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Original article

Negative-Pressure Wound Therapy: Systematic Review of Randomized Controlled Trials

Dtsch Arztebl Int 2011; 108(22): 381-9; DOI: 10.3238/arztebl.2011.0381

Peinemann, F; Sauerland, S

Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Köln:
Dr. med. Peinemann, M.Sc., PD Dr. med. Sauerland, MPH

Background: In negative-pressure wound therapy (NPWT), a wound is covered with an airtight dressing, and negative pressure is applied. This is thought to promote healing. We evaluated NPWT with an updated, systematic review of the literature.

Methods: We systematically searched the PubMed and Cochrane Library databases for randomized, controlled trials (RCTs) of NPWT for the treatment of acute or chronic wounds. The primary outcome was complete wound closure.

Results: We found reports of 9 RCTs in addition to the 12 covered by earlier IQWiG reviews of this topic. Five of the 9 new trials involved NPWT systems that are not on the market. The frequency of complete wound closure is stated in only 5 of the 9 new reports; a statistically significant effect in favor of NPWT was found in only two trials.The results of 8 of the 9 new trials are hard to interpret, both because of apparent bias and because diverse types of wounds were treated.

Conclusion: Although there may be a positive effect of NPWT, we did not find clear evidence that wounds heal any better or worse with NPWT than with conventional treatment. Good RCTs are still needed to evaluate NPWT.

Negative-pressure wound therapy (NPWT) is a sealed wound-care system and is particularly indicated for large chronic persistent wounds and acute complicated wounds (1, 2). The system consists of an electronically controlled pump and a foam dressing that drains the wound. An adjustable negative pressure is applied via an airtight adhesive film that covers the wound. NPWT drains wound exudate and is thought to promote blood circulation and healing.

This systematic review aims to update the systematic reviews on NPWT previously published by the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) (35). The aim of these reports was to evaluate wound healing and adverse events following NPWT in comparison to conventional treatment in patients with acute or chronic wounds.

Methods

The reports within this systematic review were compiled in accordance with the principles of the PRISMA statement (e1).

Inclusion criteria

The research included randomized controlled trials (RCTs) involving patients with acute and chronic wounds. Because of the increasing number of RCTs conducted in recent years, non-randomized trials were not included in the evaluation. The intervention under examination was NPWT. As in the previous reports, studies of systems not commercially available were included in addition to commercially available systems. In the systems that were not commercially available, negative pressure was generated by a suction pump for chest drainage, a central vacuum system or Redon bottles, for example. The comparator treatment was conventional dressings, generally saline-soaked gauze dressings. There was no minimum number of patients per trial. There was no restriction on language or year of publication. However, articles in languages other than English or German were only included in the review if there were translations available that made it possible to assess the trials concerned.

Search strategy

Unlike the earlier IQWiG reports, this review included only RCTs (3, 4). The simplified search strategy used (eTable 1 gif ppt) identified all 12 RCTs already included in PubMed and the Cochrane Library’s Clinical Trials on November 7, 2010. EMBASE and CINAHL were not searched, as they had not yielded any additional relevant results in previous searches (6). The search results from the two included databases were imported into EndNote X3 (Thomson Reuters) and duplicates were deleted manually.

The electronic trial registers ClinicalTrials.gov (URL: http://clinicaltrials.gov/; registration numbers: NCT followed by eight digits) and the International Standard Randomised Controlled Trial Number Register (URL: www.controlled-trials.com/; registration numbers: ISRCTN followed by eight digits) were searched for completed and ongoing trials on January 15, 2011, using the following search terms: “vacuum assisted closure;” “vac;” “negative pressure wound therapy;” “npwt.”

Study selection

First of all, articles were excluded on the basis of their title and abstract if these did not mention NPWT or it was clear that the trials were not randomized. The full text of the remaining articles was then examined. The reasons for excluding each individual study were recorded internally. All stages of study selection were performed independently by two separate individuals. Differences of opinion were discussed until a common decision could be made.

Potential for bias

The risk of bias within trials was examined using the criteria stated in Table 1 (gif ppt). A positive answer in all five categories was established at the outset as indicating a low potential for bias. The potential effect of publication bias was assessed by updating a previous study (6) identifying all the trials that were terminated early.

Data collection and analysis

All stages of data extraction were performed by one person (Frank Peinemann) and checked by another (Stefan Sauerland). Where there were differences of opinion, consensus was reached following discussion. The results were subjected to descriptive analysis. Study characteristics were extracted as shown in Table 2 (gif ppt).

