Systematic review of Lower Limbs` Superficial Venous

Systematic review of Lower Limbs’ Superficial Venous Thrombosis’ treatments, their results
and complications
AUTHORS:
OLIVEIRA, Ana Camila Barroso Carvalho de – [email protected]
FREITAS, Ana Catarina Ribeiro – [email protected]
BARBOSA, Ana Luísa Castro – [email protected]
RAMOS, Ana Rita Saldanha – [email protected]
VILELA, António José Oliveira Pereira – [email protected]
DIAS, Daniel Martinho Ferreira Dias – [email protected]
MARQUES, Daniela Cristina Guimarães Marques – [email protected]
NEVES, Emmanuel Rebelo – [email protected]
FONTES, Mário Rui Ascensão Dias de Lima – [email protected]
ABREU, Vasco Rafael Lima Sousa – [email protected]
ADVISER: Teacher Sérgio Sampaio.
Class number 20.
ABSTRACT AND KEY-WORDS
Importance: Recently, there’s been established a connection between patients who develop
Superficial Venous Thrombosis (SVT) and those who develop subsequent problems such as Deep
Venous Thrombosis (DVT) and Pulmonary Embolism (PE). The research for treatments has
increased lately, resulting in a somewhat wide variety of the former and doctors cannot choose with a
great amount of certainty which treatments to use.
Aim: To build a systematic review based on the literature published in some medical databases
about the available treatments for SVT, their results and complications in order to find the treatment
or association of treatments that give us the best outcome.
Methods: We conducted a systematic review using literature published in Pubmed, Scops and ISI
Web of Knowledge. After defining a query, and applying the selection criteria we obtained 11 articles.
These criteria were: articles written in English, Portuguese or Spanish; article with original data (not
systematic reviews); studies that fully described the treatments applied to more than one patient and
the evolution of SVT; articles whose full text was available.
For data collection, we extracted the information in order to characterize the article (year, type, total
number of participants), treatment groups (treatment applied, number of patients, their age and sex,
number of drop-outs, treatments' efficiency and complications).
Results: Out of 361 articles obtained with the query, we selected 11. After analyzing them we found a
wide variability of treatments applied in 4412 people. These treatments included: elastic bandages,
warfarin, heparin, non-steroidal anti-inflammatory (NSAI), anticoagulants, long saphenous ligation,
ultra-sound guided microfoam sclerotherapy (UGFS), Vitamin K antagonists, Fondaparinux and some
of these treatments combined.
Conclusion: The treatments more applied are Heparin (mostly high doses) and Heparin associated
with other treatments such as NSAI drugs or elastic compression. According to the information
gathered and combining the efficiency and affordability this is the most effective SVT’s treatment and
it could be seen as a standard treatment. In addition, high doses of this agent have the potential to
reduce the risk of subsequent thromboembolic complications. There are no statistical differences
between treating with liposomal spray-gel or subcutaneous injections, therefore spray-gel application
should be preferred due to being more attractive to patients. The isolated heparin was the second
therapy most used. In contrast, vitamin K antagonists were applied in fewer patients.
Nevertheless, it is important to ensure that there are no studies that prove directly that heparin
associated with other treatments is the ideal option. Consequently, this final conclusion derived from
the conjugation of independent results and inference methods.
Venous Thrombosis
Lower Extremity
Humans
Blood supply
Pulmonary Embolism
Systematic review
Therapeutics
Anticoagulants
Syntomatic control
Heparin, Low-Molecular-Weight
Surgery
Warfarin
Heparin
Xa factor inhibitors
INTRODUCTION
Superficial Venous Thrombosis (SVT) is a condition in which there is the formation of a blood clot in a
superficial vein. Most commonly, it affects the lower limbs, being this particular case the object of our
study.
Under normal physiological conditions, there is a continuous formation of clots within the veins,
followed by the quick disintegration of them, and therefore they cause no harm. However, in some
other cases, clots become bigger than usual and obstruct the blood flow.
Usually, Superficial Venous Thrombosis evolves without the appearance of symptoms, but
sometimes, characteristic symptoms may occur. There are lots of risk factors, that may occur alone or
associated, that contribute to the appearance of SVT.
