Statins for the prevention of primary venous thromboembolism

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the efficacy and safety of statins in preventing primary venous thromboembolism (VTE) in people with no previous history of VTE.

Background

Description of the condition

Venous thromboembolism (VTE) is a clinical condition that has two different manifestations: deep venous thrombosis (DVT) and pulmonary embolism (PE). In VTE, a blood clot (thrombus) forms in an intact vein as red blood cells, fibrin, and, to a lesser extent, platelets and leucocytes (white blood cells) form a clot. Blood flow through the affected vein is limited by the clot, causing swelling and pain. Venous thrombosis most commonly occurs in the 'deep veins' in the lower legs, thighs, or pelvis, so it is usually called DVT. An embolism is created if a part or all of the blood clot breaks off from the site where it is created and travels through the venous system. If the clot lodges in the lungs, the very serious condition PE arises.

The crude annual incidence per 1000 population is 0.83 for VTE, 0.52 for DVT, and 0.31 for PE. The annual incidence per 1000 population after age adjustment to the World Health Organization World Standard Population is 0.57 for VTE, 0.35 for DVT, and 0.21 for PE. If the crude annual incidence of VTE is externally valid, then VTE affects approximately 3.7 million people across the world annually (Ho 2008; Raju 2009). The estimated average annual incidence rate of overall VTE among persons of European ancestry ranges from 104 to 183 per 100,000 person‐years (Heit 2016). Studies from Western Europe, North America, Australia and southern Latin America (Argentina) yielded consistent results, with annual incidence rates ranging from 0.75 to 2.69 per 1000 individuals in the population (ISTH 2014). The Tromsø study in Norway showed that the overall age‐adjusted average incidence rate of VTE per 100,000 per year (standardised to the WHO standard population, 2000 to 2025) was 86 (95% confidence interval (CI) 59 to 113), with corresponding rates of 48 (95% CI 29 to 68) for DVT and 37 (95% CI 19 to 56) for PE with or without DVT (Arshad 2017). The Q‐VTE Study Cohort found that the age‐ and sex‐adjusted incidence rates of definite or probable VTE, DVT, and PE in Canada were 1.22, 0.78, and 0.45 per 1000 person‐years, respectively (Tagalakis 2013). The AB‐VTE Population‐Based Study reported the age‐ and sex‐adjusted incidence rate per 1000 person‐years in Canada to be 1.38 (95% CI 1.37 to 1.40) for VTE, 0.38 (95% CI 0.36 to 0.40) for PE, and 1.0 (95% CI 0.99 to 1.1) for DVT (Alotaibi 2016). Lee 2017 reviewed the evidence for the incidence of symptomatic VTEs in Asia, and found that VTE rates ranged from 11 to 88 cases per 10,000 admissions.

Retrospective studies have reported that mortality rates during the few months after VTE range from 5% to 23% (Goldhaber 2004), although mortality was 1% to 2% in symptomatic people with adequate anticoagulation (Douketis 1998; Lassila 2014). The one‐year survival rate was 0.47 for people with definite or probable VTE and cancer, 0.93 for people with unprovoked VTE, and 0.84 for people with venous thromboembolism secondary to a major risk factor (Tagalakis 2013). It is estimated that more than 900,000 Americans develop DVT each year, and 500,000 of these develop PE, with 30% of PEs being fatal (Heit 2005). Heit 2005 reported that about two‐thirds of all VTE events were related to hospitalisation. Heit 2002 reported that VTE is the third most common cause of hospital‐related deaths in the United States and the most common preventable cause of hospital deaths.

The risk factors for VTE are complex, and include: hospitalisation for surgery or acute illness, active cancer, neurological disease with leg paresis, nursing‐home confinement, trauma or fracture, superficial vein thrombosis, non‐O blood groups, factor V Leiden mutation, advanced age, long‐haul travel, and — in women — pregnancy and puerperium, oral contraception, and hormone therapy (Heit 2015; Wolberg 2015). The estimated risk of developing VTE is approximately 4‐ to 6.5‐fold higher in people with cancer compared to the general population; people with cancer account for about 18% of the total number of VTE cases (Citro 2020). Malignancy itself induces a thrombophilic state by increasing the risk of venous stasis, endothelial injury and an imbalance of prothrombotic and antithrombotic factors leading to a hypercoagulable state (Leiva 2020). Indeed, people with cancer have a prothrombotic state resulting in both increased expression of procoagulants and suppression of fibrinolytic activity (Citro 2020). Surgery is another risk factor for VTE. The aggregate prevalence of VTE following rectal surgery has been reported as 1.25%, with DVT and PE occurring in 0.68% of people and 0.57% of people (Hayes 2019). The overall rate of VTE after nephrectomy was 1.2% (0.5% for PE; 0.8% for DVT) (Jordan 2017).

