Efficacy and safety of negative pressure wound therapy for the treatment of diabetic foot ulcers: A meta-analysis

Abstract

BACKGROUND

Diabetic foot ulcers (DFUs) are a significant challenge in diabetic care, and the efficacy of negative pressure wound therapy (NPWT) in treating them remains a subject of continuous investigation.

AIM

To provide a comprehensive meta-analysis of the role of NPWT in the management of DFUs.

METHODS

A systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, searching databases like PubMed, Embase, Web of Science, and the Cochrane Library. Randomized clinical trials (RCTs) were included to compare NPWT to other dressings for DFUs. Outcomes measured were wound healing time and rate, granulation tissue formation time, amputation rate, and adverse events. Study quality was evaluated using Cochrane's risk of bias tool. Analyses utilized χ², I², fixed or random-effects models via Stata v17.

RESULTS

Of the 1101 identified articles, 9 RCTs were selected for meta-analysis. Studies spanned from 2005 to 2020 and originated from countries including the United States, Chile, Pakistan, Italy, India, and Germany. Meta-analysis demonstrated a significant improvement in wound healing rate [risk ratio (RR) = 1.46, 95%CI: 1.22-1.76, P < 0.01] and a reduction in amputation rate (RR = 0.69, 95%CI: 0.50-0.96, P = 0.006) with NPWT. Furthermore, the time for granulation tissue formation was significantly reduced by an average of 19.54 days. However, the incidence of adverse events did not significantly differ between NPWT and control treatments.

CONCLUSION

NPWT significantly improves wound healing rates and reduces amputation rates in DFUs. It also hastens the formation of granulation tissue. However, the therapy does not significantly alter the risk of adverse events compared to alternate treatments.

Key Words: Negative pressure wound therapy; Diabetic foot ulcer; Wound healing; Amputation; Adverse events; Meta-analysis

Core Tip: This comprehensive meta-analysis synthesizes data from randomized controlled trials to evaluate the impact of negative pressure wound therapy (NPWT) on diabetic foot ulcers, a prevalent and challenging complication in diabetic care. Our analysis not only reaffirms the efficacy of NPWT in enhancing wound healing rates and reducing amputation risks but also emphasizes its role in accelerating granulation tissue formation without increasing adverse events.

INTRODUCTION

Diabetes mellitus (DM) is a metabolic disorder resulting from inadequate insulin secretion or functional deficiency. It is a significant global public health issue that is increasing in incidence[1]. Diabetic foot ulcers (DFUs) are among the most prevalent and serious consequences of diabetes, impacting 12% to 25% of patients with the condition. The majority of these patients are at high risk for recurrence within 5 years post-treatment, adversely affecting their quality of life and imposing a considerable strain on healthcare systems[2]. Multiple etiological factors contribute to the onset of DFUs, including inadequate glycemic management, trauma, callus formation, foot deformities, unsuitable footwear, dry skin, peripheral neuropathy, and compromised circulation. Chronic, non-healing DFUs may ultimately result in limb amputation, presenting a significant risk to the patient's physical and psychological well-being[3]. The obstinate characteristics of DFUs, along with elevated amputation and recurrence rates, impose a substantial socio-economic burden on patients and society, posing a considerable challenge to healthcare professionals globally[4].

