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334 Chapter 33 Compression therapy for chronic venous disease and venous ulceration
https://t.me/med1917
The ESCHAR trial evaluated compression plus surgery
versus compression alone in patients with venous ulceration. Legs with open or recently healed venous ulcers were
treated with multilayer compression bandages or supercial venous surgery plus compression. There were 112 legs
randomized to compression and 102 to compression plus
surgery. Compression was with multilayer bandaging followed by class 2 ECS after healing. Ulcer healing was 64%
in both groups at 24 weeks, but ulcer recurrence was halved
in the surgery group.
58
80 consecutive patients with 87 venous ulcers to treatment
with compression or minimally invasive surgery. Compression was with a foam bandage and an inelastic dressing
followed by 20–30 mmHg ECS after healing. Healing was
100% at 31 days in the surgical group and 96% at 63 days
in the compression group (P < 0.02). Follow-up was for 3
years. Recurrence was 9% in the surgical group and 38%
in the compression group (P < 0.05). QoL was also better
in the surgical group. The remarkable healing rates in the
Italian study may have been in part due to patient selection, as exclusions were ulcers >12 cm and patients with
secondary reux or deep venous reux.
The EVRA trial randomized 450 venous ulcer patients
to receive, along with compression therapy, either early or
33.8 A CircAid legging orthosis. Compression is adjusted by
how tightly the Velcro strips are pulled.
delayed endovenous ablation of supercial venous reux.
Endovenous ablation was operator determined with thermal, foam, or nonthermal, nontumescent techniques all
allowed. Compression was also determined locally with
improvement in ulcer healing, but pump patients may elevate
their legs longer each day than nonpump patients. Despite
results of the few available studies indicating pneumatic compression may be useful in the treatment of CVD and venous
ulcer refractory to ambulatory compression alone, intermittent compression for CVD is not widely accepted.
53
multilayer elastic compression bandages (two to four
layers), short-stretch bandages, or ECS acceptable. The
primary result was shorter healing time in the early intervention group. Recurrence was also lower and treatment
more cost-effective in the early intervention group.
A smaller Italian study randomized
63
60,61
33.5 COMPRESSION VERSUS
SURGERY OR AS AN ADJUNCT
TO OPEN OR ENDOVENOUS
PROCEDURES
Comparing compression therapies with venous surgery for
venous ulcer is difcult. Major reviews indicate insufcient
evidence to favor one form of compression over another.
Compression often is used as an adjunct to open or endovenous surgery. However, when to use compression, what
form of compression to use, what strength, and for how long
as an adjunct to venous procedures is unknown. Comparisons are hampered by lack of high-powered randomized
controlled studies, different criteria for study patient entry,
variable use/types of compression, and unknown compliance
with postoperative compression.
55,56
A systematic review of
compression therapy after surgical intervention for supercial venous insufciency found 1–2 weeks of compression
therapy after intervention was associated with a mean
reduction of 11 (95% CI: 8–13) points on a 100-mm visual
analogue pain scale compared with a shorter duration (P
< 0.001) and was associated with improved QoL scores.
54
57
33.6 CONCLUSION
Compression therapy remains important in the treatment
of CVD and venous ulceration through:
Improved venous and lymphatic return and enhanced
•
calf pump function leading to a better inammatory
milieu and symptom control
Detoxication of ulcer beds and enhanced tissue oxy-
•
genation favoring wound healing
Venous ow enhancement and brinolytic activities
•
potentially reducing venous stasis and related thrombo-inammation
Compression therapy alone and in combination with surgical or endovenous ablations improves care quality and
outcomes in CVD patients, justifying use and inclusion
in societal guidelines (see the guidelines later).
research is needed to better characterize the various methods of compression therapy, selection of optimal delivery
methods, and dosage and durations of compression therapy in limbs with varying durations and severity of CVD,
preferably with careful stratication according to Clinical, Etiologic, Anatomic, and Pathologic (CEAP) class and
venous clinical severity scoring.