Complete wound closure, a variable used both as raw data and as a Kaplan–Meier estimator, was the primary endpoint. The U.S. Food and Drug Administration’s (FDA) 2006 Guidance for Industry (7) defines complete wound closure as “skin closure without drainage or dressing requirements.” No meta-analysis was performed, as the primary trials were highly heterogenous.

The following dependent variables were used as secondary endpoints:

  • Adverse events, such as:

  – Death

  – Secondary amputations

  – Fistula formation

  – Wound infection

  • Time to complete wound closure
  • Reduction in wound size
  • Health-related quality of life.

Results

Search of the literature

Of the 249 articles initially imported, 176 remained after duplicates had been deleted. In 137 cases it was clear from the title and/or abstract that the article did not meet the inclusion criteria (eFigure gif ppt). A further 30 potentially relevant articles were excluded after they had been read in full. A total of nine new RCTs were identified in the updated search (816). Five of the nine new RCTs examined systems that were not commercially available (1216). This left a total of 21 RCTs available for our research: seven (e2e8) from IQWiG’s Final Report N04–03 (3), five RCTs in four articles (e9e12) from IQWiG’s Rapid Report N06–02 (4), and nine RCTs from the updated search.

Underlying data

An overview of trial characteristics is provided in Table 2. The mean age of the participants, most of whom were male, was generally over 50. The mean wound surface area was numerically slightly greater in intervention groups than in control groups in all trials in which this information was given separately. Detailed descriptions of inclusion and exclusion criteria, treatments under research, comparator treatments, analyzed endpoints, and their definitions can be found in eTables 2 (gif ppt) and 3 (gif ppt). In most trials comorbidities were not reported. The trials examined many different types of acute and chronic wound (eTable 4 gif ppt).

Potential for bias

Eight of the nine trials had a high potential for bias (Table 1). The conditions for generating randomization sequences and treatment blinding were unclear in some trials, with the result that random allocation of patients to treatment groups was not traceable in these trials. In eight of the nine trials it was not reported or not clear that endpoints had been measured in blinded conditions, although this was feasible. It should be stressed that quality-of-life results from non-blinded trials are prone to a particularly high potential for bias. Only one of the trials met all five criteria for low potential for bias. In six of the nine new trials, up to 20% of the data from randomized patients were not included in the evaluation, and there was thus no appropriate intention-to-treat analysis.

Investigation of publication bias revealed a further four RCTs that had been terminated early, in addition to the five that had already been reported on: NCT00121537, NCT00691821, NCT00837096, and NCT01108276.

The following reasons were given for terminating trials early:

  • Inclusion criteria not met
  • Patient withdrawal
  • Low recruitment levels
  • Changes in clinical practice
  • Errors in study planning.

Eight ongoing RCTs were also identified among the registered trials (NCT00582179, NCT00582998, NCT00635479, NCT01200563, NCT01191567, NCT00548314, and NCT00789659).

Primary endpoint

The proportion of patients with complete wound closure was reported in only five of the nine new trials (8, 1215) (Table 3 gif ppt). In four trials the difference between groups was statistically insignificant. Only two trials showed a statistically significant effect in favor of NPWT (15).

Secondary endpoints

Time to wound closure was reported in four of the nine new trials (8, 13, 14, 16) (Table 4 gif ppt). Three trials showed a statistically significant difference between groups in favor of NPWT (8, 14, 16), and in one trial the difference was statistically insignificant (13). There was a statistically significant difference in reduction in wound size in favor of NPWT in one of the nine new trials (8).

Adverse events were investigated in eight of the nine new trials (8, 9, 11, 12). Statistically significant differences in favor of NPWT were reported in three trials. The adverse events concerned were secondary amputations (8), the proportion of patients with deep wound infections (11), and the secondary surgery rate (14).

Differences in mortality rates between treatment groups were statistically insignificant (8, 12, 15, 16). This was also the case for most of the wound complication rates in four trials (8, 9, 12, 13).

One trial investigated health-related quality of life, using questionnaires (11). The results for the physical component (following treatment) were better in the NPWT group, and the difference was statistically significant. For the mental component, meanwhile, the results were comparable.

Another trial revealed more fear of treatment, e.g. due to possible pain, in the NPWT group than in the control group, and the difference was statistically significant (10).

Summary of results

Table 5 (gif ppt) shows the qualitative results of all 21 RCTs included in the present systematic review, in terms of the endpoints studied. The quantitative results of the 12 older RCTs covered in IQWiG reports can be found in the corresponding publications (3, 4), and the results of the nine new RCTs are shown in Tables 3 and 4.

