Statins for adults with a first episode of venous thromboembolic disease

Objectives

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

To evaluate the benefits and harms of statins in the secondary prevention of Recurrent Venous ThromboEmbolic disease (RVTE): Deep Vein Thrombosis (DVT), Pulmonary ThromboEmbolism (PTE) and Post‐Thrombotic Syndrome (PTS) in patients with a first episode of deep vein thrombosis

Secondary objective

To evaluate the benefits and harms of statins in the secondary prevention of RVTE, DVT, PTE and PTS in patients with or without cancer, in different sexes and in the general population aged over 70 years

Background

Description of the condition

Venous thromboembolic disease (VTE) is caused by the activation of coagulation in the context of dysregulation or loss of inhibitory mechanisms that prevent the formation of the thrombus (fibrinolysis). It is characterised by the presence of a clot, made up of compressed red blood cells (polyhedrocytes), platelets and fibrin, in the deep venous system, which can extend, fragment and embolise to the pulmonary circulation [1].

In the acute stage, VTE mainly includes deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) [2]. DVT rates are 4 to 13 per 100,000 person‐years, and PTE rates are 15 to 29 per 100,000 person‐years, respectively [3]. VTE is the third leading cause of cardiovascular death after heart attack and stroke, and one of the main preventable causes of in‐hospital death [4]. The annual incidence of VTE is approximately 0.75–2.69 cases per 1000 individuals, and it is three times higher in the population over 70 years of age [2]. VTE treatment comprises anticoagulants and other therapeutic measures described in Table and Table [5, 6, 7, 8, 9, 10, 11, 12, 13].

1. Usual standard of care for the first VTE episode (treatment).

Type of Treatment	Time	Description
Initial stage (acute)	First 5 to 7 days (up to 21 days)	Parenteral (heparins or fondaparinux) or oral treatment with some DOACs: rivaroxaban and apixaban with loading doses and duration corresponding to each anticoagulant
Primary treatment stage (long‐term)	5/10 days‐3/6 months	First three to six months of treatment: VKAs, DOACs, LMWH
Extended treatment	3/6 months‐indefinite	After the first three to six months of treatment, continuation of treatment without a defined end date and periodic re‐evaluation of the risk/benefit balance (VKAs, ACOD, LMWH)

DOACs: Direct Oral Anticoagulants
LMWH: Low Molecular Weight Heparin
UFH: UnFractionated Heparin 
VKAs: Vitamin K Antagonists
Currently, multiple treatment regimens are available for the treatment of VTE, including: 
1 – Monotherapy with apixaban or rivaroxaban;
2 – Low molecular weight heparin or unfractionated heparin (LMWH or UFH) followed by dabigatran or edoxaban;
3 – LMWH or UFH with a vitamin K antagonist (VKA);
4 – LMWH monotherapy; and 
5 – fondaparinux with a VKA.

