Accepted Manuscript A prospective randomised study comparing polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer Walter Campos, Jr., MD, Inez Ohashi Torres, MD, Erasmo Simão da Silva, PhD, Ivan Benaduce Casella, PhD, Pedro Puech-Leão, PhD PII:
S0890-5096(15)00337-4
DOI:
10.1016/j.avsg.2015.01.031
Reference:
AVSG 2355
To appear in:
Annals of Vascular Surgery
Received Date: 2 October 2014 Revised Date:
3 January 2015
Accepted Date: 24 January 2015
Please cite this article as: Campos W Jr., Torres IO, da Silva ES, Casella IB, Puech-Leão P, A prospective randomised study comparing polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer, Annals of Vascular Surgery (2015), doi: 10.1016/j.avsg.2015.01.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Original Article
A prospective randomised study comparing polidocanol foam sclerotherapy with
RI PT
surgical treatment of patients with primary chronic venous insufficiency and ulcer.
Walter Campos Jr. MD, Inez Ohashi Torres* MD, Erasmo Simão da Silva PhD, Ivan
SC
Benaduce Casella PhD, Pedro Puech-Leão PhD
Endovascular Surgery Department
*Corresponding author: Inez Ohashi Torres
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Clinics Hospital of São Paulo University Medical School, São Paulo, Brazil, Vascular and
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São Paulo University Clinics Hospital, Vascular and Endovascular Surgery Department Rua Oscar Freire, 1546, ap 33. CEP 05409-010. São Paulo – SP. Brazil
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EP
Tel.: +55 (11) 98638-1138
2
ACCEPTED MANUSCRIPT Abstract
Objective: To compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and active ulcer treated at a single vascular center. Design and Methods: 58 limbs of 56 patients with active ulcers were prospectively
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randomized to undergo either surgical treatment or foam sclerotherapy. Patients completed the Aberdeen Varicose Veins Questionnaire (AVVQ), the Venous Clinical Severity score
SC
(VCSS) and Venous Disability Score (VDS). The follow-up was 502 ± 220 days.
Results: The ulcer healed in 100% and 91.3% of patients treated with surgery or foam
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sclerotherapy, respectively (P > 0.05). There were no significant differences in AVVQ, VCSS and VDS between the two groups after the procedures (P = 0.
45, 0.58 and 0.66, respectively; Mann–Whitney U test). Complications occurred in 14.2% and 13.0% in the surgical and foam sclerotherapy groups, respectively.
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Conclusion: Surgical treatment and foam sclerotherapy achieved high rates of ulcer healing, without a statistically significant difference. Both treatments led to significant improvements
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EP
in VCSS, VDS, AVVQ scores, demonstrating improvements in clinical outcomes and QoL.
3
ACCEPTED MANUSCRIPT 1. Introduction
Chronic venous ulceration is a condition that affects millions of people worldwide. It severely impairs health-related quality of life (HRQoL) and imposes a considerable burden on
RI PT
healthcare resources.1-4 Data from the Brazilian Social Security System revealed that chronic venous disease is ranked 14th for causes of temporary work absenteeism and 32nd for permanent disability and
SC
public financial assistance.1
Surgical treatment has been the main method of treating patients with lower limb venous
M AN U
disease associated with saphenous incompetence. Promising results have since been reported for alternative treatments, including endovascular radiofrequency or laser ablation. However, the use of these methods has been limited in many countries because of their cost.5 Foam sclerotherapy is an inexpensive and simple method that is easy to perform by experienced clinicians.5 Numerous clinical series have used foam sclerotherapy to treat
TE D
disorders of the great saphenous vein (GSV).1,3–18 However, there are limited outcomes data for patients with CEAP C5 (healed ulcer) and C6 (active ulcer) disease.6,7
EP
Therefore, the aim of this study was to compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer, with a particular
AC C
focus on healing, complications, and QoL in the patients with venous disorders treated at the Clinics Hospital of São Paulo University Medical School (HC-FMUSP).
4
ACCEPTED MANUSCRIPT 2. Objective
The objective of the present study was to compare the effects of polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency
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EP
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SC
complications, and improvements in QoL.
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and active ulcer. Study outcomes included the time taken for ulcers to heal, the incidence of
5
ACCEPTED MANUSCRIPT 3. Methods 3.1 Patients and methods
This was a prospective, open, randomized controlled study performed at the Clinics Hospital of São Paulo University Medical School. The local Ethics Committee for Research Affairs
RI PT
approved the study, and patients gave written informed consent for their inclusion in this study. The Study was registered at Plataforma Brasil (number: 0158.0.015.000-0), and approved by Brazilian National Ethics Comitee (CEP) under the numer: 0170/09 before the firs patient
SC
was randomized.
