REVIEWER COMMENTRESPONSE
1. Are the objectives, scope, and methods for this review clearly described?
Yes
Yes
Yes
Yes
Yes
Yes. This report represents a monumental work effort. It is, in my judgment, the most comprehensive and objective review I have seen to date. The persons who prepared this report are to be commended for their efforts.Thank you.
2. Is there any indication of bias in our synthesis of the evidence?
Not sure that like was compared to like. I would worry about your RCT grading system if RCTs used for FDA approval (PDGF and synthetic skin) are graded lower than a NPWT study that was not really blinded. I also worry at all of your studies did not treat similar groups of individuals. For example, the HBO RCTs were very inconsistent with respect to the Wagner grade.We assigned grades based on established criteria for evaluating risk of bias in RCTs. These criteria may be different than criteria for FDA approval.

We agree that the populations varied from study to study and attempted to clarify that in the description of the studies.
No
No
No (reviewer provided citation for Lancet article [2012] on spray-applied cell therapy)Thank you. We reviewed this citation. The treatment is not FDA approved (this was a phase 2 trial) and therefore is not eligible for inclusion in our review.
No
No
3. Are there any published or unpublished studies that we may have overlooked?
Yes – total contact cast literatureWe did not consider total contact casting to be an “advanced wound care product.” Although it may be an important therapeutic option, it was not recommended by our topic stakeholders and is outside the scope of our review.
No
No
Yes
Considering collagen dressings as a stand-alone category presents challenges as they are frequently used as deliver vehicles for silver, growth factors, protease inhibitors, etc. This should be acknowledged as a limitation. As such there may be other studies to be considered for inclusion under collagen [1-5]; apligraf [6]; and silver.[2]
  1. Blume, P., et al., Formulated collagen gel accelerates healing rate immediately after application in patients with diabetic neuropathic foot ulcers. Wound Repair & Regeneration, 2011. 19(3): p. 302-8.
  2. Gottrup, F., et al., Collagen/ORC/silver treatment of diabetic foot ulcers; A randomised controlled trial. Wound Repair and Regeneration, 2011. 19(2): p. A24.
  3. Letendre, S., et al., Pilot trial of biovance collagen-based wound covering for diabetic ulcers. Advances in Skin & Wound Care, 2009. 22(4): p. 161-6.
  4. Motzkau, M., et al., Expression of matrix-metalloproteases in the fluid of chronic diabetic foot wounds treated with a protease absorbent dressing. Experimental & Clinical Endocrinology & Diabetes, 2011. 119(5): p. 286-90.
  5. Mulder, G., et al., Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial. Wound Repair & Regeneration, 2009. 17(6): p. 772-9.
  6. Sams, H.H., J. Chen, and L.E. King, Graftskin treatment of difficult to heal diabetic foot ulcers: one center's experience. Dermatologic Surgery, 2002. 28(8): p. 698-703
We have clarified that the studies included in the collagen section are studies of an inert collagen matrix product.
We have reviewed the suggested references:
  1. This trial has been added.
  2. An abstract – not eligible for inclusion (we were unable to find the data in a peer-reviewed publication)
  3. A case series – not eligible for inclusion
  4. This study has been mentioned in the collagen section but due to a difference in the goal of the study and incomplete reporting is not given as much attention as other trials
  5. A “cohort study – not eligible for inclusion
  6. This report presents data from one site of a multisite trial that is included in the report (Veves 2001)
No. To the best of my knowledge, this report appears to have reviewed all of the pertinent information relevant to the topics studied.Thank you
4. Please write any additional suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.
I am concerned that the device assessments were not as rigorous as the FDA approved products. Care needs to be made in recommendations. Also you did assess that HBO was inferior to shockwave and therapy that was later shown in the US to not be superior to standard off-loading of diabetic feet.We identified and discussed one HBO trial conducted in Taiwan that directly compared HBO to shockwave therapy. We did not identify any trials meeting our inclusion criteria that directly compared shockwave therapy to standard off-loading of diabetic feet. We have added a paragraph with results from strictly controlled off-loading studies for comparison purposes.
