Chronic venous leg ulcer treatment: Future research needs Gerald Lazarus, MD1; M. Fran Valle, DNP, MS2; Mahmoud Malas, MD, MHS1; Umair Qazi, MD, MPH1; Nisa M. Maruthur, MD, MHS1,3,4; David Doggett, PhD1; Oluwakemi A. Fawole, MBCHB, MPH1; Eric B. Bass, MD, MPH1; Jonathan Zenilman, MD1 1. Departments of Dermatology, Medicine and Surgery, School of Medicine, Johns Hopkins University, Queenstown, 2. School of Nursing, University of Maryland, 3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and 4. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland [Correction added after online publication: 06-November-2013: Affiliation 2 has been updated.]
Reprint requests: Dr. G. Lazarus, MD, Department of Dermatology, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Baltimore, MD 21224, USA. Tel: +410-490-0813; Fax: +410-550-7301; Email: [email protected] Manuscript received: July 19, 2013 Accepted in final form: July 31, 2013 DOI:10.1111/wrr.12102
ABSTRACT The prevalence and costs of chronic venous ulcer care in the US are increasing. The Johns Hopkins University Evidence-Based Practice Center recently completed a systematic review of the comparative effectiveness of advanced wound dressings, antibiotics, and surgical management of chronic venous ulcers. Of 10,066 citations identified in the literature search, only 66 (0.06%) met our liberal inclusion criteria for providing evidence on the effectiveness of interventions for chronic venous ulcers. Based on review of those studies, members of our team and a panel of informed stakeholders identified important research gaps and methodological deficiencies and prioritized specific future research needs. Based on that review, we provide the results of our assessment of future research needs for chronic venous ulcer care. Advanced wound dressings were considered to have the highest priority for future research, followed by venous surgery and antibiotics. An imperative from our assessment is that future research evaluating interventions for chronic venous ulcers meet quality standards. In a time of increasing cost pressure, the wound care community needs to develop high-quality evidence to justify the use of present and future therapeutic modalities.
INTRODUCTION Cutaneous ulcers are a major cause of morbidity and mortality throughout the world. Direct costs for ulcer care are approximately 25 billion dollars per year in the US.1 Leg ulcers can have multiple causes including diabetes mellitus, peripheral neuropathy, immobility and pressure, atherosclerosis, infections, rheumatologic diseases, and venous dysfunction. Chronic venous leg ulcers (CVLUs) affect between 500,000 and 2 million persons annually in the USA and account for over 50% of leg ulcers.2–4 Their prevalence will almost certainly increase as the population ages and risk factors such as obesity and congestive heart failure become more prevalent.5,6 The current standard approach to therapy for CVLUs includes aggressive compression of the lower limbs and debridement, which heals 50–60% of venous leg ulcers.7 Widely used additional interventions include wound dressings with active components (defined here as “advanced wound dressings”), local or systemic antimicrobials, and venous surgery.4 In practice, venous ulcers are cared for by a wide variety of practitioners including internists, family practitioners, surgeons, podiatrists, certified wound nurses, and physical therapists in different settings using many different interventions. The public health burden of venous ulcers and rapidly increasing costs of venous ulcers, and their complications have necessitated analysis of the evidence on the effectiveness of therapy for these disabling lesions. Recently, the Center for Medical Technology and Policy authored an Effectiveness Guidance Document analyzing therapeutic interventions for chronic wounds.8 This excellent Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
review attempted to evaluate interventions for all types of cutaneous ulcers. The Johns Hopkins University EvidenceBased Practice Center (EPC) recently performed a systematic review focusing on the effectiveness and safety of advanced wound dressings, systemic antibiotics, and surgical interventions compared with one another or with compression systems (as the standard of care) for treatment of CVLUs.9 To quantify and simplify the subject, we focused our analysis on active CVLUs, defined as stationary or enlarging lesions present for 6 weeks or more, with evidence of earlier stages of venous disease such as varicose veins, edema, pigmentation, and venous eczema but without active infection. Clinical diagnosis was frequently confirmed by functional assessment of the venous system, most commonly by venous duplex ultrasound. By using strict diagnostic criteria, one can carefully select patients that have the least medically confounded type of cutaneous leg ulcer. The purpose of the present article is to present the recommendations of a panel of stakeholders on future research needs for treatment of CVLUs10 based on our systematic review published elsewhere9 and Valle MF, Maruthur NM, Wilson LM, Malas M, Qazi U, Haberl E, et al., unpublished data. Results of systematic review of therapeutic interventions for venous ulcer care
Our review9 used a series of predefined key questions (Table 1) using the analytical framework shown in Figure 1; 1
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Table 1. Key questions, findings, and strength of evidence in the systematic review of the comparative effectiveness of treatments for chronic venous leg ulcers
Key question KQ 1. For patients with chronic venous leg ulcers, what are the benefits and harms of using dressings that regulate wound moisture with or without active chemical, enzymatic, biologic, or antimicrobial components in conjunction with compression systems when compared with using solely compression systems?
Finding
Hydrocolloid dressings were not more effective than compression therapy alone in healing chronic venous ulcers. Human skin equivalent dressings, containing living human cells, produced more rapid wound healing than compression therapy alone. Cadexomer iodine dressings produced modest improvements in wound healing rates and wound area compared with nonantimicrobial dressings. Silver dressings did not improve wound healing compared with nonsilver dressings. For all other types of dressings, the evidence was insufficient to support a conclusion. KQ 2a. For patients with chronic venous leg ulcers Only one study addressed this question, and it provided that do not have clinical signs of cellulitis and are insufficient evidence to determine the benefits and harms of being treated with compression systems, what are systemic antibiotics compared with compression therapy alone. the benefits and harms of using systemic antibiotics when compared with using solely compression systems? KQ 2b. For patients with chronic venous leg ulcers No studies addressed this question. that do not have clinical signs of cellulitis and are being treated with dressings that regulate wound moisture with or without active chemical, enzymatic, biologic, or antimicrobial components, what are the benefits and harms of using systemic antibiotics when compared with using dressings alone? KQ 3a. For patients with chronic venous leg ulcers, Surgical procedures targeting superficial vein reflux produced what are the benefits and harms of surgical similar rates of wound healing compared with compression procedures aimed at the underlying venous therapy alone but had lower ulcer recurrence rates at 3 years. abnormalities when compared with using solely Selected surgical procedures targeting perforator vein reflux compression systems? produced similar rates of wound healing compared with compression therapy alone. One of these procedures (Conservative Hemodynamic treatment of Insufficiency of the Venous system in an Ambulatory setting [CHIVA]) had a lower ulcer recurrence rate. The evidence was insufficient regarding the benefits and harms of sclerotherapy, vein stripping, radiofrequency ablation, or endovenous laser therapy for superficial vein reflux, or surgery for deep vein disease. KQ 3b. For patients with chronic venous leg ulcers, The evidence was insufficient to answer this question because of what are the comparative benefits and harms of the small number, small size, and poor quality of studies. different surgical procedures for a given type of venous reflux and obstruction?
Strength of evidence* Low Moderate
Moderate
Moderate Insufficient Insufficient
Insufficient
Moderate
Low to High
Insufficient
Insufficient
*Strength of evidence was defined as: High = high confidence that the evidence reflects the true effect. Further research is unlikely to change our confidence in the estimate of the effect. Moderate = moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of the effect and may change the estimate. Low = low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of the effect and is likely to change the estimate. Insufficient = evidence is unavailable or does not permit a conclusion. KQ, key question.