Discussion

Primary endpoint: complete wound closure

The results on complete wound closure are not homogenous, and it is impossible to be sure that NPWT performs better than the control treatments. Effects in favor of NPWT were reported in some trials, and no opposing effects could be detected in other trials. As a result, other systematic reviews also currently conclude that an additional benefit of NPWT in comparison to other types of wound treatment has not been proved (17, 18).

Secondary endpoints

Time to wound closure: In terms of the endpoint “time to wound closure,” effects in favor of NPWT groups were reported in most cases. However, there were considerable differences between trials in terms of the methods used to measure and evaluate wound closure; particularly problematic is the fact that no blinding was used when this endpoint was measured. In addition, most trials did not investigate whether wounds that had healed successfully actually remained closed in the longer term. The results thus cannot be interpreted as showing definitively that any one treatment is superior.

Adverse events: The results on adverse events were not homogenous. For some specific complications, such as secondary amputations, statistically significant effects in favor of NPWT groups were reported, but for a number of other adverse events no statistically significant difference was detected. No opposing results, i.e. statistically significant effects in favor of comparator groups, were recorded.

The difference between the number of patients included in trials and the number of patients treated worldwide is particularly striking when describing adverse effects. Data from the RCTs are of only limited use in evaluating the frequency of adverse events. It would be more appropriate if sufficiently large-scale RCTs were conducted.

The FDA recently issued a report on six deaths and 77 other complications that were reported within a two-year period in connection with NPWT (19). All the deaths were caused by acute hemorrhages, and known contraindications for NPWT (e.g. a large blood vessel exposed) had clearly been overlooked. Many of the deaths occurred in outpatient care or care homes, which highlights the need to monitor therapy. In this regard, it should be noted that trials of NPWT were generally conducted in hospitals.

Potential for bias

Of the nine included RCTs, eight have a high potential for bias. This limits the value of the results on the endpoints reported on. The difficulties of conducting RCTs and the arguments for and against including non-randomized trials when assessing medical devices and surgeries have been extensively described (e13, e14).

Heterogeneity

Strikingly, almost all the trials of commercially available NPWT systems were conducted in the USA. It seems that in developing countries the commercially available systems are very difficult to afford, and as a result such countries have developed their own NPWT systems, sometimes from very simple materials. Trials of these are now being conducted. This wide variety of NPWT systems makes the data considerably more difficult to interpret, although it is still largely unclear whether or not there are genuine differences between commercially available NPWT systems and those that are not commercially available. Also, the treatments administered to comparator groups (conventional dressings) were defined in different ways in different trials, probably as a result of differences between patient populations. This too can cause heterogeneity between trials and so limit the comparability of trial results.

Publication bias

According to the website of manufacturer KCI (August 2010), NPWT has been prescribed to more than 3 million patients, and some 600 peer-reviewed articles have been published on the subject. This and the low total number of RCTs make it astonishing that despite the frequency of acute and chronic wounds and the widespread use of NPWT a considerable number of trials have apparently had to be terminated due to recruitment problems. Although it seems that some planned RCTs had not even been started or were terminated soon after they began, the fact that there are RCTs on which nothing has been published casts doubt on the completeness of the data available for assessment of the benefits of NPWT.

Summary

Pool of trials

As the wounds for which NPWT is used vary greatly in their etiology, chronicity, size, and location, there is considerable variation between trials in the selection and definition of endpoints. This alone makes a quantitative summary of all trials of questionable value. In trials that provide results on wound healing, these results are mostly favorable for NPWT. These results are partly supported by statistically significant effects regarding the primary endpoint “complete wound closure” and the secondary endpoints “time to complete wound closure,” “reduction in wound size,” and “amputations.”

The results on overall mortality and total adverse events are inconsistent. A considerable proportion of the total deaths were probably not caused by treatment. Individual adverse events are reported too infrequently and inconsistently for conclusions to be drawn. Also, the group of adverse events as a whole is highly heterogenous. Some of the few results on quality of life are limited to the endpoint “fear” alone. Only a few trials investigated pain (in particular when dressings were changed).

The available pool of only 21 RCTs remains too small to provide a clear answer to the question of whether or not NPWT is superior to conventional wound treatment. The difficulty of interpreting the RCTs is caused essentially by the heterogeneity of the various indications for NPWT on the one hand, and the considerable qualitative and quantitative shortcomings of the trials on the other.

