INTERNATIONAL ANGIOLOGY THE IMPORTANCE OF THE SMALL SAPHENOUS VEIN REFLUX ON THE SYMPTOMS OF CHRONIC VENOUS INSUFFICIENCY

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1 INTERNATIONAL ANGIOLOGY EDIZIONI MINERVA MEDICA This provisional PDF corresponds to the article as it appeared upon acceptance. A copyedited and fully formatted version will be made available soon. The final version may contain major or minor changes. THE IMPORTANCE OF THE SMALL SAPHENOUS VEIN REFLUX ON THE SYMPTOMS OF CHRONIC VENOUS INSUFFICIENCY Amélia Cristina SEIDEL, Nathália Cabral BERGAMASCO, Fausto MIRANDA JR., Isolde PREVIDELLI, Emerson BARILI Int Angiol 2014 Jun 12 [Epub ahead of print] INTERNATIONAL ANGIOLOGY Rivista di Angiologia pissn eissn Article type: Original Article The online version of this article is located at Subscription: Information about subscribing to Minerva Medica journals is online at: Reprints and permissions: For information about reprints and permissions send an to: journals.dept@minervamedica.it - journals2.dept@minervamedica.it - journals6.dept@minervamedica.it COPYRIGHT 2014 EDIZIONI MINERVA MEDICA

2 THE IMPORTANCE OF SMALL SAPHENOUS VEIN REFLUX ON CHRONIC VENOUS DISEASE CLINIC Short Title: Small Saphenous Vein and CVI Amélia C. Seidel 1, Nathália C. Bergamasco 2, Fausto Miranda Jr 3, Isolde Previdelli 4, Emerson Barili 5 1. Adjunct Professor of Angiology and Vascular Surgery at Medicine Course of the State University of Maringá. Vascular Sonographer by Brazilian Society of Angiology and Vascular Surgery / Brazilian College of Radiology (BSAVS / BCR). 2. 6th year Medicine student at Maringá State University. 3. Full Professor of Vascular and Endovascular Surgery at the Surgery Department of Paulista Medical School of the Federal University of São Paulo. Vascular Sonographer BSAVS and BCR. 4. Associate Professor of the Statistics Department of the State University of Maringá. 5. Specialist in Statistical Modeling Presented at: 1. 39th Brazilian Congress of Angiology and Vascular Surgery VII EPCC International Meeting of Scientific Production º EAIC Annual Meeting of Scientific Initiation 2012 Correspondence to: Amélia Cristina Seidel Rua Dr. Gerardo Braga 118 Phone: fax: Jardim Vila Rica Maringá PR BR. E mail: seidel@wnet.com.br

3 Abstract Context: It is estimated that between 5 to 20% of the adult population in developed countries is affected by chronic venous insufficiency (CVI), thus being the most frequent vascular disorder. Recent studies show that, in most CVI patients, their junctions are competent and the correlated superficial reflux is present along the saphenous vein. Objective: Correlating the presence and distribution of reflux in the saphenous vein with the signs and symptoms of CVI, through CEAP, in female patients. Methods: Record review of patients with CVI signs and symptoms who underwent clinical and ultrasound examinations in order to classify them according to CEAP. The sample was divided into three groups according to the presence of saphenous vein insufficiency: Group I SSV, group II GSV, and Group III SSV and GSV. Results: 312 lower limbs of 259 female patients aged between 15 and 85 years were examined. The most prevalent clinical classes in the three groups were C2 (44.55%) and C3 (46.48%). Four patterns of reflux were identified in isolated SSV, with the highest incidence of proximal reflux (69.23%). SPJ impairment was most likely to occur in clinical cases of greater severity. Five patterns of reflux were identified in GSV, with the proximal one the most prevalent (64.42%). Conclusion: There is a correlation between the clinical severity of CVI and the reflux along the SSV in association with GSV; the risk of moderate to high clinical severity in group III was 3.6 times higher than in group I and 4.6 times higher than group II. Keywords: venous reflux, saphenous vein, color Doppler ultrasound, venous insufficiency. Introduction

