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390 Compression therapy for venous ulceration
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●
29. Partsch H Clark M, Bassez S etal. Measurement of
lower leg compression in vivo: Recommendations
for the performance of measurements of interface pressure and stiffness: Consensus statement.
Dermatol Surg 2006;32:224–32.
30. Partsch H, Partsch B, and Braun W. Interface pressure and stiffness of ready made compression
stockings: Comparison of in vivo and in vitro measurements. JVasc Surg 2006;44:809–14.
★
31. Cullum N, Nelson EA, Fletcher AW, and Sheldon
TA. Compression for venous leg ulcers. Cochrane
Database Syst Rev 2002;(2):CD000265.
★
32. Blair SD, Wright DD, Backhouse LM etal. Sustained
compression and healing of chronic venous ulcers.
BMJ 1988;297:1159–61.
33. Meyer FJ, Burnand KG, Lagattolla RF etal.
Randomized clinical trial comparing the efficacy of
two bandaging regimens in the treatment of venous
leg ulcers. Br J Surg 2002;89:40–4.
34. Nelson EA, Iglesias CP, Cullum N etal. Randomized
clinical trial of four-layer and short-stretch compression bandages for venous leg ulcers (VenUS I).
BrJSurg 2004;91:1292–9.
●
35. Milic DJ, Zivic SS, Bogdanovic DC etal. A randomized trial of the Tubulcus multilayer bandaging
system in the treatment of extensive venous ulcers.
JVasc Surg 2007;46:750–5.
36. Ashby R, Gabe R, Ali S etal. Clinical and costeffectiveness of compression hosiery versus
compression bandages in treatment of venous
legulcers. (Venous leg Ulcer Study IV, VenUS
IV): A randomised controlled trial. Lancet
2014;383:871–79.
37. Spence RK and Cahall E. Inelastic versus elastic compression in chronic venous insufficiency: A comparison of limb size and venous hemodynamics. J Vasc
Surg 1996;24:783–7.
38. Pekanmaki K, Kolari PJ, and Kiistala U. Intermittent
pneumatic compression treatment for postthrombotic leg ulcers. Clin Exp Dermatol 1987;12:350 – 6.
39. Coleridge-Smith P, Sarin S, Hasty J etal. Sequential
gradient pneumatic compression enhances
venous ulcer healing: A randomized trial. Surgery
1990;108:871–7.
40. Fletcher A, Cullum N, and Sheldon TA. A systematic
review of compression treatment for venous leg
ulcers. BMJ 1997;315:576 – 80.
41. Palfreyman S, Nelson EA, and Michaels JA.
Dressings for venous leg ulcers: Systematic review
and meta-analysis. BMJ 2007;335:7613–17.
42. Gohel MS, Barwell JR, Earnshaw JJ etal.
Randomized trial of compression plus surgery versus
compression alone in chronic venous ulceration
(ESCHAR study)—Haemodynamic and anatomical
changes. Br J Surg 2005;92:291–7.
43. Wright D. The ESCHAR Trial: Should it change
practice? Perspect Vasc Surg Endovasc Ther
2009;21(2):69–72.
44. Zamboni P, Cisno C, Marchetti F etal. Minimally
invasive surgical management of primary venous
ulcers vs. compression treatment: A randomized clinical trial. Eur J Vasc Endovasc Surg 2003;25:313–18.
45. Guest M, Smith JJ, Tripuraneni G etal. Randomized
clinical trial of varicose vein surgery with compression versus compression alone for the treatment of
venous ulceration. Phlebology 2003;18:130–6.
Drug treatment of varicose veins,
https://t.me/med1917
venousedema, and ulcers
PHILIP D. COLERIDGE SMITH
32
32.1 Introduction 391
32.2 Varicose veins and edema 391
32.3 Venous ulcers 392
32.4 Drugs used for venous ulcers 393
32.1 INTRODUCTION
e treatment of venous disease in the lower limbs has been
revolutionized in the last two decades by the development
of new methods of endovenous ablation. ese are now
widely incorporated into medical practice throughout the
world and have led to considerable advantages for patients
as well as for clinicians. Similar advances have not been
achieved by drug therapy for varicose veins and chronic
venous disease, although the development of orally active
direct inhibitors of the clotting cascade have led to considerable advances in the management of venous thrombosis.
