Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation

Abstract

Background

Oral anticoagulants may improve the survival of people with cancer through an antithrombotic effect, yet increase the risk of bleeding.

Objectives

To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), with no standard therapeutic or prophylactic indication for anticoagulation.

Search methods

We conducted comprehensive searches on 14 June 2021, following the original electronic searches performed in February 2016 (last major search). We electronically searched the following databases: CENTRAL, MEDLINE, Embase. In addition, we handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified.

Selection criteria

We included randomised controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in ambulatory people with cancer (i.e., not hospital inpatients during the time of their participation in trials) These people are typically undergoing systemic anticancer therapy, possibly including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.

Data collection and analysis

Using a standardised form, two review authors independently extracted data on study design, participants, intervention outcomes of interest, and risk of bias. Outcomes of interest included all‐cause mortality, pulmonary embolism, symptomatic deep vein thrombosis (DVT), major bleeding, minor bleeding and health‐related quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach.

Main results

Of 12,620 identified citations, 10 RCTs fulfilled the inclusion criteria. The oral anticoagulant was a vitamin K antagonist (VKA) in six of these RCTs, and a direct oral anticoagulant (DOAC) in the remaining four RCTs (three studies used apixaban; one used rivaroxaban). The comparator was either placebo or no prophylaxis.

Compared to no prophylaxis, vitamin K antagonists (VKAs) probably reduce mortality at six months slightly (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.77 to 1.13; risk difference (RD) 22 fewer per 1000, 95% CI 72 fewer to 41 more; moderate‐certainty evidence), and probably reduce mortality at 12 months slightly (RR 0.95, 95% CI 0.87 to 1.03; RD 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate‐certainty evidence). One study assessed the effect of a VKA compared to no prophylaxis on thrombosis; the evidence was very uncertain about the effect of VKA compared to no VKA on pulmonary embolism and symptomatic DVT (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low‐certainty evidence; RR 0.08, 95% CI 0.01 to 1.42; RD 35 fewer per 1000, 95% CI 37 fewer to 16 more; very low‐certainty evidence, respectively). Also, VKAs probably increase major and minor bleeding at 12 months (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate‐certainty evidence for major bleeding, and RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate‐certainty evidence for minor bleeding).

Compared to no prophylaxis, at three to six months, direct oral anticoagulants (DOACs) probably reduce mortality slightly (RR 0.94, 95% CI 0.64 to 1.38, RD 11 fewer per 1000, 95% CI 67 fewer to 70 more; moderate‐certainty evidence), probably reduce the risk of pulmonary embolism slightly compared to no prophylaxis (RR 0.48, 95% CI 0.24 to 0.98; RD 24 fewer per 1000, 95% CI 35 fewer to 1 fewer; moderate‐certainty evidence), probably reduce symptomatic DVT slightly (RR 0.58, 95% CI 0.30 to 1.15; RD 21 fewer per 1000, 95% CI 35 fewer to 8 more; moderate‐certainty evidence), probably do not increase major bleeding (RR 1.65, 95% CI 0.72 to 3.80; RD 9 more per 1000, 95% CI 4 fewer to 40 more; moderate‐certainty evidence), and may increase minor bleeding (RR 3.58, 95% CI 0.55 to 23.44; RD 55 more per 1000, 95% CI 10 fewer to 482 more; low‐certainty evidence).

Authors' conclusions

In ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), the current evidence on VKA thromboprophylaxis suggests that the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism. With DOACs, the benefit of reduction in venous thromboembolic events outweighs the risk of major bleeding.

Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the 'What's new' section in the  Cochrane Database of Systematic Reviews for the current status of this review.

Plain language summary

Are oral blood thinners safe and effective for people being treated for cancer?

Key messages

‐ It is reasonable to give direct oral anticoagulants (a type of blood thinning medicine) to people being treated for cancer, especially if they have an increased risk of blood clots, because the benefit of reduction in blood clots appears to outweigh the risk of major bleeding.

‐ For a different type of blood thinner, vitamin K antagonists (warfarin), the risk of major bleeding might outweigh the benefit of a reduction in formation of blood clots in the legs and lungs.

‐ More research is needed on the effects of blood thinners in people with different types and stages of cancers.

What are blood thinners

Blood thinners are medicines that help prevent blood from clotting. People at a high risk of getting blood clots can take blood thinners to reduce their chances of developing serious conditions such as heart attacks and strokes.

Why might blood‐thinning treatment be helpful for people with cancer?

People with cancer undergoing systemic treatment (any medication that travels through your body in the bloodstream to find, damage or destroy cancer cells, including chemotherapy, radiotherapy, immunotherapy and target therapy) are at increased risk of blood clots. While blood thinners can decrease the risk of getting blood clots, they can also increase the risk of serious and fatal bleeding. Therefore, it is important to understand the benefits and harms of using blood thinners in these people to allow them and their doctors to make informed decisions.

What did we want to find out?

We wanted to find out if giving preventative, oral (by mouth) blood thinners was better than no preventative treatment for people being treated for cancer. We focused on people with cancer who were not admitted to hospital for their cancer treatment.

We were interested in the effects of blood thinners on:

‐ death;

‐ formation of blood clots in veins (venous thromboembolism). Venous thromboembolism includes deep vein thrombosis (DVT) where a clot lodges in the lower leg, thigh or pelvis, and pulmonary embolism where a clot lodges in the lungs;

‐ major and minor bleeding.

What did we do?

We searched for studies that examined the benefits and harms of blood thinners for people being treated for cancer who otherwise had no signs, symptoms or conditions that suggested blood thinning was definitely needed.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 10 studies that involved 2934 people with cancer. The biggest study had 841 people and the smallest had 24 people. The studies used two types of blood thinner:

‐ the vitamin K antagonist, warfarin; or

‐ direct [ER1] oral anticoagulants (specifically, apixaban and rivaroxaban).

Main results

Compared to no preventative treatment, warfarin, the vitamin K antagonist medicine:

‐ probably reduces death at 6 months and at 12 months slightly (22 and 29 fewer deaths, respectively, per 1000 people);

‐ may have little to no effect on formation of blood clots, but we are very uncertain about the results;

‐ probably increases major bleeding and minor bleeding at 12 months (107 more major bleeds and 167 more minor bleeds per 1000 people).

Compared to no preventative treatment, direct oral anticoagulant medicines:

‐ probably reduce death at 3 to 6 months slightly (11 fewer deaths per 1000 people);

‐ probably reduce blood clots in the lungs and legs slightly (24 fewer in the lungs and 19 fewer in the legs per 1000 people);

‐ probably do not increase major bleeding (9 more major bleeds per 1000 people);

‐ may increase minor bleeding (55 more minor bleeds per 1000 people).

This suggests that:

with a vitamin K antagonist, the risk of major bleeding might outweigh the benefit of any reduction in the risk of blood clots in the legs and lungs;

with direct oral anticoagulants, the benefit of reduction in the risk of blood clots in the legs and lungs outweighs the risk of major bleeding.

What are the limitations of the evidence?

We are moderately confident in the evidence for death, major bleeding and minor bleeding. In eight of the studies, the methods used may have affected the results.

We are not confident in the evidence for blood clots in people who were given vitamin K antagonist medicine because the evidence came from one study only. This study gave the medicine in a fixed rather than variable dose, which is not current best practice.

How up to date is this evidence?

This review updates our previous review. The evidence is up to date to June 2021.

Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the 'What's new' section on the Cochrane Database of Systematic Reviews for the current status of this review.

Background

Please refer to the glossary for definitions of technical terms (Table 3).

