Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism

  • Protocol
  • Intervention

Authors


Abstract

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

To compare the efficacy and safety of the available oral therapeutic options (aspirin, warfarin, new oral anticoagulants (NOACs)) for extended thromboprophylaxis in adult patients with a first unprovoked VTE in order to prevent VTE recurrence after completion of an acceptable initial anticoagulant treatment period as defined in the individual studies.

Background

Description of the condition

Venous thromboembolism (VTE), a disease comprised of deep vein thrombosis (DVT), pulmonary embolism (PE) or both, is a common (1 to 2 per 1000 person-years) (Oger 2000; Spencer 2006), preventable and treatable condition. However, it is a potentially fatal disease with a short-term mortality rate of approximately 25% (Kyrle 2005; Murin 2002; NÆSS 2007). The risk of recurrence during the first few weeks after the acute phase of VTE is high and remains about 10% per year for non-provoked VTE with a case-fatality rate of 3.6% to 12% (Carrier 2010; Douketis 2007; Kyrle 2010). The implications of recurrent VTE are not just mortality but also considerable morbidity with post-thrombotic syndrome (Leizorovicz 1998). The likelihood of recurrence varies among patients and is influenced by a number of factors including the presence or absence of trigger risk factors, characteristics of the index event (proximal DVT or PE compared to distal DVT) and patients' clinical features (male sex, post-thrombotic syndrome, overweight, age). While risk factors for recurrence have been identified, and indeed predictive rules determining duration of anticoagulation have been developed (Vienna Score, Men Do and Her 2 Do from Canada and Italy), these are not universally adopted in clinical practice (Eichinger 2010; Rodger 2008; Tosetto 2012).

VTE can be either provoked by triggers, such as a cast, surgery, immobilization, recent trauma, or unprovoked with no apparent trigger. Patients with VTE are treated initially with therapeutic parenteral anticoagulants (usually subcutaneous low molecular weight heparin (LWMH)) and with a vitamin K antagonist (VKA) (that is, warfarin). Parenteral therapy is continued until the international normalised ratio (INR) is ≥ 2 for at least 24 hours, after which parenteral therapy is stopped. All patients are treated with anticoagulants for at least three months; after this time it is recommended to extend treatment for unprovoked VTE if the bleeding risk is low to moderate (Kearon 2012).

Recently, new oral anticoagulants (NOACs) such as direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban) and direct thrombin inhibitors (dabigatran) have emerged as a treatment option in the acute phase of VTE, with similar (or better) efficacy as the VKAs but with potentially lower bleeding rates and easier administration (Agnelli 2013; Bauersachs 2010; Hokusai-VTE 2013; Schulman 2009).

Description of the intervention

Provoked VTE has a low annual risk of recurrence, therefore oral anticoagulation can be safely discontinued after three months of therapy (Baglin 2003; Heit 2000; Prandoni 1996; Research Committee British Thoracic Society 1992; Segal 2007). Treatment with anticoagulants can significantly reduce the recurrence of unprovoked VTE but the risk of bleeding is increased during such treatment. The optimal duration of extended treatment for unprovoked VTE is unknown because of limited data in the literature. Physicians have to decide upon extended treatment based on the benefit (that is, prevention of VTE recurrence) and risk (that is, of bleeding) due to anticoagulation treatment (Carrier 2010). The recurrence risk increases once anticoagulation is stopped, whether a short or prolonged period of treatment has been recommended to the patient (Boutitie 2011).

For many decades, and according to the American College of Chest Physicians guidelines (Kearon 2012), VKA (that is, warfarin) has been the drug of choice for long-term treatment of VTE. Warfarin is not an ideal drug since it has a narrow therapeutic window and multiple food and drug interactions. It therefore requires close monitoring and dose adjustment in order to avoid the risk of VTE recurrence or bleeding, or both (Weitz 2005).

Antiplatelet therapy (that is, acetylsalicylic acid (aspirin)) may have a role in long-term prevention of recurrent VTE after initial VKA therapy of VTE. Two studies that were published recently demonstrated a reduction of VTE recurrence and major vascular events by a third (two to three fold less than anticoagulants), with a low annual risk of bleeding (0.3%) (Becattini 2012; Brighton 2012).