Outlook

Germany’s statutory health insurers jointly invited tenders for two RCTs on NPWT in July 2010 (20, e15). Patients with diabetic foot ulcers or iatrogenic wounds must be randomized to receive NPWT or conventional wound treatment, and patient numbers must be sufficient in each treatment group and for each indication. It is hoped that these trials will provide the further evidence needed for a decision on NPWT to be made. Eight other ongoing registered RCTs were also identified.

Conclusion

Although NPWT may have a positive effect on wound healing, there is no proof that it is either superior or inferior to conventional wound treatment. Further RCTs of good methodological quality are required.

Conflict of interest statement
The authors declare that no conflict of interest exists.

This article was sponsored by the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG).

Manuscript received on September 10, 2010, revised version accepted on February 7, 2011.

Translated from the original German by Caroline Devitt, MA.

Corresponding author
Dr. med. Frank Peinemann, M.Sc.
IQWiG Institut für Qualität u. Wirtschaftlichkeit im Gesundheitswesen
Dillenburger Str. 27
51105 Köln, Germany
frank.peinemann@iqwig.de

@For eReferences please refer to:
www.aerzteblatt-international.de/ref2211

eFigure and eTables available at:
www.aerzteblatt-international.de/11m0381

1.
Argenta LC, Morykwas MJ: Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Annals of plastic surgery 1997; 38: 563–77. MEDLINE
2.
Fleischmann W, Strecker W, Bombelli M, Kinzl L: Vakuumversiegelung zur Behandlung des Weichteilschadens bei offenen Frakturen. Unfallchirurg 1993; 96: 488–92. MEDLINE
3.
IQWiG. Vakuumversiegelungstherapie von Wunden. Abschlussbericht N04–03. Köln: IQWiG Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; 2006. www.iqwig.de
4.
IQWiG: Vakuumversiegelungstherapie von Wunden. Rapid Report N06–02. 2007. www.iqwig.de
5.
Gregor S, Maegele M, Sauerland S, Krahn JF, Peinemann F, Lange S: Negative pressure wound therapy: a vacuum of evidence? Arch Surg 2008; 143: 189–96. MEDLINE
6.
Peinemann F, McGauran N, Sauerland S, Lange S: Negative pressure wound therapy: potential publication bias caused by lack of access to unpublished study results data. BMC Med Res Methodol 2008; 8: 4. MEDLINE
7.
FDA: Draft guidance for industry. Chronic cutaneous ulcer and burn wounds—developing products for treatment. 2006. www.fda.gov /
8.
Blume PA, Walters J, Payne W, Ayala J, Lantis J: Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008; 31: 631–6. MEDLINE
9.
Chio EG, Agrawal A: A randomized, prospective, controlled study of forearm donor site healing when using a vacuum dressing. Otolaryngol Head Neck Surg 2010; 142: 174–8. MEDLINE
10.
Keskin M, Karabekmez FE, Yilmaz E, Tosun Z, Savaci N: Vacuum-assisted closure of wounds and anxiety. Scand J Plast Reconstr Surg Hand Surg 2008; 42: 202–5. MEDLINE
11.
Stannard JP, Volgas DA, Stewart R, McGwin G Jr, Alonso JE: Negative pressure wound therapy after severe open fractures: a prospective randomized study. J Orthop Trauma 2009; 23: 552–7. MEDLINE
12.
Bee TK, Croce MA, Magnotti LJ, Zarzaur BL, Maish GO 3rd, Minard G, et al.: Temporary abdominal closure techniques: a prospective randomized trial comparing polyglactin 910 mesh and vacuum-assisted closure. J Trauma 2008; 65: 337–42. MEDLINE
13.
Mody GN, Nirmal IA, Duraisamy S, Perakath B: A blinded, prospective, randomized controlled trial of topical negative pressure wound closure in India. Ostomy Wound Manage 2008; 54: 36–46. MEDLINE
14.
Perez D, Bramkamp M, Exe C, von Ruden C, Ziegler A: Modern wound care for the poor: a randomized clinical trial comparing the vacuum system with conventional saline-soaked gauze dressings. Am J Surg 2010; 199: 14–20. MEDLINE
15.
Saaiq M, Hameed Ud D, Khan MI, Chaudhery SM: Vacuum-assisted closure therapy as a pretreatment for split thickness skin grafts. J Coll Physicians Surg Pak 2010; 20: 675–9. MEDLINE