1. Glossary.

Term	Meaning
Adjuvant therapy	Assisting in the amelioration or cure of disease.
Anticoagulation	Process of hindering the clotting of blood especially by treatment with an anticoagulant.
Antithrombotic	Used against or tending to prevent thrombosis (clotting).
Apixaban	Oral direct factor Xa inhibitor used for anticoagulation.
Coagulation	Clotting.
Direct oral anticoagulant (DOAC) factor Xa inhibitor	Oral direct factor Xa inhibitor used for anticoagulation. Apixaban is an oral direct factor Xa inhibitor.
Deep vein thrombosis (DVT)	Condition marked by the formation of a thrombus within a deep vein (e.g. leg or pelvis) that may be asymptomatic or symptomatic (as swelling and pain) and that is potentially life‐threatening if dislodgment of the thrombus results in pulmonary embolism.
Fibrin	White insoluble fibrous protein formed from fibrinogen by the action of thrombin especially in the clotting of blood.
Fondaparinux	An anticoagulant medication.
Hemostatic system	The system that shortens the clotting time of blood and stops bleeding.
Heparin	Enzyme occurring especially in the liver and lungs that prolongs the clotting time of blood by preventing the formation of fibrin. Two forms of heparin that are used as anticoagulant medications are: unfractionated heparin (UFH) and low‐molecular‐weight heparins (LMWH).
Major bleeding	Bleeding that is intracranial or retroperitoneal, if it leads directly to death, or if results in hospitalisation or transfusion.
Metastasis	Spread of cancer cells from the initial or primary site of disease to another part of the body.
Minor bleeding	Any bleeding not classified as major bleeding.
Oncogene	Gene having the potential to cause a normal cell to become cancerous.
Osteoporosis	Condition that affects mainly older women and is characterised by decrease in bone mass with decreased density and enlargement of bone spaces, producing porosity and brittleness.
Pulmonary embolism (PE)	Embolism of a pulmonary artery or one of its branches that is produced by foreign matter and most often a blood clot originating in a vein of the leg or pelvis and that is marked by laboured breathing, chest pain, fainting, rapid heart rate, cyanosis, shock and sometimes death.
Stroma	The supporting framework of an organ typically consisting of connective tissue.
Thrombin	Proteolytic enzyme formed from prothrombin that facilitates the clotting of blood by catalysing conversion of fibrinogen to fibrin.
Thrombocytopaenia	Persistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions.
Vitamin K antagonist (VKA)	Anticoagulant medications. Warfarin is a vitamin K antagonist.
Warfarin	Anticoagulant medication that is a vitamin K antagonist.
Ximelagatran	Anticoagulant medication.

Description of the condition

Studies have implicated the tumour‐mediated activation of the haemostatic system in both the formation of tumour stroma and in tumour metastasis (Dvorak 1986; Francis 1998; Levine 2003). In one cohort study of over 3000 healthy participants with 15 years' follow‐up, cancer mortality was three times more common in participants who were hypercoagulable at baseline than in participants who were not (Miller 2004).

Description of the intervention

Vitamin K antagonists (VKAs) have been the mainstay of oral anticoagulant therapy since the mid‐1950s. Well‐designed clinical trials have shown their effectiveness for the primary and secondary prevention of several venous and arterial thrombotic diseases (Ansell 2008). In recent years, direct oral anticoagulants (DOACs) have become an alternative option, in addition to low‐molecular‐weight heparins (LMWH), for the treatment of thrombosis, mainly due to their rapid onset of action and convenience of oral administration (Farge 2019).

How the intervention might work

Since the 1930s, scientists have been exploring the effects of anticoagulation on cancer (Smorenburg 2001), and there is evidence that warfarin has an inhibitory effect on tumour growth and metastasis. Schulman 2000 showed that in people with a first episode of venous thromboembolism (VTE), cancer incidence was lower when treated with oral anticoagulants for six months rather than for six weeks. These observations led to the hypothesis that the antitumour effect of oral anticoagulants, in addition to their antithrombotic effect, may improve outcomes of people with cancer.

Why it is important to do this review

In the early 1980s, one large United States (US) Veterans Administration Cooperative Study suggested that warfarin, as a single anticoagulant agent, may favourably modify the course of some types of human malignancy, such as small cell lung cancer (SCLC) (Zacharski 1981). Conversely, in another trial, warfarin did not improve the outcomes of people with SCLC receiving chemotherapy and radiotherapy (Maurer 1997). The last update of this Cochrane Review, published in 2017, identified six trials enrolling 1373 participants (Chahinian 1989; Levine 1994; Levine 2012; Maurer 1997; Stanford 1979; Zacharski 1984), and concluded that the existing evidence did not suggest a mortality benefit from oral anticoagulation in people with cancer, while the risk for bleeding was increased (Akl 2014a). Since then, there has been a growing body of evidence on the use of DOACs in people with cancer (Carrier 2019 (AVERT); Khorana 2019 (CASSINI)).

Living systematic review approach: since the publication of the 2017 update of the review, we are maintaining it as a living systematic review: we will be continually running the searches and incorporating newly identified studies (for more information about the living systematic review approach being piloted by Cochrane, see Appendix 1). We consider that a living systematic review approach is appropriate for this review for three reasons. First, the review addresses an important subject for clinical practice; people with cancer have a high rate of VTE, up to 17.7% (Ay 2010). In addition, VTE is associated with a 2.3 times increased risk of death in people with non‐small cell lung cancer (NSCLC) and breast cancer, a 2.5 times lengthening of hospital stay among people with lung cancer, and 50% increased total costs for people with lung cancer (Chew 2007; Chew 2008; Connolly 2012). Second, there is uncertainty in the existing evidence; the 2017 update of this systematic review did not provide definitive results about suspected subgroup effects on all‐cause mortality and the effect of DOACs. Third, this living systematic review may be used as part of a living guideline project (Akl 2017).

Objectives

To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), with no standard therapeutic or prophylactic indication for anticoagulation.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

Ambulatory people with cancer (i.e., not hospital inpatients during the time of their participation in the trials) of any age (including children) with cancer with no standard indication for prophylactic anticoagulation (e.g. for acute illness, for central venous line placement, perioperatively) or for therapeutic anticoagulation (e.g. for the treatment of deep vein thrombosis (DVT) or pulmonary embolism). Typically, these people are undergoing chemotherapy, target therapy, immunotherapy, or radiotherapy.

Types of interventions

Intervention

• oral pharmacological thromboprophylaxis with VKA (e.g. warfarin)

• oral pharmacological thromboprophylaxis with DOAC (e.g. apixaban, rivaroxaban, edoxaban)

Control

• no pharmacological thromboprophylaxis

We included any comparison of a combination of the three management options listed above. The protocol from original studies should have planned to provide all other co‐interventions (e.g. chemotherapy) similarly.

Types of outcome measures

Primary outcomes

• All‐cause mortality

Secondary outcomes

• Symptomatic DVT: events had to be suspected clinically, and diagnosed using an objective diagnostic test such as: venography, ¹²⁵I‐fibrinogen‐uptake test, impedance plethysmography, or compression ultrasound

• Pulmonary embolism: events had to be suspected clinically, and diagnosed using an objective diagnostic test such as: pulmonary perfusion/ventilation scans, computed tomography, pulmonary angiography, or autopsy

• Major bleeding: we accepted the authors' definitions of major bleeding

• Minor bleeding: we accepted the authors' definitions of minor bleeding

• Health‐related quality of life (HRQoL): had to be measured using a validated tool

We assessed the primary and secondary outcomes up to 12 months.

Search methods for identification of studies

Electronic searches

The search strategy was part of a comprehensive search for studies of anticoagulation in people with cancer. We did not use language restrictions. We conducted comprehensive searches on 14 June 2021 following the original electronic searches performed in February 2016 (last major search). We electronically searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 6) in the Cochrane Library; MEDLINE via Ovid (1946 to June 14 2021 ); and Embase via Ovid (1980 to 2021 week 24). For each database, the search strategies combined MeSH terms and keywords for anticoagulants, terms for cancer, and a search filter for RCTs. An information specialist revised the search strategy in 2020 to ensure it was fit for purpose in the changing clinical environment. We report details on the full search strategies for each of the electronic databases in Appendix 2.

Living systematic review approach: we will update the searches using auto‐alerts on a monthly basis. We will incorporate new evidence rapidly after it is identified, and publish an update report every six months. We will report a minor update in the 'What's new' section, and a major update in the form of an update of the full review. This update of the systematic review is based on the findings of a literature search conducted on 14 June 2021. We will review search methods and strategies approximately yearly, to ensure they reflect any terminology changes in the topic area, or in the databases.

Searching other resources

We handsearched the conference proceedings of the American Society of Clinical Oncology (ASCO, starting with its first volume in 1982 up to June 2021) and of the American Society of Hematology (ASH, starting with its 2003 issue up to June 2021). We also searched ClinicalTrials.gov and WHO International Clinical Trials Registry Platform for ongoing studies. We reviewed the reference lists of studies included in this review and of other relevant systematic reviews. In addition, we contacted experts in the field to check for unpublished and ongoing trials.

Living systematic review approach: we will search on a regular basis the conference proceedings of ASCO and ASH soon after their publications, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform. As an additional step, we will contact corresponding authors of ongoing studies as they are identified and ask them to advise when results are available. We will continue to review the reference lists for any prospectively identified studies.

