Nonhealing ulcers (those that are unresponsive to initial. Review

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1 Review Annals of Internal Medicine Advanced Wound Care Therapies for Non 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: Non 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 advanced wound care therapies for non diabetic, venous, and arterial ulcers. Data Sources: MEDLINE (1995 to June 2013), the Cochrane Library, and reference lists. Study Selection: English-language randomized trials reporting ulcer or time to complete in adults with non 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 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 trials (9 therapies) met eligibility criteria. There was moderatestrength evidence for improved 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 with a biological skin equivalent compared with standard care. Overall, strength of evidence was low for ulcer and low or insufficient for time to complete. Limitations: Only studies of products approved by the U.S. Food and Drug Administration were reviewed. Studies were predominantly 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 and reduce time to, although evidence is limited. Primary Funding Source: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. Ann Intern Med. 2013;159: For author affiliations, see end of text. See also: Web-Only Supplement Non ulcers (those that are unresponsive to initial therapy or persist despite appropriate care) affect patient quality of life and productivity and represent a substantial financial burden on the health care system (1 3). More than 6 million persons in the United States are affected, and this number is expected to increase as the population ages and more people develop diabetes (1). Identifying ulcer cause is an important factor in determining appropriate wound care interventions (4). Non ulcers are typically categorized as diabetic, venous, or arterial. Standard treatment for ulcers may include debridement of necrotic tissue, revascularization surgery, infection control, mechanical offloading, management of blood glucose, foot care education, mechanical compression, or limb elevation (4 6). If ulcers do not adequately heal with standard treatment, advanced wound care therapies (therapies used when standard treatments have failed) are considered. 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, controlled trials of the efficacy and harms of advanced wound care therapies compared with either usual care or another advanced therapy for lower-extremity, non, diabetic, venous, and arterial ulcers in adult patients. This report is part of a Department of Veterans Affairs Evidence-based Synthesis Program review, which is available at -care.cfm. METHODS Data Sources and Searches We searched MEDLINE (Ovid interface) for randomized, controlled trials published from 1995 through June 2013 (see the search strategy in Appendix Table 1, available at We limited the search to Englishlanguage studies involving adults aged 18 years or older. We obtained additional references from a search of the Cochrane Library, existing systematic reviews, and reference lists of pertinent studies October 2013 Annals of Internal Medicine Volume 159 Number 8

2 Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers Review Study Selection Investigators and research associates reviewed abstracts identified from the literature search for relevance. We included randomized, controlled studies of adults with non diabetic, venous, or arterial ulcers receiving treatment 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 at study completion or time to complete ulcer. 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 investigator confirmed key characteristic and outcome data. Our primary outcome of interest was the percentage of ulcers at study completion. Additional outcomes of interest included time to complete ulcer, patient global assessment, and return to daily activities. We also assessed pain, ulcer infection, amputation, revascularization surgery, ulcer recurrence, time to ulcer recurrence, hospitalization, all-cause mortality, adverse events, and adverse reactions to treatment. The quality of individual studies was rated as good, fair, or poor using a modification of the Cochrane approach to determining risk of bias (7), which involved evaluation 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 (arterial, 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 I 2 statistic (with cutoffs of 25.0%, 50.0%, and 75.0% for low, moderate, and substantial heterogeneity, respectively) (8). We calculated absolute risk differences (ARDs) with 95% CIs for the primary outcome of ulcers. All other data are narratively summarized. Strength of evidence was determined for the percentage of ulcers and time to complete ulcer. 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. 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 articles. 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 (Appendix Figure 1, available at Most studies compared advanced wound care therapies with standard care or placebo. Direct comparison of one advanced therapy 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 summarizes baseline patient 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 cm 2, although it was greater than 10 cm 2 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 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 remaining trials, 16 had inclusion or exclusion criteria related 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 ulcers at study conclusion are presented in Figure 1 and Table 1. InFigure 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 October 2013 Annals of Internal Medicine Volume 159 Number 8 533