4 Chronic venous insufficiency (CVI) is the most frequent vascular disorder. It is estimated that 5 20% of the adult population in developed countries is affected by it, and 1 to 3.6% of them is active or healed 1 venous ulcers. Several risk factors have been associated with the development of CVI, such as obesity, age, gender, lifestyle, occupation, diet, hormone use, pregnancy, family history, and others 2. Reflux presence in the superficial venous system plays an important role in the CVI signs and symptoms 3,4,5,6 spectrum, manifesting from fatigue to chronic ulcers. Currently it is considered as the most frequent cause of morphological and functional changes in patients with primary varicose veins in lower limbs 3. The impairment of the small saphenous vein (SSV) alone or in combination with the impairment of the great saphenous vein (GSV) 3,4,5, together with the extent of their reflux has been associated with more severe clinical cases, suggesting a clinical deterioration related to higher distribution of venous insufficiency 4,5,6. It is known that CVI has a high prevalence in the today s population and that the superficial venous reflux plays a significant hemodynamic and clinical role in the genesis of skin lesions. Some types of reflux are also predictors for the formation of venous ulcers, besides its intrinsic relationship with recurrent varicose veins. The correlation between the clinical manifestation of CVI and the mapping of superficial venous reflux is of fundamental importance for a timely intervention, with preventive or therapeutic measures, in order to avoid the poor prognosis of the disease. The color echodoppler allows the detection of venous reflux at the saphenopopliteal junction (SPJ) and along the SSV 7, frequent local of relapses due to its anatomic variations and difficulty in treatment 4. This exam has increased the sensitivity and specificity without the complications of venography; thus, the color echodoppler is recommended for preoperative mapping of varicose vein surgery. The aim of this study was to correlate the presence and distribution of reflux on SSV to the signs and symptoms of CVI in female patients using the CEAP classification. The study was approved by the Standing Committee on Ethics in Research Involving Human Subjects at the State University of Maringá.

5 Methods We conducted a retrospective review on the Image Lab Med database prospecting for patients. Three hundred and twelve (312) lower limbs from 259 female patients, showing signs and symptoms of CVI due exclusively to valvular insufficiency in the superficial venous system (GSV, SSV, tributaries) and perforating veins, were included. Data for each patient were collected searching for risk factors for venous insufficiency, such as age, number of pregnancies and weight. Data regarding the clinical examination and color echodoppler of the lower limbs were also recorded. All patients were examined by a vascular surgeon with a major in vascular ultrasound by the Brazilian Society of Angiology and Vascular Surgery/Brazilian College of Radiology in order to classify the lower limbs according to CEAP; only limbs with a primary etiology disease (C 1 6,Ep, As, Pr). Male patients and women with a history of deep vein thrombosis, varicose vein surgery, and congenital vascular malformation were excluded. The color echodoppler was performed on all limbs considered, using linear (5 7 MHz) and convex (2 3 MHz, for the obese) transducers, in accordance with the literature. Individuals were divided in three groups with 104 members each: Group I SSV reflux with or without insufficient perforating veins; group II GSV reflux with or without insufficient perforating veins; Group III GSV and SSV reflux with or without insufficient perforating veins. The classification presented at Engelhorn et al 8 (Figure 1) was used to assess the superficial reflux patterns. Figure 1: Distribution pattern of reflux. For a better statistical analysis, clinical classes were grouped as C1 C2, C3, and C4 C6 according to clinical severity. The results were submitted to a descriptive analysis. The

6 interrelationships of the variables, type and distribution of reflux with the clinical presentation were tested, using Fisher s exact test with a 95% confidence level. Results Female patients aged between 15 and 85 years (mean 49 years) were examined. Nine (9) patients had no mention of age. There was an increased prevalence of reflux with age, significantly more frequent between ages 40 and 60, Table 1, according to the descriptive analysis. Table 1: Patient s age. Total (%) 29 years 21(6.9) years 60 (19.8) years 72 (23.8) years 69 (22.8) years 53 (17.5) years 25 (8.2) 80 years 3 (1) Total 303 (100) Among the lower limbs evaluated, 41 were on the right side, 59 on the left and 106 bilateral. There was no statistically significant difference in the CVI frequency between the right and left lower limb (p value <0.05). The number of pregnancies, one of the risk factors for CVI, increased the frequency of venous reflux, being more significant in the range 2 3 pregnancies. Based on the BMI, 80% of the lower limbs were from patients with a BMI <30kg/m 2. Forty eight percent (48%) of the lower limbs belonged to classes C1 and C2 (mild presentation), 46.5% to C3 (moderate presentation) and 6.7% to C4, C5 and C6 (severe presentation), according to table 1. CVI signs and/or symptoms were present in all limbs. Table 2: Lower limbs distribution according to CEAP classification per group.

