Abstract
Purpose
Recurrence after initial control of acute internal hemorrhoidal bleeding remains a common and clinically relevant challenge. Escin, a venotonic and anti-inflammatory compound, may augment the therapeutic effects of micronized purified flavonoid fraction (MPFF). This study aimed to evaluate whether the addition of escin to MPFF reduces recurrence of acute internal hemorrhoidal bleeding.
Methods
In this double-blind randomized controlled trial, adults with grade 1 or 2 acute bleeding internal hemorrhoids received MPFF 3,000 mg/day for 7 days in combination with either escin 120 mg/day or a matched placebo. Patients who achieved hemostasis subsequently continued MPFF 1,000 mg/day with escin or placebo for 2 months. The primary endpoint was recurrence within 90 days, defined clinically and confirmed by proctoscopy. Secondary outcomes included time to hemostasis, the Short Health Scale for Hemorrhoids (SHSHD), and safety outcomes.
Results
Among 108 patients who achieved hemostasis, recurrence occurred in 0% vs 7.84% at 1 month and 7.02% vs 23.52% at 3 months in the escin and placebo groups, respectively. Combination therapy significantly reduced recurrence (P=0.009). Time to bleeding cessation was shorter in the escin group (median, 2 days vs. 4 days; P<0.001). Improvement in SHSHD scores was greater with escin. No adverse events were observed in either group.
Conclusion
The combination of escin and MPFF reduces recurrence and accelerates symptom resolution in acute internal hemorrhoidal bleeding, with a favorable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT06748014.
Keywords: Hemorrhoids, Flavonoids, Micronized purified flavonoid fraction, Escin, Reparil
INTRODUCTION
Hemorrhoids are a prevalent anorectal disorder that substantially affects quality of life through symptoms such as pain, bleeding, and prolapse [1, 2]. Acute internal hemorrhoids, characterized by a sudden exacerbation of these symptoms, require effective management strategies to prevent recurrence and improve patient outcomes. For grade 1 and 2 hemorrhoidal disease, conventional treatment approaches include dietary modification, topical agents, and oral medications, with micronized purified flavonoid fraction (MPFF) receiving particular attention because of its venotonic and anti-inflammatory properties [3, 4].
Recent studies have demonstrated the efficacy of MPFF in the management of acute hemorrhoidal symptoms by improving venous tone and reducing capillary permeability, thereby decreasing bleeding episodes [5–8]. Nevertheless, despite these benefits, recurrence after initial symptom control remains a persistent clinical problem, underscoring the need for adjunctive therapies that can provide more sustained relief.
Escin, a natural saponin extracted from horse chestnut seeds, exhibits antiedematous, anti-inflammatory, and venotonic effects that may complement the pharmacological actions of MPFF [9, 10]. A recent study indicated that, when used in combination with flavonoids, escin can synergistically improve control of hemorrhoidal bleeding and reduce mass-related effects in acute clinical settings [11].
Our group previously conducted a randomized trial evaluating the combined use of MPFF and escin limited to the acute phase of internal hemorrhoidal bleeding, with primary emphasis on early hemostasis and symptom control during a short 7-day treatment period [11]. Although that study demonstrated more rapid bleeding cessation with the combination regimen, it did not assess long-term outcomes, and recurrence following initial hemostasis was not evaluated. Because recurrence remains a major unresolved clinical challenge and evidence supporting maintenance therapy after acute control is limited, a focused investigation addressing longer treatment duration and systematic follow-up was needed. Accordingly, the present trial was designed to extend and complement our earlier work by examining the recurrence phase through the incorporation of a 2-month maintenance regimen and prospective follow-up over 3 months to assess recurrence, recurrence-free survival, and patient-reported outcomes.
Therefore, this randomized controlled trial was conducted to determine whether the addition of escin to MPFF reduces recurrence after initial hemostasis and improves patient-reported outcomes during a 3-month follow-up period.