3 Review Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers Figure 1. Healed diabetic ulcers. Versus Standard Care Advanced Therapy Total Patients Randomly Assigned, n Advanced Therapy Superior No Difference Between Groups Strength of Evidence Collagen 489 BSE (Dermagraft*) 576 BSE (Apligraf ) 359 Moderate PDGF 813 PRP 72 Silver cream 66 NPWT 341 Moderate HBOT 240 Ozone oxygen therapy 61 Versus Another Advanced Therapy Advanced Therapy Total Patients Randomly Assigned, n No Difference Between Groups Strength of Evidence Biological dressing 124 BSE (Dermagraft) 26 BSE (Apligraf) 28 PDGF 211 PRP 24 Silver cream 40 Silver dressing 134 HBOT 86 <50 randomly assigned 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 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). A second study of silver cream did not report the proportion of 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 Study design (for example, duration of intervention and time of final outcome assessment) and clinical heterogeneity (for example, ulcer size, duration, and location and comorbid conditions) precluded 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 1; and Appendix Figure 2, available at Although effect sizes were similar for all 3 therapies, the findings were statistically significant for only 2. We found moderate-strength evidence for improved with the biological skin equivalent Apligraf (Organogenesis, Canton, Massachusetts) (2 fair-quality trials; ARD, 21% [95% CI, 9% to 32%]; RR, 1.58 [CI, 1.20 to 2.08]; I 2 0%) (19, 20) and low-strength evidence for improved 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]; I 2 85%) (23 30). The rating of low October 2013 Annals of Internal Medicine Volume 159 Number 8

4 Advanced Therapies for Non 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). -strength evidence suggested no statistically significant effect with the biological skin equivalent Dermagraft (Shire Regenerative Medicine, San Diego, California) (3 fair-quality trials; ARD, 10% [CI, 2% to 18%]; RR, 1.49 [CI, 0.96 to 2.32]; I 2 43%) (16 18). We found moderate-strength evidence of improved with negative pressure wound therapy (1 goodquality trial; ARD, 14% [CI, 4% to 24%]; RR, 1.49 [CI, 1.11 to 2.01]) (37) and low-strength evidence of improved 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 (Reference) Treatment Control Healed Diabetic Ulcers, n/n (%) ARD* (95% CI), % RR* (95% CI) 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 ) 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 ) 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, 2006 (32) PRP Placebo gel ITT: 13/40 (33) PP: 13/19 (68) ITT: 9/32 (28) PP: 9/21 (43) ITT: 4 ( 17 to 26) PP: 26 ( 4 to55) ITT: 1.16 (0.57 to 2.35) 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: 10/40 (25) treatment: 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) (4.22 to ) 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, 2003 (44) HBOT Sham treatment 5/8 (63) 0/8 (0) 63 (27 to 98) (0.71 to ) 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. Organogenesis, Canton, Massachusetts. Soluble Systems, Newport News, Virginia October 2013 Annals of Internal Medicine Volume 159 Number 8 535

5 Review Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers results from multiple trials of the same therapy were mixed (collagen, biological skin equivalent [Dermagraft], plateletderived 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 another (Figure 1 and Table 1), ARDs ranged from 8% to 30%. One poor-quality study found that extracorporeal shock wave therapy statistically significantly improved ulcer compared with hyperbaric oxygen therapy (ARD, 30% [CI, 10% to 49%]) (40). Strength of evidence was low for the effect on the proportion of 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 improvement in time to ulcer for collagen (12, 13), biological dressings (14, 15), or silver products (35, 36) compared 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 factor compared with standard care or another advanced therapy (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 standard care (38, 39). Strength of evidence was low or insufficient for all findings related to time to ulcer (Appendix Table 3). One study of silver versus calcium dressings reported no difference between groups for a global outcome of 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 amputations 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 therapy [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 hospitalization. Overall, few deaths were reported and the results did not show a statistically significant benefit of advanced therapies in reducing all-cause mortality (reported in 16 studies) (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 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 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 cm 2, with mean ulcer sizes of greater than 10 cm 2 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 remaining 8 trials required patients to have adequate arterial circulation or excluded patients with known arterial insufficiency (33, 50, 57 62, 66). Ulcers Healed: Advanced Wound Care Products Versus Standard Care Findings for our primary outcome of interest proportion of ulcers are presented in Figure 2, Table 2, and Appendix Table 5 (available at Meta-analyses (Appendix Figure 3, available at showed an overall benefit of keratinocyte therapy compared with standard care (2 fair-quality trials; ARD, 14% [CI, 5% to 23%]; RR, 1.57 [CI, 1.16 to 2.11]; I 2 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]; I 2 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]; I 2 67%) (59, 61, 62) showed no overall benefit of silver products. In single trials, there was low-strength evidence of improved ulcer 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 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) compared with placebo or standard care (Table 2). Results for electromagnetic therapy were mixed (64, 65). Strength of evidence was low (Appendix Table 5) October 2013 Annals of Internal Medicine Volume 159 Number 8