Importance:
Superficial Venous Thrombosis rarely causes serious complications, however, studies have proved
that it can evolve to more serious health problems like Deep Venous Thrombosis (6-40% of the
cases) and to Pulmonary Embolism (2-13% of the cases). Therefore, there is a need of a systematic
review because there are no guidelines of standards implemented treatment of Superficial Venous
Thrombosis.
Hence, it is crucial to determinate the best treatment for Superficial Venous Thrombosis, because
there is a chance both of ineffective and unsafe treatment of patients with SVT, so that it can be
controlled in a much earlier phase, avoiding this other kinds of complications.
Our proposal is to make a systematic review of the literature published in some medical databases
about the available treatments. A systematic review of the studies with original data would allow an
understanding of each treatment, their results and complications; the actual state of knowledge in this
area; clarification of which treatment (or association of treatments) provides better results. Ideally, it
could provide an insight on a possible standard treatment.
PARTICIPANTS AND METHODS
The target population of our study consists of articles/research papers from three databases online,
after application of different queries, each of these queries being adapted to this database. In
addition, each of which was built based on the goals of our work and related to the theme of our
systematic review, responding similarly to our research question.
The method of selection of the articles was based on various inclusion and exclusion criteria. The
inclusion criteria applied was: studies that fully describe treatment(s) applied to SVT, studies
describing the evolution of SVT according to the applied treatment and studies comparing
Treatments. We excluded articles without original data (e.g. Systematic Review), articles not written
in English, Portuguese or Spanish, whose full-text articles was not available and articles describing
only one clinical case.
Our study was a systematic review since our unit of analysis is articles and research. Thus based on
information obtained from these, we seek to achieve the main objective of our work, responding to
the research question, analyzing the main differences between the various treatments for SVT, to
conclude which is the most effective treatment for this disease (taking into account the economic
factor of each).
From these articles we only extracted information that interested us, such as general information
about patients who are the subject of study in these papers, such as age, sex or other health
problems, information on the type of treatment applied, the results that emerged after treatment and
complications associated with the treatment in question.
Data were collected and then compiled according to variables that were: number of article, year,
database, study type, number of participants, age, follow-up, number of females, number of males,
drop-out, number of groups and treatments. We compared and analyzed these variables through the
different articles included in our study in order to find a possible standard treatment for SVT.
The software considered appropriate to conduct a statistical analysis was SPSS.
RESULTS, TABLES AND GRAPHICS
After the search we have found several articles and, following the inclusion and exclusion
criteria was thus possible to obtain information on general characteristics, i.e., data able to be applied
to SVT in clinical practice.
From the various articles were found the following results.
In one of the articles was analyzed an antibiotic treatment. This way, an antithrombotic therapy using
enoxaparin (8.3% for 40-mg enoxaparin; 6.9% 1.5 mg/kg enoxaparin; Table 1) seems to be more
efficient preventing the incidence of SVT and DVT comparing to the administration of a placebo
(30.6%), after a period of 12 days. Besides, the percentage of the incidents of DVT and SVT (Table 2)
is higher in the group who received 40-mg enoxaparin (8.3%) comparing to 1.5mg/kg enoxaparin
(6.9%), suggesting that different doses have influence in the outcomes. However, the incidence of
DVT in the two groups with enoxaparin is similar.
An alternative treatment to this is the administration of Fondaparinux (indirect Xa factor inhibitor) that
decreases the incidence of the development of pulmonary embolism or DVT (0.2%; Table 3) when
compared with a placebo group (1.3%). The same tendency occurs in the case of delayed surgery
(Table 4) that is higher in patients who received placebo (3.5%) instead of Fondaparinux (0.5%).
Apart from this first treatment, it was decided to evaluate another, and for that, individually compare
elastic compression vs anti-coagulants and surgery.
Thus, with treatment based only on elastic compression (Table 5), 41% of subjects developed a
thrombus extension at three months, 7.7% developed DVT up to three months, and 16.7% of these
people were 6 months later diagnosed with thrombus extension, so the total of complications was
65.4% for this treatment.
