Anti-inflammatory effects of diosmin as adjunctive therapy in acute deep vein thrombosis: Impact on venous recanalization,quality of life and post-thrombotic syndrome

Abstract

Background

Deep vein thrombosis (DVT) is associated with inflammatory response that may contribute to incomplete venous recanalization and post-thrombotic syndrome (PTS). Diosmin, a venoactive flavonoid, may provide additional benefit when combined with standard anticoagulation.

Objectives

To evaluate whether adjunctive diosmin therapy reduces inflammation, improves recanalization, enhances quality of life, and decreases PTS severity in acute DVT.

Methods

This retrospective cohort study analyzed 612 patients with acute proximal DVT receiving anticoagulation alone (control, n = 298) or anticoagulation plus diosmin 600 mg daily (n = 314). Propensity score matching (1:1) yielded 230 pairs. C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR) were assessed at baseline and day 30. Recanalization was evaluated by duplex ultrasound at 3 and 12 months. Quality of life was measured using VEINES-QOL, and PTS was assessed using the Villalta scale at 12 months.

Results

The diosmin group showed greater reductions in CRP (−13.9 vs −11.8 mg/L; p = 0.038), NLR (−1.72 vs −1.43; p = 0.019), and ESR (−17.2 vs −14.1 mm/hr; p = 0.031) at day 30. Complete recanalization rates were higher with diosmin at 12 months (91.3% vs 76.5%; p < 0.001). VEINES-QOL scores were better in the diosmin group at 12 months (71.8 ± 13.2 vs 66.9 ± 12.6; p = 0.024). While overall PTS incidence was similar (14.9% vs 16.3%; p = 0.72), moderate-to-severe PTS was less frequent with diosmin among PTS patients (21% vs 40%; Fisher’s exact p = 0.062), suggesting a trend that requires confirmation.

Conclusions

Adjunctive diosmin was associated with greater inflammatory marker reductions, improved recanalization, and better quality of life. A trend toward reduced PTS severity was observed but should be interpreted cautiously given the small number of events. Prospective randomized trials are needed to confirm these findings.

Keywords

deep vein thrombosis diosmin post-thrombotic syndrome venous recanalization quality of life inflammatory markers C-reactive protein

Introduction

Deep vein thrombosis (DVT) affects approximately 1–2 per 1,000 individuals annually and represents a major cause of morbidity and mortality worldwide.^1,2 Despite adequate anticoagulation, 20–50% of patients develop post-thrombotic syndrome (PTS), a chronic condition characterized by leg pain, swelling, skin changes, and in severe cases, venous ulceration.^3,4 The pathophysiology of PTS involves persistent venous obstruction, valvular incompetence, and chronic inflammation leading to venous hypertension and tissue damage.⁵

Inflammation plays a central role in DVT pathogenesis and resolution. Elevated inflammatory markers, including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR), have been associated with thrombus burden, delayed recanalization, and increased PTS risk.^6–8 Consequently, therapeutic strategies targeting inflammation may improve outcomes beyond standard anticoagulation alone.

Diosmin is a naturally occurring flavonoid glycoside with well-documented venoactive and anti-inflammatory properties.^9,10 It inhibits leukocyte adhesion, reduces endothelial activation, decreases capillary permeability, and improves venous tone.^11–13 While diosmin is widely used in chronic venous insufficiency,¹⁴ its role in acute DVT management remains insufficiently explored. A recent systematic review of randomized controlled trials identified preliminary evidence supporting diosmin and micronized purified flavonoid fraction (MPFF) as adjunctive treatments to anticoagulation for the prevention of PTS, although the quality of available evidence was variable,¹⁵ and a comprehensive review of venoactive compounds in chronic venous disease further supports their pharmacological rationale.¹⁶

The present study aimed to evaluate whether adjunctive diosmin therapy in patients with acute proximal DVT reduces inflammatory markers, improves venous recanalization, enhances health-related quality of life, and decreases PTS incidence and severity compared to standard anticoagulation alone.