6 Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers Review Figure 2. Healed venous ulcers. Versus Standard Care Advanced Therapy Total Patients Randomly Assigned, n Advanced Therapy Superior No Difference Between Groups Strength of Evidence Collagen 73 Biological dressing 120 BSE (Dermagraft*) 71 BSE (Apligraf ) 309 Keratinocyte therapy 425 Moderate PRP 86 Silver cream 203 Silver dressing 255 IPC 54 EMT 63 HBOT 16 Versus Another Advanced Therapy Advanced Therapy Total Patients Randomly Assigned, n No Difference Between Groups Strength of Evidence Keratinocyte therapy Silver cream Silver dressing 281 <50 randomly assigned 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 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 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 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 ulcers (ARD, 21% [CI, 6% to 37%]) than a copper-based cream (57). We found no differences in proportion of ulcers between 2 forms of keratinocyte therapy (1 moderate-size, poor-quality trial) (53), keratinocyte therapy compared with pneumatic compression therapy (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). Other Outcomes Few studies reported time to ulcer. One study of the biological skin equivalent Apligraf found shorter time to ulcer 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 compared silver products with other active treatments reported higher global assessment outcomes in the silver groups (57, 60), whereas a study that compared electromagnetic therapy 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 October 2013 Annals of Internal Medicine Volume 159 Number 8 537

7 Review Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers Table 2. ARDs and RRs for Percentages of Healed Ulcers: Venous Ulcer Studies Study, Year (Reference) Vin et al, 2002 (46) Mostow et al, 2005 (47) Falanga et al, 1998 (48) Krishnamoorthy et al, 2003 (50) Omar et al, 2004 (51) Pooled studies (54, 55) Lindgren et al, 1998 (52) Navrátilová et al, 2004 (53) Stacey et al, 2000 (56) Pooled studies (33, 57, 58) Pooled studies (59, 61, 62) Harding et al, 2012 (60) Bishop et al, 1992 (57) Schuler et al, 1996 (63) Ieran et al, 1990 (64) Kenkre et al, 1996 (65) Hammarlund and Sundberg, 1994 (66) Treatment Control Healed Venous Ulcers, n/n (%) ARD* (95% CI), % RR* (95% CI) Treatment Control Collagen (Promogran ) Standard care ITT: 18/37 (49) PP: 15/37 (41) ITT: 12/36 (33) PP: 11/36 (31) ITT: 15 ( 7 to38) PP: 10 ( 12 to 32) ITT: 1.46 (0.83 to 2.58) PP: 1.33 (0.71 to 2.49) Biological dressing Standard care 34/62 (55) 20/58 (34) 20 (3 to 38) 1.59 (1.04 to 2.42) (OASIS ) BSE (Apligraf ) Standard care 92/146 (63) 63/129 (49) 14 (3 to 26) 1.29 (1.04 to 1.60) BSE (Dermagraft ) Standard care 5/13 (38) (12 pieces) 5/13 (38) (4 pieces) 2/13 (15) (12 pieces) 2/13 (15) (4 pieces) 23 ( 10 to 56) (both) 2.50 (0.59 to 10.64) (both) BSE (Dermagraft) Standard care 5/10 (50) 1/8 (12) 38 ( 1 to 76) 4.00 (0.58 to 27.70) Keratinocytes Standard care 80/211 (38) 50/207 (24) 14 (5 to 23) 1.57 (1.16 to 2.11) Keratinocytes (cryopreserved, allogeneic cells) Cryopreserved keratinocytes Compression bandages Lyophilized keratinocytes 2/15 (13) 2/12 (17) 3 ( 31 to 24) 0.80 (0.13 to 4.87) 21/25 (84) 20/25 (80) 4 ( 17 to 25) 1.05 (0.81 to 1.36) PRP Placebo 33/42 (79) 34/44 (77) 1 ( 16 to 19) 1.02 (0.81 to 1.27) Silver cream Standard care or placebo 44/102 (43) 33/97 (34) 9 ( 4 to 23) 1.65 (0.54 to 5.03) Silver dressings Nonsilver 79/125 (63) 69/125 (55) 8 ( 4 to 20) 1.27 (0.80 to 2.01) dressings Silver dressing Silver dressing 24/145 (17) 21/136 (15) 1 ( 7 to 10) 1.07 (0.63 to 1.83) (AQUACEL ) (Urgotul**) Silver cream Tripeptide 6/28 (21) 0/29 (0) 21 (6 to 37) (0.79 to ) cream IPC Unna boot 20/28 (71) 15/25 (60) 11 ( 14 to 37) 1.19 (0.80 to 1.77) dressing EMT Sham treatment 12/18 (67) 6/19 (32) 35 (5 to 65) 2.11 (1.01 to 4.42) EMT Sham treatment 2/10 (20) 2/9 (22) 2 ( 39 to 35) 0.90 (0.16 to 5.13) HBOT Sham treatment 2/8 (25) 0/8 (0) 25 ( 8 to 58) 5.00 (0.28 to 90.18) 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. 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 reporting 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 electromagnetic therapy noted a significant reduction in pain from baseline to 30 days in patients receiving electromagnetic therapy compared with sham treatment (65). However, 9 other studies reported no difference in pain between an advanced therapy and standard care or between 2 advanced therapies. No studies reported amputation, revascularization or other surgery, time to recurrence, or need for home care. Two studies reported hospitalization (47, 54) and 1 reported quality of life (61, 62) and found no difference between advanced therapy and standard care. No significant 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 October 2013 Annals of Internal Medicine Volume 159 Number 8

