Sclerotherapy with 3% polidocanol foam to treat second‐degree haemorrhoidal disease: Three‐year follow‐up of a multicentre, single arm, IDEAL phase 2b trial

Sclerotherapy with 3% polidocanol foam is becoming increasingly popular for the treatment of symptomatic I–II or III degree haemorrhoidal disease (HD). However, there are no studies that have reported a follow‐up of more than 1 year. The purpose of this study was to analyse the long‐term outcomes of sclerotherapy with 3% polidocanol foam in the treatment of II–degree HD.


INTRODUC TI ON
The treatment of haemorrhoidal disease (HD) is becoming more and more tailored and symptom-based [1]. A recent online survey including 81 members of the European Society of Coloproctology (ESCP) has further highlighted the limitations of the Goligher classification especially for the decision-making process of II and III-degree HD [2]. These results were consistent with another survey in which a total of 329 gastrointestinal surgeons, residents and fellows from Netherlands were asked to rate the Goligher HD degree of 25 photographs and whose findings were a fair agreement between respondents concerning the II and III degree HD (k statistic 0.206 and 0.37) [3].
This new belief in the patient's symptom and quality of life has led to greater use of office-based procedures with a step-up approach from the least invasive to the most invasive treatment.
Sclerotherapy with 3% polidocanol foam is becoming increasingly popular for the treatment of symptomatic I-II or III degree HD, who failed conservative treatment [4,5], particularly in those patients with bleeding HD, or in those who could not undergo surgical treatment due to the presence of comorbidities or bleeding disorders [6].
Several studies have demonstrated its safety and efficacy in the last 10 years [6][7][8][9][10][11][12]. Among the main advantages that favoured its acceptance, especially during the COVID-19 pandemic where the availability of operating rooms had been reduced and elective procedures stopped or suspended [13], were the low cost, repeatability, almost total absence of complications as well as of procedural pain and discomfort for the patient even at the cost of a recurrence rate still not well defined.
However, to date, there are no studies that have reported a follow-up of more than 1 year.
The purpose of this study was to assess the long-term effectiveness of sclerotherapy with 3% polidocanol foam (Aethoxysklerol 3%, Chemische Fabrik Kreussler & Co. GmbH).
to medical treatment, were included in the study and underwent sclerotherapy with 3% polidocanol foam. The efficacy was evaluated in terms of bleeding score, haemorrhoidal disease symptom score (HDSS) and short health scale for HD (SHS-HD) score. Successful treatment was defined as the complete absence of bleeding episodes after 7 days (T1) according to the bleeding score.
There were no intraoperative complications in redo-sclerotherapy nor additional adverse events (AEs) compared to the first 12 months.
Conclusions: Sclerotherapy with 3% polidocanol foam is gradually establishing itself in the treatment of bleeding HD due to its repeatability, safety, convenience in terms of direct and indirect costs with the absence of discomfort for the patient as well as AEs rather than an excellent overall success rate.

K E Y W O R D S
bleeding haemorrhoids, follow-up, haemorrhoidal disease, polidocanol foam, sclerofoam trial, sclerotherapy

What does this paper add to the literature?
This is the first trial evaluating the long-term efficacy and safety of 3% polidocanol foam for the treatment of symptomatic II degree haemorrhoidal disease. The absence of adverse events or major complications, even after repeating the procedure, and the high-success rate at 3 years represent the clinical rationale for the use of foam sclerotherapy.

PATIENTS AND ME THODS
This multicentre, open label, single-arm, IDEAL phase 2b [14] trial involved 10 tertiary referral centres for HD belonging to the Italian Society of Colorectal Surgery (Società Italiana di Chirurgia Colorettale, SICCR). It represents the three-year follow-up of the SCLEROFOAM trial [7].
Demographics, type, and severity of symptoms of HD, HD-related quality of life, continence level and procedural details were prospectively collected. A constant monthly data check was performed with the participating centres for the entire duration of the study. The study protocol was approved by the ethics committees and was reg- Here, we report data up to 3 years after the first sclerosing agent injection. Full details of the study design, the patient eligibility criteria, and the outcomes of the study after 1 year of follow-up have been already published [7]. Apart from enrollment (baseline, T0),

