The reality of routine practice: a pooled data analysis on chronic wounds treated with TLC-NOSF wound dressings

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1 joural of woud care C W C VOLUME 26. NUMBER 2. FEBRUARY 2017??? The reality of routie practice: a pooled data aalysis o chroic wouds treated with TLC-NOSF woud dressigs K.C. Müter, 1 MD; S. Meaume, 2 MD; M. Augusti, 3 MD; P. Seet, 4 MD; J.C. Kérihuel, 5 MD Correspodig author c.mueter@t-olie.de 1 Joit Practice For Iteral Medicie, Geeral Medicie, Phlebology & Pai Therapy, Hamburg, Germay. 2 Geriatric Departmet, Rotschild Uiversity Hospital, APHP, Paris, Frace. 3 Istitute for Health Services Research i Dermatology ad Nursig, Uiversity Medical Ceter Hamburg, Hamburg, Germay. 4 Departmet of Dermatology, Uiversity Hospital Paris Est, APHP, Paris, Frace. 5 Vertical, Paris, Frace.

2 The reality of routie practice: a pooled data aalysis o chroic wouds treated with TLC-NOSF woud dressigs Objective: A umber of radomised cotrolled trials (RCT) have compared cotrol groups with TLC-NOSF dressigs (UrgoStart) o chroic wouds. Our aim was to determie whether the cliical trials results traslate ito routie maagemet of such wouds, by poolig the data from real-life observatioal studies. Method: Observatioal studies, coducted i Frace ad Germay, evaluatig curret practices i patiets sufferig from o-selected chroic wouds treated with a TLC-NOSF dressig were idetified. Demographic data, baselie descriptio of wouds ad descriptio of their evolutio durig treatmet were extracted ad combied. We used two mai idicators of cliical outcomes to measure the impact of the TLC-NOSF dressig o this populatio: time to woud closure ad time to 50% reductio of the Pressure Ulcer Scale for Healig (PUSH) score. Results: I total, data from 10,220 patiets were icluded, with 7903 leg ulcers (LUs), 1306 diabetic foot ulcers (DFUs) ad 1011 pressure ulcers (PUs). The overall closure rate was 30.8 % [95 % cofidece iterval (CI): %]. While the coutry, patiet age, ad umber of wouds were idetified as idepedet progosis factors of healig, the most sigificat were woud duratio ad baselie area. The delay i iitiatig TLC-NOSF dressigs treatmet was also foud to be sigificat. Overall the average time to complete closure was days [95%CI: ] for LUs, 98.1 days [95 %CI: ] for DFUs ad days [95%CI: ] for PUs. Based o a subgroup aalysis of the Frech cohort, time to closure is substatially shorter for wouds treated with the TLC-NOSF dressig as a first-lie itervetio compared with those where it has bee prescribed as a secod-lie itervetio. Coclusio: Compared with available data o time to complete closure of chroic wouds maaged by stadard care, the data from this pooled data aalysis showed healig time is reduced, which is cosistet with the results of RCTs o TLC-NOSF. That these data are i agreemet with those from the RCTs is testimoy to their geeralisability ad importat for routie practice. This idicates that usig TLC-NOSF dressigs i routie woud maagemet ca reduce the healig time of LUs, DFUs ad PUs. These data also suggest that the earlier the decisio to use this dressig, the shorter the time to closure, whatever the severity ad the ature of these chroic wouds. Declaratio of iterest: All icluded studies were fiacially supported by Urgo (Cheôve, Frace). Authors have received a mtary compesatio as preseters for Urgo. Data maagemet ad statistical aalyses were coducted idepedetly by Vertical (Paris, Frace). TLC-NOSF dressig UrgoStart dressig MMP modulator chroic wouds healig time observatioal study Reducig healig time of chroic wouds is recogised as a priority by Health Authorities. 1 Their treatmet is complex requirig accurate evaluatio of aetiological factors ad selectio of the most appropriate programme for local care. 2 4 Pathophysiologically, the role of excess matrix metalloprotease (MMP) levels i chroic wouds is recogised as impedig the healig process ad some therapies directed at modulatig MMPs may have promise i healig of such wouds. 5,6 There is evidece that some moder dressigs ad procedures K.C. Müter, 1 MD; S. Meaume, 2 MD; M. Augusti, 3 MD; P. Seet, 4 MD; J.C. Kérihuel, 5 MD Correspodig author c.mueter@t-olie.de 1 Joit Practice For Iteral Medicie, Geeral Medicie, Phlebology & Pai Therapy, Hamburg, Germay. 2 Geriatric Departmet, Rotschild Uiversity Hospital, APHP, Paris, Frace. 3 Istitute for Health Services Research i Dermatology ad Nursig, Uiversity Medical Ceter Hamburg, Hamburg, Germay. 4 Departmet of Dermatology, Uiversity Hospital Paris Est, APHP, Paris, Frace. 5 Vertical, Paris, Frace. that modulate MMP levels may be effective i improvig healig rates. 