Methods

Study design and population

This retrospective cohort study was conducted at a university vascular surgery clinic. We reviewed medical records of consecutive patients diagnosed with acute proximal DVT between January 2018 and December 2023. Reporting follows the STROBE recommendations for observational cohort studies.¹⁷

Inclusion criteria were: (1) age ≥18 years; (2) objectively confirmed acute proximal DVT (popliteal vein or above) by compression duplex ultrasonography; (3) symptom duration ≤14 days; and (4) initiation of therapeutic anticoagulation within 24 h of diagnosis. Exclusion criteria included: (1) isolated distal DVT; (2) active malignancy; (3) severe renal impairment (eGFR <30 mL/min); (4) pregnancy or breastfeeding; (5) contraindication to diosmin; (6) prior use of venoactive drugs within 3 months; (7) surgical thrombectomy, pharmacomechanical catheter-directed thrombolysis, or any other interventional thrombus removal procedure at any time during the study period¹⁸; (8) symptomatic pulmonary embolism at presentation requiring escalated treatment; (9) ongoing therapeutic anticoagulation for other indications (e.g., atrial fibrillation, mechanical heart valves) prior to the index DVT; and (10) inability to attend follow-up visits.

The study was approved by the institutional ethics committee and conducted in accordance with the Declaration of Helsinki. The requirement for individual informed consent was waived due to the retrospective nature of the study.

Treatment groups

Patients were classified into two groups based on the treatment received at the discretion of the attending physician:

Control group: Standard therapeutic anticoagulation alone, consisting of either rivaroxaban 15 mg twice daily for 21 days followed by 20 mg once daily, or low-molecular-weight heparin bridged to warfarin (target INR 2.0–3.0). For patients receiving LMWH/warfarin, INR was monitored at least weekly during the first month and monthly thereafter, with a target therapeutic range of 2.0–3.0.

Diosmin group: Standard anticoagulation plus diosmin 600 mg (two 300 mg tablets) once daily for 6 months.

All patients received compression therapy with graduated compression stockings (30–40 mmHg) and were encouraged to mobilize early.

Propensity score matching

To minimize selection bias inherent to the non-randomized design, we performed 1:1 nearest-neighbor propensity score matching without replacement. The propensity score was estimated using logistic regression with the following covariates: age, sex, body mass index (BMI), DVT location (popliteal, femoropopliteal, or iliofemoral), baseline C-reactive protein (CRP), baseline neutrophil-to-lymphocyte ratio (NLR), anticoagulation type (DOAC vs LMWH/VKA), hypertension, diabetes mellitus, chronic venous insufficiency, previous venous thromboembolism, first DVT episode, and limb circumference difference.

From 612 enrolled patients (298 allocated to control, 314 allocated to diosmin), propensity score matching yielded 230 matched pairs (460 patients) for analysis. Matching quality was assessed using standardized mean differences (SMD), with values <0.10 considered indicative of adequate balance.

Outcomes

Primary outcome: Incidence and severity of PTS at 12 months, assessed using the Villalta scale. PTS was defined as a Villalta score ≥5, with mild PTS defined as scores 5–9, moderate PTS as scores 10–14, and severe PTS as scores ≥15 or presence of venous ulcer. For patients with a history of previous ipsilateral DVT, baseline Villalta scores were recorded to distinguish pre-existing PTS from new-onset PTS. The 12-months PTS assessment was interpreted in the context of the baseline score.

Secondary outcomes: (1) Change in inflammatory markers (CRP, NLR, ESR, D-dimer) from baseline to day 30. Reference ranges at our institution were: CRP <5.0 mg/L; ESR <20 mm/hr (males) and <25 mm/hr (females); NLR 1.0–3.0; D-dimer <0.50 µg/mL; IL-6 <7.0 pg/mL. (2) Complete or near-complete venous recanalization (≥90% lumen patency) at 3 and 12 months by duplex ultrasound. (3) Health-related quality of life measured by the VEINES-QOL questionnaire at baseline, 1, 3, 6, and 12 months. (4) Safety outcomes including major bleeding, clinically relevant non-major bleeding, recurrent VTE, and adverse events attributed to diosmin.

Statistical analysis

Continuous variables are presented as mean ± standard deviation or median (interquartile range) as appropriate. Categorical variables are expressed as frequencies and percentages. Between-group comparisons in the matched cohort were performed using paired t-tests or Wilcoxon signed-rank tests for continuous variables, treating matched pairs as dependent observations. For binary categorical outcomes in the full matched cohort (e.g., PTS incidence, recanalization), McNemar’s test was used to account for the paired structure. For comparisons within subsets where the matched-pair structure was no longer preserved (e.g., PTS severity among PTS patients only), chi-square or Fisher’s exact tests were used; Fisher’s exact test was applied when expected cell counts were below 5.

