The progression of chronic venous disease (CVD) can primarily be defined as the worsening of clinical symptoms, marked by an advancement in CEAP classification or a change in clinical symptoms. The progression of CVD is highly diverse, and advanced forms may be asymptomatic or may exhibit clinical symptoms even in the absence of obvious varicose veins (1).

Current hypotheses about the progression of CVD focus on local inflammatory responses associated with venous hypertension and venous stasis. This mechanism originates from local hypoxia associated with capillary stasis. These processes, presumed to cause pain in CVD, also appear to be involved in the process of varicose remodeling. Over time, varicose remodeling results in the loss of structural integrity and elastic properties of the vein wall. Continued venous dilatation leads to further structural changes and deterioration of the vein (2).

Understanding the progression of CVD requires long-term follow-up and an exploration of its natural characteristics. In our review, we summarized research to discern disease progression in clinical trials, focusing on studies related to CVD progression across different periods. Using the search terms “chronic venous disease” and “chronic venous insufficiency,” PubMed was interrogated until October 31st, 2023, to identify relevant papers on this topic. Additionally, the reference lists of review papers and published systematic reviews were searched for relevant articles that may have been missed during the electronic search.

The Framingham study reported the incidence of varicose veins in 1988 (3). From 1966 to 1982, 3,822 adults were biannually followed up for 16 years. Initially, 1,720 men and 2,102 women did not have varicose veins. Over this 16-year period, 396 men and 639 women developed varicose veins for the first time. The incidence of varicose veins was 39.4 per 1,000 men and 51.9 per 1,000 women. Potential risk factors included obesity in women, high blood pressure, low physical activity, a sedentary lifestyle, smoking, and cardiovascular disease. The study concluded that increasing physical activity and controlling body weight may help prevent varicose veins.

Sarin et al. (4) reported clinical and ultrasound findings of CVD progression patterns. The study included 36 patients with 56 limbs (43 primary, 13 recurrent) on the National Health Service waiting list for varicose veins treatment. The median waiting time was 20 months (range, 15∼27 months). Among these patients, 3 developed additional varicose veins along the greater saphenous vein (GSV), and 11 developed new varicose veins along the small saphenous vein (SSV). Additionally, one patient developed lipodermatosclerosis. Ultrasound revealed that 27% of patients developed reflux at a new site, and 18% showed progression of reflux compared to the initial test. Notably, venous refill time was not significantly reduced. Furthermore, initially normal contralateral limbs developed new reflux in 25% of cases.

Heit et al. (5) reported the incidence trend of venous ulcers. In this retrospective epidemiological study using Medicare data from 1966 to 1990, 945 patients with venous stasis were examined, and 60 (6.3%) patients developed venous ulcers. The mean duration from the diagnosis of venous stasis to the development of venous ulcers was 5.0 years (SD±5.0, range 14 days to 24 years).

Labropoulos et al. (6) reported patterns of CVD progression and provided detailed ultrasound findings. The study included 90 patients with symptomatic CVD, totaling 116 limbs that did not receive treatment. Over a 43-month period, symptoms worsened in 13 out of 116 limbs (14.4%). Progression occurred in 29 (29.6%) symptomatic limbs and only in 2 (11.1%) asymptomatic limbs (p=0.18). Of the 116 limbs with venous reflux, 31 (26.7%) showed progression. Notably, progression was most frequently observed in most extremities within 6 months from the initial diagnosis. Patients awaiting surgery may need another ultrasound if the time interval is prolonged.

Labropoulos et al. (7) are conducting additional research and prospectively comparing progression rates over 5 years in patients with a history of deep vein thrombosis (DVT), patients with varicose veins, and normal patients. The study included 41 patients with proximal DVT, 41 patients with primary varicose veins, and 15 controls without CVD. Results showed that patients with previous DVT exhibited significantly more skin changes compared to patients with primary varicose veins (p=0.019) and patients without CVD (p<0.01). The progression was faster in patients with DVT. Skin changes occurred significantly more frequently in patients with combined superficial reflux and deep vein obstruction (p=0.12). Secondary CVD is more affected by leukocyte adhesion, inflammation, venous wall hypoxia, increased capillary pressure, and platelet hyperaggregability than primary CVD (8).

