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. 2016 Sep 26;2016(9):CD012369. doi: 10.1002/14651858.CD012369

Antiplatelet agents for the treatment of deep venous thrombosis

Carolina DQ Flumignan 1,✉, Ronald LG Flumignan 1, Jose CC Baptista‐Silva 1,2
PMCID: PMC6457577

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of antiplatelet agents in addition to current best medical practice (BMP) compared to current BMP, with or without placebo for the treatment of deep venous thrombosis.

Background

Description of the condition

Venous thromboembolism (VTE) describes the formation of thrombus (blood clot) in the deep veins, most commonly in the legs (deep venous thrombosis or DVT), or the subsequent embolisation of all or part of the thrombus to the pulmonary circulation (pulmonary embolism or PE), or both. DVT is caused by the acute formation of a thrombus on veins situated under the muscular fascia of the limbs, or in the central deep veins. In general, the DVT situated between the popliteal vein and the iliacs and inferior cava veins is called a 'proximal DVT' (Vedantham 2009). The clinical signs may vary, depending on the extension of the clot, and which veins are affected but include localised pain, swelling and erythema. Although DVT may cause discomfort, of utmost importance are the complications of this disorder, PE in the short term and post‐thrombotic syndrome (PTS) in the long term (Flumignan 2015; Watson 2014). PE occurs when a thrombus breaks away in the limb and follows the bloodstream to the lungs, blocking the circulation in part of the lung tissue. At least one‐third and sometimes one‐half of people with VTE develop PTS due to the damage to the vessel wall. PTS comprises a wide variety of symptoms ranging from relatively light symptoms (slight oedema, venous eczema, pigmentation and minor complaints) to more severe venous symptoms (severe swelling, venous claudication, pain and chronic recurrent ulcers). PTS can develop after DVT at any time, mostly during the two years following diagnosis (Guanella 2013). The incidence of recurrent DVT in the PTS population is between 20% and 50% (de Wolf 2012; Guanella 2013).

After stroke and myocardial infarction, VTE is the third most common cardiovascular disease in world. In the USA and Europe, an estimated 50,000 deaths per year, and 300,000 hospitalisations are due to DVT and 600,000 hospitalisations are due to PE (Nicolaides 2001). The incidence of DVT is growing with the ageing population and the rates estimated vary from 1 to 2/1000 people per year, with approximately 100 to 180,000 deaths per year due to PE (Galanaud 2012; Goldhaber 2012; Matielo 2008; Naess 2007; Tagalakis 2013).

DVT is a multifactorial disease in which genetic and environmental factors interact with each other, leading to the onset of the disease (Rosendaal 2005). Risk factors for DVT include older age (Anderson 1991), immobilisation (Sevitt 1961), previous VTE (Samama 2000), obesity (Tsai 2002), type of anaesthesia (Urwin 2000), cancer (Heit 2000), chemotherapy (Falanga 1999), pregnancy and delivery (McColl 1997), hormonal contraceptives (Gomes 2004), and hormone replacement (Rossouw 2002), and it is associated with other conditions such as polycythaemia vera, essential thrombocytopaenia and conditions that increase blood viscosity. It is clear that there are genetic changes that can lead to situations of hypercoagulability, facilitating the development of DVT and appearing in families prone to thrombosis, such as alterations in coagulation factor genes ‐ Factor V Leiden (Franco 2001) and prothrombin 20210 (Poort 1996); increased factor VIII (Koster 1995) and factor XI (Meijers 2000); depletion of natural anticoagulants such as antithrombin (Tabernero 1991), protein C (Bertina 1982) and protein S (Comp 1984); and fibrinolytic activity (Johansson 1978). Another factor also connected to the development of DVT is hyperhomocysteinaemia, which can be acquired, but also appears to have a genetic component (de Franchis 2000). There are also acquired factors of hypercoagulability. In many people diagnosed with apparently idiopathic thrombosis, further investigations showed that the thrombosis was an early manifestation of another complication, such as autoimmune disease and cancer, or that other factors influencing Virchow's triad were present (Wood 2009). There is no consensus in several population studies if gender is a differential factor for VTE incidence.

Anticoagulants are the standard mainstay of treatment for DVT (Guyatt 2012; Kearon 2016). These reduce the formation of clots and prevent further VTE. Other options of additional treatment for DVT include thrombolysis, mechanical thrombectomy and angioplasty (with or without stents) (Flumignan 2015; Robertson 2015a; Watson 2014).

Description of the intervention

Antiplatelet agents are drugs commonly used to decrease platelet aggregation and inhibit thrombus formation. Various antiplatelet agents are available such as acetylsalicylic acid (ASA), clopidogrel, phosphodiesterase inhibitors (dipyridamole and cilostazol) and glycoprotein IIb/IIIa inhibitors (tirofiban and abciximab).