Studies have also found that cholesterol might be associated with VTE. Everett 2009 found that extreme tertiles of high‐density lipoprotein cholesterol (HDL‐C) and apolipoprotein A1 (apo A‐I) were positively associated with VTE risk in women (HDL‐C: hazard ratio (HR) 1.75, 95% CI 1.13 to 2.73; apo A‐I: HR 1.70, 95% CI 1.10 to 2.62). This was confirmed by Ageno and colleagues, who found that the risk of VTE was 1.16 (95% CI 0.67 to 2.02) for people with hypercholesterolaemia compared to those in a control group (Ageno 2008). Mi 2016 found that total cholesterol and triglyceride concentrations were significantly higher in people with VTE compared to those without VTE (weighted mean difference (WMD) 8.94 mg/dL, 95% CI 3.52 to 14.35 mg/dL; and WMD 14.00 mg/dL, 95% CI 8.85 to 19.16 mg/dL, respectively), but HDL‐C concentrations were significantly lower in people with VTE than without VTE (WMD −2.03 mg/dL, 95% CI −3.42 to −0.63 mg/dL). People with venous thrombosis had significantly lower levels of HDL particles, large HDL particles, HDL‐C and apo A‐I, and had significantly higher levels of low‐density lipoprotein (LDL) particles and small LDL particles (Deguchi 2005). In men, VTE was associated with elevated LDL‐cholesterol (odds ratio (OR) 2.32, 95% CI 1.07 to 5.01); LDL/HDL‐cholesterol (OR 2.76, 95% CI 1.69 to 4.50) and apolipoprotein B/apolipoprotein A‐I ratios (OR 1.86, 95% CI 1.16 to 2.97) (Delluc 2012).

Thrombosis prophylaxis can be achieved by physical or pharmacological means. The decision about which prophylaxis to use depends on an individual's risk factors, the availability of recommended medication, and the clinical judgment of the treating doctor (Chapman 2009). Effective anticoagulants include the low molecular weight heparins (LMWH), factor Xa inhibitor (fondaparinux) (Alpert 2001; Diuguid 2001), vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) (Song 2019). Mechanical prophylaxis (that is, intermittent pneumatic compression (IPC) stockings or graduated compression stockings (GCS)) is recommended for people with a higher than normal risk of bleeding, or as an adjunct to more efficacious pharmacological prophylaxis (Chapman 2009; Diuguid 2001).

Description of the intervention

Statins, 3‐hydroxy‐3‐methylglutaryl (HMG)‐coenzyme A (CoA) reductase inhibitors, are the most powerful cholesterol‐lowering drugs available, and include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Statins inhibit cholesterol biosynthesis via down‐regulation of HMG CoA reductase, an enzyme that is rate‐limiting for cholesterol biosynthesis (Ginter 2009; Istvan 2002). Statins have also been shown to exhibit several vascular protective effects with antithrombotic properties (Undas 2005). As a result, the benefits of statins might accrue not only from their effects on lipid levels but also through their influence on thrombosis and inflammation (Albert 2001; Kaba 2004; Undas 2005).

