Hrev_master Veins and Lymphatics 2016; volume 5:5764 [Veins and Lymphatics 2016; 5:5764] [page 45] Effective prophylaxis of visual and neurological disturbances with an anti-endothelin drug: analysis of 1642 sclerotherapy sessions Alessandro Frullini,1 Angelo Guastini,2 Demetrio Guarnaccia,3 O. Walter Loparco,4 Domenico Maurano,5 Sabino Paradiso,6 Antonio M. Previtera,7 Michele Rendace,8 Serafino Viviani,9 Patrizia Pavei10 1Studio flebologico, Figline Incisa Valdarno (FI); 2Private practice, Chiavari (GE); 3Vascular Surgery, Clinica Santa Lucia, San Giuseppe vesuviano (NA); 4Studio flebologico, Pescara; 5A.O. Cosenza; 6Centro Medico Paradiso, Trani; 7Specialist in Angiology and Cardiology, Catania; 8Vascular Surgery, A.S.P. Cosenza; 9Private practice, Castelnuovo Garfagnana (LU); 10U.O.C. Day Surgery Multidisciplinare, A.O. Padova, Italy Abstract In the literature cases of stroke and tran- sient neurological symptoms have been described after sclerotherapy for chronic venous disease The initial interpretation of these phenome- na was that of a micro air embolism in associ- ation with a patent foramen ovale. This expla- nation did not always manage to justify all neu- rological manifestations. Recent theories have demonstrated that in the area of sclerosis, a significant amount of endothelin 1. We carried out a retrospective assessment of sclerothera- py case studies on 540 patients at ten phlebo- logical centres to search for a relationship between the use of aminaftone (a venotropic drug with demonstrated anti-endothelin action) and the occurrence of side effects after sclerotherapy was performed. Significant reduction of side effects was observed in scle- rotherapy for teleangectasias and in patients with migraine history. Introduction Sclerotherapy for lower limb varicose veins reticular veins and teleangectasias is a tech- nique that has been used for many years; how- ever, it was only after the introduction of scle- rosing foam that its use spread across the world and it now plays an important role in the treatment of chronic venous disease.1 In addi- tion, recently, national and international guidelines have included ultrasound guided foam sclerotherapy (UGFS) among the avail- able selection of therapies for the treatment of varicose disease. Case studies increasingly report results that substantially overlap with those obtained with methods of thermal abla- tion or surgery but with a significantly lower impact on QoL and, if performed correctly, scle- rotherapy with foam is a safe procedure with low incidence of complications.2-10 A recent meta-analysis of the complications of sclerosing foam identified a low incidence of adverse events and thus confirmed the sub- stantial safety of treatment with foam solu- tions.11 However, scotomas or paresthesia occur immediately after 1.4 % of treatments, and in migraineurs the onset of a migraine crisis is not uncommon. Moreover, cases of stroke and transient neurological symptoms have been described and myocardial infarction without ST-segment elevation.12,13 The appearance of these serious complications, although extremely rare, has led the scientific commu- nity to seek a pathogenetic explanation. The initial interpretation of these phenome- na was that of a micro air embolism in patients with a patent foramen ovale (PFO) or another type of left-right shunt; this explanation did not always manage to justify all neurological manifestations. Recent theories have demon- strated that in the area of sclerosis, a signifi- cant amount of endothelin 1 (ET-1), our body’s most powerful vasoconstrictor, is released.14 In the literature, the relationship between the presence of high quantities of ET-1 and the cerebral and retinal vasospasm or one of the phases of the migraine crisis is clear.14 A rela- tionship between the release of endothelin and the onset of myocardial infarction without ST- segment elevation after sclerotherapy has also recently been documented.13 In previously published studies, it has been demonstrated that in an animal model of scle- rotherapy, a significant increase in systemic ET-1 occurs after sclerosis with polidocanol (POL) or with sodium tetradecyl sulphate (STS) both in liquid form and foam. In addi- tion, in a study carried out in patients subject- ed to sclerotherapy where systemic endothelin was measured in a vein in the vicinity of the sclerosed vein, we also demonstrated a signif- icant increase in ET-1 both at systemically and locally with a significant relationship between the two values.15 Some anti-endothelin drugs such as ami- naftone (AMNA) are currently available which, in the absence of significant side effects, have proven to have significant anti-ET-1 proper- ties. In a study published in 2014, we demon- strated that in both the animal model and in the model built on Human Umbilical Vein Endothelial Cells (HUVEC) it was possible to significantly reduce the release of ET-1 after sclerotherapy by performing a pretreatment with aminaftone.16 Aim of the study Aminaftone is used extensively in clinical practice in Italy and, for this reason, we carried out a retrospective assessment of sclerothera- py case studies at ten phlebological centres to search for a relationship between the use of aminaftone and the occurrence of side effects after sclerotherapy. Due to the retrospective design of the study it was not possible