Patients fulfilling the following criteria were eligible for the study: primary chronic venous
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insufficiency caused by reflux in superficial veins, GSV diameter of 0.7–1.4 cm as measured by duplex ultrasound, presence of an active ulcer (maximum 5 cm diameter), and an ankle– brachial index (ABI) of 0.9–1.3. Patients with any of the following were excluded: history of deep vein thrombosis, deep vein thrombosis or deep vein reflux in duplex assessment, arterial
TE D
disease of the lower limbs (ABI 1.3), superficial thrombosis, diabetes, thrombophilia, pregnancy, or allergy to polidocanol. Between August 2007 and February 2010, 58 consecutive limbs of 56 meeting the eligibility
EP
criteria were prospectively randomized (simple randomization) to undergo either surgical
AC C
treatment (29 limbs) or foam sclerotherapy (29 limbs) as described in Figure 1. The intervention occurred within 30 days of the randomization. All of the patients had previously received elastic compression therapy with a 30mmHg above knee elastic stocking for at least six months before enrolling in the present study. Most of the ulcers were recurrent. Patients in both groups completed the Aberdeen Varicose Veins Questionnaire (AVVQ), except for the first question, because of the patients experienced difficulty in drawing their veins. The Venous Clinical Severity Score (VCSS) and Venous Disability Score (VDS) were
6
ACCEPTED MANUSCRIPT
determined by a vascular surgeon. The ulcers were photographed and analysed using image analysis software (Image Tool program). Duplex ultrasound was performed in all of the patients before undergoing treatment. Ultrasound was performed while the patients stood with their weight on the contralateral
RI PT
limb. The following venous segments were evaluated: femoral vein; popliteal vein, saphenofemoral and saphenopopliteal junctions, perforator veins, the entire length of the GSV, and the short saphenous veins. All veins were assessed for patency and compressibility.
SC
Reflux was induced by manually squeezing the calf, and was defined as reverse flow persisting for >0.5 s.
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The mean ± standard deviation (SD) follow-up time was 502 ± 220 days.
3.2 Treatments
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Surgery was performed under spinal anaesthesia in a surgical room. It consisted of major saphenous stripping (saphenofemoral junction disconnection and stripping of the long saphenous vein to the ankle), phlebectomy of tributaries, and ligation of perforating veins. A
EP
compressive bandage was applied and kept in place for 72 h after surgery. Afterwards, the
AC C
patients wore a 30 mmHg elastic stocking above the knee for >8 h/day. The patients were released from work for 2 weeks. During this time, they could rest in supine position, but they were advised to walk for at least 15 minutes/hour. After that time, they were instructed to go back to usual daily activities using the elastic stocking. Foam sclerotherapy was performed in the ambulatory clinic. The polidocanol foam was prepared by using two 10mL syringes that were connected by a two-way stopcock connector. One of the syringes was filled with 8mL of air. After aspiration of 2mL of 3% polidocanol into the other syringe, the syringes were rapidly and alternately pumped until the mixture
7
ACCEPTED MANUSCRIPT
turned into foam. The GSV was cannulated under ultrasound guidance with a butterfly 21 G needle (the most common site was around 5cm bellow the knee). The leg was elevated to around 45° during foam injection. In each procedure, we injected 8–10 mL of 3% polidocanol foam under ultrasound monitoring. The saphenofemoral junction was compressed during
RI PT
foam injection. Following treatment, the patients stayed in a supine position for 20 min. A compressive bandage was then applied and kept in place for 72 h. Afterwards, the patients wore a 30 mmHg elastic stocking above the knee for >8 h/day. The patients were advised to
SC
continue their normal daily activities following the procedure. and to wear elastic stocking
3.3 Follow-up assessments
M AN U
during the entire follow up period.
Follow-up assessments were done at 7 days after the procedure, and every 2 months thereafter. At every follow-up visit, a vascular surgeon performed a clinical investigation to
TE D
assess the outcomes and complications of surgery and sclerotherapy. The Aberdeen Varicose Veins Questionnaire (AVVQ), VCSS and VDS were determined before and 12 months after the procedure.
EP
In the sclerotherapy group, duplex ultrasound was performed at 6 and 12 months after
AC C
treatment. In the surgical treatment group, only patients with symptoms or signs suggestive of deep vein thrombosis or thrombophlebitis underwent duplex ultrasound. Ulcer healing was defined as complete re-epithelisation of the leg.
3.4 Statistics Non-paired quantitative variables were compared using the Mann–Whitney U test, while categorical variables were compared using the χ2 test or Fisher’s test. Wilcoxon’s signed ranks test was used to analyse paired quantitative variables before and after therapy. Survival
8
ACCEPTED MANUSCRIPT
curves for ulcer healing were plotted using the Kaplan–Meier method, and were compared using the log-rank test. For all analyses, values of P < 0.05 were considered statistically significant. Statistical analyses were performed for all patients who underwent surgery or
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SC
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sclerotherapy.
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ACCEPTED MANUSCRIPT 4. Theory
Chronic venous disorders are part of a multifactorial syndrome with a significant social and economic impact. 1,19
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As an alternative to surgery, new and less-invasive methods have been developed to control insufficiency of the truncal vein.20
Minimally invasive procedures have several advantages, including reduced discomfort and
SC
morbidity secondary to groin incision, and can be performed in an outpatient clinic.15
This study was performed at the Clinics Hospital of São Paulo University Medical School. It
M AN U
is the major public hospital in Latin America, responsible for around 120.000 outpatients visits/month and 5000 surgical procedures/month. Nevertheless, some patients have to wait for months or even years to undergo surgical procedures. If we have a good result with a
public health system.
