Effectiveness of Negative Pressure Wound Therapy in Treating Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

© 2024 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Wounds or HMP Global, their employees, and affiliates.

NPWT, or vacuum-assisted wound closure, is a treatment method for complex wounds. It involves applying a foam dressing coupled to a negative pressure vacuum pump through which the wound exudate is collected in a canister.¹ Physical therapies like NPWT have a minimal chance of causing microbial resistance. Although studies on the function of NPWT in biofilm formation are scarce, this therapy has been demonstrated to prevent biofilm-associated infections when applied as early as feasible.²

The vacuum is applied to the wound after debridement and hemostasis. The wound is covered with a sterile foam dressing in which a fenestrated tube is fixed and connected to a vacuum pump. The vacuum sucks the fluids from the wound on recommended suction pressure varying from 50 mm Hg to 125 mm Hg to avoid wound bleeding.³

Studies indicate that the NPWT can be used in different anatomical sites and lesions of various etiologies as an adjuvant method in the healing process because it accelerates the preparation of the wound bed for definitive coverage.^1,3 The system can absorb large volumes of exudate, improve blood flow, and induce granulation and angiogenesis, thus reducing the frequency of dressing changes. It also reduces odor and local edema by decreasing bacterial colonization.^1,3

Although NPWT is a popular treatment for DFUs, and some clinical trial results show that it promotes wound healing and reduces infection risk, there is no evidence that it is better than conventional wound dressing procedures, which are less expensive.⁴ The lack of clinical evidence is due to the existence of low-quality randomized clinical trials that lack adequate comparisons and evaluation of the outcomes.⁴

A systematic review of the effectiveness of NPWT in DFUs can empower clinicians with the information they need to make informed decisions by identifying gaps in current knowledge and areas requiring further research. Such a review can guide future research efforts and inform clinical practice by pinpointing areas where evidence is lacking, thereby enhancing the quality of health care delivery. Meta-analyses provide valuable insights into the generalizability of findings by assessing the heterogeneity of study results and determining whether treatment effects vary across different study populations or settings.

The current study reviews the effectiveness of NPWT in the management of DFUs and evaluates the clinical outcomes of full and partial wound healing, taking into consideration the methodologies and heterogeneity of the studies.

A systematic review and meta-analysis of randomized controlled trials was carried out according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines,⁵ as outlined by the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions version 6.4.⁶ The International Prospective Register of Systematic Reviews (PROSPERO) number is CRD42019119715.

The authors followed the PICO (population/patients, intervention, comparison/control, outcomes) study design to formulate the following question: What is the effectiveness of NPWT, compared with different types of dressings or placebo, in healing, partial healing, and reducing the occurrence of amputations in patients with DFU?

Eligibility criteria included randomized controlled trials as a methodological design; published or unpublished; any sample size; application of NPWT in patients with DFU in 1 arm of the study; 1 or more comparison groups who received alternative methods of exudate control coverage; and analysis of at least 1 of the proposed outcomes. Study selection was not restricted based on language or date of publication.

Exclusion criteria consisted of crossover clinical trials, the use of NPWT in amputations, studies with another methodological design, and the infeasibility of data available for analysis.

In May 2021, the literature search was performed using 3 electronic databases: PubMed, Cochrane Library, and Web of Science (Table 1). A manual search was also performed for grey literature in Google Scholar and the US National Library of Medicine ClinicalTrials.gov database. The reference lists of retrieved studies were also examined to identify potentially eligible studies that had not previously been located.

Two reviewers (M.M.D., C.K.L.C.) independently assessed the identified articles, extracted data, and cross-referenced them. After applying the eligibility criteria, each reviewer selected eligible articles and excluded irrelevant studies. The 2 lists obtained were compared and, in case of disagreement (for inclusion or exclusion of studies), a third reviewer (S.O.I.) helped in the judgment process. The literature screening process consisted of 2 stages: a first screening (reading the study title) and a second screening (reading the full text).

From the list of included studies, the methodological quality (internal validity) of each clinical trial was determined. Next, the narrative synthesis was carried out by extracting qualitative data—that is, author or authors, year of publication, country of origin, journal, and publication database—as well as clinical data, that is, the total number of participants, intervention group (number of individuals and type of intervention), control group (number of individuals and type of intervention), analyzed outcomes, and adverse events.