7 However, demostratig advatages of a give type of dressig i terms of favourig complete closure is a highly challegig task. 8,9 While some evidece supports the beefit of usig advaced woud dressigs, the geeralisability of study results is questioable. 10 A TLC-NOSF dressig (UrgoStart) is a MMP modulatig dressig which has demostrated efficacy i acceleratig healig of chroic wouds, such as leg ulcers. 11,12 The ao-oligosaccharide factor (NOSF) compoud, icorporated i a lipido-colloid matrix (TLC), modulates the actio of excess MMPs ad restores the biochemical balace i the woud. There have bee two radomised cotrolled trials (RCTs) coducted with TLC-NOSF dressigs i the maagemet of veous leg ulcers (VLUs). The first 12 was a ope-label trial comparig the TLC-NOSF dressig with a collage-orc matrix. The secod (Challege study) 11 was a double-blid study

3 Table 1. Mai characteristics of selected observatioal studies No. icluded i data poolig Coutry Study ame Year Ivestigators Total No. of ivestigators No. icluded LU DFU PU Total selected Plaed FU duratio Auto Quest Mai study efficacy outcomes Frace Cofiace 2012 MD weeks Yes Woud size, colorimetry, Other study objectives Frace Speed 2011 MD, Nurses weeks Yes PUSH score, Frace Repose 2009 MD, Nurses weeks Yes PUSH score, Frace Opus 2010 MD, Nurses weeks Yes PUSH score, Frace Start 2008 MD, Nurses weeks Yes PUSH score, Frace Starter 2009 MD, Nurses weeks No PUSH score, Germay UrgoStart 2011 MD weeks Yes Woud size, colorimetry, exudatio, Germay UrgoStart Tül 2012 MD weeks No Woud size, colorimetry, exudatio, Total , ,220 Impact of iitial colorimetric aspect o PUSH score reductio Time to woud closure Impact of ecoomic status o woud respose, QoL Impact of UrgoStart dressig prescriptio (1st or 2d itetio) o woud evolutio No. umber; FU follow-up; LU leg ulcer; DFU diabetic foot ulcer; PU pressure ulcer; Auto Quest questioaires about woud discomfort give to patiets ad to be completed at home ad retured directly to study coordiator; QoL Quality of life istrumet (5D EuroQOL i all cases); PUSH pressure ulcer scale for healig v3.0; woud size measuremet of the largest ad shortest woud axis QoL comparig the TLC-NOSF dressig with the same dressig without NOSF (cotrol group). Compared with cotrol groups, both studies demostrated a sigificat effect of TLC-NOSF dressigs i terms of woud area regressio ( 54.4 % versus 13.0 % at 12 weeks i study 1, p<0.0287; 58.3 % versus 31.6 % at 8 weeks i study 2, p=0.002). While reproducibility of the dressig effect o woud healig trajectory is cofirmed, either study was desiged to evaluate its impact o complete woud closure. As for ay RCT, extrapolatio of results to real-life practices eeds to be evaluated To attempt to appreciate the extrapolability of results issued from these RCTs, we pooled data obtaied i large observatioal studies coducted i Frace ad Germay, desiged to describe the evolutio of various ad broadly selected woud types treated with the TLC-NOSF dressig. We used two idicators of favourable woud respose: time to woud closure ad to a 50 % reductio of the Pressure Ulcer Scale for Healig (PUSH) score, a tool measurig healig progress, to explore if the results detected i observatioal studies were cosistet with those from the RCTs. Material ad methods Study idetificatio ad selectio No-itervetioal studies maily desiged to evaluate efficacy of TLC-NOSF dressigs (Urgostart, Urgo, Cheôve, Frace) i real-life coditios were searched through medical literature databases (MedLie, Embase) ad direct iteret screeig as

4 well as by directly askig Urgo. We idetified 10 studies ad full study documetatio ad databases were obtaied (for 6 studies, databases were available from of the authors who coordiated ad aalysed the study ad for the other four, databases were provided by Urgo). I of these trials coducted i early 2007 i Frace, oly 78 patiets out of 1005 received the TLC-NOSF dressig; i a secod coducted i Germay (1831 icluded patiets), the structure of the provided database was iappropriate to allow accurate data retrieval. Overall, six Frech ad two Germa studies were fially selected for data processig ad their mai characteristics are preseted i Table 1. Mai idividual results of most of the selected studies have already bee preseted i a geeral review. 