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treatment that can be done with no necessity of hospitalization, it might impact positively our
Additionally, many patients with venous ulcers are elderly and are either reluctant or unfit for surgery. Therefore, these patients seem to be very suitable for foam sclerotherapy. 15
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Foam sclerotherapy is inexpensive, is easy to perform by experienced clinicians, requires
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very little equipment, and can be repeated several times to improve its outcome.5 As the procedure is very quick and painless, it can be performed under local or no anaesthesia. Additionally, the patient can continue habitual activities after the procedure. Therefore, the aim of this study was to compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer.
10
ACCEPTED MANUSCRIPT 5. Results 5.1 Patients
The two groups were similar in terms of age, sex distribution, and other characteristics. There were no significant differences between the two groups in terms of baseline AVVQ, VCSS,
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and VDS. However, skin ulceration area was greater in the surgical treatment group. The
SC
clinical and demographic characteristics of patients in both groups are presented in Table I.
5.2 Ulcer healing
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Ulcer healing was achieved in 100% (28/28) of the patients in the surgical treatment group and in 91.3% (21/23) of patients in the foam sclerotherapy group (P = 0.19; Fisher’s test). The 12 and 24-week cumulative healing rates were respectively 7,2 and 28,6% for the surgery group and 8,7 and 13,1% for the foam group. Two patients from the foam group did
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not show ulcer healing at the 1-year follow-up. The mean time to ulcer healing was 37.1 ± 22.1 days in the surgical treatment group and 56.4 ± 39.4 days in the foam sclerotherapy
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group (P = 0.008; log-rank test), as shown in Figure 2. 5.3 Improvements in VCSS, VDS, and AVVQ
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Both interventions resulted in significant improvements in clinical factors and QoL from baseline to the follow-up visit. In the surgical treatment group, the mean VCSS and VDS decreased by 72.8% and 44.8%, respectively. There was also an improvement in QoL, as determined using the Aberdeen questionnaire, which decreased by 69.4%. Similar results were obtained with foam sclerotherapy, as VCSS and VDS scores decreased by 65.2% and 45.5%, respectively, and QoL decreased by 57.7% compared to the preoperative evaluation. The means and standard deviations for each parameter are presented in Table II.
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ACCEPTED MANUSCRIPT
When the follow-up values were compared between the two groups, there were no significant differences in VCSS, VDS, or QoL between the two groups (P = 0.58, 0.66, and 0.45, respectively), as shown in Figure 3.
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5.4 Complications
Complications occurred in 14.2% and 13.0% of patients in the surgical and foam sclerotherapy groups, respectively (P = 1.0; Fisher’s test). There were no severe
SC
complications.
Surgical complications considered related to treatment included saphenous neurapraxia,
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incision infection, lymphorrhea, and cellulitis. Complications in the foam sclerotherapy group included transitory visual disturbances, skin pigmentation, and transient dyspnea. One patient developed extensive thrombophlebitis after foam injection, and required a short course of low-dose heparin (enoxaparin) therapy. The complications are presented in table III.
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The saphenous neurapraxia consisted of an area of hypoesthesia on the medial behalf of a patient’s leg, only related by the patient after being active interrogated by the physician. The infections and the lymphorrhea were treated with no permanent consequences. The visual
EP
disturbance and dyspnea were transitory, lasting for only a few minutes. The patients
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underwent investigation with tomography, excluding stroke and pulmonary embolism respectively.
5.5 Recurrence Rates
We have had 2/29 recurrent ulcers in the surgery group and 1/23 in the sclerotherapy group during the follow up period.
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ACCEPTED MANUSCRIPT 6. Discussion
In the present study, the ulcers healed in all of the patients who underwent surgery. This is a high rate compared with the result of other studies, like the ESCHAR study.21 A possible explanation is that we applied more restrictive eligibility criteria relative than the ESCHAR
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study. Consequently, we did not treat any patients with deep venous reflux or previous deep vein thrombosis. By contrast, 18% and 35% of patients who underwent surgical treatment in the ESCHAR study had previous deep vein thrombosis and deep vein reflux, respectively.21
SC
We have chosen to study only the patients with superficial reflux because they represent the greatest amount of patients in our hospital (about 70%). Nevertheless, as long as it is a single
more homogeneous group.
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center study and we didn’t have a very large number of patients, we have chosen to have a
In this study the ulcer healed in 91.3% of patients treated with foam sclerotherapy, which was not significantly different from the rate in the surgical treatment group (P = 0.19; Fisher’s
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test). It’s interesting that the ulcers healed in 100% of the patients that were treated with surgery, even so the main area of the ulcer in this group was bigger. Maybe the surgical
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treatment can more completely treat superficial vein reflux by treating the GSV, stripping the varicose veins, and ligating the perforating veins presenting with reflux. In the sclerotherapy
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group, some of these veins exhibited only partial thrombosis. Nevertheless, we think that healing could have been achieved in more patients in the sclerotherapy group if we had permitted more than one sclerotherapy session and treated the GSV together with other varicose veins.