No drug will cure varicose veins, although some benet
venous edema and ulceration. e greatest expansion of
drug treatment in the management of venous disease has
been the use of foamed sclerosants in the management of
varicose veins, which is discussed in other chapters. e
most economically important eld of venous disease is leg
ulceration. Presently available drugs have modest benet in
this disease and cannot be recommended in every patient.
Research in the eld of venous leg ulcers has not revealed
any biological process that, when suppressed or enhanced
by drug treatment, would dramatically enhance the process
of wound healing.
32.2 VARICOSE VEINS AND EDEMA
Varicose veins are a common problem aecting about 25%
of the adult population in westernized countries. is disease infrequently results in serious illness, although in
some patients, severe skin changes (lipodermatosclerosis
[LDS]) and leg ulceration may develop. Varicose veins are
32.5 Drug treatment for chronic venous disease 396
32.6 Summary 396
References 397
associated with a wide range of symptoms (aching, pain,
cramps, restless legs, feeling of heaviness, itching, and
feeling of swelling). e symptoms are commonly managed
by elastic compression, sclerotherapy, surgery, or a venous
ablation technique. Is drug treatment useful in managing
any of the consequences of varicose veins?
In some countries drugs are widely prescribed, but
in others few drugs are used in the treatment of varicose
veins. A range of phlebotonic drugs is used (Table 32.1).
e origin of these is from plants or synthetic sources.
Little new evidence regarding the ecacy of these drugs on
symptoms arising from varicose veins has been published
in recent years. A Cochrane review of the ecacy of these
drugs was published in 2005
subsequently. In all, 110 studies were considered for inclusion in the analysis; however, valid methodology and data
were only present in 44 studies, covering a range of commonly prescribed drugs. e scope of this review included
the following avonoids: rutoside, French maritime pine
bark extract, grape seed extract, Diosmin and Hesperidin,
disodium avonate, and the saponside centella asiatica.
e synthetic products included were calcium dobesilate,
fantazone, aminaone, and chromocarbe. e overall ndings were that there appeared to be an eect on edema, but
amongst the symptoms mentioned above, only restless legs
were moderated. For the more frequently prescribed drugs,
the following eects were observed: calcium dobesilate
reduced cramps and restless legs; Diosmin and Hesperidin
benetted trophic disorders as well as cramps and swelling;
and rutosides were found to benet edema. On the basis of
their review, the authors concluded that there is insucient
evidence to support the global use of phlebotonics in the
1
and has not been updated
391
392 Drug treatment of varicose veins, venousedema, and ulcers
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Table 32.1 Classification of the main venoactive drugs
Number of
Group Substance Origin Dosage (mg/day)
Benzopyrones
α-benzopyrones Coumarin Melilot (Melilotus
officinalis L.)
Woodruff (Asperula
odorata L.)
γ-benzopyrones
(flavonoids)
Saponins Escin Horse chestnut (Aesculus
Other plant
extracts
Synthetic products Dobesilate Synthetic 1000–1500 2–3
Source: Reproduced from Ramelet AA etal. Clin Hemorheol Microcirc 2005;33:309–19.
Diosmin Citrus spp.
Sophora japonica L.
Micronized purified
flavonoid fraction
Rutin and rutosides Sophora japonica L.
O-(β-hydroxyethyl)-
rutosides (troxerutin,
hydroxyrutoside [HR])
Ruscus extract Butcher’s broom (Ruscus
Anthocyans Bilberry (Vaccinium
Proanthocyanidines
(oligomers)
Ginkgo biloba Ginkgo biloba L. 2 sachets (extracts of
Benzarone Synthetic 400–600 2–3
Naftazone Synthetic 30 1
Eucalyptus spp.
Fagopyrum esculentum
Moench
hippocastanum L.)
aculeatus L.)
mytrillus L.)
Grape pips (Vitis vinifera) 100–300 1–3
Maritime pine (Pinus
maritima Lank)
(Pycnogenol)
90 combined with
troxerutin (540)
300–600 1 or 2
1000 1 or 2
1000 1 or 2
120, then 60 3
2–3 tablets 2–3
116 2
300–360 3
ginkgo, heptaminol
and troxerutin)
doses/day
3
2
management of the signs and symptoms described above.