7 Classification (CEAP) Group Mild (C1 C2) Moderate (C3) Severe (C4 C6) n (%) n (%) n (%) Total (%) I SSV 57 (54.8) 40 (38.5) 7 (6.7) 104 (100) II GSV 63 (60.6) 36 (34.6) 5 (4.8) 104 (100) III SSV+GSV 26 (25.0) 69 (66.3) 9 (8.7) 104 (100) Total 146(46.8%) 145(46.5% 21(6.7%) 312 ) n = number of cases; % = percentage of cases Fisher s exact test showed a significant difference between the three groups concerning the clinical picture (CEAP), with a significance level of 5%. Two binomial logistic regression tests were used to assess which group was correlated to the greater clinical severity. Clinical classes were classified as "not serious" (C1 and C2) and "severe" (C3, C4, C5 and C6 ); groups I and II are the reference variables in tables 3 and 4, respectively. Group III showed a higher correlation to severe clinical manifestation, with risk of clinical severity (C3 to C6) 3.6 times higher than group I and 4.6 times higher than group II. Table 3: Distribution of lower limb groups following the CEAP classification, according to the binomial logistic regression test using group I as reference. Not severe Severe Group n (%) n (%) OddsRatio (OR) Confidence Interval I SSV II GSV III SSV+GSV n = number of cases; % = percentage of cases; p value < 0.05.

8 Table 4: Distribution of lower limb groups following the CEAP classification, according to the binomial logistic regression test using group II as reference. Not severe Severe Group n (%) n (%) OddsRatio (OR) Confidence Interval I SSV II GSV III SSV+ GSV n = number of cases; % = percentage of cases; p value < Table 5 shows all reflux patterns found in group I distributed in their clinical classes. Fisher s test showed a statistical significance for all reflux patterns in this group (p valor 0.05). This is evidence that reflux patterns belonged to different CEAP and that this difference was significant in a statistical point of view. A higher prevalence of proximal reflux (69.2%) was observed, followed by diffused (27.9%), segmental (1.9%) and distal (1.0%), with no case of multi segmental pattern. Table 5: Distribution o reflux types in group according to CEAP classification CEAP Classification Reflux Pattern C1 C2 C3 C4 C6 n (%) n (%) n (%) Total (%) Proximal 47 (45.2) 21 (20.2) 4 (3.8) 72 (69.2) Distal 0 (0) 1 (0.9) 0 (0.00) 1 (0.9) Segmental 1 (0.9) 1 (0.9) 0 (0.00) 2 (1.92) Diffused 9 (8.6) 17 (16.3) 2 (2.9) 29 (27.9) Total 57 (54.8) 40 (38.5) 7 (6.7) 104 (100)

9 n = number of cases; % = percentage of cases; p value: As for group II, the following reflux patterns were found: proximal 64.4%l, diffused 26.9%, segmental 2.9%, 2.9% multi segmental, and distal 2.9%. As shown on table 6, there was a worsening in the clinical picture with the change of the reflux pattern, i.e., in the mild group the most frequent pattern was segmental or proximal, whereas the multi segmental or diffused was seen in the severe group. Table 6: Distribution of reflux types in group II according to CEAP classification CEAP Classification Reflux Pattern C1 C2 C3 C4 C6 n (%) n (%) n (%) Total (%) Proximal 43 (41.3) 21 (20.2) 3 (2.9) 67 (64.4) Distal 2 (1.9) 1 (0.9) 0 (0.0) 3 (2.9) Segmental 3 (2.9) 0 (0,0) 0 (0.0) 3 (2.9) Multi segmental 0 (0.0) 1 (0.9) 2 (1.9) 3 (2.9) Diffused 15 (14.4) 13 (12.5) 0 (0.0) 28 (26.9) Total 57 (54.81) 40 (38.46) 7 (6.73) 104 (100) n = number of cases; % = percentage of cases; p value: The most prevalent reflux patterns of SSV and GSV in group III was the proximal proximal (29.8%), followed by diffused diffused (8.6%), diffused proximal (9.6%) or proximal diffused (8.6%), and combinations with distal, segmental and multi segmental pattern.

