170 Original Article

Management of Varicose Veins and Chronic Venous

Insufficiency in a Comparative Registry with Nine
Venoactive Products in Comparison with Stockings
G. Belcaro1 M. Dugall1 R. Luzzi1 M. Corsi1 A. Ledda1 A. Ricci1 L. Pellegrini1 M. R. Cesarone1
M. Hosoi1 B.M. Errichi1 U. Cornelli1 R. Cotellese1 G. Agus1 B. Feragalli1

1 Irvine 3 Labs, Circulation Sciences, CH-PE University, Italy, Address for correspondence Gianni Belcaro, MD, PHD, Irvine3
Circulation/Vascular Labs, CH-PE University, Str Stat 16 bis, 94,
Int J Angiol 2017;26:170–178. Spoltore, Italy (e-mail: [email protected]).

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Abstract The aim of this registry study was to compare products used to control symptoms of
CVI. Endpoints of the study were microcirculation, effects on volume changes, and
symptoms (analogue scale). Pycnogenol, venoruton, troxerutin, the complex diosmin-
hesperidin, Antistax, Mirtoselect (bilberry), escin, and the combination Venoruton-
Pycnogenol (VE-PY) were compared with compressions.
No safety or tolerability problems were observed. At inclusion, measurements in the
groups were comparable: 1,051 patients completed the registry. Best performers:
Venoruton, Pycnogenol, and the combination VE-PY produced the best effects on
skin flux. These products and the combination VE-PY better improved PO2 and PCO2.
The edema score was decreased more effectively with the combination and with
Pycnogenol. Venoruton; Antistax also had good results. Considering volumetry, the best
performers were the combination PY-VE and the two single products Venoruton and
Pycnogenol. Antistax results for edema were also good. The best improvement in
Keywords symptoms score were obtained with Pycnogenol and compression. A larger decrease in
► chronic venous oxidative stress was observed with Pycnogenol, Venoruton, and with the VE-PY
insufficiency combination. Good effects of Antistax were also observed. Parestesias were lower
► venous disease with Pycnogenol and with Antistax. Considering the need for interventions, the best
► varicose veins performers were Pycnogenol, VE-PY, and compression. The efficacy of Pycnogenol and
► elastic stockings the combination are competitive with stockings that do not have the same tolerability in
► venoactive warmer climates. A larger and more prolonged evaluation is suggested to evaluate cost-
compounds efficacy (and non-interference with drugs) of these products in the management of CVI.
► edema The registry is in progress; other products are in evaluation.

Venous disease, varicose veins, and chronic venous insuffi- mainly clinical and is defined by ultrasound.1–3 Main man-
ciency (CVI) are very common clinical conditions associated agements and treatments are compression, surgical and
with impaired venous circulation causing discomfort, edema, interventional treatments (including sclerotherapy), and
and skin changes.1,2 Causes of CVI are untreated venous skin and wound care if indicated.3 CVI is socially very relevant
disease and varicose veins, consequences of deep venous as it affects some 5% of patients in the United States. According
thrombosis (DVT), and conditions resulting in venous hyper- to a recent consensus,4 the management of CVI is based on
tension, alterations in venous competence, and venous valve limb elevation, compression, topical treatments, and skin
disruption (as seen after DVT).1,2 The diagnosis of CVI is management and interventions (surgery or sclerotherapy).

published online Copyright © 2017 by Thieme Medical DOI https://doi.org/

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 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al. 171

Several drugs and non-prescription products are also patients had chosen to opt, temporarily, for personal reasons,
available and may be used to improve signs and symptoms for conservative treatments for at least 1 year, and had
of CVI as supplementary treatment. These compounds—in- temporarily requested conservative management. Most pa-
cluding prescription products and products considered nutri- tients were on a waiting list for sclerotherapy or minimal
tional or pharmaceutical-standard (PS) supplements—are surgery. CVI was defined as indicated in previous classifica-
available for supportive management of CVI in its evolution. tions (Haimovici’s Vascular Surgery, 3). All included patients
Compression and stockings cannot be used in all patients, all (in all groups) were equally characterized by varicose veins,
the time, and it is very difficult to use elastic stockings in perimalleolar edema, initial skin changes and discoloration
summer or in hot climates and warmer countries. (without present or previous ulcerations), symptoms (heavy
In this registry study, 10 supplementary managements legs after standing), minimal paresthesias,4 and by ultrasound
(including nine products) were used for supportive, symp- indicating in all “registry” limbs, superficial reflux. Hemody-
tomatic management of CVI.5 Self-medication and individual namic (increased ambulatory venous pressure) parameters
management are concepts in great expansion, particularly were defined according to previous publications and as
interesting in this context as PS supplements (all these defined by the recent international consensus.4 All products