METHODS
Ethics statement
This study was approved by the Research Ethics Committee of the Faculty of Medicine, Chiang Mai University (No. SUR2567-0485). Written informed consent was obtained from all participants prior to enrollment. The study was registered at ClinicalTrials.gov (identifier: NCT06748014). The study was conducted in accordance with the CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines.
Study setting
The primary endpoint was time to recurrence of acute internal hemorrhoidal bleeding within 90 days after achieving hemostasis. “Recurrence” was defined as new-onset bright-red rectal bleeding attributable to internal hemorrhoids occurring after the index date and meeting at least one of the following objective criteria: (1) hemorrhoid bleeding score (HBS) [12] (HBS type ≥1 or HBS frequency ≥1); and (2) healthcare utilization or treatment escalation: any unscheduled medical contact for bleeding, or initiation of rescue therapy (e.g., additional oral or topical agents beyond the assigned regimen, rubber-band ligation, sclerotherapy, or surgery) due to bleeding. Secondary endpoints included time to initial hemostasis, Short Health Scale for Hemorrhoids (SHSHD), and adverse events.
Participants
Between November 2024 and March 2025, patients were recruited from the Surgical Outpatient Clinic of the Division of Colorectal Surgery, Faculty of Medicine, Chiang Mai University. Consecutive outpatients of either sex, aged over 20 years, with a history of hemorrhoidal disease of less than 12 months and presenting with acute rectal bleeding lasting fewer than 7 days were considered eligible. Inclusion criteria also required visibly distended or displaced anal cushions consistent with grade 1 or 2 internal hemorrhoids, as confirmed by anoscopic examination.
For patients aged over 50 years, colonoscopy was required to exclude alternative causes of bleeding. Exclusion criteria included a history of bleeding disorders, colorectal cancer, inflammatory bowel disease, chronic kidney disease, anal fissure identified on physical examination, pregnancy, or any prior treatment for hemorrhoidal disease.
Pretreatment phase
Before initiation of treatment, all participants underwent a baseline evaluation that included a brief questionnaire and a physical examination. Collected data included hemorrhoid grade (grade 1, bleeding without prolapse; or grade 2, bleeding with prolapse that spontaneously reduces) and associated comorbidities. Additional assessments included the Wexner score [13], SHSHD [14], and HBS [12].
Anoscopic examination was performed in all patients. A comprehensive panel of laboratory investigations, including complete blood count, prothrombin time, partial thromboplastin time, international normalized ratio, liver function tests, blood urea nitrogen, and serum creatinine, was conducted, unless results from the preceding 3 months were available.
Treatment phase
Randomization and blinding
Participants were randomized in a 1:1 ratio using computer-generated block randomization (block size 4). The allocation list was maintained exclusively by the hospital research pharmacist, who was unblinded but had no role in screening, enrollment, clinical care, outcome assessment, or statistical analysis. The trial employed a double-blind design; patients, treating clinicians, outcome assessors, and data analysts remained unaware of treatment assignments. Escin (Reparil, Madaus) is a commercially available 20-mg oral formulation routinely used at our institution. The placebo consisted of pharmaceutical-grade starch tablets manufactured and packaged by the hospital pharmacy to be identical in appearance and packaging to the escin tablets in order to maintain blinding.
Allocation concealment
The research pharmacy prepared sequentially numbered, identical medication kits according to the concealed allocation list. After eligibility confirmation and informed consent, the study nurse requested the next medication kit in sequence; assignment was therefore concealed from investigators and participants until database lock. Sealed code-break envelopes, along with a 24-hour pharmacist contact, were available for emergency unblinding; however, no emergency unblinding occurred during the study.