Fortunately, few side eects of this treatment have been
reported.
Aescin (horse chestnut seed extract) is the subject of a
separate Cochrane review.
2012, but no publication later than 2002 was included. e
authors found evidence for ecacy on symptoms including
leg pain, edema, itching, leg volume, and circumference in
comparison with placebo. ey recommended that, in view
of the low frequency of adverse events, horse chestnut seed
extract was appropriate for the short-term treatment of the
symptoms of chronic venous disease.
A Cochrane review identied three studies addressing
edema and varicose veins of the lower limbs in pregnancy.3
One study (69 patients) showed that rutoside treatment
reduced symptoms associated with varicose veins. A clinical trial (35 patients) addressing the use of stockings in
pregnancy failed to reduce ankle edema.
2
e review was conducted in
A Cochrane review has addressed the ecacy of rutosides
4
for the treatment of post-thrombotic syndrome.
Primary
outcome measures were the occurrence of leg ulceration and
deterioration of post-thrombotic syndrome. Secondary outcomes included reduction of edema, pain, recurrence of deep
venous thrombosis or pulmonary embolism, compliance
with therapy, and adverse eects. e authors concluded that
there was no evidence that rutosides were superior to the use
of placebo or elastic compression stockings.
In summary, phlebotonic drugs have a modest eect on
the symptoms of chronic venous disease, including edema.
ese become less apparent or disappear when compression
is used as a comparator treatment.
32.3 VENOUS ULCERS
Venous ulceration is conventionally managed by compression treatment, which may be combined with ablation
32.4 Drugs used for venous ulcers 393
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or surgery to varicose veins, perforating veins, and less
frequently with deep vein reconstruction. Compression
treatments have been found to lead to acceleration of healing with a greater proportion of healed ulcers. A signicant problem remains in terms of the rate of recurrence of
ulcers aer healing with compression. Can this be reduced?
Surgical ablation of incompetent supercial veins apparently does not lead to more rapid healing, but does prevent
recurrence of ulceration.5 is is certainly a very valuable
adjunct to compression treatment. e costs of dressing
a leg ulcer in the U.K. National Health Service are in the
range of €6000–20,000 per year. is compares with the
cost of surgical management of varicose veins of around
€2000. Not all patients are prepared to undergo surgical
treatment, especially the elderly. However, ultrasoundguided foam sclerotherapy has been reported to be eective in the management of venous ulceration by Pang etal.6
ese authors noted that healing of leg ulcers was achieved
in 82% of patients following foam sclerotherapy to saphenous trunks and varices, with an ulcer recurrence rate of
4.9% at 2 years.
ese are the standard methods of management, but
is there any advantage of drug treatment in this group?
A small number of drugs has been studied for activity in
promoting leg ulcer healing and some are of historical
interest only. e mechanisms of pathogenesis of venous
ulcers have been investigated at length by several authors,
including myself. Although many factors have been found
to be involved in the inammatory process leading to
leg ulceration, it has not been possible to identify any
“ crucial” step which could readily be inhibited by pharmacological means. I believe that it is too simplistic to consider that such an easy solution could be found. Instead, it
may be better to modify a range of processes observed in
developing leg ulcers. is may lead to useful therapeutic
advance.
on the basis of poor study design. Eight studies addressed
the use of wound dressings, but none showed conclusive
advantage of any other dressing in accelerating wound healing. A further seven studies addressed the subject of topical
growth factor application. e list of compounds applied
topically included platelet lysate, keratinocyte lysate, vasoactive intestinal peptide, granulocyte colony-stimulating
factor (G-CSF), and becaplemin. Of these, only G-CSF
improved ulcer healing signicantly, and these data were
conned to one clinical trial. In ve studies, human skin
equivalents were investigated. ese included Dermagraf,
cultured keratinocytes, Apligraf, Epidex, and cultured epidermal allogras. Amongst these, evidence of improved
healing was found in only one, a study of the use of Apligraf
involving 275 patients.
In summary, wound dressings, growth factors, and
human skin equivalents showed limited ecacy in accelerating wound healing in the trials included. I conclude that
whilst wound dressings of modern design may facilitate the
management of leg ulcers, none has the power to heal ulcers
above the eects of compression bandaging applied alone.