In recent years, our expanding knowledge of the cellular and molecular mechanisms of wound healing has enabled the development of numerous new wound treatment methods. These encompass hyperbaric oxygen therapy, the use of topical growth factors, the use of bioengineered skin and tissue replacements, and negative pressure wound therapy (NPWT)[2]. NPWT has garnered significant attention owing to its distinctive mechanism of action and effectiveness. Although the exact underlying mechanisms of NPWT activity are not fully understood, it is thought that there are several synergistic effects. NPWT is thought to create a vacuum at the wound site, influencing microvascular hemodynamics to enhance blood flow and consequently improve the delivery of oxygen and nutrients, which are critical for wound healing[5]. Minimizing wound exudate can diminish local inflammation and related consequences. Moreover, the enhancement of granulation tissue, an essential component of the healing process, is another proposed consequence of NPWT. The therapy may also limit bacterial contamination in the wound environment, hence minimizing the likelihood of wound infection and associated consequences[6]. Moreover, NPWT is thought to facilitate wound closure by employing mechanical forces that approximate wound margins, while preserving a moist wound environment that is favorable for healing. Moreover, NPWT is well-aligned with the tissue, inflammation/infection, moisture, edge (TIME) strategy, a fundamental framework in modern wound care[7]. Through these multimodal effects, NPWT creates an optimized wound healing environment, reinforcing its role as a crucial therapeutic approach in DFU management[8].

Notwithstanding the recognized efficacy of NPWT in promoting wound healing, a substantial disparity exists between theoretical and empirical evidence and the results obtained in practical settings. This mismatch underscores the necessity for additional exploration to fully harness the potential of NPWT and enhance its application in clinical environments. Systematic reviews and meta-analyses offer rigorous approaches to synthesize findings from numerous studies, improving the accuracy of overall estimates while minimizing random mistakes and biases. We hypothesize that NPWT significantly enhances wound healing outcomes and reduces the risk of amputation in DFU patients, without increasing the incidence of adverse events. Therefore, we performed a systematic review and meta-analysis to comprehensively evaluate the effectiveness and safety of NPWT compared to traditional dressings in the clinical management of DFUs. Specifically, we seek to assess its impact on wound healing rate, granulation tissue formation, amputation risk, and the incidence of adverse events. This research endeavor aims not only to contribute to the growing body of evidence regarding DFU treatment strategies but also to provide clinically relevant insights that can inform and optimize patient management.

MATERIALS AND METHODS

Search strategy

Throughout the course of this research, standards set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[9] were rigorously followed. On September 28, 2024, comprehensive searches were conducted across four digital repositories: PubMed, Embase, Web of Science, and the Cochrane Library, without any temporal restrictions. The search terminology and query structure were meticulously tailored to each individual database's specifications. The specific search terms of PubMed were: ("negative pressure wound therapy" OR "NPWT") AND ("diabetic foot" OR "diabetic foot ulcer" OR "DFU") AND ("randomized" OR "clinical trial"). No language limitation was applied. Reference lists of relevant articles were screened manually for possible additional records.

Inclusion criteria

The inclusion criteria were as follows: (1) Studies involving patients with DFUs regardless of the severity or grade; (2) Experimental group must receive intervention using various negative pressure devices; (3) Control group must be treated using different wound dressings; (4) Must be a prospective randomized controlled trial (RCT); and (5) Outcome measures should include wound healing time, wound healing rate, granulation tissue formation time, amputation rate, and the incidence of adverse events.

The exclusion criteria were as follows: (1) Studies in which NPWT was not used properly, for instance, studies where instances of leakage were not addressed promptly; (2) Studies with incomplete data or where data could not be accessed; or (3) Case reports, commentaries, expert opinion and narrative reviews.

Data extraction

During review, two independent assessors undertook the tasks of literature screening and data extraction. Following this, mutual verification was performed. If any disparities arose, a collaborative discussion between the reviewers was conducted. If a consensus remained elusive, a third evaluator was consulted for arbitration. The extraction process encompassed critical data points from the selected articles, including the primary author, date of publication, research setting and participant count, study methodology, ulcer severity, and in-depth details concerning the intervention-ranging from application methods and distinctive features of the NPWT apparatus to the specific treatments administered to individual cohorts. Additionally, therapeutic duration, follow-up intervals, and specified outcome metrics were recorded. If pertinent data was missing or not delineated in the publication, primary authors of the study were contacted via email seeking access to the undisclosed data.