Data collection and analysis

Selection of studies

Four pairs of review authors independently screened for eligibility the titles and abstracts of identified articles. We retrieved the full texts of articles judged as potentially eligible by at least one review author. The pairs then independently screened the full‐text articles for eligibility using a standardised form with explicit inclusion and exclusion criteria. We resolved any disagreements through discussion or by consulting another review author.

Living systematic review approach: for the monthly searches, we will immediately screen any new citations retrieved each month. As the first step of monthly screening, we will apply the machine learning classifier (RCT model) available in the Cochrane Register of Studies (CSR‐Web; Wallace 2017). The machine learning classifier currently has a specificity/recall of 99.98%  and it assigns a probability score (from 0 to 100) to each citation for being a true RCT. . Two review authors will independently screen any citations assigned a score from 10 to 100. Citations that score nine or less will be screened by Cochrane Crowd (Cochrane Crowd). Any citations deemed to be potential RCTs by Cochrane Crowd (i.e., scored 10 and above) will be returned to the authors for screening.

Data extraction and management

Pairs of review authors independently extracted data from each included study and resolved any disagreements through discussion. We aimed to collect data related to the following.

Participants

• Number of participants randomised to each study arm

• Population characteristics (e.g. age, gender, comorbidities, co‐interventions, history of VTE, type of cancer, stage of cancer)

Interventions

• Type of anticoagulant: VKA or DOAC

• Intensity of VKA therapy (international normalised ratio (INR) target) or dose

• Duration of treatment

• Control: placebo or no intervention

• Co‐interventions including chemotherapy, target therapy, immunotherapy or radiotherapy (type and duration)

Outcomes

We collected outcome data in terms of number of events for dichotomous outcomes, and mean and standard deviation for continuous outcomes. We collected these data separately for each study arm. When we could not obtain the number of events at the time points of interest (i.e. up to 12 months) from the paper or from the authors, two review authors independently calculated these numbers from survival curves, if available (Zacharski 1984). We used the mean of the two estimates when they differed. In addition, we collected the number of participants with incomplete data for each outcome in each study arm.

Other

• Source of funding

• Ethical approval

• Conflicts of interest

Assessment of risk of bias in included studies

We assessed the risk of bias at the study level using Cochrane's risk of bias tool (Higgins 2011). Two review authors independently assessed the methodological quality of each included study and resolved any disagreements through discussion.  In some instances, when details for certain criteria were not clearly reported, we made the following risk of bias judgments:
 

• adequate sequence generation: if sufficient details of sequence generation were not provided, we assumed that a trial is probably randomized if it explicitly states that it has been randomized; hence we judged the risk of bias to be low;

• allocation concealment: if sufficient details of the allocation concealment were not provided, we assumed that a trial is probably not concealed; hence we judged the risk of bias to be high;

• blinding of participants and personnel: we followed specific instructions for estimating unclearly reported blinding status (Akl 2012). In brief, when sufficient details of blinding participants and personnel were not provided, we assumed that they were probably not blinded. However, since the knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of co‐interventions), we judged the risk of bias to be high

• blinding of outcome assessment: we followed specific instructions for estimating unclearly reported blinding status (Akl 2012). In brief, when sufficient details of blinding outcome assessors were not provided, we assumed that they were probably not blinded. However, since the knowledge of the assigned intervention is unlikely to have impacted the assessment of the hard outcomes studied in this review (e.g., mortality, VTE, and bleeding), we judged the risk of bias to be low

• incomplete outcome data: our judgment was based on the comparison between rate of participants with missing data and event rate for the main outcome in each arm. If the rate of participants with missing data was substantively higher than the event rate, then we judged risk of bias to be high. To assess the risk of bias associated with missing data at the meta‐analysis level, please refer to Dealing with missing data section;

• selective reporting: we checked whether the outcomes reported in any available protocol or registration record were all reported in the results section of the main paper. When trial was not registered or had no published protocol, we checked whether all outcomes listed in the methods section were reported in the results section. In that case, we judged risk of bias to be low

• other bias: when trial was stopped early for benefit, we assumed risk of bias to be high

Measures of treatment effect

We analysed risk ratios (RRs) for dichotomous outcomes and mean differences (MD) for continuous data, with 95% confidence intervals (CI).

Unit of analysis issues

The unit of analysis was the participant.

Dealing with missing data

Identifying participants with missing data

It was not clear whether certain categories of participants (e.g. those described as 'withdrew consent' or 'experienced adverse events') were actually followed up by the trial authors (versus had missing data) (Akl 2016). To identify participants with missing data, we followed the guidance suggested by Kahale and colleagues (Kahale 2019), and used the following categories.

• Definitely not missing data: (1) participants explicitly reported as followed‐up; (2) participants who died during the trial; (3) participants belonging to centres that were excluded.

• Definitely missing data: (1) participants explicitly reported as not followed‐up; (2) participants with unclear follow‐up status and (a) excluded from the denominator of the analysis (i.e. complete case analysis), or (b) included in the denominator of the analysis and their outcomes were explicitly stated to be imputed. However, we did not treat them as missing data unless it was possible to obtain the number of observed/actual events (i.e. excluding imputed events) to avoid double counting.

• Potentially missing data: Participants with unclear follow‐up status (e.g. included in the denominator of the analysis and their outcomes were not explicitly stated to be imputed).

Dealing with participants with missing data in the primary meta‐analysis

In the primary meta‐analysis, we used a complete‐case analysis approach; that is, we excluded participants considered to have missing data (Guyatt 2017; Kahale 2020).

For categorical data, we used these calculations for each study arm:

• denominator: (number of participants randomised) ‐ (number of participants definitely with missing data);

• numerator: number of participants with observed events (i.e. participants who experienced at least one event for the outcome of interest during their available follow‐up time).

Assessing the risk of bias associated with participants with missing data

When the primary meta‐analysis of a specific outcome found a statistically significant effect, we conducted sensitivity meta‐analyses to assess the risk of bias associated with missing outcome data. Those sensitivity meta‐analyses used a priori plausible assumptions about the outcomes of participants considered to have missing data. The assumptions we used in the sensitivity meta‐analyses were increasingly stringent in order to challenge the statistical significance of the results of the primary analysis progressively (Akl 2013; Kahale 2020).

For categorical data and for a RR showing a reduction in effect (RR < 1), we used the following increasingly stringent but plausible assumptions.

• For the control arm, relative incidence (RI) among those with missing data (lost to follow‐up (LTFU)) compared with those with available data (followed up, FU) in the same arm (RI_LTFU/FU) = 1; for the intervention arm, RI_LTFU/FU = 1.5;

• For the control arm, RI_LTFU/FU = 1; for the intervention arm, RI_LTFU/FU = 2;

• For the control arm, RI_LTFU/FU = 1; for the intervention arm, RI_LTFU/FU = 3;

• For the control arm, RI_LTFU/FU = 1; for the intervention arm, RI_LTFU/FU = 5.

For RR showing an increase in effect (RR > 1), we switched the above assumptions between the control and interventions arms (i.e. used RI_LTFU/FU = 1 for the intervention arm).

Specifically, we used these calculations for each study arm:

• denominator: (number of participants randomised);

• numerator: (number of participants with observed events) + (number of participants definitely with missing data with assumed events).

Assumed events are calculated by applying the a priori plausible assumptions to the participants with definitely missing data.

Assessment of heterogeneity

We assessed heterogeneity between trials by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials that could not be ascribed to sampling variation (I² test; Higgins 2003), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). If there was evidence of substantial heterogeneity, we attempted to investigate the possible reasons for this (see Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

We explored whether the study was included in a trial registry and whether a protocol was available. We planned to create funnel plots for outcomes including 10 or more trials.

Data synthesis

For dichotomous data, we calculated the RR separately for each study (DerSimonian 1986; Review Manager 2014). As noted earlier, in the primary meta‐analysis, we used a complete case analysis approach; that is, we excluded participants considered to have missing data (Guyatt 2017). When analysing data related to participants who were reported as not compliant, we attempted to adhere to the principles of intention‐to‐treat (ITT) analysis. We approached the issue of non‐compliance independently from that of missing data (Alshurafa 2012). We then pooled the results of the different studies using a random‐effects model.

Living systematic review approach: whenever new evidence (studies, data or information) that meets the review inclusion criteria is identified, we will immediately assess risk of bias, extract the data, and incorporate it in the synthesis, as appropriate. We will not adjust the meta‐analyses to account for multiple testing, given that the methods related to frequent updating of meta‐analyses are under development (Simmonds 2017).