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Effect modifiers • Study setting • Ulcer area and depth • Duration of ulcer (short vs. long term) • Comorbid conditions • Venous duplex testing (KQs 1, 2, & 3)
Final health and patient-centered outcomes (KQs 1, 2, & 3)
Chronic Venous Ulcers
Treatments • • •
Time to complete wound closure Proportion of ulcers healed at 12 weeks Wound recurrence at 24 weeks and at 1 year Quality of life Pain Mortality Functional status
Intermediate outcomes Wound healing at 4 weeks Quality of wound bed (e.g., necrotic tissue, exudates)
Dressings Systemic Antibiotics Surgery
Adverse effects of treatments (KQs 1, 2, & 3) General Maceration Infection Contact dermatitis Venous or arterial impairment Cellulitis
Antibiotic-specific Hypersensitivity Antibiotic resistance Systemic absorption Drug toxicity Clostridium difficile diarrhea PICC line infection Selection of resistant organisms
Surgery Death Infection Bleeding Skin irritation and burning DVT Long-term recurrence of reflux & ulceration
Figure 1. Analytic framework for comparative effectiveness of treatments. DVT, deep vein thrombosis; KQ, key question; PICC, peripherally inserted central catheter.
specifically, we studied the effectiveness of advanced wound dressings, surgery, and systemic antibiotics. We included randomized controlled trials (RCTs) of advanced wound dressings, antibiotics, and surgical interventions, with two-layer compression therapy as a minimum comparison intervention. The review team consisted of clinical experts in wound care and experienced clinical epidemiologists. We conducted a comprehensive search of electronic databases covering citations from 1980 through July, 2012. Titles, abstracts, and full text articles in English were reviewed in duplicate by two investigators. Data were abstracted using standardized forms with a second investigator reviewing the results of the first abstraction. A review of the quality of each article was completed independently by at least two investigators. We screened the titles and abstracts of more than 10,066 articles.6,7 Only 66 studies (0.06%) met the criteria for inclusion in the analysis. Most questions in the systematic review did not have definitive answers because of a dearth of well-designed RCTs that addressed the comparative effectiveness of the treatments analyzed. Methodological limitations included lack of information on allocation concealment and lack of masking patients or outcome assessors to treatment assignment. Because of the dearth of well-performed RCTs, we expanded the review to include observational studies, but these studies were largely limited to convenience populations, which have a substantial risk of bias. Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
We found that the publications were heterogeneous and had major methodological problems that limited our ability to make firm conclusions about the effectiveness and safety of treatments for CVLUs. Major limitations of the published data threatened both internal and external validities. These limitations included the lack of standard definitions of CVLUs, inconsistent outcome measures, suboptimal comparison groups, and inconsistent duration of interventions. Deficiencies also included suboptimal patient enrollment, inadequate characterization of important clinical variables, poor construction of control groups, variable lengths of study time, imprecise definitions of complete wound healing, bias and inadequate blinding, and lack of standards for measuring wound healing rates, pain, and quality of life. Studies often had large losses to follow-up or did not report on this critical parameter. Many of the studies did not report statistical analyses beyond simple healing rates, generally not reporting stratification or adjustment to account for potential confounding variables, or sample size calculations. Most studies were small and had limited statistical power. Nevertheless, moderate strength of evidence indicated that dressings containing viable human cells and the use of cadexomer iodine accelerated venous wound healing (Table 1). Surgical procedures, which target the superficial venous system, appeared to reduce recurrence of ulcers. Lack of data did not allow any conclusions about the utility of systemic antibiotics in clinically noninfected wounds. 3
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These disappointing findings should not be interpreted to indicate that many of the currently used interventions are without merit. Rather, we found insufficient high-quality studies to demonstrate that these therapeutic interventions were efficacious, perhaps because many of the interventions are classified as devices that require less rigorous evidence for regulatory approval than medications. The number of evidence gaps was remarkable, and this is the subject of the remainder of the present article. Methods for identifying future research needs
We sought to develop a prioritized list of research needs in sufficient detail for researchers and funders to formulate research proposals or develop solicitations. The methods for identifying evidence gaps and developing them into a prioritized list of research needs involved the following steps. Identification of evidence gaps
Evidence gaps were identified in the systematic review based on the strength of evidence, applicability, and limitations of the systematic review. Using the analytic scheme described in Figure 1, we started with the key questions in the systematic review that had low strength of evidence or insufficient evidence. A subset of seven of the systematic review authors constituted the EPC’s Future Research Needs Team (FRNT). The FRNT met multiple times and circulated lists of potential questions to identify gaps, with specific reference to study design using the PICOTS framework (lack of information or insufficient evidence for Populations and subpopulations; Interventions; Comparisons of interventions to each other; Outcome measures; Timing of interventions and outcomes; and Settings). The evidence gaps identified by the FRNT were presented to a stakeholder panel as described below. Because the systematic review identified strikingly pervasive issues with the design of studies that limited their interpretation, we also asked the stakeholders to consider methodological issues in study design, conduct of studies, reporting of outcomes, and statistical analysis. Engagement of stakeholders, researchers, and funders
We recruited nine stakeholders to participate in the identification and prioritization of evidence gaps after obtaining input from patients/advocates, clinical experts, and payers. Five outside stakeholders were chosen from the key informants and technical expert panel that previously provided advice on the systematic review. In addition, four new participants were chosen to fill out the stakeholder panel. The systematic review investigators suggested some of these newly recruited members. We also searched websites of advocacy organizations to identify patient advocates who appear to be independent of payers and manufacturers according to the voting membership requirements and funding mechanisms of their organizations. The list was summarized in a table of their individual strengths, and the list was presented to the team’s task order officer at the Agency for Healthcare Research and Quality (AHRQ). Stakeholders signed a conflict of interest form declaring professional activities and financial ties rel4
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evant to the clinical area. It was made clear to them that accepting the invitation and returning the conflict of interest form constituted agreement to be identified as a stakeholder contributor to the final document. Manufacturers were not solicited to be part of the stakeholder panel, but they could provide comment during the 4-week public posting period for this report. By email, we provided the stakeholders with a description of the future research needs project and how it was related to the systematic review. We also sent them the draft of the executive summary of the systematic review. A web link to the complete draft report was also provided, noting that the draft was only temporarily available and that reading the executive summary should be sufficient to contribute to the process of identifying evidence gaps and future research needs. Stakeholder role in identifying additional information gaps and prioritization of future research needs
Round 1 The EPC team’s list of research gaps, derived from the systematic review, was presented to the stakeholders by email for review. They were also provided the full systematic review. The stakeholders were instructed to carry out a preliminary prioritization of the gaps and to identify additional gaps. To perform this preliminary prioritization, they were asked to use the following criteria adapted from AHRQ’s Effective Health Care Topic Selection Criteria:11 (1) importance—the importance of the condition to patients and the healthcare system; and (2) impact—the extent to which new research with definitive findings could potentially impact decision making by patients, providers, or policymakers. Other prioritization criteria were determined to be less useful or relevant for future research need prioritization. Uncertainty is not a useful criterion because all identified evidence gaps are uncertain by definition. Feasibility of research on an evidence gap is a secondary concern independent of the need for evidence. In the Round 1 questionnaire, each stakeholder was presented with three lists. List 1 presented three general categories of CVLU treatments: antibiotics, dressings, and surgery. The stakeholders were asked to rank these from 1 (highest) to 3 (lowest), based on the criteria described above. List 2 sorted these into specific populations and asked the stakeholders to write in for each population the specific treatment that should be given the highest priority in future research. Stakeholders were also asked to suggest additional gaps within the scope of the systematic review to indicate if they were aware of any ongoing studies addressing a gap and to comment on the feasibility of research to address the gap. The suggested treatments were given a priority based on how many stakeholders suggested each one. This was considered the preliminary priority ranked list of gaps. List 3 focused on study design, reporting, definitions, and other methodological issues. The stakeholders were presented with 14 items in this list and asked to rate each one high, medium, or low priority for future research. There was also a comment box for each item, and stakeholders were invited to add any additional methodological items. Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