Interventions and dispensing
During the initial 7-day acute treatment phase, both groups received MPFF 1,000 mg 3 times daily. In the combination group, patients additionally received escin (Reparil) 20 mg, 2 tablets 3 times daily, whereas the control group received a matched placebo administered on the same schedule. On day 8, patients were reevaluated by anoscopy and were asked to report the day on which bleeding ceased or, in the case of grade 2 hemorrhoids, the day on which the prolapsed mass disappeared. Adverse events were monitored using open-ended questioning, and medication adherence was assessed through tablet counts (Fig. 1). Treatment failure was defined as failure to achieve hemostasis. Patients who achieved bleeding cessation continued treatment for an additional 2 months with MPFF 1,000 mg once daily combined with either escin 20 mg, 1 tablet twice daily, or matched placebo. Follow-up visits at 1 and 3 months included clinical history assessment using the SHSHD questionnaire and a physical examination, as well as digital rectal examination and proctoscopy to evaluate hemorrhoidal status. Adverse events were defined as any unfavorable or unintended symptom, sign, or disease occurring after initiation of the study medication, regardless of suspected causal relationship. At each scheduled visit, patients were actively questioned regarding potential adverse events, including headache, dizziness, gastrointestinal discomfort, rash, or allergic reactions.
Fig. 1.
CONSORT (Consolidated Standards of Reporting Trials) flowchart. MPFF, micronized purified flavonoid fraction.
Patients who experienced recurrent or new-onset acute bleeding during or after treatment of the acute phase were considered to have failed medical therapy and were referred for surgical intervention. These patients were permitted to return outside scheduled visits for urgent clinical care.
Statistical analysis
The primary outcome was recurrence of grade 1 or 2 internal hemorrhoidal bleeding at 1 and 3 months. Secondary outcomes included time to initial hemostasis, SHSHD, and adverse events. Two analysis populations were prespecified. Acute-phase outcomes, including time to initial hemostasis, were analyzed in both the intention-to-treat (ITT) population, comprising all randomized patients, and the per-protocol (PP) population, which excluded patients who failed to achieve hemostasis during the 7-day acute phase, as defined a priori. Recurrence outcomes at 1 and 3 months were analyzed in the PP population by design, as recurrence could only be evaluated in patients who had achieved initial hemostasis. To increase transparency, an ITT sensitivity analysis of recurrence was also conducted, in which acute-phase nonresponders were classified as immediate recurrences to confirm the robustness of the findings.
Sample size calculation assumed a 90-day recurrence rate of 25% in the MPFF+placebo group and 10% in the MPFF+escin group, corresponding to an absolute risk reduction of 15% and an approximate 60% relative reduction (hazard ratio [HR], 0.40). These assumptions were based on published recurrence estimates for pharmacologic therapy in hemorrhoidal disease and prior evidence demonstrating faster acute hemostasis with the combination regimen [11, 15]. With a 2-sided α of 0.05 and 80% power using a log-rank framework, and allowing for approximately 10% attrition, the required sample size was calculated as 60 patients per group (total n=120). Baseline continuous variables were compared using the rank sum test, and categorical variables were analyzed using Fisher exact test. For non-normally distributed data, the Wilcoxon rank sum test was used to compare within- and between-group changes. A 2-sided P-value of <0.05 was considered statistically significant. All statistical analyses were performed using Stata ver. 16.0 (Stata Corp).
RESULTS
A total of 120 patients were enrolled and evenly randomized into 2 groups. Supplementary Table 1 summarizes the baseline characteristics, which were comparable between groups, with no significant differences in age, sex, body mass index, comorbidities, smoking status, disease duration, hemorrhoid grade, bleeding severity, or constipation scores.
After exclusion of patients who failed to respond during the acute phase (3 in the MPFF+escin group and 9 in the MPFF+placebo group), Table 1 presents the baseline characteristics of patients who continued into the follow-up phase. The 2 groups remained well balanced across all baseline variables, confirming the comparability of the study arms after exclusion of acute-phase nonresponders.
Table 1.
