (⫺4 to 55) PP: 1.60 (0.89 to 2.85)
Belcaro et al, Silver ointment Standard care 13/34 (39) 5/32 (16) 23 (2 to 43) 2.45 (0.98 to 6.09)
2010 (33)
Jacobs and Tomczak, Silver cream Advanced therapy 6/20 (30) 8/20 (40) ⫺10 (⫺39 to 19) 0.75 (0.32 to 1.77)
2010 (34)
Jude et al, 2007 (35) Silver dressing Advanced therapy 21/67 (31) 15/67 (22) 9 (⫺6 to 24) 1.40 (0.79 to 2.47)
Blume et al, NPWT Standard care 73/169 (43) 48/166 (29) 14 (4 to 24) 1.49 (1.11 to 2.01)
2008 (37)
Wang et al, HBOT Extracorporeal shock First course of First course of ⫺30 (⫺49 to ⫺10) 0.46 (0.25 to 0.84)
2011 (40) wave therapy treatment: treatment:
10/40 (25) 24/44 (55)
Löndahl et al, HBOT Sham treatment 25/48 (52) 12/42 (29) 24 (4 to 43) 1.82 (1.05 to 3.16)
2010 (41)
Duzgun et al, HBOT Standard/multidisciplinary 33/50 (66) 0/50 (0) 66 (53 to 79) 67.00 (4.22 to 1064.23)
2008 (42) wound therapy
Kessler et al, HBOT Standard/multidisciplinary 2/14 (14) 0/13 (0) 14 (⫺7 to 36) 4.67 (0.24 to 88.96)
2003 (43) wound therapy
Abidia et al, HBOT Sham treatment 5/8 (63) 0/8 (0) 63 (27 to 98) 11.00 (0.71 to 170.98)
2003 (44)

ARD ⫽ absolute risk difference; BSE ⫽ biological skin equivalent; HBOT ⫽ hyperbaric oxygen therapy; ITT ⫽ intention-to-treat population; NaCMC ⫽ sodium
carboxymethylcellulose; NPWT ⫽ negative pressure wound therapy; PDGF ⫽ platelet-derived growth factor; PP ⫽ per-protocol population; PRP ⫽ platelet-rich plasma;
rhPDGF ⫽ recombinant human platelet-derived growth factor; RR ⫽ relative risk.
* Differences in reported ARDs and given percentages for each group may vary because of rounding.
† Systagenix, Gatwick, United Kingdom.
‡ DFB Pharmaceuticals, Fort Worth, Texas.
§ Shire Regenerative Medicine, San Diego, California.
㛳 Organogenesis, Canton, Massachusetts.
¶ Soluble Systems, Newport News, Virginia.

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 Review Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers
results from multiple trials of the same therapy were mixed
(collagen, biological skin equivalent [Dermagraft], platelet-
derived growth factor, or hyperbaric oxygen therapy).
Absolute risk differences typically ranged from 4% to
30% (Table 1). Strength of evidence was low (Appendix
Table 3).
Ulcers Healed: Comparative Effectiveness of Advanced Wound
Care Products
In 9 trials comparing one advanced therapy with an-
other (Figure 1 and Table 1), ARDs ranged from 8% to
30%. One poor-quality study found that extracorporeal
shock wave therapy statistically significantly improved ul-
cer healing compared with hyperbaric oxygen therapy
(ARD, 30% [CI, 10% to 49%]) (40). Strength of evidence
was low for the effect on the proportion of healed ulcers
when one advanced therapy was compared with another.
For 6 of the 8 comparisons, data were available from only
1 trial.
Other Outcomes
No studies reported a statistically significant improve-
ment in time to ulcer healing for collagen (12, 13), biolog-
ical dressings (14, 15), or silver products (35, 36) com-
pared with standard care or another advanced therapy.
Results were mixed but generally negative for biological
skin equivalents compared with standard care or another
advanced therapy (16, 18 –20), platelet-derived growth fac-
tor compared with standard care or another advanced ther-
apy (14, 24 –26, 28 –30), platelet-rich plasma compared
with standard care or another advanced therapy (31, 32),
and negative pressure wound therapy compared with stan-
dard care (38, 39). Strength of evidence was low or insuf-
ficient for all findings related to time to ulcer healing (Ap-
pendix Table 3). One study of silver versus calcium
dressings reported no difference between groups for a
global outcome of healed or improved ulcers (35). No
studies reported on return to daily activities.
No studies reported a statistically significant difference
in ulcers infected during treatment or ulcer recurrence for
any of the reviewed advanced therapies compared with
standard care or another advanced therapy. Fewer amputa-
tions were reported in the advanced therapy group in 3
studies (1 each of a biological skin equivalent [19], negative
pressure wound therapy [37], and hyperbaric oxygen ther-
apy [42], all compared with standard care), and 5 studies
reported no difference (13, 20, 41, 44, 45). Few studies
reported on the need for revascularization or hospitaliza-
tion. Overall, few deaths were reported and the results did
not show a statistically significant benefit of advanced ther-
apies in reducing all-cause mortality (reported in 16 stud-
ies) (11, 13, 14, 20, 24, 26, 28 –30, 32, 35–37, 39, 41, 43,
44). Similarly, there were no observed reductions in pain,
withdrawals due to adverse events, or allergic reactions to
treatment (Tables 2 to 4 of the Supplement). Studies
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lacked adequate power to assess the effect of an advanced
therapy on these outcomes.
Venous Ulcers
We identified 20 eligible trials of 9 advanced therapies
for venous ulcers (33, 46 – 66). A summary of baseline
characteristics is presented in Appendix Table 4 (available
at www.annals.org). Enrollees were predominately older
white women. Studies enrolled 16 to 309 patients, and
treatment duration ranged from 4 to 26 weeks. Mean ulcer
size ranged from 1.2 to 11.1 cm2, with mean ulcer sizes of
greater than 10 cm2 in 4 of the 12 studies reporting. Mean
ulcer duration ranged from 12 to 207 weeks. Complete
study characteristics, including the risk-of-bias assessment,
are presented in Table 1 of the Supplement.
The ulcer was described as a “leg” ulcer in 14 trials
(46, 47, 50, 51, 53–56, 58, 59, 61, 62, 64 – 66) and a
“lower-extremity” ulcer in 3 trials (52, 57, 60), whereas 3
trials did not report the ulcer location but described it only
as a “venous” ulcer (33, 48, 63). In 12 trials, diagnosis of a
venous ulcer was based on clinical signs or symptoms of
venous insufficiency (46 – 48, 51–56, 63– 65). The remain-
ing 8 trials required patients to have adequate arterial cir-
culation or excluded patients with known arterial insuffi-
ciency (33, 50, 57– 62, 66).
Ulcers Healed: Advanced Wound Care Products Versus
Standard Care
Findings for our primary outcome of interest—
proportion of healed ulcers—are presented in Figure 2,
Table 2, and Appendix Table 5 (available at www
.annals.org). Meta-analyses (Appendix Figure 3, available
at www.annals.org) showed an overall benefit of keratino-
cyte therapy compared with standard care (2 fair-quality
trials; ARD, 14% [CI, 5% to 23%]; RR, 1.57 [CI, 1.16 to
2.11]; I2 ⫽ 0%), with moderate strength of evidence (54,
55). Data from 3 studies of silver cream versus standard
care (1 good-quality and 2 fair-quality studies; ARD, 9%
[CI, ⫺4% to 23%]; RR, 1.65 [CI, 0.54 to 5.03]; I2 ⫽
84%) (33, 57, 58) and 2 studies of silver dressing versus
nonsilver dressing (both of fair quality; ARD, 8% [CI,
⫺4% to 20%]; RR, 1.27 [CI, 0.80 to 2.01]; I2 ⫽ 67%)
(59, 61, 62) showed no overall benefit of silver products.
In single trials, there was low-strength evidence of im-
proved ulcer healing with biological dressing (1 fair-quality
trial; ARD, 20% [CI, 3% to 38%]) (47) and the biological
skin equivalent Apligraf (1 fair-quality trial; ARD, 14%
[CI, 3% to 26%]) (48) compared with placebo or standard
care (Figure 2 and Table 2). Absolute risk differences in
ulcer healing ranged from 1% to 38% for collagen (46),
the biological skin equivalent Dermagraft (50, 51),
platelet-rich plasma (56), hyperbaric oxygen therapy (66),
or intermittent pneumatic compression therapy (63) com-
pared with placebo or standard care (Table 2). Results for
electromagnetic therapy were mixed (64, 65). Strength of
evidence was low (Appendix Table 5).
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 Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers Review