NOACs such as dabigatran, rivaroxaban and apixaban have been studied for extended treatment of VTE after the initial anticoagulation period, and randomized controlled trials have been published in recent years (Agnelli 2013; Bauersachs 2010; Schulman 2013). When compared to placebo or warfarin, all NOACs demonstrated efficacy in the reduction of VTE recurrence, some with lower bleeding rates compared to warfarin (Agnelli 2013; Bauersachs 2010; Schulman 2013). When compared to placebo, increased bleeding rates were found with dabigatran and rivaroxaban but apixaban demonstrated no increase in the rate of major bleeding (Agnelli 2013; Bauersachs 2010; Schulman 2013).

Risk factors for the recurrence of VTE have been identified, and predictive scores determining the duration of anticoagulation have been developed (Eichinger 2010; Rodger 2008; Tosetto 2012). Overall, none of these models has been incorporated into clinical use because management studies and external prospective validation are still needed.

Why it is important to do this review

Prolonged treatment with anticoagulation prevents VTE recurrence. However, the current standard treatment with a VKA is associated with bleeding complications. Thus, the question regarding the duration of therapy for secondary prevention of VTE recurrence, and which is the best anticoagulant to achieve this goal, remain open. NOACs or antiplatelet agents may offer a simple and relatively safe alternative to VKAs to prevent secondary VTE in patients with unprovoked VTE. No Cochrane review has compared the available oral therapeutic options (aspirin, warfarin and NOACs). To date, there is a lack of best evidence to guide decision making for either the optimal duration of extended prophylaxis or the type of oral anticoagulant for preventing secondary unprovoked VTE. In order to assess which is the best oral anticoagulant currently available for the secondary prevention of VTE, we will perform a systematic review and meta-analysis of all randomized controlled trials that are available in the literature. We intend to reach this decision based on both the efficacy of the oral anticoagulants in preventing VTE recurrence and their safety as regards bleeding complications.

Objectives

To compare the efficacy and safety of the available oral therapeutic options (aspirin, warfarin, new oral anticoagulants (NOACs)) for extended thromboprophylaxis in adult patients with a first unprovoked VTE in order to prevent VTE recurrence after completion of an acceptable initial anticoagulant treatment period as defined in the individual studies.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials, irrespective of language, date of publication and publication status. Studies with drugs which are omitted from the market (for example, ximelagatran) will be excluded. Studies of the treatment of acute phase VTE will be excluded and we will also exclude people with provoked VTE.

Types of participants

Adult patients (> 18 years) with their first symptomatic objectively confirmed unprovoked VTE after completion of an acceptable initial anticoagulant treatment period as defined in the individual studies.

Types of interventions

Interventions

VKAs (including warfarin), antiplatelet agents (including aspirin) and NOACs (including dabigatran, rivaroxaban, edoxaban and apixaban)

We will consider two types of comparisons.

1. VTE extended prophylaxis (either antiplatelets, NOACs or VKAs) versus no prophylaxis or placebo.

2. VTE extended prophylaxis (either antiplatelets, NOACs or VKAs) versus any other VTE extended prophylaxis (either antiplatelets, NOACs or VKAs).

Extended prophylaxis is defined as treatment in patients with VTE who have completed at least three months of anticoagulation therapy to four years after initial treatment.

Types of outcome measures

Primary outcomes
  • VTE related mortality

  • Recurrence rate of symptomatic, objectively confirmed VTE (either DVT or PE) during follow-up

  • Major bleeding events: a major bleeding episode is defined as clinically overt bleeding that is associated with at least one of a fall in haemoglobin levels of 20 g/L or more; transfusion of at least two units of packed red blood cells; involvement of the intracranial or retroperitoneal space or a body cavity; death (International Society on Thrombosis and Haemostasis definition) (Schulman 2005); or as defined by the investigators of each trial

Secondary outcomes
  • All-cause mortality

  • Bleeding: all events (including clinically relevant non-major bleeding as defined in each trial)

  • Stroke (both ischaemic and haemorrhagic) or transient ischaemic attack (TIA)

  • Serious adverse events: including acute myocardial infarction; acute coronary syndrome; any life-threatening or grade 3 to 4 non-haematological events (such as hepatotoxicity or renal toxicity)

Search methods for identification of studies

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) will search the Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (www.the cochranelibrary.com). See Appendix 1 for details of the search strategy which will be used to search CENTRAL. 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 Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).