Topical growth factors have no consistent eect, and of the
skin-equivalent dressings, only Apligraf has been shown to
have benecial eects for venous ulcers.
A further Cochrane review has considered the ecacy
of antibiotics and antiseptics for venous leg ulcers.10 No
evidence was found for ecacy of topical antiseptic applications, honey, or silver-based products. Possible evidence
exists of ecacy for cadexomer iodine. Antibiotics are
considered in more detail below.
32.4.1 Systemic drugs for wound healing
Many drugs have been used in the hope of healing leg ulcers.
I have included below those for which reasonable evidence
of ecacy or lack of ecacy has been published.
32.4 DRUGS USED FOR VENOUS ULCERS
A range of drugs has been used in the management of leg
ulcers. ese may be given systemically or applied topically.
In addition, a wide range of wound dressings has become
available, some of which have “active” properties which
might promote wound healing. Honey has been applied to
leg ulcers as a wound dressing in the expectation that this
will lead to more rapid healing. A recent Cochrane review
has found that there is very limited evidence of ecacy for
this treatment amongst low-quality studies.
review assessed the published data in 42 clinical trials in
which hydrocolloid, foam, alginate, and hydrogel dressings were assessed.8 e authors concluded that there
was no evidence that any of these approaches accelerated
wound healing when these were applied beneath compression. A further review has investigated published data
concerning wound dressing and other topical applications.
e authors considered 68 studies for inclusion in their
analysis and eliminated all but 20, excluding the remainder
7
A Cochrane
32.4.1.1 ZINC AND VITAMINS
Greaves and Skillen, in an old but widely quoted paper,
reported complete healing in 13 of 18 patients with previously intractable ulceration aer a 4–month course of
220 mg zinc sulfate three times daily.
11
is might simply
have reected dietary inadequacy in this group. However,
a Cochrane systematic review of zinc supplements considered six small trials which comprised the only available
evidence.12 No benecial eect of oral zinc treatment on
venous ulcer healing was found in these studies.
Adequate nutrition is essential for leg ulcer healing, as
it is for wound healing of other types. A group of authors
in the United States found deciencies of vitamins A, E,
carotenes, and zinc in patients being treated for venous leg
ulcers.13 ey speculated that this reected compromised
nutritional status, which might inuence leg ulcer healing
rates. A further study found that the dietary intake of
9
protein, vitamin C, and zinc may be inadequate in elderly
patients with leg ulcers.
14
is has led to renewal of the sug-
gestion that dietary supplements should be givento elderly
394 Drug treatment of varicose veins, venousedema, and ulcers
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patients with leg ulcers15; however, a broader approach than
single-vitamin supplements was used.
32.4.1.2 FIBRINOLYTIC THERAPY
e concept of an oxygen diusion barrier causing skin
hypoxia was rst proposed by Browse and Burnand in
1982.16 is theory led to attempts to reverse the damaging cutaneous eects of venous hypertension by enhancing brinolysis. e eect of stanozolol, an anabolic steroid
with pro-brinolytic properties, was evaluated in 14 patients
with long-standing LDS, without active ulceration.17 Aer
3 months, all showed clinical improvement both subjectively and objectively (by mapping the area of LDS). Serum
parameters of brinolytic activity improved in all cases.
Fibrinolytic treatment for venous ulceration has been evaluated in one trial of 75 patients.18 Patients were allocated
to receive either stanozolol or placebo for up to 420 days,
with conventional compression treatment in all cases. In an
interim report, the authors found complete healing in 26 of
40 ulcers in the stanozolol group and 27 of 44 in the placebo
group, indicating no benet from active over placebo treatment. No further study has appeared in the 30 years since
this publication. Stanozolol has been withdrawn from clinical use in the U.K.
In a further study, tissue plasminogen activator has been
added as a topical treatment to leg ulcers as an ointment.19
e presence of peri-capillary brin on skin biopsies was
assessed before and aer the treatment, but no dierence
was found. However, despite this, three out of six ulcers
studied healed during the 12 weeks of the investigation.