The association between elastic compression, Low-molecular Weight Heparin (LMWH) and delayed
surgery (Table 6) shows a decrease in the total of complications comparing with only elastic
compression since the value is 6.6%. To better understand, 5.3% of individuals who have received
this treatment developed thrombus extension at 4 months, while none of them developed DVT in the
same period. In turn, 1.3% developed thrombus extension at 6 months.
Alternatively another combined treatment was also evaluated: elastic compression associated with
oral anti-coagulant (Table 7). Of the individuals in whom this treatment was applied, 7.0% developed
thrombus extension at 3 months while none of the patients developed DVT in the same period.
Besides, 7.0% of subjects developed thrombus extension at 6 months, thus making 14% for the total
of complications.
In another article, studies comparing the use of high versus low doses of Low Molecular Weight
Heparin (LMWH) present several results. Investigators established comparisons between doses of
LMWH (high/low) and the period of evaluation (whether during or after treatment). Concerning the
incidence of thromboembolic complications (Table 8) during the treatment period, results show that
high doses of LMWH are associated with an absence of these (0%), while the use of low doses of
LMWH are associated with 13.3% of the cases. The discontinuation of the use of high doses of
LMWH is associated with an incidence of 3.3% of cases of thromboembolic complications, while the
discontinuation of the use of low doses of LMWH is associated with 6.7% of the cases.
With regard to the incidence of thrombus extension (Table 9) during the treatment period, the use of
high doses of LMWH is associated with an incidence of 10%, while the use of low doses makes up
for 23.3%. After the discontinuation of the use of high doses LMWH, there is an incidence of 0%
related to thrombus extension. Moreover, the discontinuation of the use of low doses of LMWH is also
associated with an incidence of 0% in the thrombus extension.
Finally, tests comparing the use of Prophylactic vs therapeutic doses of LMWH were also conducted.
They show that patients treated with doses Prophilactic (Table 10) only 5 (6.2%) had complications
during treatment. As regards the incidence of complications after discontinuation of use of such dose,
this corresponds to 2.5%.
Regarding the use of therapeutic doses (Table 11), is associated with a complication rate of 2.4%.
After stopping four cases were recorded during treatment of complications (4.8%).
Another result was found and it is represented in these following graphs (Graphs 1 and 2): Lipohep
spray-gel is a lipossomal gel-spray of heparin that has recently appeared on the market. Its effect has
been compared with subcutaneous injections of heparin. The intensity of pain in both groups is similar
after day 7, but on the other hand the area of erythema (cm2) is higher in the Lipohep spray-gel
group comparing to heparin injections group.
Antithrombotic therapy vs placebo:
Table 1: Incidence of DVT by day 12
Table 2: Incidence of DVT and SVT by day 12
Table 3: Incidence of pulmonary embolism or DVT
Table 4: Incidence of delayed surgery by day 77
Elastic compression vs anti-coagulants and surgery:
Table 5: Elastic compression only
Table 6: Elastic compression associated with LMWH and delayed surgery
Table 7: Elastic compression associated with oral anti-coagulant
High vs low doses of LMWH:
Table 8: Incidence of thromboembolic complications
Table 9: Incidence of thrombus extension
Prophylactic vs therapeutic doses of LMWH:
Table 10: Prophylatic doses of LMWH
Table 11: Therapeutic doses of LMWH
Lipossomal gel-spray heparin vs heparin injections:
Graph 1: Intensity of pain in Lipohep group in comparison with
enoxaparin group
Graph 2: Area of erythema in Lipohep group in comparison with
enoxaparin group
DISCUSSION
Lower limbs’ SVT has been shown to be associated with an unexpected high risk of venous
thromboembolic complications, i.e., extension to the common femoral vein, non-continuous deep vein
thrombosis (DVT) and pulmonary embolism (PE). In fact, the location of the thrombus has influence in
the risk of developing DVT. Patients with SVT confined to the area above the knee have an higher
risk of developing DVT compared to the ones with SVT below the knee. [1, 3, 4]
Skillman and Kent (1990) reported many associated factors in patients with SVT. The single most
common risk factor was varicose veins, followed by pregnancy, childbirth or cesarean section. Other
surgical procedures and bed rest were also described as predisposing factors for the development of
SVT. Moreover, other studies refer active malignancies, autoimmune diseases, use of oral
contraceptives and previous venous thromboembolism as other risk factors.[3, 10]
SVT treatment has suffered some progress over time and currently there are three major forms:
symptomatic control, surgery and drugs.