Subgroup analysis and investigation of heterogeneity

We planned to explore substantial heterogeneity by conducting subgroup analyses based on the type of oral anticoagulant and the characteristics of participants (type and stage of cancer, and whether participants were on cancer treatment or not). In particular, we conducted subgroup analyses for participants with lung cancer (either SCLC or NSCLC) versus participants with non‐lung cancer. We included in the lung versus non‐lung subgroup analysis data from:

• studies that recruited only participants with lung cancer (either SCLC or NSCLC) and studies that recruited only participants with non‐lung cancer;

• studies that recruited both lung and non‐lung cancer participants if they provided data for subgroups of participants with lung cancer AND data for subgroups of participants with non‐lung cancer;

• studies that recruited both participants with lung and non‐lung cancer but did not provide subgroup data, if more than 75% of participants had lung cancer or more than 75% of participants had non‐lung cancer.

Sensitivity analysis

We decided a priori to consider abstracts and completed studies published exclusively on ClinicalTrials.gov in the main analysis only if study authors supplied us with full reports of their methods and results; otherwise, abstracts were included only in the sensitivity analysis. As described earlier, we also planned for sensitivity meta‐analyses to assess the risk of bias associated with missing outcome data when the primary meta‐analysis of a specific outcome found a statistically significant effect.

Summary of findings and assessment of the certainty of the evidence

We assessed the certainty of evidence at the outcome level using the GRADE approach (GRADE handbook). We followed the guidance developed by the GRADE working group to communicate the findings of the systematic review (Santesso 2020).

Results

Description of studies

Results of the search

Figure 1 shows the study flow diagram. As of June 2021, the search strategy identified 3583 unique citations. The title and abstract screening identified 40 potentially eligible citations. The full‐text screening of the full texts of these 40 citations identified 10 eligible RCTs: eight RCTs published as full reports (Carrier 2019 (AVERT); Chahinian 1989; Khorana 2019 (CASSINI); Levine 1994; Levine 2012; Maurer 1997; Stanford 1979; Zacharski 1984), one RCT published as an abstract but for which we were unable to obtain the necessary data from the authors (Ciftci 2012), and one completed RCT that published its results exclusively on ClinicalTrials.gov (NCT00320255).

1.

Study flow diagram

Included studies

Six included RCTs used the vitamin K antagonist warfarin as the intervention (Chahinian 1989; Ciftci 2012; Levine 1994; Maurer 1997; Stanford 1979; Zacharski 1984); four RCTs used DOACs as the intervention (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 2012; NCT00320255).

Chahinian and colleagues recruited 189 participants with extensive SCLC undergoing chemotherapy and with a Cancer and Leukemia Group B (CALGB) performance status of 0 to 3 (Chahinian 1989). Participants were randomised to receive either warfarin (to maintain prothrombin time between 1.5 and 2) or no warfarin. Therapy was started on the first day of chemotherapy and continued throughout the chemotherapy course. Assessed outcomes included mortality, major bleeding, and minor bleeding. Follow‐up rate was 97.3%.

Ciftci and colleagues recruited 91 participants with lung cancer undergoing chemotherapy (Ciftci 2012). Participants were randomised to receive warfarin 5 mg daily or no warfarin starting day one of chemotherapy. Assessed outcomes included mortality and bleeding. Participants were followed up for six months. Information about the follow‐up of participants was not reported.

Levine and colleagues recruited 315 participants with stage IV breast cancer, undergoing chemotherapy, with a minimum life expectancy of three months, and with a good performance status based on the Eastern Cooperative Oncology Group (ECOG) assessment (ECOG less than 3) (Levine 1994). Participants were randomised to receive either warfarin at a "therapeutic dose" (to maintain INR between 1.3 and 1.9) or a placebo. Treatment began either at the start of chemotherapy or within four weeks, and continued until one week after termination of chemotherapy. Assessed outcomes included mortality, DVT, pulmonary embolism, major bleeding, and minor bleeding. Follow‐up rate was 99%.

Maurer and colleagues recruited 369 participants with limited‐stage SCLC undergoing chemotherapy and radiotherapy, with a minimum life expectancy of two months and a CALGB performance status of less than 3 (Maurer 1997). Participants were randomised to receive either warfarin at a "therapeutic dose" (to maintain prothrombin time between 1.4 and 1.6) or no warfarin. Treatment was started on the first day of chemotherapy and continued three weeks after the last cycle of chemotherapy. Assessed outcomes included mortality, major bleeding, and minor bleeding. The study reported complete follow‐up.

Stanford and colleagues recruited 24 participants with a small cell carcinoma (at least stage T3 disease) of the bronchus receiving chemotherapy; 75% of participants were males and 79% had extrathoracic metastases (Stanford 1979). Participants were randomised to receive heparin or warfarin or dextran at different time intervals during chemotherapy or no anticoagulant. Assessed outcomes were mortality and bleeding. The study reported complete follow‐up.

Zacharski and colleagues recruited 431 participants with different types of cancer undergoing chemotherapy and with a minimum life expectancy of two months (Zacharski 1984). Participants were randomised to receive either warfarin (to approximately double prothrombin time) or no warfarin. Treatment was given until death or the end of the study. Assessed outcomes included mortality and major bleeding. The authors reported data on 418 participants, omitting 13 participants who had resection with curative intent for Duke's C carcinoma of the colon because "no conclusions could be reached for this category". The authors had reported earlier on a subgroup of 50 participants with SCLC (Zacharski 1981). The study reported 97% follow‐up.

Carrier and colleagues recruited 563 participants who had a newly diagnosed cancer or progression of known cancer (Khorana score of 2 or higher) after complete or partial remission, and who were initiating a new course of chemotherapy with a minimum treatment intent of three months (Carrier 2019 (AVERT). The most common types of primary cancer were gynaecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). Participants were randomised to receive apixaban at a dose of 2.5 mg twice daily or identical placebo tablets twice daily for 180 days. Assessed outcomes were mortality, VTE, and bleeding. The study reported 92% follow‐up.

Khorana and colleagues recruited 841 participants with various solid tumours or lymphomas, initiating a new systemic regimen and at high risk of VTE (Khorana score of 2 or higher) (Khorana 2019 (CASSINI)). Participants were randomised to receive rivaroxaban 10 mg once daily or placebo once daily for 180 days. Assessed outcomes were mortality, VTE, and bleeding. The study reported complete follow‐up despite 54% premature drug discontinuation.

Levine and colleagues recruited 125 participants with advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian, or prostate cancers; cancer of unknown origin; myeloma; or selected lymphomas, receiving either first‐line or second‐line chemotherapy. Half of the participants had an ECOG assessment of 0, and 30% had a central venous catheter (CVC), a VTE risk factor (Levine 2012). Participants were recruited from six sites in Canada and eight sites in the USA. Participants were randomised to receive placebo, or apixaban 5 mg, 10 mg or 20 mg once daily for 12 weeks, beginning within four weeks of the date on which the first‐line or second‐line chemotherapy was begun. Assessed outcomes were mortality, major bleed, clinically relevant non‐major bleed, VTE, symptomatic DVT, and symptomatic pulmonary embolism. For this review, we only included the dosages 5 mg and 10 mg. The study reported complete follow‐up.

The Ontario Clinical Oncology Group (OCOG) recruited 130 participants with advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian, prostate, myeloma, selected lymphomas, or cancer of unknown origin receiving first‐line or second‐line chemotherapy (NCT00320255). Participants were randomised to receive a placebo, or apixaban 5 mg, 10 mg, or 20 mg once daily for 12 weeks].  For this review, we only included the dosages 5 mg and 10 mg. Assessed outcomes were mortality, VTE, and bleeding. The study did not provide more details on ClinicalTrials.gov.

Excluded studies

We excluded 96 reports of 53 studies for the following reasons: not our population of interest: hospitalised people (4 studies); people having surgery (28 studies); people with CVC (two studies); people with VTE (11 studies); not our intervention of interest: parenteral anticoagulation (6 studies); not our intervention of interest: aspirin (two studies).

Risk of bias in included studies

The judgments for the risk of bias are summarised in Figure 2 and Figure 3.

2.

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

The method of sequence generation was reported to be random but not clearly detailed in three studies (Chahinian 1989; Ciftci 2012; NCT00320255). We judged these as low risk of bias. The method of sequence generation was adequate for the remaining seven, which we judged as low risk (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 1994; Levine 2012; Maurer 1997; Stanford 1979; Zacharski 1984).