Dermatan sulfate (DS) is a glycosaminoglycan which
selectively catalyzes the inactivation of thrombin by heparin
cofactor II without interacting with antithrombin III. DS
does not interact with other coagulation factors and, unlike
heparin, is able to inactivate thrombin bound to brin or to
the surface of an injured vessel. Two DS-containing compounds—sulodexide and, particularly, mesoglycan—have
been clinically studied in a number of trials and found to be
eective in the treatment of venous and arterial leg diseases.
Sulodexide is a highly puried glycosaminoglycan with
pro-brinolytic properties.
20
A total of 235 patients were
randomized to receive sulodexide or placebo for 3 months.
e authors reported improved healing in the active treatment group compared to placebo. No further detailed work
on this compound has been published.
32.4.1.3 ANTIBIOTICS
Venous ulcers contain a wide range of bacteria, and this has
led some practitioners to use topical and systemic antibiotics in an attempt to eradicate the bacteria. is is probably a
forlorn hope, since until the ulcer heals, bacteria will colonize the ulcer, although usually these are not the cause of
the problem. ere are some disadvantages to antibiotics as
well. e use of topical antibiotics in leg ulcers may lead to
the emergence of resistant organisms and the risk of sen-
24,25
sitizing the patient to the antibiotic.
Some topical anti-
septics and antibiotics exhibit cellular toxicity that exceeds
their bactericidal activities and has been found to impair
wound epithelialization.
26
A Cochrane systematic review of the use of antibiotics and antiseptics (already mentioned above)10 in chronic
wounds has been published and includes an analysis of 45
clinical trials (4486 participants) of randomized design.
Within this collection of trials were ve addressing the use
of systemic antibiotics, and the remainder assessed the use
of topical antimicrobial drugs and antiseptics. No conclusive evidence of improved wound healing was found with
systemic antibiotic treatment. However, the authors concluded that the limitations of the clinical trials were such
that they could not determine whether systemic antibiotics
could promote healing in patients with clinically infected
ulcers. Lack of ecacy for most topical applications, with
the possible exception of cadexomer iodine, was also found.
I accept that clinical infection of an ulcer should be
treated, and this can be achieved by wound debridement
combined with systemic antibiotics where evidence of cellulitis or septicemia is present.
32.4.1.4 DRUGS WHICH MODIFY
LEUKOCYTE METABOLISM
e discovery of the involvement of leukocytes in the development of venous ulceration has opened new avenues of
investigation in this area.21 A number of drugs which modify white cell activation have been evaluated in patients with
venous ulceration.
32.4.1.4.1 Pentoxifylline
Pentoxifylline is indicated in the management of peripheral
arterial disease, but has also been used in the management
of venous ulceration. Research on this drug indicates that it
has a potent eect on the inhibition of cytokine-mediated
neutrophil activation.22 It has also been shown to reduce
white cell adhesion to endothelium and to reduce the release
of superoxide free radicals produced in the respiratory
burst, which is characteristic of neutrophil degranulation.
A recent Cochrane review identied 12 clinical trials
involving 572 patients in which pentoxifylline has been
used with the aim of improving venous ulcer healing.
Overall, there was an absolute increase in healing of 21%
(95% CI: 8%–34%) in favor of pentoxifylline as an adjuvant
to compression. Healing in the control groups ranged from
a high of 62.2% to a low of 16.67%, so the number needed to
treat may range from 3 (95% CI: 2–12) to 11 (95% CI: 6–43).
ere is evidence that pentoxifylline may be useful in the
management of leg ulcers, especially when combined with
compression.
32.4.1.4.2 Prostaglandin E
1
Prostaglandin E1 (PGE-1) has a number of profound eects
on the microcirculation, including reduction of white cell
activation, platelet aggregation inhibition, small vessel vasodilatation, and reduction of vessel wall cholesterol levels.
has been evaluated in the treatment of various aspects of
arterial disease; less work has been done on its use in venous
23
27
It
32.4 Drugs used for venous ulcers 395
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ulceration. An early trial of the use of intravenous PGE-1
in ulcers of both arterial and venous etiology reported
improvement in four out of ve venous ulcers on PGE-1 as
opposed to four out of seven on placebo—hardly a dramatic
result.28 A further trial yielded more impressive ndings.29 A
total of 44 patients with proven venous ulceration took part
in a double-blind, placebo-controlled trial. Each received
an infusion of PGE-1 (or placebo) over 3 hours daily for 6
weeks, in addition to standard dressings and compression
bandaging. ose on PGE-1 showed a signicant improvement in such parameters as edema reduction, symptoms,
and “ulcer score,” based on depth, diameter, etc. Perhaps
more importantly, eight out of 20 patients on active treatment healed their ulcers completely within the trial period,
whereas only two out of 22 controls did so.