to have homogeneous procedures in the treatment of patients. Materials and Methods Aminaphtone is frequently used in the phle- bological practice in Italy. We carried out a ret- rospective assessment of the case study of treatments with sclerotherapy at ten Italian phlebological centres for a period from January 2013 to February 2014. All the doctors involved had substantial experience with sclerotherapy. At the Centres where Aminaphtone (Capillarema Laboratori Baldacci Pisa-Italy) was used, the drug was administered orally at a dose of 150 mg in two daily administrations starting the treatment three to seven days prior to sclerotherapy. The drug used is regu- larly recorded in Italy as a vein protector and, as the study is retrospective, there was not a true randomization. The sclerosis was carried out according to the routine protocols of each centre and no provision has been issued to change the treatments that were carried out. All the centres involved had a database where the characteristics of the therapy and any adverse events were recorded thus facilitating Correspondence: Alessandro Frullini, Studio medico flebologico, Piazza Caduti di pian d’albero 20, Figline Incisa Valdarno (FI), Italy. E-mail: info@venevaricose.it Key words: Chronic venous disease; foam scle- rotherapy; endothelin 1; visual and neurological complications. Received for publication: 21 January 2016. Revision received: 1 August 2016. Accepted for publication: 12 September 2016. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright A. Frullini et al., 2016 Licensee PAGEPress, Italy Veins and Lymphatics 2016; 5:5764 doi:10.4081/vl.2016.5764 No n c om me rci al us e o nly Article [page 46] [Veins and Lymphatics 2016; 5:5764] data collection. The statistical analysis was performed with the statistical package SPSS version 23 by IBM for MAC. Two tails Chi square statistics with the con- ventional significance level of 0.05 was applied for the comparison of the percentages of differ- ent outcomes in different subgroups. Yates continuity correction and exact tests were per- formed were indicated. Results 1642 sclerotherapy sessions for 540 patients were assessed. In 1212 cases, a concomitant therapy with aminaftone was used, while in 430 cases, sclerosis was not performed with associated AMNA therapy. No other associated therapies with potential anti-endothelin effect have been used. In patients with no associated aminaftone treatment, the sclerosis was performed with STS in 11.1% of cases while in the remaining 88.8% cases, POL was used. In the group where AMNA was used, 96.7% of cases had been injected with polydocanol and only 2.3% with sodium tetradecyl sulphate. The average con- centration of the sclerosing agent was differ- ent to the concentration in the STS group where it was 1.78% while in patients treated with POL it was 2.6%. The mean volume of sclerosants was 4.4 ml in the group without prophylaxis and 4.1 in the AMNA group. The adverse events considered in this analy- sis were transient visual disturbances (usually scotoma), neurological disorders (typically transient paraesthesias or hyposthenias) and the onset of migraine crises. Figures 1 and 2 indicate the distribution of veins subjected to sclerotherapy in the two groups. In the sessions carried out without associat- ed therapy with aminaftone, complications occurred in 1.62% of cases (one of these even after a sclerotherapy with liquid), while in patients undergoing therapy in conjunction with the administration of aminaftone the per- centage of complications was 0.57%. In partic- ular, the analysis of just the subset of sessions carried out with aminaftone and a total amount of sclerosing agent less than 5 cc revealed a lower percentage of complications: 0.18% (P=NS). In the subgroup analysis, it was possible to identify the numerically more significant group in patients treated for telangiectasias, to determine that in the absence of a concomi- tant treatment with aminaftone the percent- age of complications recorded was 2.3% while there were no adverse events among the treat- ed patients (P=0.02). In other groups for example, in the treat- ment of recurrences, positive trends were recorded (with AMNA 0% adverse events recorded – without AMNA 4.7% adverse events recorded), but due to the limited number of observations it was not possible to reach sta- tistical significance. In saphenous veins, per- centages of complications were 1.08% (AMNA) and 0.95% (no AMNA) (P=NS) respectively, despite the analysis having been carried out in the group where a volume of foam lower than 5 cc was used. Regarding the migraine crises in patients where the sclerosis was carried out without concomitant treatment with aminaftone, 3% reported a history of headaches, while in the group with aminaftone, as much as 7.6% of the sessions were carried out in a patient with a history of headaches. In 38.4% of the sessions conducted in the presence of a history of headaches and without concomitant treatment with aminaftone, an adverse event occurred. On the contrary if the patient was taking aminaftone only 3.2% of cases showed a complication (P=0.002). Discussion The use of sclerotherapy in the treatment of chronic venous disease has seen a significant increase in recent years.4 Current guidelines now consider that sclerotherapy, and in partic- ular that with foam, is an adequate