Allocation was done centrally in two studies (Carrier 2019 (AVERT); Maurer 1997). We assessed these as low risk of bias. It was unclear whether allocation was adequately concealed in the remaining eight studies (Chahinian 1989; Ciftci 2012; Khorana 2019 (CASSINI); Levine 1994; Levine 2012; NCT00320255; Stanford 1979; Zacharski 1984). We assessed these as high risk.

Blinding

We judged participants and personnel to be definitely blinded in five studies and assessed these as low risk of bias (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 1994; Levine 2012; NCT00320255). We considered that participants and personnel were probably not blinded in the remaining five studies as methods were not clearly reported (Chahinian 1989; Ciftci 2012; Maurer 1997; Stanford 1979; Zacharski 1984). We judged these as high risk of bias as the knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention, or differential administration of co‐interventions).

We judged outcome assessors to be definitely blinded in five studies and assessed these as low risk of bias (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 1994; Levine 2012; NCT00320255). We considered that outcome assessors were probably not blinded in the remaining five studies as these details were not clearly reported (Chahinian 1989; Ciftci 2012; Maurer 1997; Stanford 1979; Zacharski 1984). However, we assessed these as low risk of bias because the knowledge of the assigned intervention is unlikely to have impacted the assessment of the outcomes of interest as none of the outcomes are subjective.

Incomplete outcome data

Three studies reported a complete follow‐up rate, and we judged these as low risk of bias (Khorana 2019 (CASSINI); Levine 2012; Stanford 1979). Three studies did not report on follow‐up rates, and we assessed these as unclear risk (Ciftci 2012; Maurer 1997; NCT00320255). The rate of participants with missing data in the remaining four studies ranged between 1.2% and 4.5%, and we judged these as low risk of bias (Carrier 2019 (AVERT); Chahinian 1989; Levine 1994; Zacharski 1984). Only one study reported follow‐up data per outcome and not per participant (Chahinian 1989).

Selective reporting

Most studies reported on the outcomes listed either in the methods section of the main paper (Chahinian 1989; Levine 1994; Levine 2012; Maurer 1997; NCT00320255; Stanford 1979; Zacharski 1984), or in the protocol (Carrier 2019 (AVERT); Khorana 2019 (CASSINI). We assessed these as low risk of bias. Reporting was unclear in one study (Ciftci 2012), and we judged it as unclear risk of bias.

Other potential sources of bias

None noted.

Effects of interventions

See: Table 1; Table 2

Summary of findings 1. Vitamin K antagonist (VKA) prophylaxis compared to no prophylaxis in ambulatory people with cancer without venous thromboembolism (VTE) receiving systemic therapy.

Vitamin K antagonist prophylaxis compared to no prophylaxis in ambulatory people with cancer without venous thromboembolism receiving systemic therapy
Population: ambulatory people with cancer without venous thromboembolism receiving systemic therapy Setting: outpatient Intervention: vitamin K antagonist prophylaxis Comparison: no prophylaxis
Outcome:  Follow‐up	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)
				Risk with no prophylaxis	Risk difference with VKA prophylaxis
Mortality at 6 months: main analysis	946 (3 RCTs)	⊕⊕⊕⊝ Moderatea,b	RR 0.93 (0.77 to 1.13)	Study population
				313 per 1000	22 fewer per 1000 (72 fewer to 41 more)
Mortality Follow‐up: 12 months	1281 (5 RCTs)	⊕⊕⊕⊝ Moderatea,b	RR 0.95 (0.87 to 1.03)	Study population
				574 per 1000	29 fewer per 1000 (75 fewer to 17 more)
Pulmonary embolism Follow‐up: 12 months	311 (1 RCT)	⊕⊝⊝⊝ Very lowc,d	RR 1.05 (0.07 to 16.58)	Study population
				6 per 1000	0 fewer per 1000 (6 fewer to 98 more)
Symptomatic deep vein thrombosis Follow‐up: 12 months	311 (1 RCT)	⊕⊝⊝⊝ Very lowc,e	RR 0.08 (0.01 to 1.42)	Study population
				38 per 1000	35 fewer per 1000 (37 fewer to 16 more)
Major bleeding Follow‐up: 12 months	1281 (5 RCTs)	⊕⊕⊕⊝ Moderatef	RR 2.93 (1.86 to 4.62)	Study population
				55 per 1000	107 more per 1000 (48 more to 201 more)
Minor bleeding Follow‐up: 12 months	863 (4 RCTs)	⊕⊕⊕⊝ Moderatef	RR 3.14 (1.85 to 5.32)	Study population
				78 per 1000	167 more per 1000 (66 more to 337 more)
Quality of life ‐ not reported	‐	‐	‐
*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; RR: risk ratio; OR: odds ratio
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.

^aSome concern with risk of bias associated with unclear allocation concealment, taken into account when downgrading from high to moderate certainty. Typically, lack of allocation concealment would direct the effect estimate in the direction of overestimation.
^bDowngraded by one level due to serious imprecision. Confidence interval of absolute effect suggests both potential harm and potential benefit, with large number of events.
^cDowngraded by one level due to serious indirectness. Levine 1994: the intervention of this trial is not representative of current practice of VKA dose adjustment; instead, fixed dose was used.
^dDowngraded by two levels due to very serious imprecision. Confidence interval of absolute effect suggests both potential no effect and potential harm, with small number of events.
^eDowngraded by two levels due to very serious imprecision. Confidence interval of absolute effect suggests both potential benefit and potential harm, with small number of events.
^fDowngraded by one level due to serious risk of bias associated with lack of blinding of participants and personnel and unclear allocation concealment.

Summary of findings 2. Direct oral anticoagulant (DOAC) prophylaxis compared to no prophylaxis in ambulatory people with cancer without venous thromboembolism (VTE) receiving systemic therapy.

Direct oral anticoagulant prophylaxis compared to no prophylaxis in ambulatory people with cancer without venous thromboembolism receiving systemic therapy
Population: ambulatory people with cancer without venous thromboembolism receiving systemic therapy Setting: outpatient Intervention: direct oral anticoagulant prophylaxis Comparison: no direct oral anticoagulant prophylaxis
Outcome: Follow‐up	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)
				Risk with no prophylaxis	Risk difference with DOAC prophylaxis
Mortality Follow‐up: range 3 months to 6 months	1440 (3 RCTs)	⊕⊕⊕⊝ Moderatea,b,c	RR 0.94 (0.64 to 1.38)	Study population
				185 per 1000	11 fewer per 1000 (67 fewer to 70 more)
Pulmonary embolism Follow‐up: range 3 months to 6 months	1440 (3 RCTs)	⊕⊕⊕⊝ Moderatea,d	RR 0.48 (0.24 to 0.98)	Study population
				46 per 1000	24 fewer per 1000 (35 fewer to 1 fewer)
Symptomatic deep vein thrombosis Follow‐up: range 3 months to 6 months	1440 (3 RCTs)	⊕⊕⊕⊝ Moderatea,d,e	RR 0.61 (0.31 to 1.21)	Study population
				49 per 1000	19 fewer per 1000 (34 fewer to 10 more)
Major bleeding Follow‐up: range 3 months to 6 months	1440 (3 RCTs)	⊕⊕⊕⊝ Moderatea,f	RR 1.65 (0.72 to 3.80)	Study population
				14 per 1000	9 more per 1000 (4 fewer to 40 more)
Minor bleeding Follow‐up: range 3 months to 6 months	1440 (3 RCTs)	⊕⊕⊝⊝ Lowa,f,g	RR 3.58 (0.55 to 23.44)	Study population
				21 per 1000	55 more per 1000 (10 fewer to 482 more)
*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; RR: risk ratio; OR: odds ratio.
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.

^aConcern with unclear allocation concealment.
^bConcern with some unexplained inconsistency. I²= 39%.
^cDowngraded by one level due to serious imprecision. Confidence interval of absolute effect suggests both potential benefit and potential harm, with large number of events.
^dDowngraded by one level due to serious imprecision. Confidence interval of absolute effect suggests both potential no effect and potential benefit, with large number of events.
^eThe Carrier 2019 (AVERT) trial reported on both symptomatic and incidentally detected DVT together. This trial contributed to 38% to the pooled effect estimate.
^fDowngraded by one level due to serious imprecision. Confidence interval of absolute effect includes both potential no effect and potential harm, with large number of events.
^gDowngraded by one level due to serious unexplained heterogeneity. I²= 59%.

