Servier – Phlebolymphology

The first work chosen by the Editor of Phebologie is the paper by Ferrara F et al (Phlebologie. 2017;2), which analyzed the role of the echographic alterations of the venous lumen in the evaluation of sclerotherapy effectiveness. Saphenofemoral junctions that were treated with compression sclerotherapy (n=2000) were divided into two groups, depending on the intensity of the intraluminal echogenicity (C strong and F soft). Each group was divided into two subgroups, depending on the diffuse or localized distribution of this alteration in the vein lumen. The authors found significant differences between the two groups in the failure rates, with the lowest incidence of recurrences in both subgroups of group C. They concluded that the main criterion of sclerotherapy effectiveness is a diffuse or localized echogenicity of the vein lumen, with the same density of subcutaneous tissue. The reliability of this echographic sign, if associated with a significant reduction in the vein caliber, is independent from the existence of reflux in a central residual lumen.

The second chosen paper was published by JM Pernes, a French vascular radiologist (Pernes JM et al. Phlebologie. 2017). The editor explained the reasons for this choice, which are linked to the desire to give an important position to innovative and controversial phlebological topics. The authors experimented on percutaneous pharmacomechanical thrombectomy using the “Trerotola PTD system,” which is introduced through the jugular route. They achieved a technical success rate of 95% in less than 3 hours, without bleeding morbidity, and with a 1-year permeability rate of 92%. The recommendations of a number of scientific societies suggest that these techniques should be offered to subjects with low hemorrhagic risk presenting with a thrombosis diagnosed within the previous 3 weeks.

The trial conducted by Foegh P et al (Eur J Vasc Endovasc Surg. 2017;53(3):419- 424) demonstrates that outcomes in terms of competent veins after catheter directed thrombolysis (CDT) in iliofemoral deep vein thrombosis is better in patients with symptom duration <14 days if compared with patients with longer symptom duration. In this nonrandomized, observational, cohort study, from 1999 to 2013, 191 consecutive patients (203 limbs) attending a tertiary vascular center at Gentofte University Hospital, Denmark underwent CDT. All patients had ultrasonically verified acute iliofemoral deep vein thrombosis with open distal popliteal vein and calf veins. Patients were seen in the outpatient clinic 6 weeks, 3, 6, and 12 months after the procedure, and then annually thereafter. A successful outcome was defined as patent deep veins without reflux on Duplex ultrasound scanning. Median age was 27 years (range, 14 to 74 years) and the overall median lysis time was 56 hours (range, 22 to 146 hours). A stent was placed in 106 limbs (52%); 6 patients had major bleeding. The median follow-up time was 5 years (range, 1 month to 14.3 years). The cumulative rate of patients with deep veins without reflux at 7 years was 79%. Multivariate Cox regression analyses showed that symptom duration >2 weeks (hazard ratio (HR), 2.78; 95% CI, 1.14-6.73) and chronic postthrombotic lesions (HR, 19.3; 95% CI, 7.29-51.2) were significantly associated with poorer outcome, while the pulse-spray technique (HR, 0.15; 95% CI, 0.05-0.48) was associated with a better outcome. Age, sex, sidedness, inferior vena cava atresia, stenting, and lysis duration did not affect the outcome. Thus, it was demonstrated that symptom duration <2 weeks, absence of chronic postthrombotic lesions, and the use of the pulse-spray technique for CDT resulted in better primary patency, including normal valve function in the long term. The study by Sinabulya H et al (Eur J Vasc Endovasc Surg. 2017;53(5):710-716) is a large follow-up trial involving a cohort of patients with an active and healed venous ulcer treated with endovenous laser for superficial venous incompetency. The study confirms the findings that endovenous laser ablation can be safely offered to patients with active and healed venous ulcers, even the elderly with significant comorbidities, achieving low ulcer recurrence rates after more than 3 years. Consecutive patients treated with endovenous laser ablation because of a healed or active venous ulcer between 2006 and 2013 were identified in the medical records and quality registry and invited for a follow-up, including clinical history, study examination, Duplex ultrasound scanning, ankle brachial pressure, photoplethysmography, venous clinical severity score, and health-related quality of life measured with EQ5D. Of 228 patients, 170 (195 legs) fulfilled the inclusion criteria. Univariate and multivariate regression analyses were performed to identify possible risk factors for recurrence. The mean follow-up time was 41 months. The average age was 66.6 years (range, 36 to 87 years). In 86 limbs with an active ulcer, all ulcers healed, but recurred in 14 patients (16%). In 109 legs operated on for a healed ulcer, the ulcer recurred in 17 legs (16%). Thirty legs (15%) were retreated for superficial venous incompetence. Reduced ankle mobility was a risk factor for recurrence in both univariate and multivariate analysis (P=0.048). Therefore, these mid-term results demonstrate that endovenous laser ablation of superficial venous incompetence in patients with healed or active venous ulcers achieves good healing and low ulcer recurrence rates, with a low rate of complications and an acceptable reintervention rate.