Multivariate logistic regression was performed to identify independent predictors of moderate-to-severe PTS, adjusting for baseline characteristics. Logistic regression was fitted in the matched sample without explicit modeling of matched pairs; this is further discussed in the Limitations section. Patients were analyzed according to the initially prescribed treatment (intention-to-treat principle), irrespective of subsequent diosmin discontinuation.

Treatment adherence was assessed by patient self-report at each follow-up visit. Anticoagulation adherence was defined as intake of ≥80% of prescribed doses. Diosmin adherence was recorded as the proportion of patients reporting regular intake at 3- and 6-months visits. Compression stocking adherence was defined as use on ≥5 days per week.

All outcome analyses were conducted in the propensity score–matched cohort of 230 pairs. A two-sided p-value <0.05 was considered statistically significant. Statistical analyses were performed using R version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Study population and baseline characteristics

From 847 patients assessed for eligibility, 612 met inclusion criteria and were enrolled (298 control, 314 diosmin). After propensity score matching, 230 pairs (460 patients) were included in the analysis. All subsequent results refer to the matched cohort unless otherwise specified (Figure 1).

Figure 1.

Study flow diagram.

Baseline characteristics were well balanced between groups after matching (Table 1). Mean age was 56.8 ± 14.3 years in the control group and 56.1 ± 13.9 years in the diosmin group. Males comprised 54.8% and 53.0% of patients, respectively. Iliofemoral DVT was present in 20.9% of patients in both groups. All standardized mean differences were <0.10 after matching, indicating adequate covariate balance (Supplemental Figure S1).

Table 1.

Baseline characteristics of the propensity score–matched cohort.

Characteristic	Control Group (n = 230)	Diosmin Group (n = 230)	SMD
Demographics
Age, years (mean ± SD)	56.814.3	56.113.9	0.05
Male sex, n (%)	126 (54.8)	122 (53.0)	0.04
BMI, kg/m² (mean ± SD)	28.64.7	28.44.5	0.04
DVT characteristics
DVT location, n (%)
Popliteal	86 (37.4)	84 (36.5)	0.02
Femoropopliteal	96 (41.7)	98 (42.6)	0.02
Iliofemoral	48 (20.9)	48 (20.9)	<0.01
First DVT episode, n (%)	189 (82.2)	192 (83.5)	0.03
Comorbidities
Hypertension, n (%)	98 (42.6)	94 (40.9)	0.04
Diabetes mellitus, n (%)	38 (16.5)	36 (15.7)	0.02
Chronic venous insufficiency, n (%)	52 (22.6)	56 (24.3)	0.04
Previous VTE, n (%)	41 (17.8)	38 (16.5)	0.03
Anticoagulation
Anticoagulation type, n (%)
DOAC	168 (73.0)	172 (74.8)	0.04
LMWH/VKA	62 (27.0)	58 (25.2)	0.04
Baseline inflammatory markers
CRP, mg/L (mean ± SD)	18.4 ± 6.2	18.1 ± 5.9	0.05
NLR (mean ± SD)	4.21 ± 1.18	4.16 ± 1.14	0.04
ESR, mm/hr (mean ± SD)	32.4 ± 12.1	31.8 ± 11.6	0.05
Fibrinogen, g/L (mean ± SD)	4.52 ± 0.94	4.48 ± 0.91	0.04
D-dimer, μg/mL (median, IQR)	2.84 (1.62–4.38)	2.76 (1.58–4.21)	0.06
Baseline Clinical parameters
VAS pain score (mean ± SD)	6.4 ± 1.8	6.6 ± 1.9	0.08
Limb circumference difference, cm (mean ± SD)	3.2 ± 1.1	3.4 ± 1.2	0.09
VEINES-QOL score (mean ± SD)	43.2 ± 9.1	42.8 ± 8.9	0.04

Data are presented as mean ± SD, median (IQR), or n (%), as appropriate.

BMI: body mass index; CRP: C-reactive protein; DOAC: direct oral anticoagulant; DVT: deep vein thrombosis; ESR: erythrocyte sedimentation rate; IQR: interquartile range; LMWH: low-molecular-weight heparin; NLR: neutrophil-to-lymphocyte ratio; SD: standard deviation; SMD: standardized mean difference; VAS: visual analog scale; VEINES-QOL: Venous Insufficiency Epidemiological and Economic Study Quality of Life; VKA: vitamin K antagonist; VTE: venous thromboembolism.