10 As for reflux in the perforating veins in the examined limbs, we observed a significant difference in Fisher's exact test (p value: ) between the groups of the lower limbs and the number of affected perforating veins. Group II (37 lower members with insufficient perforating veins) had the highest prevalence, followed by group III (36 members) and group I (15 members), as shown in Table 7. Table 7: Distribution of insufficient perforating veins per group. Lower limb group Presence of reflux in perforating veins Group I Group II Group III n (%) n (%) n (%) Total Absence of reflux 89 (85.5) 67 (64.5) 68 (65.4) 224 Reflux in 1 vein 11 (10,5) 26 (25.0) 28 (27.0) 65 Reflux in 2 or more Veins 4 (4.0) 11 (10.5) 8 (7.6) 23 Total 104 (100) 104 (100) 104 (100) 312 n = number of cases; % = percentage of cases; p value: There was a prevalence of reflux in the perforating veins in clinical categories C3 ( 54.5 % ), followed by C1 C2 ( 38.7 % ) and C4 C6 ( 6.8 % ), found mostly at the medial side of the leg in all clinical groups and classes. No statistically significant difference was found

11 between the number of affected perforating veins and the clinical CEAP class, after Fisher s test. Discussion Besides age, several risk factors have been associated with the development of CVI, such as obesity, sex, hormone use, pregnancy, lifestyle, work, diet and familial history 2,5,6,7,8. The descriptive analysis of this study showed that number of pregnancies influenced positively the presence of venous reflux, agreeing with the works reviewed 2,5,6,7,8. However, the BMI and venous reflux correlation was not in accordance with Seidel study, since most patients with compromised lower limbs presented a BMI < 30kg/m2. The superficial venous reflux is currently considered the most common cause of morphological and functional changes of CVI, a highly prevalent disease with relevant social repercussions. In most patients, the signs and symptoms caused by venous reflux predominate over the obstruction, corroborating a study of Labropoulos et al 9 (1996) which showed that, even in patients with previous venous thrombosis, the most common finding associated to the severity of venous disease was the reflux in the superficial venous system. The SSV incompetence has been associated with the development of signs and symptoms of CVI, including venous ulcers. Similar to other studies 3,5,6,10, a significant correlation was found between the presence of reflux in the SSV associated with GSV incompetence and a more severe clinical picture, i.e., C3 to C6 (Tables 3 and 4). The logistic regression tests (binomial logit multipleregression) has found that clinical severity was determined by the simultaneous involvement of both saphenous veins; a limb in group III had a 3.6 higher chance of risk of moderate to high clinical severity (OR: 3,638) than a limb in group I. The risk was 4.6 times larger than a limb in group II (OR: 4.610). Similarly, Labropoulos et al 11 (1994) observed the presence of venous ulcers in 8 % of a group with diffused pattern of isolated GSV and in 14% (nearly doubled frequency) of the group that showed association in both saphenous reflux (SSV and GSV). Given the logistic regression tests cited, one may suggest that the clinical severity of group III (SSV + GSV) was principally caused by the involvement of the small saphenous vein. Since group II (GSV) was not considered an aggravating factor in relation to group I (OR < 1, Table 2), whereas the involvement of SSV (group I) was evidenced as an aggravating or a major risk factor associated to group II (OR > 1, table 4). Although p