Our systematic review included 12 specific treatments, however the heparin associated with others
was the most applied. The isolated heparin was the second therapy most used. In contrast, vitamin K
antagonists were applied in fewer patients. Besides, high and low doses of heparin were usually
mentioned in included articles.
Firstly, when comparing non fractioned heparin with LMWH, studies refer better results in patients
treated with the second therapeutic option. However, to our knowledge no properly designed
comparative trial has been performed addressing the relative efficacy and safety of the two
therapeutic strategies. Uncu (2009) also conclude that LMWH is at least as safe and effective as
standard heparin in the treatment of venous thromboembolism.[4, 5]
In this point, many studies evaluate the influence of the dose of LMWH and their results suggested
that high doses of this agent have the potential to reduce the risk of subsequent thromboembolic
complications remarkably in patients with acute thrombophlebitis of the great saphenous vein without
enhancing the risk of major bleeding. The advantage was particularly evident in the first weeks of
treatment and was further supported by the considerably lower incidence of extension of superficial
trombophlebitis. [1, 4]
The Vesalio Investigators Group (2005) compared therapeutic doses and prophylactic doses of
LMWH. Their findings show that therapeutic doses of LMWH, administered for 1 month, do not
improve results obtained by prophylactic doses, administered for the same period, in terms of
composited end-point made of extending SVT and VTE complications during 3 months of follow-up.
Although therapeutic doses, given for 1 month, seem to provide a more effective protection against
progression of SVT than prophylactic doses, their effect is lost after drug discontinuation.
Although there is consensus in using LMWH as treatment of SVT, little is known on the most
appropriate application method. Pleban and Szopiński (2008) concluded that penetration of heparin
through the skin by means of liposomal spray was threefold better in comparison to the gel form. Use
of lipohep and subcutaneous low molecular weight heparin demonstrated that liposomal spray-gel
heparin is a safe and effective in treatment of local superficial thrombophlebitis symptoms.[6]
In addition, many are the studies which prove that the effects of LMWH are upgraded when this drug
is associated with other treatment. These associated treatments can be, for example, non-steroid
anti-inflammatory agents (NSAI) or compression therapy. In the first case, investigators report a
significant relief in pain and tenderness. [5, 6]
Chapman-Smith and Browne (2009) studied a new therapeutic, namely ultrasound-guided foam
sclerotherapy (UGFS), for the treatment of SVT. This technique was well accepted by all patients,
who felt strongly that UGFS was effective in treating their varicose veins, would recommend it to a
friend and would have UGFS repeated in the future if required. This outpatient technique with patients
reflects ease of treatment, lower cost, lack of downtime and elimination of venous signs and
symptoms. It has been demonstrated to be an extremely safe, effective and popular office treatment
suitable for the management of varicose veins associated with GSV reflux.
[8]
Furthermore, another output/conclusion obtained from the analysis was the fact that when it is
possible the removal of thrombus allows a quicker recovery, reduces inflammation and pain in the
area. Patients treated surgically had reduced to less than one third the hospital stay and the cost per
patient was approximately half as compared to those treated with anticoagulants.
By analyzing all the results of each included article, we can deduce an optimal treatment. We would
appoint high doses of LMWH associated with NSAI drugs or elastic compression as the standard
treatment. However, it is important to ensure that there are no studies that prove directly that this is
the ideal option. Consequently, this final conclusion derived from the conjugation of independent
results and inference methods.
Nevertheless, there is a major necessity of more studies that compare the great variety of treatments
applied in patients with SVT, specifically UGFS because it is a very recent technique.
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