2. Drugs for the treatment of venous thromboembolic disease.

Drug family	Description
UFH	Treatment was a bolus intravenous infusion of 80 IU/kg of weight followed by an infusion of 18 IU/kg/hour, recommending controls of its action by measuring the activated partial thromboplastin time (aPTT) initially every 6 h and subsequently according to the results of the controls. The aPTT values with which heparin is considered unfractionated in the therapeutic range are between 1.5 and 2.5 times the normal value.
LMWH: bemiparin, dalteparin, enoxaparin, nadroparin, and tinzaparin	Bemiparin, dalteparin, enoxaparin, nadroparin, and tinzaparin have different dosages and administration schedules, but their efficacy is comparable in most clinical circumstances for patients with DVT. They are administered subcutaneously, with a dosage of once every 12 or 24 hours, adjusted simply to the patient's weight (except in certain circumstances such as cases of renal insufficiency, extreme ages, and weights), with at least the same efficacy as UFHs and with greater safety.
Fondaparinux	Fondaparinux is administered subcutaneously, with doses adjusted according to patient weight (5,000 U for < 50 kg and 10,000 U for > 100 kg) and renal function, similar to LMWH. This facilitates fondaparinux use, although clinical application has remained marginal and limited to specific scenarios where LMWH cannot be used.
VKAs (coumarins): sintrom and warfarin	In the acute phase, coumarins should be started on the first day. Unfractionated heparin (UFH) should not be discontinued until the INR is > 2 for two consecutive measurements. The initial dose is acenocoumarol 2 to 4 mg or warfarin 5 to 10 mg, depending on age.
DOACs: apixaban,rivaroxaban, dabigatran and edoxaban	Apixaban: An acute treatment phase of 7 days is established, during which the dose is double the dose usually used in the long‐term treatment phase (5 mg every 12 hours). In patients with VTE who start treatment with apixaban, the treatment should last 7 days at a dose of 10 mg every 12 hours. Rivaroxaban: A higher dose than the usual long‐term treatment dose (20 mg/day, in a single daily dose) is used. The daily dose is divided into two doses, 15 mg every 12 hours, and the duration of treatment at this dose is 21 days to 27 days. Dabigatran: Treatment is initiated with parenteral anticoagulation (LMWH) for at least 5 days, followed by a fixed dose of 150 mg every 12 hours of dabigatran once an INR of at least 2.0 is achieved. Edoxaban: Treatment is initiated with parenteral anticoagulation (LMWH) for at least 5 days, followed by a dose of edoxaban of 60 mg/day (adjusted to 30 mg/day only in patients with a creatinine clearance between 30 and 50 mL/min, a weight less than 60 kg, or if they were receiving a potent P‐glycoprotein inhibitor) once an INR of at least 2.0 is achieved.

aPTT: activated Partial Thromboplastin Time
DOACs: Direct Oral Anticoagulants
DVT: Deep Vein Thrombosis
INR: International Normalised Ratio
LMWH: Low Molecular Weight Heparin
UFH: Unfractionated Heparin
VKAs: Vitamin K Antagonists

Approximately 30% of patients experience recurrent venous thromboembolic disease (RVTE) within 10 years [14]. Reported RVTE rates range from 19 to 39 per 100,000 person‐years. Post‐thrombotic syndrome (PTS) is a clinical syndrome characterised by oedema, pain, venous ectasia, and skin induration, with a chronic onset in patients who have suffered a DVT [15]. PTS is usually measured using the Villalta Scale (VS), with a VS > 4 considered diagnostic. Regarding PTS, the incidence following the index DVT episode is approximately 30% at six months, 40% at one year, and up to 50% at two years. Severe PTS, including venous ulceration, has an incidence of 2.5% at two years [16].

Furthermore, cancer patients face a significantly heightened risk of venous thromboembolism (VTE) due to a malignancy‐induced hypercoagulable state, which is further exacerbated by dyslipidaemia and chronic systemic inflammation, positioning statins as a promising adjunctive strategy [17, 18, 19, 20]. Beyond these general pathophysiological mechanisms, individual patient factors such as advanced age and biological sex critically modulate thrombotic vulnerability; specifically, older adults experience age‐related endothelial senescence and impaired fibrinolytic capacity, while sex‐specific hormonal and genetic profiles differentially alter hypercoagulable responses [20, 21]. Evaluating these variables alongside clinical cancer status is therefore essential to account for potential effect modifiers, ensuring intervention equity and generalisability across distinct clinical subpopulations [22].

Description of the intervention and how it might work

Statins are a group of drugs that inhibit 3‐hydroxy‐3‐methylglutaryl (HMG)‐coenzyme A (CoA) reductase, thereby blocking the main pathway for cholesterol synthesis, and are usually prescribed to lower blood lipids, playing a major role in primary and secondary prevention of cardiovascular disease [23, 24]. Statins have also shown pleiotropic effects, including vascular protection and antithrombotic properties, (resulting from decreased platelet activation and aggregation, and modulation of tissue factor and plasminogen activator inhibitor) [25, 26, 27] and anti‐inflammatory effects [28, 29, 30, 31]. This is why they are one of the main therapeutic options for both primary and secondary prevention of cardiovascular disease [23, 24]. According to the Anatomical Therapeutic Chemical (ATC) code [32], statins are a drug class and have an average daily maintenance dose for their main indication in adults (see Table), known as the defined daily dose (DDD) [32]. In addition to their impact on arteries, evidence suggests that statins may play an important role in venous thromboembolism (VTE) [33], both in its primary prevention [25, 26, 27] and in reducing its recurrence [34, 35, 36]. These functions position statins as an adjunct to anticoagulation treatment in current management and as a potential long‐term strategy for preventing RVTE and PTS, due to their antithrombotic properties [37].