Figure 2. Healed venous ulcers.

Versus Standard Care

Advanced Therapy Total Advanced No Difference Strength of

Patients Therapy Between Groups Evidence
Randomly Superior
Assigned, n

Collagen 73 Low
Biological dressing 120 Low
BSE (Dermagraft*) 71 Low
BSE (Apligraf†) 309 Low
Keratinocyte therapy 425 Moderate
PRP 86 Low
Silver cream 203 Low
Silver dressing 255 Low
IPC 54 Low
EMT 63 Low
HBOT 16 Low

Versus Another Advanced Therapy

Advanced Therapy Total Patients No Difference Strength of

Randomly Between Groups Evidence
Assigned, n

Keratinocyte therapy 77 Low

Silver cream 63 ‡ Low
Silver dressing 281 Low

<50 randomly assigned 50–100 randomly assigned >100 randomly assigned

Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Appendix Figure 3, available at www.annals.org).
BSE ⫽ biological skin equivalent; EMT ⫽ electromagnetic therapy; HBOT ⫽ hyperbaric oxygen therapy; IPC ⫽ intermittent pneumatic compression;
PRP ⫽ platelet-rich plasma.
* Shire Regenerative Medicine, San Diego, California.
† Organogenesis, Canton, Massachusetts.
‡ Found silver cream to be more effective than tripeptide copper cream (57).

Ulcers Healed: Comparative Effectiveness of Advanced Wound Other Outcomes

Care Products
Only 4 studies compared one advanced therapy with
another (52, 53, 57, 60). Strength of evidence was low for
the effect on the proportion of healed ulcers (Figure 2 and
Appendix Table 5). In 1 moderate-size, fair-quality trial,
use of a silver cream resulted in a greater proportion of
healed ulcers (ARD, 21% [CI, 6% to 37%]) than a
copper-based cream (57). We found no differences in pro-
portion of healed ulcers between 2 forms of keratinocyte
therapy (1 moderate-size, poor-quality trial) (53), keratin-
ocyte therapy compared with pneumatic compression ther-
apy (1 small, fair-quality trial) (52), or 2 forms of silver
dressing (1 large, fair-quality trial) (60). The magnitude of
the differences between treatment groups ranged from 1%
to 4% (Table 2).
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Few studies reported time to ulcer healing. One study
of the biological skin equivalent Apligraf found shorter
time to ulcer healing than with standard care (48), as did a
study comparing a keratinocyte product with standard
care (55). No other studies reported a significant difference
(53, 54, 61, 62). Strength of evidence was low for these
comparisons (Appendix Table 4). Two studies that com-
pared silver products with other active treatments reported
higher global assessment outcomes in the silver groups (57,
60), whereas a study that compared electromagnetic ther-
apy with sham treatment reported no difference between
groups (64).
Advanced wound care products did not consistently
improve ulcer infection rate, ulcer recurrence, or pain, al-
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 Review Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers

Table 2. ARDs and RRs for Percentages of Healed Ulcers: Venous Ulcer Studies

Study, Year Treatment Control Healed Venous Ulcers, n/N (%) ARD* (95% CI), % RR* (95% CI)
(Reference)
Treatment Control
Vin et al, Collagen (Promogran†) Standard care ITT: 18/37 (49) ITT: 12/36 (33) ITT: 15 (⫺7 to 38) ITT: 1.46 (0.83 to 2.58)
2002 (46) PP: 15/37 (41) PP: 11/36 (31) PP: 10 (⫺12 to 32) PP: 1.33 (0.71 to 2.49)
Mostow et al, Biological dressing Standard care 34/62 (55) 20/58 (34) 20 (3 to 38) 1.59 (1.04 to 2.42)
2005 (47) (OASIS‡)
Falanga et al, BSE (Apligraf§) Standard care 92/146 (63) 63/129 (49) 14 (3 to 26) 1.29 (1.04 to 1.60)
1998 (48)
Krishnamoorthy BSE (Dermagraft㛳) Standard care 5/13 (38) (12 pieces) 2/13 (15) (12 pieces) 23 (⫺10 to 56) 2.50 (0.59 to 10.64)
et al, 2003 5/13 (38) (4 pieces) 2/13 (15) (4 pieces) (both) (both)
(50)
Omar et al, BSE (Dermagraft) Standard care 5/10 (50) 1/8 (12) 38 (⫺1 to 76) 4.00 (0.58 to 27.70)
2004 (51)
Pooled studies Keratinocytes Standard care 80/211 (38) 50/207 (24) 14 (5 to 23) 1.57 (1.16 to 2.11)
(54, 55)
Lindgren et al, Keratinocytes Compression 2/15 (13) 2/12 (17) ⫺3 (⫺31 to 24) 0.80 (0.13 to 4.87)
1998 (52) (cryopreserved, bandages
allogeneic cells)
Navrátilová Cryopreserved Lyophilized 21/25 (84) 20/25 (80) 4 (⫺17 to 25) 1.05 (0.81 to 1.36)
et al, keratinocytes keratinocytes
2004 (53)
Stacey et al, PRP Placebo 33/42 (79) 34/44 (77) 1 (⫺16 to 19) 1.02 (0.81 to 1.27)
2000 (56)
Pooled studies Silver cream Standard care 44/102 (43) 33/97 (34) 9 (⫺4 to 23) 1.65 (0.54 to 5.03)
(33, 57, 58) or placebo
Pooled studies Silver dressings Nonsilver 79/125 (63) 69/125 (55) 8 (⫺4 to 20) 1.27 (0.80 to 2.01)
(59, 61, 62) dressings
Harding et al, Silver dressing Silver dressing 24/145 (17) 21/136 (15) 1 (⫺7 to 10) 1.07 (0.63 to 1.83)
2012 (60) (AQUACEL¶) (Urgotul**)
Bishop et al, Silver cream Tripeptide 6/28 (21) 0/29 (0) 21 (6 to 37) 13.45 (0.79 to 228.07)
1992 (57) cream
Schuler et al, IPC Unna boot 20/28 (71) 15/25 (60) 11 (⫺14 to 37) 1.19 (0.80 to 1.77)
1996 (63) dressing
Ieran et al, EMT Sham treatment 12/18 (67) 6/19 (32) 35 (5 to 65) 2.11 (1.01 to 4.42)
1990 (64)
Kenkre et al, EMT Sham treatment 2/10 (20) 2/9 (22) ⫺2 (⫺39 to 35) 0.90 (0.16 to 5.13)
1996 (65)
Hammarlund and HBOT Sham treatment 2/8 (25) 0/8 (0) 25 (⫺8 to 58) 5.00 (0.28 to 90.18)
Sundberg,
1994 (66)

ARD ⫽ absolute risk difference; BSE ⫽ biological skin equivalent; EMT ⫽ electromagnetic therapy; HBOT ⫽ hyperbaric oxygen therapy; IPC ⫽ intermittent pneumatic
compression; PRP ⫽ platelet-rich plasma; RR ⫽ relative risk.
* Differences in reported ARDs and given percentages for each group may vary because of rounding.
† Systagenix, Gatwick, United Kingdom.
‡ DFB Pharmaceuticals, Fort Worth, Texas.
§ Organogenesis, Canton, Massachusetts.
㛳 Shire Regenerative Medicine, San Diego, California.
¶ ConvaTec Professional Services, Skillman, New Jersey.
** Urgo Medical, Loughborough, United Kingdom.

