FormalPara Key Points

Evidence from real-world studies can be used to complement data obtained from randomised controlled trials and to provide support for guideline recommendations.

Several large-scale real-world studies have demonstrated the effectiveness of micronised purified flavonoid fraction in the management of chronic venous disease.

The ongoing multinational VEINSTEP study (chronic VEnous dIsorders maNagement and treatment effectivenesS evaluaTion in chronic vEnous disease, an international Program; NCT04574375) will provide further evidence of the effectiveness of conservative treatment (including venoactive drugs, such as micronised purified flavonoid fraction) for chronic venous disease in a real-world setting.

1 Introduction

Chronic venous disease (CVD) is a very common medical problem. Although estimates vary, studies undertaken in a general practice setting suggest that between 45 and 60% of adults have CVD [1,2,3]. Global prevalence estimates range from 45.6 to 83.6%, with most patients having early-stage disease according to the Clinical, Etiological, Anatomical and Pathophysiological (CEAP) classification system [4]. A meta-analysis of global prevalence estimates indicate the prevalence by CEAP class to be 9% for C0s, 26% for C1, 19% for C2, 8% for C3, 5% for C4, 1% for C5 and 0.42% for C6 [4]. Therefore, most physicians will encounter patients with CVD on a regular basis and should be aware of the impact and management of this condition.

The aim of this article is to describe real-world evidence on the use of micronised purified flavonoid fraction (MPFF) for the treatment of CVD, including what we can expect to learn from the soon-to-be-completed VEINSTEP (chronic VEnous dIsorders maNagement and treatment effectivenesS evaluaTion in chronic vEnous disease, an international Program) study. The review also addresses how this research can be applied in clinical practice and how best to support patients with CVD.

2 Real-World Data with MPFF

Micronised purified flavonoid fraction has been studied in a number of large-scale real-world studies that included more than 1000 patients, including the international RELIEF study [5] and the French DECIDE study [6].

2.1 RELIEF Study

The Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids (RELIEF) study was conducted among 5052 patients with CEAP class C0 to C4 CVD in 23 countries over 2 years [5]. Patients were stratified into those with (43%) or without (57%) venous reflux, and treated with MPFF 1000 mg/day for 6 months. Every 2 months, patients were evaluated for symptoms (rated on a 4-point scale from 0 [absent] to 3 [severe]), pain (rated on a 10-cm visual analogue scale), oedema (rated by leg circumference) and quality of life (QoL; rated using the validated 20-item Chronic Venous Insufficiency Quality of Life Questionnaire [CIVIQ-20]).

After 6 months of treatment with MPFF, there were statistically significant reductions in symptoms of leg heaviness, sensation of swelling, cramps, and pain, as well as a significant reduction in the severity of oedema, in the overall group and in the subgroups of patients with or without reflux (all p = 0.0001). There was also a statistically significant reduction in the number of patients with CEAP class 3 or 4 CVD and an increase in those with C0 to C2 classes (p < 0.001), in both subgroups and in the overall study population. Using the global index of the CIVIQ-20, patients without reflux had better QoL throughout than those with reflux, but both groups had statistically significantly better QoL after 6 months of MPFF treatment compared with baseline (p = 0.0001 for both) [5].

2.2 DECIDE Study

The DECIDE study was conducted at 1323 general practices in France, and enrolled 13,131 patients with suspected CVD [6]. Although physicians were not asked to rate the patient’s CEAP class in this study, all patients were considered to fall into class C0s, C1s, C2s or C3s, based on their symptomatology. The principal aim of this study was to evaluate the use of a CVD symptom checklist in primary care, but a secondary aim was to evaluate the effects of treatment on QoL, using the CIVIQ-20 questionnaire, at the next follow-up visit. Of the 9345 treated patients with follow-up data, 8834 (94.5%) received MPFF 500 mg/day and 511 (5.5%) received another venoactive drug. Follow-up was a median of 63 days after starting treatment.

Treatment with MPFF markedly reduced the prevalence of CVD symptoms: heaviness by 25%, sensation of swelling by 48%, leg pain by 57%, night cramps by 61% and ‘pins and needles’ by 58% [6]. Overall, 7103 patients were included in the comparison of CIVIQ-20 scores between baseline and follow-up. All dimensions of QoL improved with CVD treatment, with the greatest improvement seen in the pain domain. The CIVIQ global score for overall QoL increased by a mean of 15.8 in patients receiving MPFF, which was statistically significantly greater than the mean increase of 10.3 in patients who received another type of venoactive drug (p < 0.001).

3 VEINSTEP Study

The chronic VEnous dIsorders maNagement and treatment effectivenesS evaluaTion in chronic vEnous disease, an international Program (VEINSTEP) study (NCT04574375) is currently assessing the effectiveness of conservative treatment for CVD in a real-world setting (Table 1). This observational study is being conducted in nine countries, Costa Rica, China, Dominican Republic, Honduras, Mexico, Morocco, Panama, Romania and Ukraine, and has enrolled 6419 participants. Eligible patients are adults who present spontaneously or are referred for symptomatic CVD that does not require surgical intervention and who are not receiving treatment for CVD, including venoactive drugs or compression stockings. No specific intervention is prescribed in this study, and physicians can prescribe whatever pharmacological or nonpharmacological treatment they think is appropriate based on their usual clinical practice [7].