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Round 2: final prioritization The EPC team incorporated the stakeholder comments and additional suggestions from Round 1 into three lists for final prioritization. These lists of general treatment categories, specific treatments, and methodology issues included the preliminary rankings from the previous round. Each stakeholder was presented with these lists by email and asked to choose their top five choices in each list and prioritize them. We asked them to base their ratings on the same criteria as in Round 1, importance and potential impact. Stakeholders were again asked to indicate whether they were aware of any ongoing studies addressing the gaps (duplication) and to comment on the feasibility of research addressing the gaps. We calculated a global priority ranking of the evidence gaps from the stakeholders’ individual ratings. The calculation of priorities included calculation of cut points between high and low priorities. If the global ranking was a continuum with no apparent cutoff, the top half of the gaps or the top 10, whichever was fewer, was chosen as the top tier and considered the high priority needs. Treatment gaps outside the scope of the comparative effectiveness review, and thus not included in comprehensive searches, were identified separately. To develop the future research needs (top tier gaps) into research questions, we divided the future research needs into the clinical areas of wound dressings, antibiotics, and surgery, and members of the team with specialty experience in these areas formulated appropriate questions. They developed the needs into research questions using a PICOTS approach (populations, interventions, comparisons, outcomes, timing, and setting) and suggestions for appropriate study designs.12 These formulations were then circulated to the entire group by email and discussed and further developed in multiple meetings. Findings regarding future research needs
Eight stakeholders returned Round 1 and 2 questionnaires. In Round 1, the stakeholders did not suggest any additional gaps within the scope of the systematic review. However, they suggested additional items they considered gaps but that were outside the scope of the original systematic review. From the final prioritization in Round 2, the stakeholders had a near unanimous consensus in ranking wound dressings as the type of treatment having the highest priority for future research, followed by the role of venous surgery and the use of antibiotics on CVLUs (Table 2). The categories are not necessarily competing with one another. Table 3 presents spe-
cific evidence gaps in more detail and indicates how our stakeholders ranked their importance. The prioritization of future research needs was constrained by the scope of the systematic review and the specific questions we asked the stakeholders to answer. Other related information gaps and needs exist, as indicated by the comments that stakeholders made in the blank comment boxes. Because these items were not reviewed in our comprehensive literature searches in the systematic review, we could not verify these potential evidence gaps. These comments are summarized in Table 4. Most of the evidence gaps were because of the limited quality and number of studies. An underlying cause of this lack of useful evidence is not lack of asking appropriate questions but rather a consequence of poor design and execution of the experimental protocols and poor reporting. Specific methodological deficiencies were all considered very important and are presented unranked in Table 5.
DISCUSSION Limitations
Our approach to identifying and prioritizing future research needs has limitations. Although we attempted to engage stakeholders with a variety of backgrounds, most were clinicians with experience in the nonsurgical management of CVLUs, and only one was a surgeon. Others have suggested that the precise priority ranking of small, informally composed stakeholder groups may have limited validity.13 Another similarly composed group might have provided somewhat different gap identifications and rankings. For that reason, our top tier of future research needs was large and inclusive, and we do not recommend that relative rankings within the top tier be taken as precise. It also is possible that the priority ratings would have been different if we had used a more intensive approach to engaging the stakeholders; however, the approach we used was effective in engaging a diverse group of stakeholders in a short interval of time so that the future research needs report could be finished soon after completion of the systematic review. The future research needs selected and presented in this article were constrained by the scope of the systematic review and the specific questions we asked the stakeholders to answer. Other potential gaps and needs exist. Although we did not verify these with comprehensive searches, they were listed separately.
Table 2. Prioritization of gaps in knowledge about general categories of treatment for clinically noninfected chronic venous leg ulcers
General categories
Raw score*
Number of stakeholder votes for highest priority
Priority rank (1 = highest priority)
Wound dressings Venous surgery Systemic antibiotics
36 22 18
6 1 1
1 2 3
*Sum of votes by eight stakeholders voting 1 for lowest priority to 5 for highest. Maximum raw score was 40. There were five choices, and only the top three were chosen as high priority (the remaining two topics received no votes for highest priority). Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
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Table 3. Gaps in knowledge about specific types of treatments for clinically noninfected chronic venous leg ulcers Raw Number of stakeholder Priority rank† score* votes for highest priority (1 = highest priority)
Specific clinical topics Top tier topics 1. Biological dressings containing living cells 2. Collagen dressings for recalcitrant‡ ulcers 3. Dressings with enzymatic debriding agents 4. Laser ablation for superficial veins with reflux 5. Ligation for incompetent perforating veins 6. Valvular surgery for deep veins with reflux 7. Topical antibiotic or antiseptic-impregnated dressings for clinically noninfected chronic venous leg ulcers 8. Radiofrequency ablation for superficial veins with reflux 9. Sclerotherapy for superficial veins with reflux Other topics 10. Alginate fiber dressings for exudative ulcers 11. Hydrogels and hydrocolloid dressings for dry ulcers 12. Balloon angioplasty for obstructed deep veins
18 10 8 8 7 7 5
2 1 0 0 1 0 1
1 2 3 3 4 5 6
5 5
1 0
6 7
3 0 0
0 0 0
8 9 9
*Sum of votes by eight stakeholders voting 1 for lowest priority to 5 for highest. Maximum raw score was 40. † Multiple gaps with the same priority rank had tied priority rating scores. ‡ “Recalcitrant” denotes ulcers that have persisted for more than 6 months despite treatment.
Implications of findings
Our purpose was to identify and prioritize the evidence gaps revealed by the systematic review of treatments for CVLUs.9 The goal and scope of that review was to determine, for patients with CVLUs, the effectiveness and safety of advanced wound dressings (key question 1), systemic antibiotics (key question 2), and surgical interventions (key question 3), compared with either one another or to a mandatory compression system established as the standard of care. For all of the key questions, there were few, if any, well-conducted RCTs that provided moderate to high-quality evidence. The review rated the strength of evidence of most aspects of all Table 4. Potential evidence gaps outside scope of systematic review General categories Topical growth factors Topical antiseptics and topical antibiotics Specific clinical topics Compression garments Dressings with growth factors Wound cleansing agents Negative pressure wound therapy for edematous chronic venous leg ulcers Arterial/venous surgery for chronic venous leg ulcers caused by mixed arterial and venous disease Adjuvant treatments (e.g., pentoxiphylline) for all types of chronic venous leg ulcers
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three key questions as low or insufficient. For the purposes of the future research needs report, low or insufficient strength of evidence is the definition of an evidence gap. Therefore, for this future research needs report, we divided the key questions into specific individual components that constituted the evidence gaps within the scope of the review. We presented these evidence gaps to a group of stakeholders representing clinical experts, payers, decision makers, and consumer advocates. In two engagements by emailed questionnaires, these stakeholders prioritized the gaps on the basis of importance (severity and burden for patients and society) and potential impact on decision making by patients, providers, or policymakers. In terms of the general categories of treatments, the stakeholders ranked them: (1) wound dressings, (2) venous surgery, and (3) systemic antibiotics. Of the specific evidence gaps, we chose the top nine prioritized by the stakeholders, based both on the number of stakeholders voting for a gap, as well as the fact that some stakeholder ranked it as their highest, or next highest priority. These top tier future research needs are: • • • • • • • •
biological dressings containing living cells; collagen dressings for recalcitrant ulcers; dressings with enzymatic debriding agents; laser ablation for superficial veins with reflux; valve surgery for deep veins with reflux; ligation for incompetent perforating veins; sclerotherapy for superficial veins with reflux; topical antibiotic or antiseptic-impregnated dressings for clinically noninfected CVLUs; and • radiofrequency ablation for superficial veins with reflux. Because rankings might vary with a different set of stakeholders, we advise the reader not to place undue emphasis on this Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
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Table 5. Methodological evidence gaps identified as future research needs Evidence gap Standards for studying combinations of simultaneous treatments Standards for studying sequential treatments Standards for allocating patients to treatment groups Standards for estimating proper sample sizes Standards for recruiting patients Standards for describing participating patients and their ulcers
Context and recommendations The synergistic effect of treatments currently used simultaneously cannot be determined without appropriate statistical methods. Patients with chronic venous leg ulcers are often treated with sequential treatments without an evidence-based rationale for the order or timing. Studies of sequential treatment strategies are especially important in understanding the best use of surgery for chronic venous leg ulcers. The severity of chronic venous ulcers is apparent and can easily influence treatment allocation in the absence of randomized, concealed allocation. Well-developed statistical methods for estimating the number of patients/ulcers needed to address a research question exist and should be used in studies of treatments for chronic venous ulcers. Ethical methods for obtaining study participants’ informed consent should be used in all studies. The characteristics of participating patients and their ulcers allow assessment of the generalizability of study results to different patient populations and can highlight imbalances in characteristics between intervention and comparison groups that confound results. The duration, size, and number of ulcers appear relevant to the effectiveness of some dressings. Standard terms to describe and quantify wound beds need to be developed (e.g., dressings that absorb moisture should not be tested on dry ischemic wounds). Universal definitions of chronic venous leg ulcers should be developed and address physical characteristics, location, bacteriology, duration, and relation to venous flow.