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products can be considered PS supplements) represent ideal were used at the suggested or recommended dosage. The
solutions for self-medication, for most patients considering duration of the observational, open, registry period was of at
their accessibility without prescription (with a single initial least 12 months.
indication by physicians). The safety of these products is Brief description of the products: the composition and
optimal even when other concomitant drugs are used (i.e., characteristics of most products in this field are often not
antihypertensives.) to treat clinical conditions or control risk detailed. Some products do not specify the dosages or the
conditions (i.e., statins). rationale for its use in the compositions.5 All products are
Main endpoints of this registry study were objective considered as safe. Venoruton (Paroven in U.K.) (Novartis) has
changes in microcirculation and limb volume (assessed by been present in the market for decades. It is very safe; one
volumetry) and clinical CVI symptoms assessed on a visual study reports the use of Venoruton for 5 years without side
analogue scale. effects in CVI. Venoruton improves peripheral edema in CVI
The aim of this registry study was a comparative evalua- and diabetic microangiopathy, decreasing their progression.
tion of products (used as a single medication) in controlling Pycnogenol (Horphag)6–12 can be considered a “model” prod-
signs and symptoms of CVI. uct as per several recent studies. It improves CVI and affects
oxidative stress with a mild antiaggregating and, possibly, an
antithrombotic activity. This specific extract can be used as a
Patients and Methods
supplement in symptomatic varicose veins and in CVI. Pyc-
The registry included patients with CVI and signs/symptoms nogenol6–12 well evaluated in technical studies, has shown a
(CEAP grades 3–4a; moderate to severe clinical symptoms).1–4 significant effect even at low dosages (100 mg/d); it improves
Otherwise healthy patients, using no other drugs, without (CVI-related edema) comparatively more and better than
diabetes or metabolic disorders were included. The patients other compounds.11 Supplementation is effective in micro-
were characterized by varicose veins, present for > 5 years, circulatory disorders with a specific activity on peripheral
ankle swelling, partially relieved by leg elevation, no ortho- edema (even during long flights) and equally in venous and
pedic problems, and body mass index (BMI) < 27. All these diabetic microangiopathy.

Table 1 The nine venoactive products used in the study

Dosage Doses per day

Venoruton (Novartis) 1,500 mg 0-(β-hydroxyethyl)-rutosides
Pycnogenol (Horphag) 150 mg French Maritime Pine bark extract
Troxerutin 1,000 mg several preparations available
Diosmin þ hesperidin diosmin mg 450 flavonoids (esperidine ¼ mg 50)
Antistax (Boehringer Ing) 750 mg 360 mg extract red grape leaf
Mirtaven 600 mg Mirtoselect (standardized bilberry extract with
(Mirtoselect) Indena 36% anthocyanins)
Troxerutin generic 800 mg troxerutin 300 mg
ESSAVEN-Escin 100 g dry extract of horse chestnut Triterpene glycosides (triterpene 22.5%)
(Aventis-Sanofi, generic)
Ve-Pycno (Novartis and Horphag; 150 þ 1,500 mg Supercompound
noncombined preparation)

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172 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al.

The brand Troxerutin (produced by five international only elastic stockings on CVI in the same period of time. In the
producers) is used at the dosage of some 600 to 1,000 mg/d reference or “standard” management group, below-knee
and is found in several generic preparations. The product has elastic stockings (Sigvaris, Winterthur, Switzerland; with
been available for years, but studies have been fragmentary compression at the ankle of 20–25 mm Hg) were used daily
and often limited. Troxerutin is generally effective for the during standing and the working activities and removed only
treatment of the pre-varicose and varicose syndrome, as a for bed rest.
supplementary management in varicose ulcers, in controlling Ultrasound evaluation was performed according to de-
symptoms of thrombophlebitis, postthrombotic conditions, fined standard.3,4,17–21 The registry was based on objective
and hemorrhoids. Troxerutin has also been used to control and subjective technical measurements useful to quantify CVI
muscle pain and edema. by monitoring the clinical attributes specific of CVI.4,22–24
The complex diosmin þ hesperidin (90% diosmin and 10% The microcirculation was non-invasively evaluated (standard
other flavonoids expressed as hesperidin) has also been room temperature of 22°C) at the internal perimalleolar region
widely studied; it appears to be less powerful and effective using a laser Doppler flowmeter (Laserflo, Vasamedics, St. Paul,
than Venoruton and Pycnogenol in CVI patients (considering Minnesota, United States). The resting flux (in flux units) was

