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classes are available applying variable level of compression, but unfortunately there is no
uniform agreement on the nomenclature of compression classes.
Pathophysiology and Mechanism of Compression
Several mechanisms are responsible for the improvement of symptoms of varicose veins
and healing of venous ulcers by leg compression. Leg compression reduces the volume of
blood pooled inside the varicose veins and restores the valvular function of the long or
short saphenous vein or even occludes them; this prevents venous over-distension and
minimises venous wall tension, which is responsible for local symptoms like ache, pain,
itching, etc. Similarly, high-grade compression reduces popliteal vein reflux in post-
thrombotic patients (2).
Elastic compression has been shown to reduce the venous filling index (VFI); (3–5)
it is not known if this is the result of reducing the rate of venous wall expansion or because
the reduction of the diameter of superficial venous segments abolishes reflux. VFI
improvement has been shown to be greater with inelastic compression (4,6). It is also
thought that compression diverts blood toward the deep veins via the perforating veins, or
in cases where the latter are incompetent, that compression prevents the outward surge of
blood during walking. This could be responsible for the improvement in muscle pump
function expressed as reduction in residual volume fraction observed both during resting
(3,5) and walking (7). The combination of inelastic (Unna boot) and elastic compression
is probably more effective in normalizing venous hemodynamics, and one study has
demonstrated further increases in venous refill time (8). Higher grades of compression
could also improve deep vein hemodynamics, a significant problem in post-thrombotic
legs. As a result of improving venous hemodynamics, elastic stockings reduce ambulatory
venous pressure (9,10). Partsch has shown that thigh compression at the pressure range of
40 to 60 mm Hg with strongly applied short-stretch bandages on the thigh, but not class II
thigh-length compression stockings, is able to significantly reduce venous diameter or
venous reflux (11).
Compression increases interstitial pressure in the skin and subcutaneous tissues,
preventing their expansion and reducing edema formation; (12–14) this is probably
accomplished by improvement in lymphatic drainage resulting in improvement of patient
symptoms, including leg heaviness and promotes ulcer healing. A result of direct skin
compression is the improvement of venous hypertensive microangiopathy (15). Long-term
use of elastic compression has been shown to improve venous elasticity (16), and prevent
Table 1 Different Types of Compression
Types of compression Characteristics Indications
Elastic compression Stockings or bandages (short or
long-stretch) made from woven textile
with elastic properties
Varicose veins, varicose
vein surgery
Sclerotherapy
Inelastic compression Rigid compression garments or bandages
with no elastic properties
Varicose veins, venous
ulcers
Compression systems Multiple layers of bandages able to
sustain a high compression profile for
several days
Venous ulcers
Intermittent pneumatic
compression
Pneumatic sleeves, periodically inflated Venous ulcers
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anatomical deterioration of the disease pattern (12). Labropoulos reported that
the beneficial effect of elastic stockings on the venous hemodynamics is present
mainly when the stockings are worn and completely abolished within a day after their
removal (17).
Limbs with chronic venous insufficiency (CVI) have a reduced ankle range of
movement (ROM), which may contribute to poor calf pump function (18). ROM is worse
in advanced venous disease (18), and is a predictor of poor healing of venous ulcers by
compression (19).
Level of Compression Applied According to Disease Severity
Advanced venous disease, especially if complicated with edema or ulcers, typically
necessitates stronger compression, as shown in Table 2. This is to compensate the
higher ambulatory pressure observed especially in post-thrombotic syndrome. In the
latter case, compression pressure at the ankle level should be as strong as the four-layer
compression system (40 mmHg) (20). High compression is more effective than low
compression (21), but limitations of this are patient concordance. Occasionally, and
mainly in cases of phlebolymphedema compression, should be even higher, above
45 mmHg.
Effectiveness of Compression
Compression therapy has shown variable success in treating varicose veins and its
complications. Graded elastic stockings reduce leg symptoms, including edema and
pain (22–24), and improve quality of life (24). In a recent study, severity score reduction
for lower extremity swelling, pain, skin discoloration, activity tolerance, depression and
sleeping problems after 1 and 16 months of treatment with compression stockings varied
from 25% to 54% (25). In mesomorphic patients, noncustom graded compression
stockings are equally effective with custom stockings (26).
