1
Leg venous ulcers. Results from an ambulatory conservative and unchanged
treatment of 1.000 consecutive patients during 17 years. A cohort study of ulcer
closure.
E.G. Bertranou;1
S.E. Gonorazky;1
1
Surgery Division and Department of Research, Hospital Privado de Comunidad de
Mar del Plata, Argentina.
Email: egbertranou@yahoo.com.ar
Objective: This work aims at presenting the results of a venous ulcer cohort study of a
17-year unchanged treatment, based on a conservative, ambulatory approach with
compression therapy, in terms of ulcer closure and the risk factors involved (gender,
age, ulcer size, diabetes and time between ulcer onset and first visit).
Method: This study comprises a cohort of 1.000 consecutive patients diagnosed with
venous leg ulcers between 1990 and 2007. The treatment consisted in daily treatment
(self care) with silver sulfadiazine ointment, cotton and elastic bandages. Controls for
debridement were conducted every fortnight or monthly. To favour actuarial evaluation,
ulcers were stratified into three groups based on their size surface area: A ≤10 cm²; B
10–30 cm², and C>30 cm². Kaplan-Meier actuarial analysis and Cox regression
technique were applied.
Results: Taking into account the healing percentages corresponding to the three
surfaces and 4 periods (3, 6, 9 and 12 months), results were as follows: 3 months: A)
62% (95% CI: 58–66%), B) 35% (95% CI: 28–43%) and C) 21% (95% CI: 14–31%); 6
months: A) 81% (95% CI: 78–84%), B) 65% (95% CI: 58–72%) and C) 41% (95% CI:
32–52%); 9 months: A) 87% (95% CI: 84–90%), B) 76% (95% CI: 69–82%) and C)
52% (95% CI: 42–62%); 12 months: A) 90% (95% CI: 87%-92%); B) 80% (95% CI: 74–
86%) and C) 57% (95% CI: 47–67%).The predictor variables of late ulcer closure (risk
factors) were ulcer surface, time of ulcer evolution, and patient age.
Conclusions: By the end of the sixth month, 81% (95% CI: 78%-84%) of ulcers ≤ 10
cm2 were closed (epithelisation). Ulcer size was the most important risk factor for late
closure. This study could help to compare treatment innovations and provide a
prognosis for healing time.
Keywords: varicose ulcer; leg venous ulcer cohort studies; actuarial analysis;
multivariate analysis; outpatient care; risk factors
Leg venous ulcers constitute a pathology that seriously affects a person’s quality of life.
It is estimated that 1% of the adult population suffers from this type of ulcer in their
lifetime, with its prevalence ranging from 0.1% to 0.3% of the population1–3.
In 1990 we responded to the challenge of managing several patients with venous leg
ulcer with efficacy, good patient compliance/collaboration, easy treatment application, a
good cost-effectiveness equation, and a conservative approach. Our first step back in
that time was to open an Ulcer Clinic.
The numerous and dissimilar treatments suggested in the literature at that time made
us rework and extend an assistance program dealing with the objectives mentioned
above and, specifically, based on encouraging dressing practice in patients at home. It
included wound cleansing, antiseptic ointment use and the application of one layer of
soft cotton bandage and one 3 meter long layer of spiral elastic bandage to treat
venous insufficiency. Lesion progress was measured at the Ulcer Clinic every 2 to 4
weeks; and the results obtained were reported to the Hospital authorities and to
scientific meetings held once a year 4.
2
After our visit to the London Charing Cross Hospital and to the St George’s Hospital,
and having read the work by Moffat et al.9, which reported the results from 475 patients
coming from six community clinics from the London area treated as determined by
actuarial techniques, we realized that we were in the right track. In Moffat’s words:
“Ulcer treatment is rarely based on scientific principles but rather on the market forces
determining the healing process, without taking into account their efficiency9.” We
decided then to continue our work sustaining that the ointment would not change the
final result. More patients were enrolled throughout the cohort study with no changes in
the treatment protocol. A definite contrast could be noticed with respect to several
others that varied compression bandage as well as the ointment used, applying
randomized techniques. 1-19.