though these were not primary outcomes in the studies
(Tables 2 to 4 of the Supplement). Of 8 studies reporting
ulcer infection during treatment, only 1, a collagen study,
found fewer infected ulcers in the collagen group than in
the standard care group (46). Similarly, of 7 studies report-
ing ulcer recurrence, only 1, a biological dressing study,
saw fewer recurring ulcers in the active treatment group
than in the standard care group (47). One study of elec-
tromagnetic therapy noted a significant reduction in pain
from baseline to 30 days in patients receiving electromag-
netic therapy compared with sham treatment (65). How-
ever, 9 other studies reported no difference in pain between
an advanced therapy and standard care or between 2 ad-
vanced therapies.
538 15 October 2013 Annals of Internal Medicine Volume 159 • Number 8
No studies reported amputation, revascularization or
other surgery, time to recurrence, or need for home care.
Two studies reported hospitalization (47, 54) and 1 re-
ported quality of life (61, 62) and found no difference
between advanced therapy and standard care. No signifi-
cant differences were seen in all-cause mortality, study
withdrawals due to adverse events, or allergic reactions to
treatment, although there were few events and studies were
not adequately powered to assess these outcomes.
Arterial Ulcers
We identified 1 small (n ⫽ 31), fair-quality study that
enrolled patients specifically identified as having arterial
ulcers (67). Mean age of the patients was 70 years, and
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 Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers
75% were men. Mean ulcer size was 4.8 cm2; ulcer dura-
tion was not reported. There were significant differences in
ulcer healing (ARD, 46% [CI, 12% to 80%]) and time to
healing, suggesting that a biological skin equivalent may be
more effective than standard care when used on ischemic
foot ulcers or partial open-foot amputations after revascu-
larization surgery. Other outcomes did not differ signifi-
cantly compared with standard care.
DISCUSSION
We found moderate-strength evidence for improved
healing compared with standard care in patients with dia-
betic ulcers treated with the biological skin equivalent Ap-
ligraf or negative pressure wound therapy. There was also
moderate-strength evidence for improved healing in pa-
tients with venous ulcers treated with keratinocyte therapy
compared with standard care. Strength of evidence was low
for all treatment comparisons reporting time to ulcer heal-
ing, but a few therapies were associated with significant
improvement. No studies reported a significant difference
in adverse events for any treatment comparison.
Although a wide range of patients were enrolled in
studies, many were older than 60 years, male, and white
and were probably adherent to treatment protocols and
had ulcers with relatively small surface areas. Most studies
excluded patients with infected ulcers, and few monitored
adherence to standard care or intervention components.
Study authors rarely reported outcomes by patient demo-
graphic, comorbidity, adherence, or ulcer characteristics.
Therefore, we found insufficient evidence about whether
efficacy differs according to these factors.
The overall low strength of evidence reflects method-
ological flaws; the small number of trials; and heterogeneity
of the comparators, study durations, and how outcomes
were assessed. For each ulcer type (diabetic, venous, or
arterial), specific advanced wound care therapies were eval-
uated in only a few studies, often in highly selected popu-
lations and frequently with conflicting findings. Several
types of interventions were used within each category of
wound care therapy, making it difficult to determine
whether results were replicable in other studies or general-
izable to broader clinical settings.
The quality of the individual studies reviewed was pre-
dominantly fair or poor. Common factors limiting study
quality were inadequate allocation concealment, lack of
blinding (including blinding of outcome assessment), fail-
ure to use intention-to-treat analysis methods, and failure
to adequately describe study dropouts and withdrawals.
Most studies compared advanced therapies with stan-
dard care or placebo; little comparative effectiveness re-
search has evaluated one advanced therapy against another.
Despite the clinical importance of arterial ulcers, we iden-
tified only 1 study of an advanced therapy (which was
compared with standard care) for this type of ulcer. Pa-
tients with arterial disease may have been included in the
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Review
studies of diabetic ulcers or venous ulcers (that is, mixed
cause).
Our literature search identified recent systematic re-
views on many of the advanced therapies included in our
review. Although we were able to use these reviews to iden-
tify references our search may have missed, direct compar-
isons of the findings from existing reviews and those from
our review are difficult. Many of the reviews included stud-
ies of ulcers that were not diabetic, venous, or arterial;
many allowed studies with any outcome that reflected heal-
ing (including changes in area or volume); and some were
not limited to randomized, controlled trials.
We identified methodological limitations. Few studies
provided a run-in period with carefully monitored stan-
dard care to exclude patients for whom this would obviate
the need for advanced therapy. Although failure to exclude
these patients may bias the study of the advanced therapy,
it may, in fact, represent a more clinically relevant situa-
tion. Much of the existing research on advanced wound
care therapies has attempted to minimize the influence of
ulcer area, depth, duration, and location; patient comorbid
conditions; and patient adherence to the treatment proto-
col through strict inclusion and exclusion criteria. The
broader applicability to patients seen in many clinical set-
tings is not clear (68, 69). Results from our included stud-
ies may overestimate benefits and underestimate harms in
nonstudy populations. More than half of the trials in our
review were industry-sponsored, and the role of the spon-
sor in study design and analysis was typically not stated. To
minimize the potential for selective outcome reporting, we
excluded studies that reported changes in ulcer size without
providing data on complete healing. Although we at-
tempted to minimize publication bias, the possibility of
missed publications and unreported data exists. Definitions
of “chronic” ulcers varied widely, and few studies were of
sufficient duration to assess whether healing was main-
tained (69, 70).
We limited our review to studies of products approved
by the U.S. Food and Drug Administration. We excluded
studies with wounds of multiple causes (for example, vas-
cular, pressure, trauma, or surgery) if they did not report
results by cause. We also excluded studies if they did not
report healed wounds or time to complete healing. Many
studies report change in ulcer size, but the clinical benefit
of change in ulcer size has not been established.
Our review highlights future research needs. Although
additional randomized trials that compare advanced
wound care therapies with standard care are needed to rep-
licate or refute current findings, comparative effectiveness
research is also needed to evaluate the relative benefits and
harms of different advanced therapies. In both effectiveness
and comparative effectiveness research, the sample sizes
should be adequate for outcome reporting according to key
patient and ulcer characteristics, including age; race; sex;
and ulcer size, location, and depth. In addition, patients
15 October 2013 Annals of Internal Medicine Volume 159 • Number 8 539
 Review Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers
should be followed for sufficient time to assess whether
healing has been maintained.
Cost-effectiveness analyses are needed to assess
whether and for whom advanced wound care products are
high-value care. Advanced wound care products are expen-
sive. They may be cost-effective or even cost-saving in ap-
propriate patients and ulcers when their effect on medical
complications and other ulcer-related costs is considered.
However, a substantial proportion (generally a third or
more) of patients with nonhealing ulcers who were ran-
domly assigned to standard care had complete wound heal-
ing with this approach over study durations of 4 to 12
weeks. These findings suggest that a more rigorous “stan-
dard care approach” than might occur in clinical practice
may be beneficial in many patients.
We conclude, on the basis of our findings from pub-
lished randomized, controlled trials, that in highly con-
trolled settings, advanced wound care therapies may im-
prove the proportion of healed diabetic and venous ulcers
compared with standard care in adults with nonhealing
ulcers. A few therapies may reduce the time to ulcer heal-
ing, but evidence is limited. Limitations in the quality of
evidence and the number of studies directly comparing
different advanced therapies decrease the strength and gen-
eralizability of our findings.
From Minneapolis Veterans Affairs Health Care System and University
of Minnesota, Minneapolis, Minnesota.
Disclaimer: The views expressed in this article are those of the authors
and do not necessarily reflect the position or policy of the Department of
Veterans Affairs or the U.S. government.
Financial Support: This article is based on research conducted by the
Minneapolis Evidence-based Synthesis Program and was supported by
the Department of Veterans Affairs, Veterans Health Administration,
Office of Research and Development, Quality Enhancement Research
Initiative.
Potential Conflicts of Interest: Disclosures can be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M13
-1027.
Requests for Single Reprints: Nancy Greer, PhD, Minneapolis Veter-
ans Affairs Health Care System, One Veterans Drive, Mail Code 152,
Minneapolis, MN 55417; e-mail, nancy.greer@va.gov.
Current author addresses and author contributions are available at
www.annals.org.
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dressing on healing of chronic venous leg ulcers. Int Wound J. 2012;9:285-94.
[PMID: 22066961]
61. Michaels JA, Campbell B, King B, Palfreyman SJ, Shackley P, Stevenson
M. Randomized controlled trial and cost-effectiveness analysis of silver-donating
antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg. 2009;
96:1147-56. [PMID: 19787753]
62. Michaels JA, Campbell WB, King BM, Macintyre J, Palfreyman SJ, Shack-
ley P, et al. A prospective randomised controlled trial and economic modelling of
antimicrobial silver dressings versus non-adherent control dressings for venous leg
ulcers: the VULCAN trial. Health Technol Assess. 2009;13:1-114, iii. [PMID:
19939335]
63. Schuler JJ, Maibenco T, Megerman J, Ware M, Montalvo J. Treatment of
chronic venous ulcers using sequential gradient intermittent pneumatic compres-
sion. Phlebology. 1996;11:111-6.
64. Ieran M, Zaffuto S, Bagnacani M, Annovi M, Moratti A, Cadossi R. Effect
of low frequency pulsing electromagnetic fields on skin ulcers of venous origin in
humans: a double-blind study. J Orthop Res. 1990;8:276-82. [PMID: 2303961]
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 Review Advanced Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers

65. Kenkre JE, Hobbs FD, Carter YH, Holder RL, Holmes EP. A randomized
controlled trial of electromagnetic therapy in the primary care management of
venous leg ulceration. Fam Pract. 1996;13:236-41. [PMID: 8671131]
66. Hammarlund C, Sundberg T. Hyperbaric oxygen reduced size of chronic leg
ulcers: a randomized double-blind study. Plast Reconstr Surg. 1994;93:829-33.
[PMID: 8134442]
67. Chang DW, Sanchez LA, Veith FJ, Wain RA, Okhi T, Suggs WD. Can a
tissue-engineered skin graft improve healing of lower extremity foot wounds after
revascularization? Ann Vasc Surg. 2000;14:44-9. [PMID: 10629263]
68. Carter MJ, Fife CE, Walker D, Thomson B. Estimating the applicability of
wound care randomized controlled trials to general wound-care populations by
estimating the percentage of individuals excluded from a typical wound-care
population in such trials. Adv Skin Wound Care. 2009;22:316-24. [PMID:
20375969]
69. Wu SC, Marston W, Armstrong DG. Wound care: the role of advanced
wound-healing technologies. J Am Podiatr Med Assoc. 2010;100:385-94.
[PMID: 20847352]
70. Sullivan N, Snyder DL, Tipton K, Uhl S, Schoelles KM. Negative Pressure
Wound Therapy Devices. Technology Assessment Report. (Prepared by the
ECRI Institute under contract 290-2007-10063.) Rockville, MD: Agency for
Healthcare Research and Quality; 2009. Accessed at www.ahrq.gov/research
/findings/ta/negative-pressure-wound-therapy/index.html on 25 April 2013.