Internal validity was verified using the Risk of Bias Tool in the ReviewManager software (version 5.3; The Cochrane Collaboration). Studies were judged for the following domains: selection bias (random sequence generation), performance bias (masking of participants and professionals), detection bias (masking of outcome raters), reporting bias (selective outcome reporting), and segment bias (participant losses that produce statistical heterogeneity between groups). Each domain was classified as "low risk of bias," "high risk of bias," or "undetermined risk of bias."

The included studies were classified according to allocation concealment, defined by the Cochrane Handbook for Systematic Reviews of Interventions.⁶ Category A: Adequate description of the allocation process. Category B: Although the allocation process has not been described, the performance of randomization is evident. Category C: Allocation secrecy was conducted inappropriately (eg, arrival list, currency). Category D: The randomization process was not evidenced.

In addition, the TIDieR checklist was applied. This tool is designed to improve the description of interventions in clinical trials by establishing standards for reporting these procedures.⁷ Following the overall structure of the TIDieR checklist, the following data were recorded for each study: (1) name of intervention, (2) clinical indication and rationalization, (3) description of materials, (4) description of procedures, (5) provider, (6) how the intervention was applied, (7) where the intervention took place, (8) when the intervention was delivered and for what duration, (9) adaptation of the technique between patients, (10) intervention modifications during the study, (11) how well-planned the intervention was, and (12) whether the intervention was delivered as planned.

The GRADE system was applied to validate the meta-analytical results to evaluate the quality of the evidence (external validity) and qualify the completeness of the results obtained. The certainty assessments of the GRADE evidence are determined by considering 5 domains: risk of bias, inconsistency, indirect evidence, imprecision, and publication bias.⁸

The search strategy resulted in the retrieval of 3621 studies (Figure 1). Of these, 5 articles were published in more than 1 electronic database, and these duplicates were removed; an additional 3552 articles were excluded in the first screening. Of the remaining 64 studies that were analyzed in total, 50 did not meet the eligibility criteria. Thus, 14 studies made up the final sample of the systematic review.

In assessing the methodological quality of the studies, individual judgment of the 5 domains was performed and is shown in Figure 2.

In the first domain (selection bias), about 43% of the studies did not adequately describe the distribution of individuals between the research arms.^10,13,18-21 However, most studies showed performance bias because, due to the intervention characteristics, it was impossible to blind participants and evaluators.^9-17,19,20

Sixty-four percent of the studies did not identify the blinding approach used for the evaluator of the obtained results (n = 9); thus, an unknown risk of bias was set for the "results evaluation" area (detection bias).^{10,12-14,17,19-22}

For the segment bias domain, 14% of the studies showed significant participant losses in 1 of the evaluated arms, with resulting statistical heterogeneity.^19,20

Most studies reported all previously established outcomes. Funding of studies was considered reporting bias. Funded studies were classified as having a high risk of bias for this domain.²²

In the critical evaluation of the studies concerning allocation concealment, 4 were classified as category A because they reported a random component in the sequence generation process, such as a computer-generated table of random numbers or a randomization schedule^9,11,12,15; 4 were classified as category B for mentioning the method of randomization of participants^10,14,17,21; 5 studies inappropriately allocated participants and thus were classified as category C^{13,16,18,20,22}; and 1 study¹⁹ was identified as category D and was excluded at this stage of the systematic review.

Nine studies were evaluated based on the standards recommended by TIDieR for reporting interventions in randomized clinical trials.^{10,12,14,15,17,18,20-22}

All studies reported the name of the intervention, the clinical indication, and the scientific rationale for its use. However, no protocol described the details of the material used, and only 2 studies presented the steps for applying the intervention.^12,17 It should be noted that 4 studies did not offer a minimal description of the intervention.^14,17,18,22 There was no description of the intervenor in any clinical trial.

The treatments took place in outpatient clinics or hospitals. The studies did not clarify the length of each session or the frequency of dressing changes. Technique adaptations for individual cases were not mentioned. One study carried out intervention modifications over the study period.²¹ Four studies did not report any strategies to ensure intervention fidelity^12,14,17,18 and 4 showed no faithfulness of the findings.^10,15,20,22 The information from the included studies is summarized in Table 2 and Table 3.