22 Data processig I total, 11,523 patiets were icluded, ivolvig 2792 ivestigators: of these 10,220 were selected if the treated woud was idetified as either a leg ulcer (LU), a diabetic foot ulcer (DFU) or a pressure ulcer (PU), if the dressig prescribed at iclusio was uambiguously the TLC-NOSF dressig ad if at least follow-up visit was documeted. From origial databases, the followig parameters were extracted whe available by coutry, study ame ad visit (iclusio ad latest follow-up visit): type of maagemet (by a hospital team or by private practitirs), geder, age, body mass idex (BMI), presece of diabetes, overall evaluatio of health status (poor, moderate, fair), umber of wouds preset at iclusio ( or more tha ), woud Table 2. Mai characteristics of icluded populatios Leg ulcers DFUs Pressure ulcers N (%) N (%) N Frech patiets Followed by hospital team Female patiets Age >80 years Body mass idex (kg/m 2 ) < > Health status Diabetic More tha woud Oe previous episode LU type 7498 Veous Mixed/arterial Woud duratio <2 moths moths moths >6 moths No PWS problem Factors of poor healig progosis* N Oe Two TLC-NOSF dressig as 1st itetio $ PUSH score (mea ± SD) = ± 3 =879 9 ± 3 = ± 3 PWS periwoud ski; N total umber of documeted cases i the aalysis; umber of cases cocered by the parameter oted o the lie; DFUs diabetic foot ulcers; LU leg ulcers; $ TLC-NOSF dressig used for the first time by ivestigators i give patiet (data oly available for the Frech cohort);* Based o previous works by Margolis et al. o evaluatig simple scores to idetify leg ulcers ad DFUs healig progosis (%)

5 type (LU, DFU or PU) accordig to the ivestigator s diagosis, type of LU (veous or mixed/arterial), akle brachial pressure idex (ABPI) value available or ot, presece or ot of a europathy if DFU was selected, locatio of PU, woud duratio before iclusio, history of previous chroic woud, details of the PUSH tool dimesios (if this tool was ot used, woud size, colorimetric aspect ad exudatio level were extracted to allow secodary PUSH score calculatio), periwoud ski coditio (o problem or/ad at least problem), type of TLC-NOSF dressig prescriptio (first-lie i a patiet see for the first time or secod-lie i a patiet already followed but ot treated with this type of dressig), applicatio or ot of a veous compressio badage/ hosiery, applicatio or ot of a off-loadig system if DFU was oted, date of iclusio ad latest visit ad calculatio of follow-up duratio. Mai outcomes Our two study outcomes were: Woud closure Time to 50 % reductio of the PUSH score. Closure was cosidered as reached if this was clearly oted by cliicias at the last visit ad if the correspodig calculated PUSH score was at zero. I other cases, closure was ot cosidered as obtaied. I 66 cases, this status was regarded as ot determied (PUSH score value at zero but closure ot formally oted by ivestigator). The PUSH tool is a well-defied istrumet iitially developed to documet PU evolutio over time. It has bee employed i both LU ad DFU studies. 20, It cosists of three compts: Woud size, scored 0 for a healed woud to 10 for a woud larger tha 24 cm 2 Tissue type based o woud colorimetric aspect 0 4 Exudate amout scale 0 3. The total score rage from 0 for a healed woud to 17 at a maximum. A 50 % or more decrease from baselie of the total PUSH score idetifies a clear favourable healig trajectory of a give ulcer at the evaluatio time. Takig ito accout the high weight of the woud size dimesio of the PUSH, this correspods i almost all cases to a 40 % or more reductio i woud area, a threshold value Table 3. Populatio characteristics accordig to the presece or ot of a least factor of poor healig progosis N=5159 N Risk factor =4490 documeted as well predictive of the probability to obtai woud closure at weeks or earlier. 26 Based o previous works by Margolis ad colleagues o evaluatig simple scores to idetify LUs (ad eve DFUs) healig progosis, we categorised our populatio accordig to the presece or ot of poor healig progosis factors (score 1, 2 or 0): 1 presece of a woud 6 moths or presece of a PUSH woud size dimesio 8 (calculated area obtaied by multiplyig axis >8 cm 2 ) 2 both criteria are preset 0 of these are preset. Statistical aalysis Statistical aalysis was performed usig SPSS software (%) N (%) Followed by hospital team Geder (females) Age >80 years Body mass idex class (kg/m 2 ) < > Diabetics Good health status Sigle woud Woud type Leg ulcer DFU Pressure ulcer First episode of woud No PWS problem Mea PUSH score = ± 2.8 = ± 2.8 PWS periwoud ski;n total umber of documeted cases i the aalysis; umber of cases cocered by the parameter oted o the lie; DFU diabetic foot ulcer: PUSH pressure ulcer scale for healig v3.0 Table 4. Closure rate accordig to woud type ad coutry Frace Germay Total N (%) N (%) N (%) 95% Cofidece iterval Leg ulcer Diabetic foot ulcer Pressure ulcer Total N total umber of documeted cases i the aalysis; umber of closed wouds