ANNALS OF INTERNAL MEDICINE JUNIOR INVESTIGATOR AWARDS

Annals of Internal Medicine and the American College of Physicians

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tigators with annual awards for original research and scholarly review
articles published in Annals in each of the following categories:

● Most outstanding article with a first author in an internal medicine

residency program or general medicine or internal medicine sub-
specialty fellowship program

● Most outstanding article with a first author within 3 years following

completion of training in internal medicine or one of its subspecialties

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ological rigor; clarity of presentation; and potential to influence practice,
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sentatives from Annals’ Editorial Board and the American College of
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Papers published in the year following submission are eligible for the
award in the year of publication. First author status at the time of
manuscript submission will determine eligibility. Authors should indicate
that they wish to have their papers considered for an award when they
submit the manuscript, and they must be able to provide satisfactory
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 Annals of Internal Medicine
Current Author Addresses: Drs. Greer and Wilt, Mr. MacDonald, Mr.
Fitzgerald, and Mr. Rutks: Center for Chronic Disease Outcomes Re- Appendix Table 1. Search Strategy
search, Minneapolis Veterans Affairs Health Care System, One Veterans
Drive, Mail Code 152, Minneapolis, MN 55417. 1 exp Skin Ulcer/
Drs. Foman and Dorrian: Dermatology Service, Minneapolis Veterans 2 exp Foot Ulcer/
3 exp Leg Ulcer/
Affairs Health Care System, One Veterans Drive, Mail Code 111K, 4 exp Varicose Ulcer/
Minneapolis, MN 55417. 5 exp Diabetic Foot/
6 exp Wound Healing/
7 exp Venous Insufficiency/
Author Contributions: Conception and design: N. Greer, N.A. Foman, 8 or/1-7
T.J. Wilt. 9 limit 8 to (clinical trial, all or clinical trial, phase i or clinical trial,
phase ii or clinical trial, phase iii or clinical trial, phase iv or
Analysis and interpretation of the data: N. Greer, N.A. Foman, R. Mac-
clinical trial or controlled clinical trial or meta analysis or
Donald, J. Dorrian, P. Fitzgerald, T.J. Wilt. randomized controlled trial)
Drafting of the article: N. Greer, N.A. Foman, R. MacDonald, J. Dor- 10 randomized controlled trial.pt.
rian, T.J. Wilt. 11 controlled clinical trial.pt.
Critical revision of the article for important intellectual content: N. 12 random*.ti,ab.
13 placebo.ti,ab.
Greer, N.A. Foman, J. Dorrian, T.J. Wilt. 14 or/10-13
Final approval of the article: N. Greer, N.A. Foman, R. MacDonald, I. 15 (animals not (humans and animals)).sh.
Rutks, T.J. Wilt. 16 14 not 15
Provision of study materials or patients: I. Rutks. 17 8 and 16
18 9 or 17
Statistical expertise: R. MacDonald, T.J. Wilt.
19 limit 18 to (english language and humans and yr⫽⬙1995-Current⬙)
Obtaining of funding: T.J. Wilt. 20 artificial skin.mp. or exp Skin, Artificial/
Administrative, technical, or logistic support: N. Greer, P. Fitzgerald, I. 21 19 and 20
Rutks, T.J. Wilt. 22 biological dressings.mp. or exp Biological Dressings/
Collection and assembly of data: N. Greer, R. MacDonald, J. Dorrian, 23 19 and 22
24 exp Negative-Pressure Wound Therapy/ or exp Lower Body
P. Fitzgerald, I. Rutks, T.J. Wilt. Negative Pressure/ or negative pressure.mp.
25 19 and 24
26 exp Collagen/ or collagen.mp.
27 19 and 26
28 exp Silver/ or exp Silver Proteins/ or silver.mp.
29 19 and 28
30 exp Oxygen/ or topical oxygen.mp.
31 19 and 30
32 exp Hyperbaric Oxygenation/ or hyperbaric oxygen*.mp.
33 19 and 32
34 electromagnet*.mp. or exp Electromagnetic Phenomena/
35 19 and 34
36 exp Platelet-Derived Growth Factor/ or platelet-derived.mp. or
exp Growth Substances/
37 19 and 36
38 exp Platelet-Rich Plasma/ or platelet-rich.mp.
39 19 and 38
40 exp Intermittent Pneumatic Compression Devices/ or pneumatic
compress*.mp. or compress* therapy.mp. or compress*
pump.mp.
41 19 and 40
42 21 or 23 or 25 or 27 or 29 or 31 or 33 or 35 or 37 or 39 or 41

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 Appendix Figure 1. Summary of evidence search and selection.

MEDLINE and Cochrane

search results (n = 1322)

Excluded during abstract

review (n = 1135)

Full text reviewed

(n = 187) Excluded (n = 147)
Not a randomized, controlled
trial: 85
Published before 1995: 1
Did not involve treatments of
interest: 14
Did not report outcomes of
interest: 47
Full text included
(n = 40)

Hand-search or
reviewer
suggestion (n = 19)

References included in
evidence review (n = 59)

Diabetic ulcers Venous ulcers Arterial ulcers

(n = 36 [35 trials])* (n = 22 [20 trials])* (n = 1 [1 trial])

* One article provided outcomes for both diabetic and venous ulcers.

