Valentin Sojar, Nina Turk, Breda Barbič-Žagar

Key words

micronized disomin, hemorrhoids, acute hemorrhoidal disease

Abstract

Objectives: Acute hemorrhoidal disease (AHD), one of the most common proctological diseases, is most often cured by surgical intervention (e.g. ligature), which is unpleasant for the patient. Treatment with micronized diosmin, despite its official indication, is not yet so widespread and doctors use it less frequently. The aim of this study was to examine the effectiveness of micronized diosmin (Flebaven^®*) treatment in the presentation of AHD and thus contribute to the understanding of the management of AHD.

Methods: This prospective, observational, non-interventional study included 34 patients with symptoms of acute hemorrhoidal disease who did not opt for surgical intervention for personal reasons. Enrolled patients were treated with Flebaven^® in line with regular clinical practice and based on the investigator’s decision. Over the course of the 15-day treatment, the results were monitored at 3 data collection visits (baseline, day 7 and day 15 of the treatment).

Results: After 7 days of treatment, an improvement in AHD symptoms (reduced intensity and frequency of bleeding and cessation of bleeding) was observed. 88.9% of patients (N = 27) who attended all 3 visits reported a reduction in bleeding from baseline after 15 days of treatment, and physician‘s AHD severity assessment improved in 85.2% of patients compared to baseline. A slight trend of reduction in anal pain, itching and discharge was noted during treatment. At the 3rd visit, 42.9% of patients (N = 28) no longer needed surgical procedure (intervention). The patients tolerated the treatment well, with only mild to moderate adverse events, mainly expressed as digestive disturbances.

Conclusion: Flebaven^® effectively alleviates AHD symptoms and severity, potentially postponing the need for surgery (surgical intervention). Additional studies involving larger patient cohorts and extended treatment durations are warranted.

Background

Haemorrhoidal disease (HD) is the most common proctological disease with an estimated prevalence rate of 4.4%. It primarily affects individuals aged from 45 to 65 years.¹ Furthermore, 50% of the general population over 50 years old have encountered symptoms related to HD.²

HD is characterized by prolapse of the inflamed and bleeding vascular tissues of the heamorhoidal tissue and is associated with a high recurrence rate as well as a considerable burden to individuals.³ The most common presentation of HD is painless rectal bleeding that occurs during or immediately after defecation. Other common associated symptoms include swelling, prolapse, soiling, perianal skin irritation, itching, and discomfort. Pain is rare in case of uncomplicated HD and its presence may indicate other simultaneous painful conditions (e.g., fissure, abscess, pudendal neuropathy). HD is a benign condition and its severity is not only determined by the frequency of symptoms but rather by how the patient perceives them. The impact on a patient’s lifestyle and quality of life can vary significantly from one individual to another, even when experiencing similar symptoms.⁴

The diagnosis of HD should focus on the collection of medical history to identify symptoms indicative of the disease as well as risk factors such as constipation, a low fiber diet, sedentary lifestyle, and pregnancy. Confirming the diagnosis involves a clinical visual examination of the buttocks and digital rectal exam, coupled with an endoscopic assessment to evaluate the state of HD.⁴

Goligher’s classification categorises HD into four grades based on clinical severity, depending on whether there is no prolapse (grade I) or, if there is a prolapse, whether it reduced spontaneously (grade II) or manually (grade III), or was irreducible (grade IV).⁵

Treatment options for HD range from conservative methods (e.g., dietary and lifestyle modifications) and medical management (e.g., venoactive drugs, also known as phlebotonics, such as micronized diosmin) to less invasive procedures such as sclerotherapy, rubber band ligation, infrared coagulation, radiofrequency ablation, or invasive surgery procedures. Recurrence commonly occurs in people with HD with real-world evidence studies reporting recurrence rates ranging from 0% to 56.5% following surgery or other procedural treatment.³

The goal of HD treatment is the control of symptoms and not the correction of pathophysiological changes. A balanced diet with adequate fiber and oral fluid intake may improve stool consistency and is one of the main purposes of lifestyle changes of the conservative treatment for HD. Constipation and in particular hard stools typically worsen symptoms related to hemorrhoidal prolapse. Therefore, regular defecation and avoiding prolonged periods on the toilet to prevent straining during attempts at defecation may improve symptoms.³