6 Table 5. Biary logistic regressio model for complete closure A. All patiets (=5603) Variables i the equatio Coutry Germay versus Frace 95% CI for OR B SE Wald df p-value OR Lower Upper < Geder: M versus F Age groups < versus < >70 versus < < BMI Diabetes: Yes versus No Risk factor: versus < Costat < B. Frech cohort (=1900) 95% CI for OR B SE Wald df p-value OR Lower Upper Geder: M versus F Age groups < versus < >70 versus < < BMI Diabetes: yes versus o Risk Factor: at least vs. Type FU: hospital versus o-hospital team Number of wouds: two versus Start: 1st versus 2d itetio < < < Costat < M male; F female; SE stadard error of B; df degree of freedom; OR odds ratio; CI cofidece iterval; BMI body mass idex; FU follow-up (IBM Ic.). Biary logistic regressio aalysis used a etry stepwise model ad icluded a costat i model. Odds ratio (OR) were calculated for covariates with their 95 % cofidece iterval (CI). Mea estimates of time to closure ad time to 50 % PUSH score reductio were calculated usig a Kapla-Meier approach followed by log-rak tests. Scale variables are preseted by their mea, stadard deviatio (±SD) ad rage. Nomial ad ordial variables are preseted by their frequecy ad percetages. Ethics All studies were coducted accordig to atioal regulatios applyig to o-itervetioal studies (for Frech studies, all study documetatio icludig fiacial agreemets betwee sposor ad participats were submitted to the Frech Natioal Medical Coucil, who gave approval). I all cases, patiets received detailed iformatio ad were ot icluded if they declied to participate. Idividual data were idetified by a code idetifyig the coutry, study ame, cliicia umber ad patiet iclusio umber. Directly or idirectly idetifyig data, for example, date of birth, patiets iitials, ame of ivestigator icludig subjects, were ot icluded i the databases. Results Patiets ad wouds at iclusio Overall, 10,220 patiets (Table 2; 8102 i Frech ad 2118 i Germa studies) were icluded (7903 with LUs, 1306 with DFUs ad 1011 with PUs). Cosiderig the total umber of wouds (more tha 10,000 wouds), most were followed i the commuity (as they were VLUs). Whe lookig at DFUs, 45 % were followed by a hospital team. More LU patiets (62.0 %) were females tha DFU (36.4 %) or PU subjects (53.1 %).The mea age of the total populatio was 72.9 ± 12.4 years (rage: years) with 44.5 % of PU patiets aged over 80 years. BMI was 27.9 ± 5.9 kg/m 2 o average with LU ad DFU patiets more frequetly over-weighted tha PU patiets. Health status was cosidered as good i more tha 50 % of LU ad DFU patiets but i oly 24.8 % of PU subjects. Prevalece of diabetes mellitus was high (>30 %) i LU ad PU groups while i 31 patiets cosidered as sufferig from DFU, diabetes had ot bee recorded by the health professioal. Betwee % of patiets had more tha woud ad LUs were recurret i 50 % of the cases compared with 27 % ad 32 % i PUs ad DFUs respectively. For the icluded woud, the overall total PUSH score at baselie was 11.1 ± 3.2 (rage: 2 17). It was similar for LU ad PU (11 ± 3) but lower for DFU (9 ± 3). Furthermore, 48.6 %, 35.2 % ad 45.0 % of LU, DFU ad PU respectively, were older tha 6 moths ad/or of a area of 8 cm 2 or more. For LU patiets, 74.7 % were of veous aetiology ad 25.3 % were of mixed or arterial aetiology. Overall, whatever the ature of LU (veous, mixed or arterial), applicatio or ot of compressio was clearly metid i 3934 LU cases (50 %), with compressio prescribed i 62.2 % of these patiets. I DFU patiets, use of a off-loadig medical device was rarely metid: out of the 1306 cases cosidered as DFU by ivestigators, oly 57 aswered to the questio Is your patiet wearig a off-loadig system? I 24 cases, the aswer was yes. For PUs, the mai woud locatios were the heel (=436, 43.1 %) or the pelvis (=407, 40.3 %). Wouds were split accordig to the presece or ot

7 of at least risk factor of poor healig progosis (Table 3). Apart from mea PUSH score, the mai differeces observed were a higher percetage of patiets i more severe woud group treated by hospital teams, as well as a higher prevalece of reoccurrig ad of multiple wouds. Differece betwee the Frech ad Germa cohorts The Frech cohorts were asked, i all studies, whe the TLC-NOSF dressig was prescibed (first or secod itetio). This was a first-lie itervetio i 25.7 % of cases whereas, i the remaiig patiets, this prescriptio was decided after previously usig aother type of primary dressig. The mea duratio of follow-up was 50 ± 34 days (rage: >7 days up to more tha year). Patiets ad woud profiles were differet accordig to coutries. More Frech patiets were older tha 80 years (31.6 %, =2414 versus 23.0 %, =487) ad less had a BMI>35 kg/m 2 (9.6 %, =716 versus 13.9%, =292). Diabetes was also less frequetly reported i the Frech cohort (33.4 %, =1661 versus 54.7%, =1,158). The percetage of woud types was quite differet accordig to coutries (Frech versus Germa cohort; LUs: 81.8%, =6628 versus 60.2%, =1275; DFUs: 