Quality assessment

In evaluating the quality of the studies incorporated, the Cochrane Collaboration's risk of bias instrument[10] was utilized. Two independent evaluators examined several domains: random sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other potential bias sources. Each domain was classified as having a low, uncertain, or high risk of bias. Discrepancies in evaluations were resolved through discussion, and a third reviewer was consulted when necessary.

Statistical analysis

Statistical heterogeneity of the included studies was assessed using χ² statistics, and the extent of heterogeneity was measured by the I² value. In instances where the I² value was below 50% and the corresponding P value was ≥ 0.10, this indicated a lack of significant heterogeneity, leading to the application of the fixed-effect model to calculate the overall effect size. If the I² value was ≥ 50% or the corresponding P value was < 0.10, this indicated considerable heterogeneity. In instances of observed statistical heterogeneity, the random-effects model was utilized to ascertain the composite effect size. The weighted mean difference and its 95%CI were utilized as the effect size for the study of continuous variables. The risk ratio (RR) with its 95%CI was the chosen metric for effect size in dichotomous variables. The symmetry of the funnel plot was examined to identify any possible publishing bias. A balanced distribution of data points on both sides of the funnel plot's peak indicated lower probability of publication bias affecting the meta-analysis results. Egger's linear regression test was utilized as a quantitative method to identify the existence of publication bias. All statistical analyses were performed using a two-tailed approach. A P value less than 0.05 was considered statistically significant. All data analyses were conducted utilizing Stata software, version 17 (StataCorp, College Station, TX, United States).

RESULTS

Search results and study selection

In the preliminary search across the electronic databases, a total of 1101 pertinent articles were identified. Upon eliminating duplicates, assessing titles and abstracts, and rigorously applying the predefined inclusion and exclusion criteria, 25 relevant articles were shortlisted. Out of these, 16 were excluded upon a detailed review, resulting in 9 articles that were ultimately included in the meta-analysis[11-19]. The flowchart illustrating the literature selection process is depicted in Figure 1.

Figure 1  Selection process of included studies.

Study characteristics

The characteristics of studies included in this systematic review are presented in Table 1. The meta-analysis compiles studies spanning from 2005 to 2020 originating from the United States, Chile, Pakistan, Italy, India, and Germany. While study grades and durations varied, treatment modalities predominantly focused on NPWT, vacuum-assisted closure, vacuum sealing drainage, and negative pressure sealed drainage dressing. The treatment durations, where specified, ranged up to 16 weeks, and follow-ups extended up to 10 months. Predominant observational indices across these studies were 90% granulation tissue formation time, wound healing rate, amputation rate, and the incidence of adverse events, though the depth of detail varied among studies.

Table 1 Characteristics of studies included in the meta-analysis.

Ref.	Study site	Year	Grade	Duration	Treatment	Treatment time	Follow-up time	Observational indices
Armstrong et al[11]	United States	2005	TX University 2-3	Exp (1.2 ± 3.9) months, Con (1.8 ± 5.9) months	NPWT 50-200 mmHg	16 weeks	16 weeks	90% granulation tissue formation time, wound healing rate, incidence of adverse events
Blume et al[12]	United States	2008	Wagener 2-3	Exp (198.3 ± 323.5) days, Con (206.03 ± 365.9) days	VAC 100 mmHg	Exp (63.6 ± 36.57) days, Con (78.1 ± 39.29) days	16 weeks	90% granulation tissue formation time, wound healing rate, amputation rate, incidence of adverse events
Sepúlveda et al[13]	Chile	2009	Not given	Not given	VAC	Not given	Not given	90% granulation tissue formation time
Riaz et al[14]	Pakistan	2010	Not given	3-5 months	VAC 50-125 mmHg	Not given	6 months	90% granulation tissue formation time
Paola et al[15]	Italy	2010	TX University 2-3	Not given	VSD 125 mmHg	8 weeks	8 weeks	90% granulation tissue formation time, amputation rate
Nain et al[19]	India	2011	Not given	Not given	Negative pressure sealed drainage dressing 15.96-59.85 kPa	Exp 2345 days, Con 46145 days	3 months	Wound healing rate
Lone et al[16]	India	2014	Armstrong 2-3	Not given	NPWT 80-125 mmHg	8 weeks	6-10 months	90% granulation tissue formation time, amputation rate
James et al[17]	India	2019	≥ Wagener 2	Exp (51.4 ± 36.3) days, Con (52.6 ± 27.6) days	NPWT 125 mmHg	Not given	1 week, 2 weeks, 1 month, 2 months	Amputation rate
Seidel et al[18]	Germany	2020	Wagener 2-4	> 4 weeks	VAC	16 weeks	6 months	90% granulation tissue formation time, wound healing rate, amputation rate, incidence of adverse events