A recent Cochrane review confirmed that compression increases ulcer healing
rates compared with no compression (21). Compression significantly improves quality
of life in patients with venous ulcers as estimated with the SF-36 (27), and EuroQol
questionnaires (28), comparable with surgery (28). Similarly elastic stockings, compared
to placebo stockings, improve quality of life in patients with symptomatic varicose veins
as estimated by the CIVIC questionnaire (24).
In patients with venous ulcers, healing rate with the four-layer bandaging has
been reported to be about 65%–80% at 6 to 12 months (19,29,30), significantly better (19),
Table 2 Severity of Venous Disease and Recommended Compression
Compression level
(mmHg) Indication
15–20 mmHg Mild varicose veins, including those which appear during pregnancy
Post-surgery
21–30 mmHg Symptomatic varicose veins
Post-sclerotherapy
31–45 mmHg Post-thrombotic syndrome
Healed venous ulcer to prevent recurrence
O45 mmHg Phlebolymphedema
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and faster compared to inelastic compression (19,31), or usual practice (32). A recent
Cochrane review concluded that multi-layered systems are more effective than single-
layered systems (21).
Compression effectiveness is affected by proper use. Bad or no usage due to
compliance problems was associated with 97% of recurrent ulcerations in one study (33).
Two studies have shown that although compression is equally effective with
superficial venous surgery in healing leg ulcers (29,34), recurrence rate is higher with
compression when this is stopped. Recurrence varied from 28% to 36% at one to three
years (29,34). Based on these results, surgical correction should be offered, ideally when
all ulcers have healed and edema is minimal. Similarly, treatment failures of compression
should be managed with superficial or deep venous surgery in fit patients. Although
improved diagnostic and operative techniques make possible more active approaches to
venous ulceration (35), unfortunately, some patients with post-thrombotic syndrome will
need to use compression indefinitely; this is because surgery is not feasible or because it is
partially or not effective whatsoever.
Special Indications of Compression (Post-Surgery, Sclerotherapy)
Elastic stockings are routinely used after sclerotherapy is performed; this has been
shown to increase efficacy from 80% to 92% and reduce the incidence of superficial
thrombophlebitis (36). Provided that high compression stockings are worn, the additional
use of elastic compression is not necessary (37).
Adequate compression bandaging can decrease subcutaneous haematoma formation
after varicose vein stripping (38). This is replaced after a variable period of time with
elastic stockings. Low compression stockings (15–20 mmHg) are preferred because they
are more comfortable and equally effective in controlling bruising and thrombophlebitis
compared to high compression stockings (40 mmHg) (37).
Compliance, Cost-Effectiveness, and Complications
of Leg Compression
In some 20–25% of patients, compliance or concordance with elastic stockings is
moderate or poor (24). Socio-economic and cost issues are a major reason for non-
compliance (33,39). Non-compliance with elastic compression stockings significantly
decreases ulcer healing and increases recurrence. One study has shown that all patients
who were noncompliant had recurrent ulceration by 36 months (40).
Cost-effectiveness analysis has shown that elastic stockings in patients with prior
venous ulceration are cost saving, even with the most conservative of assumptions (41).
Similarly, four-layer bandaging is associated with lower treatment cost compared to two-
layer compression and short-stretch bandaging (42,43).
The four-layer bandage offers advantages over the two-layer bandage in terms of
fewer adverse events and withdrawals from treatment (42,44). Skin maceration,
excoriation, dryness or other damage, ulcer deterioration or infection or bandage failure
have been reported (19). Ischemic complications associated with the use of these stockings
also appears to be more common than previously thought (45). Toe ulceration associated
with compression bandaging has been also reported (46). In order to prevent these
ischemic complications, an ankle/arm index !0.6 is a contraindication for compression
hosiery therapy (47). Other contraindications include peripheral neuropathy and allergy to
the elastic material used.
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Durability of Compression
Elastic compression material loses its elasticity over time. Three new stockings each year
have been recommended to ensure an effective function (48). Similarly, compression
systems maintain their compression profile up to a week; this is significantly better than
single layer compression (20).