12 values were significant, the relation between groups I and II had variable confidence intervals (OR values less and greater than one), further analysis with the larger number of limbs in the respective groups is needed to establish a more significant reliability between SSV and GSV reflux. This study showed that the ssociation of SSV and GSV reflux was statistically significant and determined the severity of venous disease. Accepting that not only the extent of reflux but also the reflux in both saphenous veins determine the clinical deterioration, it is necessary to encourage research on superficial venous reflux with the color echo Doppler in the entire length of saphenous veins to early diagnose CVI, and thus, treat a greater number of patients. Based on the classification adopted in this work, the proximal reflux was most often found in both SSV and GSV. These data are corroborated by the findings of Andrade et al 3 that identified that 37.8 % of reflux is located in the proximal portion SSV and 31.7 % in GSV. Reflux patterns found in group I were proximal, diffused, segmental and distal, with a descending frequency respectively, similar to the result of another study 8, which has also not detected the multisegmental pattern. The results of this study demonstrated a direct relationship between the severity of clinical manifestations and the extent of SSV reflux, since a CVI clinical deterioration increases the prevalence pattern of diffused reflux. This evidence was also observed by Labropoulos et al 5 (2000) whose work showed that 86% of limbs of clinical classes C4 to C6 had two or more venous segments compromised against 8.5% of classes C1 to C3; Engelhorn et al 8 also showed a change from the segmental reflux pattern to multisegmental in a three year interval in the SSV incompetence group. A progression from proximal to distal and diffused pattern was observed as the clinical severity evolved, suggesting an anterograde development of CVI. Similarly, Labropoulos et al 11 (1994) also observed a higher incidence of CVI symptoms and signs in limbs with reflux in veins below the knee. Pittaluga et al 6 (2008) corroborated this anterograde pathophysiology, by suggesting a suprafascial onset of venous disease, without compromising the SSJ and FSJ. Thus, the authors showed that the early treatment with sclerotherapy or surgery influences on the development of superficial venous insufficiency and prevents clinical and hemodynamic deterioration.

13 Stuart et al 10 (2000) associated the severity of the disease to the number of insufficient perforating veins together with superficial veins, particularly SSV. Similarly, Andrade et al 3 (2009) showed that the compromising of perforating vein associated with GSV reflux determined the clinical deterioration. There was no significant statistical correlation between the number of insufficient perforating vein and clinical picture in this study, which showed a greater number of compromised perforating vein in class C3 in group I (53% of all limbs with compromised perforating veins) and classes C1 and C2 (51% of limbs with compromised perforating veins) in group II, which showed a higher incidence of compromised perforating veins (35.5%). A survey shows the CVI polymorphism, which associated to the high frequency of SSV venous reflux in patients with or without complicated varicose veins 7, recommends a research of reflux in the color echodoppler examination as a routine in patients with any degree of CVI 5,12. This test allows the reflux location and extent, which will determine the clinical severity of the disease. Conclusions The results suggest a correlation between the extent of the SSV venous reflux together with the GSV with the CVI clinical severity. The proximal reflux pattern was the most frequent one; the distal and diffused compromising were more likely to occur in the most severe clinical manifestation. References 1. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology. 1997;48: Seidel AC, Mangolim AS, Rossetti LP, Gomes JR, Miranda FJ. Prevalence of lower limbs superficial venous insufficiency in obese and non obese patients. J Vasc Br. 2011;10(2): Andrade ART, Pitta GBB, Castro AA, Miranda JF. Evaluation of venous reflux by color duplex scanning in patients with varicose veins of the lower limbs: correlation with clinical severity by CEAP classification. J Vasc Bras. 2009;8(1): Engelhorn CA, Engelhorn, AL, Cassou MF, Salles cunha SX. Patterns of saphenous reflux in women with primary varicose veins. J Vasc Surg.2005;41(4):645 5.

14 5. Labropoulos N, Giannoukas AD, Delis K, Kang SS, Mansour MA, Buckman J, et al. The impact of isolated lesser saphenous vein system incompetence on clinical signs and symptoms of chronic venous disease. J Vasc Surg. 2000;32(5): Pittaluga P, Chastanet S, Rea B, Barbe R. Classification of saphenous refluxes: implications for treatment. Phlebology. 2008;23: Secchi F, Miyamotto M, França GJ, Oliveira A, Vidal EA, Timi JRR, et al. Prevalence of short saphenous vein reflux in primary uncomplicated varicose veins by Doppler ultrasonography. J Vasc Br. 2006;5(1): Engelhorn CA, Manetti R, Baviera MM, Bombonato GG, Lonardoni M, Cassou MF, et al. Progression of reflux patterns in saphenous veins of women with chronic venous valvular insufficiency. Phlebology. 2012;27: Labropoulos N, Delis K, Nicolaides AN, Leon M, Ramaswami G, Volteas N. The role of the distribution and anatomic extent of reflux in the development of signs and symptoms in chronic venous insufficiency. J Vasc Surg.1996;23(3): Stuart WP, Adam DJ, Allan PL, Ruckley CV, Bradbury AW. The relationship between the number, competence, and diameter of medial calf perforating veins and the clinical status in healthy subjects and patients with lower limb venous disease. J Vasc Surg. 2000;32: Labropoulos N, Leon M, Nicolaides AN, Giannoukas AD, Volteas N, Chan P. Superficial venous insufficiency: Correlation of anatomic extent of reflux with clinical symptoms and signs. J Vasc Surg. 1994;20(6): Cassou MF, Gonçalves PCZ, Engelhorn CA. Reflux probability in saphenous veins of women with different degrees of chronic venous insufficiency. J Vasc Br. 2007;6(3): Delis KT, Ibegbuna V, Nicolaides AN, Lauro A, Hafez H. Prevalence and distribution of incompetence perforating veins in chronic venous insufficiency. J Vasc Surg. 1998;28(5):