Pharmacological treatment, including natural active compounds like flavonoids, extracted from plants, such as phlebotonics or venoactive drugs, significantly alleviate hemorrhoidal disease symptoms (bleeding, pain, itching, and symptoms recurrence). These compounds enhance the vascular tone and the lymphatic drainage, reduce vascular capacity, and stabilize capillary permeability. Moreover, they exhibit antioxidant and antiinflammatory effects, which contribute to their vasoprotective actions. While their precise mechanism of action is not fully understood, they are generally well tolerated, with few adverse effects, primarily manifesting as mild symptoms such as headaches, gastrointestinal symptoms, or tingling sensations. In a meta-analysis, the effects of flavonoids were examined across 14 trials involving 1514 patinets. Their findings revealed that the use of flavonoids decreases the risk of symptoms worsening or persisting by 58%. Additionally, there was an apparent reduction in the risk of bleeding, persistent pain, itching, and symptom recurrence.^{4, 5}

Despite the established indication of micronized diosmin for alleviating symptoms of acute hemorrhoidal disease, its integration into clinical practice currently remains less widespread than surgical interventions, such as ligature. The latter can be painful, stressful, and unpleasant for the patient. Moreover, there is a lack of understanding about how micronized diosmin can reduce disease severity and its symptoms, potentially postponing surgical intervention. This understanding is crucial for clinical decision-making and tailoring individualized treatments for HD. Therefore, this non-interventional study was initiated to address the current knowledge gaps concering the efficacy of micronized diosmin in managing AHD. The aim is to provide nuanced insights that can inform evidence-based clinical decision-making and enhance our understanding of the therapeutic potential of micronized diosmin in tailoring individualized treatments for HD.

Patients and methods

The non-interventional study was conducted in Slovenia at the Iatros medical centre from March 2021 to July 2022, encompassing the challenging period of the COVID-19 pandemic. Three physicians were actively involved in the study. The aim of the study was to investigate the impact and demonstrate the efficacy of Flebaven^® (Krka, d. d., Novo mesto) in patients with AHD. Flebaven^® contains the active ingredient micronised diosmin.

Patients of both sexes, aged 18 years and older, were enrolled in the study if they met the following criteria: presented symptoms of AHD listed in the therapeutic indications in the Summary of Product Characteristics (SmPC) of Flebaven^®; experienced bleeding due to AHD; had not received any pharmacological and/or non-pharmacological treatment of AHD in the previous three months; were able to follow the instructions in the protocol. The patient’s informed consent after instruction and consent to the collection, analysis and processing of personal data were also required.

Five patients had undergone various surgical interventions in the past, encompassing a range of possible surgical procedures such as ligature, sclerosing, coagulation, laser, and excision. Additionally, 32.4% of the included patients were receiving concomitant therapy, mainly antihypertensives, antithrombotics, and medicines for the treatment of thyroid disease and diabetes.

Patients visited the physician as part of their regular clinical practice. Data were collected at three data captures. The first data collection was performed at the time of patient enrolment (baseline) and Flebaven^® treatment was initiated in line with clinical practice, Flebaven^® SmPC and the physician’s decision. The second data collection was performed at follow-up visit on day 7 (+/- 1 day) of treatment, and the third data collection was performed at follow-up on day 15 of treatment (+/- 1 day). Follow-up visits were planned in accordance with standard clinical practice. The method for data collection was chosen by the investigator based on current clinical practice and the situation regarding COVID-19 at the time.

Flebaven^® was prescribed to all patients on the day of their enrolment in the study; 73.5% of patients were prescribed 1000 mg tablets, and 26.5% of patients were prescribed 500 mg tablets. All patients took the same daily dose of Flebaven^®: 3000 mg per day from days 1 to 4 inclusive, 2000 mg per day from days 5 to 7 inclusive, and 1000 mg per day from days 8 to 15 inclusive.