SMD <0.10 indicates adequate balance between groups after propensity score matching.

Treatment adherence was high in both groups. Anticoagulation adherence (≥80% of prescribed doses) was 94.8% in the control group and 95.2% in the diosmin group. Diosmin adherence was 87.4% at 3 months and 81.2% at 6 months. Compression stocking adherence (≥5 days/week) was 78.3% in the control group and 80.9% in the diosmin group at 3 months, declining to 62.1% and 64.7%, respectively, at 12 months.

Inflammatory markers

Both groups showed significant reductions in inflammatory markers from baseline to day 30 (Table 2). However, the diosmin group demonstrated significantly greater reductions in CRP, NLR, and ESR compared to controls (Figure 2).

Table 2.

Inflammatory markers at baseline and day 30 in the matched cohort.

Parameter	Control group (n = 230)			Diosmin group (n = 230)			Between-group p-value^a
Parameter	Baseline	Day 30	p ^b	Baseline	Day 30	p ^b	Between-group p-value^a
CRP, mg/L	18.4 ± 6.2	6.6 ± 2.4	<0.001	18.1 ± 5.9	4.2 ± 1.8	<0.001	0.038
ΔCRP	−11.8 ± 5.1			−13.9 ± 4.8
NLR	4.21 ± 1.18	2.78 ± 0.72	<0.001	4.16 ± 1.14	2.44 ± 0.64	<0.001	0.019
ΔNLR	−1.43 ± 0.58			−1.72 ± 0.61
ESR, mm/hr	32.4 ± 12.1	18.3 ± 7.8	<0.001	31.8 ± 11.6	14.6 ± 6.2	<0.001	0.031
ΔESR	−14.1 ± 7.2			−17.2 ± 6.8
Fibrinogen, g/L	4.52 ± 0.94	3.42 ± 0.68	<0.001	4.48 ± 0.91	3.18 ± 0.62	<0.001	0.068
D-dimer, μg/mL^c	2.84 (1.62–4.38)	0.68 (0.42–1.12)	<0.001	2.76 (1.58–4.21)	0.54 (0.36–0.92)	<0.001	0.042
IL-6 subset
IL-6, pg/mL^d	12.4 ± 3.8	8.9 ± 2.8	<0.001	12.1 ± 3.6	7.1 ± 2.2	<0.001	0.016

Data are presented as mean ± SD unless otherwise indicated.

CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IL-6 = interleukin-6; NLR: neutrophil-to-lymphocyte ratio.

Institutional reference ranges: CRP <5.0 mg/L; ESR <20 mm/hr (males), <25 mm/hr (females); NLR 1.0–3.0; D-dimer <0.50 µg/mL; IL-6 <7.0 pg/mL.

^aBetween-group comparisons were performed using the paired t-test on matched pairs (i.e., the difference in day 30 values within each matched pair was tested against zero).

^bWithin-group comparison (baseline vs day 30) using paired t-test.

^cData presented as median (interquartile range); p-values calculated using Wilcoxon signed-rank test.

^dIL-6 was measured in a subset of 98 patients (47 control, 51 diosmin) enrolled in a concurrent biomarker substudy.

Figure 2.

Change in inflammatory markers from baseline to day 30. Bars represent mean change; error bars represent 95% confidence intervals. CRP = C-reactive protein; NLR = neutrophil-to-lymphocyte ratio; ESR = erythrocyte sedimentation rate. *p < 0.05 for between-group comparison.

Mean CRP reduction was greater with diosmin (−13.9 vs −11.8 mg/L; between-group difference in change −2.1 mg/L, 95% CI −3.0 to −1.2; p = 0.038). Similarly, NLR showed greater reduction with diosmin (−1.72 vs −1.43; difference −0.29, 95% CI −0.47 to −0.11; p = 0.019), as did ESR (−17.2 vs −14.1 mm/hr; difference −3.1, 95% CI −5.4 to −0.8; p = 0.031). D-dimer reduction was also greater with diosmin (−2.22 vs −2.16 µg/mL; difference −0.06; p = 0.042).

In a subset of 98 consenting patients during a predefined enrollment period, IL-6 levels were measured. The diosmin group showed greater IL-6 reduction (−5.0 vs −3.5 pg/mL; between-group difference −1.5 pg/mL; p = 0.016).