Searching other resources

We will search the conference proceedings of the American Society of Hematology (2006 to 2013), International Society of Thrombosis and Hemostasis (2006 to 2013) and proceedings of the European Hematology Association (2002 to 2013) for relevant abstracts.

We will search all conference proceedings electronically.

We will broaden the search for conferences and use the term venous thromboembolism (VTE) only in order not to miss any eligible abstracts.

We will search the following databases of ongoing and unpublished trials, using the term venous thromboembolism (VTE) only:

We will contact the first or corresponding author of each included study and the researchers active in the field for information regarding unpublished trials or to obtain complementary information on their own trial.

We will check the citations of included trials and major reviews for additional studies.

Data collection and analysis

Selection of studies

Two review authors (DB, NER) will inspect the title and, when available, the abstract of each reference identified in the search and apply the inclusion criteria. Where relevant articles are identified, the full article will be obtained and inspected independently by two review authors and the inclusion criteria applied. In the case of disagreement between the two review authors, a third author (AGG) will independently apply the inclusion criteria. We will document the justification for excluding studies.

We will include trials regardless of publication status, date of publication and language.

We will screen the titles and abstracts and if in doubt obtain the full texts and check them against the inclusion criteria.

We will exclude trials regarding anticoagulants which are currently, or were previously, omitted from the market (for example, ximelagatran).

We will also exclude trials that include patients with other indications or contraindication for treatment with anticoagulants or anti-aggregants; or patients treated with other antiplatelet agents or non-steroidal anti-inflammatory drugs (NSAIDs).

Data extraction and management

Two review authors will independently perform data extraction using data extraction forms. We will extract data on the:

  • study design;

  • length of follow-up;

  • dates of study;

  • location of study;

  • characteristics of participants, their age, sex, race (ethnic group);

  • co-morbidity (diabetes, hyperlipidaemia, hypertension, smoking, ischaemic heart disease);

  • previous DVT or PE;

  • creatinine clearance;

  • weight at baseline;

  • risk factors for VTE recurrence (known thrombophilia, persistent immobilization, previous cancer);

  • type of VTE at initial diagnosis (DVT, PE, etc);

  • methodological quality (risk of bias);

  • characteristics of interventions (name of drug, dose, duration of treatment);

  • description of primary and secondary outcomes (as defined above).

Assessment of risk of bias in included studies

Two review authors (DB, NER) will independently assess the trials for methodological quality. We will describe and assess allocation concealment, sequence generation, blinding, incomplete outcome data, and selective outcome reporting individually, according to the Cochrane Collaboration's tool for assessing bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion. If disagreement persists, a third review author (AGG) will extract the data independently. We will discuss the data extraction, document disagreements and their resolution and, where necessary, contact the authors of the studies for clarification. If this is unsuccessful, disagreements will be reported.

Measures of treatment effect

We will estimate risk ratios (RRs) with 95% confidence intervals (CI) for dichotomous data using the Mantel–Haenszel method.

Unit of analysis issues

The unit of analysis will be the individual patient.

We will not include crossover trials and cluster-randomized trials.

Dealing with missing data

Whenever data are missing, we will attempt to contact the authors of the study and request the missing information.

We will impute missing dichotomous data for patients who were lost to follow-up after randomization (dichotomous data) assuming a poor outcome (worse case scenario) for missing individuals.

We will perform a sensitivity analysis of the primary outcome excluding trials in which more than 20% of participants were lost to follow-up.

Assessment of heterogeneity

We will assess heterogeneity (the degree of difference between the results of different trials) using the Chi2 test of heterogeneity and the I2 statistic for inconsistency as described within the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will define statistically significant heterogeneity as P value < 0.10 or an I2 statistic greater than 50%. An I2 of < 25% will be considered as low-level heterogeneity and 25% to 50% as a moderate level of heterogeneity. Potential sources of heterogeneity will be explored through stratifying by type of therapy, DVT or PE, allocation concealment, blinding, and size of studies.

Assessment of reporting biases

We will inspect the funnel plot of the treatment effect against the precision of trials (plots of the log of the relative risk for efficacy against the standard error) in order to estimate potential asymmetry that may indicate selection bias (the selective publication of trials with positive findings) or methodological flaws in small studies as described within the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Data synthesis

We will enter the data into RevMan and undertake analysis according to recommended guidelines (Higgins 2011). We will pool RRs with 95% CIs for dichotomous data. Exclusions after randomisation will be reported. We will use a fixed-effect model (Mantel-Haenszel method) unless significant heterogeneity (P < 0.10) is detected, in which case we will use a random-effects model (DerSimonian 1986). If it is not possible to pool data, we will describe the results in the text.