Antiplatelet agents, mostly ASA, are already used routinely in clinical practice to treat various cardiovascular problems. The routine use of ASA is already established in cases of arterial thrombosis ‐ being of cardiac, cerebrovascular or peripheral origin. In coronary artery disease, ASA is part of the well‐established treatment protocol (Braunwald 2012). Clinical and experimental evidence suggests that antiplatelet agents can prevent the onset and spread of venous thrombus, minimising the adverse consequences of PE and DVT (Castro 2006). In one multicentre, double‐blind study, over 400 people with VTE were randomised to ASA or placebo, concomitant with best medical practice (BMP) after discontinuation of anticoagulation. The study found a statistically significant difference in the reduction of recurrent VTE with ASA after discontinuing anticoagulation (Becattini 2012). However, Brighton 2012, with a similar protocol (ASA after the end of anticoagulation therapy) found no significant reduction in the rate of recurrence of VTE but did find a reduction in the rate of major vascular events. Similar to treatment with anticoagulants, antiplatelet therapy may require monitoring of blood tests, mainly due to the high incidence of resistance to ASA and clopidogrel, as well as resistance to glycoprotein IIb/IIIa (Brar 2011; El‐Atat 2011; Lugo 2008; Matzdorff 2005). However, monitoring blood tests for antiplatelet agents are not routinely available in most practice.

How the intervention might work

Platelets are the principal effector cells on haemostasis, coagulation and thrombosis that are unique to mammals. They are a large part of the 'haemostatic plug', a plug of platelets and proteins, adhering at the site of vascular lesions. The secretion of von Willebrand factor by the damaged cells of the endothelium and other mediators of thrombosis from intracellular granules cause the amplification of platelet adhesion and its aggregation. This receptor‐mediated activation event has been intensely studied because it is a fundamental part of physiopathology of several diseases including DVT (Vieira‐de‐Abreu 2012). Treatments affecting platelet function may therefore be an alternative treatment for DVT.

ASA inhibits platelet aggregation by arachidonic acid metabolism through inactivation of the enzyme cyclooxygenase, which is an irreversible inactivation during the life of the platelet. Other antiplatelet agents have different mechanisms of action, such as clopidogrel. Clopidogrel is a thienopyridine, chemically and pharmacologically similar to ticlopidine, which acts by selectively and irreversibly modifying the P2Y12 adenosine diphosphate (ADP) receptor on the platelet surface, and thus inhibiting platelet aggregation. ADP is an important activator of platelet aggregation and it is found in high concentrations in the platelet granules. ADP induces platelet aggregation by activating a specific receptor located on the outer surface of its membrane, resulting in changes in intracellular calcium concentration and the expression of receptors for fibrinogen on the platelet surface (Lugo 2008).

Because antiplatelet agents act at Virchow's triad as inhibitors of clot formation, they may be an alternative to current treatment, potentially changing morbidity and mortality related to DVT, PE and PTS.

Why it is important to do this review

This review is particularly important at this time. VTE is a growing public health problem largely due to an ageing population (Tagalakis 2013). The most serious complication of DVT is PE, where almost one‐quarter of the initial clinical presentation is sudden death (Heit 2008). Any attempt to improve the standard treatment for DVT, reducing the incidence of both acute complications such as PE and chronic complications such as PTS should be studied. With this review, we will investigate if there is evidence for the use of antiplatelet agents (in addition to or after stopping anticoagulation) with BMP (e.g. anticoagulation, compression stockings and clinical care such as physical exercises, skin hydration, etc.) to improve the treatment of DVT in relation to the presence of recurrent VTE and PTS, and if there are harms such as bleeding and mortality.

Objectives

To assess the effectiveness and safety of antiplatelet agents in addition to current best medical practice (BMP) compared to current BMP, with or without placebo for the treatment of deep venous thrombosis.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all randomised controlled trials (RCTs) comparing antiplatelet therapy plus current BMP (including anticoagulants, compression stockings and clinical care) versus placebo plus BMP for the treatment of DVT. We will consider any antiplatelet agent by any route of administration. This review will focus on proximal DVT. Therefore, we will exclude trials about DVT in other regions (upper members, cerebral, etc.).

Types of participants

We will include participants of both sexes and of any age diagnosed with DVT (acute or chronic) by a medical specialist on clinical assessment and further investigation (Doppler vascular ultrasound, multi‐slice computed tomography or angiography). We will consider the DVT as acute if diagnosed within 21 days of onset of signs/symptoms (Flumignan 2015; Watson 2014). We will consider all participants that received any form of expected interventions or BMP (control group). For chronic DVT, we will not consider studies with anticoagulant treatment for less than three months because there is evidence of increased rate of recurrence after less than three months of anticoagulation, but no significant difference with various longer periods of treatment (Boutitie 2011; Robertson 2015b).

Types of interventions

We will consider the following comparisons.

Acute DVT

  • Antiplatelet agents plus BMP versus BMP alone.

  • Antiplatelet agents plus BMP versus BMP plus placebo.

Chronic DVT

  • Antiplatelet agents plus BMP versus BMP alone.

  • Antiplatelet agents plus BMP versus BMP plus placebo.