Please see my comments within the body of the paper. (Investigator NOTE: comments from body of paper have been added to list below) The first 18 pages of the document need major revisions. After page 18, the material is written in more scientific manner which it appears more accurate than what is presented on the first initial pages.
  1. Page 1 Please define what you mean by diabetic ulcers. Arterial and venous ulcers can also happen in diabetic patients. How about neuropathic ulcers? Were they studied or reported in this paper?
  2. Page 1 Is your paper focused only on foot ulcers? Most venous ulcers occur in the legs. When studying the effectiveness of a device, please be more specific on location of the ulcers where the product was used.
  3. Page 1 How about the impact of PVD and plantar pressures? I can heal a wound that is neuropathic or has infection as long as there is blood flow to the tissue!!!!
  4. Page 1 I am not sure the statement “venous disease accounts for the majority of chronic ulcers” is correct. Venous ulcers is seen mostly on non-American populations, but current research shows occurrence of PAD related ulcers in US population
  5. Page 1 Please define what you mean by diabetic ulcers? Are these patients who are diabetic with normal arterial, venous and nerve supplies? How are these patient populations different than those who have “arterial” ulcers or “venous ulcers?
  6. Page 3. Is this study shared with Dr. Robbins, our VA Central Office Chief of Podiatry? He needs to be informed on this study as this study can impact the podiatry field at the VA tremendously. His input on who should review this paper is important.
  7. Page 3 – overview of sizes of ulcers – Where are these ulcers? On the leg/shin area? Dorsal foot? Plantar foot? Each location will respond differently to different wound care product)
  8. Page 3 – KQ1 (diabetic ulcers) – Did all the subject studied for this question have normal blood flow and sensate feet?
  9. Page 4 – Collagen – Were there any beneficial effect in using collagen? Are you then telling the reader that using collagen on wounds is a waste of money? Is there any wound type that collagen can be helpful, i.e., draining wound? As a reader, I get the conclusion that I will be wasting my money and time if I used collagen. Is that what you want your readers to get out of this paragraph?
  10. Page 4 – Biological Dressings – Did all the subjects have normal blood flow? Please define what you mean by biological dressing. Are these different than biological skin equivalents?
  11. Page 4 – Biological Skin Equivalents – a) I am not sure what you mean metabolically active dermagraft. As a practitioner who uses dermagraft, I have never heard of this terminology. b) It is helpful to include how many (in average) dermagraft or apligraf application took in order to heal the wounds, as there is always the cost of care than can also impact treatment regimen used. Also in the past we were told that one application of apligraf was enough to get the wound to heal but now they are recommending weekly applications. The same goes for dermagraft. When dermagraft first hit the market, we could only use it up to 3 applications and now it is up to 7 applications. It is important to include how many graft applications these studies used in order to get the reported results.
  12. Page 5 – Platelet-rich Plasma – Please add how many applications of PRP it took to get the wound to heal? Was it daily, weekly, monthly application?
  13. Page 5 – Silver Products – Please be more specific as to exact type of silver products used. The silver ointment used for many years is silvadene cream which is cheaper than most other wound products. Now we have so many silver dressings with nano and micro size silver in it and each product is different based on its technology! So not all silver products are the same. The paragraph above can be very misleading, does not have any scientific value to it as it does not specify which specific silver technology you are referring to.
  14. Page 5 – NPWT – Please be more specific. How much better improvement? 50%?, 60%, 70% better? Was it significantly or marginally better? How about time to gain complete healing? Or was this study based on wound reduction size only. Page 6-7 – KQ1 summary a) under Secondary Outcomes – were these ulcers “diabetic ulcers” or “arterial” ulcers? b) The above summary does not cover the answer to all of the questions specifically “Is efficacy dependent on ancillary therapies?” – not clearly covered for each individual treatment regimen and “Does efficacy differ according to patient demographics, comorbid conditions, treatment compliance, or activity level?” – not clearly covered for each individual treatment regimen
  15. Page 7 - Biological Skin Equivalents – The comments above contradict the FDA reported studies. Apligraf was initially approved by the FDA in 1998 for use in venous ulcers. Later, its indication expended to include arterial/diabetic ulcers in 2000. So is FDA wrong?