63,64
62
More
Guidelines 33.0 of the American Venous Forum on compression therapy*
https://t.me/med1917
No. Guidelines Grade of
33.1 For patients with symptomatic varicose veins and axial reux in the supercial truncal
veins, we suggest compression therapy for primary treatment if the patient’s ambulatory
status and/or underlying medical conditions warrant a conservative approach or if the
patient prefers conservative treatment for either a trial period or denitive management.
33.2 For patients with symptomatic varicose veins and axial reux in the GSV or SSV who
are candidates for intervention, we recommend supercial venous intervention over
long-term compression stockings.
33.3 For patients with symptomatic varicose veins and axial reux in the AAGSV or PAGSV
who are candidates for intervention, we suggest supercial venous intervention over
long-term compression stockings.
33.4 In patients with symptomatic varicose veins who are candidates for endovenous therapy and wish to proceed with treatment, we suggest against a 3-month trial of compression therapy prior to intervention.
33.5 In patients with chronic venous insufciency (C3–C6), we recommend compression
therapy either alone or as an adjuvant treatment to interventions.
33.6 In patients with leg ulcers, we suggest multicomponent compression bandages over
single-component bandages.
33.7 In patients with venous leg ulcers and underlying arterial disease, we suggest against
compression bandages if the ankle-brachial index is <0.50 or the ankle pressure is <60
mmHg.
33.8 In patients undergoing thermal ablation for saphenous incompetence, with or without
concomitant phlebectomy, we suggest postprocedure compression therapy for a minimum of 1 week for pain reduction.
recommendation
2
(weak)
1
(strong)
2
(weak)
2
(weak)
1
(strong)
2
(weak)
2
(weak)
2
(weak)
References 335
Quality of
evidence
C
(low to very low)
B (moderate)
C
(low to very low)
B
(moderate)
A
(high)
B
(moderate)
C
(low to very low
B
(moderate)
33
* Based on recommendations in References 62, 63, and 64.
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33
https://t.me/med1917
CHAPTER
34.1 INTRODUCTION
https://t.me/med1917
Recent developments in endovenous techniques have
brought welcome attention to chronic venous disease
(CVD). Thermal or nonthermal endovenous ablations are
safe and effective to treat reuxing pathologic supercial
veins, and catheter-directed interventions with balloons
and stents are effective and durable to recanalize large
veins even several years after deep vein obstruction.
Despite improvement in minimally invasive treatments,
patients with CVD may still have persistent symptoms,
including pain and swelling, new or recurrent varicose
veins, inammatory skin changes, or venous leg ulcers
(VLUs). Venoactive drugs (VADs) are safe and effective
therapeutic options and complement well venous interventions and compression therapies to improve quality of
life (QoL). Most VADs have been utilized for decades and
are incorporated into medical practice in many parts of
the world. They have been much more popular in European countries, where VADs were discovered and rst registered as prescription drugs. In regions with hot climates,
VADs are frequently preferred over compression therapy
to control CVD symptoms and swelling. VADs are good
therapeutic options when compliance with and tolerance
of compression stockings are less satisfactory. These products are currently not registered as drugs in the United
States by the Food and Drug Administration (FDA), but
they might be available as nutritional supplements or
medical foods.
This chapter will focus on VAD treatment either as primary therapy or as adjuvant treatment to interventions for
CVD.
34.2 TERMINOLOGY AND
CLASSIFICATION
VADs, also called phlebotonics or venotonics, include a
heterogeneous group of plant-derived or synthetic products
with an effect on signs and symptoms of chronic venous
disorders of the lower extremities. The most widely used
plant-based VADs are the benzopyrones. Coumarin belongs
to the alpha-benzopyrones group. Several VADs belong
to the gamma-benzopyrones or the avonoids family.
34
Drug treatment for chronic
venous disease
Monika L. Gloviczki and Joseph D. Raffetto
β
Diosmin, rutin, and O-(
tin, hydroxyethylrutoside [HR]) are the part of the a-
vones/avonols subgroup. Flavonoids might have various
other effects (hepatoprotective, anti-allergic). The avanes/
avolones subgroup contains hesperidin, pycnogenol, and
others. Micronized puried avonoid fraction (MPFF) is
composed of 90% diosmin and 10% hesperidin fraction.