A review of recent literature, including a meta-analysis of the Cochrane system,
highlights a number of research works resulting from double-blind trials on small series
of randomised patients. All these studies include compression therapy as their primary
treatment, reporting, in their conclusion, either improvement or progress in ulcer
closure within a few months10–20. Several novel therapeutic approaches, both physical
and/or pharmacological, are being tested as adjuvants to treatment; however, few
provide any significant evidence of improved efficacy compared to compression
therapy alone1–19. Only one article has demonstrated the effectiveness of its
intervention. It was a randomised study conducted with 82 patients on the use of
compression alone compared to a combination of compression therapy and ameloginin
(a protein of the extracellular matrix protein family), with the group with ameloginin
achieving a significant reduction in ulcer size20. Despite this, the generalizability of the
method and cost-effectiveness of the approach remain to be ascertained.
Encouraged by the fact that elastic compression therapy remains the gold standard for
leg venous ulcer, we ran the same program for several years in order to assess the
treatment in the long run, and to evaluate the risk factors associated with healing.
This paper aims at presenting the results obtained from treating 1.000 patients with
venous leg ulcers with compression therapy between 1990 and 2007. Despite the large
number of patients and long research period, the treatment protocol remained
unchanged, with no new therapeutic approaches adopted during the course of the
study. Moreover, care was provided by the same staff and in the same clinic
throughout the research period. This allowed us to accurately estimate healing time, as
well as the risk factors connected to this pathology (gender, age, TUE=time of ulcer
evolution or ulcer age, diabetes, etc.) based on the supposition that our cohort was
representative of the general population with leg venous ulcer.
Methods
The study was conducted in the Phlebology Service of the Hospital Privado de
Comunidad de Mar del Plata, Argentina, between 1990 and 2007. Inclusion criteria:
One-thousand consecutive patients suffering from leg venous ulcer resulting either
from superficial and/or deep vein insufficiency whether congenital or after a deep vein
thrombosis were enrolled every month in the study. Patients were included irrespective
of their ulcer size, location, depth, and swelling and of the healthy appearance of the
wound. Exclusion criteria: Insufficient peripheral arterial perfusion. Whenever possible,
ABPI had to be > 70 mmHg. For some patients, the test was impracticable (peripheral
edema, huge ulcer involving areas of peripheral arteries, painful ulcer, reluctant patient,
etc.). In those cases we resorted to portable ultrasound equipment or to toe capillary
filling (less than 5 seconds after 5 seconds of compression). The rationale behind this
criteria was to have a foot arterial pressure greater than the bandage pressure in the
foot and ankle (60 mmHg measured by sphyngomanometer) to avoid arterial
3
compression and to facilitate venous return. If patients tolerated these parameters with
their leg horizontal or when walking, the treatment was considered efficient. Otherwise,
the bandage pressure had to be adequately fixed. Age, gender, ulcer age and diabetes
were not exclusion criteria. Ulcer size was calculated by multiplying the two maximum
perpendicular diameters6.
The Hospital’s Ethics Committee did not evaluate this study for considering that the
treatment was standard. The programme was assessed on a periodic basis and the
first results were published in 19924.
Treatment Protocol
The conservative ambulatory treatment protocol was based on educating patients and
families, and started with a long training session on self-care and compression
bandage given by trained nurses. The aim of such training was to teach patients how to
apply the bandage. A brochure with key information and advice on eating without salt
(to avoid peripheral edema in inactive patients) and taking regular walks, among
others, was handed to the patients/family. Education is a never-ending task. Treatment
was initiated after the clinical diagnosis of venous leg ulcer and after verifying the
inclusion and exclusion criteria above specified.