Some reports have presented similar healing rates after foam sclerotherapy. For example, Cabrera et al. treated 116 patients with severe chronic venous disorders over 10 years. At 6 months after treatment, complete healing of the venous ulcers was achieved in 83% (96/116) of the patients. The median time to healing was 2.7 months.16
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In our study, the mean time for ulcer healing was 37.1 ± 22.1 days in the surgical treatment group versus 56.4 ± 39.4 days in the foam sclerotherapy group, which was significantly different (P = 0.008; log-rank test). One explanation for this difference is that the patients who underwent surgery were released from work and could rest for 2 weeks after the
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procedure, whereas the patients who underwent foam sclerotherapy were allowed to resume daily activities immediately after the intervention.
The reason why we have chosen to release that patients from work, was that during the
SC
surgery, we make a great number of flebectomies, and the patients use to have pain, small
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bleedings and limb edema if they go back to work very soon.
We are aware that this rest could influence the result, nevertheless that’s the protocol in our service, which was determined by patients’ tolerance. This is a negative point of the surgery, once the inability of working for some days after the procedure is one of the reasons that
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some young patients refuse the surgical treatment.
The patients of the foam sclerotherapy group were advised to continue their normal daily activities following the procedure, because they tolerated it easily and, in face of that, we
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believe that the difference in healing time is not clinically important, which is illustrated by
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the marked improvement in QoL in both groups shown by AVVQ. The AVVQ is a sensitive and responsive disease-specific questionnaire that is well correlated with generic and clinical outcomes.22 The score ranges from 0 to 77.6, after excluding the first question, and higher scores represent worse QoL. We did not use the first question in this study because the patients experienced difficulty in drawing their veins. Notably, both treatments led to significant improvements in QoL as the AVVQ decreased by 69.4% in the surgical treatment group and by 57.7% in the foam sclerotherapy group, as
14
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compared with the baseline score. The reductions in Aberdeen questionnaire scores observed in this study are consistent with those reported by other researchers.12,17 Darvall et al.12 conducted a prospective study of 296 patients, and analysed generic (Short Form 12) and disease-specific (AVVQ) HRQoL in patients who underwent foam
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sclerotherapy for varicose veins. They concluded that ultrasound-guided foam sclerotherapy of the GSV and small saphenous varicose veins significantly improved generic and diseasespecific HRQoL that was maintained for ≥12 months after treatment.12
SC
This improvement in HRQoL is a very important finding. Kahn et al.4 reported that patientreported QoL is an important component in evaluating treatment outcomes, particularly 4
Similarly, Smith et al.8 proposed that the most
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changes in illness severity over time.
comprehensive way of assessing the impact of an intervention is to assess the impact of the intervention on QoL. They also proposed that, when the assessment of QoL is combined with clinical and laboratory tests, it is possible to assess the true impact of the condition, and its
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severity, on the patient.8 Therefore, besides evaluating ulcer healing and patient-reported QoL, we also analysed clinical parameters.
The VCSS was developed from elements of the CEAP classification system, as an evaluative
EP
instrument that would be sensitive to changes in disease severity over time and the response
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to treatment.23,24 It ranges from 0 to 18, where 18 is the most severe venous disease. In this study, VCSS improved markedly in both groups, decreasing from 12.5 to 3.3 in the surgical treatment group and from 12.2 to 4.2 in the foam sclerotherapy group. These results are consistent with those reported by Blaise et al., who noted improvements in clinical severity and QoL scores of >20% at 6 months after polidocanol foam sclerotherapy.17 Figueiredo et al comparing VCSS in C5 patients treated by surgery or foam sclerotherapy have also shown statiscally significant reductions of all scores in both patients groups.25
15
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A clinical improvement was also implied by the reduction in VDS in both groups. The VDS score ranges from 0 (asymptomatic disease) to 3 (the patient is unable to perform daily activities, even when wearing an elastic stocking). The median baseline score was 2, and decreased to 1 in the foam sclerotherapy group and 1.18 in the surgical treatment group. The
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follow-up values were consistent with those reported by Masuda et al., who studied 80 limbs after ultrasound guided sclerotherapy of the perforator veins using 5% sodium morrhuate.18 Besides the ulcer healing and the improvement in patient’s quality of life, we noticed a low
SC
recurrence rate. We’ve had only 7,1% recurrent ulcers in the surgical group and 8,7% in the sclerotherapy group, probably because these patients had a very close follow up, with
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frequent evaluations and a good support with the compression therapy.
In the present study, anatomical and hemodynamic measurements were not prioritized because they show poor correlations with functional parameters measured before and after
possible complications.