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edema, microcirculation, and the most common signs/symp- measured (as a continuous measurement over 1 minute of
toms). It is definitely less potent than Pycnogenol alone recording, after 3 minutes of stabilization). Transcutaneous PO2
(to obtain comparable results, i.e., on edema). It needs a and PCO2 were measured at the distal, internal perimalleolar
dosage some 10 times higher than Pycnogenol. region with a Kontron Combi Sensor (Kontron Instruments, U.K.)
Antistax (Boehringer-Ingelheim, Germany; tablets 360 mg) after 20 minutes of heating of the probe at 40°C.22
has red grape leaf extracts (GLE) as active ingredients.13–16 It is Edema. The rate of ankle swelling (in mL/min/100 cc of
a single specific preparation. It is used at a dosage of some 700 tissue) was measured with a straingauge plethysmograph
to 1,000 mg/d. Signs/symptoms are positively affected. CVI- (Hokanson SPG16, St. Paul, Minnesota, United States). The
related edema is less affected; progression studies in CVI need patient was resting supine for 10 minutes and then asked to
to be completed and, possibly, dosage studies may evaluate stand. A straingauge had been applied at the lower ankle
higher dosages. circumference at the nonsupporting limb, with the patient
Mirtoselect (used at the dosage of some 600 mg/d) is a holding onto a frame and supporting his/her weight on the
proprietary product (Indena, Milan, Italy) extracted from opposite leg. The tangent to the 10th minute was considered
bilberry. The venous circulation of the retina is a specific proportional to capillary filtration.18,20
target application for this products that also has a significant Volume. The volume evaluation was measured in a Plexi-
activity on peripheral venous microcirculation and on edema glas chamber including the knee and the leg (5 cm proximal to
in CVI. A specific combination (Mirtogenol, including Mirto- the distal edge of the rotula). The first volumetric evaluation
select þ Pycnogenol) has been mainly developed for retinal was defined as 100% and the following variations were
and eye microcirculatory problems, but it also has a signifi- measured as a percent change. Ankle circumference was
cant efficacy in venous insufficiency and CVI-related micro- self-measured (in cm) with a tape, in the morning at 8 AM,
circulatory alterations. at the minimal ankle circumference. All measurements,
Non-branded, generic troxerutin (used at doses around standards and reproducibility values, for these tests have
800 mg/d) is available as various generic products, broadly been established in several previous studies and described in
comparable to branded Troxerutin. details in previous publications.10–14
Oral escin (used at the dose of some 600 mg) has been used The clinical attributes linked to CVI are shown in ►Table 2.
in several preparations. The product is derived from horse The attributes were rated on a visual, analogue scale line from
chestnut. The main product (Essaven, Aventis) includes an 0 (none/absent) to 5 (severe). At inclusion, all registry
alcoholic extract of horse chestnut, triterpenic glycosides and patients were between the moderate and severe level. No
escin þ sutin. The exact composition (including 50 mg of the previous DVT or post-thrombotic syndrome had been
active component escin) is not completely clear. Three cap- recorded or documented or detected at inclusion. Duplex
sules daily are generally used for patients with CVI. Dosages ultrasound indicated that the deep venous system was patent
are not well defined for the different degrees of CVI. and that there was no significant obstruction with a predom-
A supplement association Venoruton-Pycnogenol (VE-PY) inant venous incompetence at superficial level.
1,500 mg þ 150 mg/d has been evaluated recently (using the Previous surgery and/or sclerotherapy were performed
two separate compounds). The combination product improves (but not in all patients and limbs) at least 1 year before the
the efficacy of the single products without side effects. There is start of the registry.
a very significant effect on CVI-derived edema. The cost of this Common complications due to CVI (possible hemorrhage
combination is, however, relatively high. or thrombotic complications of the varices and possible skin
alterations and ulcerations) were evaluated during the obser-
Compression vation period. Oxidative stress was evaluated—in peripheral
“Standard management” for CVI was considered compres- venous blood—in a random (20%) subgroup of patients for
sion1,3,4 to be associated with surgical or interventional each management group.25
methods when indicated. A group of comparable patients Limb thermography was performed to evaluate possible,
with CVI was monitored to evaluate effects and tolerability of localized, superficial thromboses or inflammatory conditions