3. General statin's characteristics.

ACT Code	Name	DDD/Mg
C10AA01	Simvastatin	30
C10AA02	Lovastatin	45
C10AA03	Pravastatin	30
C10AA04	Fluvastatin	60
C10AA05	Atorvastatin	20
C10AA06	Cerivastatin	0.2
C10AA07	Rosuvastatin	10
C10AA08	Pitavastatin	2

ACT: Anatomical Therapeutic Chemical
DDD: Defined Daily Dose
Mg: milligrams

The adverse effects of treatment with statins are usually rare and include myopathy (rhabdomyolysis: < 0.1%), hepatic dysfunction (hepatotoxicity is around 0.001%) [38], cognitive impairment, depression, sleep disturbance, peripheral neuropathy, acute kidney injury or renal failure, interstitial lung disease, and pancreatitis [39].

Why it is important to do this review

VTE is a major cause of morbidity and mortality, affecting millions of people worldwide. Individuals with a first episode of VTE have a higher risk of recurrence [40]. Because statins have a good safety profile, are inexpensive, and do not increase the risk of bleeding [41], they are an important and interesting option for preventing RVTE and PTS [41, 42].

Objectives

To evaluate the benefits and harms of statins in the secondary prevention of Recurrent Venous ThromboEmbolic disease (RVTE): Deep Vein Thrombosis (DVT), Pulmonary ThromboEmbolism (PTE) and Post‐Thrombotic Syndrome (PTS) in patients with a first episode of deep vein thrombosis

Secondary objective

To evaluate the benefits and harms of statins in the secondary prevention of RVTE, DVT, PTE and PTS in patients with or without cancer, in different sexes and in the general population aged over 70 years

Methods

We will follow the Methodological Expectations for Cochrane Intervention Reviews [43] when conducting the review, and PRISMA 2020 [44] for the reporting.

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) and cluster RCTs, as they represent the gold standard design for evaluating the comparative efficacy and safety of healthcare interventions. By randomly allocating participants to intervention and control groups, RCTs effectively minimise both known and unknown confounding factors and selection bias, providing the most robust and reliable evidence base to answer our research question, following the guidelines in Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions [45].

We will exclude cross‐over trials because the carryover effects of statin therapy and the chronic nature of recurrent venous thromboembolic disease render this design inappropriate for our outcomes of interest. Furthermore, we will exclude quasi‐RCTs (controlled trials utilising non‐random or inadequate allocation methods, such as alternation or date of birth), following the algorithm described in Chapter 24 of the Cochrane Handbook [46], to prevent potential selection bias, given the sufficient availability of standard RCTs addressing this review's scope.
We will include fully published studies, as well as those available only as abstracts and unpublished reports, provided they report sufficient information to determine their eligibility.

Types of participants

We will include studies focusing on people over 18 years of age with a first episode of VTE (both provoked and unprovoked) including DVT and PTE, regardless of the completeness of the first VTE event treatment (see Table and Table for a description of regimens and drugs available for VTE treatment). DVT must be diagnosed by venous Doppler ultrasound, and PTE by computed tomography angiography (CT) or ventilation‐perfusion scintigraphy, or both. Participants must not require treatment with a vena cava filter (VCF), thrombolytics, or graduated compression stockings only [47] [48], as they usually do not require treatment with anticoagulants or antiaggregants.

We will include studies in which only a subset of participants is relevant to this review, provided that data are available separately for that subset, or that more than 80% of participants meet the inclusion criteria.

Types of interventions

We will include studies comparing statins with placebo or no intervention. Both options consider the standard of care (as described in Table and Table).