9.4 %, =759 versus 25.8 %, =547; PUs: 8.8 %, =715 versus 14.0 %, =296). Whereas 53.7 % (=4,049) ad 52.8 % (1,110) of wouds had o risk factor of poor healig progosis i the Frech ad Germa cohorts respectively, more Frech patiets had wouds preset for at least 6 moths (33.4 %, =2519 versus 16.1 %, =335). At baselie, PUSH score was higher o average i the Frech populatio (11.2 ± 3.1 versus 9.8 ± 3.6) ad these patiets were followed for a loger period (51.7 ± 35.8 days versus 44.8 ± 25.0 days). Closure rate ad prevalece of 50 % reductio of PUSH score Of the 10,220 patiets, woud closure or ot was reported at the last available visit i 10,154 cases (99.4%) ad a PUSH score at baselie ad last follow-up visit was reported i 7047 patiets (69.0 %). I this series, the overall closure rate was 30.8 % (3124/10,154; Table 4) [95% CI: ]. I order to detect idepedet factors explaiig closure rate, six covariates were icluded i a biary logistic regressio model (5603 patiets available for this aalysis; Table 5). Coutry was highly sigificat odds ratio for Germay versus Frace: 1.64; 95 % [CI: ; p<0.001]) with age classes (compared with patiets aged 50, the higher the age, the lower the chace of closure) as well as the presece of at least risk factor of poor healig progosis (odds ratio for a risk preset versus o risk: 0.38; 95% CI: 0.33 to 0.43; p<0.001). O the other had, geder, BMI ad presece of diabetes mellitus were ot statistically sigificat. To further precise the impact of risk factors, the Table 6. Mea estimates of time to closure ad to 50% PUSH score reductio. Total populatio (a) Populatio displayed accordig the presece or ot of at least risk factor of poor healig progosis (b) a Woud type Time to closure Mea estimate 95% CI Time to 50% PUSH reductio Mea estimate 95% CI LU DFU PU Global b Woud type Risk factor Time to closure Mea estimate 95% CI Time to 50% PUSH reductio Mea estimate 95% CI LU N Global DFU N Global PU N Global All wouds N Global LU leg ulcer; DFU diabetic foot ulcer; PU pressure ulcer; CI cofidece iterval; total umber of documeted cases i the aalysis; PUSH pressure ulcer scale for healig v3.0 Fig 1. Mea estimates of time to closure ad time to 50% PUSH score reductio accordig to woud type ad the presece or ot of at least factor of poor healig progosis at baselie (Bars represet 95% cofidece itervals) 180 Closure 160 PUSH50 Days N N N Leg ulcer Diabetic foot ulcer Pressure ulcer

8 Fig 2. Kapla-Meier curves accordig to the umber of baselie risk factors of poor healig progosis (all wouds icluded) 1.0 Closure % PUSH score reductio Cum probability of o-closure Severity score Cum probability ot reachig probability Severity score Follow-up duratio (days) Follow-up duratio (days) Fig 3. Kapla-Meier curves accordig to the type of TLC-NOSF dressig prescriptio (first or secod itetio; all wouds icluded) Cum probability of o-closure Closure TLC-NOSF dressig 1st itetio First visit Already followed Cum probability ot reachig probability 1, % PUSH score reductio TLC-NOSF dressig 1st itetio First visit Already followed Follow-up duratio (days) Follow-up duratio (days) same aalysis was coducted by replacig the covariate presece or ot of at least risk factor by woud duratio classes ad a baselie total PUSH score of 10. This latter value was selected based o a receiver operatig characteristic (ROC) curve aalysis showig that this cut-off value has a sesitivity of 53.9% ad a specificity of 63.9% to predict o closure for higher values i this series. Based o this model, woud duratio was highly sigificat (p<0.001). Compared with wouds preset for less tha 3 moths, odds ratio were 0.29 [95 % CI: ] ad 0.63 [95 % CI: ] for wouds preset for 3 6 moths ad >6 moths respectively. A 10 poit PUSH score was also highly sigificat (p<0.001), compared with a score 10, a odds ratio of 0.58 [95 % CI: ] for a score >10. A secod biary logistic regressio model was coducted o the Frech cohort usig the same covariates (except for coutry) but umber of wouds, the type of follow-up (by hospital team or by commuity practitirs) ad the type of TLC-NOSF dressig prescriptio (first prescriptio i a give patiet or secod itetio use) were added (these variables were specifically reported i this cohort; Table 5b). Age ad presece or ot of a risk factor of poor healig were sigificat predictive parameters, also the umber of wouds [odds ratio of more tha versus sigle woud: 0.38; 95 % CI: ; p<0.001] as well as the type of TLC-NOSF dressig prescriptio [odds ratio of first versus secod itetio: 2.2; 95 % CI: ; p<0.001]. A tred for a lower probability of closure rate was observed for the type of follow-up [odds ratio for o-hospital versus hospital: 1.48; 95% CI: ; p=0.084].