The first paper selected by the Editor is a systematic review of the literature regarding the clinical impact and treatment of incompetent accessory saphenous veins performed by The American College of Phlebology Guidelines Committee (Gibson K et al; American College of Phlebology Guidelines Committee. Phlebology. 2017;32(7):448-452). It is the opinion of the Guidelines Committee that further studies dedicated to the management of isolated accessory vein reflux are not necessary and may not be ethical. The large body of work that has already been published regarding great saphenous vein (GSV) and small saphenous vein (SSV) incompetence, and the benefit of treatment can be confidently extrapolated to the accessory saphenous veins. The data regarding accessory saphenous vein reflux and its treatment led to the following conclusions: (i) reflux from the saphenofemoral vein into accessory veins (anterior accessory GSV [AAGSV] and posterior accessory GSV [PAGSV]) is common in patients with primary venous reflux disease; (ii) accessory venous reflux is a common source of varicose vein recurrence, even after a successful prior intervention; (iii) accessory venous reflux causes patient morbidity, and patients possess similar disease severity when compared with GSV reflux; (iv) treatment of accessory venous reflux using endovenous thermal ablation or ultrasound-guided foam sclerotherapy is as safe and effective as treatment of the GSV and SSV with the same modalities; (v) vein closure rates and improvement in patient symptoms and quality of life in the treatment of accessory veins are similar to results achieved with treatment of the GSV and SSV. Therefore, the authors recommend that patients with symptomatic incompetence of the accessory GSVs (AAGSV and PAGSV) be treated with endovenous thermal ablation (laser or radiofrequency) or ultrasound-guided foam sclerotherapy to reduce symptomatology (strength of recommendation grade 1, level of evidence C).

The second paper selected was a prospective randomized controlled study of patient compliance in using a compression stocking (Uhl JF et al. Phlebology. 2018;33(1):36- 43). Forty active females classified as C_2S were enrolled to wear compression stockings providing a pressure of 15 to 20 mm Hg at the ankle. A thermal probe was inserted in the stocking (Thermotrack), recording the skin temperature every 20 min for 4 weeks. The patients were randomized to two groups of 20. Patients in group 1 received minimal recommendations by their physician at the office and patients in group 2 received in-depth recommendations by the physician, reinforced with SMS messages that were repeated once a week for 4 weeks. The basic clinical, etiological, anatomical, pathophysiological (CEAP) classification and the quality of life (QOL) were recorded before and after 4 weeks. The analysis of the thermal curves showed a significant increase (33%) in the average daily wearing time in group 2: 8 hours vs 5.6 hours (group 1) (P<0.01). The average number of days worn per week also increased: 3.4 (group 1) vs 4.8 (group 2), thus improving patient compliance from 48.5% to 70% as a direct result of the physician recommendations (P<0.001). In conclusion, this study shows that better and repeated recommendations by the practitioner results in an increase in the time that compression is used by 33%. The study also suggests that the number of days that compression stockings are worn is a good criterion of patient compliance.

The association between deep vein thrombosis and atherosclerosis is still controversial. Bilore et al examined the rate of subsequent symptomatic atherosclerosis in patients with unprovoked deep vein thrombosis vs secondary deep vein thrombosis (Bilora F et al. Int Angiol. 2017;36(2):156-159). They performed a retrospective follow-up of a cohort of patients who had developed an episode of deep vein thrombosis not preceded by arterial cardiovascular events14 years earlier. They collected information from 138 patients with unprovoked and 123 with secondary deep vein thrombosis on the development of coronary heart disease, ischemic stroke, peripheral artery disease, or sudden otherwise unexplained death. The cumulative incidence of symptomatic atherosclerosis was 17.6% (95% CI, 8.3-26.0) in patients with unprovoked deep vein thrombosis and 5.1% (95% CI, 0.0-10.7) in those with secondary deep vein thrombosis. After adjusting for age, sex, smoking, hypertension, diabetes, and dyslipidemia, the hazard ratio (HR) for the development of symptomatic atherosclerosis among patients with unprovoked vs secondary deep vein thrombosis was 2.89 (95% CI, 1.06-7.88; P=0.038). Therefore, the risk of subsequent symptomatic atherosclerosis among patients with unprovoked deep vein thrombosis seems approximately three times higher than that of patients with secondary events.

Another paper chosen is a review that summarized the literature on venous recanalization after rivaroxaban treatment as well as data on its impact on postthrombotic syndrome development (Ramacciotti E et al. Int Angiol. 2018;37(1):1- 3). Early recanalization of veins in patients with deep vein thrombosis treated with rivaroxaban: do we need to move from bedside to bench again?). The EINSTEIN investigators conducted a post hoc subgroup analysis of the EINSTEIN deep vein thrombosis trial (336 patients) and concluded that treatment of acute deep vein thrombosis with rivaroxaban was associated with a numerically lower, but statistically nonsignificant reduction in the risk of postthrombotic syndrome compared with enoxaparin/vitamin K antagonist treatment. The same interesting results were observed by Jeraj L et al. Thromb Res. 2017;157:46-48 who followed 100 consecutive patients treated for deep vein thrombosis, 61 patients treated with rivaroxaban, and 39 treated with a vitamin K antagonist. They assessed symptoms and signs of postthrombotic syndrome and calculated the Villalta score 23 months after an acute index deep vein thrombosis. Patients in the rivaroxaban group had a lower prevalence of postthrombotic syndrome than those treated with warfarin (25% vs 49%; P=0.013). The possible explanations for such findings could be the more intense initial anticoagulant regimen achieved with rivaroxaban (15 mg twice daily for the first 21 days of treatment) and a possible class effect of direct anti–Xa drugs, where the fibrinolytic effects are yet to be elucidated. Therefore, new studies are needed in this setting.