Interventions

We will consider studies using any statin as described in Table. We will include studies administering statins from the time of diagnosis of the VTE episode and up to 180 days after the diagnosis of the first VTE episode [17]. We will include studies that administer statins within 30 to 360 days of the index VTE episode [49] [17].

We will consider co‐interventions, such as receiving usual care for their first VTE event, when this usual care treatment is not part of the randomisation process. We will exclude studies administering statins in commercial presentations combined with other active components, such as:

• Statin + ezetimibe (example: simvastatin/ezetimibe, rosuvastatin/ezetimibe, atorvastatin/ezetimibe);

• Statin + fibrates (example: simvastatin/fenofibrate);

• Statin + bile acid sequestrants (example: lovastatin/colesevelam);

• Statin + niacin (example: simvastatin/niacin) and;

• Statin + omega‐3 (example: atorvastatin + omega‐3 fatty acids).

Comparators

We will define the comparator as no statin intervention or placebo. Both options should consider the standard of care (including anticoagulation during the first episode) [50].

Outcome measures

We will not consider the measurement of the outcomes assessed in this review as an inclusion criterion.

Critical outcomes

Recurrent venous thrombosis (RVTE): defined as a new episode of VTE diagnosed in follow‐up after the index VTE date, either DVT by venous Doppler ultrasound [51] or PTE by CT angiography [52] or ventilation‐perfusion scintigraphy [53].

Post‐thrombotic syndrome (PTS): defined as a clinical syndrome characterised by oedema, pain, venous ectasia, and skin induration, with chronic onset in patients who have suffered a DVT. PTS is usually measured using the Villalta Score (VS) (diagnosis of PTS, VS > 4): it is a clinical measure that incorporates the evaluation of five subjective venous symptoms (rated by the patient) (pain, cramps, heaviness, paraesthesia and itching) and six objective venous signs (rated by the physician) (pretibial oedema, skin induration, hyperpigmentation, redness, venous ectasia and pain on compression of the calf), as well as the presence or absence of ulcer in the leg affected by DVT [54].

Adverse events: Defined as the number of participants with any undesired effect due to the administration of the intervention. We will classify adverse events as serious and non‐serious adverse events, following the Medical Dictionary of Regulatory Activities (MedDRA) [55].

• Serious Adverse Events (SAEs): Defined as any untoward medical occurrence that results in death, is life‐threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability, or is a medically important event [55].

• Non‐serious Adverse Events (NSAEs): Defined as any mild‐to‐moderate untoward medical occurrence associated with statin use (e.g. mild myalgia without creatine kinase elevation, gastrointestinal discomfort, or asymptomatic transaminase elevation) that does not meet the criteria for a serious adverse event [55].

Important outcomes

All‐cause mortality: defined as the number of participants experiencing death from any cause, including diseases related to DVT or organ failure [56].

Major bleeding: defined as the number of participants suffering extensive bleeding according to the following characteristics [57, 58]:

• Critical location: intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular, pericardial, or intramuscular haemorrhage with compartment syndrome;

• Significant clinical compromise: a drop in haemoglobin ≥ 2 g/dL;

• Need for transfusion: the administration of ≥ 2 units of packed red blood cells;

• Death: any bleeding event that directly contributes to the patient's death.

Quality of life: defined by the World Health Organisation (WHO) as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns [59]. We will include studies assessing QoL using EuroQol‐5D (EQ‐5D) [60], the Short‐Form 36 (SF‐36) [61, 62], or the specific test for venous insufficiency (Chronic Venous Insufficiency Questionnaire, CIVIQ) [63]. We will consider studies reporting quality of life with other validated instruments. Currently, no studies report specific Minimal Important Difference (MID) values for the EQ‐5D, the SF‐36 or the CIVIQ in patients with VTE. We will consider a MID of 0.5 standard deviations [64] for this review.

If studies use several instruments to assess QoL, we will prioritise general quality‐of‐life data (e.g. EQ‐5D).

Patient satisfaction: We will define this as the patient's subjective assessment of the prescribed medication, determined by the balance between perceived therapeutic benefits and the drawbacks or side effects of the treatment. This will be quantified using the Medication Satisfaction Questionnaire (MSQQ or MSQQ‐9), which evaluates efficacy, side effects, convenience, and overall satisfaction on a standardised scale of 0 to 100 [65].