  16. Page 8 – Silver Products – please be specific on type of silver dressing used
  17. Page 8 – Intermittent Pneumatic Compression Therapy – How about time to healing? Did the IPC reduce the time to healing? How about ulcer recurrence rate?
  18. Page 10 – KQ3 – How come this is different than the answers to other questions above? Are not there device/product-specific studies for arterial ulcers? How about use of collagen? skin substitutes i.e., apligraf? How about HBO therapy? PRP? This section is too brief and does not do the justice to treatment of Arterial ulcers which are the most common ulcers seen in our practices.
  19. Page 10 Discussion – In your discussion, please focus on positive findings. The studies may be of poor or moderate quality as such studies are often difficult to do. Please remember (and emphasize in your paper) that there are many reasons and factors affecting the occurrence of a wound, the needed treatment and the effectiveness of therapy. Each wound is different as it is the patient who owns the wound! That is not what was concluded previously in the previous pages!!
  20. Page 10 – “No treatment produced greater healing when compared to another advanced therapy.” This statement is inaccurate! I do not believe that many of the studies (except a handful) compared one advanced therapy against another!
  21. Page 11 Paragraph beginning with “The findings for venous ulcers .. silver products (that is not what was concluded previously in the previous pages!! ), electromagnetic therapy (this contradicts what was concluded previously in the previous pages!!), significantly better healing (really? How come this was not noted in the sections above?)
  22. Page 11 Paragraph beginning with “We identified only one study of … “ Were these ulcers revascularized before use of apligraf or were they all ischemic wounds???
  23. w. Main Report – Venous Leg Ulcer Description (70-90% of leg ulcers) – NOT foot ulcers! Location makes a huge difference on the etiology of the ulcer!
  24. Main Report – Arterial Leg Ulcer Description (6-10% of lower extremity ulcers) - Do these include ulcers in the foot? Or is it all in the leg. Please note, there is an anatomical difference when you talk about lower extremity, leg, or foot. Having said that you cannot combine the wound healing rate and success (or failure of) for all of these regions as each region heals differently?
  25. Main Report – Topical Oxygen Therapy Description – Is this even discussed in the above reported studies?
The first 18 pages of the document are the executive summary and we attempted to condense a great deal of information into a more readable format. As the reviewer has noted, there are many important details about the studies and we have attempted to include the essential elements in the executive summary without simply repeating the full text of the report.
  1. The studies included in the section on diabetic ulcers are studies of populations described by the study authors as having diabetic ulcers. Diabetic ulcers are caused by peripheral neuropathy and/or peripheral vascular disease. The most common cause of neuropathic ulcers is diabetes and many of these studies included only patients with neuropathic ulcers. Most studies excluded patients with inadequate circulation. We have added that information to the report when it was provided by the study authors.
  2. The paper is not focused on foot ulcers. We have added the location of the ulcers (an overview in the executive summary and more information in the body of the report).
  3. As noted in the overview of studies for KQ1, only one trial enrolled patients with strictly ischemic diabetic ulcers; in 27 of 35 trials, the ulcers were either neuropathic or patients with vascular disease were excluded.
  4. This statement is correct. In the US, venous disease is responsible for 72% of leg ulcers, mixed venous and arterial disease for 22%, and pure arterial disease for about 6%.References have been added.