VAC: Vacuum assisted closure; VSD: Vacuum sealing drainage; Con: Control group; Exp: Experimental group; NPWT: Negative pressure wound therapy.

Results of quality assessment

The evaluation of bias risk was conducted across multiple domains in the 9 studies that were included. Two studies demonstrated a low risk of bias in all categories, indicating a high level of methodological rigor. However, 33% of the studies were found to have a high risk of bias in the domain of blinding of participants and personnel. This suggests that the potential for performance bias might have influenced the outcomes in these studies. Furthermore, in 21% of the included randomized controlled trials, a high risk of selective reporting bias was observed. This indicates that the possibility of incomplete or selective outcome reporting may have affected the overall results of these studies (Figure 2).

Figure 2 Quality assessment of included studies using Cochrane Collaboration's tool criteria. Red in figure indicates high risk, and green means low risk.

Wound healing rate in meta-analysis

A total of 5 studies reported on wound healing rate. The combined effect size indicated no significant heterogeneity amongst these studies (I² = 0%, P = 0.707). Utilizing the fixed-effects model for meta-analysis, we identified a statistically significant difference (RR = 1.46, 95%CI: 1.22-1.76, P < 0.01). A Forest plot of the results across the studies is shown in Figure 3A.

Figure 3 Forest plots. A: The wound healing rate; B: The amputation rate; C: The 90% granulation tissue formation time; D: The adverse event incidence rate.

Amputation rate in meta-analysis

We conducted a meta-analysis on the amputation rate reported across studies, with all included studies exclusively documenting minor amputation events. Among the studies reviewed, six provided data regarding these minor amputation events. The aggregated effect size revealed a moderate heterogeneity among the studies, though it was not statistically significant (I² = 25.7%, P = 0.241). When consolidating the findings using a fixed-effects model, we detected a statistically significant difference (RR = 0.69, 95%CI: 0.50-0.96, P = 0.006). The distribution and individual study contributions to the collective effect size are visualized in the Forest Plot (Figure 3B). The obtained RR of 0.64 with a 95%CI indicates a 31% reduction in the rate of minor amputations for the investigated intervention compared to the control or alternative therapy.

Granulation tissue formation duration in meta-analysis

In the realm of wound healing, the time taken for granulation tissue formation is a pivotal marker. The endpoint for granulation tissue formation is typically defined as the percentage of the wound surface covered by healthy, vascularized granulation tissue. In clinical studies, a wound is often considered to have achieved adequate granulation tissue formation when a predetermined threshold, commonly around 80% coverage, is reached. Our meta-analysis considered findings from seven studies that reported on the duration of granulation tissue formation. Upon assessing the heterogeneity between these studies, our analysis deduced a fairly consistent methodology and outcome across them, as indicated by the statistically non-significant heterogeneity (P = 28.4%, P = 0.232). When synthesizing the results using a fixed-effects model, we identified a significant difference in the duration of granulation tissue formation. Specifically, the mean difference was -19.54 days, with a 95%CI ranging from -21.32 to -17.76 days (P < 0.001; Figure 3C). This suggests a substantial decrease in the time required for granulation tissue formation with the intervention in focus relative to the control or alternative treatments.