How the intervention might work

The mechanism of statins in the prevention of VTE is not well established; multiple mechanisms have been proposed (Wallace 2017). Plausible biological links can be found between statin therapy and reduction of thrombotic risk, mainly targeting blood coagulation, lipid metabolism, immune system, endothelium and inflammation (Lippi 2013). Increasing evidence indicates that statins modulate the blood coagulation cascade at multiple levels, including down‐regulation of tissue factor expression, increased protein C activity, increased factor V and VII inactivation, and enhanced thrombomodulin expression (Ridker 2012; Riva 2015; Undas 2005; Wallace 2017). Differences between individual statin medications may be due to differences in metabolism (Corsini 1999). For example, simvastatin impairs the activation of prothrombin, factor V (FV) and FXIII, and enhances FVa inactivation by activated protein C (Undas 2001), which may lead to a reduced risk of venous thrombosis. Statin therapy might also have an active anti‐inflammatory component that contributes to decreased thrombus formation (Wallace 2017). A systematic review showed that statin therapy reduces interleukin 6 (IL‐ 6) induced expression of C‐reactive protein (CRP) and monocyte chemoattractant protein‐1 (MCP‐1), which has been linked to vein wall fibrosis, promoting post‐thrombotic syndrome (PTS) and recurrent DVT (Rodriguez 2012). This suggests that the antithrombotic effects are likely to be exhibited through the anti‐inflammatory properties of statins (Rodriguez 2012). Besides the anti‐inflammatory effects, statins reduce the hepatocyte cholesterol content, thus promoting enhanced expression of LDL receptors on the cell membrane, leading to increased receptor‐mediated endocytosis of LDL and decreased serum levels of LDL (Orsi 2019). Studies have also confirmed that statins may decrease VTE risk by inhibiting platelet activation and aggregation, which play key roles in the initiation of thrombus formation (Biedermann 2016; Moraes 2013; Pawelczyk 2015).

Why it is important to do this review

The optimal drug for the primary prevention of VTE is one that is efficacious, associated with minimal bleeding risk, and easy to administer. Statins fulfil the latter two criteria, but their efficacy and side effects remain unproven (Ray 2003). In this review, we aim to assess their efficacy and safety by evaluating randomised controlled trials (RCTs) using statins for the primary prevention of VTE.

The Heart and Estrogen/Progestin Replacement Study, a randomised trial of postmenopausal hormone therapy in American women with cardiovascular disease, first observed a lower risk of VTE in women using statins (Grady 2000). In this trial of 2763 women there were nearly 1000 women using statins, and the relative risk (RR) of VTE was 0.5. In a study of administrative data, Ray 2001 reported that statins users in Ontario had a 22% lower risk of VTE than those prescribed thyroid replacement therapy. An analysis by Yang 2002 of the General Practice Research Database (GPRD) in the UK was not able to detect an association between statin use, or other lipid‐lowering drug use, and the risk of unprovoked VTE, but the study was limited by the analysis of a small number of cases. Huerta 2007 also examined GPRD data using a longer time period and assessing over 6550 cases, and reported a 15% lower risk of VTE with the use of statins, although this was not statistically significant (OR 0.85, 95% CI 0.66 to 1.09). In a study that included 4538 people who had previously experienced a single episode of DVT or PE and 5914 people in a control group, 3.3% of participants using statins experienced a VTE as compared to 5.7% of controls, which yielded a 59% lower risk of VTE with statin use (Ramcharan 2009). This association was not seen with other lipid‐lowering medications, and was not associated with a lower, or higher, risk of VTE. Two prospective observational studies showed that substantial and significant reductions in the risk of VTE were associated with the use of statins: a 50% reduction in the risk among statin users in the Heart and Estrogen/progestin Replacement Study (Grady 2000), and a 22% reduction among statin users in Ontario, Canada, as calculated on the basis of administrative claims data (Ray 2001). Skajaa and colleagues found that statin use was associated with a slightly decreased risk of VTE (adjusted HR 0.95, 95% CI 0.92 to 0.97), driven by a reduced risk of unprovoked VTE (adjusted HR: 0.92, 95% CI 0.89 to 0.95) among 601,011 statin initiators and over 1.8 million matched population cohort members during 2005 to 2015 (Skajaa 2019). Another study showed a statistically significant protective effect for statins compared to no treatment in terms of a lower risk of DVT for people with leukaemia (HR 0.77, 95% CI 0.61 to 0.99) and a lower risk of PE in people with colorectal cancers (HR 0.80, 95% CI 0.64 to 0.99) (El‐Refai 2017). Four case‐control studies also showed reductions in the risk of venous thrombosis associated with the use of statins, ranging from 26% to 58% (Doggen 2004; Lacut 2004; Lacut 2008; Ramcharan 2009; Sørensen 2009).

However, there is still uncertainty about whether statins should be recommended for use in the prevention of VTE, and there are calls for further information to quantify the risk reduction for VTE with statin use (Gaertner 2016; Ray 2001). Although several meta‐analyses have been published that assess the preventive effects of statins on VTE (Kunutsor 2017; Miksza 2019; Rahimi 2012), the preventive role of statins is not well established. We intend to clarify the efficacy and safety of statins for the primary prevention of VTE in this review.