16.
Sepúlveda G, Espindola M, Maureira M, Sepúlveda E, Ignacio Fernández J, Oliva C, et al.: Negative-pressure wound therapy versus standard wound dressing in the treatment of diabetic foot amputation. A randomised controlled trial. Cir Esp 2009; 86: 171–7. MEDLINE
17.
AHRQ: Negative pressure wound therapy devices. Technology assessment report, project ID: WNDT1108. 2009. www.ahrq.gov /
18.
Ubbink DT, Westerbos SJ, Evans D, Land L, Vermeulen H: Topical negative pressure for treating chronic wounds. Cochrane Database Syst Rev 2008; (3): CD001898. MEDLINE
19.
FDA: Serious complications associated with negative pressure wound therapy systems. 2009. www.fda.gov /
20.
EUTED: Vergabeverfahren Studie zur Vakuumversiegelungstherapie. European Union Tenders Electronic Daily. 2010. www.ted.europa.eu
e1.
Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097. MEDLINE
e2.
Armstrong DG, Lavery LA: Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet 2005; 366: 1704–10. MEDLINE
e3.
Eginton MT, Brown KR, Seabrook GR, Towne JB, Cambria RA: A prospective randomized evaluation of negative-pressure wound dressings for diabetic foot wounds. Ann Vasc Surg 2003; 17: 645–9. MEDLINE
e4.
Ford CN, Reinhard ER, Yeh D, Syrek D, De Las Morenas A, Bergman SB, et al.: Interim analysis of a prospective, randomized trial of vacuum-assisted closure versus the healthpoint system in the management of pressure ulcers. Ann Plast Surg 2002; 49: 55–61. MEDLINE
e5.
Joseph E, Hamori CA, Bergman S, Roaf E, Swann NF, Anastasi GW: A prospective randomized trial of vacuum-assisted closure versus standard therapy of chronic nonhealing wounds. Wounds: A Compendium of Clinical Research and Practice 2000; 12: 60–7.
e6.
Moisidis E, Heath T, Boorer C, Ho K, Deva AK: A prospective, blinded, randomized, controlled clinical trial of topical negative pressure use in skin grafting. Plast Reconstr Surg 2004; 114: 917–22. MEDLINE
e7.
Mouës CM, Vos MC, van den Bemd GJ, Stijnen T, Hovius SE: Bacterial load in relation to vacuum-assisted closure wound therapy: a prospective randomized trial. Wound Repair Regen 2004; 12: 11–7. MEDLINE
e8.
Wanner MB, Schwarzl F, Strub B, Zaech GA, Pierer G: Vacuum-assisted wound closure for cheaper and more comfortable healing of pressure sores: a prospective study. Scand J Plast Reconstr Surg Hand Surg 2003; 37: 28–33. MEDLINE
e9.
Braakenburg A, Obdeijn MC, Feitz R, van Rooij IA, van Griethuysen AJ, Klinkenbijl JH: The clinical efficacy and cost effectiveness of the vacuum-assisted closure technique in the management of acute and chronic wounds: a randomized controlled trial. Plast Reconstr Surg 2006; 118: 390–7; discussion 8–400. MEDLINE
e10.
Llanos S, Danilla S, Barraza C, Armijo E, Pineros JL, Quintas M, et al.: Effectiveness of negative pressure closure in the integration of split thickness skin grafts: a randomized, double-masked, controlled trial. Ann Surg 2006; 244: 700–5. MEDLINE
e11.
Stannard JP, Robinson JT, Anderson ER, McGwin G Jr, Volgas DA, Alonso JE: Negative pressure wound therapy to treat hematomas and surgical incisions following high-energy trauma. J Trauma 2006; 60: 1301–6. MEDLINE
e12.
Vuerstaek JD, Vainas T, Wuite J, Nelemans P, Neumann MH, Veraart JC: State-of-the-art treatment of chronic leg ulcers: A randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg 2006; 44: 1029–37; discussion 38. MEDLINE
e13.
Gottrup F, Apelqvist J: The challenge of using randomized trials in wound healing. Br J Surg 2010; 97: 303–4. MEDLINE
e14.
Hartling L, McAlister FA, Rowe BH, Ezekowitz J, Friesen C, Klassen TP: Challenges in systematic reviews of therapeutic devices and procedures. Ann Intern Med 2005; 142(12 Pt 2): 1100–11. MEDLINE
e15.
AOK: Studie zur Vakuumversiegelungstherapie bei chronischen Wunden ausgeschrieben. Pressemitteilung Allgemeine Ortskrankenkassen. 2010. www.aok-bv.de /