We will define BMP as anticoagulation, compression stockings and clinical care as defined previously (Flumignan 2015; Robertson 2015b; Watson 2014). It is important to clarify that 'anticoagulation' means any anticoagulation therapy (heparin or oral anticoagulation, or both) for more than two days. Since the actual role of compression stockings for DVT is still under discussion (Kearon 2016; Kolbach 2004), we will not exclude RCTs only because they do not use compression stockings in their interventions. We will perform a subgroup analysis (with and without compression stockings) if there are sufficient data. In addition, we have to mention that when anticoagulation stops (e.g. 3, 6 or 12 months after the DVT diagnosis), the BMP does not necessarily stop, because other BMP components may still continue to be used.

We will consider all RCTs utilising antiplatelet therapy either at the same time or after anticoagulation and we will analyse these two distinct groups separately.

We will not evaluate comparisons in which antiplatelet agent use is not the unique difference.

We will exclude all RCTs utilising thrombectomy, catheter direct thrombolysis and any form of percutaneous endovascular interventions except vena cava filter because it is addressed in other Cochrane Reviews (Flumignan 2015; Robertson 2015a; Robertson 2015b; Watson 2014). If we find any data utilising the vena cava filter, we will consider this in a subgroup analysis.

Types of outcome measures

We will present the outcomes at three different time points following the start of the intervention:

  • early outcomes (at one year or less after intervention);

  • intermediate outcomes (more than one to three years after intervention) and

  • long‐term outcomes (more than three years after intervention).

Primary outcomes

  • Recurrent VTE: including recurrent DVT and PE, first episode or recurrent, fatal or non‐fatal. Both diagnosed by clinical examination and diagnostic assessment including ultrasonography, computed tomography or angiography.

  • Major bleeding: defined by a decreased haemoglobin concentration of 2 g/dL or more, a retroperitoneal or intracranial bleed, a transfusion of two or more units of blood, or fatal haemorrhagic events, as defined by International Society on Thrombosis and Haemostasis (ISTH) (Schulman 2005; Schulman 2010).

  • PE (fatal/non‐fatal): confirmed by computed tomography pulmonary angiography (CTPA) or ventilation/perfusion (V/Q) scan, or both.

Secondary outcomes

  • Mortality: all‐cause and VTE‐related.

  • PTS: diagnosed by clinical examination objective (signs and symptoms), with or without the support of any of the severity ratings as CEAP (clinical findings, etiological, anatomical and pathological elements), VCSS (Venous Clinical Severity Score) or Villalta scores (de Wolf 2012).

  • Quality of life (QoL) or participant's subjective perception of improvement (yes or no) as reported by the study authors. If we are unable to pool data on QoL due to use of different measurements, we will attempt to extract data on improvement (Soosainathan 2013).

  • Duration of hospitalisation.

  • Adverse events, such as gastrointestinal adverse effects, allergic reaction, renal failure and minor bleeding.

We will also report on costs or financial impact if this is reported by the study authors.

Search methods for identification of studies

We will not apply any language restrictions.

Electronic searches

The Cochrane Vascular Group Trials Search Co‐ordinator (TSC) will search the Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Register of Studies (CRS) (www.metaxis.com/CRSWeb/Index.asp). See Appendix 1 for details of the search strategy which will be used to search the CRS. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, Embase, CINAHL and AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Vascular Group module in the Cochrane Library (www.cochranelibrary.com).

The TSC will search the following trial databases for details of ongoing and unpublished studies:

  • World Health Organization International Clinical Trials Registry (apps.who.int/trialsearch/);

  • ClinicalTrials.gov (clinicaltrials.gov/);

  • ISRCTN Register (www.isrctn.com/).

Authors' searches

We will search LILACS (Latin American and Caribbean Health Science Information database) and IBECS (Indice Bibliográfico Español de Ciencias de la Salud) (both in lilacs.bvsalud.org/). See Appendix 2 for details of the search strategy that we will use. We will not use a filter but will select the RCTs manually in the LILACS and IBECS databases. Two review authors (CDQF and RLGF) configured this strategy, which was revised by the Cochrane Brazil TSC and the third review author (JCCBS). The review authors, in collaboration with the Cochrane Brazil TSC, will search these databases.

Searching other resources

We will check the bibliographies of included trials for further references to relevant trials. We will contact specialists in the field and authors of the included trials for any possible unpublished data.

Data collection and analysis

Selection of studies

We will examine titles and abstracts to select the relevant reports after merging the search results and removing duplicate records. Two review authors (CDQF and RLGF) will independently screen the trials identified by the literature search. We will retrieve and examine the full text of the selected trials for compliance with the eligibility criteria. We will document the reason for exclusion of individual trials in the 'Characteristics of excluded trials' table. We will consult a third review author (JCCBS) in the case of any disagreement. If trials include more than one type of treatment beyond those specified in Types of interventions, we will use only the specific data that fit our criteria. Any appropriate method of randomisation will be eligible and we will take into account any differences in methodological quality in the analyses.