Comparison 1: vitamin K antagonist versus no prophylaxis

We did not create funnel plots for any of the outcomes as none of the analyses included 10 or more studies.

All‐cause mortality

Mortality at six months: meta‐analysis of three RCTs including 946 participants found that a VKA probably reduces mortality at six months slightly compared to no prophylaxis (RR 0.93, 95% CI 0.77 to 1.13; I² = 6%; risk difference (RD) 22 fewer per 1000, 95% CI 72 fewer to 41 more; moderate‐certainty evidence; Analysis 1.1) (Chahinian 1989; Maurer 1997; Zacharski 1984). We downgraded the certainty of the evidence to moderate due to serious imprecision (Table 1).

1.1. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 1: Mortality at 6 months (main analysis)

In a subgroup analysis of participants with lung cancer (SCLC and NSCLC) versus non‐lung cancer, the test for subgroup effect was not statistically significant (P value = 0.14; Analysis 1.2) (Chahinian 1989; Maurer 1997; Zacharski 1984). Of note, Maurer 1997 recruited participants with limited SCLC, while Chahinian 1989 recruited participants with extensive SCLC.

1.2. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 2: Mortality at 6 months (subgroup analysis‐lung cancer)

Mortality at 12 months: meta‐analysis of five RCTs including 1281 participants found that a VKA probably reduces mortality at 12 months slightly compared to no prophylaxis (RR 0.95, 95% CI 0.87 to 1.03; I² = 0%; RD 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate‐certainty evidence; Analysis 1.3) (Chahinian 1989; Levine 1994; Maurer 1997; Stanford 1979; Zacharski 1984). We downgraded the certainty of the evidence to moderate due to serious imprecision (Table 1).

1.3. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 3: Mortality at 12 months (main analysis)

In a subgroup analysis of participants with lung cancer (SCLC and NSCLC) versus non‐lung cancer, the test for subgroup effect was not statistically significant (P value = 1.00; Analysis 1.4) (Chahinian 1989; Levine 1994; Maurer 1997; Stanford 1979; Zacharski 1984). Of note, Maurer 1997 recruited participants with limited SCLC, while Chahinian 1989 recruited participants with extensive SCLC.

1.4. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 4: Mortality at 12 months (subgroup analysis‐lung cancer)

Symptomatic venous thromboembolism

One study reported on the incidence of pulmonary embolism and symptomatic DVT (Levine 1994). The evidence was very uncertain about the effect of a VKA compared to no prophylaxis on pulmonary embolism and symptomatic DVT (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low‐certainty evidence (Analysis 1.5)); RR 0.08, 95% CI 0.01 to 1.42; RD 35 fewer per 1000, 95% CI 37 fewer to 16 more; very low‐certainty evidence (Analysis 1.6), respectively). We downgraded the certainty of the evidence for both outcomes to very low certainty due to serious indirectness and very serious imprecision (Table 1).

1.5. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 5: Pulmonary embolism at 12 months

1.6. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 6: Symptomatic deep vein thrombosis at 12 months

Major bleeding

Meta‐analysis of five RCTs including 1281 participants found that a VKA probably increases major bleeding at 12 months compared to no prophylaxis (RR 2.93, 95% CI 1.86 to 4.62; I² = 6%; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate‐certainty evidence; Analysis 1.7) (Chahinian 1989; Levine 1994; Maurer 1997; Stanford 1979; Zacharsky 1985). We downgraded the certainty of the evidence to moderate due to serious risk of bias (Table 1).

1.7. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 7: Major bleeding at 12 months (main analysis)

These results did not change in a meta‐analysis including the study published as an abstract (RR 2.89, CI 2.07 to 4.04; RD 106 more per 1000, 95% CI 60 more to 170 more; Analysis 1.8) (Ciftci 2012).

1.8. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 8: Major bleeding at 12 months: sensitivity analysis

Since the primary meta‐analysis found a statistically significant effect, and in order to assess the risk of bias associated with missing outcome data, we conducted sensitivity meta‐analyses using the a priori plausible assumptions detailed in the Methods section. The effect estimate remained statistically significant even when using the most stringent plausible assumption of RI_LTFU/FU = 5 (RR 2.70, 95% CI 1.92 to 3.79).

In subgroup analyses of participants with lung cancer (SCLC and NSCLC) versus non‐lung cancer, the test for subgroup effect was not statistically significant (P = 0.16; Analysis 1.9) (Chahinian 1989; Maurer 1997; Stanford 1979; Zacharski 1984). Of note, Maurer 1997 recruited participants with limited SCLC while Chahinian 1989 recruited participants with extensive SCLC.

1.9. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 9: Major bleeding at 12 months (subgroup analysis‐lung cancer)

Minor bleeding

Meta‐analysis of four RCTs including 863 participants found that a VKA probably increases minor bleeding at 12 months compared to no prophylaxis (RR 3.14, 95% CI 1.85 to 5.32; I² = 18%; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate‐certainty evidence; Analysis 1.10) (Chahinian 1989; Levine 1994; Maurer 1997; Stanford 1979). We downgraded the certainty of the evidence to moderate due to serious risk of bias (Table 1).

1.10. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 10: Minor bleeding at 12 months (main analysis)

Since the primary meta‐analysis found a statistically significant effect, and in order to assess the risk of bias associated with missing outcome data, we conducted sensitivity meta‐analyses using the a priori plausible assumptions detailed in the Methods section. The effect estimate remained statistically significant even when using the most stringent plausible assumption (RR 2.89, 95% CI 1.96 to 4.27).

In subgroup analyses of participants with lung cancer (SCLC and NSCLC) versus non‐lung cancer, the test for subgroup effect was not statistically significant (P = 0.59; Analysis 1.11) (Chahinian 1989; Levine 1994; Maurer 1997; Stanford 1979). Of note, Maurer 1997 recruited participants with limited SCLC, while Chahinian 1989 recruited participants with extensive SCLC.

1.11. Analysis.

Comparison 1: Vitamin K antagonist (VKA) versus no prophylaxis, Outcome 11: Minor bleeding at 12 months (subgroup analysis‐lung cancer)

Health‐related quality of life

We found no data for health‐related quality of life.

Comparison 2: direct oral anticoagulant (DOAC) versus no prophylaxis

Mortality

Meta‐analysis of three RCTs including 1440 participants found that a DOAC probably reduces mortality at three to six months slightly compared to no prophylaxis (RR 0.94, 95% CI 0.64 to 1.38; I² = 39%; RD 11 fewer per 1000, 95% CI 67 fewer to 70 more; moderate‐certainty evidence; Analysis 2.1) (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 2012). We downgraded the certainty of the evidence to moderate due to serious imprecision (Table 2).

2.1. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 1: Mortality at 3 to6 months (main analysis)

These results did not change in a meta‐analysis including the study published as an abstract (RR 0.94, CI 0.64 to 1.38; RD 11 fewer per 1000, 95% CI 64 fewer to 67 more; (Analysis 2.2) (NCT00320255).

2.2. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 2: Mortality at 3 to6 months (sensitivity analysis)

Symptomatic venous thromboembolism

Meta‐analysis of three RCTs including 1440 participants found that a DOAC probably reduces the risk of pulmonary embolism at three to six months slightly compared to no prophylaxis (RR 0.48, 95% CI 0.24 to 0.98; I² = 19%; RD 24 fewer per 1000, 95% CI 35 fewer to 1 fewer; moderate‐certainty evidence; Analysis 2.3) (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 2012). We downgraded the certainty of the evidence to moderate due to serious imprecision (Table 2).

2.3. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 3: Pulmonary embolism at 3 to6 months (main analysis)

These results did not change in a meta‐analysis including the study published as an abstract (RR 0.46, CI 0.23 to 0.88; RD 25 fewer per 1000, 95% CI 35 fewer to 5 fewer; Analysis 2.4) (NCT00320255).

2.4. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 4: Pulmonary embolism at 3 to6 months (sensitivity analysis)

Since the primary meta‐analysis found a statistically significant effect, and in order to assess the risk of bias associated with missing outcome data, we conducted sensitivity analyses using the a priori plausible assumptions detailed in the Methods section. The sensitivity analysis showed the robustness of these results when considering the potential effect of missing data (Appendix 3).

Meta‐analysis of three RCTs including 1440 participants found that a DOAC probably reduces symptomatic DVT at three to six months slightly compared to no prophylaxis (RR 0.58, 95% CI 0.30 to 1.15; I² = 28%; RD 21 fewer per 1000, 95% CI 35 fewer to 8 more; moderate‐certainty evidence; Analysis 2.5) (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 2012). We downgraded the certainty of the evidence to moderate due to serious imprecision (Table 2).