Standards for defining and classifying “chronic venous leg ulcers” Standards for selecting valid The use of an appropriate comparison group is necessary for reducing confounding and for comparison groups understanding the performance of the active intervention relative to the comparison treatment. Standards for measuring Validated measures of outcomes in studies of chronic venous ulcers with acceptable inter and outcomes intra-rater reliability are critical. Needs include a standardized definition of epithelialization; validation of healing rates as an intermediate outcome; and validated measures of patient-reported outcome, such as pain and quality of life. Standards for reporting Patients enrolled in studies of chronic venous ulcer treatment should be monitored actively for harms any adverse events that could be related to treatment. All such events should be described in the articles that report the results of such studies. Standards for establishing Studies should be designed to follow patients long enough to ascertain the completeness and the needed duration of durability of ulcer healing. observation Standards for analyzing data Analytic plans should include estimation of sample size, intention-to-treat analysis, and statistical methods to account for confounding, effect modification, and clustering of patients. Standards for reporting all All patients enrolled in studies should be tracked throughout the studies and their “flow” patients’ flow through through the studies reported. “Completers analyses” are biased toward showing a benefit of studies the active intervention, as patients who have benefitted are more likely to complete a study. Intention-to-treat analysis and emphasis on retention of enrolled participants are essential. Knowledge of the reasons for losses to follow up (e.g., adverse events) is critical, and use of analytic techniques to handle missing data can reduce the chance of bias. Standards for conducting Standardization of caregivers to minimize variation in interventions such as ability to apply trials dressings, compression, perform surgical procedures, etc. Needs to be a separation of those applying interventions from evaluators of progress to prevent problems with blinding and bias. Standards of consistency All multicenter trials should standardize application of intervention and analysis of result between for multicenter trials study sites.
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particular order but to consider all of these as high-priority future research needs. We searched databases for ongoing but yet unpublished trials and did not find that any of these research needs are likely to be answered by ongoing research in the near future. Therefore, we consider all of the listed future research needs as good prospects for those funding future research in this field, and we believe such research would substantially advance the treatment of CVLUs. There was universal agreement on the need to produce higher quality data. We found a profound lack of highquality evidence for many types of wound therapy. Our findings do not mean that frequently used clinical interventions do not work; rather, there was no quality data to sustain such claims. The evidence gaps in this field are not merely due to a lack of studies but to a lack of adherence to study designs, research methodologies, and reporting standards capable of producing a body of interpretable studies with clear results that can be compared across studies and treatments. If the future clinical research needs we identified are addressed with the same poor quality studies published in the past, those gaps will remain. The FRNT identified specific study design and methodology issues that need to be improved in future research on treatments for wound healing in general and CVLUs specifically. Resolution of the substantial evidence gaps on therapies for CVLUs is feasible and should draw upon the extensive expertise found within the wound healing community. We suggest organizing a conference that draws serious distinguished investigators and providers including nurses, physicians, surgeons, patient advocates, clinical epidemiologists, clinical trial designers, statisticians, physical therapists, and pharmaceutical innovators to design remedies for the deficiencies highlighted in this report. This group should also consider the development of a wound healing “cooperative group” to deal with multicenter enrollment of patients in a timely fashion and ensure collection of high-quality clinical data. With healthcare payers increasingly demanding evidence to support coverage of expensive healthcare services, it will be essential to establish the efficacy of present modalities of care for CVLUs. Promising new interventions need to be evaluated in a high-quality cost-effective manner if we are to make progress toward our goals of better wound care for our seriously afflicted patients.
ACKNOWLEDGMENTS The authors would like to acknowledge Dr. Chad Boult, Ms. Lisa Wilson, and Ms. Elisabeth Haberl for their assistance in preparing the manuscript. The authors would like to thank the members of the stakeholder panel: Laura Bolton, PhD; Anthony Disser; Robert Kirsner, MD, PhD; Peter Lawrence, MD; David Margolis, MD, PhD; David Martin, MD; Marcia Nusgart, R.Ph; Robert Snyder, DPM; and Charles Turkelson, PhD. Source of Funding: This project was funded under Contract No. HHS 290-2007-10061-I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the US Department of Health and Human Services. Conflicts of Interest: None of the authors have any potential conflicts of interest to disclose. 8
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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: perspective article. Wound Repair Regen 2009; 17: 763–71. 2. Raju S, Neglen P. Clinical practice. Chronic venous insufficiency and varicose veins. N Engl J Med 2009; 360: 2319– 27. 3. Margolis DJ, Bilker W, Santanna J, Baumgarten M. Venous leg ulcer: incidence and prevalence in the elderly. J Am Acad Dermatol 2002; 46: 381–6. 4. van Gent WB, Wilschut ED, Wittens C. Management of venous ulcer disease. BMJ 2010; 341: c6045. 5. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 2008; 32: 1431–7. 6. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood) 2007; 26: 38–48. 7. Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med 2006; 355: 488–98. 8. Sonnad S, Goldsack J, Mohr P, Whicher D. Methodological recommendations for comparative effectiveness research on the treatment of chronic wounds. Version 2: final. Center for Medical Technology Policy. 2012. Available at http://www .cmtpnet.org/effectiveness-guidance-documents/negativepressure-wound-therapy-egd/ (accessed October 31, 2012). 9. Zenilman J, Valle F, Malas M, Maruthur N, Qazi U, Suh Y, et al. Chronic venous ulcers: a comparative effectiveness review of treatment modalities. Rockville, MD: Agency for Healthcare Research and Quality, in press. 10. Lazarus G, Valle F, Malas M, Qazi U, Maruthur N, Zenilman J, et al. Chronic venous leg ulcer treatment: future research needs. Future Research Needs Paper No. 34 (Prepared by the Johns Hopkins University Evidence-Based Practice Center under Contract No. 290-2007-10061-I.) AHRQ Publication No.13EHC034-EF. Rockville, MD: Agency for Healthcare Research and Quality, in press. 11. Whitlock EP, Lopez SA, Chang S, Helfand M, Eder M, Floyd N. AHRQ series paper 3: identifying, selecting, and refining topics for comparative effectiveness systematic reviews: AHRQ and the effective health-care program. J Clin Epidemiol 2010; 63: 491– 501. 12. Carey TS, Sanders GD, Viswanathan M, Trikalinos TA, Kato E, Chang S. Framework for considering study designs for future research needs. Methods Future Research Needs Paper No. 8 (Prepared by the RTI-UNC Evidence-based Practice Center under Contract No. 290-2007-10056-I.) AHRQ Publication No. 12-EHC048-EF. Rockville, MD: Agency for Healthcare Research and Quality, 2012. Available at http://www .effectivehealthcare.ahrq.gov/reports/final.cfm (accessed October 31, 2012). 13. Trikalinos TA, Dahabreh IJ, Lee J, Moorthy D. Defining an optimal format for presenting research needs. Methods Future Research Needs Report No. 3. (Prepared by the Tufts Evidencebased Practice Center under Contract No. 290-2007-10057-I.) AHRQ Publication No. 11-EHC027-EF. Rockville, MD: Agency for Healthcare Research and Quality, 2011. Available at http:// www.effectivehealthcare.ahrq.gov/reports/final.cfm (accessed October 31, 2012).