Venous recanalization

Complete or near-complete recanalization rates were significantly higher in the diosmin group at both time points. At 3 months, recanalization was achieved in 79.1% of diosmin patients versus 68.7% of controls (p = 0.012). At 12 months, recanalization rates were 91.3% versus 76.5% (p < 0.001).

The difference was particularly pronounced in patients with iliofemoral DVT, where 12-months recanalization rates were 85.6% in the diosmin group versus 67.4% in controls (p = 0.003) (Figure 3).

Figure 3.

Complete or near-complete venous recanalization rates (≥90% lumen patency) at 3 and 12 months. Bars represent proportions; error bars represent 95% confidence intervals. **p < 0.01, ***p < 0.001.

Quality of life

VEINES-QOL scores improved in both groups over the 12-months follow-up period. At baseline, scores were similar (42.8 ± 8.9 diosmin vs 43.2 ± 9.1 control; p = 0.68). However, the diosmin group showed significantly better scores from month 3 onward.

At 12 months, VEINES-QOL scores were 71.8 ± 13.2 in the diosmin group versus 66.9 ± 12.6 in controls (difference 4.9 points, 95% CI 2.1–7.7; p = 0.024). This difference exceeds the minimal clinically important difference (MCID) of 4 points for VEINES-QOL. Twelve-month VEINES-QOL was available for 378 patients (188 control, 190 diosmin) (Figure 4).

Figure 4.

VEINES-QOL scores over 12-months follow-up. Data points represent mean scores; error bars represent 95% confidence intervals. *p < 0.05, **p < 0.01 for between-group comparison.

Post-thrombotic syndrome

Villalta assessment at 12 months was available for 372 patients (184 control, 188 diosmin; 80.9% retention). Overall PTS incidence was similar between groups: 16.3% (30/184) in controls versus 14.9% (28/188) in the diosmin group (p = 0.72) (Figure 5).

Figure 5.

Post-thrombotic syndrome at 12 months. (a) Overall PTS incidence (McNemar test, p = 0.72). (b) PTS severity distribution among patients who developed PTS (χ² p = 0.039; Fisher’s exact p = 0.062).

However, among patients who developed PTS, the severity distribution differed: moderate-to-severe PTS was observed in 40% (12/30) of controls versus 21% (6/28) of diosmin-treated patients (χ² p = 0.039; Fisher’s exact p = 0.062). Given the small number of PTS events, this difference should be interpreted cautiously as a trend suggesting potentially reduced PTS severity with diosmin. On multivariate analysis, diosmin treatment was associated with reduced odds of moderate-to-severe PTS (OR 0.61, 95% CI 0.39–0.94; p = 0.026) (Table 3). However, with only 18 moderate-to-severe PTS events and 8 predictor variables, the events-per-variable ratio (≈2 EPV) is well below the recommended minimum of 10, raising concerns about model stability and the precision of estimates. A sensitivity analysis using a reduced model with three key predictors (diosmin treatment, DVT location, and 3-months recanalization) yielded consistent results (OR 0.58, 95% CI 0.36–0.96); however, these exploratory findings require validation in larger cohorts.

Table 3.

Multivariate logistic regression analysis in the matched cohort: Predictors of moderate-to-severe post-thrombotic syndrome at 12 months.

Full Model (8 predictors)
Variable	Odds Ratio	95% CI	p-value
Diosmin treatment (vs. control)	0.61	0.39–0.94	0.026
Age (per year increase)	1.02	0.99–1.05	0.184
Male sex (vs. female)	1.18	0.72–1.94	0.512
BMI (per kg/m² increase)	1.04	0.98–1.11	0.216
Iliofemoral DVT (vs. non-iliofemoral)	2.68	1.59–4.52	<0.001
Baseline CRP (per mg/L increase)	1.08	1.02–1.14	0.008
Poor 3-month recanalization (<70%)	3.24	2.01–5.22	<0.001
Anticoagulation type (LMWH/VKA vs. DOAC)	1.22	0.74–2.01	0.438

Sensitivity Analysis: Reduced Model (3 predictors)
Variable	Odds Ratio	95% CI	p-value
Diosmin treatment (vs. control)	0.58	0.36–0.96	0.034
Iliofemoral DVT (vs. non-iliofemoral)	2.84	1.72–4.68	<0.001
Poor 3-month recanalization (<70%)	3.41	2.14–5.44	<0.001

Analysis includes 372 patients (81%) with complete 12-months Villalta assessment (184 control, 188 diosmin).