2.5. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 5: Symptomatic deep vein thrombosis at 3 to6 months

Major bleeding

Meta‐analysis of three RCTs including 1440 participants showed that a DOAC probably does not increase major bleeding at three to six months compared to no prophylaxis (RR 1.65, 95% CI 0.72 to 3.80; I² = 10%; RD 9 more per 1000, 95% CI 4 fewer to 40 more; moderate‐certainty evidence; Analysis 2.6) (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 2012). We downgraded the certainty of the evidence to moderate due to serious imprecision (Table 2).

2.6. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 6: Major bleeding at 3 to6 months (main analysis)

These results did not change in a meta‐analysis including the study published as an abstract (RR 1.12, CI 0.37 to 3.40; RD 2 more per 1000, 95% CI 10 fewer to 36 more; Analysis 2.7) (NCT00320255).

2.7. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 7: Major bleeding at 3 to6 months (sensitivity analysis)

Minor bleeding

Meta‐analysis of three RCTs including 1440 participants showed that a DOAC may increase minor bleeding at three to six months compared to no prophylaxis (RR 3.58, 95% CI 0.55 to 23.44; I² = 59%; RD 55 more per 1000, 95% CI 10 fewer to 482 more; low‐certainty evidence; Analysis 2.8) (Carrier 2019 (AVERT); Khorana 2019 (CASSINI); Levine 2012). We downgraded the certainty of the evidence to low due to serious inconsistency and serious imprecision (Table 2).

2.8. Analysis.

Comparison 2: Direct oral anticoagulants (DOAC) versus no prophylaxis, Outcome 8: Minor bleeding at 3 to 6 months

Health‐related quality of life

We found no data for health‐related quality of life.

Discussion

Summary of main results

Compared to no prophylaxis, vitamin K antagonists probably reduce mortality at 6 and 12 months slightly in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. However, they probably increase major and minor bleeding at 12 months. The evidence is very uncertain about the effect of VKAs on VTE. A subgroup analysis suggested no difference in mortality or risk of bleeding in people with lung cancer compared to people with non‐lung cancer.

Compared to no prophylaxis, direct oral anticoagulants probably reduce mortality at three to six months and probably slightly reduce VTE in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. They probably do not increase major bleeding. However, they may increase minor bleeding at three to six months.

Overall completeness and applicability of evidence

Unfortunately, the available data were insufficient to assess the statistical significance of potentially clinically significant benefit in different types of cancer, such as SCLC and NSCLC. The results apply directly to the types of cancer the eligible studies have focused on; that is, mostly lung cancer.

Quality of the evidence

For the comparison of VKAs versus no prophylaxis, the certainty of the evidence across all outcomes ranged from moderate to very low. We downgraded the following outcomes to moderate certainty mainly due to serious imprecision (the confidence interval of absolute effect suggests both potential benefit and potential harm) and serious risk of bias (lack of blinding of patients and personnel, and unclear allocation concealment): mortality at six months, mortality at 12 months, major bleeding, and minor bleeding. We further downgraded to very low certainty the evidence for pulmonary embolism and symptomatic DVT, mainly due to serious indirectness (the intervention by Levine 1994 is not representative of the current practice of VKA dose adjustment; instead, fixed‐dose was used) and very serious imprecision (the confidence interval of absolute effect suggests both potential benefit or no effect and potential harm).

For the comparison of DOACs versus no prophylaxis, the certainty of the evidence across all outcomes ranged from moderate to low. We downgraded all the outcomes, except for minor bleeding, to moderate certainty, mainly due to serious imprecision (the confidence interval of absolute effect suggests either (1) both potential benefit and potential harm, (2) both no effect and potential harm, or (3) both potential benefit and no effect), concern with unclear allocation concealment, and some unexplained inconsistency. We further downgraded the evidence for minor bleeding to low due to serious imprecision, serious unexplained inconsistency, and concern with unclear allocation concealment.

Potential biases in the review process

Our systematic approach to searching, study selection, and data extraction should have minimised the likelihood of missing relevant studies or relevant data. The inclusion of different types of cancer in the same study precluded us from conducting the subgroup analyses to explore effect modifiers such as stage of cancer. We had to calculate the number of mortality events at 6, 12, and 24 months from the survival curves for only one study (Zacharski 1984). Also, there might be potential bias associated with multiple testing in the planned meta‐analyses. Currently, there are no plans to adjust meta‐analyses for multiple testing.

Another potential limitation is that we used the DerSimonian‐Laird meta‐analysis approach in the presence of a small number of included studies and low to moderate heterogeneity (I² ranged between 0 and 59%). This approach might have underestimated uncertainty associated with the effect estimate (Cornell 2014; Veroniki 2016 ).

Agreements and disagreements with other studies or reviews

One recent systematic review by Becattini and colleagues evaluated the role of anticoagulants in the prevention of VTE in ambulatory people with cancer treated with chemotherapy (Becattini 2019). The meta‐analysis of oral anticoagulants included the same trials that we included and showed similar findings to the current systematic review. They did not assess the certainty of the evidence.

Another recent systematic review by Li and colleagues assessed the effect of DOACs for the prevention of VTE in ambulatory adults with cancer receiving systemic therapy (Li 2019). The main meta‐analysis showed similar findings to the current systematic review with a slight difference (lower RR for symptomatic DVT). This slight difference is likely due to the fact that Li and colleagues excluded the Levine 2012 trial, because it was a dose‐finding study that included multiple apixaban doses, and did not have efficacy as a primary study outcome. However, Li and colleagues state that in a sensitivity analysis that incorporated the Levine 2012 trial, the results of the meta‐analysis did not change significantly. They did not assess the certainty of the evidence.

The systematic review performed by Rutjes and colleagues assessed the efficacy of primary VTE thromboprophylaxis in ambulatory people with cancer receiving chemotherapy (Rutjes 2020). Their meta‐analysis for symptomatic DVT included the same trials that we included and showed a comparable but slightly lower relative effect (RR 0.51) to ours (RR 0.58). This slight difference is likely due to different analytical approaches to handling missing data in the main analysis. Also, Rutjes and colleagues downgraded the certainty of the evidence of this outcome one level lower than we did. This difference appears to be due to different judgments about the inconsistency of findings and of the risk of bias associated with missing data. Similarly, for major bleeding, Rutjes and colleagues' meta‐analysis showed a comparable but slightly higher relative effect (RR 1.74) to ours (RR 1.64). This slight difference is likely due to the fact they did not include the Carrier 2019 (AVERT) trial in the meta‐analysis of major bleeding.

Authors' conclusions

Implications for practice.

This systematic review shows that the current evidence suggests that, with vitamin K antagonists (VKAs), the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism (VTE). With direct oral anticoagulants (DOACs), the benefit of reduction in VTE events outweighs the risk of major bleeding. Based on this, it would be reasonable to start an individual on oral thromboprophylaxis, particularly if they are judged to be at increased risk of developing VTE. Direct oral anticoagulants appear to have a safer profile and do not require the unnecessary need for periodic checking of international normalized ratio levels. Several other important factors should be considered before starting people on oral thromboprophylaxis. Some of these factors include cost, drug interactions with concomitant pharmacotherapy, and lack of readily accessible reversal agents in case of major bleeding. Ideally, a person’s risk of bleeding with the addition of a VKA or DOAC needs to be individualised prior to initiation of anticoagulation, by considering other factors of their clinical picture (i.e. drug interactions, inherent clotting disorders) (Pelletier 2021).

Implications for research.

Future research should investigate the effects of oral anticoagulation in people with different cancer subtypes (e.g. small cell lung cancer, non‐small cell lung cancer) and different cancer stages. There is also a need to investigate the effects of oral anticoagulants compared to parenteral anticoagulants in people with different types and stages of cancer and various medical and surgical histories.

What's new

Date	Event	Description
20 December 2022	Amended	This is a Living Systematic Review. Searches are run and screened monthly. Last search date 14 December 2022 (no new studies found). As such, results of all included studies identified have been incorporated. The conclusions of this Cochrane Review are therefore considered up to date.