Incidence of adverse events in the meta-analysis

One of the key evaluative criteria in assessing the safety and effectiveness of any intervention is understanding the incidence of adverse events. Four studies included in our meta-analysis shed light on the incidence of specific adverse events, namely edema, infection, pain, and bleeding. Notably, among these adverse outcomes, infection emerged as the most frequently reported complication. Upon evaluating the consistency of results across these studies, our meta-analysis found a relatively low level of heterogeneity, with an I² value of 19.6% and a corresponding P value of 0.292. Such a result underscores a general alignment in the methodologies and outcomes of these studies, enhancing the credibility of our collective conclusions. However, when we pooled the results using a fixed-effects model, the observed differences in the incidence of adverse events were not statistically significant. Specifically, the RR was 1.40 with a 95%CI spanning from 0.85-2.28 (P = 0.16; Figure 3D). This indicates that the intervention being evaluated did not significantly alter the risk of experiencing adverse events compared to the control or alternate treatments.

Publication bias

The funnel plot, visualized from the data of the incorporated studies, demonstrated a symmetrical distribution, underscoring the absence of notable publication bias (Figure 4). Additionally, the Egger's linear regression analysis reaffirmed this observation, revealing that there was not any statistically significant publication bias across various analyzed parameters (all P values > 0.05). Consequently, these findings bolster the integrity and reliability of our meta-analysis outcomes.

Figure 4  Funnel plot for publication bias in all included studies.

DISCUSSION

DM patients exhibit histological and cellular alterations in skin tissue even when structural integrity appears intact. Chronic hyperglycemia induces abnormal cell proliferation, persistent inflammation, endothelial dysfunction, and microenvironmental imbalances, all of which impair wound healing. These pathophysiological complexities make DFUs particularly challenging to manage. NPWT has demonstrated significant therapeutic efficacy in DFUs, potentially through mechanisms involving differential gene expression and microvascular modulation[20]. This meta-analysis represents a significant advancement in understanding the clinical efficacy and safety of NPWT in DFU management. By integrating data from nine RCTs conducted across diverse geographic regions, our study demonstrates that NPWT significantly enhances wound healing rates, expedites granulation tissue formation, and reduces the risk of minor amputations, all without a substantial increase in adverse events[21]. Notably, these findings highlight the multimodal benefits of NPWT, which align with the TIME strategy, thereby reinforcing its comprehensive role in optimizing wound care. Clinically, these results provide robust evidence supporting the incorporation of NPWT into standard treatment protocols for DFUs, potentially improving patient outcomes and reducing the socio-economic burden associated with diabetic foot complications. This insight into NPWT's specific molecular mechanisms has the potential to revolutionize clinical applications and spearhead new therapeutic innovations. NPWT facilitates wound healing through a multimodal approach, including enhanced microvascular perfusion, mechanical stress-induced cellular proliferation, exudate management, and bacterial load reduction[22]. Additionally, it promotes granulation tissue formation and epithelialization by modulating local cytokine and growth factor expression, reinforcing its role in optimizing wound healing conditions. While NPWT effectively manages wound exudate and promotes debridement through negative pressure, it does not inherently eliminate the need for manual removal of necrotic or built-up tissue during dressing changes. Regular assessment and debridement remain essential components of wound care to ensure optimal healing outcomes[23]. However, comprehensive validation through further research is necessary.

Traditional dressings and treatment approaches for DFUs frequently fail to address the underlying problems of the wound. Despite continuous advancements in dressing materials, they often adhere to the tissue, potentially damaging the newly produced granulation tissue during changes. Furthermore, extended arid conditions at the wound site can impede the migratory activity of epithelial cells, hence delaying wound healing. Conversely, NPWT is essential for enhancing wound microcirculation and the wound bed structure, promoting the favorable regeneration of fibroblasts and endothelial cells[24]. NPWT significantly expedites the healing process by managing wound infections, preserving wound hydration, and promoting epithelial cell migration. Post-vascular treatment for venous and arterial ulcers generally facilitates healing via wound care; nevertheless, the intrinsic properties of DFUs may occasionally need amputations. Amputations significantly diminish the quality of life for DM patients and are associated with a reduced life expectancy, averaging around 2 years following the procedure[25].