The study collected demographic data, data on symptoms of acute hemorrhoidal disease, disease severity, disease improvement, use of Flebaven^® in accordance with SmPC, adverse events, and selected and concomitant treatments. All adverse events were monitored and the relevant data was collected throughout the study.

Sample size (patients with data), maximum value (max.), minimum value (min.), mean, and sample standard deviation (stdev) were selected as numeric variables. Numbers and proportions by individual categories were selected as categorical variables. The numbers and proportions of missing values are shown where this was possible or reasonable. When the percentages are given by category, it is possible that the sum of the percentages may not add up to 100% due to rounding. The sum of the respective non-rounded percentages is 100%. No method was used to make up for missing values. All patients were considered, and this applies to each variable with a sample size corresponding to the number of patients with specific data. Calculations were made with Microsoft Office Excel 2019^©, and the report was written in Microsoft Office Word 2019^©.

On 14 July 2020, the National Medical Ethics Committee of the Republic of Slovenia (KME) issued a positive opinion for the non-interventional study. The Agency for Medicinal Products and Medical Devices of the Republic of Slovenia (JAZMP) issued its positive opinion for the start of the study on 10 August 2020. The first patient was enrolled on 12 March 2021, and the treatment of the last enrolled patient ended on 18 July 2022.

Results

The study included 34 patients, of that 41.2% women and 58.8% men. The mean age of the included patients was 45.6 ± 13.6 years. The first data collection captured data for 34 patients, the second one (on day 7 of treatment) for 30 patients, and the third one (on day 15 of treatment) for 28 patients. 27 patients participated in all data collections. All patients for whom data was collected two or three times were taking Flebaven^® as prescribed in the medicine’s SmPC. Two patients stopped Flebaven^® treatment early at their own request and did not participate in the third data collection. In one patient, all symptoms of acute hemorrhoidal disease disappeared, while another patient reported subjective improvement of symptoms.

Efficacy results

The primary study endpoints, characterized by improvements in bleeding intensity and frequency scores, can also be interpreted as a decrease in bleeding intensity and frequency. Higher bleeding intensity and frequency scores indicate greater severity. Consequently, the observed improvements signify a positive outcome, as they show a decrease in rectal bleeding severity and frequency. All patients enrolled in the study experienced rectal bleeding at the baseline. On day 7 of Flebaven^® treatment, bleeding intensity decreased in 80.0% (N = 24) of patients and bleeding frequency decreased in 76.7% (N = 23) of patients (Figure 1).

Figure 1: Proportion of patients who met primary endpoints on day 7 of treatment compared to baseline (N = 30)

By day 7 of Flebaven^® treatment, bleeding ceased completely in 60.0% of the patients. The baseline mean pain severity score (first data collection) according to visual analogue scale (VAS, 0–100) decreased by 6 (from a mean value of 10.0 to a mean value of 4.0) in absolute terms at second data collection (day 7 of treatment). At baseline, 64.7% of patients were pain-free, which is why the mean pain severity score was so low.

The itching intensity score improved in 33.3% of patients after 7 days of treatment compared to baseline, with 64.7% of patients being free of anal itching at baseline (Figure 2).

Figure 2: Proportion of patients reporting different itching intensity scores at baseline and on day 7

The anal discharge score improved in 16.7% of patients compared to baseline (20.5% of patients [N = 7] reported anal discharge at baseline, and 6.6% of patients [N = 2] reported anal discharge after 7 days of treatment).

Anal pain, itching and discharge intensity score improvements can also be defined as decreased anal pain, itching, and discharge. Higher scores indicate greater severity, and improvements a reduction in their severity.

On day 7 of treatment, the physician’s assessment of AHD severity score improved in 73.3% of patients (N = 22). An overview is presented on Figure 3. As an improvement of the disease severity score indicates a reduction in its severity, it can also be defined as a decreased severity of the disease. In 16.7% of patients (N = 5), the disease severity score showed a marked improvement. In 26.7% of patients (N = 8), the disease severity score showed a medium improvement, and in 30% of patients (N = 9), the disease severity score showed a marginal improvement. No changes from baseline were reported only in 26.7% of patients (N = 8).