Medication burden: We will operationalise the cumulative physical, cognitive, logistical, and temporal demands placed on patients to sustain their treatment regimens. Within the context of VTE management and the integration of adjunctive therapies such as statins, these demands capture the complexities of polypharmacy, dosing organisation, laboratory surveillance, and administrative healthcare tasks. This construct will be quantified using the Treatment Burden Questionnaire (TBQ), a 13‐item self‐administered tool that measures the perceived severity of treatment‐related tasks on a scale ranging from 0 (no burden) to 10 (maximum burden) [66].

Treatment acceptability: We will define and assess acceptability in accordance with the Theoretical Framework of Acceptability (TFA). The instrument comprises seven Likert‐type items designed to capture the distinct constructs of the TFA (affective attitude, burden, ethicality, perceived effectiveness, intervention coherence, self‐efficacy, and opportunity costs), plus one general acceptability item. The measure is structurally adaptable, allowing researchers to substitute placeholder terms with the specific name and actions of the evaluated intervention across diverse study designs [67].

Time points for outcome measurement

We will consider outcomes measured up to:

acute‐term: the first 5 to 10 days at < 3 months;
short‐term: > 3 at 6 months, and;
long‐term > 6 months in relation to the treatment [68, 69].

Search methods for identification of studies

Electronic searches

We will conduct systematic searches of electronic databases in accordance with the methods specified in the Cochrane Handbook for Systematic Reviews of Interventions [70].

This review will incorporate the results of electronic database searches conducted from database inception up to the present date. We will not impose language or publication status restrictions on these searches. We will search the following databases:

• MEDLINE (Ovid MEDLINE ALL 1946 to search date);

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (to search date);

• Embase (Ovid; 1974 to date);

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);

• World Health Organisation International Clinical Trials Registry Platform (WHO ICTRP) (trialsearch.who.int).

We will review the included studies for any retractions, modifications, or comments.

Details of the search strategies are available in Supplementary material 1.

Searching other resources

We will handsearch the reference lists of included studies, relevant systematic reviews, meta‐analyses, and health technology assessment reports to identify potentially eligible studies that were not retrieved through database searches.

Data collection and analysis

Selection of studies

Two review authors (HJP and SR) will independently assess the titles and abstracts of all records retrieved through the search and remove irrelevant ones. Subsequently, we will retrieve the full texts of all potentially eligible records, and two reviewers will independently assess them according to our eligibility criteria and record the reasons for exclusion of ineligible studies. If necessary, we will resolve discrepancies through discussion or by consulting a third review author (LIG). If consensus is not met, we will categorise the study as awaiting classification and contact the study authors for clarification. We will compile multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review.

We will document all the selection process in detail to generate a PRISMA flow diagram [44]. We will use Covidence software [71] to manage the study selection process and the removal of duplicates.

Data extraction and management

Two independent reviewers (HJP and SR) will extract essential data on participants, interventions, and comparators using a previously validated data extraction form. We will resolve discrepancies between the two reviewers through discussion, and, if necessary, a third reviewer (LIG) will contribute their opinion to reach consensus. One review author will be responsible for entering the collected data into RevMan [72]. Subsequently, two other review authors will verify and transfer the study data for analysis.

We will extract the following information from the study reports:

• Methods:

  • Study design: This includes start and end dates (if unavailable), the language of publication, and the study identifier.

• Participants:

  • Selection criteria (inclusion and exclusion criteria) used for participant selection;

  • General participant data at baseline (e.g. mean age, age range, sex, place of residence, type of venous thromboembolic disease: deep vein thrombosis and pulmonary thromboembolism, or both);

  • Number of participants in each prespecified group (statins or placebo/no intervention) who experienced the specified outcome events;

  • Additional participant characteristics related to equity and defined by PROGESS‐Plus [73, 74], such as sex, cancer status, and age.

• Interventions: For the interventions and comparisons, we will use the checklist from the Template for Intervention Description and Replication (TIDieR) [75].