Demographic data of the patients after excluding cases of failed medication in the acute phase treatment (n=108)
| Characteristic | MPFF+escin group (n=57) | MPFF+placebo group (n=51) | P-value |
|---|---|---|---|
| Age (yr) | 35.70±11.81 | 34.25±12.20 | 0.533 |
| Sex | >0.999 | ||
| Male | 34 (59.6) | 31 (60.8) | |
| Female | 23 (40.4) | 20 (39.2) | |
| Body mass index (kg/m2) | 25.62±3.35 | 25.07±3.34 | 0.393 |
| Underlying disease | |||
| Diabetes mellitus | 3 (5.3) | 3 (5.9) | >0.999 |
| Hypertension | 6 (10.5) | 8 (15.7) | 0.568 |
| Dyslipidemia | 7 (12.3) | 7 (13.7) | >0.999 |
| Smoking | 9 (15.8) | 5 (9.8) | >0.999 |
| Duration of disease (mo) | 2 (1–4) | 2 (1–3) | 0.425 |
| Hemorrhoid grading | 0.564 | ||
| Grade 1 | 30 (52.6) | 30 (58.8) | |
| Grade 2 | 27 (47.4) | 21 (41.2) | |
| Duration of acute bleeding (day) | 4 (3–5) | 4 (3–5) | 0.509 |
| Severity of bleeding | 0.549 | ||
| Mild | 37 (64.9) | 34 (66.7) | |
| Moderate | 16 (28.1) | 16 (31.4) | |
| Severe | 4 (7.0) | 1 (2.0) | |
| Wexner score | 4.53±1.68 | 4.14±1.59 | 0.220 |
Values are presented as mean±standard deviation, number (%), or median (interquartile range). Percentages may not total 100 due to rounding.
MPFF, micronized purified flavonoid fraction.
During the acute treatment phase, the MPFF+escin group demonstrated superior clinical efficacy compared with the MPFF+placebo group. A higher proportion of patients in the combination group achieved bleeding cessation within 7 days (95.0% vs. 85.0%), although this difference did not reach statistical significance (P=0.125). In contrast, the median time to bleeding cessation was significantly shorter in the MPFF+escin group than in the placebo group (2 days [interquartile range (IQR), 2 to 3 days] vs. 4 days [IQR, 3 to 5 days]; P<0.001) (Supplementary Table 2).
Subgroup analysis according to disease severity demonstrated consistent trends favoring the combination therapy. In the mild subgroup, patients receiving MPFF+escin achieved significantly faster bleeding cessation compared with those receiving placebo (2 days vs. 3.5 days; P<0.001), whereas differences observed in the moderate and severe subgroups did not reach statistical significance (Supplementary Table 3).
Medication adherence remained high in both treatment groups throughout the study period. Mean adherence during the maintenance phase exceeded 90% for both MPFF and escin, with no statistically significant differences between groups (Table 2).
Table 2.
Medication adherence during the maintenance phase (n=108)
| Medication | Compliance (%) | P-value | |
|---|---|---|---|
| MPFF+escin group (n=57) | MPFF+placebo group (n=51) | ||
| MPFF | 95.66±8.31 | 93.49±11.68 | 0.266 |
| Escin or placebo | 94.48±8.37 | 94.25±10.37 | 0.214 |
Values are presented as mean±standard deviation.
MPFF, micronized purified flavonoid fraction.
Table 3.
Efficacy of treatment at 3 months (per-protocol population analysis, n=108)
| Parameter | MPFF+escin group (n=57) | MPFF+placebo group (n=51) | P-value |
|---|---|---|---|
| Pretreatment SHSHD | 10 (9 to 14) | 10 (9 to 13) | 0.852 |
| Difference in SHSHD | |||
| After 1 mo | 5 (3 to 9) | 3 (–1 to 5) | <0.001 |
| After 3 mo | 6 (4 to 9) | 4 (1 to 6]) | 0.003 |
Values are presented as median (interquartile range).
MPFF, micronized purified flavonoid fraction; SHSHD, Short Health Scale for Hemorrhoids.
The primary endpoint, recurrence of bleeding within 90 days after hemostasis, was evaluated at 1 and 3 months. At 1 month, no patients (0%) in the MPFF+escin group experienced recurrent bleeding, compared with 4 patients (7.8%) in the MPFF+placebo group. At 3 months, recurrence was observed in 4 patients (7.0%) in the MPFF+escin group and 12 patients (23.5%) in the MPFF+placebo group. Analyses were conducted in the PP population, which comprised 57 patients in the MPFF+escin group and 51 patients in the MPFF+placebo group after exclusion of 12 acute-phase nonresponders (3 and 9 patients, respectively). Kaplan-Meier analysis demonstrated a significantly lower recurrence rate in the MPFF+escin group (P=0.009) (Fig. 2). The recurrence-free survival curve for the placebo group declined sharply after day 45, whereas the MPFF+escin group maintained higher recurrence-free survival throughout the follow-up period. A similar number of patients remained at risk in both groups over time, supporting the validity of the comparison.