Data extraction and management

Two review authors (CDQF and RLGF) will extract data independently and collect data on a paper data extraction form. We will resolve discrepancies by discussion. We will consult a third review author (JCCBS) in the case of any disagreement. We will collect the following information:

  • Study features: publication details (e.g. year, country, authors); study design; population data (e.g. age, comorbidities, severity, duration, history concerning treatments and responses); number of participants randomised into each treatment group; number of participants in each group who failed treatment; number of participants lost to follow‐up; duration of follow‐up.

  • Outcomes: types of outcomes measured; timing of outcomes; adverse events.

Assessment of risk of bias in included studies

Two review authors (CDQF and RLGF) will evaluate independently the quality of the studies included in the analysis in order to assess the risk of bias according to the domains and criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will evaluate the following domains and characterise them as low risk of bias, high risk of bias or unclear risk of bias.

  • Random sequence generation (randomisation).

  • Allocation ‐ secrecy appropriate.

  • Blinding/masking of participants, assessors and results.

  • Data on the incomplete results.

  • Selective publication of results.

  • Any other potential threat to validity.

We will report these assessments for each study individually in the 'Characteristics of included studies' risk of bias table. We will contact the author(s) of the included study(ies) to ask for clarification if in doubt about the data.

Measures of treatment effect

We will calculate the risk ratios (RR) and 95% confidence intervals (CI) for dichotomous variables using Review Manager 5 software (RevMan 2014). We will calculate the mean difference (MD) and 95% CI for continuous variables that used similar scales. We will calculate the standardised mean difference (SMD) and 95% CI for continuous variables that used different scales. If the authors have not reported all the necessary information for this detail, we will insert the data from these non‐parametric primary studies (e.g. the effects reported as medians, quartiles, etc.) or without sufficient statistical information (e.g. deviations, number of participants, etc.) in an additional table.

Unit of analysis issues

We will consider the individual participant as our review unit (unit to be distributed randomly for interventions to be compared), that is, the number of observations in the analysis should match the number of randomised participants. If we find cross‐over studies and consider them appropriate for inclusion in the meta‐analysis, we will include data using the results of the paired analysis (Elbourne 2002). We will group studies evaluating various treatment groups relevant to the review to create a single pair comparison. In studies which consider many types of intervention in the same group, we will analyse only the data of interest.

Dealing with missing data

We will contact the study authors for additional information where there are missing or unavailable data. In the case of non‐response, irrespective of the type of data, we will report dropout rates in the 'Characteristics of included studies' tables of the review, and we will use intention‐to‐treat analysis.

Assessment of heterogeneity

We will quantify inconsistency among the pooled estimates using the I2 statistic (where I2 = ((Q ‐ df)/Q) x 100% where Q is the Chi2 statistic, and 'df' represents the degree of freedom). This illustrates the percentage of variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2011). We will interpret the thresholds for the I2 statistic as follows: 0% to 25% = low heterogeneity; 25% to 75% = moderate heterogeneity and more than 75% = substantial heterogeneity (Higgins 2003).

Assessment of reporting biases

We will assess reporting biases or small‐study effects by drawing a funnel plot (trial effect versus trial size) if we include a sufficient number of studies (more than 10) in the review (Higgins 2011).

Data synthesis

If we do not identify substantial heterogeneity (I2 greater than 75%), we will compute pooled estimates of the intervention effect for each outcome using a fixed‐effect model. If we identify substantial heterogeneity, we will perform a random‐effects model analysis. If we are unable to pool data on QoL due to use of different measurements, we will attempt to extract data on improvement (Soosainathan 2013).

Subgroup analysis and investigation of heterogeneity

If possible, we will perform subgroup analyses to consider the following:

  • age;

  • gender;

  • different types of antiplatelet agents used;

  • forms of administration (orally or intravenous) used for the antiplatelet agents or the anticoagulation as part of the BMP;

  • dosage of antiplatelet agents used;

  • location of DVT;

  • vena cava filter;

  • compression stocking.

If we find substantial heterogeneity, and there are enough data, we will investigate the possible causes, exploring further the impact of the condition of participants and interventions (i.e. participant characteristics, adjuvant drugs) using subgroup analyses. We will test for subgroup differences using interaction tests.

Sensitivity analysis

If there are enough studies, we will perform sensitivity analyses based on the separation of studies according to allocation concealment quality (high, low or unclear risk of bias) and masking evaluation of the results (high, low or unclear risk of bias). We will perform sensitivity analyses excluding trials of low and moderate methodological quality, as defined by the 'Risk of bias' table. We will present these results and compare them with the overall findings.

'Summary of findings' table

We will use the GRADE approach to interpret the findings of this review (GRADE Working Group). We will develop a 'Summary of findings' table for all primary outcomes (recurrent VTE, major bleeding and PE (fatal/non‐fatal)), using GRADEpro 2015 software. We will assess the quality of the body of evidence by considering the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, and the risk of publication bias (GRADE Working Group). According to GRADE recommendations (fhsed.mcmaster.ca/onlineModules/GRADE/outcomes/), we will present 'Summary of findings' results of one time point. We will base this table on methods described in Chapter 11 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011); we will justify any departures from the standard methods.