Study design
The degree of HD was assessed by proctological examination including digital rectal examination and anoscopy. Except at T1, where only an external clinical evaluation was performed, the other followups, from T2 to T8, included a complete proctological evaluation.
The haemorrhoidal disease symptom score (HDSS), considering pain, itching, bleeding, soiling and prolapse, based on a 5 point-scale (0 = never, 1 = less than once a month, 2 = less than once a week, 3 = 1-6 days per week, 4 = every day or always), and the short health scale for HD (SHS-HD) score, based on a 7-point Likert scale for each question (1 = minimum score, 7 = maximum score), were used, to evaluate symptoms severity and HD-related quality of life preoperatively, at T3 and from T5 to T8, respectively [16].
The procedural pain, the amount and type of painkillers and the resumption of normal activities were evaluated in our previous study, but we considered inappropriate to include them in the 3-year outcome assessment due to insufficient numbers involved.
For the same reason we preferred to avoid the evaluation of symptoms from the patient's clinical diary.
Successful treatment was already defined as the complete absence of bleeding episodes at T1 according to the Giamundo bleeding score [15].
Recurrences were defined as the new onset of bleeding after T1 in the successfully treated patients, namely, from a bleeding score of 0 to at least 2 at any time point between T2 and T8.

Eligibility criteria
Patients aged between 18 and 75 years with symptomatic HD according to the Goligher classification and unresponsive to medical treatment were included in the study.
Patients were excluded if they had a history of cardiac disease, coagulopathy, and anticoagulant therapies, colorectal or anal neoplasia, IBD, or other proctological diseases (anal fistulas and fissures; thrombosed internal or external HD); or if they had previous anal surgical procedures, previous sclerotherapy or rubber band ligation in the last 12 months; or if they had positive pregnancy test and breastfeeding, HBV, HCV or HIV infection, proctitis, known allergy to polidocanol, or pelvic radiotherapy were excluded. The inability or unwillingness to attend the follow-up visit were also considered an exclusion criterion.

Procedure (treatment plan)
The procedure was performed on an outpatient basis as previously described and the details of the pre-, intra-and postoperative management as well as of the preparation and pathophysiology of action of the foam have already been published [7,9,18]. The patient was discharged approximately 20 min after the procedure following a clinical safety check. Stool softeners and flebotonics were administered postoperatively.

Outcomes
Complete resolution of bleeding at T1 was the primary outcome.
Predefined secondary outcomes were as follows: success rate in terms of partial or complete resolution of the symptoms at 12 months; the average number of sessions necessary to obtain the complete resolution of the bleeding; the rate of complications and adverse events (AEs). Patients' quality of life and the average time required to resume normal daily activities, including work, were evaluated as well.

Safety
Safety was recorded by reporting AEs, serious adverse events (SAEs), and toxicity after each polidocanol foam injection. Toxicity was defined according to the WHO toxicity scale [19]. The AEs were classified as none, remote, possible, probable, or not assessable based on the relation with the foam.

Statistical analysis
The results are reported as counts and percentages for categorical variables and as the mean ± SD (range) for continuous normally distributed variables and the median (interquartile range [IQR]) for ordinal categorical variables and for continuous non-normally distributed variables. The chi-square test was used for crosstabulations and independent samples t-test to evaluate differences between means. The time to recurrence was evaluated as the time elapsed from treatment success to the relapse of bleeding (at least 2 for the Giamundo bleeding score). Kaplan-Meier curves were used to evaluate freedom from recurrence. The changes in the HDSS, the SHS score and the Vaizey score over time were analysed with the Friedman test because these scores were not normally distributed.
The results associated with a p-value <0.05 were considered statistically significant. Statistical data analysis was performed using IBM SPSS Statistics 20 and MedCalc 12.5.

RE SULTS
A total of 183 patients with II-degree HD underwent sclerotherapy with 3% polidocanol foam in the selected referral centres from January and June 2019. The baseline demographics as well as the clinicopathological characteristics of the patients have already been described in detail [6] and are reported in Table 1.
During the study period, 87% (143) patients underwent one sclerotherapy session and 12% (20) and 1% (2), respectively, underwent two and three sessions. Most of the redo-sclerotherapy was performed at T6 (12). Eight out of 12 of those patients have become successes while the other four underwent surgery.
The remaining three patients who recurred at T6 had preferred to wait for the next follow-up and underwent surgery at T7. Two out of five patients who recurred at T7 underwent a successful second sclerotherapy session. The other three recurred patients underwent surgery together with one patient who stopped bleeding but had a worsening of the prolapse at T7 (Figure 1).
Four out of the 169 patients who were considered at T8 still had a bleeding score of 1 according to the Giamundo bleeding score ( Table 3).
There were no intraoperative complications in redo-sclerotherapy nor additional AEs or SAEs compared to the first 12 months ( Table 2).
The number of patients converted to surgery rose from 1.6% (3/183) to 7.7% (14/183), of which 10 underwent dearterialization and mucopexy and four excisional haemorrhoidectomy. In particular, four patients were excluded from follow-up at T7, and seven at T8.
Only one of these had undergone a second unsuccessful sclerotherapy session.
Interestingly, the number of recurrences in males was more than double that of females with respect to the primary outcome ( recurrences in male patients ( Table 6). Moreover, 12 out of the 14 patients converted to surgery (85.7%) were male (p = 0.087).
In this context, there has been a correlation trend between weight and conversion to surgery, recurrences, and overall success rate ( Table 5.). This was probably due to the greater representation of male patients in the respective categories. There was no other correlation with the clinical-demographic variables.