The compound is subjected to a micronization process to
decrease the size of the particles to optimize absorption.
Saponins have two major representative compounds: horse
chestnut seed extract (HCSE) with escin derivatives and
Ruscus extract (ruscogenin and avonoids). Ruscus extract
is composed of Ruscus aculeatus, hesperidin methyl chalcone, and ascorbic acid. Other plant extracts contain avonoids with various active compounds such as anthocyans
(e.g., bilberry), proanthocyanidines (e.g., red vine leaf), or
gingko biloba (extracts of gingko). Three synthetic VADs
are well known: calcium dobesilate, benzarone, and naftazone (Table 34.1).
34.3 PHARMACOLOGIC PROPERTIES
VADs belong to different families, but they share many
similar modes of action on venous tone, the macro and
microcirculation, permeability, lymphatic drainage, leukocyte adhesion, and blood viscosity, and many have anti-inammatory properties (Table 34.2).
Coumarin can be used alone or in combination with
troxerutin. It has fast absorption and a short 1-hour halflife. Both coumarin and its metabolites are excreted in
urine. The compound is effective for lymphedema by facilitating the proteolysis of high-molecular-weight proteins.
Contrary to dicoumarols, coumarin has no anticoagulant
properties. Because of its hepatotoxicity, however, it is
rarely used.
Valvular incompetence and consequent development of
venous hypertension have been considered one of the cornerstones of CVD. Therefore, the demonstrated effect of
VADs on venous tone has been important.
mechanisms include induction of extracellular Ca(2+)-dependent contraction for escin,
by alpha-adrenoceptors for Ruscus,
epinephrine metabolism by MPFF
rutosides.
10
-hydroxyethylrutosides (troxeru-
1–5
The precise
6
mediation by calcium and
7
or decrease of nor-
8,9
and hydroxyethyl-
DOI: 10.1201/9781003328971-38
339339
340 Chapter 34 Drug treatment for chronic venous disease
https://t.me/med1917
TABLE 34.1 Classication of the main venoactive drugs
Group Substance Origin Dosage (mg/day) Number of
Benzopyrones a-benzopyrones Coumarin Melilot (Melilotus officinalis L.) 90 combined with
troxerutin (540)
Woodruff (Asperula odorata L.)
γ-Benzopyrones (avonoids)
Diosmin Citrus spp. Sophora japonica L.300–600 1 or 2
doses/days
3
Micronized puried avonoid
fraction (MPFF)
Rutin and rutosides Sophora japonica L. 1000 1 or 2
O-(β-hydroxyethyl)-rutosides
(troxerutin, hydroxyrutoside [HR])
Saponins Escin Horse chestnut (Aesculus
Ruscus extract Butcher’s broom (Ruscus
Other plant extracts Anthocyans Bilberry (Vaccinium mytrillus L.) 116 2
Proanthocyanidines (oligomers) Red vine leaf or grape pips
Ginkgo biloba
Synthetic products Calcium Dobesilate Synthetic 1000–1500 2–3
Benzarone Synthetic 400–600 2–3
Naftazone Synthetic 30 1
Source: Reproduced from Ramelet AA et al. Clin Hemorheol Microcirc 2005;33:309–19.
Eucalyptus spp. Fagopyrum
esculentum Moench
hippocastanum L.)
aculeatus L.)
(Vitis vinifera)
Maritime pine (Pinus maritima
Lank)
Ginkgo biloba L. 2 sachets (extracts
1000 1 or 2
120, then 60 3
2–3 tablets 2–3
100–300 1–3
300–360 3
of ginkgo, heptaminol, and troxerutin)
TABLE 34.2 Pharmacologic properties of the main VADs used in CVD
VAD Increased
venous
tone
Micronized puried
avonoid fraction
(MPFF)
Diosmin + + +
Hydroxyethylrutosides (HR)
Gingko biloba
extracts
Horse chestnut
extract (HCSE)/
escin
Ruscus extracts + + + + + +
Red vine leaf
extract
Calcium dobesilate + + + + +
Sulodexide* + +
Source: Adapted from International Union of Angiology Guidelines.