Two of the included studies analyzed the outcome of wound healing, reporting a statistically significantly higher number of wounds healed in the NPWT group compared with the control group.^11,16 Among the 13 studies, 9 addressed the outcome of wound area reduction^{9,10,12-14,17,20-22}; in 7 of these, NPWT wound area reduction was superior to the different comparator interventions.

In a study that compared NPWT with NPWT plus photon therapy, there was no significant difference in reduction of wound surface area between the 2 groups.²¹ However, a study that compared 3 interventions (NPWT vs bovine collagen vs conventional treatment) demonstrated more marked mean percentage wound area reduction with collagen treatment (26.4%) than with NPWT (19.8%) or conventional therapy (17.0%).²²

For the secondary outcome, "reduction in the occurrence of amputations," 3 studies reported fewer amputations in the NPWT group than in the control group,^10,11 and 1 reported no statistically significant difference between the groups.²¹ None of the selected studies reported adverse effects related to the intervention.

Among the included studies, 11 showed significant clinical heterogeneity.^{10-12,14-19,21,22} This dichotomy was mainly attributed to the different forms of treatment adopted in the comparator groups. However, 3 studies showed clinical homogeneity (I² = 100%), which allowed for a meta-analysis and a statistical analysis of the effectiveness of NPWT vs the application of wet saline gauze in a total of 90 participants, considering the level of reliability of 95% (95% CI) (Figure 3).^9,13,20

One of the studies included in the meta-analysis did not report the weighted mean of the analyzed result, and its measurement parameter was different.¹³ Thus, an independent statistician was consulted to convert the measurement units and estimate the standard deviation.

The meta-analytical measure risk ratio (RR, 1.00; 95% CI, 0.91–1.10) remains in the intervention scenario represented by the confidence interval and the diamond, Figure 3, showing a difference between the intervention and control groups for the resolution outcome injury clinic. The result suggests a difference in effectiveness between the 2 interventions (vacuum, gauze and saline).

However, a determining factor of bias in the results is the prolonged study period (1 year) in 1 study²⁰ compared with the meantime of 19 days in the other 2 studies.^9,13

Another dominant factor that can influence outcomes concerns the variability of the pressure configuration of NPWT systems between studies, with emphasis on the alternation of negative pressure values between –75 mm Hg and 38.5 mm Hg,⁹ negative pressure between 80 mm Hg and 150 mm Hg,²⁰ and negative pressure of 125 mm Hg.¹³

The quality of evidence from the meta-analysis results (external validity) for the outcome wound area reduction was determined using the GRADE system (Figure 4). The risk in the intervention group (95% CI) is based on the assumed risk of the comparator group and the relative effect of the intervention. The evidence was classified as moderate, which indicates that further studies may modify the confidence in the effect estimate.

The objective of the current systematic review was to evaluate the effectiveness of NPWT in treating patients with DFUs compared with different alternatives for topical treatment of the ulcers. A total of 945 patients were analyzed in the current systematic review in 14 randomized clinical trials, randomly assigned to the outcomes healing, partial healing (wound area reduction), and reduction in the occurrence of amputations.

A Cochrane meta-analysis evaluated the use of NPWT in wounds of multiple etiologies, including amputations, on the lower limbs of patients with diabetes.¹ The primary outcome measures were the number of wounds healed and time to healing. In patients with postamputation wounds, more healed wounds were observed in the NPWT group than in the conventional treatment group. Furthermore, when applied to DFUs, NPWT was identified as a potential treatment with higher healing rates in less time than conventional dressings.¹

NPWT is a noninvasive adjunctive therapy that promotes healing by reducing edema and improving granulation tissue formation. A meta-analysis comparing NPWT with conventional treatment suggested that duration of therapy, decrease in wound size, and rate of effectiveness were significantly different between the 2 groups (mean difference = −12.86; 95% CI, −12.86 to −8.52; P < .00001; mean difference = 8.71; 95% CI, 3.25-14.17; P = .002; relative risk = 1.41; 95% CI, 1.22-1.62; P < .00001, respectively).²³

A multicenter randomized controlled trial compared NPWT vs standard coverage after partial diabetic foot amputation in 162 patients for the outcomes of full wound closure and wound area reduction.²⁴ Complete healing was more prevalent and occurred sooner in the intervention group compared with the control group. The rate of secondary amputations was also lower in the NPWT group.