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interventions.22 Instead, we performed duplex ultrasound at the follow-up visits to identify
The incidence rates of complications were minor in both groups. In the surgical treatment groups, the main complications involved groin incision (two patients developed postoperative
EP
infection and one patient developed lymphorrhea). In the sclerotherapy group, the most
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frequent complications were skin pigmentation and phlebitis. One patient also developed extensive phlebitis, which required low-dose heparin therapy. In a systematic review published in 2007,14 the most common complications after foam sclerotherapy were thrombophlebitis (4.7%), skin pigmentation (17.8%), and injection site pain (25.6%). Some patients also experienced headache (4.2%) and visual disturbances (1.4%). Pulmonary thromboembolism and deep vein thrombosis occurred in
S0890-5096(15)00337-4
DOI:
10.1016/j.avsg.2015.01.031
Reference:
AVSG 2355
To appear in:
Annals of Vascular Surgery
Received Date: 2 October 2014 Revised Date:
3 January 2015
Accepted Date: 24 January 2015
Please cite this article as: Campos W Jr., Torres IO, da Silva ES, Casella IB, Puech-Leão P, A prospective randomised study comparing polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer, Annals of Vascular Surgery (2015), doi: 10.1016/j.avsg.2015.01.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Original Article
A prospective randomised study comparing polidocanol foam sclerotherapy with
RI PT
surgical treatment of patients with primary chronic venous insufficiency and ulcer.
Walter Campos Jr. MD, Inez Ohashi Torres* MD, Erasmo Simão da Silva PhD, Ivan
SC
Benaduce Casella PhD, Pedro Puech-Leão PhD
Endovascular Surgery Department
*Corresponding author: Inez Ohashi Torres
M AN U
Clinics Hospital of São Paulo University Medical School, São Paulo, Brazil, Vascular and
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São Paulo University Clinics Hospital, Vascular and Endovascular Surgery Department Rua Oscar Freire, 1546, ap 33. CEP 05409-010. São Paulo – SP. Brazil
AC C
EP
Tel.: +55 (11) 98638-1138
2
ACCEPTED MANUSCRIPT Abstract
Objective: To compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and active ulcer treated at a single vascular center. Design and Methods: 58 limbs of 56 patients with active ulcers were prospectively
RI PT
randomized to undergo either surgical treatment or foam sclerotherapy. Patients completed the Aberdeen Varicose Veins Questionnaire (AVVQ), the Venous Clinical Severity score
SC
(VCSS) and Venous Disability Score (VDS). The follow-up was 502 ± 220 days.
Results: The ulcer healed in 100% and 91.3% of patients treated with surgery or foam
M AN U
sclerotherapy, respectively (P > 0.05). There were no significant differences in AVVQ, VCSS and VDS between the two groups after the procedures (P = 0.
45, 0.58 and 0.66, respectively; Mann–Whitney U test). Complications occurred in 14.2% and 13.0% in the surgical and foam sclerotherapy groups, respectively.
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Conclusion: Surgical treatment and foam sclerotherapy achieved high rates of ulcer healing, without a statistically significant difference. Both treatments led to significant improvements
AC C
EP
in VCSS, VDS, AVVQ scores, demonstrating improvements in clinical outcomes and QoL.
3
ACCEPTED MANUSCRIPT 1. Introduction
Chronic venous ulceration is a condition that affects millions of people worldwide. It severely impairs health-related quality of life (HRQoL) and imposes a considerable burden on
RI PT
healthcare resources.1-4 Data from the Brazilian Social Security System revealed that chronic venous disease is ranked 14th for causes of temporary work absenteeism and 32nd for permanent disability and
SC
public financial assistance.1
Surgical treatment has been the main method of treating patients with lower limb venous
M AN U
disease associated with saphenous incompetence. Promising results have since been reported for alternative treatments, including endovascular radiofrequency or laser ablation. However, the use of these methods has been limited in many countries because of their cost.5 Foam sclerotherapy is an inexpensive and simple method that is easy to perform by experienced clinicians.5 Numerous clinical series have used foam sclerotherapy to treat
TE D
disorders of the great saphenous vein (GSV).1,3–18 However, there are limited outcomes data for patients with CEAP C5 (healed ulcer) and C6 (active ulcer) disease.6,7
EP
Therefore, the aim of this study was to compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer, with a particular
AC C
focus on healing, complications, and QoL in the patients with venous disorders treated at the Clinics Hospital of São Paulo University Medical School (HC-FMUSP).
4
ACCEPTED MANUSCRIPT 2. Objective
The objective of the present study was to compare the effects of polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency
AC C
EP
TE D
M AN U
SC
complications, and improvements in QoL.
RI PT
and active ulcer. Study outcomes included the time taken for ulcers to heal, the incidence of
5
ACCEPTED MANUSCRIPT 3. Methods 3.1 Patients and methods
This was a prospective, open, randomized controlled study performed at the Clinics Hospital of São Paulo University Medical School. The local Ethics Committee for Research Affairs
RI PT
approved the study, and patients gave written informed consent for their inclusion in this study. The Study was registered at Plataforma Brasil (number: 0158.0.015.000-0), and approved by Brazilian National Ethics Comitee (CEP) under the numer: 0170/09 before the firs patient
SC
was randomized.