  5. As noted in item “a” above, we categorized studies based on the study authors' descriptions of their included populations. We have added an overview of the studies which shows that, in most cases, studies of patients with diabetic ulcers excluded patients with inadequate blood flow. We recognize that patients with diabetes who are judged to have “adequate circulation” via clinical examination including pulses and blood pressure assessment may have microvascular arterial insufficiency. Nonetheless, we have categorized patients according to authors' definitions and included descriptions of the individual studies.
  6. Dr. Robbins was a member of the Technical Expert Panel for the report, provided input on the key questions, scope of review, study inclusion criteria and outcomes of interest (including categorization of populations and interventions) and has reviewed the report.
  7. We have added location to the overview of the studies. We also added this information to the results section in the full report and in the executive summary if there appeared to be differences in outcomes based on ulcer location.
  8. We have added this information to the overview of the studies.
  9. One study of collagen as a matrix material found a benefit for ulcer healing. We have clarified that other treatments may use collagen as a vehicle for delivery of the active substance (e.g., silver).
  10. One study excluded patients with severe arterial disease and the other included only patients with adequate circulation. We have defined biological dressings as acellular matrices with a biologically active component. We have defined biological skin equivalents as tissue constructs designed to resemble layers of human skin.
  11. The finding about metabolically active dermagraft was from an early trial (Naughton 1997). They found that some samples had lower metabolic activity (non-therapeutic range) and suggest that, as a result, the manufacturing process was modified to ensure that all samples have an appropriate therapeutic level. We have clarified this. We have also added information about the number of applications to the full report
  12. We have added this information to the executive summary and the report.
  13. This information was in the main report and has now been clarified in the executive summary.
  14. We have added the absolute risk difference for NPWT and the other treatments.
  15. We found significant improvement in percentage of ulcers healed with Apligraf for both diabetic and venous ulcers. We did not review FDA reasoning behind their approval process (which may have included studies and data not available or eligible for this report) and make no statement regarding their approval.
  16. We have added this information.
  17. The IPC trial did not report time to healing or ulcer recurrence.
  18. We agree that arterial ulcers and treatment for these are important. However, we identified only one trial specifically focused on arterial ulcers. We noted in the text that some of the patients in the diabetic ulcer studies may have had microvascular disease despite the fact that most studies excluded patients with macrovascular disease. Similarly, patients may have had mixed venous and arterial disease. This is an important area requiring future research.
  19. We have reported the findings from our review of RCTs. We highlight findings (both positive and negative) where data support strong evidence to affect practice and policy. We agree that it is important to highlight positive findings if there is at least moderate certainty of benefit. However, it is also important to note areas where treatments are not effective or there is insufficient evidence, so that clinicians and patients can avoid use of treatments of low value/low effectiveness. We recognize that all patients have unique clinical circumstances-this is not unique to patients with chronic wound care needs. As with any condition, intervention, and outcome we summarize the findings from the available evidence, rate the quality of individual studies, determine strength of evidence, and make comments about the broader applicability to patients typically seen. Based on this evidence clinicians can make judgments regarding extrapolation to individual patients though we suggest that our findings can serve as the foundation for implementation.
  20. We have clarified that far fewer of the studies eligible for our review included an advanced therapy comparator.
  21. We have clarified this section. Overall the findings were mixed for each product group but there were some individual trials with positive results.
  22. We have clarified that the patients had undergone revascularization.
  23. We have clarified ulcer location for studies cited throughout the report.
  24. The literature typically refers to arterial ulcers as a group in the lower extremity. It does not tease out foot vs. leg. We agree that there are different factors involved in healing of the foot vs. the leg. We have clarified ulcer location for studies cited throughout the report.
  25. The topic nominators requested that we include topical oxygen but no studies met our inclusion criteria. We have noted that in the report.
The report and tables are comprehensive but limitations to the methodology are not highlighted in test. For example, recurrence of ulceration (or amputation) are usually lacking. Additionally, whether or not compliance with standard wound healing practices,(debridement, off-loading) is equally allocated between treatment and control groups is not highlighted.We reported recurrence and amputation if reported by the study authors.