9 Time to closure ad to 50 % PUSH score reductio Based o the total populatio, (Table 6a) mea estimates of time to closure were days [95% CI: ]. Accordig to woud types, these estimates were days [95% CI: ] for LUs, 98.1 days [95 % CI: ] for DFUs ad days [95 % CI: ] for PUs. The mea time to 50 % decrease of PUSH score values for LUs, DFUs ad PUs were, respectively 66.2 days (95 % CI: 64.5 to 68.0], 59.9 days [95 % CI: ]) ad 62.0 days [95 % CI: ]. Whe the populatio is categorised accordig to the presece or ot of at least factor of poor healig progosis (Table 6b, Fig 1 ad 2), whatever the ature of the woud, time to complete closure is substatially ad sigificatly shorter i patiets free from ay risk factor. Based o the subgroup aalysis of the Frech cohort, time to closure appears to be substatially shorter for wouds that are treated for the first time with a TLC-NOSF dressig compared with those where this prescriptio has bee decided after usig aother primary dressig (mea time: 70.2 days versus days; log-rak test: p<0.001; Table 7 ad Fig 3). This applies to all woud aetiologies. This is also oted for LUs idepedetly from the baselie woud severity score, both for time to closure ad time to 50 % PUSH score reductio. Discussio These aalysis are based o the poolig of data derived from eight observatioal studies coducted i Frace ad Germay o over 10,000 patiets. All these observatioal studies used very broad selectio criteria i order to iclude a populatio as close as possible from patiets see i daily routie care settigs for maagemet of chroic wouds. The oly particular criteria for selectig subjects was the decisio of cliicias to prescribe, for ay reaso, a TLC-NOSF dressig. Patiets were followed accordig to the usual practice of participatig ivestigators who were of three mai types: GPs, commuity urses ad hospital teams. They were usig commo tools to record woud status chage such as the PUSH tool, but protocols did ot specify visit schedules or local woud care. The mai purpose of these studies was to observe the applied practices ad to collect data to describe them. Where it is ot possible to accurately verify the represetativeess of our sample of cliicias ad of patiets, the large diversity of participats as well as the large size of the populatio that has bee followed meas that these trials are very likely to reflect reallife practices. The first parameter used was the closure rate; approximately 31 % of wouds were closed by the ed of the follow-up which was ragig from 8 to 20 weeks accordig to the pooled data aalysis. This level is ot idicative by itself as the actual healig Table 7. Estimates of time to closure accordig to the type of TLC-NOSF dressig prescriptio ad of the woud aetiology (Frech cohort) Start dressig prescriptio Woud type Time to closure rate of chroic wouds i real-life settigs. This is highly variable ad poorly uderstood, so we have few referece data to compare with. I the UK, Guest et al. have show that i primary care, fewer tha 10 % of VLUs were healed i 26 weeks. 31 By usig logistic biary regressio models, we observed strog ad expected idepedet predictive factors of complete closure. Ulcer size ad age are poor Mea estimate 95% CI 1st lie itervetio Leg ulcer DFU Pressure ulcer Overall d lie itervetio Leg ulcer DFU Pressure ulcer Overall DFU diabetic foot ulcer; CI cofidece iterval; umber of documeted cases Fig 4. Estimates of time to closure derived from aalysed observatioal studies, SNIIRAM data aalysis ad from the TLC-NOSF ad cotrol dressig groups of the Challege study Leg ulcers Pressure ulcers 98 Diabetic foot ulcers Veous leg ulcers SNIIRAM database* TLC-NOSF observatioal studies Cotrol Challege RCT TLC-NOSF Challege RCT * SNIIRAM: database recordig prescriptios ad care through the life course of the full Frech populatio 60 millio ihabitats 1 110

10 progostic idicators for LUs as well as for DFUs I the same way, the lower healig rate i oldest patiets oted i our series is also well-kow. 32,33 More surprisig is the differece i closure rate betwee Frech ad Germa cohorts. While the healig rate for LUs is higher i Germa populatio, the mai differece comes from patiets cosidered as sufferig from DFUs (48.0 % versus 29.9 %). This is difficult to explai but a combiatio of factors is probably ivolved icludig variace i baselie populatio ad woud characteristics betwee Frech ad Germa patiets, as well as difficulties for ospecialised cliicias to accurately diagose true foot ulcers of europathic origi. The ucertaity of whether or ot off-loadig was used is also importat. However, this heterogeeity of patiet ad woud profiles betwee ad withi coutries has bee observed by others i various health fields. For istace, i radomised ad double-blid cotrolled trial 34 coducted maily i Frace, Demark ad Germay ad comparig two dressigs i the maagemet of VLUs, woud ad patiet characteristics were very differet accordig to coutries despite usig similar selectio criteria. Furthermore, these baselie differeces have had a strog impact o healig rate ad bluted betweegroup differece for mai outcome. Accordig to authors, differeces i health-care systems seemed to be the mai explaatio of this heterogeeity. Whatever the actual explaatio, this experiece as well as our observatios highlight the importace of takig ito accout betwee-coutry variaces whe plaig, iterpretig or extrapolatig results i woud care settigs. 