* Sulodexide is not classified as a VAD.
+ + + + + + + +
+ + + + + +
? ? ? ? ? ? ? ?
+ + +
Venous
wall and
valve protection
Decrease
of capillary
hyperpermeability
40
Lymphatic
drainage
improvement
Hemorheological
disorders
counteraction
Antioxidant
property
+ +
Anti-inflammatory
property
2
Protection of the
endothelial
function
34.4 Evidence of safety and efficacy 341
https://t.me/med1917
The inammatory process is another factor that plays an
important role in the pathophysiology of CVD and leads to
alterations in the venous wall and valves. Anti-inammatory
properties of VADs can be related to the different effects. One
mechanism is the antioxidant activity of avonoid substances,
studied and proven in venous disease and other pathologies
(arthritis, cancer, cardiovascular diseases, and diabetes). Several VADs, such as MPFF,
dobesilate,
16–18
were reported to act as free-radical scavengers
11–13
rutosides,14 escin,15 and calcium
in experimental models and showed anti-inammatory and
antioxidant potential. Leucocyte adhesion molecules were
reduced by MPFF in patients with CVD.
19,20
In activated
human macrophages, rutoside inhibited inammation gene
expression and reduced the release of nitric oxide, tumor
necrosis factor (TNF)–alpha, interleukin (IL)-1, and IL-6.
21
In women with varicose veins, MPFF improved antioxidant
imbalance and vascular dysfunction by effectively decreasing
the levels of endothelin-1 and TNF-alpha.
VADs (calcium dobesilate,23 escin,24 MPFF,
27
and others) reduce capillary hyperpermeability,
sides,
22
25,26
ruto-
responsible for edema formation. Recently, preservation of
endothelial function was demonstrated to be dependent on
the glycocalyx, a thin endoluminal layer composed of proteoglycans, glycoproteins, glycosaminoglycans, albumin,
and various adhesion molecules. Two compounds, diosmin and sulodexide, were studied in the rat carotid artery
model and showed a glycocalyx restorative effect.
28,29
Hemorheological abnormalities, such as increased blood
viscosity and erythrocyte aggregation, can be observed in
CVD. These are mitigated by the pharmacological activity
of calcium dobesilate,
rutosides.
32
In the advanced stages of CVD, lymphatic drain-
30
MPFF,31 and Ruscus extract and
age is inadequate and edema develops. Experiments with
alpha-(coumarin) and gamma-benzopyrones (rutosides,
MPFF), calcium dobesilate, and Ruscus extracts reported a
signicant lymphagogue activity (enhanced lymphatic motility) and improvement of the lymphatic function.
33–37
34.4 EVIDENCE OF SAFETY AND
EFFICACY
In 2005, a Cochrane review assessed the safety and efcacy of VADs used for treatment of chronic venous insufciency (CVI).
59 RCTs with many different VADs; 44 were considered
of good quality. The 2020 update identied 69 RCTs—56
studies with quantiable data for the efcacy analysis.
Among the 7690 participants 83% were female, with a
mean age of 50 years (range: 32–62). Most of the studies used the CEAP classication and included patients
with varicose veins, edema, lipodermatosclerosis, and
post-thrombotic syndrome. Unfortunately, the heterogeneity of the data prevented inclusion of numerous RCTs in the
meta-analysis for the specic effects, and the conclusions
were limited to moderate-certainty evidence of a probable benecial effect on restless legs, cramps, paresthesias,
sensation of swelling, edema, trophic disorders, and QoL.
