Nancy Greer, PhD; Neal A. Foman, MD, MS; Roderick MacDonald, MS; James Dorrian, MD; Patrick Fitzgerald, MPH; Indulis Rutks, BS; Timothy J. Wilt, MD, MPH
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 Veterans Affairs Health Care System, One Veterans Drive, Mail Code 152, Minneapolis, MN 55417; e-mail, email@example.com.
Current Author Addresses: Drs. Greer and Wilt, Mr. MacDonald, Mr. Fitzgerald, and Mr. Rutks: Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Mail Code 152, Minneapolis, MN 55417.
Drs. Foman and Dorrian: Dermatology Service, Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Mail Code 111K, Minneapolis, MN 55417.
Author Contributions: Conception and design: N. Greer, N.A. Foman, T.J. Wilt.
Analysis and interpretation of the data: N. Greer, N.A. Foman, R. MacDonald, J. Dorrian, P. Fitzgerald, T.J. Wilt.
Drafting of the article: N. Greer, N.A. Foman, R. MacDonald, J. Dorrian, T.J. Wilt.
Critical revision of the article for important intellectual content: N. Greer, N.A. Foman, J. Dorrian, T.J. Wilt.
Final approval of the article: N. Greer, N.A. Foman, R. MacDonald, I. Rutks, T.J. Wilt.
Provision of study materials or patients: I. Rutks.
Statistical expertise: R. MacDonald, T.J. Wilt.
Obtaining of funding: T.J. Wilt.
Administrative, technical, or logistic support: N. Greer, P. Fitzgerald, I. Rutks, T.J. Wilt.
Collection and assembly of data: N. Greer, R. MacDonald, J. Dorrian, P. Fitzgerald, I. Rutks, T.J. Wilt.
Greer N, Foman NA, MacDonald R, Dorrian J, Fitzgerald P, Rutks I, et al. Advanced Wound Care Therapies for Nonhealing Diabetic, Venous, and Arterial Ulcers: A Systematic Review. Ann Intern Med. 2013;159: 532-542. doi: 10.7326/0003-4819-159-8-201310150-00006
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Published: Ann Intern Med. 2013;159(8): 532-542.
Nonhealing ulcers affect patient quality of life and impose a substantial financial burden on the health care system.
To systematically evaluate benefits and harms of advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers.
MEDLINE (1995 to June 2013), the Cochrane Library, and reference lists.
English-language randomized trials reporting ulcer healing or time to complete healing in adults with nonhealing ulcers treated with advanced therapies.
Study characteristics, outcomes, adverse events, study quality, and strength of evidence were extracted by trained researchers and confirmed by the principal investigator.
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 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.
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.
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.
Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.
Appendix Table 1. Search Strategy
Summary of evidence search and selection.
* One article provided outcomes for both diabetic and venous ulcers.
Appendix Table 2. Baseline Characteristics: Diabetic Ulcer Studies
Table 1. ARDs and RRs for Percentages of Healed Ulcers: Diabetic Ulcer Studies
Healed diabetic ulcers.
Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Figure 2 and Appendix Figure 2). 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 healed ulcers (36).
¶ Found extracorporeal shock wave therapy to be more effective than HBOT (40).
Appendix Table 3. Strength of Evidence for Advanced Wound Care Therapies: Diabetic Ulcers
Meta-analyses of the proportion of diabetic ulcers healed.
BSE = biological skin equivalent; M–H = Mantel–Haenszel; PDGF = platelet-derived growth factor.
* Shire Regenerative Medicine, San Diego, California. † Organogenesis, Canton, Massachusetts.
Appendix Table 4. Baseline Characteristics: Venous Ulcer Studies
Healed venous ulcers.
Each dot represents 1 trial. Shaded rows indicate therapies for which meta-analyses were possible (see Appendix Figure 3). BSE = biological skin equivalent; EMT = electromagnetic therapy; HBOT = hyperbaric oxygen therapy; IPC = intermittent pneumatic compression; PRP = platelet-rich plasma.
‡ Found silver cream to be more effective than tripeptide copper cream (57).
Table 2. ARDs and RRs for Percentages of Healed Ulcers: Venous Ulcer Studies
Appendix Table 5. Strength of Evidence for Advanced Wound Care Therapies: Venous Ulcers
Meta-analyses of the proportion of venous ulcers healed.
M–H = Mantel–Haenszel.
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