Objectives

To assess the efficacy and safety of statins in preventing primary venous thromboembolism (VTE) in people with no previous history of VTE.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), without language or publication status restrictions. We will include RCTs that compare treatment with statins versus placebo, usual care or any control intervention. We will exclude studies that investigate the secondary prevention of VTE. We will exclude studies which did not prospectively collect information on VTE.

Types of participants

We will include studies where participants are healthy people, or who have diseases other than VTE. We will include participants who have VTE risk factors providing they have not had previous VTE (see Appendix 1). We will exclude participants with previous VTE when this information is available. We will carry out a sensitivity analysis to investigate the impact of including studies that included a subgroup of participants with previous VTE.

Types of interventions

We will include studies that compare statins (all types) versus placebo, usual care or any control intervention. Concomitant interventions are accepted, provided they were given to both arms of the study.

Types of outcome measures

Primary outcomes

• Any VTE (provoked or unprovoked)

• DVT (provoked or unprovoked)

• PE (provoked or unprovoked)

The primary outcome of VTE for this review can be assessed as either a primary, secondary, exploratory, or adverse event outcome of any included study, providing it was preplanned and assessed appropriately.

VTE should be detected by imaging using venous ultrasonography or venography for confirmation of DVT; angiography, computed tomography (CT) or a ventilation and perfusion scan (V/Q) for confirmation of PE; or any other recognised confirmatory tests for either DVT or PE. Unprovoked VTE is defined as occurring in the absence of known malignancy (diagnosed either before, or up to three months after, the VTE), trauma, hospitalisation, or surgery within the three months before the event. Provoked VTE includes events that occurred in people with cancer or during, or shortly after, trauma, hospitalisation, or surgery. We will consider DVT that occurred in any part of the human body, including the lower legs, thighs, pelvis, or upper limb.

We will exclude studies if they did not assess the primary outcome of this review; we will decide this only after contacting the study authors to check if this information was recorded but not reported or published.

Secondary outcomes

• Serious adverse events (SAEs)

SAEs are any adverse events that result in death, are life‐threatening, require inpatient hospitalisation or prolong existing hospitalisation, result in a persistent or significant disability or incapacity, or a congenital anomaly or birth defect. Important medical events are those that may not result in death, be life‐threatening, or require hospitalisation but are considered to be serious.

• Adverse events (myopathy, tendon manifestations, etc.)

• Mortality (all cause mortality and fatal PE)

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist aims to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).

The Information Specialist will search the following databases for relevant trials:

• Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web);

• Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO);

• MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) (1946 onwards);

• Embase Ovid (from 1974 onwards);

• CINAHL Ebsco (Cumulative Index to Nursing and Allied Health Literature; from 1982 onwards).

The Information Specialist has devised a draft search strategy for RCTs for MEDLINE, which is displayed in Appendix 2. The Information Specialist will use this as the basis for search strategies for the other databases listed.

The Information Specialist will search the following trials registries:

• ClinicalTrials.gov (clinicaltrials.gov);

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

Searching other resources

We will examine the bibliographies of study reports identified in our search in order to identify other relevant articles. We will also search the reference lists of available reviews, systematic reviews, and meta‐analyses. We will contact the authors of relevant articles by email to request data and identify other unpublished RCTs.

Data collection and analysis

Selection of studies

Two review authors (LL and JHT) will independently select trials for inclusion in this review. We will resolve any disagreement by discussion with a third review author (KHY). We will illustrate the study selection process in a PRISMA diagram (Liberati 2009). We will list all articles excluded after full‐text assessment in a 'Characteristics of excluded studies' table and will provide the reasons for their exclusion. We will contact the study authors for all studies when VTE is not reported or published to check if these data are available.

Data extraction and management

Two review authors (LL and JHT) will independently extract relevant data from the included studies using a data collection form. We will collect the following information and include it in the table of characteristics of included studies:

• methods (study design, number of participants, exclusions postrandomisation, losses to follow‐up, intention‐to‐treat (ITT) analysis, duration of the study);

• participant characteristics (country, setting, age, sex, inclusion and exclusion criteria);

• interventions (statin used, dose, etc.);

• comparisons and outcomes;

• funding source, and declarations of interest by the study authors.