Different classications of CVD, lack of standardization
in measured variables, subjectivity of variables, and differences between VADs were quoted as potential causes
of heterogeneity. However, the Guidelines of the European
Venous Forum (EVF), the International Union of Angiology (IUA), the Cardiovascular Disease Educational and
Research Trust (UK), and the Union Internationale de
Phlébologie (UIP) estimated that complete pain relief in
the VADs versus the placebo groups was 63% vs 37% (p
< 0.00001), similar to the effect on leg heaviness (60% vs
33%, p < 0.00001), sensation of swelling (63% vs 38%, p
< 0.0001), cramps (68% vs 45%, p = 0.003), and restless
legs (46% vs 33%, p < 0.006).
vidual VADs provide the best evidence of benet for each
VAD. The observed clinical effects in CVD with estimates
of levels of scientic evidence and side effects are summarized in the Table 34.3.
38
The review and meta-analyses included
40
Meta-analyses for indi-
39
34
TABLE 34.3 Levels of VADs’ scientic evidence for efcacy, their safety, and presence in the United States
VAD Venous symptoms Edema Skin changes Venous
Micronized
puried avonoid fraction
(MPFF)
Diosmin B C No Ye s
Hydroxyethyl-
rutosides (HR)APain, cramps, heaviness, itch-
Gingko extracts
A
Pain, burning sensation,
cramps, fatigue, functional
discomfort, heaviness, itching,
paresthesia, sensation of swelling, tightness, global symptoms
score
ing, paresthesia,
restless legs, sensation of
swelling
C
Pain, cramps, heaviness
ulcers
A A A B No Yes
A C No No
C No Yes
Perioperative
use
Safety issues
(yes/no)
Presence
in the USA
(Yes/No)
(Continued)
342 Chapter 34 Drug treatment for chronic venous disease
https://t.me/med1917
TABLE 34.3 Levels of VADs’ scientic evidence for efcacy, their safety, and presence in the United States
VAD Venous symptoms Edema Skin changes Venous
Horse chestnut extract
(HCSE)/escin
Ruscus extracts
Red vine leaf
extract (Vitis
vinifera)
Calcium dobesilate
Sulodexide* C
Pentoxifylline* A No Yes
Source: Adapted from International Union of Angiology Guidelines.
Abbreviations: Levels of scientific evidence:
A: More than two quality randomized controlled trials (RCTs), systematic reviews, and meta-analyses with results applicable to the CVD population. Further
research is unlikely to change the confidence in the estimate of effect.
B: Single RCT or several RCTs with methodological problems or with less consistent results. Further research is likely to modify the estimate of effect.
C: Poorly designed trials, observational studies, case series. Further research is very likely to modify the estimate of effect.
* Pentoxifylline and sulodexide are not classified as VADs.
A
Pain, itching
A
Pain, cramps, heaviness, paresthesia, sensation of swelling,
global symptoms score
B
Pain, leg heaviness, sensation of
swelling, tingling
A
Pain, cramps, discomfort, heaviness, paresthesia, restless legs,
sensation of swelling
Pain, cramps, heaviness, paresthesia, sensation of swelling,
total symptoms score
A No Yes
A No Yes
C No Yes
A Yes Yes
C B B No No
40
ulcers
Perioperative
use
Safety issues
(yes/no)
Presence
in the USA
(Yes/No)
34.4.1 Micronized purified flavonoid
fraction
Seven low risk of bias, randomized, double-blind MPFF
versus placebo trials in CVD were included in a recent
systematic review and meta-analysis.
ing 1692 patients revealed a signicant effect of MPFF
on symptoms related to venous disease: pain, heaviness,
sensation of swelling, tightness, fatigue, cramps, paresthesia, itching, burning sensation, functional discomfort,
and global symptoms score. As for the categorical variable
evaluation, MPFF reduced pain, leg heaviness, sensation
of swelling, cramps, paresthesias, and functional discomfort, with a risk ratio (RR) from 0.35 to 0.53, p values
between 0.03 and <0.00001, and number needed to treat
(NNT) between 2.0 and 4.8. The same symptoms assessed
as continuous variables compared with placebo showed a
standardized mean difference (SMD) from –0.25 (95% CI
–0.38 to –0.11) to –0.99 (95% CI –1.25 to –0.73). Objective signs of venous disease (edema, leg redness, and skin
changes) were signicantly diminished. The ankle circumference as edema measurement showed a reduction, with
SMD –0.59 (95% CI –1.15 to –0.02), and leg redness
with SMD –0.32 (95% CI –0.56 to –0.07). QoL was also
improved, parallel to the clinical assessment by the physicians. The authors concluded that the evidence has minimal heterogeneity and is mostly high quality, leading to
the statement that “MPFF is highly effective in improving
41
The analysis involv-
leg symptoms, edema and quality of life in patients with
41
CVD.”
