«Authors: Alice Marinho (amomarinho Carlos Veterano (carlos_veterano Maricruz Nunes (maricruznunes Patrícia ...»
The best treatment for iliofemoral thrombosis
Alice Marinho (firstname.lastname@example.org)
Carlos Veterano (email@example.com)
Maricruz Nunes (firstname.lastname@example.org)
Patrícia Baptista (email@example.com)
Pedro Aguiar (firstname.lastname@example.org)
Pedro Campelo (email@example.com)
Rosana Dias (firstname.lastname@example.org)
Sandra Santos (email@example.com)
Sara Peixoto (firstname.lastname@example.org)
Adviser name: Sérgio Manuel Moreira Sampaio Class number: 20 Abstract Iliofemoral vein is one of the most important veins that returns blood of lower limbs to the heart, therefore the thrombosis of this vein can cause chronic venous insufficiency which results on a significant decrease of the patient‟s life quality. For this condition there are two main courses of thrombolytic therapy: anticoagulation therapy or catheter directed thrombolysis. There is no consensus about which is the best treatment to this disease, and this is why we will conduct this study. Thus, our biggest aim is understand which the best treatment is. We approached this problem making a review of written articles and gathering the information required to solve this problem, therefore we made a meta-analysis. In data collection methods, some queries were formulated and then introduced at the Pubmed, Scopus and Cochrane. The articles were selected based on their title. On each study, it will be researched if some of the variables of our study are present. In this work we will consider some variables for example if there is total thrombus destruction, if each treatment can cause death, among others. In this type of study, units of analysis are articles already published so we can‟t refer that our study has study participants. The variables that we pretend to analyse in our work are death caused by each treatment, thrombus destruction and side effects of each treatment. These are qualitative and dichotomous variables. Thus, in statistical methods we will use weighted regression that consists in a variable transformation to measure association and accuracy. The results will be represented in forest charts. We predict that catheter directed thrombolysis is the most effective and safe treatment since it has less harmful consequences for the patient.
Key-words thrombosis femoral vein thrombolytic therapy anticoagulation therapy catheter directed thrombolysis Introduction This revision article aims to clearly conclude about the best course of treatment for iliofemoral thrombosis. The elaboration of this work holds up to the need of reaching a consensus.
Deep venous thrombosis (DVT) is a significant cause of morbidity and mortality in the general population.  This disease affects 5,6% to 12,2% of the population.  For this condition there are two main courses of treatment: systemic anticoagulation therapy, using drugs like heparin and vitamin K antagonists, or catheter directed thrombolysis. These will act on the clot and inhibit the action of enzymes responsible for the blood coagulation, leading to the thrombus fragmentation. Heparin, which is the main anticoagulant used, works that way, however, other types of anticoagulants may work differently. The second method (CDT) acts directly on the blood clot. The catheter is inserted through the skin into the vein using x-ray guidance and a contrast material that helps define the blood vessel and conducting the catheter to the affected area. The blockage is dissolved by delivering the medication directly on the site or by positioning a mechanical device that breaks it.
There are advantages and risks to be considered on both treatments. This isn‟t at all a consensual matter. Thus, evaluating complication rates of each treatment and measure other variables like mortality, recover of limb function, efficiency of the thrombus destruction (total or partial lysis) and recurrence is one of this study‟s main aim, since it is essential to determine the treatment‟s success rate.
By approaching the advantages and disadvantages of both methods we hope to help solve this need for consensus in the medical community.
Research question and aims The question that we pretend to give an answer to is: “What„s the best treatment for iliofemoral thrombosis: anticoagulation therapy or catheter directed thrombolysis?”.
So, in order to answer our research question, our main aims are measuring mortality, checking if thrombus destruction is total, evaluating side effects and recover of limb function after six months, for each treatment.
Participants and methods Study participants As it was already referred, this work is a systematic review and a meta-analysis. In this type of study, there aren‟t any participants to consider because our observation units are scientific papers already published. Thus, since our observation unit isn‟t a population it can‟t be referred that the study has study participants.
Study design Concerning the study design, it can be classified as: observational, retrospective and analytical.
In this study there isn't direct control of intervention/factor and no random attribution of intervention/factor. It just analyzes and extrapolates conclusions of studies already made. Therefore, being the study object investigations already concluded, there is no chance of our intervention on the study factor. Thus, as for manipulation of direct interventions on the study object and randomization, our study is classified as observational.
As for reference time, our study is retrospective, since data will be collected on treatments that occurred in the past.
The study performed is a systematic review with meta-analysis, therefore, this study's objective is to gather and resume the available information on the theme. Like it has been referred before, the observation and analysis units are previously published research papers and not human participants, so, it can't be considered a following period concerning the study.
Concerning the study‟s objective, it is an analytical study. The study performed pretended not only to describe the study variables as well to establish relations between these same variables, therefore being an analytical study. By making an interconnection between variables, it was concluded which the best treatment is.
Since there isn't direct control of intervention/factor and no random attribution of intervention/factor, there will be an imperfect control of the multiple sources of bias (selection error and confusion variables).
To make the query, it was defined some Mesh terms and their synonyms. It was tested some queries. However, at the end, different terms were compiled into only one embracing query. The query used was “(femoral vein OR iliofemoral vein) AND (venous thrombosis OR thrombus OR clot OR venous blockage) AND (heparin OR catheter directed thrombolysis OR anticoagulation therapy OR thrombolytic therapy)”. The databases used were PUBMED, SCOPUS and COCHRANE.
It was extracted a total of 215 articles to analyze. First it was read the title and
of the articles, and it was selected 32 articles.
If the article‟s title was related with deep venous thrombosis (DVT) of iliofemoral vein, it was analyzed in order to conclude if it talked about the treatments:
anticoagulation therapy or catheter directed thrombolysis. Then, the full text of each article was read.