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Topic These scores have been inverted so that the highest value (5) is the highest priority.
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Collagen dressings for recalcitrant* ulcers Wound cleansing agents Debridement agents Laser ablation for superficial veins with reflux Valvular surgery for deep veins with reflux Ligation for incompetent perforating veins Sclerotherapy for superficial veins with reflux Topical antibiotic- or antiseptic-impregnated dressings for clinically noninfected CVUs Radio frequency ablation for superficial veins with reflux Alginate fiber dressings for exudative ulcers Negative pressure wound therapy for edematous CVUs Arterial/venous surgery for CVUs caused by mixed arterial and venous disease Adjuvant treatments (e.g., pentoxiphylline) for all types of CVUs Hydrogels and hydrocolloid dressings for dry ulcers Balloon angioplasty for obstructed deep veins
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List 1. Gaps in knowledge about the general categories of treatments for clinically non-infected chronic venous ulcers 5 5 4 5 5 5 2 5 2 3 3 4 3 3 3 3
4 Topical antiseptics and topical antibiotics 1 4 2 1 2 4 4 5 Systemic antibiotics 4 2 1 2 1 2 5 List 2. Gaps in knowledge about specific types of treatments for clinically non-infected chronic venous ulcers
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Appendix 1. Chronic venous leg ulcer future research needs stakeholder priority master list
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Reprint requests: Dr. G. Lazarus, MD, Department of Dermatology, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Baltimore, MD 21224, USA. Tel: +410-490-0813; Fax: +410-550-7301; Email: [email protected] Manuscript received: July 19, 2013 Accepted in final form: July 31, 2013 DOI:10.1111/wrr.12102
ABSTRACT The prevalence and costs of chronic venous ulcer care in the US are increasing. The Johns Hopkins University Evidence-Based Practice Center recently completed a systematic review of the comparative effectiveness of advanced wound dressings, antibiotics, and surgical management of chronic venous ulcers. Of 10,066 citations identified in the literature search, only 66 (0.06%) met our liberal inclusion criteria for providing evidence on the effectiveness of interventions for chronic venous ulcers. Based on review of those studies, members of our team and a panel of informed stakeholders identified important research gaps and methodological deficiencies and prioritized specific future research needs. Based on that review, we provide the results of our assessment of future research needs for chronic venous ulcer care. Advanced wound dressings were considered to have the highest priority for future research, followed by venous surgery and antibiotics. An imperative from our assessment is that future research evaluating interventions for chronic venous ulcers meet quality standards. In a time of increasing cost pressure, the wound care community needs to develop high-quality evidence to justify the use of present and future therapeutic modalities.
INTRODUCTION Cutaneous ulcers are a major cause of morbidity and mortality throughout the world. Direct costs for ulcer care are approximately 25 billion dollars per year in the US.1 Leg ulcers can have multiple causes including diabetes mellitus, peripheral neuropathy, immobility and pressure, atherosclerosis, infections, rheumatologic diseases, and venous dysfunction. Chronic venous leg ulcers (CVLUs) affect between 500,000 and 2 million persons annually in the USA and account for over 50% of leg ulcers.2–4 Their prevalence will almost certainly increase as the population ages and risk factors such as obesity and congestive heart failure become more prevalent.5,6 The current standard approach to therapy for CVLUs includes aggressive compression of the lower limbs and debridement, which heals 50–60% of venous leg ulcers.7 Widely used additional interventions include wound dressings with active components (defined here as “advanced wound dressings”), local or systemic antimicrobials, and venous surgery.4 In practice, venous ulcers are cared for by a wide variety of practitioners including internists, family practitioners, surgeons, podiatrists, certified wound nurses, and physical therapists in different settings using many different interventions. The public health burden of venous ulcers and rapidly increasing costs of venous ulcers, and their complications have necessitated analysis of the evidence on the effectiveness of therapy for these disabling lesions. Recently, the Center for Medical Technology and Policy authored an Effectiveness Guidance Document analyzing therapeutic interventions for chronic wounds.8 This excellent Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
review attempted to evaluate interventions for all types of cutaneous ulcers. The Johns Hopkins University EvidenceBased Practice Center (EPC) recently performed a systematic review focusing on the effectiveness and safety of advanced wound dressings, systemic antibiotics, and surgical interventions compared with one another or with compression systems (as the standard of care) for treatment of CVLUs.9 To quantify and simplify the subject, we focused our analysis on active CVLUs, defined as stationary or enlarging lesions present for 6 weeks or more, with evidence of earlier stages of venous disease such as varicose veins, edema, pigmentation, and venous eczema but without active infection. Clinical diagnosis was frequently confirmed by functional assessment of the venous system, most commonly by venous duplex ultrasound. By using strict diagnostic criteria, one can carefully select patients that have the least medically confounded type of cutaneous leg ulcer. The purpose of the present article is to present the recommendations of a panel of stakeholders on future research needs for treatment of CVLUs10 based on our systematic review published elsewhere9 and Valle MF, Maruthur NM, Wilson LM, Malas M, Qazi U, Haberl E, et al., unpublished data. Results of systematic review of therapeutic interventions for venous ulcer care
Our review9 used a series of predefined key questions (Table 1) using the analytical framework shown in Figure 1; 1
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Table 1. Key questions, findings, and strength of evidence in the systematic review of the comparative effectiveness of treatments for chronic venous leg ulcers
Key question KQ 1. For patients with chronic venous leg ulcers, what are the benefits and harms of using dressings that regulate wound moisture with or without active chemical, enzymatic, biologic, or antimicrobial components in conjunction with compression systems when compared with using solely compression systems?
Finding
Hydrocolloid dressings were not more effective than compression therapy alone in healing chronic venous ulcers. Human skin equivalent dressings, containing living human cells, produced more rapid wound healing than compression therapy alone. Cadexomer iodine dressings produced modest improvements in wound healing rates and wound area compared with nonantimicrobial dressings. Silver dressings did not improve wound healing compared with nonsilver dressings. For all other types of dressings, the evidence was insufficient to support a conclusion. KQ 2a. For patients with chronic venous leg ulcers Only one study addressed this question, and it provided that do not have clinical signs of cellulitis and are insufficient evidence to determine the benefits and harms of being treated with compression systems, what are systemic antibiotics compared with compression therapy alone. the benefits and harms of using systemic antibiotics when compared with using solely compression systems? KQ 2b. For patients with chronic venous leg ulcers No studies addressed this question. that do not have clinical signs of cellulitis and are being treated with dressings that regulate wound moisture with or without active chemical, enzymatic, biologic, or antimicrobial components, what are the benefits and harms of using systemic antibiotics when compared with using dressings alone? KQ 3a. For patients with chronic venous leg ulcers, Surgical procedures targeting superficial vein reflux produced what are the benefits and harms of surgical similar rates of wound healing compared with compression procedures aimed at the underlying venous therapy alone but had lower ulcer recurrence rates at 3 years. abnormalities when compared with using solely Selected surgical procedures targeting perforator vein reflux compression systems? produced similar rates of wound healing compared with compression therapy alone. One of these procedures (Conservative Hemodynamic treatment of Insufficiency of the Venous system in an Ambulatory setting [CHIVA]) had a lower ulcer recurrence rate. The evidence was insufficient regarding the benefits and harms of sclerotherapy, vein stripping, radiofrequency ablation, or endovenous laser therapy for superficial vein reflux, or surgery for deep vein disease. KQ 3b. For patients with chronic venous leg ulcers, The evidence was insufficient to answer this question because of what are the comparative benefits and harms of the small number, small size, and poor quality of studies. different surgical procedures for a given type of venous reflux and obstruction?