8 Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers Review 75% were men. Mean ulcer size was 4.8 cm 2 ; ulcer duration was not reported. There were significant differences in ulcer (ARD, 46% [CI, 12% to 80%]) and time to, 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 revascularization surgery. Other outcomes did not differ significantly compared with standard care. DISCUSSION We found moderate-strength evidence for improved compared with standard care in patients with diabetic ulcers treated with the biological skin equivalent Apligraf or negative pressure wound therapy. There was also moderate-strength evidence for improved in patients with venous ulcers treated with keratinocyte therapy compared with standard care. Strength of evidence was low for all treatment comparisons reporting time to ulcer, 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 demographic, 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 methodological 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 evaluated in only a few studies, often in highly selected populations 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 generalizable to broader clinical settings. The quality of the individual studies reviewed was predominantly fair or poor. Common factors limiting study quality were inadequate allocation concealment, lack of blinding (including blinding of outcome assessment), failure to use intention-to-treat analysis methods, and failure to adequately describe study dropouts and withdrawals. Most studies compared advanced therapies with standard care or placebo; little comparative effectiveness research has evaluated one advanced therapy against another. Despite the clinical importance of arterial ulcers, we identified only 1 study of an advanced therapy (which was compared with standard care) for this type of ulcer. Patients with arterial disease may have been included in the studies of diabetic ulcers or venous ulcers (that is, mixed cause). Our literature search identified recent systematic reviews on many of the advanced therapies included in our review. Although we were able to use these reviews to identify references our search may have missed, direct comparisons of the findings from existing reviews and those from our review are difficult. Many of the reviews included studies of ulcers that were not diabetic, venous, or arterial; many allowed studies with any outcome that reflected (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 standard 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 situation. 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 protocol through strict inclusion and exclusion criteria. The broader applicability to patients seen in many clinical settings is not clear (68, 69). Results from our included studies 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 sponsor 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. Although we attempted 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 was maintained (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, vascular, pressure, trauma, or surgery) if they did not report results by cause. We also excluded studies if they did not report wounds or time to complete. 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 replicate 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

9 Review Advanced Therapies for Non Diabetic, Venous, and Arterial Ulcers should be followed for sufficient time to assess whether 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 expensive. They may be cost-effective or even cost-saving in appropriate 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 non ulcers who were randomly assigned to standard care had complete wound with this approach over study durations of 4 to 12 weeks. These findings suggest that a more rigorous standard care approach than might occur in clinical practice may be beneficial in many patients. We conclude, on the basis of our findings from published randomized, controlled trials, that in highly controlled settings, advanced wound care therapies may improve the proportion of diabetic and venous ulcers compared with standard care in adults with non ulcers. A few therapies may reduce the time to ulcer, but evidence is limited. Limitations in the quality of evidence and the number of studies directly comparing different advanced therapies decrease the strength and generalizability 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 M Requests for Single Reprints: Nancy Greer, PhD, Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Mail Code 152, Minneapolis, MN 55417; , nancy.greer@va.gov. Current author addresses and author contributions are available at References 1. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, et al. Human skin wounds: a major and snowballing threat to public health and the economy [Editorial]. Wound Repair Regen. 2009;17: [PMID: ] 2. Jones KR, Fennie K, Lenihan A. Evidence-based management of chronic wounds. Adv Skin Wound Care. 2007;20: [PMID: ] 3. Spentzouris G, Labropoulos N. The evaluation of lower-extremity ulcers. 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