15 Total (%) 29 anos anos anos anos anos anos 80 anos Total 21(6,9) 60 (19,8) 72 (23,8) 69 (22,8) 53 (17,5) 25 (8,2) 3 (1) 303 (100)

16 Grupo Leve (C1 - C2) Classificação clínica (CEAP) Moderada (C3) Grave (C4 - C6) n (%) n (%) n (%) I VSP 57 (54,8) 40 (38,5) 7 (6,7) II VSM 63 (60,6) 36 (34,6) 5 (4,8) III VSP+VSM 26 (25,0) 69 (66,3) 9 (8,7) Total 146(46,8%) 145(46,5%) 21(6,7%) Total (%) 104 (100) 104 (100) 104 (100) 312 n = número de casos; % = percentual de casos

17 Não grave Grave Grupo n (%) n (%) OddsRatio (OR) Intervalo de confiança I VSP II VSM ,789 0,455-1,370 III VSP+VSM ,638 2,020-6,552 n = número de casos; % = percentual de casos; p-valor <0,05.

18 Não grave Grave Grupo n (%) n (%) OddsRatio (OR) Intervalo de confiança I VSP ,267 0,730-2,199 II VSM III VSP+VSM ,610 2,548-8,341 n = número de casos; % = percentual de casos; p-valor <0,05.

19 Classificação CEAP (clínica) Padrão de Refluxo C1 - C2 C3 C4 - C6 n (%) n (%) n (%) Proximal 47 (45,2) 21 (20,2) 4 (3,8) Distal 0 (0,0) 1 (0,96) 0 (0,00) Segmentar 1 (0,96) 1 (0,96) 0 (0,00) Difuso 9 (8,65) 17 (16,35) 2 (2,88) Total 57 (54,81) 40 (38,46) 7 (6,73) Total (%) 72 (69,2) 1 (0,96) 2 (1,92) 29 (27,88) 104 (100) n = número de casos; % = percentual de casos; p-valor: 0,0150.

20 Classificação CEAP (clínica) Padrão de Refluxo C1 - C2 C3 C4 - C6 n (%) n (%) n (%) Proximal 43 (41,35) 21 (20,19) 3 (2,88) Distal 2 (1,96) 1 (0,96) 0 (0,00) Segmentar 3 (2,88) 0 (0,00) 0 (0,00) Multissegmentar 0 (0,00) 1 (0,96) 2 (1,96) Difuso 15 (14,42) 13 (12,50) 0 (0,00) Total 57 (54,81) 40 (38,46) 7 (6,73) Total (%) 67 (64,42) 3 (2,88) 3 (2,88) 3 (2,88) 28 (26,92) 104 (100) n = número de casos; % = percentual de casos; p-valor: 0,0236.

21 Ocorrência de refluxo em veias perfurantes Grupo de membros inferiores Grupo I Grupo II Grupo III n (%) n (%) n (%) Ausência de refluxo 89 (85,5) 67 (64,5) 68 (65,4) Refluxo em 1 veia 11 (10,5) 26 (25,0) 28 (27,0) Refluxo em 2 ou mais veias 4 (4,0) 11 (10,5) 8 (7,6) Total 104 (100) 104 (100) 104 (100) n = número de casos; % = percentual de casos; p-valor: 0, Total

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