  • The name of the intervention (types of statins);

  • Dose of statins;

  • Information about the frequency and duration of the intervention implementation.

• Outcomes: The definitions of relevant outcomes, the methods used, and the timing of their measurement will be reported, as well as any subgroups relevant to the review.

• The study’s funding sources will be disclosed.

• The principal investigators’ statements of financial interest will be taken into account.

We will present the extracted information in the “Overview of Included Studies and Synthesis” table (see the example in Table). In addition, we will contact the authors of the included studies to request any missing relevant information, and we will keep records of these communications.

4. Overview of included studies and synthesis table illustrating key characteristics of studies, outcomes and analysis methods, sorted alphabetically.

Study	Study design	Population	Type of intervention	Comparator	Specific outcomes
Author/year

Risk of bias assessment in included studies

We will assess the risk of bias using the Cochrane RoB 2 tool. Two review authors (HJP and SR) will independently assess the risk of bias for all outcomes included in the summary of findings tables (see Certainty of the evidence assessment) [76, 77]. We plan to assess the risk of bias based on the intention‐to‐treat principle (i.e. the effect of assignment to the intervention) [78]. Any discrepancies in the assessment will be resolved by consulting a third review author (LIG). If we do not have sufficient details in the published reports, trial protocols, clinical study reports, or other resources, we will contact the original study investigators to obtain further information on the elements of risk of bias.

We will consider all RoB 2 domains (bias caused by the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results), classifying each as “high risk of bias,” “some concerns,” or “low risk of bias.” We will use the RoB 2 Excel tool to manage our risk of bias assessments. We will use the answers to the signalling questions and the algorithms built into the RoB 2 tool for each assessment. We will provide information justifying our ratings in the risk of bias table, and if our judgement deviates from the algorithm’s recommendation, we will explicitly state the reasons for this divergence. All data will be made publicly available as supplementary material in a designated repository (https://osf.io/).

For cluster RCTs, we will use the RoB 2 tool, assessing an additional domain specifically for cluster RCTs (domain 1b – "bias arising from the timing of identification and recruitment of participants"). We will use the cluster RCT‐specific Excel tool for these assessments (available at www.riskofbias.info).

Measures of treatment effect

We will define the measures of treatment effects in accordance with Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions [79]. For dichotomous outcomes (such as adverse events, recurrent venous thrombosis, or post‐thrombotic syndrome), we will report results as risk ratios (RR) with 95% confidence intervals (CI). We will report continuous outcomes, such as quality of life, as the mean difference (MD) with its 95% CI. If studies use different instruments to assess the same continuous outcome, we will calculate the standardised mean difference (SMD) with its 95% CI.

We will conduct meta‐analysis only when appropriate, that is, when the treatments, participants, and key clinical issues are sufficiently similar to allow for a meaningful pooling of the data.

Unit of analysis issues

The participant with episodes of venous thromboembolic disease (VTE): deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), or both, will constitute the unit of analysis. The level of randomisation will be a key factor, and we will account for repeated observations of outcomes. In cases where a single study provides multiple comparisons eligible for a given meta‐analysis, we will either pool the groups to form a single pairwise comparison or reduce the sample size by dividing any shared group into two or more groups. While this latter approach offers some means of adjusting the precision of the comparison, it does not fully address the correlation arising from the inclusion of identical sets of participants in multiple comparisons [80].

For cluster‐randomised controlled trials, the cluster, rather than the individual participant, will be treated as the unit of analysis to reduce unit‐of‐analysis errors, as recommended in Section 23.1.1 of the Cochrane Handbook for Systematic Reviews of Interventions [45]. We will account for potential unit‐of‐analysis errors that arise when data are analysed without considering the intracluster correlation coefficient (ICC). When included studies do not fit the clustering, we will augment the standard errors using the design effect, derived from the average cluster size (m), and a robust ICC estimate. Rather than relying on generic hypothetical values, we will obtain ICC estimates directly from similar studies within the review, external literature, or expert consensus, in accordance with the Cochrane Handbook (Chapters 23.1.4 and 23.1.5). The robustness of these choices will be explored through sensitivity analyses. Furthermore, we will explicitly separate our methodological approaches for handling cluster‐level randomisation from those dedicated to repeated measures over time [45].