therapy in the case of saphenous insufficiency and some consider it more appropriate than surgical treatment.2,17 A meta-analysis conducted by Jia revealed the substantial safety of the treatment with minimum percentage of transient complica- tions and a very low incidence of major compli- cations.11 In spite of this, it is necessary to understand the mechanism of these complications if we want to make the treatment even safer. The initial explanation of the onset of tran- sient visual and neurological events was air microembolism. Indeed, the study by Guex18 revealed that the incidence of these complica- tions increases with the introduction of scle- rosing foam in clinical practice. However, the same study shows that these complications are also present, albeit at a lower percentage, in patients being treated with the sclerosing drug in liquid form. Indeed, both visual and neuro- logical complications were reported in the lit- erature concerning sclerosis with liquid.18-20 In these cases, a cause linked to the presence of air or gas that can cause a paradoxical embolism through a PFO or another type of Figure 1. Vein distribution without aminaftone prophylaxis (coll, tributaries; saph, saphens; rec, recurrences; perf, perforators; ret, reticular veins; tel, teleangectasias). Figure 2. Vein distribution with aminaftone prophylaxis (coll, tributaries; saph, saphens; rec, recurrences; perf, perforators; ret, reticular veins; tel, teleangectasias). No n c om me rci al us e o nly Article [Veins and Lymphatics 2016; 5:5764] [page 47] shunt cannot be established. It is also surpris- ing that adverse events occur almost exclusive- ly in the cerebral region or in the eye. A precise relationship between high levels of endothelin 1 and cerebral and retinal vasospasm has been described in the litera- ture. ET-1 is also one of the mediators in the vasoconstrictive phase of migraine.14-16 We published a pathogenetic hypothesis to explain these events where we assumed that the sclerosed vein releases ET-1. Generally, endothelin passes through the pulmonary cir- culation, but in the presence of a PFO a faster flow of blood rich in ET-1 in the left sections of the heart may occur. Indeed, endothelin has a very short half-life and pulmonary vessels are rich in ET-1 receptors.14 Therefore, in the event of a fast flow of blood rich in ET-1 in the left ventricle, it is easy to understand how vasospastic type complications can occur (Figures 3 and 4). The actual onset of these complications may be modified by a number of factors: - increased release of ET-1 from the sclerosed vein, which is greater using large quantities of foam or treating large endothelial sur- faces. In addition, the data in the literature also indicates an increased basal release of ET-1 from varicose veins; - the presence of PFO or other types of shunt with a more rapid passage of endothelin in arterial circulation; - incomplete venous spasm of the sclerosed segment: the formation of a lumen with an inflamed endothelium and therefore with a persistent flow will allow greater release of ET-1, contrary to a spasmed vessel and therefore without flow; - variability between patients: the endothelin receptor expression is variable; - interaction with anti-endothelin sub- stances. Even if there is not any demonstration of the role of additional mediators in the pathogenesis of complication, the hypothesis of additional substances in this process must be considered. Conclusions The role of microbubbles in the development of visual and neurological complications after sclerotherapy is greatly overestimated in the absence of valid proof of a relationship between the presence of air or gas and the symptoms. Moreover, it does not explain the almost total absence of reports of complica- tions in other locations or the onset of these complications with the use of liquid, when air or gas are not clearly present. This analysis has clear limits because it is not a prospective, randomised study but it pro- vides significant data for the prophylaxis of complications in the treatment of telangiec- tasias and especially in patients with a history of migraines. Indeed, in the latter, a prophylax- is with a molecule with anti-ET-1 properties like aminaftone has led to a tenfold reduction in the risk of the onset of a transient complica- tion. Furthermore, in this study, there was a clear trend in favour of increased safety by lim- iting the total volume of 5 cc sclerosing agent per session. In view of these results and the excellent safety profile of the drug, it would be interesting to assess these preliminary results with a prospective study, which we consider highly advisable. References 1. Cabrera Garrido JR, Cabrera Garcia Olmedo JR, Garcia Olmedo D. Nuevo meto- do de esclerosis en las varices tronculares. Pathol Vasc 1993;1:55-72. 2. Rabe E, Breu F-X, Cavezzi A, et al. European Guidelines for Sclerotherapy in Chronic Venous Disorders. Phlebology 2014;29:338-54. 3. Gallucci M, Antignani PL, Allegra C. Quality of life after ultrasound guided foam sclerotherapy in elderly patients with severe invalidating CVI. Acta Phlebol 2011;12:83-9. 4. Bradbury AW, Bate G, Pang K, et al. Ultrasound-guided foam sclerotherapy is a safe and clinically effective treatment for superficial venous reflux. J Vasc Surg 2010;52:939-45. 5. 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