Fig. 2.
Kaplan-Meier recurrence analysis of bleeding hemorrhoids. MPFF, micronized purified flavonoid fraction; HR, hazard ratio; CI, confidence interval.
In the ITT sensitivity analysis, in which acute-phase nonresponders were classified as early recurrences, the between-group difference remained statistically significant (P=0.002) (Supplementary Fig. 1), further confirming the robustness of the treatment effect. These findings indicate that exclusion of acute-phase failures in the PP analysis did not materially influence the estimated benefit of combination therapy.
With respect to quality-of-life outcomes, both groups demonstrated substantial improvement in SHSHD scores at 1 and 3 months compared with baseline. However, the MPFF+escin group exhibited significantly greater improvement at both time points (median difference in SHSHD score at 1 month: 5 [IQR, 3 to 9] vs. 3 [IQR, −1 to 5], P<0.001; at 3 months: 6 [IQR, 4 to 9] vs. 4 [IQR, 1 to 6], P=0.003), indicating greater relief of hemorrhoid-related symptoms and improved overall well-being.
No adverse events were reported in either treatment group during the study period. Active surveillance at all scheduled visits and interim contacts confirmed the absence of symptoms such as headache, vertigo, gastrointestinal discomfort, or rash. No patients discontinued treatment because of adverse effects, and no serious adverse events occurred, indicating that the combination therapy was safe and well tolerated.
Overall, these results indicate that the addition of escin to MPFF therapy provides clinically meaningful benefits, including faster hemostasis, reduced recurrence of bleeding, and greater improvement in quality of life over a 3-month follow-up period in patients with acute internal hemorrhoids.
DISCUSSION
The findings of this study demonstrate that combining MPFF with escin significantly reduces the recurrence of bleeding in patients with acute internal hemorrhoids compared with MPFF monotherapy. The substantially lower recurrence rates observed at both 1 month (0% vs. 7.8%) and 3 months (7.0% vs. 23.5%) in the combination therapy group indicate a sustained therapeutic benefit that extends beyond the acute treatment phase.
Our findings regarding early control of bleeding and mass effect are particularly noteworthy and are consistent with recent evidence. In a randomized controlled trial of 120 patients, Sanmee et al. [11] demonstrated that combination therapy with MPFF and escin achieved bleeding cessation significantly faster than MPFF alone (median, 2 days vs. 4 days; P<0.001). Their study also reported superior resolution of mass effect in grade 2 hemorrhoids with combination therapy (median, 4 days vs. 5 days; P=0.002). These results corroborate our observations and suggest that the synergistic effects of MPFF and escin contribute to more rapid symptom relief. Particularly compelling was their finding that combination therapy achieved higher rates of bleeding cessation within 7 days (93.3% vs. 86.7%) and greater resolution of mass effect in grade 2 hemorrhoids (87.5% vs. 60.0%; P=0.029), indicating enhanced therapeutic efficacy across multiple clinically relevant outcomes.
These results build upon previous research demonstrating the effectiveness of MPFF in managing hemorrhoidal symptoms [16]. Godeberge et al. [17] reported that MPFF improves venous tone and reduces capillary permeability, leading to decreased hemorrhoidal bleeding. Our study extends these findings by showing that the addition of escin further enhances these therapeutic effects. This synergistic benefit may be explained by escin’s complementary mechanisms of action, including its antiedematous and anti-inflammatory properties [18], as described by Ezberci and Ünal [9] in their comprehensive review of natural compounds used in hemorrhoid management.