A third review author (PZ) will cross‐check the data extracted. Statistical analysis will comply with the standard methods of Cochrane Vascular.

Assessment of risk of bias in included studies

Two review authors (LL and JHT) will independently perform a risk of bias assessment of all included studies, using Cochrane's risk of bias tool (Higgins 2011). The tool assesses random sequence generation, allocation concealment methods, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and any other potential biases. Each domain receives a rating of high, low, or unclear risk of bias. We will resolve any disagreement by discussion with a third review author (KHY). We will contact study authors if clarification is required to assess risk of bias.

Measures of treatment effect

We will define the measures of treatment effects according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). For dichotomous outcomes, we will express results as odds ratio (OR) with 95% confidence intervals (CI). If studies use continuous scales of measurement to assess the effects of treatment, we will use the mean difference (MD), or the standardised mean difference (SMD) if studies have used different scales.

Unit of analysis issues

We will use individual participants as the unit of analysis.

Dealing with missing data

We will attempt to contact all the study authors of the original studies to request any missing data. If the authors of the study do not respond, we will extract the available data from the original article. If data are missing because participants dropped out or there were losses to follow‐up, we plan to conduct a primary analysis based on the provided data, and a sensitivity analysis with missing data imputed based on the worst‐case and best‐case scenarios, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Assessment of heterogeneity

We plan to examine heterogeneity among trials using the I² statistic. We will consider an I² statistic estimate greater than 50% as indicating substantial or considerable heterogeneity. To investigate possible causes of heterogeneity, we will perform subgroup analyses or sensitivity analyses by excluding studies thought to cause the heterogeneity.

Assessment of reporting biases

We plan to assess reporting biases by using funnel plots, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Data synthesis

We will use meta‐analysis to determine the measure of effect if the search yields a group of trials sufficiently homogeneous in terms of measured outcomes. We will use Review Manager to perform all statistical analyses and generate figures (Review Manager 2020; RevMan Web 2019), based on an intention‐to‐treat analysis. We will use a fixed‐effect model if there is an I² statistic estimate of 40% or less or a random‐effects model if there is an I² statistic estimate greater than 40%. If we detect considerable heterogeneity, we plan to report the results narratively.

Subgroup analysis and investigation of heterogeneity

We will undertake relevant subgroup analyses for different ages, gender, population (healthy people versus people considered to be at risk (people who underwent surgery, cancer patients without surgery, cancer patients with surgery)), and different types of statin.

Sensitivity analysis

We will use sensitivity analysis to explore the impact of missing data or studies thought to cause heterogeneity on the stability of the treatment effect. We will also use sensitivity analysis to assess the impact of including studies that included a subgroup of participants with previous VTE.

Summary of findings and assessment of the certainty of the evidence

We will prepare a summary of findings table using the GRADEpro Guideline Development Tool (GRADEpro GDT), to present the main findings of the review for the time point at which the most relevant data are available from the included studies (Atkins 2004; Guyatt 2008). We will include the main outcomes listed under Types of outcome measures. The outcomes that we consider essential for decision‐making are: any VTE, DVT, PE, serious adverse events, and mortality. We will evaluate the certainty of the evidence using the GRADE approach (Guyatt 2011). We will assign one of four levels of certainty: high, moderate, low, or very low, based on overall risk of bias, directness of evidence, inconsistency of results, precision of estimates, and risk of publication bias, as previously described (Higgins 2021). We will justify all decisions to downgrade the certainty of evidence using footnotes; we will make comments to aid the reader's understanding of the review where necessary. We have included a draft summary of findings table (Table 1).