For control purposes, ulcers were photographed in the initial assessment visit and after
their complete closure, and evidence was stored in a database. Deep ulcer
debridement was performed under local anaesthetics. This procedure was mostly
conducted by specialized nurses at the beginning of the treatment in the Ulcer Clinic,
and comprised the removal of necrotic tissues with the aid of scissors and a scalpel.
Mechanical debridement followed, and it was achieved with cotton gauze embedded in
a hydrophilic antiseptic ointment, and wrapped with an elastic bandage. The gauze
pressed on the ulcer producing such debridement when it was removed the day after.
Wound care comprised applying moisturizing cream around the ulcer, followed by silver
sulfadiazine-lidocaine ointment of hydrophilic composition. Some controversies exist
regarding the use of silver sulfadiazine in wounds. The Cochrane Database of
Systematic Reviews of January 2006 (Bergin SM and Wraight P) concludes that
“Despite the widespread use of dressings and topical agents containing silver for the
treatment of diabetic foot ulcers, no randomised trials or controlled clinical trials exist
that evaluate their clinical effectiveness”. Indeed, trials are needed to determine clinical
benefits and cost-effectiveness as well as long term outcome, including adverse
events. Throughout the study, we used Platsul® with silver sufadiazide 10 mg.,
dimecaine 6.66 mg., and vitamin A 2.5 mg. in a basic hydrophilic ointment. No
intolerance or allergy was ever reported by our patients. As postulated before, the
ointment is not what matters but rather the way in which the dressing is applied.
After that, sterile cotton gauze was placed over the wound and a cotton bandage was
loosely wrapped down from the foot to below the knee to prevent the elastic bandage
from hurting or irritating the leg skin. The elastic bandage was applied starting from the
forefoot (living the heel free) following with the ankle and finishing below the knee.
Pressure in the forefoot and ankle was approximately 60 mmHg, so as not to hinder
arterial circulation, 40 mmHg at the mid leg segment, and 20 mmHg below the knee,
thereby favouring venous return through the perforators (the saphenous and posterior
arch veins) toward the deep veins. The service used a device with an inflatable rubber
end, calibrated with a mercury manometer, to measure the approximate bandage
pressure. The dressing was changed by the patient/family on a daily basis.
4
Curiously leg venous ulcers are not extremely painful unless they are grossly infected.
Pain can be efficiently controlled with Ibuprofen and/or Tramadol. A well wrapped
elastic bandage is the best analgesic, because it controls the pain of deep venous
thrombosis. If a leg venous ulcer is painful in an unreasonable way, an arteriolar
compromise could be involved, such as in the Martorell’s arteriolar hypertensive ulcer7.
The second visit was scheduled 1 week after treatment initiation, where errors in
dressing structure were corrected, such as pressure in the elastic bandage (greater
below the knee than in the foot), incorrect use of the ointment, insufficient or to tight
cotton bandage, etc. If the pressure in the bandage was not correct, a manometer was
provided to the patient/family until the technique was properly mastered. Surgical
debridement was performed (if necessary) under topical anesthetics, and an
appointment was scheduled for follow-up every 2 weeks or monthly, until full
epithelisation took place. Once complete ulcer healing was attained, the surgical
treatment of the superficial and/or deep venous insufficiency was addressed, whenever
possible.
Throughout evolution, data were stored in the database. The primary endpoint of the
study was the full epithelisation of the ulcer.
The independent variables taken into account were:
 Ulcer size on initial assessment, stratified into three groups (A ≤10cm²; B 10–
30cm², and C >30cm²)
 TUE=Time of ulcer evolution (period between ulcer onset and first visit).
 Age
 Gender
 Diabetes
We believe that patient’s mobility is not a major risk factor in delayed healing per se.
Besides it is very difficult to evaluate for being extremely subjective, and hence it was
not include it in the analysis.