Figure 3: Proportion of patients according to the physician’s assessment of AHD severity score at baseline and on day 7 of treatment

Additional statistical analysis was prepared for the group of patients who attended all three data captures, showing improvements in the bleeding intensity score and in the physician’s assessment of AHD severity. Among patients who attended all three data collections (N = 27), bleeding intensity decreased compared to baseline in 81.5% (N = 22) of patients on day 7, and 88.9% (N = 24) on day 15 of treatment (Figure 4).

Figure 4: Proportion of patients who attended all three data collections with improved bleeding intensity score on days 7 and 15 of treatment

Among patients who attended all three data collections, physicians observed a decreased severity of AHD compared to baseline in 74.1% (N = 20) of patients on day 7 and 85.2% (N = 23) on day 15 of treatment (Figure 5).

Figure 5: Proportion of patients with improved physician’s assessment of AHD severity score on days 7 and 15 of treatment

After 15 days of Flebaven^® treatment, 42.9% of patients who attended the third data collection (N = 28) reported that their treatment was successful, and that they did not require additional surgical treatment with ligature placement.

Safety results

Safety set analysis included all 34 enrolled patients who received at least one dose of Flebaven^®. During the study, investigators recorded 14 adverse events in 11 patients (32.4%). Out of these, 11 adverse events in 9 patients (26.5%) were recorded as mainly mild, non-serious causally related (adverse reactions of Flebaven^®), and no patient reported serious causally related adverse events.

The most common adverse events were related to gastrointestinal disturbances such as dyspepsia and constipation. On day 7 of treatment, 8 patients (23.5%) reported adverse reactions, and on day 15 of treatment, 3 patients (8.9%) reported adverse reactions.

Of the patients who attended the third data collection (N = 28), 89.3% tolerated Flebaven^® treatment well.

Discussion

Throughout the follow-up period of Flebaven^® treatment, both primary endpoints (bleeding intensity and frequency) improved compared to baseline. After seven days of treatment, bleeding had stopped completely in 60.0% of patients, the bleeding intensity decreased in 80.0% of patients, and the bleeding frequency decreased in 76.7% of patients. Comparable therapeutic efficacy was demonstrated in a study of 162 patients receiving treatment with micronised purified flavonoid fraction (MPFF) for acute HD. After seven days of treatment, a significant reduction in bleeding was observed in 55.7% to 61.5% of patients, with complete cessation of bleeding in half of the patients enrolled in the study.⁶

At day 7 of treatment with Flebaven^® (N = 30), all secondary endpoints also improved compared to baseline. According to the physician’s assessment, the AHD severity score improved in 73.3% of patients. None of the patients enrolled in the study were classified as ‘severely ill’, and no patient’s condition worsened. For the parameters anal pain, itching and discharge, the proportion of patients with these symptoms was already low at baseline. This confirms the symptomatology of AHD, which in routine clinical practice mostly presents with bleeding, while symptoms such as pain, itching and discharge are significantly less frequent. Due to the small proportion of patients reporting anal pain, itching and discharge, the interpretation of results after seven days of treatment with Flebaven^® is limited. However, there was a trend towards an improvement of symptoms of AHD in patients who reported anal pain, itching or discharge at baseline.

An analysis of the group of 27 patients who attended all three data collections showed a further improvement in treatment outcomes after 15 days compared to 7 days. After 7 days of treatment, the bleeding intensity decreased in 81.5% of patients, and after 15 days in a further 7.4% of patients, for a total of 88.9% of patients compared to baseline. During the 15-day treatment, the physician’s assessment showed that the disease severity further improved in 11.1% of patients, bringing the total from 74.1% to 85.2% of patients.

In standard clinical practice, all patients included in the study would typically have been offered surgical intervention at the baseline. The exception to this would apply to patients with a medical contraindication (e.g., anticoagulation treatment) or a personal reason. Only patients who did not opt for surgical intervention for personal reasons were included in the study. Flebaven^® treatment was successful for 42.9% of patients, as they did not require additional surgical treatment with ligature placement or other surgical intervention after 15 days of treatment. Moreover, the investigators observed less hyperaemia and inflammation in patients treated with Flebaven^® during clinical examination that included an endoscopic assessment of AHD. The assessment is of course subjective, but reliable enough for an experienced clinician to confirm the change.