Acknowledgements

We wish thank Cochrane Vascular, Cochrane Brazil and the Discipline of Vascular and Endovascular Surgery of Universidade Federal de São Paulo, Brazil.

Appendices

Appendix 1. CRS search strategy

#1 MESH DESCRIPTOR Thrombosis
#2 MESH DESCRIPTOR Thromboembolism
#3 MESH DESCRIPTOR Venous Thromboembolism
#4 MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES
#5 (thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol*):TI,AB,KY
#6 MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES
#7 (PE or DVT or VTE):TI,AB,KY
#8 ((vein* or ven*) near thromb*):TI,AB,KY
#9 (blood near3 clot*):TI,AB,KY
#10 (pulmonary near3 clot*):TI,AB,KY
#11 (lung near3 clot*):TI,AB,KY
#12 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
#13 MESH DESCRIPTOR Platelet Aggregation Inhibitors EXPLODE ALL TREES
#14 MESH DESCRIPTOR Phosphodiesterase Inhibitors EXPLODE ALL TREES
#15 MESH DESCRIPTOR Tetrazoles
#16 (antiplatelet* or anti‐platelet* or antiaggreg* or anti‐aggreg*):TI,AB,KY
#17 (((platelet or thromboxane or thrombocyte or cyclooxygenase or cyclo‐oxygenase or phosphodiesterase or fibrinogen or PAR‐1) near3 (antagonist or inhibitor))):TI,AB,KY
#18 ((gp* or glycoprotein* or protease or P2Y12 or TXA2) near3 inhibit*):TI,AB,KY
#19 thienopyridine:TI,AB,KY
#20 (ticlopidine or Ticlid):TI,AB,KY
#21 (clopidogrel or Plavix):TI,AB,KY
#22 (Prasugrel or Effient or Efient or Prasita):TI,AB,KY
#23 (ticagrelor or AZD6140 or Brilinta):TI,AB,KY
#24 (elinogrel or PRT060128 or PRT‐060128):TI,AB,KY
#25 (cangrelor or AR‐C6993* or ARC6993*):TI,AB,KY
#26 (SCH530348 or SCH‐530348):TI,AB,KY
#27 E5555:TI,AB,KY
#28 (terutroban or Triplion):TI,AB,KY
#29 (aspirin* or nitroaspirin or ASA):TI,AB,KY
#30 (acetylsalicylic acid):TI,AB,KY
#31 (acetyl salicylic acid*):TI,AB,KY
#32 (triflusal or disgren):TI,AB,KY
#33 (Cilostazol or Pletal or Pletaal):TI,AB,KY
#34 (dipyridamol* or Persantine):TI,AB,KY
#35 (OPC‐13013 or OPC13013):TI,AB,KY
#36 (picotamide or picotinamide):TI,AB,KY
#37 satigrel:TI,AB,KY
#38 vorapaxar:TI,AB,KY
#39 indobufen:TI,AB,KY
#40 #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39
#41 #12 AND #40
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Appendix 2. LILACS search strategy