DISCUSS ION
Sclerotherapy with 3% polidocanol foam is certainly one of the emerging approaches in the treatment of HD [20]. So far, the immediacy of action of the foam which promotes a consistent vasospasm with endothelial damage, inflammatory reaction and a localized sclerosis and fibrosis following the injection has been recognized.  Although several studies have recently been published, there is no standardization regarding the quantity and type of foam to be used [20].
Our foam has been prepared by using the EasyFoamKit syringe system mixing 1.6 ml of 3% liquid polidocanol and 7.4 ml sterile air and the injection was performed using a 20G needle. In fact, while  52  52  52  52  52  45  45  45  45  45  45  45   45  45  45  45  45  50  50  58  58  60  60  61  71   3  6  9  12  15  Furthermore, a concept that should be developed is that of standardization of foam that is independent of human error, as Tessari's method can certainly induce.
Recently, we published the preliminary results, with 3 months of follow-up and 78% success rate, of the first 50 patients undergoing sclerotherapy with the foam produced using an automated device that allowed us to maintain a liquid / gas ratio between 1: 5 and 1: 7 without the need to re-emulsify the foam before each injection [12].
It will be necessary to treat large numbers with prolonged follow-up but it seems that this is the way to go.
The use of 3% polidocanol foam allowed a consistent reduction of local and systemic complications in comparison with previous sclerosing agents used in the past [21]. In fact, apart from one episode of acute prostatitis, described by Moser et al. [10], and some of external thrombosis [7,9], there were no major complications or adverse events [6][7][8][9][10][11][12].
Moreover, recurrences are not only higher in male patients but occur both more quickly and in the long term, compared to female patients that have no recurrence after 18 months (Figure 2A,B).
In our first study on sclerotherapy in patients with II-III degree HD we correlated tenesmus (p = 0.029) to recurrences hypothesizing excessive defaecation stimuli caused by foam as the cause. In the present study, the greater representation of male patients (110/183; 60.7%) and the increased physiological muscle representation may be the rationale [22].
The rubber band ligation is still the most commonly used officebased procedure [23], not only for the simplicity of execution and for the repeatability, but also because of the lack of substantial innova- p = 0.002). However, future trials will be necessary to confirm this trend. Interestingly, when RBL was compared to the haemorrhoidal artery ligation in the biggest trial published so far, the recurrence rate was higher (49% vs. 30%) [26] but the procedure was less painful.
The main limitation of the study continues to be the lack of a control group. Moreover, we did not consider some variables, that is, procedural pain, the amount and type of painkillers, the resumption of normal activities and the patient's clinical diary, that would not have had the same objective value as the scores considered. In addition, patients were selected with no comorbidities or factors that could alter the results. Interestingly, contrary to the latter concept, sclerotherapy is becoming an arrow in the bow of every proctologist even in unfit for surgery patients regardless of the degree of HD [27]. Future studies in this direction will be able to clarify this point.

CON CLUS ION
Sclerotherapy with 3% polidocanol foam is gradually establishing itself in the treatment of bleeding HD due to its repeatability, safety, TA B L E 5 Correlation between conversion to surgery, recurrence and final success rates and clinical-demographic variables convenience in terms of direct and indirect costs with the absence of discomfort for the patient as well as AEs rather than an excellent overall success rate.

ACK N OWLED G EM ENT
The preliminary results of the study were awarded the "Ohio Valley

Society of Colon and Rectal Surgeons (ASCRS) Annual Scientific
Meeting in Tampa.

FU N D I N G I N FO R M ATI O N
None.

CO N FLI C T O F I NTE R E S T
All authors declare no personal conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.