Patients fulfilling the following criteria were eligible for the study: primary chronic venous
M AN U
insufficiency caused by reflux in superficial veins, GSV diameter of 0.7–1.4 cm as measured by duplex ultrasound, presence of an active ulcer (maximum 5 cm diameter), and an ankle– brachial index (ABI) of 0.9–1.3. Patients with any of the following were excluded: history of deep vein thrombosis, deep vein thrombosis or deep vein reflux in duplex assessment, arterial
TE D
disease of the lower limbs (ABI 1.3), superficial thrombosis, diabetes, thrombophilia, pregnancy, or allergy to polidocanol. Between August 2007 and February 2010, 58 consecutive limbs of 56 meeting the eligibility
EP
criteria were prospectively randomized (simple randomization) to undergo either surgical
AC C
treatment (29 limbs) or foam sclerotherapy (29 limbs) as described in Figure 1. The intervention occurred within 30 days of the randomization. All of the patients had previously received elastic compression therapy with a 30mmHg above knee elastic stocking for at least six months before enrolling in the present study. Most of the ulcers were recurrent. Patients in both groups completed the Aberdeen Varicose Veins Questionnaire (AVVQ), except for the first question, because of the patients experienced difficulty in drawing their veins. The Venous Clinical Severity Score (VCSS) and Venous Disability Score (VDS) were
6
ACCEPTED MANUSCRIPT
determined by a vascular surgeon. The ulcers were photographed and analysed using image analysis software (Image Tool program). Duplex ultrasound was performed in all of the patients before undergoing treatment. Ultrasound was performed while the patients stood with their weight on the contralateral
RI PT
limb. The following venous segments were evaluated: femoral vein; popliteal vein, saphenofemoral and saphenopopliteal junctions, perforator veins, the entire length of the GSV, and the short saphenous veins. All veins were assessed for patency and compressibility.
SC
Reflux was induced by manually squeezing the calf, and was defined as reverse flow persisting for >0.5 s.
M AN U
The mean ± standard deviation (SD) follow-up time was 502 ± 220 days.
3.2 Treatments
TE D
Surgery was performed under spinal anaesthesia in a surgical room. It consisted of major saphenous stripping (saphenofemoral junction disconnection and stripping of the long saphenous vein to the ankle), phlebectomy of tributaries, and ligation of perforating veins. A
EP
compressive bandage was applied and kept in place for 72 h after surgery. Afterwards, the
AC C
patients wore a 30 mmHg elastic stocking above the knee for >8 h/day. The patients were released from work for 2 weeks. During this time, they could rest in supine position, but they were advised to walk for at least 15 minutes/hour. After that time, they were instructed to go back to usual daily activities using the elastic stocking. Foam sclerotherapy was performed in the ambulatory clinic. The polidocanol foam was prepared by using two 10mL syringes that were connected by a two-way stopcock connector. One of the syringes was filled with 8mL of air. After aspiration of 2mL of 3% polidocanol into the other syringe, the syringes were rapidly and alternately pumped until the mixture
7
ACCEPTED MANUSCRIPT
turned into foam. The GSV was cannulated under ultrasound guidance with a butterfly 21 G needle (the most common site was around 5cm bellow the knee). The leg was elevated to around 45° during foam injection. In each procedure, we injected 8–10 mL of 3% polidocanol foam under ultrasound monitoring. The saphenofemoral junction was compressed during
RI PT
foam injection. Following treatment, the patients stayed in a supine position for 20 min. A compressive bandage was then applied and kept in place for 72 h. Afterwards, the patients wore a 30 mmHg elastic stocking above the knee for >8 h/day. The patients were advised to
SC
continue their normal daily activities following the procedure. and to wear elastic stocking
3.3 Follow-up assessments
M AN U
during the entire follow up period.
Follow-up assessments were done at 7 days after the procedure, and every 2 months thereafter. At every follow-up visit, a vascular surgeon performed a clinical investigation to
TE D
assess the outcomes and complications of surgery and sclerotherapy. The Aberdeen Varicose Veins Questionnaire (AVVQ), VCSS and VDS were determined before and 12 months after the procedure.
EP
In the sclerotherapy group, duplex ultrasound was performed at 6 and 12 months after
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treatment. In the surgical treatment group, only patients with symptoms or signs suggestive of deep vein thrombosis or thrombophlebitis underwent duplex ultrasound. Ulcer healing was defined as complete re-epithelisation of the leg.
3.4 Statistics Non-paired quantitative variables were compared using the Mann–Whitney U test, while categorical variables were compared using the χ2 test or Fisher’s test. Wilcoxon’s signed ranks test was used to analyse paired quantitative variables before and after therapy. Survival
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curves for ulcer healing were plotted using the Kaplan–Meier method, and were compared using the log-rank test. For all analyses, values of P < 0.05 were considered statistically significant. Statistical analyses were performed for all patients who underwent surgery or
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sclerotherapy.
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ACCEPTED MANUSCRIPT 4. Theory
Chronic venous disorders are part of a multifactorial syndrome with a significant social and economic impact. 1,19
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As an alternative to surgery, new and less-invasive methods have been developed to control insufficiency of the truncal vein.20
Minimally invasive procedures have several advantages, including reduced discomfort and
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morbidity secondary to groin incision, and can be performed in an outpatient clinic.15
This study was performed at the Clinics Hospital of São Paulo University Medical School. It
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is the major public hospital in Latin America, responsible for around 120.000 outpatients visits/month and 5000 surgical procedures/month. Nevertheless, some patients have to wait for months or even years to undergo surgical procedures. If we have a good result with a
public health system.