INTERMITTENT PNEUMATIC COMPRESSION
It has been shown that intermittent pneumatic leg compression (IPC) plus compression
increased ulcer healing more than compression alone, the relative risk for healing being
11.4 (49). However, in view of the small size of this study, a Cochrane Review suggested
that further trials are required to determine whether IPC increases the healing of venous
leg ulcers (50). Since compression alone frequently fails, the additional use of IPC by
these difficult-to-heal ulcer patients is probably helpful, as indicated by Rowland, who
found that a crossover policy (compression to IPC and vice-versa) is more effective in
healing ulcers (51). Home use of impulse compression of the foot and compression
stockings has also been proposed for patients with CVI, with patients reporting significant
improvement of swelling and pain (52). Awaiting methodologically rigorous research
designed to identify the optimal choice of compression therapy or optimal protocol for
patients with CVI or venous ulcers, Medicare USA has issued a decision that pneumatic
compression will only be covered for patients with refractory edema with significant
ulceration of the lower extremities after a six-month trial of standard therapies, such as
compression stockings, has failed (53).
SUPERVISED EXERCISE
CVI is associated with impaired calf muscle pump function (3). Structured exercise has
been shown not only to improve not only dynamic calf muscle strength but also calf
muscle pump function (54,55). It remains unclear if exercise will improve leg ulcer
healing rate and further research is warranted.
SKIN SUBSTITUTES
Acceleration of wound closure particularly in wounds that are slow to heal may be
achieved through the application of skin substitutes. Commercially available skin sub-
stitutes hold a number of advantages over autologous skin grafts; they do not generate a
donor site or cause associated acute wound pain, they therefore avoid the not need for the
administration of an anaesthetic and they avoid the risk of scarring at the donor site (56).
Additionally it has been found that the donation of connective tissue to the wound may
enhance the strength of the wound and reduce scarring (57–59).
Bio-engineered skin substitutes applied to a wound can donate both epidermal
and dermal components. Fibroblasts found in the dermis are important contributors to
healing through the synthesis of collagen, the expression of cytokines and the formation
of myofibroblasts.
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Fibroblasts may be applied to the wound in the form of an allograft (sometimes
called homograft) or as an autograft. In either case fibroblasts are harvested from dermal
cells and then cultured in the laboratory in a suitable growth medium. It can take up to four
weeks to “grow” the graft ready for application to the wound. Wounds should be free of
infection and patients should be checked for any known hypersensitivities to agents
(e.g., bovine proteins) that may have been used during the manufacturing process or in
storage solutions.
Cultured fibroblast may be used on a variety of wounds and provide a “high tech”
off-the-shelf approach to achieving wound closure (60).
Views on cost effectiveness vary. When considering skin substitutes and ulcer
healing, Sibbald et al. (61) and Harding et al. (62) remain sceptical, although Sibbald
et al. (61) indicated that greater gains were evident when the ulcers were of longer
duration. Others have found a positive cost benefit. Kirsner et al. found reduced healing
time and fewer complications together with a cost benefit (63). Positive findings have
also been recorded by Nunez-Gutierrez with burns (64) and Redekop in diabetic foot
patients (65).
Although undoubtedly expensive when compared on a unit cost basis with wound
dressings, skin substitutes would appear to offer a useful therapeutic alternative. Their
advantage would appear to currently lie in the treatment of those wounds that are resistant
to “traditional” approaches (60). Brief details are provided of two commercial products
that are widely available.
Apligraf
w
consists of living cells and proteins and is the only bi-layered skin
substitute available. Apligraf does not contain all of the cells and structures normally
found in skin and in common with other substitutes is limited to providing a stimulus to
healing through the donation of growth factors and matrix components while at the same
time affording a degree of protection to the wound bed. Keratinocytes are found in the
upper (epidermal) layer of Apligraf and type one collagen and fibroblasts in the lower
dermal layer.
Dermagraft
w
is also composed of human fibroblasts that are derived, like Apligraf,
from neonatal foreskin. The graft is presented as a cryo-preserved sheet where the
fibroblasts are seeded onto a bio-absorbable mesh scaffold.
Apligraf and Dermagraft do not contain melanocytes, Langerhans’ cells, macro-
phages, or lymphocytes.
Lindgren et al. reported on a randomized controlled trial where 27 venous leg ulcers
were treated with cryopreserved cultured allogenic keratinocytes and compression or
compression only (66). Their results are inconclusive and inferred that the cryopreserved
nature of the skin substitute adversely effected the capacity of the keratinocytes to produce
cytokines and growth factors.
Encouraging results with a bilayed product were, however, reported by Falanga
and Sabolinski (67). In this randomized controlled trial (nZ120), patients with venous
leg ulcers of at least one year’s duration were treated with compression only or with
compression and the bilayered skin substitute. The results showed that the bilayered
product was able to significantly accelerate healing in long-standing venous leg ulcers.