((MH:"Platelet Aggregation Inhibitors" OR MH:"Inhibidores de Agregación Plaquetaria" OR MH:"Inibidores da Agregação de Plaquetas" OR "Antiagregadores de Plaquetas" OR "Agentes Antiplaquetas" OR "Antagonistas de Plaquetas" OR "Antiagregantes de Plaquetas" OR MH:"Phosphodiesterase Inhibitors" OR MH:"Inhibidores de Fosfodiesterasa" OR MH:"Inibidores de Fosfodiesterase" OR MH:"Antagonistas da Fosfodiesterase" OR MH:"Inibidores de Fosfodiester Hidrolase" OR MH:"Tetrazoles" OR MH:"Tetrazóis" OR MH:"Thienopyridines" OR MH:"Tienopiridinas" OR MH:"D02.886.778.823" OR MH:"D03.383.725.849" OR MH:"D03.383.903.830" OR MH:"D03.438.928" OR MH:"Ticlopidine" OR MH:"Ticlopidina" OR MH:"D02.886.778.823.500" OR MH:"D03.383.725.849.500" OR MH:"D03.383.903.830.500" OR MH:"D03.438.928.500" OR "ticlid" OR "Plavasc" OR "Plaketar" OR "Ticlobal" OR "Desagreg" OR "clopidogrel" OR "Plavix" OR "Plaq" OR "Lopigrel" OR "Iscover" OR "Prasugrel" OR "Effient" OR "Efient" OR "Prasita" OR "ticagrelor" OR "AZD6140" OR "Brilinta" OR "elinogrel" OR "PRT060128" OR "PRT‐060128" OR "cangrelor" OR AR‐C6993$ OR ARC6993$ OR "SCH530348" OR "SCH‐530348" OR "E5555" OR "terutroban" OR "Triplion" OR aspirin$ OR "nitroaspirin" OR "ASA" OR "AAS" OR "acetil" OR "alidor" OR "aspisin" OR "buferin" OR "caas" OR "ecasil" OR "ronal" OR "somalgin" OR "acetylsalicylic acid" OR acetyl salicylic acid$ OR "ácido acetilsalicílico" OR "triflusal" OR "disgren" OR "Cilostazol" OR "Pletal" OR "Pletaal" OR "vasogard" OR "vasativ" OR "elmiron" OR "claudic" OR "cebralat" OR dipyridamol$ OR "Persantine" OR "dipiridamol" OR "OPC‐13013" OR "OPC13013" OR picotamid$ OR "picotinamide" OR "satigrel" OR "vorapaxar" OR indobufen$ OR antiplatelet$ OR anti‐platelet$ OR antiaggreg$ or anti‐aggreg$ OR ((platelet OR thromboxane OR thrombocyte OR cyclooxygenase OR cyclo‐oxygenase OR phosphodiesterase OR fibrinogen OR PAR‐1) AND (antagonist OR inhibitor)) OR ((gp$ OR glycoprotein$ OR protease OR P2Y12 OR TXA2) AND (inhibit$))) AND (MH:"Thrombosis" OR MH:"Trombosis" OR MH:"Trombose" OR "Trombo" OR MH:"Embolism and Thrombosis" OR MH:"Embolia y Trombosis" OR MH:"Embolia e Trombose" OR "Trombose e Embolia" OR MH:"Venous Thrombosis" OR MH:"Trombosis de la Vena" OR MH:"Trombose Venosa" OR "Flebotrombose" OR "Trombose de Veias Profundas" OR "Trombose de Veia Profunda" OR "Trombose Venosa Profunda")) AND (DB:("IBECS" OR "LILACS"))

Contributions of authors

CDQF: is the contact person, co‐ordinated the contributions of the co‐authors and wrote the final version of the protocol, developed the clinical sections of the introduction and answered the clinical observations of the arbitrators, responded to comments from referees on methodology and statistics, and is responsible for the final review. RLGF: wrote the 'Methods' section, responded to comments from referees on methodology and statistics, and helped write the protocol. JCCBS: wrote the 'Methods' section and helped write the protocol.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

Declarations of interest

CDQF and RLGF: have declared that they were sub‐investigators in a clinical trial (NCT01848210) evaluating fixed‐dose combination of coumarin and troxerutin versus placebo in the symptomatic treatment of chronic venous insufficiency. Money was paid only to their institution by Takeda and participation finished in January 2014. JCCBS: none known.