Although the standardization of endpoints in chronic wound care studies remains limited, several investigations have reported complete wound closure as a key outcome measure. This variability in endpoint definitions, ranging from the achievement of approximately 80% granulation tissue coverage to complete epithelialization, poses challenges when attempting to directly compare study outcomes. In some studies, complete wound closure is defined as the full re-establishment of an intact epidermis across the entire wound surface, whereas others consider the threshold of 80% granulation tissue formation as a significant marker of progress toward healing[26-28]. Such heterogeneity in endpoint definitions can influence the interpretation of treatment efficacy and may contribute to inconsistencies in reported outcomes across the literature. However, our meta-analysis focused on the most consistently reported endpoints-namely, granulation tissue formation and overall wound healing rates-which have been more uniformly documented across the selected studies. By concentrating on these endpoints, we were able to provide meaningful insights into the intervention's effectiveness while minimizing the impact of variable endpoint criteria. First and foremost, the findings underscored a clear enhancement in wound healing rate, as evidenced by data pooled from five studies that consistently showed significant improvements. This was further bolstered by the lack of significant heterogeneity among these studies, thereby bolstering the reliability of this outcome. In terms of amputation rates, a critical endpoint in wound care, the analysis revealed promising results. The data from six studies not only indicated a statistically significant reduction in amputation rates for patients under the given intervention, but also emphasized moderate consistency across these studies. The 31% reduction in amputation risk elucidates the intervention's potential to revolutionize patient care in this domain.

Further, the duration of granulation tissue formation, a key marker for wound healing progression, has shown remarkable reductions under the intervention. The synthesis of results from seven studies demonstrated a substantial decrease in duration of wound healing, suggesting that the intervention accelerates the wound healing process compared to control or alternative treatments. This holds immense clinical relevance, as faster granulation tissue formation often leads to better patient outcomes and may reduce the associated healthcare costs. However, every intervention comes with its own challenges. One such challenge for this intervention centers around the incidence of adverse events. Despite the occurrence of certain complications like edema, pain, and bleeding, infection surfaced as the most reported adverse event. Although heterogeneity among the four studies focusing on this aspect was low, the RR indicates that there was no statistically significant difference in adverse event incidence between the intervention and control or alternative treatments. This is a crucial consideration for clinicians, as any therapeutic decision should balance efficacy against safety.

This meta-analysis has several limitations that warrant consideration. First, the heterogeneity in outcome definitions across studies may compromise comparability and uniform interpretation of results. Additionally, potential residual confounding factors-unaccounted for in individual studies and publication lag could limit the comprehensiveness of our findings. Variability in NPWT devices, including differences in negative pressure settings and operating modes, further complicates uniform data synthesis. To address these gaps, future research should incorporate prospective, multicenter trials with standardized outcome definitions and detailed reporting of NPWT device parameters. The use of individual patient-level data could mitigate residual confounding, while stratified analyses would help elucidate the relationship between NPWT treatment duration and clinical outcomes, including differentiation between partial (minor) and full (major) amputations. Moreover, standardized adverse event reporting, especially regarding infection rates, is crucial to better delineate the safety profile of NPWT. These improvements are expected to benefit clinicians and researchers by providing robust, reproducible evidence that can optimize NPWT protocols in DFU management, thereby enhancing patient outcomes. Ultimately, such studies will help resolve current uncertainties and inform future therapeutic strategies.

CONCLUSION

In summary, NPWT demonstrably enhances wound healing and reduces amputation incidents in DFUs. It accelerates granulation tissue formation, a crucial healing phase. Nonetheless, its impact on the incidence of adverse events remains neutral, underscoring the necessity for meticulous clinical judgment when considering its implementation.

ACKNOWLEDGEMENTS

We thank all the participants for their efforts.