The significant improvement in quality of life, as measured by the SHSHD, further supports the superiority of combination therapy. The markedly lower posttreatment SHSHD scores in the MPFF+escin group (median difference in SHSHD score at 3 months: 6 [IQR, 4 to 9] vs. 4 [IQR, 1 to 6]; P=0.003) indicate improved symptom control and a reduced disease burden. This improvement in patient-reported outcomes is particularly meaningful given the substantial impact of hemorrhoidal disease on daily functioning and overall well-being, as highlighted by Rørvik et al. [19] in their quality-of-life analysis of patients with hemorrhoids.
The safety profile of the combination therapy was favorable, with no reported adverse events such as headache, vertigo, or allergic reactions. This observation is consistent with the established safety records of both MPFF and escin [20]. In addition, the high medication adherence rates observed in both treatment groups suggest that the combination regimen is well tolerated and acceptable to patients.
One particularly interesting aspect of our findings is the significantly lower risk of recurrent bleeding at 3 months in the combination therapy group. Kaplan–Meier analysis demonstrated a significantly reduced recurrence compared with MPFF monotherapy (P=0.009). This marked reduction in recurrence risk suggests that combination therapy may favorably influence the natural course of the disease, potentially through sustained effects on underlying pathophysiological mechanisms [15].
In this study, recurrence was analyzed using the PP population because only patients who achieved hemostasis during the acute phase could be meaningfully evaluated for new-onset bleeding. To enhance transparency, an ITT sensitivity analysis was also performed, in which acute-phase nonresponders were classified as immediate recurrences. The results of this analysis were consistent with those of the PP analysis, confirming that exclusion of acute-phase failures did not bias the estimated treatment effect. This concordance between analytic approaches strengthens the internal validity and reliability of the observed benefit of combination therapy.
Several limitations of this study should be acknowledged, including the relatively short follow-up period of 3 months and the restriction to patients with grade 1 and 2 hemorrhoids. Future studies should consider longer follow-up durations and include patients with more advanced disease stages. In addition, further investigation into the molecular mechanisms underlying the synergistic effects of MPFF and escin could provide valuable insights for optimizing combination therapy strategies.
The present findings have important clinical implications for the management of acute internal hemorrhoids. The superior efficacy of combination therapy in both rapid symptom control and prevention of recurrence suggests that it may represent a useful treatment option for patients with grade 1 and 2 disease. The observed improvements in quality of life and the favorable safety profile further support its potential clinical applicability.
In conclusion, this randomized controlled trial provides evidence that combining MPFF with escin is more effective than MPFF alone in improving short-term symptom control and reducing recurrence of hemorrhoidal bleeding. The rapid achievement of hemostasis and resolution of mass effect, together with sustained reductions in recurrence and an acceptable safety profile, suggest that this combination may represent a valuable addition to the medical management of hemorrhoidal disease. Further multicenter studies with larger sample sizes and longer follow-up periods are warranted to confirm and extend these findings.
Footnotes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
This study was partially supported by the Faculty of Medicine, Chiang Mai University.
Author contributions
Conceptualization: WV, PS, SJ; Data curation: WV, PS; Formal analysis: WV; Funding acquisition: PS, SS; Investigation: WV, SS; Methodology: WV, SS, SJ; Project administration: WV, ES; Resources: SJ; Software: SS; Supervision: all authors; Validation: WV, SS, ES, SJ; Visualization: WV, PS, ES; Writing–original draft: WV, ES, SJ; Writing–review & editing: WV, PS, SS, SJ. All authors read and approved the final manuscript.
Supplementary materials
Demographic data of all patients (ITT analysis, n=120)
Response to treatment in hemorrhoid disease in the acute phase (ITT analysis, n=120)
Kaplan-Meier intention-to-treat recurrence analysis of bleeding hemorrhoids.
Supplementary materials are available from https://doi.org/10.3393/ac.2025.01207.0172.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Demographic data of all patients (ITT analysis, n=120)
Response to treatment in hemorrhoid disease in the acute phase (ITT analysis, n=120)
Kaplan-Meier intention-to-treat recurrence analysis of bleeding hemorrhoids.