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Dear Authors and Editorial Board
Please accept our congratulations and appreciation for the authors’ article on an underrecognized option for medical adjunctive therapy of venous leg ulcers (VLUs) published in the July 2020 issue of Wounds. The authors’ paper highlights and educates providers in wound care and medicine on an exclusive list of potentially beneficial options.
As the authors described, micronized purified flavonoid fraction (MPFF) has an extensive history of peer-reviewed published data (> 40 studies, with 10 randomized controlled trials [RCTs], including the RELIEF study,1 the Swedish RCT,2 an MPFF meta-analysis,3 and the DECISION trial.4 As an adjunctive treatment to standard of care, MPFFs decrease inflammatory markers (ICAM, VCAM), decrease macro/microvascular permeability, improve venous and lymphatic tone, improve VLU healing rates, and decrease associated edema, pain, and discomfort. Graded levels of recommendations for use are A from the 2008 International Angiography document,5 2A from the 2015 Clinical Practice Guidelines for the European Society for Vascular Surgery,6 1B from the 2014 practice guidelines of the Society for Vascular Surgery and the American Venous Forum,7 and a 2B recommendation from the 2008 American Academy of Chest Physicians.8 Additional excellent reviews of MPFF evidence for treatment of chronic venous disease have been recently published.9-11
Micronized purified flavonoid fraction is composed of diosmin glycoside, diosmin being converted from hesperidin (found in citrus). The MPFF composition is typically 90% diosmin, 10% hesperidin, and related compounds. Trade names for MPFFs include Daflon (available in Europe, Central America, and South America) and Vasculera. The authors correctly identified Diosmiplex as an MPFF: Vasculera is the tradename for Diosmiplex (in Reference 58 of the authors’ paper; Bush et al). Vasculera is the only US Food and Drug Administration (FDA)-approved prescription MPFF available in the United States. Vasculera/Diosmiplex, as an MPFF, has an alkaline granule (alka4-complex) component to decrease the acidity and gastrointestinal symptoms. Regulated by the FDA, Vasculera was categorized as a medical food, designated as GRAS (Generally Regarded As Safe) and requires a prescription for patient utilization. Specifically, by statute, a medical food is defined as “a food which is formulated to be consumed or administrated enterally under the supervision of a physician, and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evidence.12,13 A medical food is distinctly a medication with therapeutic intent when we, as physicians and providers, prescribe Vasculera to our patients. Unlike unregulated, non-prescription supplements, medical foods are required to have an Indicated For Use (IFU) for specific diagnosis.
In the paragraph on “Flavonoids: Vasculera,” Reference 60 is noted to be NCT02936271 from ClinicalTrials.gov (accessed July 23, 2020); the current recruitment status is “withdrawn”, with a last updated date of April 28, 2017, reporting zero patients enrolled. While the intent to enroll 110 patients to evaluate efficacy on prevention of postoperative pain and edema following lower extremity treatment in an outpatient setting is admirable; given the trial is withdrawn, it offers no data for comment. Ideally, a similar study should be completed.
With reference to the Table (Page 196), given that Vasculera is in fact an MPFF, it should fall under the drug classification of MPFF and carry the label of Yes for therapeutic recommendation given the cited extensive corroborative peer-reviewed publications supporting the positive therapeutic implications for patients with chronic venous disease. Regarding the paragraph “Flavonoids: Vasculera” (Page 199), medical foods do in fact have therapeutic medicinal benefits that positively impact disease states as well recognized in the published literature. Specifically, as an MPFF and sourced from the identical European location as Daflon (Servier), Vasculera has the same general level of evidence that supports its prescriptive use, as medical therapy, that all MPFFs are indicated for chronic venous disease, VLUs, and hemorrhoids. Given that Vasculera is the only MPFF available in the United States that is FDA regulated, accuracy in description, discussion, and data evaluation is critical to provider education and consideration for utilization as an adjunctive micronutrient that has a high proven potential to improve patient care. As prescription coverage is currently limited, misunderstanding and misinformation regarding Vasculera as an MPFF may impair payor literature evaluation and consideration of benefit coverage.