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 www.annals.org

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Appendix Table 2. Baseline Characteristics: Diabetic Ulcer Studies

Characteristic Collagen Biological BSE PDGF PRP Silver Products NPWT HBOT Ozone–
Dressings Oxygen
Therapy
Studies involving therapy, n 4 2 7 9 2 4 3 5 1
Total patients randomly 489 (52–276) 124 (26–98) 989 (26–281) 990 (9–382) 96 (24–72) 280 (40–134) 418 (10–341) 326 (18–100) 61
assigned (range), n
Mean age (range), y 57 (56–59) (3 trials*) 59 (58–63) 57 (56–63) (5 trials*) 58 (51–61) 57 (1 trial*) 59 (56–60) (3 trials*) 60 (53–67) (3 trials*) 64 (61–71) 63
Mean proportion of men 74 (72–77) (3 trials*) 62 (60–69) 77 (69–86) (5 trials*) 69 (60–100) (8 trials*) 80 (1 trial*) 59 (44–74) (2 trials*) 60 (53–67) 70 (50–81) 62
(range)
Mean proportion of white 63 (63–64) (2 trials*) NR 71 (69–72) (2 trials*) 83 (81–86) (3 trials*) 60 (1 trial*) NR 58 (1 trial*) NR NR
patients (range)
Mean BMI (range), kg/m2 NR 33 (1 trial*) 32 (31–32) (2 trials*) 27 (22–33) (4 trials*) NR NR NR 30 (1 trial*) NR
Mean HbA1c level 8.4 (7.9–8.6) (3 trials*) 8.3 (1 trial*) 8.6 (8.4–8.6) (2 trials*) 8.0 (7.5–8.8) (3 trials*) 7.9 (1 trial*) 8.6 (8.0–10.7) (2 trials*) 8.2 (1 trial*) 8.2 (7.9–8.8) (3 trials*) 8.6
(range), %
Mean ulcer size 3.1 (2.7–4.3) 3.5 (1.9–4.1) 2.6 (1.9–3.0) (6 trials*) 7.3 (2.7–41.5) 5.6 (3.5–9.4) 3.2 (2.2–3.7) (2 trials*) 15.7 (12.3–32.4) (2 trials*) 2.9 (2.6–3.0) (2 trials*) 4.2
(range), cm2
Mean ulcer duration 22.1 (13.0–65.4) NR 56.6 (49.0–93.6) (4 trials*) 45.1 (12.9–78.0) (5 trials*) NR 52.5 (2.1–67.6) (2 trials*) 25.7 (9.9–28.8) (2 trials*) 39.7 (32.5–41.2) (2 trials*) NR
(range), wk
Treatment duration, wk 8–12 12 4–12 8–20 12–20 4–8 3–16 2–8 12

BMI ⫽ body mass index; BSE ⫽ biological skin equivalent; HbA1c ⫽ glycosylated hemoglobin; HBOT ⫽ hyperbaric oxygen therapy; NPWT ⫽ negative pressure wound therapy; NR ⫽ not reported; PDGF ⫽ platelet-derived
growth factor; PRP ⫽ platelet-rich plasma.
* Number of trials reporting variable if less than number of all included studies.

15 October 2013 Annals of Internal Medicine Volume 159 • Number 8

 Appendix Table 3. Strength of Evidence for Advanced Wound Care Therapies: Diabetic Ulcers

Treatment Control Outcome Studies Comments Strength of

(Ulcers*), n Evidence†
Collagen Standard care Percentage of ulcers 4 (483) One trial reported significant improvement Low
healed compared with standard care. Three
trials reported no significant difference
between collagen and standard care.
Trials were rated as fair quality.
Mean time to ulcer One trial found a significant difference Low
healing favoring standard care, whereas 2 found
no difference.
Biological dressings Advanced therapy (PDGF, BSE) Percentage of ulcers 2 (99) Two fair-quality trials showed no Low
healed difference compared with other
advanced wound care therapies.
Mean time to ulcer No trial was significantly different versus Low
healing control.
BSE (Dermagraft‡) Standard care Percentage of ulcers 3 (505) A trend toward statistically significant Low
healed improvement compared with standard
care was found (RR, 1.49 [95% CI,
0.96 to 2.32]; I2 ⫽ 43%). Trials were
rated as fair quality.
Mean time to ulcer Results were inconsistent, with 1 trial Low
healing reporting a significant difference versus
standard care. Trials were rated as fair
quality.
BSE (Apligraf§) Standard care Percentage of ulcers 2 (279) Two fair-quality trials found statistically Moderate
healed significant improvement versus standard
care (RR, 1.58 [CI, 1.20 to 2.08]; I2 ⫽
0%).
Mean time to ulcer One trial reported a significant difference Low
healing between Apligraf and standard care.
BSE (Apligraf) Advanced therapy (skin allografts Percentage of ulcers 1 (29) One fair-quality trial found no significant Low
[Theraskin㛳]) healed difference versus Theraskin.
Mean time to ulcer No significant difference versus Theraskin Low
healing was found.
Platelet-derived Placebo/standard care Percentage of ulcers 7 (685) An overall statistically significant Low
wound healing healed improvement versus placebo was found
(RR, 1.45 [CI, 1.03 to 2.05]), but results
were inconsistent (I2 ⫽ 85%). Overall
study quality was rated as fair.
Mean time to ulcer 5 (731) Overall, PDGF showed shorter Low
healing time to ulcer healing than placebo.
PDGF Advanced therapy (BSE, silver, Percentage of ulcers 3 (189) No significant differences compared with Low
NaCMC) healed an advanced therapy comparator were
found. Trials were rated as fair quality.
Mean time to ulcer No significant differences compared with Low
healing an advanced therapy comparator were
found.
PRP Placebo gel, platelet-poor plasma Percentage of ulcers 2 (96) Neither of the studies (fair to poor quality) Low
healed showed a significant difference between
PRP and its respective control.
Mean time to ulcer A significantly shorter healing time than Low
healing with platelet-poor plasma was found.
There was no significant difference
versus placebo gel.
Silver products Standard care or advanced therapy Percentage of ulcers 4 (280) One trial found silver ointment more Low
(calcium-based dressing, oak healed effective than standard care. Two trials
bark extract, polyherbal cream) found no difference in healing between
a silver cream or dressing and another
advanced care product. Studies were of
fair quality.
Mean time to ulcer 2 (174) Two trials found no difference between Low
healing silver and another advanced wound care
product.
NPWT Standard care (advanced moist Percentage of ulcers 1 (335) One good-quality trial found that 43% of Moderate
wound therapy, saline gauze) healed participants in the NPWT group had
ulcers that healed compared with 29%
in the standard care group (RR, 1.49
[CI, 1.11 to 2.01]).
Mean time to ulcer 3 (432) Results for time to healing were Low
healing inconsistent based on 3 trials of mixed
quality.