Moderate-to-severe PTS was defined as Villalta score ≥10 or presence of a venous ulcer.

Bold text indicates statistically significant predictors (p < 0.05).

DVT location was coded as a binary variable (iliofemoral vs non-iliofemoral, i.e., femoropopliteal or popliteal) given that isolated distal DVT was an exclusion criterion.

Note. The full model includes 18 moderate-to-severe PTS events with 8 predictor variables (events-per-variable ratio ≈2 EPV), which is below the recommended minimum of 10 EPV. Results should be considered exploratory. A sensitivity analysis using a reduced model with 3 key predictors (6 EPV) yielded consistent results.

BMI: body mass index; CI: confidence interval; CRP: C-reactive protein; DOAC: direct oral anticoagulant; DVT: deep vein thrombosis; EPV: events per variable; LMWH: low-molecular-weight heparin; PTS: post-thrombotic syndrome; VKA: vitamin K antagonist.

Safety

Safety outcomes were similar between groups (Table 4). Major bleeding occurred in 1 patient (0.4%) per group. Clinically relevant non-major bleeding rates were 2.2% in controls and 2.6% in the diosmin group (p = 0.761). Recurrent DVT occurred in 1.7% of controls and 1.3% of diosmin patients (p = 0.703).

Table 4.

Safety outcomes in the matched cohort.

Outcome	Control Group (n = 230)	Diosmin Group (n = 230)	p-value
Adverse Events
Any adverse event, n (%)	24 (10.4)	26 (11.3)	0.762
Gastrointestinal symptoms, n (%)	9 (3.9)	11 (4.8)	0.648
Dyspepsia	5 (2.2)	6 (2.6)	0.761
Nausea	4 (1.7)	5 (2.2)	0.736
Headache, n (%)	6 (2.6)	7 (3.0)	0.779
Skin rash, n (%)	3 (1.3)	2 (0.9)	0.654
Treatment discontinuation, n (%)	2 (0.9)	2 (0.9)	1.000
Bleeding events
Any bleeding event, n (%)	8 (3.5)	9 (3.9)	0.804
Major bleeding^a, n (%)	1 (0.4)	1 (0.4)	1.000
Clinically relevant non-major bleeding^b, n (%)	5 (2.2)	6 (2.6)	0.761
Minor bleeding, n (%)	2 (0.9)	2 (0.9)	1.000
Thromboembolic events
Recurrent DVT, n (%)	4 (1.7)	3 (1.3)	0.703
Pulmonary embolism, n (%)	2 (0.9)	1 (0.4)	0.562
All-cause mortality, n (%)	0 (0)	0 (0)	—

Data are presented as n (%). p-values calculated using χ² or Fisher’s exact test, as appropriate.

There were no significant differences in adverse events, bleeding, or thromboembolic events between groups.

DVT = deep vein thrombosis.

^aMajor bleeding defined according to International Society on Thrombosis and Haemostasis (ISTH) criteria.

^bClinically relevant non-major bleeding defined as overt bleeding not meeting criteria for major bleeding but requiring medical attention, unscheduled contact with physician, or treatment interruption.

No serious adverse events were attributed to diosmin. Mild gastrointestinal complaints (dyspepsia, nausea) were reported by 4.8% of diosmin patients, leading to treatment discontinuation in 0.9%. Importantly, no increase in bleeding events was observed with combined anticoagulation and diosmin therapy.

Discussion

This propensity score–matched cohort study suggests that adjunctive diosmin therapy in patients with acute proximal DVT may be associated with enhanced anti-inflammatory effects, improved venous recanalization, and better quality of life. Exploratory analyses suggested a trend toward reduced severity of post-thrombotic syndrome, although the small number of PTS events limits the strength of this conclusion.