A large-scale, long-term survey was conducted in Germany (9). This venous study investigated the prevalence of deep and superficial reflux in 3,072 participants from the general population. Participants were recruited in 2000 and re-surveyed between 2006 and 2007, with 1,978 patients reinvestigated over 6.6 years. The rate of progression of CEAP C2 disease to a higher grade C was 31.8% for patients with saphenous reflux and 19.8% for patients with non-saphenous reflux. After 6.6 years, the incidence of new varicose veins was 13.7%, and the incidence of new chronic venous insufficiency (CVI) was 13.0%. The prevalence of varicose veins increased from 22.7% to 25.1%, and the prevalence of CVI increased from 14.6% to 16%. Risk factors for progression included age, obesity, and arterial hypertension.

Kostas et al. (10) conducted a follow-up study on the untreated contralateral lower extremity of patients treated for varicose veins. Seventy-three patients were monitored on the contralateral limb for 5 years after the treatment of unilateral varicose veins. After this period, 48 new reflux sites were discovered in 38 limbs (including 37 in the saphenous vein, 5 in the perforator vein, and 6 in the deep vein). Approximately one-third of limbs with mild or asymptomatic venous reflux developed clinical signs over the 5-year follow-up. The study found that progression was significantly influenced by orthostasis and obesity, with a somewhat reduced progression observed with the use of compression stockings.

The Edinburgh Vein Study is another large-scale investigation into the progression of CVD (11). In this cohort study, 880 out of 1,566 baseline participants randomly selected adults were followed for 13 years. Among 334 patients with CVD at baseline, 193 (57.8%) experienced progression (12). Among the 555 patients without trunk varicose veins at baseline, 101 developed C2 class disease, resulting in an annual incidence of 1.35%. The overall progression rate was 3.54% per year. Notably, 25.3% of patients with unilateral disease developed bilateral disease yearly. Improvement was observed in 109 patients (33.5%), with 16.6% undergoing surgery or sclerotherapy. Based on the presence or absence of reflux among 554 of C0, C1 patients, 198 (43.6%) without reflux were followed up, and 51 (25.8%) progressed to C2, with 22 (11.1%) progressing to C3 or higher. Among C0 and C1 patients with reflux (256 or 56.4%), 33 (12.9%) progressed to C2, and 25 (9.8%) progressed to C3 or higher.

In the Edinburgh Vein Study (12), analyzed risk factors for CVD included age greater than 55 years (OR 3.9; 95% CI 1.1∼14.3), obesity (BMI >25; OR 1.9; 95% CI 1.1∼3.1), family history of varicose veins (OR 1.9; 95% CI 1.20∼3.04), female gender (OR 3.92; 95% CI 1.28∼12.05), superficial venous reflux (OR 2.09; 95% CI 1.31∼3.34), both superficial and deep reflux (OR 2.57; 95% CI 1.55∼4.25), reflux in the SSV (OR 4.73; 95% CI 1.37∼16.39), and reflux in SSV with deep veins (OR 4.48; 95% CI 1.91∼10.54). The progression risk tended to be higher in multi-segment reflux than in a single segment.

Engelhorn et al. (13) classified varicose vein reflux segmentally and observed progression. Among 92 female patients, 28 C1 and 64 C2 patients were included. Ultrasound follow-up was performed without surgery, and examinations were conducted twice at intervals of 33+19 (8∼89) months. The study included 76 cases of segmental reflux, 48 cases of multi-segmental reflux, 23 cases of distal reflux, 15 cases of proximal reflux, 2 cases of axial reflux, and 20 cases with no reflux. Axial reflux was defined as uninterrupted retrograde venous flow from the groin to the calf. Disease progression was observed in 23% to 47% of cases, respectively. Notably, there was no significant progression of reflux in about 60% of the GSV and 80% of the SSV examined. A further topic for discussion would be whether to treat segmental and distal saphenous reflux or not.