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 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al. 173

Table 2 Summary table: base, inclusion data

Groups Microcirculation Edema score Symptoms Oxidative stress 10 Paresthesia (number) Score 0–5
model
R-FLUX PO2 PCO2 Score 0–5
1. VENOR 2.82 51 31 4.2 3.9 388 78/83 3.7
SD 0.1 4 3.2 1.1 0.8 22 0.9
2. PYC 2.7 52 30 3.9 4 378 98/122 3.8
SD 0.11 3.2 2.4 0.7 1 23 0.5
3. TROX 2.8 53 29 4.1 3.9 398 70/77 3.7
SD 0.2 2.4 3 0.8 0.3 18 0.6
4. D-E 2.82 52 29 4.2 4 382 65/71 3.6

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SD 0.1 2.2 2.1 0.3 0.7 31 1
5. ANX 2.8 51 28 4.1 3.8 379 67/73 3.7
SD 0.11 2.1 2 0.8 0.9 24 1.1
6. MYRT 2.76 52 30 4.0 3.9 388 70/77 3.5
SD 0.1 2.6 2.5 0.7 0.8 12 1
7. FLEB 2,82 53 29 3.9 3.7 378 68/74 3.6
SD 0.2 3.2 3 0.8 0.7 22 0.8
8. ESC 2.78 52 31 4.1 4 382 55/64 3.7
SD 0.13 2.6 2.2 1 0.8 26 0.9
9. VE-PY 2.76 52 29 4.06 4.1 375 155/173 3.6
SD 0.1 3 2.5 1.1 0.4 22 0.5
10. ECOM 2.81 51 30 4.1 3.9 387 198/237 3.8
SD 0.2 2.1 2 0.5 0.7 21 1.1

Abbreviation: VE-PY, Pycnogenol þ Venoruton association.

Note: All patients were treated/supplemented according to suggested dosages for at least 12 months.
Laser Doppler flux at the internal perimalleolar region; flux expressed in flux units; PO2 and PCO2: in mmHg.
The clinical picture included symptomatic varicose veins and CVI.
This study lasted at least four seasons for all patients. These are the initial, inclusional values.
Comparative standard management with elastic compression stockings is also shown.
Measurements include SD (however, all these items should be considered nonparametric: intra-individual variation in measurements is < 8%).

(Flir, 440, Sweden). The possible presence of DVT was also ment costs or disease-related costs (including work disrup-
evaluated (by ultrasound and D-dimer). tions, consultations, tests and hospital admissions) occurring
Supplement registry studies26–29 are aimed to define the during the registry period were also recorded by the registry
field of activity of supplements and possible preventive, patients.
preferably nonclinical applications that can be associated Registry monitoring is regularly used to evaluate the
with self-management. They are planned and organized clinical meaning of individualized medicine in specific
with the full attention and participation of the evaluation patients.24,25 The treatment/supplementation is moni-
patients. tored with a registry to assess its efficacy on different
Commercial sponsorship from the producers of the tested individuals and evaluate how different dosages and thera-
supplement was not available. Safety and tolerability were peutic schemes may affect different groups of patients (i.e.,
assessed by weekly phone calls and mail contacts and diabetics).
laboratory measurements. Adverse experiences were evalu-
ated throughout the registry and communicated to the Statistical Analysis
monitors as soon as possible by SMS. All clinical adverse All results were analyzed in comparison with the results from
experiences were evaluated in terms of intensity: mild, the SM (elastic compression stockings) considered as a base-
moderate, or severe, and also considering duration, serious- line. Intra- and intergroup comparisons were performed by
ness, outcome, and relationship to the registry. A diary nonparametric tests and the ANOVA (analysis of variance)
recorded the use of any drug prescribed by the patient’s test, as appropriate. All target measurement values cannot be
physician according to needs. Treatments and other manage- considered as normally distributed.

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174 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al.