Dealing with missing data

We will prioritise obtaining missing data by attempting to contact the authors of the selected studies, whenever possible. We will conduct a risk of bias assessment that will include a thorough examination of key numerical data, such as details of the selection process, the number of randomised participants, and the characteristics of the intention‐to‐treat groups, both according to treatment received and according to protocol. In this process, we will analyse dropout rates (e.g. participants who dropped out, participants lost to follow‐up, and those withdrawn) and critically assess concerns regarding missing data and the methods used for imputation (such as last‐observation‐carried‐forward). We will base our analyses exclusively on the available data, considering missing data issues when assessing the risk of bias and the certainty of the evidence.

Reporting bias assessment

If we are able to include 10 studies or more per outcome, we plan to assess reporting bias and publication bias using funnel plots, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions [80]. Since asymmetry in funnel plots can result from various reasons — including, for example, actual variations in effect size based on study size, poor study design leading to bias in smaller studies, and selective omission of information [81] — we will interpret these plots with caution [82] and in accordance with the recommendations in Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions [80]. Although we recognise the limitations and low statistical power of statistical tests for funnel plot asymmetry, we will perform these tests (e.g. Egger's test) in conjunction with the visual inspection of the funnel plots. Furthermore, any observed asymmetry will not be interpreted in isolation; instead, we will carefully consider alternative explanations, such as chance or clinical and methodological heterogeneity (e.g. differences in study design, population risk, or intervention parameters).

Synthesis methods

We will use RevMan [72] to perform all statistical analyses and generate the figures corresponding to all our outcomes of interest under the statins versus placebo/no intervention comparison. We will account for expected clinical, methodological, or mixed heterogeneity among studies using random‐effects models. We will use the Restricted Maximum Likelihood (REML) estimator to assess between‐trial variance. We will use the Hartung‐Knapp‐Sidik‐Jonkman method to calculate a confidence interval for the meta‐analysis effect estimate when there are at least three studies, and the estimate of heterogeneity is greater than zero. In other scenarios (i.e. in pooled analyses of two studies, or where the estimate of heterogeneity is equal to zero) we will use the Wald‐type method. We will use the inverse variance method for all outcomes [83]. We will follow the guidelines described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions [83].

If a meta‐analysis is not feasible, we will narratively summarise the effect estimates of all included studies, following the guidelines for “Synthesis without meta‐analysis,” rather than a combined statistical approach. We will follow Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions [84].

Investigation of heterogeneity and subgroup analysis

We will conduct the following subgroup analyses to investigate heterogeneity:

• Type of thromboembolic disease (DVT or PTE): We have based this analysis on the potential effect of statins in different events with burden variability [85].

• Cancer: People with cancer have a higher risk of developing VTE; although studies are not conclusive, statins could modulate inflammation and hypercoagulability associated with cancer [86, 87, 88].

• Age (< 70 years, ≥ 70 years): The incidence of VTE increases with age; studies have shown that the anti‐inflammatory benefits of statins are more pronounced in older adults, although there is also a greater risk of adverse effects [89].

• Sex (female, male): Due to hormonal differences and cardiovascular risk factors, variations in response to statins may be observed. Studies have shown a sex‐related distribution of variations in coagulation parameters [90].

• Type of statin (atorvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, simvastatin, cerivastatin): It is important to note that not all statins have the same potency or pleiotropic profile. For example, rosuvastatin and atorvastatin have shown a greater effect on coagulation and fibrinolysis markers than pravastatin or fluvastatin [24].

• Timing of treatment initiation: Studies report that starting statins immediately after a thromboembolic event can improve endothelial stabilisation and reduce recurrence, suggesting that early initiation is more beneficial than late initiation [24].

We will compare differences between subgroups using the formal test for subgroup differences in RevMan Web [72].

Sensitivity analysis

We will conduct sensitivity analyses for the main outcomes (those included in the SoF tables) to investigate how different factors influence effect sizes, as described in Section 10.14 of the Cochrane Handbook for Systematic Reviews of Interventions [80], excluding studies with the following characteristics:

• High overall risk of bias;

• Unpublished data;

• Cluster design.