Subgroup analysis and investigation of heterogeneity

We will explore potential sources of heterogeneity through stratifying by the patient subgroups given below.

  • Types of comparison intervention (type of drug).

  • Age (65 years or below, above 65 years).

  • Sex.

  • Renal function.

We will attempt to perform a subgroup analysis according to the duration of initial therapy of the acute phase of VTE.

Differences between subgroups will be formally assessed using the Chi2 test.

Sensitivity analysis

If possible, we will perform sensitivity analyses to examine the effects of different trials and their methodology as described within Chapter 9 (Section 9.7) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Thus, we will conduct a sensitivity analysis of the low risk of bias trials according to allocation concealment.

We will also perform a sensitivity analysis of the primary outcome excluding trials in which more than 20% of participants were lost to follow-up.

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor: [Thrombosis] this term only
#2MeSH descriptor: [Thromboembolism] this term only
#3MeSH descriptor: [Venous Thromboembolism] this term only
#4MeSH descriptor: [Venous Thrombosis] explode all trees
#5(thrombo* or thrombus* or embol*):ti,ab,kw (Word variations have been searched)
#6MeSH descriptor: [Pulmonary Embolism] explode all trees
#7PE or DVT or VTE:ti,ab,kw (Word variations have been searched)
#8((vein* or ven*) near thromb*):ti,ab,kw (Word variations have been searched)
#9blood clot:ti,ab,kw (Word variations have been searched)
#10blood flow stasis:ti,ab,kw (Word variations have been searched)
#11vein stasis* or "venous stasis":ti,ab,kw (Word variations have been searched)
#12#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13duration:ti,ab,kw (Word variations have been searched)
#14extended:ti,ab,kw (Word variations have been searched)
#15prolong*:ti,ab,kw (Word variations have been searched)
#16recurr* or reccur* or reoccur*
#17secondary
#18months or year
#19#13 or #14 or #15 or #16 or #17 or #18
#20MeSH descriptor: [Warfarin] this term only
#21warfarin or coumadin or coumarin or Nicoumal* or phenindione or acenocoumar* or Sinthrome or Sintrom or dicoumar* or nicoumalone or phenprocoumon or Marcoumar or Marcumar or Falithrom or Dindevan:ti,ab,kw (Word variations have been searched)
#22dabigatran:ti,ab,kw (Word variations have been searched)
#23rivaroxaban:ti,ab,kw (Word variations have been searched)
#24apixaban:ti,ab,kw (Word variations have been searched)
#25betrixaban:ti,ab,kw (Word variations have been searched)
#26odiparcil:ti,ab,kw (Word variations have been searched)
#27BAY59-7939 or TTP889 or LY517717 or YM150 or DU-176b:ti,ab,kw (Word variations have been searched)
#28edoxaban or otamixaban or YM466:ti,ab,kw (Word variations have been searched)
#29MeSH descriptor: [Aspirin] this term only
#30aspirin or ASA:ti,ab,kw (Word variations have been searched)
#31clopidogrel:ti,ab,kw (Word variations have been searched)
#32dipyridamol*:ti,ab,kw (Word variations have been searched)
#33oral near/3 anticoagul*:ti,ab,kw (Word variations have been searched)
#34oral near/3 anti-coagulat*:ti,ab,kw (Word variations have been searched)
#35#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
#36#12 and #19 and #35 in Trials

Contributions of authors

Dorit Blickstein, Noa Eliakim-Raz, and Anat Gafter-Gvili all contributed to the conception and design of the meta-analysis, all will search for included trials and review all available literature, extract and analyse data and will write and approve the review.

Dorit Blickstein and Noa Eliakim-Raz will conduct double extraction and equally contribute to the meta-analysis. In the case of disagreement and if necessary, Anat Gafter-Gvili will also extract data.

Declarations of interest

None known

Sources of support

Internal sources

  • No sources of support supplied

External sources

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

    The PVD Group editorial base is supported by the Chief Scientist Office.

Ancillary