Strength of evidence* Low Moderate
Moderate
Moderate Insufficient Insufficient
Insufficient
Moderate
Low to High
Insufficient
Insufficient
*Strength of evidence was defined as: High = high confidence that the evidence reflects the true effect. Further research is unlikely to change our confidence in the estimate of the effect. Moderate = moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of the effect and may change the estimate. Low = low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of the effect and is likely to change the estimate. Insufficient = evidence is unavailable or does not permit a conclusion. KQ, key question.
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Effect modifiers • Study setting • Ulcer area and depth • Duration of ulcer (short vs. long term) • Comorbid conditions • Venous duplex testing (KQs 1, 2, & 3)
Final health and patient-centered outcomes (KQs 1, 2, & 3)
Chronic Venous Ulcers
Treatments • • •
Time to complete wound closure Proportion of ulcers healed at 12 weeks Wound recurrence at 24 weeks and at 1 year Quality of life Pain Mortality Functional status
Intermediate outcomes Wound healing at 4 weeks Quality of wound bed (e.g., necrotic tissue, exudates)
Dressings Systemic Antibiotics Surgery
Adverse effects of treatments (KQs 1, 2, & 3) General Maceration Infection Contact dermatitis Venous or arterial impairment Cellulitis
Antibiotic-specific Hypersensitivity Antibiotic resistance Systemic absorption Drug toxicity Clostridium difficile diarrhea PICC line infection Selection of resistant organisms
Surgery Death Infection Bleeding Skin irritation and burning DVT Long-term recurrence of reflux & ulceration
Figure 1. Analytic framework for comparative effectiveness of treatments. DVT, deep vein thrombosis; KQ, key question; PICC, peripherally inserted central catheter.
specifically, we studied the effectiveness of advanced wound dressings, surgery, and systemic antibiotics. We included randomized controlled trials (RCTs) of advanced wound dressings, antibiotics, and surgical interventions, with two-layer compression therapy as a minimum comparison intervention. The review team consisted of clinical experts in wound care and experienced clinical epidemiologists. We conducted a comprehensive search of electronic databases covering citations from 1980 through July, 2012. Titles, abstracts, and full text articles in English were reviewed in duplicate by two investigators. Data were abstracted using standardized forms with a second investigator reviewing the results of the first abstraction. A review of the quality of each article was completed independently by at least two investigators. We screened the titles and abstracts of more than 10,066 articles.6,7 Only 66 studies (0.06%) met the criteria for inclusion in the analysis. Most questions in the systematic review did not have definitive answers because of a dearth of well-designed RCTs that addressed the comparative effectiveness of the treatments analyzed. Methodological limitations included lack of information on allocation concealment and lack of masking patients or outcome assessors to treatment assignment. Because of the dearth of well-performed RCTs, we expanded the review to include observational studies, but these studies were largely limited to convenience populations, which have a substantial risk of bias. Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
We found that the publications were heterogeneous and had major methodological problems that limited our ability to make firm conclusions about the effectiveness and safety of treatments for CVLUs. Major limitations of the published data threatened both internal and external validities. These limitations included the lack of standard definitions of CVLUs, inconsistent outcome measures, suboptimal comparison groups, and inconsistent duration of interventions. Deficiencies also included suboptimal patient enrollment, inadequate characterization of important clinical variables, poor construction of control groups, variable lengths of study time, imprecise definitions of complete wound healing, bias and inadequate blinding, and lack of standards for measuring wound healing rates, pain, and quality of life. Studies often had large losses to follow-up or did not report on this critical parameter. Many of the studies did not report statistical analyses beyond simple healing rates, generally not reporting stratification or adjustment to account for potential confounding variables, or sample size calculations. Most studies were small and had limited statistical power. Nevertheless, moderate strength of evidence indicated that dressings containing viable human cells and the use of cadexomer iodine accelerated venous wound healing (Table 1). Surgical procedures, which target the superficial venous system, appeared to reduce recurrence of ulcers. Lack of data did not allow any conclusions about the utility of systemic antibiotics in clinically noninfected wounds. 3
Future research needs for venous ulcers
These disappointing findings should not be interpreted to indicate that many of the currently used interventions are without merit. Rather, we found insufficient high-quality studies to demonstrate that these therapeutic interventions were efficacious, perhaps because many of the interventions are classified as devices that require less rigorous evidence for regulatory approval than medications. The number of evidence gaps was remarkable, and this is the subject of the remainder of the present article. Methods for identifying future research needs
We sought to develop a prioritized list of research needs in sufficient detail for researchers and funders to formulate research proposals or develop solicitations. The methods for identifying evidence gaps and developing them into a prioritized list of research needs involved the following steps. Identification of evidence gaps
Evidence gaps were identified in the systematic review based on the strength of evidence, applicability, and limitations of the systematic review. Using the analytic scheme described in Figure 1, we started with the key questions in the systematic review that had low strength of evidence or insufficient evidence. A subset of seven of the systematic review authors constituted the EPC’s Future Research Needs Team (FRNT). The FRNT met multiple times and circulated lists of potential questions to identify gaps, with specific reference to study design using the PICOTS framework (lack of information or insufficient evidence for Populations and subpopulations; Interventions; Comparisons of interventions to each other; Outcome measures; Timing of interventions and outcomes; and Settings). The evidence gaps identified by the FRNT were presented to a stakeholder panel as described below. Because the systematic review identified strikingly pervasive issues with the design of studies that limited their interpretation, we also asked the stakeholders to consider methodological issues in study design, conduct of studies, reporting of outcomes, and statistical analysis. Engagement of stakeholders, researchers, and funders
We recruited nine stakeholders to participate in the identification and prioritization of evidence gaps after obtaining input from patients/advocates, clinical experts, and payers. Five outside stakeholders were chosen from the key informants and technical expert panel that previously provided advice on the systematic review. In addition, four new participants were chosen to fill out the stakeholder panel. The systematic review investigators suggested some of these newly recruited members. We also searched websites of advocacy organizations to identify patient advocates who appear to be independent of payers and manufacturers according to the voting membership requirements and funding mechanisms of their organizations. The list was summarized in a table of their individual strengths, and the list was presented to the team’s task order officer at the Agency for Healthcare Research and Quality (AHRQ). Stakeholders signed a conflict of interest form declaring professional activities and financial ties rel4
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evant to the clinical area. It was made clear to them that accepting the invitation and returning the conflict of interest form constituted agreement to be identified as a stakeholder contributor to the final document. Manufacturers were not solicited to be part of the stakeholder panel, but they could provide comment during the 4-week public posting period for this report. By email, we provided the stakeholders with a description of the future research needs project and how it was related to the systematic review. We also sent them the draft of the executive summary of the systematic review. A web link to the complete draft report was also provided, noting that the draft was only temporarily available and that reading the executive summary should be sufficient to contribute to the process of identifying evidence gaps and future research needs. Stakeholder role in identifying additional information gaps and prioritization of future research needs