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treatment that can be done with no necessity of hospitalization, it might impact positively our
Additionally, many patients with venous ulcers are elderly and are either reluctant or unfit for surgery. Therefore, these patients seem to be very suitable for foam sclerotherapy. 15
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Foam sclerotherapy is inexpensive, is easy to perform by experienced clinicians, requires
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very little equipment, and can be repeated several times to improve its outcome.5 As the procedure is very quick and painless, it can be performed under local or no anaesthesia. Additionally, the patient can continue habitual activities after the procedure. Therefore, the aim of this study was to compare polidocanol foam sclerotherapy with surgical treatment of patients with primary chronic venous insufficiency and ulcer.
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ACCEPTED MANUSCRIPT 5. Results 5.1 Patients
The two groups were similar in terms of age, sex distribution, and other characteristics. There were no significant differences between the two groups in terms of baseline AVVQ, VCSS,
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and VDS. However, skin ulceration area was greater in the surgical treatment group. The
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clinical and demographic characteristics of patients in both groups are presented in Table I.
5.2 Ulcer healing
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Ulcer healing was achieved in 100% (28/28) of the patients in the surgical treatment group and in 91.3% (21/23) of patients in the foam sclerotherapy group (P = 0.19; Fisher’s test). The 12 and 24-week cumulative healing rates were respectively 7,2 and 28,6% for the surgery group and 8,7 and 13,1% for the foam group. Two patients from the foam group did
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not show ulcer healing at the 1-year follow-up. The mean time to ulcer healing was 37.1 ± 22.1 days in the surgical treatment group and 56.4 ± 39.4 days in the foam sclerotherapy
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group (P = 0.008; log-rank test), as shown in Figure 2. 5.3 Improvements in VCSS, VDS, and AVVQ
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Both interventions resulted in significant improvements in clinical factors and QoL from baseline to the follow-up visit. In the surgical treatment group, the mean VCSS and VDS decreased by 72.8% and 44.8%, respectively. There was also an improvement in QoL, as determined using the Aberdeen questionnaire, which decreased by 69.4%. Similar results were obtained with foam sclerotherapy, as VCSS and VDS scores decreased by 65.2% and 45.5%, respectively, and QoL decreased by 57.7% compared to the preoperative evaluation. The means and standard deviations for each parameter are presented in Table II.
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When the follow-up values were compared between the two groups, there were no significant differences in VCSS, VDS, or QoL between the two groups (P = 0.58, 0.66, and 0.45, respectively), as shown in Figure 3.
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5.4 Complications
Complications occurred in 14.2% and 13.0% of patients in the surgical and foam sclerotherapy groups, respectively (P = 1.0; Fisher’s test). There were no severe
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complications.
Surgical complications considered related to treatment included saphenous neurapraxia,
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incision infection, lymphorrhea, and cellulitis. Complications in the foam sclerotherapy group included transitory visual disturbances, skin pigmentation, and transient dyspnea. One patient developed extensive thrombophlebitis after foam injection, and required a short course of low-dose heparin (enoxaparin) therapy. The complications are presented in table III.
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The saphenous neurapraxia consisted of an area of hypoesthesia on the medial behalf of a patient’s leg, only related by the patient after being active interrogated by the physician. The infections and the lymphorrhea were treated with no permanent consequences. The visual
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disturbance and dyspnea were transitory, lasting for only a few minutes. The patients
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underwent investigation with tomography, excluding stroke and pulmonary embolism respectively.
5.5 Recurrence Rates
We have had 2/29 recurrent ulcers in the surgery group and 1/23 in the sclerotherapy group during the follow up period.
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ACCEPTED MANUSCRIPT 6. Discussion
In the present study, the ulcers healed in all of the patients who underwent surgery. This is a high rate compared with the result of other studies, like the ESCHAR study.21 A possible explanation is that we applied more restrictive eligibility criteria relative than the ESCHAR
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study. Consequently, we did not treat any patients with deep venous reflux or previous deep vein thrombosis. By contrast, 18% and 35% of patients who underwent surgical treatment in the ESCHAR study had previous deep vein thrombosis and deep vein reflux, respectively.21
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We have chosen to study only the patients with superficial reflux because they represent the greatest amount of patients in our hospital (about 70%). Nevertheless, as long as it is a single
more homogeneous group.
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center study and we didn’t have a very large number of patients, we have chosen to have a
In this study the ulcer healed in 91.3% of patients treated with foam sclerotherapy, which was not significantly different from the rate in the surgical treatment group (P = 0.19; Fisher’s
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test). It’s interesting that the ulcers healed in 100% of the patients that were treated with surgery, even so the main area of the ulcer in this group was bigger. Maybe the surgical
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treatment can more completely treat superficial vein reflux by treating the GSV, stripping the varicose veins, and ligating the perforating veins presenting with reflux. In the sclerotherapy
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group, some of these veins exhibited only partial thrombosis. Nevertheless, we think that healing could have been achieved in more patients in the sclerotherapy group if we had permitted more than one sclerotherapy session and treated the GSV together with other varicose veins.