Continued on following page

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 Appendix Table 3—Continued

Treatment Control Outcome Studies Comments Strength of

(Ulcers*), n Evidence†
HBOT Sham treatment or standard care Percentage of ulcers 4 (233) Three long-term studies of fair quality Low
healed found significant improvement with
adjunctive HBOT versus sham or
standard care. One short-term study
found no difference.
Mean time to ulcer – This outcome was not reported. Insufficient
healing
HBOT Advanced therapy (extracorporeal Percentage of ulcers 1 (84) One poor-quality trial found that Low
shock wave therapy) healed adjunctive HBOT was less effective than
extracorporeal shock wave therapy.
Mean time to ulcer – This outcome was not reported. Insufficient
healing
Ozone–oxygen Sham treatment Percentage of ulcers 1 (61) One fair-quality trial found no significant Low
therapy healed difference between ozone–oxygen
therapy and sham treatment.
Mean time to ulcer – This outcome was not reported. Insufficient
healing

BSE ⫽ biological skin equivalent; HBOT ⫽ hyperbaric oxygen therapy; NaCMC ⫽ sodium carboxymethylcellulose; NPWT ⫽ negative pressure wound therapy; PDGF ⫽
platelet-derived growth factor; PRP ⫽ platelet-rich plasma; RR ⫽ relative risk.
* Number evaluated for primary outcome of interest.
† Rated as high, which indicates that further research is very unlikely to change the confidence in the estimate of effect (i.e., the evidence reflects the true effect); moderate,
which indicates that further research may change confidence in the estimate of effect and may change the estimate; low, which indicates that further research is very
likely to have an important effect on the confidence in the estimate of effect and is likely to change the estimate (i.e., there is low confidence that the evidence reflects the true
effect); or insufficient, which indicates that the evidence is unavailable or does not permit a conclusion.
‡ Shire Regenerative Medicine, San Diego, California.
§ Organogenesis, Canton, Massachusetts.
㛳 Soluble Systems, Newport News, Virginia.

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 Appendix Figure 2. Meta-analyses of the proportion of diabetic ulcers healed.

Study, Year (Reference) Events/Total, n/N Weight, % Relative Risk Relative Risk
M–H, Random (95% CI) M–H, Random (95% CI)
Treatment Control
BSE (Dermagraft*) vs. standard care

Gentzkow et al, 1996 (16) 6/12 1/13 4.7 6.50 (0.91–46.43)

Marston et al, 2003 (18) 39/130 21/115 42.1 1.64 (1.03–2.62)

Naughton et al, 1997 (17) 42/109 40/126 53.2 1.21 (0.86–1.72)

Subtotal 87/251 62/254 100.0 1.49 (0.96–2.32)

Heterogeneity: tau-square = 0.06; chi-square = 3.53; P = 0.172; I2 = 43%

Test for overall effect: Z = 1.78 (P = 0.075)

BSE (Apligraf†) vs. standard care

Edmonds et al, 2009 (20) 17/33 10/38 19.2 1.96 (1.05–3.66)

Veves et al, 2001 (19) 63/112 36/96 80.8 1.50 (1.11–2.04)

Subtotal 80/145 46/134 100.0 1.58 (1.20–2.08)

Heterogeneity: tau-square = 0.00; chi-square = 0.56; P = 0.45; I2 = 0%

Test for overall effect: Z = 3.26 (P = 0.001)

PDGF vs. standard care

Agrawal et al, 2009 (23) 9/14 3/14 6.7 3.00 (1.02–8.80)

Bhansali et al, 2009 (25) 13/13 11/11 18.5 1.00 (0.86–1.17)

d'Hemecourt et al, 1998 (30) 15/34 15/68 12.4 2.00 (1.11–3.59)

Hardikar et al, 2005 (24) 47/55 31/58 17.3 1.60 (1.23–2.08)

Jaiswal et al, 2010 (27) 15/25 18/25 15.2 0.83 (0.56–1.25)

Steed, 2006 (29) 29/61 14/57 13.3 1.94 (1.14–3.27)

Wieman et al, 1998 (26) 61/123 41/127 16.6 1.54 (1.13–2.09)

Subtotal 189/325 133/360 100.0 1.45 (1.03–2.05)

Heterogeneity: tau-square = 0.16; chi-square = 39.50; P < 0.001; I 2 = 85%

Test for overall effect: Z = 2.11 (P = 0.035)

0.2 0.5 1 2 5
Test for subgroup differences: chi-square = 0.15; P = 0.93; I 2 = 0%
Favors control Favors treatment

BSE ⫽ biological skin equivalent; M–H ⫽ Mantel–Haenszel; PDGF ⫽ platelet-derived growth factor.
* Shire Regenerative Medicine, San Diego, California.
† Organogenesis, Canton, Massachusetts.

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Appendix Table 4. Baseline Characteristics: Venous Ulcer Studies

Characteristic Collagen Biological BSE Keratinocytes PRP Silver Products IPC EMT HBOT
Dressings
Studies involving therapy, n 1 1 3 4 1 6 1 2 1
Total patients randomly 73 120 380 (18–309) 502 (27–225) 86 771 (42–281) 54 63 (19–44) 16
assigned (range), n
Mean age (range), y 73 64 62 (60–69) 66 (63–67) (2 trials*) 71 66 (47–71) 57 68 (66–71) Median, 67
Mean proportion of men 35 42 51 (42–61) 38 (33–39) 42 42 (35–50) (5 trials*) 46 34 (26–38) 50
(range)
Mean proportion of white NR 81 79 (76–94) (2 trials*) 100 (1 trial*) NR 62 (1 trial*) NR NR NR
patients (range)
Mean BMI (range), kg/m2 28 32 30 (1 trial*) 29 (29–30) (2 trials*) NR 30 (1 trial*) 33 NR NR
Mean ulcer size 8.2 11.1 2.5 (1.2–10.7) 9.9 (8.5–10.7) (2 trials*) 4.9 6.0 (3.2–10.5) (3 trials*) 9.9 94 mg (1 trial*) 9.9
(range), cm2
Mean ulcer duration 39.9 NR 119.3 (1 trial*) 102.7 (1 trial*) 12.0 84.4 (39.5–201.1) (3 trials*) 43.8 141.1 (112.7–207.0) NR
(range), wk
Treatment duration, wk 12 12 8–12 8–12 39 4–12 26 4–13 6

BMI ⫽ body mass index; BSE ⫽ biological skin equivalent; EMT ⫽ electromagnetic therapy; HBOT ⫽ hyperbaric oxygen therapy; IPC ⫽ intermittent pneumatic compression; NR ⫽ not reported; PRP ⫽ platelet-rich plasma.
* Number of trials reporting variable if less than number of all included studies.