Certainty of the evidence assessment

We will use the GRADE approach to assess the overall certainty of the evidence [91]; this methodology takes into account factors related to internal validity (overall risk of bias, inconsistency, imprecision, and publication bias) and external validity (directness of the results). Two review authors (HJP and SR) will independently evaluate the certainty of the evidence. We will resolve disagreements in these evaluations through discussion and, if necessary, by consulting a third review author (LIG).

We will construct a single primary summary of findings (SoF) table focusing on the main comparison of interest (statins versus placebo or no intervention). We will use GRADEpro GDT [92] for producing the SoF tables. We will justify all decisions to downgrade the certainty of the evidence using informative footnotes and the GRADE guidelines [93]. We will produce a SoF for the following comparison and outcomes:

Comparisons:

Statins versus placebo/no intervention.

Outcomes

• Recurrent venous thrombosis (RVTE) (long‐term);

• Post‐thrombotic syndrome (PTS) (long‐term);

• Serious adverse events(long‐term);

• Non‐serious adverse events(long‐term);

• All‐cause mortality(long‐term);Major bleeding (long‐term);

• Quality of life (long‐term).

Equity considerations

In alignment with methodological standards (such as Chapter 16 of the Cochrane Handbook), our evaluation framework incorporates health equity considerations to examine how intervention effects might vary across different sociodemographic, clinical, or vulnerable populations. Specifically, data collected from predefined subgroups and supplementary sources will be systematically used to:

• Evaluate applicability: Discuss how the efficacy and safety of statins for venous thromboembolism (VTE) prevention might differ across various equity‐relevant strata (using PROGRESS‐Plus factors, where reported).

• Contextualise findings: Explore whether differences in baseline risk, healthcare access, or demographic characteristics influence treatment outcomes and ensure generalisability across diverse clinical subpopulations.

We will conduct subgroup analyses related to the following PROGRESS‐plus [73] criteria:

• Age: See Investigation of heterogeneity and subgroup analysis.

• Sex: See Investigation of heterogeneity and subgroup analysis.

• Cancer: See Investigation of heterogeneity and subgroup analysis.

See additional details in Supplementary material 2.

Consumer involvement

We will not involve consumers in this review due to limited resources.

Supporting Information

Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016403.

Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.

Supplementary material 1 Search strategies

Supplementary material 2 Summary of the characteristics of participants we would expect to see in the evidence and the actual participant characteristics extracted from the included studies

New

Additional information

Contributions of authors

HJP: Conceptualisation, data curation, investigation, methodology, validation, visualisation, writing original draft.

SR: Methodology, validation, visualisation, writing review & editing.

CEL: data curation, investigation, methodology, validation, visualisation, writing original draft, supervision, writing review & editing.

LIG: Conceptualisation, data curation, investigation, methodology, validation, visualisation, writing original draft, supervision, writing review & editing, project administration.

Declarations of interest

HJP: No commercial or non‐commercial conflicts of interest relevant to this review.

SR: No commercial or non‐commercial conflicts of interest relevant to this review.

CEL: No commercial or non‐commercial conflicts of interest relevant to this review.

LIG: No commercial or non‐commercial conflicts of interest relevant to this review.

Sources of support

Internal sources

• Universidad Hospital Italiano de Buenos Aires, Argentina

  Provided salaries for HJP, SR, CEL and LIG

External sources

• No sources of support provided

Registration and protocol

Cochrane approved the proposal for this review in March 2026.

Data, code and other materials

Data sharing is not applicable to this article as it is a protocol, so no datasets were generated or analysed.

Disclosure of artificial intelligence use

We used Grammarly Pro 2026 (Grammarly Inc., San Francisco, CA, USA) for language editing, including grammar, spelling, and style. We did not use artificial intelligence tools to generate or draft the scientific content of this review. All authors reviewed and approved the suggestions from Grammarly, who take full responsibility for the manuscript's content.

Notes

Published notes in RevMan are for editor use only. Authors should leave this section blank.