Hjerppe et al. have presented data of a noncomparative series of case studies of 114
patients with 151 difficult-to-heal chronic ulcers of various etiologies (68). The chronic leg
ulcers were treated with human fibroblast-derived dermal substitute and showed the
benefits obtained with an overall reduction in size of the ulcers being 63%.
Irrespective of the encouraging results demonstrated by a variety of clinical studies,
it is important to remember that whatever improvement in healing rates are demonstrated
with whatever product is used, the underlying cause of the ulcer is not being addressed
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with the application of bio-materials, and consequently there is a high risk of recurrence if
maintenance therapy is not strictly adhered to.
PHARMACOLOGICAL TREATMENT OF CHRONIC
VENOUS DISORDERS
The term chronic venous disorders (CVD) is used to denote all abnormal clinical changes
that result from venous disease of the lower extremities and that have a chronic course
(69). According to this definition, CVD includes patients who present with so-called
symptoms and/or signs of venous disease which characterize each class of CVD in the
CEAP classification (70), from class C0s to class C6.
A review of the literature (71) shows that CVD is most commonly manifest by the
following symptoms: heaviness in the legs, pain, a sensation of swelling, restless legs,
paresthesias, nighttime cramps, tiredness, and itching.
It must be stated that none of these symptoms is specific for CVD and is even less
so pathognomonic. Since it is not possible to confirm whether such symptoms are related
to venous disease, it appears important to try to characterize these symptoms based on the
following secondary criteria:
† Variability with position or physical activity: Symptoms generally occur after
prolonged standing, at the end of the day and do not exist or are diminished in the
morning, by supine position or with the legs elevated
† Variability with temperature: Symptoms occur or are exacerbated by warmth,
the summertime season, hot baths, hot waxing to remove body hair, floor-based
heating systems, and regress; symptoms are diminished in winter and with
cold temperatures
† Variability with levels of circulating sex hormones: Symptoms fluctuate with the
menstrual cycle; they can occur with hormonal therapy (estrogens or estrogen-
progestin) and disappear with discontinuation of such treatment.
The existence of at least two secondary criteria is necessary to confirm that
symptoms are related to CVD, but the absence of such criteria does not rule out the
possible venous-related origin of the symptoms.
Whatever the therapy used, the effect of treatment on symptoms is difficult to
quantify because these symptoms are subjective variables.
Therapeutic efficacy can be assessed more readily based on a certain number of signs
such as edema or venous ulcers.
Classification of Phlebotropic Drugs
Phlebotropic drugs belong to several different chemical families. The majority of them are
plant-derived compounds. Some have been produced by chemical synthesis. The main
phlebotropic drugs (72) are summarized in Table 3.
Pathophysiological Targets of Phlebotropic Drugs
It is important to specifically identify the mode of action of phlebotropic drugs depending
on the pathophysiological mechanisms that they aim to treat. Among such mechanisms,
we can differentiate the following:
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† Those that are identified before microcirculatory disorders occur, consisting
mainly of alterations in the venous wall; and
† Those consisting of microcirculatory disorders.
Pharmacological Targets Before the Occurrence of Abnormal Changes
in the Microcirculation
Two major mechanisms may be responsible for pain in the absence of trophic changes:
† First, venous wall tension, which results from dilatation of the vein in a normal
subject in erect position and valvular incompetence during dynamic movement
in erect position in a subject with valvular insufficiency; and
† Second, hypoxia of the tunica media of the venous wall due to alteration of the
vasa vasorum.
Pain seems more related to hypoxia; indeed, in the early stages of CVD,
superficial venous distensibility is slight, while pain is more severe than in the
advanced stages of CVD where venous pressure is elevated and therefore high
venous wall pressure exists (73). However, the venous remodeling phase that
precedes the development of varicose veins, which is accompanied by the
process of venous distention, hemorrheological disturbances, and conditions of
hypoxia can be painful.
Pain and Heaviness in the Legs. Two specific targets for phlebotropic drugs exist
that aim to decrease the sensation of heaviness in the legs, pain, and ankle edema at the end
of the day. The first target of such therapy is increased venous wall pressure: indeed, it is
known that distensibility is increased by 10–50% in patients (74) according to different
studies and that this is due to a decrease in venous tone. The second target is hypoxia of the
tunica media related to disease of the vasa vasorum (73).