15 October 2013 Annals of Internal Medicine Volume 159 • Number 8

 Appendix Table 5. Strength of Evidence for Advanced Wound Care Therapies: Venous Ulcers

Treatment Control Outcome Studies Comments Strength of

(Ulcers*), n Evidence†
Collagen Standard care Percentage of ulcers healed 1 (73) One fair-quality trial found no significant differences between treatment groups. Low
Mean time to ulcer healing – This outcome was not reported. Insufficient
Biological dressings Standard care with compression Percentage of ulcers healed 1 (120) One fair-quality trial found biological dressing (OASIS‡) more effective at 12 wk Low
bandage but not 6 mo versus standard care.
Mean time to ulcer healing – This outcome was not reported. Insufficient
BSE (Dermagraft§) Standard care with compression Percentage of ulcers healed 2 (44) Two small trials (fair quality) found that Dermagraft was not more effective Low
bandage than standard care.
Mean time to ulcer healing – This outcome was not reported. Insufficient

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BSE (Apligraf㛳) Standard care with compression Percentage of ulcers healed 1 (275) One large, fair-quality trial found significant improvement with Apligraf versus Low
bandage standard compression therapy.
Mean time to ulcer healing A significant improvement with Apligraf versus standard compression therapy Low
was seen.
Keratinocyte therapy Standard care with compression Percentage of ulcers healed 2 (418) Keratinocyte therapy was more effective than standard care (RR, 1.57 [95% CI, Moderate
bandage 1.16 to 2.11]; I2 ⫽ 0%). The trials were rated fair quality.
Mean time to ulcer healing Results were inconsistent; 1 trial found a significant difference versus standard Low
care, and 1 found no difference between groups.

15 October 2013 Annals of Internal Medicine Volume 159 • Number 8

Keratinocyte therapy Advanced therapy (lyophilized Percentage of ulcers healed 1 (50) One poor-quality trial reported no differences between treatment groups. Low
(cryopreserved) keratinocytes) Mean time to ulcer healing There was no difference between groups. Low
Keratinocyte therapy Advanced therapy (pneumatic Percentage of ulcers healed 1 (27) One fair-quality trial reported no differences between treatment groups. Low
compression) Mean time to ulcer healing – This outcome was not reported. Insufficient
PRP Placebo Percentage of ulcers healed 1 (86) One fair-quality trial reported no differences between treatment groups. Low
Mean time to ulcer healing – This outcome was not reported. Insufficient
Silver dressings Controls (nonsilver dressing, Percentage of ulcers healed 3 (536) Results from 2 fair-quality trials were inconsistent; 1 found a significant Low
ionic silver, lipidocolloid difference versus nonsilver dressing, and 1 found no difference. One
silver) fair-quality trial found no difference between 2 silver dressing groups.
Mean time to ulcer healing 2 (250) Of 2 fair-quality trials, 1 found no significant difference between silver and Low
nonsilver dressings and 1 did not report significance.
Silver cream/ Controls (placebo, nonadherent Percentage of ulcers healed 3 (199) One fair-quality trial found significant benefit compared with standard care; Low
ointment dressing, standard care) 1 fair-quality trial and 1 good-quality trial found no benefit compared with
placebo or standard dressing.
Mean time to ulcer healing – This outcome was not reported. Insufficient
Silver cream Placebo, tripeptide copper Percentage of ulcers healed 1 (86) One fair-quality trial with 3 groups found silver cream to be more effective than Low
cream tripeptide copper cream but not placebo.
Mean time to ulcer healing – This outcome was not reported. Insufficient
IPC Unna boot dressing Percentage of ulcers healed 1 (53) One fair-quality trial found no significant difference between groups. Low
Mean time to ulcer healing – This outcome was not reported. Insufficient
EMT Sham treatment Percentage of ulcers healed 2 (56) Results were inconsistent between trials. Study quality was fair. Low
Mean time to ulcer healing 1 (37) Results were similar between groups. Low
HBOT Sham treatment Percentage of ulcers healed 1 (16) One good-quality trial found no significant difference between groups. Low
Mean time to ulcer healing – This outcome was not reported. Insufficient

BSE ⫽ biological skin equivalent; EMT ⫽ electromagnetic therapy; HBOT ⫽ hyperbaric oxygen therapy; IPC ⫽ intermittent pneumatic compression; PRP ⫽ platelet-rich plasma; RR ⫽ relative risk.
* Number evaluated for primary outcome of interest.
† Rated as high, which indicates that further research is very unlikely to change the confidence in the estimate of effect (i.e., the evidence reflects the true effect); moderate, which indicates that further research may change
confidence in the estimate of effect and may change the estimate; low, which indicates that further research is very likely to have an important effect on the confidence in the estimate of effect and is likely to change the estimate
(i.e., there is low confidence that the evidence reflects the true effect); or insufficient, which indicates that the evidence is unavailable or does not permit a conclusion.
‡ DFB Pharmaceuticals, Fort Worth, Texas.
§ Shire Regenerative Medicine, San Diego, California.
㛳 Organogenesis, Canton, Massachusetts.

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 Appendix Figure 3. Meta-analyses of the proportion of venous ulcers healed.

Study, Year (Reference) Events/Total, n/N Weight, % Relative Risk Relative Risk
Treatment Control M–H, Random (95% CI) M–H, Random (95% CI)

Keratinocytes vs. standard care

Harding et al, 2005 (54) 36/95 26/98 50.6 1.43 (0.94–2.17)

Vanscheidt et al, 2007 (55) 44/116 24/109 49.4 1.72 (1.13–2.63)

Subtotal 80/211 50/207 100.0 1.57 (1.16–2.11)

Heterogeneity: tau-square = 0.00; chi-square = 0.38; P = 0.54; I 2 = 0%

Test for overall effect: Z = 2.96 (P = 0.003)

Silver cream vs. standard care or placebo

Belcaro et al, 2010 (33) 19/44 8/38 38.4 2.05 (1.02–4.14)

Bishop et al, 1992 (57) 6/28 1/29 17.9 6.21 (0.80–48.38)

Blair et al, 1998 (58) 19/30 24/30 43.7 0.79 (0.57–1.10)

Subtotal 44/102 33/97 100.0 1.65 (0.54–5.03)

Heterogeneity: tau-square = 0.71; chi-square = 12.22; P = 0.002; I2 = 84%

Test for overall effect: Z = 0.88 (P = 0.38)

Silver dressings vs. nonsilver dressings

Dimakakos et al, 2009 (59) 17/21 10/21 39.3 1.70 (1.04–2.79)

Michaels et al, 2009 (61, 62) 62/104 59/104 60.7 1.05 (0.83–1.32)

Subtotal 79/125 69/125 100.0 1.27 (0.80–2.01)

Heterogeneity: tau-square = 0.08; chi-square = 2.99; P = 0.084; I 2 = 67%

Test for overall effect: Z = 1.01 (P = 0.31)

0.2 0.5 1 2 5

Test for subgroup differences: chi-square = 0.61; P = 0.74; I2 = 0% Favors control Favors treatment

M–H ⫽ Mantel–Haenszel.

www.annals.org 15 October 2013 Annals of Internal Medicine Volume 159 • Number 8

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