A meta-analysis based on 10 RCTs versus placebo or
another VAD with a total of 1010 patients aimed to compare the impact of MPFF, hydroxyethylrutoside, Ruscus
extract, and diosmin on phlebolymphedema evaluated
by ankle circumference.
42
The MPFF had the best efcacy
in the reduction of edema (p < 0.00001 vs placebo, p <
0.0001 vs hydoxyethylrutoside and Ruscus extracts, and p
< 0.00001 vs diosmin). Other VADs, with the exception of
diosmin, had a signicant effect on edema when compared
with placebo.
Water plethysmography assessment of phlebolymphedema was used in the comparative RCT with 136 patients
randomly allocated into four treatment groups: MPFF,
aminaphtone, coumarin + troxerutin, and placebo.
43
Volume reduction ≥100 mL was the most frequent in the
MPFF group, and the QoL improvement was statistically
signicant for aminaphtone (mean difference –15.4 ± 17.8,
p ≤ 0.0001) and MPFF (mean difference –11.9 ± 13.8, p =
0.028).
Another meta-analysis
44
compared the efcacy of
MPFF and several other compounds (sulodexide, HR, calcium dobesilate, Ruscus extract combined with hesperidin
methyl chalcone and vitamin C, HCSE, and pentoxifylline). Bayesian network analysis of 45 RCTs and 18 observational studies revealed MPFF as the most efcient for
improving pain assessed by visual analog scale (VAS), leg
34.4 Evidence of safety and efficacy 343
https://t.me/med1917
volume, and QoL scores evaluated by the Chronic Venous
Insufciency Questionnaire (CIVIQ-20).
The RELIEF (Reux Assessment and Quality of
Life Improvement with micronized Flavonoids) Study
45
included 5052 symptomatic patients (CEAP classes C0s–
C4) separated into two groups, with and without venous
reux, and treated with MPFF for 6 months. A preliminary
part of this study was a psychometric validation of CIVIQ
in several languages in 18 countries (Argentina, Brazil, Brunei, Czech Republic, Egypt, Hong Kong, Hungary, India,
Malaysia, Philippines, Poland, Russia, Singapore, Slovakia,
Spain, Sri Lanka, Turkey, and Venezuela).
46
Venous reux
was present in 43% of patients, supercial venous reux
alone was diagnosed in 55% of cases, and varicose veins
(CEAP C2) in 41%. Patients with venous reux were older
and had more advanced stages of venous disease (edema
present in 56% of the group), with clinical CEAP classication signicantly correlated with age. MPFF treatment
resulted in the continuous improvement through 6 months
for all symptoms, edema, and QoL.
45
Some studies reported interesting results in patients
with CVD. Plasma markers of endothelial activation
(ICAM-1 and VCAM) were decreased in 20 patients with
CVD receiving MPFF for 60 days.
19
In the same cohort
VEGF levels, elevated in the cases of skin changes related
to CVD (CEAP C4), diminished after treatment with
47
MPFF.
Ultrasonographic reux time was signicantly
reduced in the subgroup of patients with edema treated by
MPFF for 60 days in an RCT vs placebo, suggesting that
medical treatment can affect reux and that patients with
more severe CVD may benet most from the treatment.
48
The effective decrease of endothelin-1 and TNF-alpha was
observed in a group of 34 women with primary varicose
veins treated with MPFF and compared with 55 women
of a similar group without VAD therapy.
22
The oxidative/
alkali-labile DNA damage in lymphocytes of CVI patients
was signicantly reduced by MPFF therapy as compared
with control patients.