Table 1 Key features of the chronic VEnous dIsorders maNagement and treatment effectivenesS evaluaTion in chronic vEnous disease, an international Program (VEINSTEP) study (NCT04574375)
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VEINSTEP has four primary endpoints: (1) global leg symptom severity measured on a 4-point visual analogue scale; (2) global improvement using the Patient Global Impression of Change scale and time to improvement; (3) disease severity measured by the Venous Clinical Severity Score; and (4) QoL measured using CIVIQ-14. Follow-up is for 8 weeks, but the primary endpoints are measured at week 4.

To date, the complete results from the VEINSTEP study have not yet been published, but data are available from the Moroccan population (n = 3425) [7]. This subgroup had a mean age of 49.5 years and included 2845 female individuals (83.1%). Most patients in the Moroccan VEINSTEP population had class C2 (n = 1084 [31.6%]) or C3 (n = 1193 [34.8%]) CVD. Treatment included a venoactive drug in 98.9% of patients, most commonly MPFF (75.7%). Other venoactive drugs prescribed were diosmin (21.5%), Ruscus extracts (1.2%) and proanthocyanidins (1.1%). Other treatments prescribed included analgesics, topical therapies and compression.

Treatment that included venoactive drugs was associated with a statistically significant reduction in symptom severity between baseline and week 4 (p < 0.01). The greatest impact of treatment was on pain, heaviness, cramps and swelling, with reductions of 46–57%; the impact on paraesthesia, itching and burning was comparatively lower (27–39%) but still statistically significant [7]. Venoactive drug treatment, either alone or in combination with compression or topical therapy, was also associated with a statistically significant improvement across all three domains of QoL (pain, physical, psychological; p ≤ 0.001). Irrespective of treatment, 97.8% of patients reported an improvement on the Patient Global Impression of Change scale at week 4 and 98.6% at week 8, and 88% of Moroccan patients were satisfied or very satisfied with their treatment [7]. The overall results from the VEINSTEP study are awaited with interest and are expected to be published in the spring of 2023.

4 Application of Real-World Evidence in Clinical Practice

Evidence-based medicine principles were developed to support treatment decision making based on research-based evidence rather than on intuition, clinical experience or scientific rationale [8]. As a result, treatment guidelines now include information on the quality of the evidence to support their recommendations, with the highest quality evidence considered to come from randomised controlled trials, meta-analyses and systematic reviews [9]. These studies minimise bias and, therefore, provide rigorous evidence of a treatment’s efficacy [10]. Nevertheless, with carefully selected patient populations and an idealised setting, randomised trials may produce results that cannot be generalised to a more diverse population in clinical practice [11]. As a result, there is growing recognition of the importance of supplementing randomised trial data with real-world evidence to support clinical and regulatory decision making [11, 12].

The major international guidelines for CVD give MPFF the highest quality of evidence grading for its use in relieving symptoms of CVD, and is the only venoactive drug cited in guidelines as improving QoL [13, 14]. A summary of the evidence used in the 2018 guidelines (updated in 2020) from the European Venous Forum, International Union of Angiology, Cardiovascular Disease Educational and Research Trust (UK) and the Union Internationale de Phlébologie is shown in Table 2 [14, 15]. The quality rating of the MPFF recommendation reflects the weight of evidence derived from randomised controlled trials and meta-analyses.

Table 2 Effect of common venoactive drugs on the signs, symptoms and quality of life of patients with chronic venous disease for which there is Level A or B evidence, expressed as the NNT to benefit one patient (where available), from the 2018 (updated in 2020) international guidelines for chronic venous disease [14, 15]
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Real-world evidence is subject to potential confounders, and on its own may not be a reliable indicator for treatment efficacy [10]. This may be especially true when assessing subjective symptoms in the non-blinded setting of an observational study [10]. Therefore, a more rational approach to the assessment of treatment effects is to consider the ‘totality of evidence’ synthesising data from both randomised and non-randomised studies [16].

The real-world data described here are directionally consistent with the results of randomised clinical trials and provide evidential support for the guideline recommendations in a real-world clinical practice setting. In addition, real-world data also show that the effects of CVD treatment on subjective symptom severity are correlated with objective parameters of disease severity, including ankle circumference [17] and the presence of detectable reflux [18], providing additional support for a reliable treatment effect.

Finally, it is important for physicians to remember that their most important role is to relieve the patient’s suffering. To do this, they must understand the aspects of CVD that are important to the patient. Therefore, while the first question in the consultation usually elicits the reason the patient has sought medical treatment (e.g. “what brings you here today?”), the second question should always be “what bothers you most about your condition?” Only when we understand what the patient wants most from treatment (symptom relief, cosmetic improvement, increased limb mobility/function, more restful sleep) can we select the most appropriate course of treatment.

5 Conclusions

The weight of evidence from randomised controlled trials, and increasingly from real-world studies, demonstrates both the efficacy and effectiveness of MPFF in the treatment of CVD, for relieving symptoms and improving QoL, and this is reflected in international guidelines.