1. Draft summary of findings table.

Statins compared with placebo (or usual care or any control intervention) for the primary prevention of venous thromboembolism
Patient or population: participants without VTEa Settings: hospital, outpatients or community Intervention: statin (any) Comparison: placebo (or usual care or any control intervention)
Outcomes	Anticipated absolute effects *		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with statin
VTE (follow‐up)	Low risk population		OR (value) ((value) to (value))	(value) ((value))	(Delete as appropriate) ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	(value) per 1000	(value) per 1000 ((value) to (value))
	Medium risk population
	(value) per 1000	(value) per 1000 ((value) to (value))
	High risk population
	(value) per 1000	(value) per 1000 ((value) to (value))
DVT (follow‐up)	Study population		OR (value) ((value) to (value))	(value) ((value))	(Delete as appropriate) ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	(value) per 1000	(value) per 1000 ((value) to (value))
PE (follow‐up)	Study population		OR (value) ((value) to (value))	(value) ((value))	(Delete as appropriate) ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	(value) per 1000	(value) per 1000 ((value) to (value))
SAE (follow‐up)	Study population		OR (value) ((value) to (value))	(value) ((value))	(Delete as appropriate) ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	(value) per 1000	(value) per 1000 ((value) to (value))
Mortality (follow‐up)	Study population		OR (value) ((value) to (value))	(value) ((value))	(Delete as appropriate) ⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	(value) per 1000	(value) per 1000 ((value) to [value))
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; OR: odds ratio; PE: pulmonary embolism; SAE: serious adverse events; VTE: venous thromboembolism
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

^a Participants are healthy people, or with diseases other than VTE.

Notes

Parts of the Methods section of this protocol are based on a standard template established by Cochrane Vascular.

Appendices

Appendix 1. Risk factors for venous thromboembolism

(Buller 2005; Chapman 2009; Geerts 2008)

General	High risk clinical situations	Diseases associated with a prothrombotic state	Inherited thrombophilia
Older age Immobility, paresis Malignancy Obesity Family history of VTE Oral contraceptive pill, hormone replacement, tamoxifen Venous insufficiency or varicose veins	Surgery (especially hip and knee surgery or major surgery for malignancy) Pregnancy/puerperium Acute medical illness Congestive cardiac and respiratory failure Trauma Central venous catheter	Myeloproliferative disorders Antiphospholipid syndrome Paroxysmal nocturnal haemoglobinuria Nephrotic syndrome Hyperviscosity syndrome Inflammatory bowel disease	Factor V Leiden mutation Antithrombin, protein C and protein S deficiency Prothrombin gene mutation (Factor II G20210A mutation)

Appendix 2. MEDLINE search

1 Pulmonary Embolism/

2 Thromboembolism/

3 Thrombosis/

4 exp Venous Thromboembolism/

5 exp Venous Thrombosis/

6 ((vein* or ven*) adj thromb*).ti,ab.

7 (blood adj3 clot*).ti,ab.

8 deep vein thrombosis.ti,ab.

9 (lung adj3 clot*).ti,ab.

10 (DVT or VTE).ti,ab.

11 peripheral vascular thrombosis.ti,ab.

12 post‐thrombotic syndrome.ti,ab.

13 pulmonary embolism.ti,ab.

14 (pulmonary adj3 clot*).ti,ab.

15 (thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol* or microembol*).ti,ab.

16 venous thromboembolism.ti,ab.

17 or/1‐16

18 Simvastatin/

19 exp Hydroxymethylglutaryl‐CoA Reductase Inhibitors/

20 Atorvastatin/

21 Fluvastatin/

22 Pravastatin/

23 Rosuvastatin Calcium/

24 "3‐hydroxy‐3‐methylglutaryl (HMG)‐coenzyme A (CoA) reductase inhibitors".ti,ab.

25 atorvastatin.ti,ab.

26 fluvastatin.ti,ab.

27 "HMG‐CoA reductase inhibitors".ti,ab.

28 "Hydroxymethylglutaryl‐CoA Reductase Inhibitors".ti,ab.

29 lovastatin.ti,ab.

30 pitavastatin.ti,ab.

31 pravastatin.ti,ab.

32 rosuvastatin.ti,ab.

33 simvastatin.ti,ab.

34 Statin*.ti,ab.

35 or/18‐34

36 17 and 35

37 randomized controlled trial.pt.

38 controlled clinical trial.pt.

39 randomized.ab.

40 placebo.ab.

41 drug therapy.fs.

42 randomly.ab.

43 trial.ab.

44 groups.ab.

45 or/37‐44

46 exp animals/ not humans.sh.

47 45 not 46

48 36 and 47

Contributions of authors

LL: draft protocol
PZ: draft protocol
JHT: draft protocol
PZ‐Z: draft protocol
KY: draft protocol

Sources of support

Internal sources

• No sources of support provided

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

LL: none known
PZ: none known
JHT: none known
PZ‐Z: none known
KY: none known

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