The observed anti-inflammatory effects are consistent with findings from prior clinical studies of venoactive flavonoids. Shoab et al. demonstrated that micronized purified flavonoid fraction reduced leukocyte adhesion molecule expression in patients with chronic venous disease,¹² and a recent systematic review identified preliminary evidence from randomized trials suggesting that diosmin and MPFF as adjuncts to anticoagulation may reduce inflammatory markers and improve clinical outcomes in DVT.¹⁵ Importantly, while the diosmin group showed statistically greater reductions in inflammatory markers, the clinical significance of these between-group differences should be interpreted with caution. By day 30, CRP in the diosmin group (4.2 ± 1.8 mg/L) was near the upper limit of normal (<5.0 mg/L), while controls (6.6 ± 2.4 mg/L) remained mildly elevated. Similarly, NLR and ESR improved substantially in both groups. The observed differences, although consistent across multiple markers, are modest in absolute magnitude and both groups trended toward normalization. The D-dimer reduction, although statistically significant, was numerically small (between-group difference 0.06 µg/mL) and of uncertain clinical relevance.

Improved venous recanalization with diosmin is supported by mechanistic evidence. Inflammation impairs endogenous fibrinolysis and promotes fibrotic transformation of thrombus, leading to persistent obstruction.¹⁹ By reducing inflammation, diosmin may create a more favorable environment for physiological thrombus resolution. A recent systematic review by Gloviczki et al. identified preliminary evidence supporting diosmin and MPFF as adjunctive treatments to anticoagulation for improving recanalization and potentially reducing PTS.¹⁵

The recanalization rates and PTS incidence observed in this study are more favorable than those reported in several historical cohorts. This likely reflects the selected nature of our study population, including early presentation (≤14 days of symptom onset), predominant DOAC use (73–75%), exclusion of active malignancy, and consistent compression therapy. For iliofemoral DVT specifically, the 12-months recanalization rate in the control group (67.4%) exceeds the 40–50% typically reported in earlier series, many of which included patients treated predominantly with VKA without consistent compression. The broader adoption of DOACs, which have been associated with improved recanalization in recent comparative studies, may also contribute to these favorable outcomes. These favorable baseline outcomes should be considered when interpreting the incremental benefit of diosmin.

The quality of life benefits observed with diosmin are clinically meaningful. The 4.9-point difference in VEINES-QOL at 12 months exceeds the established MCID, indicating perceptible improvement from the patient perspective. These benefits likely reflect both the objective improvements in venous function and diosmin’s direct effects on venous symptoms such as leg heaviness and discomfort.

While overall PTS incidence was similar between groups, the exploratory analysis of PTS severity suggested a possible signal toward less moderate-to-severe PTS with diosmin (21% vs 40% among PTS patients). However, this finding should be interpreted with considerable caution: it is based on a small number of events (n = 58 PTS patients, 18 moderate-to-severe), the Fisher’s exact p-value (p = 0.062) does not reach conventional significance, and the multivariate model should be considered hypothesis-generating due to the low events-per-variable ratio. A consistent direction of effect was observed across the chi-square test, the multivariate model, and the sensitivity analysis, which may suggest that diosmin attenuates PTS severity; however, this remains an exploratory finding that requires confirmation in adequately powered prospective studies before any clinical conclusions can be drawn.

The interpretation of PTS outcomes in this study warrants careful consideration of the potential confounding effect of compression therapy and venoactive drugs on the Villalta scale. The landmark SOX trial (Kahn et al., Lancet 2014) demonstrated that elastic compression stockings did not prevent PTS as defined by the Villalta scale, challenging previous open-label studies.²⁰ Since the Villalta scale incorporates subjective symptoms (pain, heaviness, pruritus) alongside objective signs, interventions that alleviate venous symptoms — such as compression stockings or venoactive drugs like diosmin — may improve Villalta scores through symptomatic relief rather than through true prevention of post-thrombotic venous pathology. This distinction is particularly relevant to our findings, as the improved quality of life and PTS severity trend observed with diosmin could reflect its known venoactive properties (reduction of edema, improvement in venous tone) rather than a direct effect on thrombus-mediated venous wall damage. Notably, the same argument applies to compression therapy used in both groups: the observed low PTS rates may partly reflect symptomatic improvement from compression rather than structural PTS prevention. Future studies should incorporate objective measures of venous function, such as ambulatory venous pressure or air plethysmography, alongside clinical scales to better differentiate symptomatic improvement from structural PTS prevention.

The safety profile of diosmin in this study was reassuring. No increase in bleeding was observed despite concurrent anticoagulation, consistent with diosmin’s mechanism of action which does not involve hemostatic pathways. The low rate of gastrointestinal side effects and treatment discontinuation supports tolerability in clinical practice.