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References

Additional references

  1. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. A population‐based perspective of the hospital incidence and case‐fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Archives of Internal Medicine 1991;151(5):933‐8. [PUBMED: 2025141] [PubMed] [Google Scholar]
  2. Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, et al. Aspirin for preventing the recurrence of venous thromboembolism. New England Journal of Medicine 2012;366(21):1959‐67. [DOI: 10.1056/NEJMoa1114238] [DOI] [PubMed] [Google Scholar]
  3. Bertina RM, Broekmans AW, Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thrombosis and Haemostasis 1982;48(1):1‐5. [PUBMED: 6897135] [PubMed] [Google Scholar]
  4. Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ (Clinical Research ed.) 2011;342:d3036. [PUBMED: 21610040] [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brar SS, Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta‐analysis of individual participant data. Journal of the American College of Cardiology 2011;58(19):1945‐54. [PUBMED: 22032704] [DOI] [PubMed] [Google Scholar]
  6. Braunwald E. The rise of cardiovascular medicine. European Heart Journal 2012;33(7):838‐45, 845a. [PUBMED: 22416074] [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, et al. Low‐dose aspirin for preventing recurrent venous thromboembolism. New England Journal of Medicine 2012;367(21):1979‐87. [DOI: 10.1056/NEJMoa1210384] [DOI] [PubMed] [Google Scholar]
  8. Castro HC, Ferreira BLA, Nagashima T, Schueler A, Rueff C, Camisasca D, et al. Platelets: still a therapeutical target [Plaquetas: ainda um alvo terapêutico]. Jornal Brasileiro de Patologia e Medicina Laboratorial 2006;42(5):321‐32. [DOI: 10.1590/S1676-24442006000500004] [DOI] [Google Scholar]
  9. Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of Protein S. New England Journal of Medicine 1984;311(24):1525‐8. [PUBMED: 6239102] [DOI] [PubMed] [Google Scholar]
  10. Franchis R, Fermo I, Mazzola G, Sebastio G, Minno G, Coppola A, et al. Contribution of the cystathionine beta‐synthase gene (844ins68) polymorphism to the risk of early‐onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia. Thrombosis and Haemostasis 2000;84(4):576‐82. [PUBMED: 11057853] [PubMed] [Google Scholar]
  11. Wolf MA, Wittens CH, Kahn SR. Incidence and risk factors of the post‐thrombotic syndrome. Phlebology/Venous Forum of the Royal Society of Medicine 2012;27 Suppl 1:85‐94. [PUBMED: 22312073] [DOI] [PubMed] [Google Scholar]
  12. El‐Atat F, Sarkar K, Kodali V, Karajgikar R, Jakkulla M, Mares A, et al. A randomized pilot trial for aggressive therapeutic approaches in aspirin‐resistant patients undergoing percutaneous coronary intervention. Journal of Invasive Cardiology 2011;23(1):9‐13. [PUBMED: 21183763] [PubMed] [Google Scholar]
  13. Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta‐analyses involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140‐9. [PUBMED: 11914310] [DOI] [PubMed] [Google Scholar]
  14. Falanga A, Rickles FR. Pathophysiology of the thrombophilic state in the cancer patient. Seminars in Thrombosis and Hemostasis 1999;25(2):173‐82. [PUBMED: 10357085] [DOI] [PubMed] [Google Scholar]
  15. Flumignan RLG, Flumignan CDQ, Baptista‐Silva JCC. Angioplasty for deep venous thrombosis. Cochrane Database of Systematic Reviews 2015, Issue 1. [DOI: 10.1002/14651858.CD011468] [DOI] [Google Scholar]
  16. Franco RF, Fagundes MG, Meijers JC, Reitsma PH, Lourenco D, Morelli V, et al. Identification of polymorphisms in the 5'‐untranslated region of the TAFI gene: relationship with plasma TAFI levels and risk of venous thrombosis. Haematologica 2001;86(5):510‐7. [PUBMED: 11410415] [PubMed] [Google Scholar]
  17. Galanaud JP, Kahn SR, Khau Van Kien A, Laroche JP, Quere I. Epidemiology and management of isolated distal deep venous thrombosis [Thromboses veineuses profondes distales isolees des membres inferieurs: epidemiologie et prise en charge]. La Revue de Médecine Interne/fondee par la Societé nationale Française de Médecine Interne 2012;33(12):678‐85. [PUBMED: 22705030] [DOI] [PubMed] [Google Scholar]
  18. Goldhaber SZ. Venous thromboembolism: epidemiology and magnitude of the problem. Best Practice and Research. Clinical Haematology 2012;25(3):235‐42. [PUBMED: 22959540] [DOI] [PubMed] [Google Scholar]
  19. Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review. Archives of Internal Medicine 2004;164(18):1965‐76. [PUBMED: 15477430] [DOI] [PubMed] [Google Scholar]
  20. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ (Clinical Research ed.) 2004;328(7454):1490‐4. [PUBMED: 15205295] [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kunstman P, Nowak A, Jaeschke R. GRADEpro GDT. Hamilton (OH): GRADE Working Group, McMaster University, 2015.
  22. Guanella R. Post‐thrombotic syndrome: the forgotten complication of venous thromboembolism [Syndrome post‐thrombotique: la complication negligee de la maladie thromboembolique veineuse]. Revue Médicale Suisse 2013;9(372):321‐5. [PUBMED: 23469400] [PubMed] [Google Scholar]
  23. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):7S‐47S. [PUBMED: 22315257] [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population‐based case‐control study. Archives of Internal Medicine 2000;160(6):809‐15. [PUBMED: 10737280] [DOI] [PubMed] [Google Scholar]
  25. Heit JA. The epidemiology of venous thromboembolism in the community. Arteriosclerosis, Thrombosis, and Vascular Biology 2008;28(3):370‐2. [PUBMED: 18296591] [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ (Clinical Research ed.) 2003;327(7414):557‐60. [PUBMED: 12958120] [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
  28. Johansson L, Hedner U, Nilsson IM. A family with thromboembolic disease associated with deficient fibrinolytic activity in vessel wall. Acta Medica Scandinavica 1978;203(6):477‐80. [PUBMED: 665314] [DOI] [PubMed] [Google Scholar]