A randomized, placebo-controlled, single-blind study
from 2005 reported 87 patients with venous leg ulcers
who were treated for 20 days with an infusion of PGE-1
(Prostavasin, Schwarz Pharma, Monheim, Germany) or
placebo, in association with topical therapy. e healing of
ulcers was followed for 120 days aer the commencement
of treatment. e main outcome measure was the number of healed ulcers at the end of the study period. In the
active treatment group, all ulcers healed in under 100 days,
whereas in the placebo group, only 84% did so by the end of
the 120-day observation period (P < 0.05). is study demonstrates the eectiveness of PGE-1 in reducing the healing
time of venous ulcers.30 Subsequently, no further publication regarding the ecacy of this treatment has appeared.
32.4.1.4.3 Prostacyclin analogs
Iloprost (Schering, Berlin), a synthetic prostacyclin analog,
has been used with success in the treatment of arterial and
diabetic ulcers.31 e mechanism of action of prostacyclin
includes increased brinolytic activity,32 reduced leukocyte
aggregation, and adhesion to endothelium,
33,34
in addition to
its better-known eects on platelet inhibition.35 A study in
which this was applied topically to venous ulcers was disappointing, with no dierence observed between active treatment group and placebo.36 In 2007, a report was published
of a clinical trial in which patients with venous leg ulcers
received a daily infusion of iloprost or saline for 3 weeks.
37
All patients received standard wound management combined with elastic compression. Aer 90 days, all patients
in the iloprost group but only 50% in the control group had
healed. Aer 150 days, 84% of patients in the control group
had healed. e authors concluded that iloprost was eective at speeding venous ulcer healing. No further publication addressing the ecacy of iloprost in the management
of venous leg ulcers has appeared subsequently.
32.4.1.4.4 Diosmin–hesperidin
is combination of avonoid drugs has been used to manage the symptoms of chronic venous disease, including
edema of the lower limbs, for many years. e use of this
application has been summarized above. More recently,
a number of clinical trials has been completed in which
one avonoid drug was used to treat patients with venous
leg ulcers. Micronized puried avonoid fraction (MPFF;
®
Daon 500 mg
, Servier, Gidy, France), which consists of
90% Diosmin and 10% avonoids expressed as Hesperidin,
has been shown to protect the microcirculation from damage secondary to raised ambulatory venous pressure.38 It
decreases the interaction between leukocytes and endothelial cells by inhibiting expression of endothelial intercellular
adhesion molecule 1 and vascular cell adhesion molecule, as
well as the surface expression of some leukocyte adhesion
molecules (monocyte or neutrophil CD62L and CD11B).39
ere are few known side eects, and interactions with
other drugs have not been reported.
38
In a meta-analysis, clinical trials were sought in which
MPFF had been used as an adjunctive therapy to compression and appropriate local care.40 Outcome measures
included time to ulcer healing and proportion of healed
ulcers. Five prospective, randomized controlled studies in
which 723 patients with venous ulcers were treated between
1996 and 2001 were identied. Conventional treatment
(compression and local care) in addition to MPFF was compared to conventional treatment plus placebo in two studies (n = 309) or with conventional treatment alone in three
studies (n = 414). e primary endpoint was complete ulcer
healing at 6 months. e results are expressed as reduction
of the relative risk (RRR) of healing with 95% condence
intervals. Since the desired treatment eect is increased
ulcer healing, the RRR should be positive to indicate a benet of adjunctive MPFF over conventional therapy alone.