35,36 Whe all these factors are take ito accout, the healig rate was sigificatly better whe the TLC- NOSF dressig had bee used as a first-lie treatmet. Based o the Frech cohort data where this parameter was recorded, the weight of this factor, evaluated by Wald statistics of logistic regressio, is the secod after the impact of the presece of a risk factor of poor healig ad is substatially higher tha that of patiets age or that of the umber of wouds preset at iclusio. The effect of the type of prescriptio (first itetio versus secod itetio) is idepedet from that of the other variables icluded i our model. Furthermore, groups categorised accordig to the time of TLC-NOSF dressig prescriptio (first itetio versus secod itetio) were ot differet i terms of woud size or woud duratio. However, this does ot exclude the possible ifluece of other parameters that we do ot icorporate i our statistical aalysis. Nevertheless, this effect of the type of prescriptio (first itetio versus secod itetio) suggests that the earlier the decisio to use a TLC-NOSF dressig, the better the probability to obtai rapidly a closure, whatever the severity ad eve the ature of the treated woud. Other idicators used to uderstad the impact of a TLC-NOSF dressig o healig progosis were time to complete closure ad time to 50 % reductio i total PUSH score at last visit. The overall mea estimates of time to closure, obtaied usig Kapla-Meier method, were 112, 98 ad 119 days for LUs, DFUs ad PUs respectively. To iterpret these figures, two mai approaches are possible. The first is to cosider the results of the double-blid radomised Challege study which has compared, i VLUs, the TLC-NOSF dressig with the same without the NOSF compt. 11 Based o the regressio lies of media values of woud area regressio over the 8-week follow-up, a rough estimate of time to complete closure was calculated ad gave 90 days for the TLC-NOSF dressig group ad 180 days for the cotrol group. It ca be oted that this 90-day value is ot substatially differet from the 112 days obtaied for LUs i our series. The secod approach is based o results derived from the Frech SNIIRAM database aalysis. The SNIIRAM database has bee developed by the Frech Social Health Isurace system ad ecompasses all reimbursed medical acts delivered to the 60 millio Frech citizes durig their full lifespa. 37 A specific algorithm was used to idetify patiets maaged durig this year for a chroic woud (LUs ad PUs) as outpatiets exclusively, ad was published i There were 111,000 LUs ad 103,600 PUs idetified ad usig reimbursemet data, mea estimates of time to closure were calculated ad were 210 ad 223 days for LUs (veous or mixed aetiology) ad PUs respectively with large rages. Here agai, figures obtaied from our aalysis for these types of woud are substatially shorter (Fig 4) whereas the 180 day time to closure for LUs estimated i the cotrol group from the Challege trial is ot so largely differet from the 210 days of the SNIIRAM database aalysis. This suggests that the use of a TLC- NOSF dressig reduced healig time of chroic wouds. Aother poit of iterest is the compariso of estimates of time to closure ad those of time to obtai a 50 % PUSH score reductio, the latter beig used as a idicator of a favourable chage i the healig trajectory. Our results show that these times icreased with the baselie severity score (, ad two risk factors of poor healig progosis) of the wouds. However, the betwee score differeces for PUSH reductio are clearly less tha that for time to closure. This may suggest that whatever the severity level of a chroic woud, there is a importat stimulatio of tissue repair process whe usig a TLC- NOSF dressig. This is i lie with the results observed accordig to the delay of iitiatig this treatmet. Here agai, idepedetly from the presece or ot of risk factors of poor healig progosis, the earlier i woud history the prescriptio of the TLC-NOSF dressig, the shorter the time to closure of the woud.

11 Coclusios These results take together support the hypothesis that the data observed i real-life o over 10,000 patiets are cosistet with results from the RCTs coducted with TLC-NOSF dressigs. Therefore the coclusios derived from these RCTs i specifically selected LUs are probably geeralisable to the geeral populatio treated for chroic wouds i real-life practice. Moreover, these results suggest that the TLC-NOSF dressig may sigificatly reduce healig time of chroic wouds ad that the earlier it is iitiated, the shorter the time to closure. This would positively impact patiets quality of life ad would represet a cost-effective alterative for the treatmet of chroic wouds. However, it is importat to highlight that these coclusios are based o observatioal studies without cotrolled comparators ad the ifluece of umerous cofouders caot be ruled out. Nevertheless this type of extesive ad comprehesive approach is uique for woud dressig studies. JWC Refereces 1 [Improvig the quality of the health system ad cotrollig expeses : Health Isurace proposals for 2014, Report to the Miister resposible for Social Security ad Parliamet o the evolutio of health isurace costs for 2014]. [I Frech] July EWMA Documet: Home Care-Woud Care: Overview, Challeges ad Perspectives. J Woud Care 2014; 23: Suppl 5a, S1-S41. 