49
Considering all the MPFF properties and clinical
effects, a recent review named MPFF as a good candidate
for post-thrombotic syndrome treatment.
50
34.4.2 Diosmin
Diosmin is a major component of MPFF (90%). However,
nonmicronized diosmin (mean particle size 36.5 microns)
had signicantly lower intestinal absorption (32.7 +/–
18.8%) when compared with MPFF (mean particle size
1.79 microns, absorption rate 57.9 +/– 20.2%) in a double-blind cross-over study in healthy volunteers, using
14-C diosmin.
Diosmin and MPFF were studied in a double-blind
2-month RCT including 90 patients with CVI.
improvement was reported on venous symptoms, ankle
and calf circumferences, and strain-gauge plethysmographic parameters in both groups. However, the diosmin
group showed a signicantly lesser treatment benet than
the MPFF group.
The diosmin efcacy to reduce edema was inferior to
those of other VADs (MPFF, Ruscus extract, and HR) and
was nonsignicant vs placebo.
RCTs found that diosmin appeared to be comparable to
51
52
Outcome
42
A review of three recent
MPFF in terms of effects on symptoms. Both diosmin and
MPFF have an excellent safety prole, with adverse effects
mostly consisting of minor gastrointestinal disturbances.
34.4.3 Hydoxyethylrutosides
A systematic review identied 15 studies including 1643
patients.
revealed a signicant improvement for pain in the HR
group (SMD –1.07, 95% CI –1.44 to –0.7), cramps (SMD
–1.07, 95% CI –1.45 to –0.69), and leg heaviness (OR =
0.5, CI 0.28–0.91). The quality of available evidence was
limited, and the authors concluded that HR treatment
results in modest CVI symptom improvement. The HR
acceptability was excellent, with few side effects.
increase of the oxygen pressure saturation and content in
blood from varicose veins in nine patients receiving HR for
4 weeks compared with ve patients without treatment.
In another trial the strain gauge plethysmography maximum venous incremental volume (MVIV) was reduced
from 6.6 ± 0.48 to 5.53 ± 0.59 mL/100 mL of tissue in
10 patients treated by HR (p < 0.001) compared to 10
patients in the placebo group.
tone increase was related to HR treatment.
CVD patients demonstrated in the HR group (n = 41/102
patients) a signicant reduction in the total symptom
score.
for cramps, heaviness, and restless legs. Tolerability evaluation, based on adverse events and laboratory test monitoring, was similar for HR and placebo groups.
ferent VADs and placebo included a coumarin and troxerutin group (26 of 136 C3 patients); however, the symptoms
and edema improvement did not reach statistical signicance.
607 patients.
symptom score by Likert scale: pain, heaviness, swelling
sensation, and cramps.
circumference ± standard deviation was –0.58 ± 0.31 cm
(CI –0.64; –0.52) signicantly better compared with placebo (p < 0.0001) and diosmin (p < 0.00001), similar to
Ruscus extract and inferior to MPFF.
54
An analysis of controlled trials vs placebo
One clinical prospective study reported a signicant
56
This indicated the venous
A multicenter 6-month RCT vs placebo in elderly
57
Signicant improvement (p < 0.05) was observed
A double-blind RCT comparing the effect of several dif-
43
A recent meta-analysis included nine HR RCTs with
44
The HR was the best for mean difference
In another meta-analysis, HR mean reduction in ankle
42
34.4.4 Ginkgo biloba compound
Ginkor Fort is composed of ginkgo biloba extract, troxerutin, and heptaminol chlorhydrate. A recent review
ed two RCTs including 152 participants with CVI. Ginkor
Fort appeared to be signicantly better than placebo in
reducing venous symptoms (pain, cramps, leg heaviness)
and edema (p < 0.01 at day 20 and p < 0.05 at day 40).
34.4.5 Horse chestnut seed extract/escin
Escin is the active component of horse chestnut (Aesculus hippocastanum) seed extract (HCSE). This saponin is
available as an oral therapy and transdermal gel and has
antiedema, anti-inammatory, and venotonic properties.
58
identi-
53
34
55
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