Flebaven^® treatment was tolerated well by the patients included in the study. During the course of the study, 26.5% of patients experienced adverse reactions. They were mainly mild, with the most common manifestations being gastrointestinal disturbances (dyspepsia and constipation). After 15 days of treatment only three patients still experienced adverse reactions. Of the patients who attended the third data collection, 89.3% tolerated Flebaven^® treatment well. A similar safety profile of Flebaven^® was also reported in a clinical study evaluating the efficacy and safety of Flebaven^® in patients with chronic venous disease.⁷

The present study has several strengths. Being an observational study, it evaluated the effectiveness and safety of micronized diosmin treatment of AHD in everyday clinical practice. Moreover, as there is little evidence published in peer-reviewed literature in this clinical area, the results of this non-interventional study will contribute to the understanding of the treatment of AHD.

The main limitation of the study is its limited sample size, making certain statistical analyses, such as calculating a p-value, unfeasible. In the initial sample size calculation, the study aimed to include 100 patients. However, the emergence of the COVID-19 pandemic declared during the study planning phase altered the structure of patients referred to the clinic due to limited access to physicians at the time. Extended wait times for physician consultations from the onset of symptoms may have contributed to a higher proportion of self-treated patients, thereby influencing the altered patient structure. Investigators noted an increase in the number of patients with symptoms of AHD resorting to various self-treatment methods. Consequently, these patients did not meet the inclusion criteria for participation in the study, having undergone prior treatment. Furthermore, a larger proportion of patients still required surgical intervention at the end of this study. This trend could be attributed both to the altered patient structure and the extended period from symptom onset to visiting a physician, often resulting in a more advanced disease.

Another limitation is that because some data were collected remotely (by telephone or electronic media), clinical examination, such as endoscopic assessment of acute hemorrhoidal disease, was not feasible. While the assessment is inherently subjective, it remains reliable enough for an experienced clinician to confirm changes.

The third limitation lies in the challenge of comparing our study with existing literature, given the diverse study designs. The majority of current evidence published in peer-reviewed literature in this clinical area predominantly highlights the benefits of flavonoids immediately following surgical intervention, rather than exploring their potential for preventing or postponing surgical intervention.

Conclusion

The non-interventional study demonstrated the effectiveness of Flebaven^® treatment, with improved symptoms of AHD. After only 7 days of treatment, there was observed decreased bleeding intensity and frequency, cessation of bleeding, decreased severity of anal itching, pain and discharge, an improvement in the physician’s assessment of disease severity and overall disease condition. After 15 days of treatment, the bleeding severity score showed additional improvement, and the number of adverse reactions decreased compared to those recorded after 7 days of treatment. These findings suggest that a 15-day treatment with Flebaven^® is reasonable. Flebaven^® treatment appears to be a logical choice for patients with clinically proven AHD accompanied by bleeding, HD stage 1 or 2, when surgical intervention is not feasible due to comorbidities or personal reasons. Surgical intervention may be postponed with Flebaven^®.

In addition, the results demonstrate a favourable safety profile of the medicinal product.

Given the small number of patients included in the study, conducting a follow-up study with a larger patient cohort would be sensible. Additionally, a study to assess the efficacy and safety of prolonged treatment with micronised diosmin should be considered.

In conclusion, the 15-day treatment with Flebaven^® proves to be effective and safe in daily clinical practice, leading to a significant improvement in the symptoms of AHD without significant adverse reactions. After 15 days of treatment, 42.9% of patients avoided the need for surgical intervention, which would have otherwise been performed in standard clinical practice for all patients included in the study.

References

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* The product is marketed under different brand names in different countries.

Author

Prim. Valentin Sojar, dr. med., svetnik, spec. splošne kirurgije, MBA FEBS, valentin.sojar@iatros.si

Nina Turk, mag. farm. Krka d. d., nina.turk@krka.biz

Breda Barbič-Žagar, dr. med. Krka d. d., breda.zagar@krka.biz

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Published: March, 2024