At 6 months, the chance of healing ulcer was 32% better in patients treated with adjunctive MPFF than in those
managed by conventional therapy alone (RRR: 32%; 95% CI:
3%–70%). is dierence was present from month 2 (RRR:
44%; 95% CI: 7%–94%) and was associated with a shorter
time to healing (16 weeks vs. 21 weeks; P = 0.0034). e benet of MPFF was found in the subgroup of ulcers of between
5 and 10 cm2 in area (RRR: 40%; 95% CI: 6%–87%), as it was
in patients with ulcers of 6–12 months’ duration (RRR: 44%;
95% CI: 6%–97%).
ese results conrm that venous ulcer healing is accelerated by MPFF treatment. MPFF might be a useful adjunct
to conventional therapy in large and long-standing ulcers
which might otherwise be expected to heal slowly.
A Cochrane review has considered the ecacy of avonoid drugs in promoting leg ulcer healing.
41
e authors
included nine studies with 1075 participants and found evidence of the ecacy of avonoid drugs for promoting leg
ulcer healing. However, the authors commented on the poor
quality of reporting of the trials of these drugs.
32.4.1.5 PLATELET INHIBITORS
32.4.1.5.1 Aspirin
e use of aspirin has been reported in a small number of
patients undergoing treatment for leg ulceration.42 iseect
has never been substantiated in a clinical trial of any type
and there is no evidence of ecacy for this purpose.
396 Drug treatment of varicose veins, venousedema, and ulcers
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32.4.1.5.2 Ifetroban
Eects of the oral thromboxane A2 receptor antagonist
ifetroban (250 mg daily) on the healing of chronic lower
extremity venous stasis ulcers has been studied in a welldesigned prospective, randomized, double-blind, placebocontrolled multicenter study.43 is drug has a profound
inhibitory eect on platelet activation. e results show no
ecacy for inuencing venous ulcer healing.
32.5 DRUG TREATMENT FOR CHRONIC
VENOUS DISEASE
32.5.1 Varicose veins and edema
So when is it appropriate to prescribe phlebotonic drugs
in patients with varicose veins or edema? In temperate climates, the use of compression stockings is generally considered to be the most appropriate conservative measure.
However, in hot climates, the wearing of stockings is less
acceptable for patients, who may nd that they cause intolerable discomfort. ere may be some rationale in prescribing phlebotonic drugs in these circumstances.
Diosmin and Hesperidin may be useful in trophic disor-
ders, as well as cramps and swelling. Rutosides may benet
44
edema.
32.5.2 Venous ulcers
A detailed strategy for the management of leg ulcers has
been set out by the Society for Vascular Surgery and the
American Venous Forum.45 ese recommend against the
use of topical antimicrobial drugs (Guideline 4.15) in the
routine management of leg ulcers. Treatment of the underlying cause of the leg ulcer, where feasible, is advised. As an
ancillary measure, systemic treatment with pentoxifylline
or MPFF is recommended (Guideline 7.2).
Compression treatment and surgery to treat incompetent
supercial varices and perforating veins are the main lines
of management in patients with venous leg ulcers. Only two
drugs have been shown to have any inuence on venous
ulcer healing in a meta-analysis: pentoxifylline and MPFF.
Both should be used in combination with compression and
standard wound management. Ecacy is probably most
apparent in large (5–10 cm), long-standing ulcers (more
than 6 months). ese drugs have few side eects and could
be considered when compression alone has proved to be
ineective in countries where these compounds have been
licensed.
PGE-1 has also been shown to have ecacy in promoting
venous ulcer healing, but this is conned to one randomized controlled trial. In addition, this drug must be given by
intravenous infusion and has some signicant side eects.
More detailed work is required before a recommendation
can be made for its use in venous disease.
32.6 SUMMARY
●
Varicose veins and edema are best managed by the use
of compression, ablation techniques, or surgery to treat
incompetent saphenous trunks, varices, and perforating
veins.
●
Some phlebotonic drugs improve the symptoms and
edema associated with venous disease. ese could be
used in association with compression for the manage-
ment of troublesome symptoms.
●
Venous ulcers are best managed by strong compression
and wound management. In patients with incompetent
supercial veins and perforators, these should be man-
aged by ablation techniques or surgery.
●
Long-standing or large venous ulcers may benet from
treatment with either pentoxifylline of MPFF used in
combination with compression.