If a patient presented ulcers on both lower limbs, the largest one, or the one that had
appeared first, was analysed. If relapse occurred, only the primary ulcer was analysed.
Statistical Analysis
Descriptive: For categorial variables, absolute and relative frequencies were used.
Regarding intervalic variables, median, interquartile range and range were adopted,
because distribution was abnormal (Table 1). Predictor variables of ulcer closure were
ascertained from a Cox’s8 proportional-hazards regression model in the univariate and
multivariate analysis. In the univariate analysis, variables were considered statistically
significant at a 0.15 level, and, in these cases, they were included in the multivariate
analysis. The multivariate analysis was conducted using the stepwise method of
conditional regression and the significance level used was P≤0,05. A Relative Risk
(RR) < 1 meant late closure (Table 2).
The probability of ulcer closure was assessed based on ulcer size, stratified in 3
groups. In the 1st, 3rd, 6th and 12th month after the beginning of treatment, the
percentage of ulcer closure was estimated with a confidence interval of 95%, following
the method by Kaplan and Meier7. The analysis was conducted using the SPSS
statistical package (V11.5.1).
5
Results
The study period analysed (1990–2007) allowed us to include a total of 1.000 patients.
Median age was 70 years (24–95 years). Sixty-five per cent were women, and the
median ulcer surface area was of 4.7cm² (range 0.5–942.4 cm²). Thirteen per cent had
diabetes, and the median time of ulcer evolution (TUE) was 3 months (0.5–486
months) (Table1)
The statistically significant independent variables (risk factors) for ulcer healing were:
 Age
 TUE
 Ulcer size.
These three variables were noted to prolong healing time in a directly proportional way
being ulcer size the most relevant clinical feature, with a relative risk (RR) in the
multivariate analysis of 0,66 (95% CI: 0.59-0,75) (Table 2).
Ulcers were separated into three groups based on their surface area: A: <10cm²; B: >
10 < 30cm², and C: > 30cm² (66%, 20% and 14% of patients, respectively). The
percentage of healed patients in the different periods in the three stratified groups,
based on ulcer size, are shown in Table 3 and Figure 1.
Discussion
Despite the large number of patients and the prolonged follow-up, which characterised
our study, the treatment protocol remained unchanged throughout the series, with no
new therapeutic approaches adopted during the course of the study. On the other
hand, care was provided by the same staff and in the same clinic throughout the
research period. Finally the 1.000 patients were divided into 3 groups based on the
ulcer size with the purpose of determining the relevance of this risk factor.
We believe that we are in a position to present a basic work based on compression
bandage as the gold standard and with no need to include further elements. This
research could work as a point of reference for other researches being conducted by
adding innovation in small series and improving the treatment of this devastating
condition.
Additionally, based on this study, a surgeon faced with a venous ulcer could inform a
patient/family just by looking at the three curves, “Your ulcer is less than 10 cm2, then it
has between 78% and 84% chances of being closed after 6 months”, for instance
(Figure 1).
The results obtained from this series can be compared to those of similar works
including a large number of patients (multi-centric studies) and with ulcer closure as
their primary outcome21,22. Two articles have demonstrated the action of purified
micronised flavonoid fraction21,22. Glinski et al.21 conducted a double-blind study,
carried out on 140 patients with venous leg ulcers of area >3cm², treated for 6 months.
Patients treated with the purified micronised flavonoid fraction achieved a 71% closure,
compared to our series result of 80% closure for ulcers of area >10cm², during the
same period (Figure 1). The second work, by Guilhou et al.,22 performed on 107
patients with ulcer area <10cm², achieved 32% closure after 2 months of treatment
using purified micronised flavonoid fraction, compared to 662 patients with ulcers of up
to 10cm², achieving a 40% closure rate with compression therapy during that same
period in our study (Figure 1).
6
Nelson E A and Jones J20 found 80 systematic reviews, RCTs and observational
studies and performed a grade evaluation of quality of evidence for interventions. They
noticed an immense variety of adjuvant treatment which made it very difficult to
compare treatment results.