Round 1 The EPC team’s list of research gaps, derived from the systematic review, was presented to the stakeholders by email for review. They were also provided the full systematic review. The stakeholders were instructed to carry out a preliminary prioritization of the gaps and to identify additional gaps. To perform this preliminary prioritization, they were asked to use the following criteria adapted from AHRQ’s Effective Health Care Topic Selection Criteria:11 (1) importance—the importance of the condition to patients and the healthcare system; and (2) impact—the extent to which new research with definitive findings could potentially impact decision making by patients, providers, or policymakers. Other prioritization criteria were determined to be less useful or relevant for future research need prioritization. Uncertainty is not a useful criterion because all identified evidence gaps are uncertain by definition. Feasibility of research on an evidence gap is a secondary concern independent of the need for evidence. In the Round 1 questionnaire, each stakeholder was presented with three lists. List 1 presented three general categories of CVLU treatments: antibiotics, dressings, and surgery. The stakeholders were asked to rank these from 1 (highest) to 3 (lowest), based on the criteria described above. List 2 sorted these into specific populations and asked the stakeholders to write in for each population the specific treatment that should be given the highest priority in future research. Stakeholders were also asked to suggest additional gaps within the scope of the systematic review to indicate if they were aware of any ongoing studies addressing a gap and to comment on the feasibility of research to address the gap. The suggested treatments were given a priority based on how many stakeholders suggested each one. This was considered the preliminary priority ranked list of gaps. List 3 focused on study design, reporting, definitions, and other methodological issues. The stakeholders were presented with 14 items in this list and asked to rate each one high, medium, or low priority for future research. There was also a comment box for each item, and stakeholders were invited to add any additional methodological items. Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
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Round 2: final prioritization The EPC team incorporated the stakeholder comments and additional suggestions from Round 1 into three lists for final prioritization. These lists of general treatment categories, specific treatments, and methodology issues included the preliminary rankings from the previous round. Each stakeholder was presented with these lists by email and asked to choose their top five choices in each list and prioritize them. We asked them to base their ratings on the same criteria as in Round 1, importance and potential impact. Stakeholders were again asked to indicate whether they were aware of any ongoing studies addressing the gaps (duplication) and to comment on the feasibility of research addressing the gaps. We calculated a global priority ranking of the evidence gaps from the stakeholders’ individual ratings. The calculation of priorities included calculation of cut points between high and low priorities. If the global ranking was a continuum with no apparent cutoff, the top half of the gaps or the top 10, whichever was fewer, was chosen as the top tier and considered the high priority needs. Treatment gaps outside the scope of the comparative effectiveness review, and thus not included in comprehensive searches, were identified separately. To develop the future research needs (top tier gaps) into research questions, we divided the future research needs into the clinical areas of wound dressings, antibiotics, and surgery, and members of the team with specialty experience in these areas formulated appropriate questions. They developed the needs into research questions using a PICOTS approach (populations, interventions, comparisons, outcomes, timing, and setting) and suggestions for appropriate study designs.12 These formulations were then circulated to the entire group by email and discussed and further developed in multiple meetings. Findings regarding future research needs
Eight stakeholders returned Round 1 and 2 questionnaires. In Round 1, the stakeholders did not suggest any additional gaps within the scope of the systematic review. However, they suggested additional items they considered gaps but that were outside the scope of the original systematic review. From the final prioritization in Round 2, the stakeholders had a near unanimous consensus in ranking wound dressings as the type of treatment having the highest priority for future research, followed by the role of venous surgery and the use of antibiotics on CVLUs (Table 2). The categories are not necessarily competing with one another. Table 3 presents spe-
cific evidence gaps in more detail and indicates how our stakeholders ranked their importance. The prioritization of future research needs was constrained by the scope of the systematic review and the specific questions we asked the stakeholders to answer. Other related information gaps and needs exist, as indicated by the comments that stakeholders made in the blank comment boxes. Because these items were not reviewed in our comprehensive literature searches in the systematic review, we could not verify these potential evidence gaps. These comments are summarized in Table 4. Most of the evidence gaps were because of the limited quality and number of studies. An underlying cause of this lack of useful evidence is not lack of asking appropriate questions but rather a consequence of poor design and execution of the experimental protocols and poor reporting. Specific methodological deficiencies were all considered very important and are presented unranked in Table 5.
DISCUSSION Limitations
Our approach to identifying and prioritizing future research needs has limitations. Although we attempted to engage stakeholders with a variety of backgrounds, most were clinicians with experience in the nonsurgical management of CVLUs, and only one was a surgeon. Others have suggested that the precise priority ranking of small, informally composed stakeholder groups may have limited validity.13 Another similarly composed group might have provided somewhat different gap identifications and rankings. For that reason, our top tier of future research needs was large and inclusive, and we do not recommend that relative rankings within the top tier be taken as precise. It also is possible that the priority ratings would have been different if we had used a more intensive approach to engaging the stakeholders; however, the approach we used was effective in engaging a diverse group of stakeholders in a short interval of time so that the future research needs report could be finished soon after completion of the systematic review. The future research needs selected and presented in this article were constrained by the scope of the systematic review and the specific questions we asked the stakeholders to answer. Other potential gaps and needs exist. Although we did not verify these with comprehensive searches, they were listed separately.
Table 2. Prioritization of gaps in knowledge about general categories of treatment for clinically noninfected chronic venous leg ulcers
General categories
Raw score*
Number of stakeholder votes for highest priority
Priority rank (1 = highest priority)
Wound dressings Venous surgery Systemic antibiotics
36 22 18
6 1 1
1 2 3
*Sum of votes by eight stakeholders voting 1 for lowest priority to 5 for highest. Maximum raw score was 40. There were five choices, and only the top three were chosen as high priority (the remaining two topics received no votes for highest priority). Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
5
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Table 3. Gaps in knowledge about specific types of treatments for clinically noninfected chronic venous leg ulcers Raw Number of stakeholder Priority rank† score* votes for highest priority (1 = highest priority)
Specific clinical topics Top tier topics 1. Biological dressings containing living cells 2. Collagen dressings for recalcitrant‡ ulcers 3. Dressings with enzymatic debriding agents 4. Laser ablation for superficial veins with reflux 5. Ligation for incompetent perforating veins 6. Valvular surgery for deep veins with reflux 7. Topical antibiotic or antiseptic-impregnated dressings for clinically noninfected chronic venous leg ulcers 8. Radiofrequency ablation for superficial veins with reflux 9. Sclerotherapy for superficial veins with reflux Other topics 10. Alginate fiber dressings for exudative ulcers 11. Hydrogels and hydrocolloid dressings for dry ulcers 12. Balloon angioplasty for obstructed deep veins
18 10 8 8 7 7 5
2 1 0 0 1 0 1
1 2 3 3 4 5 6
5 5
1 0
6 7
3 0 0
0 0 0
8 9 9
*Sum of votes by eight stakeholders voting 1 for lowest priority to 5 for highest. Maximum raw score was 40. † Multiple gaps with the same priority rank had tied priority rating scores. ‡ “Recalcitrant” denotes ulcers that have persisted for more than 6 months despite treatment.