Endovenous cyanoacrylate closure is a new US Food and Drug Administration approved therapy for the treatment of clinically symptomatic venous reflux in saphenous veins. The device is indicated for the permanent closure of lower extremity superficial truncal veins, such as the great saphenous vein (GSV). The authors of the first paper chosen by the Editor–Morrison N et al. J Vasc Surg Venous Lymphat Disord. 2017;5(3):321–330 report 1-year outcomes from a randomized trial of cyanoacrylate closure. A total of 222 subjects with symptomatic great saphenous vein incompetence were randomly assigned to receive either cyanoacrylate closure (n=108) or radiofrequency ablation (n=114). After the 3-month visit, subjects could receive adjunctive therapies aimed at treating visible varicosities and incompetent tributaries. Vein closure was assessed at day 3 and months 1, 3, 6, and 12 using duplex ultrasound. Additional study visit assessments included the venous clinical severity score; clinical, etiological, anatomical, and pathophysiological classification; EuroQol-5 dimension; and aberdeen varicose vein questionnaire. Both time to closure and time to first reopening of the target vein were evaluated using survival curve analysis. Adverse events were evaluated at each visit. A 12-month follow-up was obtained for 192 subjects (95 cyanoacrylate closure and 97 radiofrequency ablation; total follow-up rate, 192/222 [86.5%]). By month 1, 100% of cyanoacrylate closure subjects and 87% of radiofrequency ablation subjects demonstrated complete occlusion of the target vein. By month 12, the complete occlusion rate was nearly identical in both groups (97.2% in the cyanoacrylate closure group and 97.0% in the radiofrequency ablation group). The 12-month freedom from recanalization was similar in the cyanoacrylate closure and radiofrequency ablation groups, although there was a trend toward greater freedom from recanalization in the cyanoacrylate closure group (P=0.08). Symptoms and quality of life improved equally in both groups. Most adverse events were mild to moderate and not related to the device or procedure. In conclusion, in patients with incompetent great saphenous veins, treatment with both cyanoacrylate closure and radiofrequency ablation results in high occlusion rates. Time to complete occlusion was faster with cyanoacrylate closure, and freedom from reopening was higher after cyanoacrylate closure. Quality of life scores improved equally with both therapies.

Murphy EH et al (J Vasc Surg Venous Lymphat Disord. 2017;5(1):8-17) analyzed the incidence of deep venous thrombosis following iliocaval stenting with two alternative techniques: (i) Wallstents with 3- to 5-cm extension into the inferior vena cava; and (ii) a modified Z-stent (Cook Medical, Bloomington, Ind) technique, in which overlapping Wallstents end at the iliac confluence and caval extension is performed with a Z-stent placed at the top of the stack. The function of the Z-stent is to provide improved radial force at the iliocaval confluence and to prevent jailing of contralateral flow with larger stent interstices. 755 limbs with consecutive Wallstent caval extensions (2006–2010) and 982 limbs with Z-stent extensions (2011–2015) were analyzed for assessing the incidence of deep vein thrombosis postoperatively. In the overall cohort, there was a female predominance (Wallstent, 69%; Z-stent, 67%) and a higher incidence of left-sided disease (Wallstent, 66%; Z-stent, 56%) in both groups. There was a slightly higher incidence of postthrombotic disease in the Z-stent subgroup (Wallstent, 53%; Z-stent, 68%). Cumulative freedom from contralateral deep vein thrombosis was 99% and 90% in the Z-stent and Wallstent groups, respectively (P<0.001), during the 5 years following stent placement. However, all three patients with deep vein thrombosis contralateral to a Z-stent actually had high placement of the Wallstent across the confluence. Thus, no patients with proper Z-stent technique had a contralateral deep vein thrombosis. Cumulative freedom from ipsilateral deep vein thrombosis was 97% and 82% in the Z-stent and Wallstent groups, respectively (P<0.001), during the 5 years following stent placement. The decrease in the incidence of ipsilateral deep vein thrombosis appeared to be attributable to decreased missed distal lesions with increased operator experience and not attributable to the Z-stent itself. In conclusion, the incidence of contralateral deep vein thrombosis was significantly lower with the Z-stent modification. In addition, the Z-stent modification provides greater radial strength at the iliac-caval confluence and simplifies simultaneous or sequential bilateral stenting. Use of proper technique and intravascular ultrasound is essential to limit the incidence of ipsilateral deep vein thrombosis.