We have added comments about compliance. Most studies indicated that off loading etc. was part of the treatment protocol but few reported compliance measures (for treatment or control groups).
  1. As expected the results of the synthesis confirms the paucity of high level evidence to support the products used every day. The recommendations for criteria for future research are appreciated and will require that publications from this review be developed to get that word out.
  2. Although the draft does speak somewhat to the limitations of the study I would recommend that it be highlighted and more specific to include important outcomes such as quality of life, recurrence, and prevention of amputations.
  1. Thank you
  2. We have added more specific information to the limitations and future research sections.
  1. None of the citations described on page 77 have accompanying references.
  2. In paragraph 3 of the discussion on page 77, greater emphasis should be placed the importance of offloading and adherence for DFU healing. The largest effect sizes for DFU healing in the literature are in offloading [1-3] causing leaders to suggest changes to the methodology for DFU trials.[4] This limitation should also be described on page 26 in the quality assessment section. Greater emphasis should also be placed on the importance of compression with VLU trials.[5]
  3. The limitations and recommendations section do not adequately convey the magnitude of the problem associated with current industry sponsored trials' DFU inclusion/exclusion criteria. For example, ischemia and infection are either excluded or causes for censoring in DFU trials despite being highly prevalent conditions in clinical practice. For example, large cohort studies suggested a prevalence of clinically infected DFU's in 58-61% of patients [6, 7]; with up to 49% having peripheral arterial disease.[7] Fife also reports other populations that are excluded, including diabetes and significant comorbidities such as renal failure, ischemia, sickle cell, tobacco abuse, and steroid dependency [8] that are frequently encountered in practice.
  4. In the executive summary, please provide point estimates for effect sizes in the silver, NPWT, and HBOT paragraphs on page 5.
  1. The reference list is now complete.
  2. We have added information about off-loading for DFU healing and compression for VLU (including the suggested references). Thank you for the reference suggestions.
  3. We have added to these sections. Thank you for the reference suggestions.
  4. We have added absolute risk reduction data to the executive summary.
  1. Armstrong, D.G., et al., Evaluation of Removable and Irremovable Cast Walkers in the Healing of Diabetic Foot Wounds: a Randomized Controlled Trial. Diabetes Care, 2005. 28(3): p. 551-4.
  2. Armstrong, D.G., et al., Off-loading the diabetic foot wound: a randomized clinical trial. Diabetes Care, 2001. 24(6): p. 1019-22.
  3. Katz, I.A., et al., A randomized trial of two irremovable off-loading devices in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care, 2005. 28(3): p. 555-9.
  4. Boulton, A.J. and D.G. Armstrong, Trials in neuropathic diabetic foot ulceration: time for a paradigm shift? Diabetes Care, 2003. 26(9): p. 2689-90.
  5. Mustoe, T.A., K. O'Shaughnessy, and O. Kloeters, Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast Reconstr Surg, 2006. 117(7 Suppl): p. 35S-41S.
  6. Lavery, L.A., et al., Validation of the Infectious Diseases Society of America's diabetic foot infection classification system. Clin Infect Dis, 2007. 44(4): p. 562-5.
  7. Prompers, L., et al., High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia, 2007. 50(1): p. 18-25.
  8. Fife, C., Wound Care in the 21st Century. US Surgery, 2007: p. 63-64.
I personally found the information related to biological skin equivalents to be most interesting. These treatment adjuncts are VERY expensive and it would appear from the report that they offer only modest benefit in wound healing compared to standard therapy and no significant improvement in shortening the time for ulcer healing. My “take home” message here was that these products should be used very judiciously, if at all.Thank you.
5. Are there any clinical performance measures, programs, quality improvement measures, patient care services, or conferences that will be directly affected by this report? If so, please provide detail.Thank you – we will share these suggestions with the people responsible for dissemination of the report.
Yes. The wound clinics, podiatry sections, and possibly plastic surgery and general surgery sections if they deal with lower extremity wound care.