This demonstrates that there is sufficient scientific evidence supporting the
recommendation for the use of a hemodynamic method, carried out by professionals
versed in vascular pathophysiology, based on compression bandage (saphenous and
posterior arch veins and perforators) with elastic bandage for venous leg ulcer
treatment. It can also be concluded that, while there are several products available for
the healing of venous leg ulcers, the scientific evidence justifying their use is weak,
probably because the series include only a small number of patients. Finally, adjuvants
appear to do little more than increase the cost-benefit equation. Treatment cost and the
high frequency of relapse is worth analysing in this type of ulcers.
Conclusions
The outcome of the complete healing (epithelisation) considering the largest group of
ulcers (≤ 10 cm2) is as follows: a) by the end of the 3rd month, 62% (95% CI: 58% 66%); by the end of the 6th month 81% (95% CI: 78%-84%); by the end of the 9th
month 87% (95% CI: 84% -90%); and by the end of the 12th month 90% (CI 87%92%).
The multivariate analysis shows that ulcers size, TUE and patient’s age are statistically
significant predictors of ulcer closure time, with ulcer size being the most important
clinical factor.
This study could serve as a platform to compare innovations in ulcer treatment and to
offer a prognosis of healing time.
References
1
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7
8
9
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Table 1
Number of Patients:
Females:
Age of females (in years):
Males:
Age of males:
Ulcer size:
TUE
Diabetes:
Follow-up:
1.000
653 (65,3%)
71 years (M); 63 - 77 years (IR); 32 - 95 years
347 (34,7%)
69 years (M); 61 - 75 years (IR); 24 - 93 years (R)
4,7 cm² (M); 1,6 - 14,1 cm² (RI); 0,5 - 942,4 cm² (R)
3 months (M); 1-3 months (IR) 1- 486 (R)
128 patients (12,8 %)
2,3 months (M); 1-5 months (IR); 0-58,2 months (R)
M: Median
IR: Interquartile range
R: Range
TUE: Time of ulcer evolution (Period between ulcer onset and first visit)
Table 2
Predictor variables of ulcer closure (RR*<1 late closure)
Univariate Analysis
Factors
Age
Gender ‡
Ulcer size §
TUE ¶
Diabetes
RR*
0,99
1,03
0,60
0,99
0,86
(IC 95%)†
(0,99-1)
(0,89-1,2)
(0,54-0,67)
(0,98-0,99)
(0,69-1,06)
Multivariate Analysis
p
0,08
0,18 &
<0,05
<0,05
0,16 &
RR*
0,99
---0,66
0,99
----
(IC 95%)†
(0,99-1)
----(0.59-0,75)
(0,990-0,997)
----
* RR= Relative risk
† 95% CI = 95% Confidence limits
‡ Gender=male
& Not significant
§ Ulcer size divided into three groups: A ≤10 cm 2; B 10-30 cm2: C >30 cm2
¶ TUE=time of ulcer evolution (period between ulcer onset and first visit)
p
<0,05
----< 0,05
<0,05
----
9
Table 3
Percentage of healed patients in different periods in the three stratified
groups, based on ulcer size.
Months
Group A
≤10cm²
n=662
Group B
10–30cm²
n=196
Group C
>30cm²
n=142
1
15% (12%; 18%)*
2% (1%; 6%)*
3% (1%; 8 %)*
3
62% (58%; 66%)*
35% (28%; 43%)*
21% (14%; 31%)*
6
81% (78%; 84%)*
65% (58%; 72%)*
41% (32%; 52%)*
9
87% (84%; 90%)*
76% (69%; 82%)*
52% (42%; 62%)*
12
90% (87%; 92%)*
80% (74%; 86%)*
57% (47%; 67%)*
* 95% confidence interval
Fig 1. Actuarial analysis conducted on 1000 patients
10