Guidelines 4.4.0 of the American Venous Forum on the drug treatment of varicose veins, venous edema, and ulcers
No. Guideline
4.4.1 We suggest venoactive drugs (Diosmin, Hesperidin,
rutosides, sulodexide, micronized purified flavonoid
fraction, horse chestnut seed extract [escin], ruscus, and
dobesilate) in addition to compression for patients with
pain and swelling due to chronic venous disease in
countries where these drugs are available.
4.4.2 Long-standing or large venous ulcers may benefit from
treatment with either pentoxifylline or micronized purified
flavonoid fraction used in combination with compression.
4.4.3 We suggest Diosmin and Hesperidin in trophic disorders as
well as cramps and swelling. We suggest rutosides in
patients with venous edema.
Grade of
recommendation
(1: strong; 2: weak)
2 B
1 B
2 B
Grade of evidence (A:high
quality; B:moderate quality;
C:low or very low quality)
References 397
https://t.me/med1917
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Liquid sclerotherapy for telangiectasia
https://t.me/med1917
andvaricose veins
EDWARD G. MACKAY
33
33.1 Introduction 399
33.2 Historical review 399
33.3 Diagnosis and examination 399
33.4 Indications 400
33.5 Contraindications 401
33.1 INTRODUCTION
In recent years, many new treatment options for varicose
veins have emerged, including endovenous thermoablation,
microfoam sclerotherapy, mechanica l chemical ablation, and
cyanoacrylate glue ablation. ese options will be covered in
other chapters. Despite the new possibilities, however, liquid
sclerotherapy serves as the main treatment option for small
varicose veins (<3 mm) and for telangiectasia, also known as
spider veins. In addition, liquid sclerotherapy may be indicated for larger veins in situations to which other options
are not well suited. Although problems in small veins are
generally considered to be cosmetic, they are nonetheless
extremely important to patients. Additionally, some patients
do describe symptoms of pain, burning, or swelling.
33.2 HISTORICAL REVIEW
Liquid sclerotherapy involves the injection of certain substances into the veins, with the goal of destroying the vein
wall, resulting in sucient damage to close the vein. As
far back as 1682, there were attempts to treat veins with an
injected substance, and from the middle of the nineteenth
century onward, following the invention of the hypodermic
syringe, there were eorts in Europe to test various sclerosants, but results were oen poor, with patients suering
allergic reactions, high levels of pain, and tissue damage.1 In
the late 1920s and early 1930s, the use of sclerotherapy with
a solution of quinine and urethane was reported at the Mayo
2,3
Clinic.
to be used as a sclerosant. At the end of the 1930s, Smith
reported poor long-term outcomes from sclerotherapy.
Beginning in the 1930s, sodium morrhuate began
4
In
33.6 Treatment 401
33.7 Adverse events 405
33.8 Clinical practice guidelines 407
Acknowledgment 407
References 407
the intervening years, however, with the introduction of
dierent sclerosants and improved techniques for administering them, sclerotherapy results have improved. Sodium
tetradecyl sulfate (STS), and polidocanol (PDL) have both
been used widely in sclerotherapy for decades. PDL received
Food and Drug Administration (FDA) marketing approval
in 2010 and is sold in the United States under the trade
name Asclera® (Merz North America, Inc.). STS, sold under
the brand name Sotradecol® (Bioniche USA, Inc.), has been
grandfathered in because of its long history of use.
In 1993, Einarsson et al. reported the results of a randomized trial of 164 patients. Good results were seen in
both compression sclerotherapy and surgical treatment
groups immediately aer procedures, but aer 5 years, there
was a much higher rate of treatment failures in the compression sclerotherapy group (74%) compared with the surgery
group (10%).
ing the results, with foam sclerotherapy techniques eventually becoming comparable to surgical methods. is will be
covered in a subsequent chapter.
6
Ultrasound-guided techniques kept improv-
5
33.3 DIAGNOSIS AND EXAMINATION
33.3.1 Clinical history
Patients oen seek treatment for reticular veins (1–3 mm
in diameter) and spider veins (<1 mm) for cosmetic rea-
sons, but a complete history and physical are necessary to
determine any underlying issues related to the patient’s concerns. A careful history may reveal important information,
such as reports of leg swelling, which may suggest potential
venous insuciency. It will also help determine whether
399
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