At the end, it was included 23 articles to do the work. Of these 23 articles, 15 of them are systematic reviews or descriptive articles, but this data can‟t be used in the meta-analysis. Only 8 clinical trials compared the two treatments in study. In the articles‟ analysis, each one was evaluated by 2 people, individually. In articles that there was no agreement, a third person was called to analyze the article.
Inclusion criteria used were: condition under study (deep-venous thrombosis), vein affected (iliofemoral vein), treatment used (anticoagulation therapy or CDT) and variables measured (mortality, efficacy, life quality after treatment, recurrence, patency, venous obstruction).
Exclusion criteria were: idiom (other than Portuguese, English or Spanish), population (other than adult humans with no other significant health problems).
Variables description The most important variables that we pretend to evaluate are lysis, patency, complications, recurrence and recovery of limb function. Lysis and patency are continuous variables, however it can be created categories, and in that case they become categorical variables. The other variables are dichotomous.
After the disease was diagnosed, the patient may undergo one of two treatments:
anticoagulation therapy or catheter directed thrombolysis. An application of a treatment can result in two ways: life or death. When the patient doesn‟t resist, death can occur after the treatment or when the treatment is being applied. When the patient resists to the treatment it can be effective or some complications may come up. The complications that will appear with the treatment applied are a way to identify the risks. To know if a treatment is efficacious, we must consider two situations: treatment failed or treatment has succeeded. When the treatment succeeded, thrombus destruction can be total or partial and it can be quantified in a scale.
The fact that the thrombus destruction is total reveals that the treatment was efficacious momentarily. However, we can‟t know if that treatment will be efficient in the future, in other words, we can‟t know if recurrence will occur. The thrombus destruction is quantified in a scale between 0% and 100% (a percentage of lysis under 50% represents unsatisfactory results (lysis grade I), while a percentage above 50% represents satisfactory results (lysis grades II and III)).
Planned statistical analyses As referred, the variables that it is pretended to analyse in the work are lysis, patency, complications, recurrence and recovery of limb function. However it was only found data to make a meta-analysis on lysis and venous obstruction. The data of meta-analysis was represented in double entry tables.
The results of the present study are represented in forest plots. This type of chart shows standardized results of each study and the synthesis value of all studies. Those results were used to conclude about the best treatment for DVT.  The studies that were included in the work have a percentage associated to them which was attributed according to their precision. The quality of the clinical trials used in the meta-analysis was quantified with Jadad scale. This scale evaluates the presence/absence of randomization and double-blinding, and if it occurs adequately. The scale varies between 0 and 5, and the clinical trials that have 3 or more points are considered quality studies. The evaluation of study quality is important, not only because of its inclusion in the meta-analysis, but also to calculate the relative weight of each clinical trial in the final odds ratio.
The odds ratio and confidence interval were calculated in SPSS and forest plots were made in Graph Pad.
Results There are many forms to apply each treatment to patients with DVT so the best way to do it was also analysed.
Anticoagulation therapy In anticoagulation therapy there are many alternatives according to the anticoagulant used.
However, nowadays, heparin is the most used, replacing classes of anticoagulants like enoxaparin and vitamin K antagonists. Heparin may be administered in two main forms: low-molecular-weight heparin and unfractionated heparin. Based on Messner, Mark (2010), low-molecular-weight is the best form of heparin for the treatment of DVT, since it provides a more rapid reduction in thrombin generation than unfractionated heparin.  According to Rahman, Ali et all (2009), different methods are used to provide heparin to the patients and subsequent treatment, mainly: intravenous infusion of unfractionated heparin and bed rest; low-molecular-weight heparin and bed rest; low-molecular-weight heparin and compression stocking; low-molecular-weight heparin and pneumatic compression. This study concluded that intravenous infusion of unfractionated heparin and bed rest and low-molecular-weight heparin and pneumatic compression are the best alternatives since they reduce leg swelling and pain .
Vitamin K antagonists, another anticoagulation type of drug, has a 3-month rate of recanalization of 24%, lower than enoxaparin, a low-molecular-weight heparin, which has a 3-month rate of recanalization of 49,1%.  Catheter-directed thrombolysis The catheter treatment may differ in some aspects: the thrombus approach, the thrombolytic agent used, the type of infusion catheter employed and the use of vena cava filters, venous stents or even other adjunctive procedures.
Catheter introduction seeks the infusion of a thrombolytic agent, mainly: streptokinase (SK), urokinase (uPA) and tissue plasminogen activator (tPA).  Regarding venous approach to iliofemoral vein, the access to this vein can be made by introducing the catheter in some specific veins, e.g. popliteal and common femoral.  Some adjunctive procedures can be used as a complement to this treatment. Venous stents, cava filters and angioplasty balloons are used combined with CDT to improve its results and lower complication rates. The first one is used to avoid blood flow constriction on a specific area.  This is often applied to patients that suffer from May-Thurner syndrome, a condition on which an anatomic abnormality makes the vessel more likely to develop blood clots.  Venous stents are applied using an angioplasty balloon. The stent is a stainless steel mesh, which is inserted in the vessel in its nonexpanded form, with a balloon on the inside. Then, the balloon is inflated, the stent expands and lodges in the vessel‟s wall, enlarging the vessel‟s diameter and increasing blood flux. The second and third one are used to decrease the risk of developing pulmonary embolisms, the filter, by keeping possible residual thrombus from travelling to the heart and from there to the lungs, and the balloon, during operative thrombectomy. It is positioned from the contralateral femoral vein with fluoroscopic  guidance and remains deflated until thrombus extraction. However, pulmonary embolism rates during therapy have proven to be unusual and do not justify the risk of the adjunctive technique itself.