Table 3 Classification of the Main Phlebotropic Drugs
1. Benzopyrones
a) Alpha-benzopyrones
Coumarin (1,2-benzopyrone; 5,6-alpha-benzopyrone)
Dicoumarols (dimers of 4 hydroxycourmarins): oral anticoagulants
b) Chromenones (flavonoids)
Micronized purified flavonoid fraction (MPFF)
Diosmin, kacinprerol, diosmethin, quercetin, rutin and derivatives, O-(b-hydroxyethyl)
rutosides (HR or oxerutins)
2. Saponins
Escin, horse-chestnut extracts
Extracts of ruscus, centella asiatica
3. Other plant extracts
Anthocyanosides: blueberry extract (protoescigenin, barringtogenol, a- and b-escin,
cryptoescin)
Proanthocyanidols: grape seed extracts
Ginkgo biloba
4. Synthetic products
Calcium dobesilate
Benzarone, naftazone
Source: Adapted from Ref. 72.
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Restless Legs, Nighttime Cramps. These symptoms most often occur during the
latter half of the night, but also can occur during prolonged seated position. They can also
be related to hypoxia of the tunica media, but more specifically may be associated with
hemorheological disorders (73). In fact, red blood cell hyperviscosity and hyperaggrega-
tion are constant findings in venous disease (75,76). It appears likely that hemorheological
disorders worsen the circulation in the vasa vasorum. Hypoxia in the tunica media, in turn,
induces deterioration of the venous wall. Indeed, hypoxia has a potent effect in inducing
metabolic disorders: triggering of enzymatic activities, such as those of matrix metollo-
proteinases (MMP), and dedifferenciation and migration of smooth muscle cells which
secrete growth factors. Fibrosis of the venous wall governs the development of the
varicose vein. The diseased venous wall generates several metabolic disorders, including
hypofibrinolysis due to elevated levels of plasminogen activating inhibitor (PAI-1).
The links between pathophysiology, symptoms and clinical signs of CVD are
summarized in Table 4.
Pharmacological Targets Related to Microcirculatory Disorders
The process of edema manifestly is due to increased capillary permeability related to
permanent venous hypertension (73), whose mechanisms vary: reflux or obstruction.
Two stages should be distinguished in the progression of capillary disorders as
venous disease becomes progressively worse: first, the existence of a functional disorder
followed by development of a lesional disorder, which characterizes chronic
venous insufficiency.
Capillary Functional Disorder. At a relatively early stage, the existence of a
reduction in capillary permeability is observed in patients, as assessed by ankle
plethysmography following proximal venous hypertension with fluorescein capillary
angioscopy and the Gibbon-Landis radioisotope test. A second aspect is capillary fragility
demonstrated by the suction cup test.
Traditionally, such disorders are taken as targets for studying the effects of
phlebotropic drugs (Table 5). However, it is not known whether they play a part in the
development of lesional disorders. An argument in support of a possible action is that they
are accompanied by micro-edema and hemorrheological disorders, which exist at an early
stage of venous disease. And yet, it is known that red blood cell hyperaggregation
promotes microcirculatory disorders.
Table 4 Possible Links Between Pathophysiological Variables, Symptoms, and Signs of Chronic
Venous Disorders
Pathophysiology Symptom Sign
Leukocyte adhesion in subvalvular
areas/areas of inflammation
Pain Early valvular reflux
Valvular incompetence Reflux
Venous hypertension and venous wall
tension
Pain Edema
Venous wall hypoxia Pain
Increased capillary pressure Sensation of heavy legs and
swelling
Edema
Hemorrheological disorders and
platelet hyperaggregability
Nighttime cramps
Restless legs
Source: Adapted from Ref. 73.
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Microvascular Lesional Disease. Alteration of the cutaneous microcirculation
in the lower extremities is the long-term result of permanent venous hypertension, as
the distal venous valves gradually become incompetent. The result is trophic changes
whose incidence is proportional to the increase in ambulatory venous pressure.