Some reports have presented similar healing rates after foam sclerotherapy. For example, Cabrera et al. treated 116 patients with severe chronic venous disorders over 10 years. At 6 months after treatment, complete healing of the venous ulcers was achieved in 83% (96/116) of the patients. The median time to healing was 2.7 months.16
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In our study, the mean time for ulcer healing was 37.1 ± 22.1 days in the surgical treatment group versus 56.4 ± 39.4 days in the foam sclerotherapy group, which was significantly different (P = 0.008; log-rank test). One explanation for this difference is that the patients who underwent surgery were released from work and could rest for 2 weeks after the
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procedure, whereas the patients who underwent foam sclerotherapy were allowed to resume daily activities immediately after the intervention.
The reason why we have chosen to release that patients from work, was that during the
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surgery, we make a great number of flebectomies, and the patients use to have pain, small
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bleedings and limb edema if they go back to work very soon.
We are aware that this rest could influence the result, nevertheless that’s the protocol in our service, which was determined by patients’ tolerance. This is a negative point of the surgery, once the inability of working for some days after the procedure is one of the reasons that
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some young patients refuse the surgical treatment.
The patients of the foam sclerotherapy group were advised to continue their normal daily activities following the procedure, because they tolerated it easily and, in face of that, we
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believe that the difference in healing time is not clinically important, which is illustrated by
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the marked improvement in QoL in both groups shown by AVVQ. The AVVQ is a sensitive and responsive disease-specific questionnaire that is well correlated with generic and clinical outcomes.22 The score ranges from 0 to 77.6, after excluding the first question, and higher scores represent worse QoL. We did not use the first question in this study because the patients experienced difficulty in drawing their veins. Notably, both treatments led to significant improvements in QoL as the AVVQ decreased by 69.4% in the surgical treatment group and by 57.7% in the foam sclerotherapy group, as
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compared with the baseline score. The reductions in Aberdeen questionnaire scores observed in this study are consistent with those reported by other researchers.12,17 Darvall et al.12 conducted a prospective study of 296 patients, and analysed generic (Short Form 12) and disease-specific (AVVQ) HRQoL in patients who underwent foam
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sclerotherapy for varicose veins. They concluded that ultrasound-guided foam sclerotherapy of the GSV and small saphenous varicose veins significantly improved generic and diseasespecific HRQoL that was maintained for ≥12 months after treatment.12
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This improvement in HRQoL is a very important finding. Kahn et al.4 reported that patientreported QoL is an important component in evaluating treatment outcomes, particularly 4
Similarly, Smith et al.8 proposed that the most
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changes in illness severity over time.
comprehensive way of assessing the impact of an intervention is to assess the impact of the intervention on QoL. They also proposed that, when the assessment of QoL is combined with clinical and laboratory tests, it is possible to assess the true impact of the condition, and its
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severity, on the patient.8 Therefore, besides evaluating ulcer healing and patient-reported QoL, we also analysed clinical parameters.
The VCSS was developed from elements of the CEAP classification system, as an evaluative
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instrument that would be sensitive to changes in disease severity over time and the response
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to treatment.23,24 It ranges from 0 to 18, where 18 is the most severe venous disease. In this study, VCSS improved markedly in both groups, decreasing from 12.5 to 3.3 in the surgical treatment group and from 12.2 to 4.2 in the foam sclerotherapy group. These results are consistent with those reported by Blaise et al., who noted improvements in clinical severity and QoL scores of >20% at 6 months after polidocanol foam sclerotherapy.17 Figueiredo et al comparing VCSS in C5 patients treated by surgery or foam sclerotherapy have also shown statiscally significant reductions of all scores in both patients groups.25
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A clinical improvement was also implied by the reduction in VDS in both groups. The VDS score ranges from 0 (asymptomatic disease) to 3 (the patient is unable to perform daily activities, even when wearing an elastic stocking). The median baseline score was 2, and decreased to 1 in the foam sclerotherapy group and 1.18 in the surgical treatment group. The
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follow-up values were consistent with those reported by Masuda et al., who studied 80 limbs after ultrasound guided sclerotherapy of the perforator veins using 5% sodium morrhuate.18 Besides the ulcer healing and the improvement in patient’s quality of life, we noticed a low
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recurrence rate. We’ve had only 7,1% recurrent ulcers in the surgical group and 8,7% in the sclerotherapy group, probably because these patients had a very close follow up, with
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frequent evaluations and a good support with the compression therapy.
In the present study, anatomical and hemodynamic measurements were not prioritized because they show poor correlations with functional parameters measured before and after
possible complications.
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interventions.22 Instead, we performed duplex ultrasound at the follow-up visits to identify
The incidence rates of complications were minor in both groups. In the surgical treatment groups, the main complications involved groin incision (two patients developed postoperative
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infection and one patient developed lymphorrhea). In the sclerotherapy group, the most
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frequent complications were skin pigmentation and phlebitis. One patient also developed extensive phlebitis, which required low-dose heparin therapy. In a systematic review published in 2007,14 the most common complications after foam sclerotherapy were thrombophlebitis (4.7%), skin pigmentation (17.8%), and injection site pain (25.6%). Some patients also experienced headache (4.2%) and visual disturbances (1.4%). Pulmonary thromboembolism and deep vein thrombosis occurred in