Implications of findings
Our purpose was to identify and prioritize the evidence gaps revealed by the systematic review of treatments for CVLUs.9 The goal and scope of that review was to determine, for patients with CVLUs, the effectiveness and safety of advanced wound dressings (key question 1), systemic antibiotics (key question 2), and surgical interventions (key question 3), compared with either one another or to a mandatory compression system established as the standard of care. For all of the key questions, there were few, if any, well-conducted RCTs that provided moderate to high-quality evidence. The review rated the strength of evidence of most aspects of all Table 4. Potential evidence gaps outside scope of systematic review General categories Topical growth factors Topical antiseptics and topical antibiotics Specific clinical topics Compression garments Dressings with growth factors Wound cleansing agents Negative pressure wound therapy for edematous chronic venous leg ulcers Arterial/venous surgery for chronic venous leg ulcers caused by mixed arterial and venous disease Adjuvant treatments (e.g., pentoxiphylline) for all types of chronic venous leg ulcers
6
three key questions as low or insufficient. For the purposes of the future research needs report, low or insufficient strength of evidence is the definition of an evidence gap. Therefore, for this future research needs report, we divided the key questions into specific individual components that constituted the evidence gaps within the scope of the review. We presented these evidence gaps to a group of stakeholders representing clinical experts, payers, decision makers, and consumer advocates. In two engagements by emailed questionnaires, these stakeholders prioritized the gaps on the basis of importance (severity and burden for patients and society) and potential impact on decision making by patients, providers, or policymakers. In terms of the general categories of treatments, the stakeholders ranked them: (1) wound dressings, (2) venous surgery, and (3) systemic antibiotics. Of the specific evidence gaps, we chose the top nine prioritized by the stakeholders, based both on the number of stakeholders voting for a gap, as well as the fact that some stakeholder ranked it as their highest, or next highest priority. These top tier future research needs are: • • • • • • • •
biological dressings containing living cells; collagen dressings for recalcitrant ulcers; dressings with enzymatic debriding agents; laser ablation for superficial veins with reflux; valve surgery for deep veins with reflux; ligation for incompetent perforating veins; sclerotherapy for superficial veins with reflux; topical antibiotic or antiseptic-impregnated dressings for clinically noninfected CVLUs; and • radiofrequency ablation for superficial veins with reflux. Because rankings might vary with a different set of stakeholders, we advise the reader not to place undue emphasis on this Wound Rep Reg (2013) •• ••–•• © 2013 by the Wound Healing Society
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Table 5. Methodological evidence gaps identified as future research needs Evidence gap Standards for studying combinations of simultaneous treatments Standards for studying sequential treatments Standards for allocating patients to treatment groups Standards for estimating proper sample sizes Standards for recruiting patients Standards for describing participating patients and their ulcers
Context and recommendations The synergistic effect of treatments currently used simultaneously cannot be determined without appropriate statistical methods. Patients with chronic venous leg ulcers are often treated with sequential treatments without an evidence-based rationale for the order or timing. Studies of sequential treatment strategies are especially important in understanding the best use of surgery for chronic venous leg ulcers. The severity of chronic venous ulcers is apparent and can easily influence treatment allocation in the absence of randomized, concealed allocation. Well-developed statistical methods for estimating the number of patients/ulcers needed to address a research question exist and should be used in studies of treatments for chronic venous ulcers. Ethical methods for obtaining study participants’ informed consent should be used in all studies. The characteristics of participating patients and their ulcers allow assessment of the generalizability of study results to different patient populations and can highlight imbalances in characteristics between intervention and comparison groups that confound results. The duration, size, and number of ulcers appear relevant to the effectiveness of some dressings. Standard terms to describe and quantify wound beds need to be developed (e.g., dressings that absorb moisture should not be tested on dry ischemic wounds). Universal definitions of chronic venous leg ulcers should be developed and address physical characteristics, location, bacteriology, duration, and relation to venous flow.
Standards for defining and classifying “chronic venous leg ulcers” Standards for selecting valid The use of an appropriate comparison group is necessary for reducing confounding and for comparison groups understanding the performance of the active intervention relative to the comparison treatment. Standards for measuring Validated measures of outcomes in studies of chronic venous ulcers with acceptable inter and outcomes intra-rater reliability are critical. Needs include a standardized definition of epithelialization; validation of healing rates as an intermediate outcome; and validated measures of patient-reported outcome, such as pain and quality of life. Standards for reporting Patients enrolled in studies of chronic venous ulcer treatment should be monitored actively for harms any adverse events that could be related to treatment. All such events should be described in the articles that report the results of such studies. Standards for establishing Studies should be designed to follow patients long enough to ascertain the completeness and the needed duration of durability of ulcer healing. observation Standards for analyzing data Analytic plans should include estimation of sample size, intention-to-treat analysis, and statistical methods to account for confounding, effect modification, and clustering of patients. Standards for reporting all All patients enrolled in studies should be tracked throughout the studies and their “flow” patients’ flow through through the studies reported. “Completers analyses” are biased toward showing a benefit of studies the active intervention, as patients who have benefitted are more likely to complete a study. Intention-to-treat analysis and emphasis on retention of enrolled participants are essential. Knowledge of the reasons for losses to follow up (e.g., adverse events) is critical, and use of analytic techniques to handle missing data can reduce the chance of bias. Standards for conducting Standardization of caregivers to minimize variation in interventions such as ability to apply trials dressings, compression, perform surgical procedures, etc. Needs to be a separation of those applying interventions from evaluators of progress to prevent problems with blinding and bias. Standards of consistency All multicenter trials should standardize application of intervention and analysis of result between for multicenter trials study sites.
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particular order but to consider all of these as high-priority future research needs. We searched databases for ongoing but yet unpublished trials and did not find that any of these research needs are likely to be answered by ongoing research in the near future. Therefore, we consider all of the listed future research needs as good prospects for those funding future research in this field, and we believe such research would substantially advance the treatment of CVLUs. There was universal agreement on the need to produce higher quality data. We found a profound lack of highquality evidence for many types of wound therapy. Our findings do not mean that frequently used clinical interventions do not work; rather, there was no quality data to sustain such claims. The evidence gaps in this field are not merely due to a lack of studies but to a lack of adherence to study designs, research methodologies, and reporting standards capable of producing a body of interpretable studies with clear results that can be compared across studies and treatments. If the future clinical research needs we identified are addressed with the same poor quality studies published in the past, those gaps will remain. The FRNT identified specific study design and methodology issues that need to be improved in future research on treatments for wound healing in general and CVLUs specifically. Resolution of the substantial evidence gaps on therapies for CVLUs is feasible and should draw upon the extensive expertise found within the wound healing community. We suggest organizing a conference that draws serious distinguished investigators and providers including nurses, physicians, surgeons, patient advocates, clinical epidemiologists, clinical trial designers, statisticians, physical therapists, and pharmaceutical innovators to design remedies for the deficiencies highlighted in this report. This group should also consider the development of a wound healing “cooperative group” to deal with multicenter enrollment of patients in a timely fashion and ensure collection of high-quality clinical data. With healthcare payers increasingly demanding evidence to support coverage of expensive healthcare services, it will be essential to establish the efficacy of present modalities of care for CVLUs. Promising new interventions need to be evaluated in a high-quality cost-effective manner if we are to make progress toward our goals of better wound care for our seriously afflicted patients.
ACKNOWLEDGMENTS The authors would like to acknowledge Dr. Chad Boult, Ms. Lisa Wilson, and Ms. Elisabeth Haberl for their assistance in preparing the manuscript. The authors would like to thank the members of the stakeholder panel: Laura Bolton, PhD; Anthony Disser; Robert Kirsner, MD, PhD; Peter Lawrence, MD; David Margolis, MD, PhD; David Martin, MD; Marcia Nusgart, R.Ph; Robert Snyder, DPM; and Charles Turkelson, PhD. Source of Funding: This project was funded under Contract No. HHS 290-2007-10061-I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the US Department of Health and Human Services. Conflicts of Interest: None of the authors have any potential conflicts of interest to disclose. 8
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Topic These scores have been inverted so that the highest value (5) is the highest priority.
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*“Recalcitrant” denotes ulcers that have persisted for more than 6 months despite treatment.
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Collagen dressings for recalcitrant* ulcers Wound cleansing agents Debridement agents Laser ablation for superficial veins with reflux Valvular surgery for deep veins with reflux Ligation for incompetent perforating veins Sclerotherapy for superficial veins with reflux Topical antibiotic- or antiseptic-impregnated dressings for clinically noninfected CVUs Radio frequency ablation for superficial veins with reflux Alginate fiber dressings for exudative ulcers Negative pressure wound therapy for edematous CVUs Arterial/venous surgery for CVUs caused by mixed arterial and venous disease Adjuvant treatments (e.g., pentoxiphylline) for all types of CVUs Hydrogels and hydrocolloid dressings for dry ulcers Balloon angioplasty for obstructed deep veins
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List 1. Gaps in knowledge about the general categories of treatments for clinically non-infected chronic venous ulcers 5 5 4 5 5 5 2 5 2 3 3 4 3 3 3 3
4 Topical antiseptics and topical antibiotics 1 4 2 1 2 4 4 5 Systemic antibiotics 4 2 1 2 1 2 5 List 2. Gaps in knowledge about specific types of treatments for clinically non-infected chronic venous ulcers
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Appendix 1. Chronic venous leg ulcer future research needs stakeholder priority master list
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