Will likely impact criteria for use
Yes, as stated above this synthesis will help us develop a guideline for the appropriate use of these expensive products using a combination of common sense and the evidence found in this study. We will have to resist the temptation to ban the use of products altogether but rather to place limits on how and where they are used. We must preserve the clinician's right to practice the art of medicine while recognizing we cannot continue to waste dollars on therapies that do not work. One telling point was that despite healing a wound faster or more completely there was no difference in all-cause mortality. This speaks to the need to develop algorithms that are interdisciplinary and address the systemic diseases as well as the wound.
This report has implications for National VA programs such as PACT and NSQIP. Results should be disseminated and presented at the VA's Annual Desert Foot Conference and HSR&D meeting. National presentations should also be considered at ADA and SAWC. The National PACT program may choose to study current use of advanced modality care in each strata using wound healing camseras to measure wound healing rates and appropriate use criteria and their effect on patient outcome in a pre & post-design.
I would hope that the use of collagen products, biological dressings and platelet rich plasma would, for the most part, cease in most clinics treating the wounds described in the studies. On the other hand, the values of negative pressure wound therapy and hyperbaric oxygen in helping with wound healing in selected cases supports my own clinical experience in this area.
6. Please provide any recommendations on how this report can be revised to more directly address or assist implementation needs.
I worry that efficacy assessments do not always translate to general care of the VAWe appreciate this concern and have added the following statement to the discussion: “Our review assessed results from randomized controlled trials in selected populations and controlled settings. It is not well known how outcomes reported in these studies will translate to findings in daily practice settings including in Veterans Health Administration facilities. Patients were likely more compliant than typical patients and received very close monitoring. Therefore, results from these may overestimate benefits and underestimate harms in nonstudy populations.”
You need to notify Dr. Jeff Robbins, the Chief of Podiatry at the VA central office about this report. He has a list of whom are most expert in the field within the VA.
As there is a number of factors in treating wounds, the paper must emphasize the difficulty in performing studies and coming up with a conclusion on what is best for healing chronic wounds. The factors affecting doing a solid, strong study include but not limited to: the type of the wound, the host barriers, the host's associated comorbidities, the host's associated level of nutritional status, compliance with treatment, location of the ulcers (plantar vs. dorsal), degree of blood flow (not all small vessel disease act the same!), the host's medications, …
We thank the reviewer for these comments. Dr. Robbins is involved with this project.
  1. This is a long report and while the tables and appendices are important they should probably come at the end and be referenced in the body of the document.
  2. We could release the executive summary widely and reference the full document. I am concerned that the field clinicians will not read a 178 page document.
  3. In addition I am interested in helping in the production of some publications based on these findings to share with the scientific community.
1 and 2) We recognize the length of the report. We believe the information included is needed to provide the “interested reader” the full body of evidence we considered. We agree clinicians and policy makers are unlikely to read the whole document. We have tried to highlight the main findings in the executive summary and are willing to conduct other dissemination activities including Cyberseminars, Management Briefs etc. to further convey the main messages to a wide audience. 3) We are considering derivative manuscripts from this report.
There is a growing chasm between operations and research. Those who conduct systematic reviews or meta-analyses frequently are not PI's conducting the studies or actively engaged in patient care.[1] A careful compilation of improvement opportunities for study designs should be created for both funding agencies (including industry) and PI's. These should also be disseminated to NIH and VA program officers.
  1. Gottrup, F., Controversies in performing a randomized control trial and a systemic review. Wound Repair Regen, 2012. 20(4): p. 447-8.
We have cited several documents detailing recommendations for future research.
The report is extremely well done and readable as it stands. I have no recommendations for improvement.Thank you.

From: APPENDIX C, PEER REVIEW COMMENTS/AUTHOR RESPONSES

Cover of Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review
Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review [Internet].
Greer N, Foman N, Dorrian J, et al.
Washington (DC): Department of Veterans Affairs (US); 2012 Nov.

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.