  29. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016;149(2):315‐52. [DOI: 10.1016/j.chest.2015.11.026] [DOI] [PubMed] [Google Scholar]
  30. Kolbach DN, Sandbrink MW, Hamulyak K, Neumann HA, Prins MH. Non‐pharmaceutical measures for prevention of post‐thrombotic syndrome. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD004174.pub2] [DOI] [PubMed] [Google Scholar]
  31. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep‐vein thrombosis. Lancet 1995;345(8943):152‐5. [PUBMED: 7823669] [DOI] [PubMed] [Google Scholar]
  32. Lugo JJ, Hurtado EF, Calderón LI, Gómez G, Castro P, Estrada G, et al. Resistance to acetylsalicylic acid and to clopidogrel: an emergent clinical entity [Resistencia al ácido acetil salicílico y al clopidogrel: una entidad clínica emergente]. Revista Colombiana de Cardiología 2008;15(4):172‐83. [Google Scholar]
  33. Matielo MF, Presti C, Casella IB, Netto BM, Puech‐Leao P. Incidence of ipsilateral postoperative deep venous thrombosis in the amputated lower extremity of patients with peripheral obstructive arterial disease. Journal of Vascular Surgery 2008;48(6):1514‐9. [PUBMED: 18829221] [DOI] [PubMed] [Google Scholar]
  34. Matzdorff A. Platelet function tests and flow cytometry to monitor antiplatelet therapy. Seminars in Thrombosis and Hemostasis 2005;31(4):393‐9. [PUBMED: 16149015] [DOI] [PubMed] [Google Scholar]
  35. McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, et al. Risk factors for pregnancy associated venous thromboembolism. Thrombosis and Haemostasis 1997;78(4):1183‐8. [PUBMED: 9364982] [PubMed] [Google Scholar]
  36. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. New England Journal of Medicine 2000;342(10):696‐701. [PUBMED: 10706899] [DOI] [PubMed] [Google Scholar]
  37. Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population‐based study. Journal of Thrombosis and Haemostasis 2007;5(4):692‐9. [PUBMED: 17367492] [DOI] [PubMed] [Google Scholar]
  38. Nicolaides AN, Breddin HK, Fareed J, Goldhaber S, Haas S, Hull R, et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. International Angiology 2001;20(1):1‐37. [PUBMED: 11342993] [PubMed] [Google Scholar]
  39. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'‐untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88(10):3698‐703. [PUBMED: 8916933] [PubMed] [Google Scholar]
  40. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  41. Robertson L, Burdess A, McBride O. Pharmacomechanical thrombectomy for iliofemoral deep vein thrombosis. Cochrane Database of Systematic Reviews 2015, Issue 2. [DOI: 10.1002/14651858.CD011536] [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database of Systematic Reviews 2015, Issue 6. [DOI: 10.1002/14651858.CD010956.pub2] [DOI] [PubMed] [Google Scholar]
  43. Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology/the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2005;2005(1):1‐12. [PUBMED: 16304352] [DOI] [PubMed] [Google Scholar]
  44. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321‐33. [PUBMED: 12117397] [DOI] [PubMed] [Google Scholar]
  45. Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Archives of Internal Medicine 2000;160(22):3415‐20. [PUBMED: 11112234] [DOI] [PubMed] [Google Scholar]
  46. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients. Journal of Thrombosis and Haemostasis 2005;3(4):692‐4. [PUBMED: 15842354] [DOI] [PubMed] [Google Scholar]
  47. Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. Journal of Thrombosis and Haemostasis 2010;8(1):202‐4. [PUBMED: 19878532] [DOI] [PubMed] [Google Scholar]
  48. Sevitt S, Gallagher N. Venous thrombosis and pulmonary embolism. A clinico‐pathological study in injured and burned patients. British Journal of Surgery 1961;48:475‐89. [PUBMED: 13750445] [DOI] [PubMed] [Google Scholar]
  49. Soosainathan A, Moore HM, Gohel MS, Davies AH. Scoring systems for the post‐thrombotic syndrome. Journal of Vascular Surgery 2013;57(1):254‐61. [PUBMED: 23182156] [DOI] [PubMed] [Google Scholar]
  50. Tabernero MD, Tomas JF, Alberca I, Orfao A, Lopez Borrasca A, Vicente V. Incidence and clinical characteristics of hereditary disorders associated with venous thrombosis. American Journal of Hematology 1991;36(4):249‐54. [PUBMED: 1826407] [DOI] [PubMed] [Google Scholar]
  51. Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and mortality from venous thromboembolism in a real‐world population: the Q‐VTE study cohort. American Journal of Medicine 2013;126(9):832.e13‐21. [PUBMED: 23830539] [DOI] [PubMed] [Google Scholar]
  52. Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Archives of Internal Medicine 2002;162(10):1182‐9. [PUBMED: 12020191] [DOI] [PubMed] [Google Scholar]
  53. Urwin SC, Parker MJ, Griffiths R. General versus regional anaesthesia for hip fracture surgery: a meta‐analysis of randomized trials. British Journal of Anaesthesia 2000;84(4):450‐5. [PUBMED: 10823094] [DOI] [PubMed] [Google Scholar]
  54. Vedantham S, Grassi CJ, Ferral H, Patel NH, Thorpe PE, Antonacci VP, et al. Reporting standards for endovascular treatment of lower extremity deep vein thrombosis. Journal of Vascular and Interventional Radiology 2009;20(7 Suppl):S391‐408. [PUBMED: 19560027] [DOI] [PubMed] [Google Scholar]
  55. Vieira‐de‐Abreu A, Campbell RA, Weyrich AS, Zimmerman GA. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Seminars in Immunopathology 2012;34(1):5‐30. [PUBMED: 21818701] [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database of Systematic Reviews 2014, Issue 1. [DOI: 10.1002/14651858.CD002783.pub3] [DOI] [PubMed] [Google Scholar]
  57. Wood KE. A history of pulmonary embolism and deep venous thrombosis. Critical Care Clinics 2009;25(1):115‐31, viii. [PUBMED: 19268798] [DOI] [PubMed] [Google Scholar]

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