A p value < 0.05 was considered statistically significant. indicated that all products were active with a prevalence on
According to previous studies, comparable CVI groups of at symptoms/signs or on the microcirculatory model.
least 30 patients were considered adequate to define a
difference in target outcomes of at least 6 months.
Best Performers
Venoruton and Pycnogenol and the combination VE-PY pro-
Results
duced the best effects on resting flux (RF, increased in these
Safety patients at the perimalleolar region). Perimalleolar flux was
No safety or tolerability problems were observed in the study decreased by more than 44% with the combination, 38% with
patients. All these products were fond to be very safe. No side Venoruton, and 43% in the Pycnogenol group (p < 0.05 in
effect was observed. Dropouts were caused by pure logistical comparison with the other groups). Elastic compression was
problems and difficulties to follow instructions suggested for significantly less effective (22% reduction in RF; p < 0.05). Also
the follow-up. Pycnogenol, Venoruton, and the combination VE-PY improved
►Table 2 shows all the most important observed, target > 11% transcutaneous PO2 (p < 0.05, better, in comparison with

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measurements at inclusion. Measurements in the 10 groups all the other groups) and better than compression (8%). The same
were comparable. The 10 groups were also comparable for trend was observed with PCO2 that decreased more in the
age and sex distribution (►Table 3). A total of 1,051 patients Venoruton group (9%) and with Pycnogenol (10%) and
completed the study with minimal variations. The measure- with the combination VE-PY group (10%) with 8% decrease
ments and the evaluations were made considering the most in the reference compression group (difference not significant;
affected limb. All patients had CVI at both limbs with a ns). The edema score was decreased significantly more than in
significant asymmetry in signs, particularly edema (having the other groups with the combination (2.4) and with Pycno-
only small varicose veins) in 184 patients. A global analysis genol (2.2; p < 0.05) versus a 2.3 average with compression

Table 3 Results of all patients treated per suggested dosages for at least 12 months

Group Numb Age Micro- PO2 PCO2 Edema Volume Symptoms Complications Skin Oxidative
(drops) sex F ¼ circulation score discoloration stress
females model
Resting mL Score 0–5 SVT Difference
flux (RF)
1.VENR 83 (4) 47; 3.2 38% þ11% 9% 1.5 103 3.9 0/83 3/83 31%
33 F
2.PYCNO 122 (5) 46; 2.6 43% þ13% 10% 2.2 107 4.3 0/122 1/122 39%
58 F
3.TROXER 77 (7) 48.2; 2,1 22% þ5% 5% 1.1 17 1.9 2/77 2/77 7%
34 F
4.DIO-ES 71 (11) 46.8; 2 9% þ5% 3% 0.6 33 1.1 4/71 7/71 4%
33 F
5.ANTX 73 (8) 47; 3.1 5% þ5% 4% 1.5 86 1.1 4/73 11/73 28%
36 F
6.MYRT 77 (6) 47.5; 2 6% þ8% -6% 0.5 43 1.3 5/74 6/77 9%
38 F
7.TRXER2 74 (7) 48.4; 2.2 5% þ5% 5% 0.2 34 1.4 4/74 5/74 12%
37 F
8.ESCIN 64 (7) 47; 3.1 7% þ7% 7% 0.9 46 2 3/64 6/64 11%
37 F
9.VE-PY 173 (12) 47; 3,2 44% þ14% 10% 2.4 112 4.6 0/173 3/173 41%
88 F
10.ECOMP 237 (18) 47.5; 3 22% þ8% 8% 2.3 117 3.3 8/237 26/237 2%
166 F
Total 1,051

Abbreviation: SVT, superficial venous thrombosis.

Note: Clinical conditions: Varicose veins and CVI. Length: Management lasted at least four seasons.
Comparative standard management (group 10): elastic compression (stockings).
Best results underlined (p < 0.05 in comparison with other groups).