3 Kirser, R.S., The Woud Healig Society chroic woud ulcer healig guidelies update of the 2006 guidelies--bledig old with ew. Woud Repair Rege 2016; 24: 1, Powers, J.G., Higham, C., Broussard, K., Phillips, T.J. Woud healig ad treatig wouds: Chroic woud care ad maagemet. J Am Acad Dermatol 2016; 74: 4, Raffetto, J.D. Which dressigs reduce iflammatio ad improve veous leg ulcer healig. Phlebology 2014; 29: 1 suppl, Lazaro, J.L., Izzo, V., Meaume, S. et al., Elevated levels of matrix metalloproteiases ad chroic woud healig: a updated review of cliical evidece. J Woud Care 2016; 25: 5, Fraks, P.J., Barker, J., Collier, M. et al. Maagemet of patiets with veous leg ulcers. Challeges ad curret best practice. J Woud Care 2016; 25: Suppl 6, S1 S67. 8 Game, F.L., Apelqvist, J., Attiger, C. et al. Effectiveess of itervetios to ehace healig of chroic ulcers of the foot i diabetes: a systematic review. Diabetes Metab Res Rev 2016; 32: Suppl 1, Price, P., Gottrup, F., Abel, M. Ewma Study Recommedatios: For Cliical Ivestigatios i Leg Ulcers ad Woud Care. J Woud Care 2014; 23 Suppl 5, S1 S Heyer, K., Augusti, M., Protz, K. et al. Effectiveess of advaced versus covetioal woud dressigs o healig of chroic wouds: systematic review ad meta-aalysis. Dermatology 2013; 226: 2, Meaume, S., Truchetet, F., Cambazard, F. et al. A radomized, cotrolled, double-blid prospective trial with a Lipido-Colloid Techology- Nao-OligoSaccharide Factor woud dressig i the local maagemet of veous leg ulcers. Woud Repair Rege 2012; 20: 4, Schmutz, J.L., Meaume, S., Fays, S. et al. Evaluatio of the ao-oligosaccharide factor lipido-colloid matrix i the local maagemet of veous leg ulcers: results of a radomised, cotrolled trial. It Woud J 2008; 5: 2, Pham, Q., Wiljer, D., Cafazzo, J.A. Beyod the Radomized Cotrolled Trial: A Review of Alteratives i mhealth Cliical Trial Methods. JMIR Mhealth Uhealth 2016; 4: 3, e Nallamothu, B.K., Hayward, R.A., Bates, E.R. Beyod the radomized cliical trial: the role of effectiveess studies i evaluatig cardiovascular therapies. Circulatio 2008; 118: 12, Flather, M., Delahuty, N., Colliso, J. Geeralizig results of radomized trials to cliical practice: reliability ad cautios. Cli Trials 2006; 3: 6, Godwi, M., Ruhlad, L., Casso, I. et al. Pragmatic cotrolled cliical trials i primary care: the struggle betwee exteral ad iteral validity. BMC Med Res Methodol 2003; 3: 1, Kogsted, H.C., Koerup, M. Are more observatioal studies beig icluded i Cochrae Reviews? BMC Res Notes 2012; 5: 1, Choi, E.P., Chi, W.Y., Wa, E.Y., Lam, C.L. Evaluatio of the iteral ad exteral resposiveess of the Pressure Ulcer Scale for Healig (PUSH) tool for assessig acute ad chroic wouds. J Adv Nurs 2016; 72: 5, Garder, S.E., Hillis, S.L., Fratz, R.A. A prospective study of the PUSH tool i diabetic foot ulcers. J Woud Ostomy Cotiece Nurs 2011; 38: 4, Ho, J., Lagde, K., McLare, A.M. et al. A prospective, multiceter study to validate use of the PUSH i patiets with diabetic, veous, ad pressure ulcers. Ostomy Woud Maage 2010; 56: 2, Pompeo, M. Implemetig the push tool i cliical practice: revisios ad results. Ostomy Woud Maage 2003; 49: 8, White, R., Cowa, T., Glover, D. Supportig evidece-based practice: a cliical review of TLC techology. MA Healthcare Ltd, Thomas, D.R., Rodeheaver, G.T., Bartolucci, A.A. et al. Pressure ulcer scale for healig: derivatio ad validatio of the PUSH tool. The PUSH Task Force. Adv Woud Care 1997; 10: 5, Ratliff, C.R., Rodeheaver, G.T. Use of the PUSH tool to measure veous ulcer healig. Ostomy Woud Maage 2005; 51: 5, Satos, V.L., Sellmer, D., Massulo, M.M. Iter rater reliability of Pressure Ulcer Scale for Healig (PUSH) i patiets with chroic leg ulcers. Rev Lat Am Efermagem 2007; 15: 3, Gilma, T. Woud outcomes: the utility of surface measures. It J Low Extrem Wouds 2004; 3: 3, Margolis, D.J., Berli, J.A. Strom, B.L. Risk factors associated with the failure of a veous leg ulcer to heal. Arch Dermatol 1999; 135: 8, Margolis, D.J., Berli, J.A., Strom, B.L. Which veous leg ulcers will heal with limb pressio badages? Am J Med : 1, Margolis, D.J., Kator, J., Sataa, J. et al. Risk factors for delayed healig of europathic diabetic foot ulcers: a pooled aalysis. Arch Dermatol 2000; 136: 12, Margolis, D.J., Alle-Taylor, L., Hoffstad, O., Berli, J.A. The accuracy of veous leg ulcer progostic models i a woud care system. Woud Repair Rege 2004; 12: 2, Guest, J.F., Taylor, R.R., Vowde, K., Vowde, P. Relative cost-effectiveess of a ski protectat i maagig veous leg ulcers i the UK. J Woud Care 2012; 21: 8, Guo, S., DiPietro, L.A. Factors Affectig Woud Healig. J Det Res 2010; 89: 3, Gould, L., Abadir, P., Brem, H. et al. Chroic Woud Repair ad Healig i Older Adults: Curret Status ad Future Research. J Am Geriatr Soc 2015; 63: 3, Seet, P., Bause, R., Jørgese, B., Fogh, K. Cliical efficacy of a silver-releasig foam dressig i veous leg ulcer healig: a radomised cotrolled trial. It Woud J, 2014; 11: 6, Ket, D.M., Rothwell, P.M., Ioaidis, J.P. et al. Assessig ad reportig heterogeeity i treatmet effects i cliical trials: a proposal. Trials 2010; 11: 1, Gabler, N.B., Elmore, J.G., Gaiats, et al. Dealig with heterogeeity of treatmet effects: is the literature up to the challege? Trials 2009; 10: 1, Goldberg, M., Carto, M., Gourmele, J. et al. [The opeig of the Frech atioal health database: Opportuities ad difficulties. The experiece of the Gazel ad Costaces cohorts]. [Article i Frech] Rev Epidemiol Sate Publique 2016; 64: 4,

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