Over the last few years, advances have been made in understanding the patho-
physiology of events, allowing better identification of the structures targeted by
phlebotropic drugs:
† Doppler-laser investigation has shown an increase in cutaneous blood flow at
rest, related to increased concentrations of circulating red blood cells. This
involves impairment of blood distribution affecting the most superficial areas
where hypoxia develops, while intra- and subcutaneous PO2 concentrations are
normal (77);
† Hypofibrinolysis increases concomitantly with increasing severity of trophic
changes, usually with very high levels of PAI-1 (78);
† The hemorheological disorder, in particular, red blood cell hyperaggregation, is
exacerbated and correlated with the clinical severity of the disease;
† Hypoxia and excess delivery of oxygenated free radicals in the most superficial
capillaries promote endothelial and leukocyte activation (79);
† Therefore, leukocyte accumulation and activation in dilated capillary loops
appears as a factor which worsens the condition, extensively involved in the
pathogenesis of venous ulcer (79).
In summary, microcirculatory disorders progressively worsen with hemo-dynamic
alterations. During this process, leukocyte adhesion to the vascular endothelium produces
endothelial activation with release of proteolytic enzymes and free radicals in the tissues
(80). In addition, in vitro studies have demonstrated the release of prostaglandin
(especially PGF2a) and basic fibroblast growth factor (bFGF) which may be directly
involved in venous wall remodeling (81). These mediators are found in an abnormal
quantity in varicose veins (82). During this process, venous valves may be the first to be
damaged (83).
Table 5 Pharmacological Targets of Phlebotropic Drugs
1. Analgesic, anti-edema and capillary protection effects: all products
2. Effect on venous tone: all products
Ruscus: partial agonist action on venular alpha-1 adrenergic receptors (neutralized by NO on the
arterial side)
3. Lymphotrophic effects: Ruscus, coumarin, micronized purified flavonoid fraction
4. Improvement of red blood cell rheology: micronized purified flavonoid fraction, troxerutin, rutin
5. Profibrinolytic action: micronized purified flavonoid fraction, troxerutin, diosmins
6. Anti-inflammatory action: micronized purified flavonoid fraction, Gingko biloba, diosmins
7. Decreased adhesive properties of neutrophils and monocytes: micronized purified flavonoid
fraction
8. Protective effect on the venous valve: micronized purified flavonoid fraction
9. Protective effect on the venous wall
9.1: inhibition of lysosomial enzymes: melitot extract, rutins, pycnogenols
9.2: protection of fibrous proteins (collagen): procyanidolic oligomers
9.3: anti-free radical properties: micronized purified flavonoid fraction, Gingko biloba
9.4: normalization of the synthesis of prostaglandine E2 : micronized purified flavonoid fraction
9.5: improvement of circulation in the vasa vasorum: troxerutin
Source: Adapted from Ref. 73.
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The interaction between leukocyte and endothelium may be the key component in
the pathogenesis of CVD and its complications, and may be an essential entity targeted by
phlebotropic drugs.
Pharmacological Action of Phlebotropic Drugs on These Different Targets
Remacle’s team has demonstrated the ability of phlebotropic drugs to inhibit the release
of mediators of inflammation in endothelial cells placed under conditions of hypoxia
(Fig. 1) (84,85).
A recent pharmacological study has demonstrated the ability of the micronized
purified flavonoid fraction (MPFF) to protect venous valves from destruction caused by
venous hypertension (86). It is by inhibiting the expression of adhesion molecules on the
surface of leucocytes and the endothelium that this phlebotropic drug would limit
leukocyte adhesion and subsequently leukocyte inflitration into the valvular
subendothelium, limiting inflammatory events (86). This effect had been demonstrated
previously with the same preparation in the microcirculation (87).
Clinical Trials of Phlebotropic Drugs
Action on Symptoms
Pain and heaviness in the legs are the two symptoms most commonly identified in studies
on symptoms of venous disease (71).
Symptoms, and in particular, pain, can be evaluated with self-evaluation rating
scales. Three types of scales have been validated: (88) the simple verbal scale, the
numerical scale and the visual analog scale. All these scales evaluate pain intensity but do
not provide information on the nature of the pain complaint. They make it possible to
compare intra-individual variations between groups of patients in evaluation studies or
longitudinal observational surveys.
Symptoms have an effect on the quality of life of patients with CVD. Overall
assessment of quality of life allows quantification of the impact of symptoms on
functional ability. Several quality of life questionnaires have been specifically adapted to
CVD (89–91).
Figure 1 Representation of the possible protective mechanism of phlebotropic drugs on the
endothelial cells. Source: Adapted from Ref. 85.
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