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 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al. 175

(value not significant in comparison with the previous two with the symptoms and elastic compression to 29% of patients
groups). Venoruton and Antistax also had good results. with symptoms.
Considering volumetry, the best performers were the Patients with positive results: the best results were ob-
combination Pycnogenol þ Venoruton (difference >100 tained with the combination (Venoruton þ Pycnogenol),
mL; p <0.05) with a comparable decrease in volume with with elastic compression and Pycnogenol (> 70% of patients
compression (ns difference) and the two single products with positive results) (p < 0.05).
Venoruton and Pycnogenol (groups 1 and 2). Antistax results Finally, considering the need for interventional treatment
for edema were also good with a decrease of 86 mL in volume. (sclerotherapy or surgery), the best performer can be consid-
The best decreases in symptoms scores were obtained with ered Pycnogenol (only 11% of patients were in need of
Pycnogenol and elastic compression (decrease > 4; p < 0.05) intervention) and the combination Venoruton þ Pycnogenol
with a good result for Venoruton (3.9; p < 0.05, in compari- (12%). With elastic compression 22% of the patients needed or
son with the other groups) and with compression (producing required interventions. Venoruton was also effective as only
a decrease of 3.3 in score). 14% required or were considered in need of interventions (in
Occurring complications of CVI (minor or very minor all other groups the need was > 15%).

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superficial thrombotic episodes) are shown in ►Table 3. The combination VE-PY and Pycnogenol resulted – globally
Venoruton, Pycnogenol, and the combination had a zero - the best supplementary, medical management considering
complication rate. However, more cases should be evaluated all measurements, outperforming elastic compression. The
for this type of evaluation. Also, these managements (groups tolerability for elastic stockings, particularly in warmer
1, 2, 9, and 10) had a significant lower rate of skin discolor- months (5 mo/y), tends to be lower in warmer climates.
ations (within the follow-up period) due to the effects of CVI.
Finally, a larger decrease (p < 0.05) in oxidative stress was
Discussion
observed (> 30%) in the Venoruton, Pycnogenol, and in the
VE-PY combination groups (41%) with no effects observable This registry indicates that patients using supplementary
with elastic compression (2%). A good effect of Antistax medical management for CVI have benefits from several
(28%) was also observed. products. Pycnogenol supplementation and the combination
►Table 4 shows some accessory observations. Thermal Venoruton þ Pycnogenol appear to have the most significant
imaging (showing an increase in skin temperature due to benefits on the microcirculation and on the most common1–3
inflammation or presence of even minimal superficial in- complaints and symptoms associated with CVI.
flammations or clots) indicated that the best performer was The best fields of application for supplements30 are self-
Pycnogenol (p < 0.05) (there were less hyperthermic areas medication31 or preclinical, borderline applications or the
during the follow-up). The rate of DVTs (documented by supplementary management of some risk conditions. Supple-
ultrasound þ D-dimer) was limited; DVT was positive in a ments—unless there are specific claims—are not generally
small number of cases and the differences cannot be consid- used for treatment of signs/symptoms or clinical conditions.
ered conclusive. Supplement studies produce additional data to be compared
Paresthesias were lower with Pycnogenol (4.1%) and Anti- with “background” historical data (based on the best available
stax (6.1%) (p < 0.05), both considering the number of pa- management) or to other management plans (i.e., the best or
tients with the symptom and the analogue score. The standard management). In this study, supplements were used
combination product was associated with 6.9% of patients according to the following rules:

Table 4 Results: other observational items

Group Thermal DVT Paresthesia Score Number of patients Need for interventional
changes numbness 0–5 with positive results (%) treatments (%)
1 33/83 18/83 2.11 55 14
2 24/122 7/122 1.2 73 12
3 31/77 9/77 2 34 18
4 44/71 1 25/71 3.4 22 26
5 54/71 1 5/73 1.3 21 26
6 29/77 22/77 2.7 24 28
7 29/74 1 23/74 3.3 21 31
8 33/64 20/64 2.3 26 22
9 12/173 12/173 1.1 78 11
10 46/237 1 69/237 2.1 77 22

Abbreviation: DVT, deep venous thrombosis.

Note: Pycnogenol and the VE-PY combination resulted as the best management in all measurements columns.

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176 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al.

In CVI, edema may be persistent and associated with

1. The use of the supplement was suggested to the evaluation significant signs that may alter the life of most patients
patients; the supplement was not prescribed but pre- and, in time, cause distal complication and even ulcerations
sented as an option, possibly capable of improving the if not properly managed. Elastic stockings are effective, but in
management of CVI. a warmer day (>25°C, i.e., 5 mo/y in Southern Europe) it is
2. The supplement was only used on top of what was difficult to work or operate all the time with compressive
considered at the time of the “standard” or “best-manage- stockings. Their compliance is therefore relatively low. Man-
ment/care,” if available, for that condition, according to agement of CVI should include other obvious steps, including
relevant international guidelines. weight control, diet, sodium restriction, exercise, and avoid-
3. The use of the supplement should not interfere with any ing prolonged standing or sitting positions.4,32 Self-medica-
other treatment or preventive measure. tion particularly with nonprescription products and with PS
4. The period of follow-up is considered variable, according supplements is becoming an important step.31–33 All these
to the needs and availability of the patients or registry venoactive products are very safe, and most patients may
patients. The observation period could be therefore vari- directly start supplementation evaluating after a period of