The pressure level used in NPWT is applied according to the patient's clinical situation and depends on the risk of ischemia or pain. The most commonly used pressure is 125 mm Hg, and pressure can be applied continuously or intermittently. However, this pressure can fluctuate between 50 mmHg and 200 mm Hg, and values outside this standard may not influence wound healing.²⁵

Among the studies included in the current systematic review, there was substantial variability in negative pressure values used in patients undergoing NPWT, ranging from 38.5 mm Hg⁹ to 200 mm Hg.^11,12 One study used values below 50 mm Hg,⁹ while 2 used negative pressure above 150 mm Hg.^11,12 Four studies did not describe the mean negative pressure used.^10,15,16,18

Zonghuan and Aixi²⁷ reported adverse effects of NPWT, such as local pain, damage to the scar tissue during foam removal, inflammatory reaction due to the deposition of fiber residues in the wound bed, and the risk of bleeding, especially in patients using anticoagulants due to the inability to achieve hemostasis. However, no adverse events were documented in the studies selected in the current systematic review.

Regarding the cost-effectiveness of NPWT, in 2014 Driver and Blume²⁶ published the results of a retrospective analysis of randomized clinical trial patient data. They evaluated the medical records of 324 patients who received either NPWT or conventional treatment for the management of chronic wounds (n = 162 for each group). A median reduction in wound area of 85% in the NPWT group was noted, compared with 61.8% in the advanced moist wound therapy group. The total cost for all patients, regardless of closure, was $1941472.07 in the intervention group and $2196315.86 in the control group. In patients who achieved complete wound healing, the mean cost of treatment per patient was $10172 (median cost of $1227 per cm²) with NPWT compared with $9505 (median cost of $1695 per cm²) with conventional treatment. The results showed a better cost-benefit ratio with NPWT due to reduced general hospitalization costs.²⁶

The results obtained indicate the potential benefit of NPWT for clinically relevant outcomes: healing, wound area reduction, and decrease in the occurrence of amputations in patients with DFUs when compared with different therapeutic strategies. However, methodological quality and clinical heterogeneity limitations make it impossible to estimate the intervention's effect and generalize the results. Furthermore, external validation of the data obtained in the subgroup meta-analysis was classified as moderate and insufficient to influence the results.

Based on a robust search strategy, the current review synthesizes the evidence available in randomized clinical trials that evaluated NPWT in the management of DFUs. Thirteen studies—conducted in Europe, the United States, and Asia and published in English, Mandarin, or Russian—evaluated various NPWT strategies, alone or in combination with other interventions, as an alternative treatment for DFUs.

The authors recommend that TIDieR guidelines be adopted to describe the treatment protocol to enable reproducibility of the methodology of clinical trials that use NPWT in the management of wounds. To facilitate comparisons between trials, the TIDieR checklist can provide a structured framework for thoroughly describing the intervention, including details on the kind of device used, pressure settings, and dressing changes; guarantee that the intervention description is comprehensive and standardized across studies; provide enough data for other researchers to duplicate the intervention in their studies; enhance clinical practice by giving health care professionals the knowledge they need to carry out the intervention successfully; and improve the quality of data available for meta-analyses and systematic reviews. 

Authors: Michel Marcos Dalmedico, MS¹; Angela do Rocio Fedalto²; Waleska Alves Martins²; Chayane Karla Lucena de Carvalho, MS¹; Beatriz Luci Fernandes, PhD¹; and Sergio Ossamu Ioshii, PhD¹

Affiliations: ¹Graduate Program in Health Technology, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil; ²Nursing Department, Universidade Positivo, Curitiba, Brazil

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Beatriz Luci Fernandes, PhD; Pontifícal Catholic University of Paraná, Graduate Program in Health Technology, Polytechnic School, R. Imaculada Conceição, 1155, Prado Velho, Curitiba, PR, 80320-030, Brazil; beatriz.fernandes@pucpr.br

Manuscript Accepted: June 14, 2024