Limitations

Several limitations warrant consideration. First, the retrospective design introduces potential for selection bias and unmeasured confounding. Although propensity score matching achieved good covariate balance, residual confounding by indication is possible, particularly regarding symptom burden (e.g., pain and edema), which was not fully captured in the propensity model.

Second, the IL-6 substudy included consenting patients during a predefined period and may be subject to selection bias. Third, loss to follow-up (approximately 19% for PTS assessment) may have introduced attrition bias, although baseline characteristics did not differ significantly between completers and non-completers.

Fourth, while paired tests and McNemar’s test were used for matched-cohort comparisons, comparisons within subsets (e.g., PTS severity among PTS patients) used standard chi-square or Fisher’s exact tests because the matched-pair structure was no longer preserved. Additionally, logistic regression was fitted without explicit modeling of matched pairs (e.g., conditional logistic regression or clustered standard errors), which may slightly affect standard error estimates. Fifth, the low number of moderate-to-severe PTS events limits the reliability of the multivariate analysis, as discussed above. Sixth, the single-center design may limit generalizability. Seventh, treatment adherence was assessed by self-report, which may overestimate actual compliance. Finally, blinding was not possible given the retrospective nature of the study. Taken together, all results should be interpreted in the context of the retrospective observational design, the possibility of residual confounding despite propensity score matching, and the limited number of moderate-to-severe PTS events for the exploratory severity analysis.

Clinical implications

These findings suggest that diosmin 600 mg daily may warrant consideration as an adjunct to standard anticoagulation in patients with acute proximal DVT, particularly those at higher risk for PTS such as patients with iliofemoral involvement. The favorable safety profile, low cost, and wide availability of diosmin support its potential role in clinical practice, pending prospective confirmation.

However, these results require confirmation in prospective randomized controlled trials before routine adoption can be recommended. Future studies should also explore optimal dosing, treatment duration, and identification of patient subgroups most likely to benefit. Incorporation of objective venous function measures alongside clinical scales would help clarify whether diosmin’s benefits reflect true PTS prevention or symptomatic improvement.

Conclusions

In this propensity score–matched retrospective cohort, adjunctive therapy with diosmin 600 mg daily in patients with acute proximal DVT was associated with greater reductions in inflammatory markers, improved venous recanalization, and better quality of life compared to standard anticoagulation alone. Exploratory analyses suggested a trend toward reduced severity of post-thrombotic syndrome among patients who developed PTS; however, this finding should be interpreted cautiously given the small number of events, the borderline statistical significance, and the inherent limitations of the retrospective design. These observational findings may support the rationale for prospective randomized controlled trials to determine the efficacy and optimal use of diosmin as adjunctive therapy in acute DVT.

Supplemental material

Supplemental material - Anti-inflammatory effects of diosmin as adjunctive therapy in acute deep vein thrombosis: Impact on venous recanalization, quality of life and post-thrombotic syndrome

Supplemental material for Anti-inflammatory effects of diosmin as adjunctive therapy in acute deep vein thrombosis: Impact on venous recanalization, quality of life and post-thrombotic syndrome by Dragan Nikolić, Janko Pasternak, Vladimir Manojlović, Slavko Budinski, Marijana Basta Nikolić and Nikola Batinić in Phlebology.

Footnotes

Acknowledgements

The authors thank the nursing and radiology teams of the University Clinical Center of Vojvodina for their assistance with patient management and follow-up evaluations.

ORCID iD

Dragan Nikolić

Ethical considerations

The study was approved by the Ethics Committee of the University Clinical Center of Vojvodina, Novi Sad, Serbia (Protocol No. UCCS-2024-153), and conducted in accordance with the Declaration of Helsinki.

Consent to participate

The requirement for individual informed consent was waived by the Ethics Committee due to the retrospective nature of the study and use of anonymized data.

Consent for publication

All data are presented in aggregate form without identifying individual patients. No images or other personal identifiers are included. Therefore, specific consent for publication was not required.

Author contributions

D.N. and J.P. conceived the study and designed the analysis. V.M., S.B. and M.B.N. collected clinical and imaging data and contributed to data interpretation. N.B. performed the statistical analyses. D.N. drafted the first version of the manuscript. All authors critically revised the manuscript, approved the final version and agree to be accountable for all aspects of the work.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

De-identified individual participant data and the analysis code are available from the corresponding author upon reasonable request and with permission of the University Clinical Center of Vojvodina.

Guarantor

D. Nikolić.

Supplemental material

Supplemental material for this article is available online.

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