All studies on progression were summarized in Table 1, and the segmentally classified reflux study by Engelhorn et al. was summarized separately in Table 2.

The 2015 European Society for Vascular Surgery guideline recommended surgical treatment rather than conservative management in non-complicated varicose veins C2 and C3 (Class I, Level of Evidence B) (14).

In the Society for Vascular Surgery guideline reported in 2023 (15), for patients with symptomatic varicose veins and axial reflux in the GSV or SSV who are candidates for intervention, they recommend superficial venous intervention over long-term compression stockings (Grade 1, Quality of Evidence B).

In the 2020 Appropriate Use Criteria (16), it was recommended that GSV ablation is appropriate for patients with C2 or higher with axial reflux in the GSV. In cases where there is reflux only in the below knee GSV or when there is segmental reflux, GSV ablation may be necessary. In cases of non-physiologic reflux or flash reflux, treatment is rarely appropriate. Compared to flash reflux or segmental reflux, axial reflux can progress to higher clinical manifestations and requires ablation. Treatment of symptomatic C1 in all types of reflux is still debated, but routine GSV ablation is rarely considered appropriate.

In the REACTIV trial (17), conservative treatment, such as compression stockings, was compared with surgery in 246 uncomplicated varicose veins. After 2 years of follow-up, the surgery group showed more symptomatic relief, better cosmetic results, and much improved quality of life compared to the conservative group. In the ESCHAR study reported in 2004 (18), 500 patients with or recently had ulcers were examined by ultrasound and randomly allocated to compression treatment alone or in combination with superficial venous surgery. The 12-month ulcer recurrence rate was significantly lower in the high ligation and stripping group than in the conservative group (12% vs. 28%, p<0.0001).

Patients with early-stage CVD (C0, C1) may exhibit disease-related symptoms such as heavy legs in an upright position, restless leg syndrome, edema, and/or evening edema. Transient reflux in the GSV occurring at the end of the day may be present in C0, C1 patients. The goals of managing C0, C1 patients are to relieve symptoms and signs, suppress the inflammatory response, and prevent progression to higher CEAP clinical grades. Early intervention, including lifestyle changes, may slow the progression of the disease and delay the onset of more severe symptoms. While there is ongoing debate, sometimes GSV ablation is performed in the early stages of CVD. However, it is advisable to first consider conservative treatment before proceeding with surgery. Treatment with micronized purified flavonoid fraction (MPFF) (1,000 mg once a day in the morning for 2 months) resulted in the elimination of evening GSV reflux in 84% (22/26) of treated patients. Additionally, it led to a decrease in vein diameter and beneficial effects on symptom relief, contributing to an improvement in the quality of life (19).

According to previous studies, the annual incidence of trunk varicose veins ranges from 1.35% to 2%, and the disease progression rate is reported to be 3.54% per year. Ultrasound reflux changes are observed in 24% to 27% of patients within a median of 20 months, and 27% of patients with reflux may develop symptoms between 6 months to 5 years after the initial diagnosis. Five years after a venous reflux diagnosis, ulcers occurred in 6.3% of patients, and for patients with uncomplicated varicose veins, the progression rate to the upper stage C was reported to be 3.5% to 7% per year. CVD is a progressive condition, and surgery has demonstrated better results than conservative management. If surgery is performed more than 6 months after the initial diagnosis, another ultrasound test might be required. In the case of C0s and C1s, early intervention helps slow the progression of the disease. GSV ablation is rarely appropriate in C0 and C1, but there is much debate. Controlling potential risk factors, such as weight loss and lifestyle changes, can help prevent the progression of early-stage CVD. Administering MPFF for 2∼3 months is effective in improving symptoms and reflux and can be used as a preliminary measure before deciding on surgery.