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able, not prefixed. Supplement administration should be weeks whether there is a positive effect on their specific
used as long as needed to see results or changes. conditions. Not all PS supplements and management act in
5. The type of evaluation for these studies is always a regis- the same way in different patients.30 The principle of indi-
try; there is no intervention from the observers. vidualized medicine (one of the main target aims of this type
6. The supplement is available without prescription and may of registry) is the direct evaluation by patients of the effects of
be voluntarily acquired by the study patients. the supplementation on their condition.31,33 Different prod-
7. In supplement studies there is no defined group allocation, ucts may produce different individual results.
no randomization organized by the monitors. Pycnogenol (the standardized extract of French Maritime
8. Patients decide—on the basis of the initial briefing—the Pine Bark) has been tested and used in several types of
management group they want to join including the control patients with CVI, symptomatic varicose veins, and in post-
(nonsupplement) group. No placebo is used. thrombotic syndrome.34 It has shown significant efficacy
particularly on the microcirculation and on distal leg edema
Open label. Patients are always informed about the sup- (the hallmark of CVI) in several studies.17,21 Venous edema is
plement or any treatment and management measure. A very positively affected by Pycnogenol supplementation. The
possible placebo effect is also carefully explained and consid- effects are comparatively larger with Pycnogenol in compari-
ered. Data and results are analyzed only after the observation son with what is observed with other venoactive com-
period—ideally, when sufficient evidence is collected or when pounds.34 Recent studies have also indicated a limited but
fund limitations would eventually stop the collection of the significant antithrombotic activity of Pycnogenol that may
observations. even protect patients with CVI and varicose veins from
Characteristics of the registry. This study was indepen- thrombotic complications. An antiplatelet activity has been
dent; the evaluation products were not prescribed but rec- documented in previous studies. Venoruton and Antistax
ommended. A supplement registry is actually more (GLE)35 have been used for symptoms related to varicose
corresponding to real, practical conditions than most clinical veins and CVI and are popular, safe self-treatments in several
studies that select groups of patients in selected conditions, countries. The potency of Pycnogenol is much higher (almost
often not corresponding to an epidemiologic reality. 10 times) than most other products as almost similar (micro-
This type of supplement studies may be particularly suited circulatory and clinical) effects can be obtained with 100 mg
for emerging countries and when expensive sponsorships for of Pycnogenol or doses of 1 g with other products.
brand products are not available.28–30 The costs of supplementation should be better evaluated in
External study reviewers. All results and data were longer studies as these products, generally, are not reim-
evaluated by an external reviewing panel, not in contact bursed by health care providers but directly paid by the
with the registry patients. patients. All the studied product can now be easily obtained
Supplementation/management with the registry products on qualified Web sites. Comparative evaluation of dose-
effectively controls signs and symptoms associated with CVI. related positive effects (targeting microcirculatory, objective
The definitive treatment is the surgical (including sclerother- parameters) are in progress as well as the evaluation of the
apy) corrections of the most incompetent segments. This type efficacy of these products in longer studies.
of patients should be treated with interventional methods, It is interesting to observe that this registry study was
but some patients do not want surgery for a conditions that it organized and completed without any interaction with the
not life-threatening. Many prefer to delay interventions and producers of the products that do not seem interested in a
most hospital have long waiting list for venous surgery that is comparative or cost analysis.
not considered urgent. Often, for most patients the only The evaluation of oxidative stress (in the peripheral
option is private surgery that is not financially possible for blood, at the perimalleolar region) may also explain, in
all patients. Therefore, there are long delays and periods time, some of the effects of desaturated, pooling blood in
before (and also after surgery) that may have benefits from the distal venous system and the evolution of skin
supplementary medical management. complications.

International Journal of Angiology Vol. 26 No. 3/2017

 A Registry of Venoactive Products: Comparison with Stockings for CVI Belcaro et al. 177

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