History

Protocol first published: Issue 2, 2006
Review first published: Issue 2, 2007

Date	Event	Description
24 October 2022	Amended	This is a Living Systematic Review. Searches are run and screened monthly. Last search date 14 October 2022 (no new studies found). As such, results of all included studies identified have been incorporated. The conclusions of this Cochrane Review are therefore considered up to date.
13 June 2022	Amended	This is a Living Systematic Review. Searches are run and screened monthly. Last search date 14 May 2022 (no new studies found). As such, results of all included studies identified have been incorporated. The conclusions of this Cochrane Review are therefore considered up to date.
29 December 2021	Amended	This is a Living Systematic Review. Searches are run and screened monthly. Last search date 14 December 2021 (no new studies found). As such, results of all included studies identified have been incorporated. The conclusions of this Cochrane Review are therefore considered up to date.
21 June 2021	New citation required and conclusions have changed	Search updated to June 2021
14 June 2021	New search has been performed	Two new studies identified (AVERT, CASSINI). Conclusions changed.
28 May 2014	New citation required but conclusions have not changed	Additional data added

Appendices

Appendix 1. Living systematic review protocol

The methods outlined below are specific to maintaining the review as a living systematic review on the Cochrane Library (Synnot 2017). They will be implemented immediately upon publication of this update. Core review methods, such as the criteria for considering studies in the review and assessment of risk of bias, are unchanged. As such, below we outline only those areas of the methods for which additional or different activities are planned or rules apply.

Search methods for identification of studies

We will rerun the majority of searches monthly. For electronic databases and other electronic sources (CENTRAL, MEDLINE, Embase), we have set up auto‐alerts to deliver a monthly search yield by email. We will search the remaining resources (conference proceedings of the American Society of Clinical Oncology (ASCO), the American Society of Haematology (ASH) and ClinicalTrials.gov) on a monthly basis. For that purpose, we will note when these conference proceedings are published.

As additional steps to inform the living systematic review, we will contact corresponding authors of ongoing studies as they are identified and ask them to advise when results are available, and to share early or unpublished data. We will manually screen the reference list of any newly included studies, and identified relevant guidelines and systematic reviews.

We will review search methods and strategies approximately yearly, to ensure they reflect any terminology changes in the topic area, or in the databases.

Selection of studies

We will immediately screen any new citations retrieved by the monthly searches. As the first step of monthly screening, we will apply the machine learning classifier (RCT model) available in the Cochrane Register of Studies (CSR‐Web; Wallace 2017). The machine learning classifier currently has a specificity/recall of 99.987%and assigns a probability score (from 0 to 100) to each citation for being a true RCT. Two review authors will independently screen any citations assigned a score from 10 to 100. Citations that score nine or less will be screened by Cochrane Crowd (Cochrane Crowd). Any citations that are deemed to be potential RCTs (i.e., scored 10 and above)  by Cochrane Crowd will be returned to the authors for screening.

Data synthesis

Whenever new evidence (studies, data, or information) that meets the review inclusion criteria is identified, we will immediately assess risk of bias and extract the data and incorporate it in the synthesis, as appropriate. We will not adjust the meta‐analyses to account for multiple testing given the methods related to frequent updating of meta‐analyses are under development (Simmonds 2017).

Other

We will review the review scope and methods approximately yearly, or more frequently if appropriate, given potential changes in the topic area, or the evidence being included in the review (e.g. additional comparisons, interventions, outcomes, or new review methods available).

Appendix 2. Full search strategies for the electronic databases ‐ Update December 2020

Database	Strategy
MEDLINE	RCTsearch strategy: 1. exp Anticoagulants/ (anticoagulant* or anti‐coagulant*).tw. (Heparin or Adomiparin or alpha‐Heparin or Arteven or "AVE‐5026" or CY 222 or "Depo‐Heparin" or "EINECS 232‐681‐7" or Fluxum or "Hed‐heparin" or Hepathrom or HSDB 3094 or KB 101 or "Lipo‐hepin" or M 118 or "M 118REH" or M118 or Octaparin or OP 386 or OP 622 or Pabyrin or Pularin or Subeparin or Sublingula or Thromboliquine or Triofiban or "UNII‐1K5KDI46KZ" or "UNII‐4QW4AN84NQ" or "UNII‐5R0L1D739E" or "UNII‐7UQ7X4Y489" or "UNII‐9816XA9004" or "UNII‐E47C0NF7LV" or "UNII‐M316WT19D8" or "UNII‐P776JQ4R2F" or "UNII‐S79O08V79F" or "UNII‐T2410KM04A" or "UNII‐V72OT3K19I" or "UNII‐VL0L558GCB" or Vetren or Vitrum AB or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or "Hep‐lock" or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Panheprin).mp. 2. (LMWH* or heparin* or nadroparin* or frixiparin* or enoxaparin* or clexane or klexane or lovenox or dalteparin or fragmin or ardeparin* or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin* or danaproid or danaparoid or orgaran or antixarin or bemiparin* or hibor or zibor or ivor or badyket or semuloparin or parnaparin or tedelparin or fluxum or lohepa or lowhepa or parvoparin or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or clivarine or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or Liquaemin or Liquemin or Multiparin or Novoheparin or Eparina or Hep‐lock or Heparinate or Heparinic acid or Panheprin or Hepalean or Heparin Leo or Heparin Lock).mp. 3. (FR‐860 or FR 860 or FR860 or PK‐10,169 or PK 10,169 or PK10,169 or PK‐10169 or PK 10169 or PK10169 or EMT‐967 or EMT 967 or EMT967 or EMT‐966 or EMT 966 or EMT966 or CY 216 or CY‐216 or CY216 or LMF CY‐216 or LMF CY 216 or LMF CY216).mp. 4. exp Coumarins/ (coumarin* or chromonar or coumestrol or esculin or isocoumarin* or psoralens or pyranocoumarins or umbelliferones).tw. 5. (4‐Hydroxycoumarin* or warfarin* or acenocoumarol or nicoumalone or sinthrome or Sintrom or phenindione or dicoumarol or coumadin or phenprocoumon or phepromaron or ethyl‐biscoumacetate or phenindione or Diphenadione or Tioclomarol or Racumi or Marcoumar or Marcumar or Falithrom or Jantoven or vitamin K antagonist* or VKA or fluindione or difenacoum or coumatetralyl or coumadin* or warfant or marevan or aldocumar).mp. 6. (Dermatan Sulfate or (Chondroitin Sulfate adj B) or Dermatan Sulfphate or DS 435 or MF‐701 or OP‐370 or b‐Heparin or Mistral or Venorix).mp. 7. (thrombin adj inhibitor*).mp. 8. (factor Xa inhibitor* or antithrombin* or anticoagul*).mp. 9. (rivaroxaban or Xarelto or apixaban or Eliquis or dabigatran etexilate or Edoxaban or Savaysa or Betrixaban or ximelagatran or pradaxa or lixiana or exanta or Darexaban or Otamixaban* or Razaxaban or Bivalirudin or Desirudin or Lepirudin or Melagatran or YM 150 or Iprivask or argatrovan or pradax* or Xarelto or BIBR‐953 or BIBR‐953ZW or BAY 59‐7939 or BMS‐562247 or DU‐176 or DU‐176b).mp. 10. RIVAROXABAN/ 11. DABIGATRAN/ (BIBR 953 or BIBR 953 ZW or Dabigatran or HSDB 8062 or Pradaxa or UNII‐I0VM4M70GC) 12. (target specific oral anticoagulant* or target‐specific oral anticoagulant* or TSOAC* or new oral anticoagulant* or novel oral anticoagulant* or NOAC* or direct‐acting oral anticoagulant* or direct acting oral anticoagulant* or direct oral anticoagulant* or DOAC*).ti,ab,kw. 13. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 14. exp Neoplasms/ 15. (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor* or glioma* or myeloma* or lymphoma* or leukemia* or leukaemia* or epithelioma* or adenoma*).tw. 16. 14 or 15 17. 13 and 16 18. randomised controlled trial.pt. 19. controlled clinical trial.pt. 20. randomized.ab. 21. placebo.ab. 22. clinical trials as topic.sh. 23. randomly.ab. 24. trial.ti. 25. 18 or 19 or 20 or 21 or 22 or 23 or 24 26. (animals not (humans and animals)).sh. 27. 25 not 26 28. 17 and 27 Systematic Review search strategy: 1. exp Anticoagulants/ 2. (anticoagulant* or anti‐coagulant*).tw. 3. (Heparin or Adomiparin or alpha‐Heparin or Arteven or "AVE‐5026" or CY 222 or "Depo‐Heparin" or "EINECS 232‐681‐7" or Fluxum or "Hed‐heparin" or Hepathrom or HSDB 3094 or KB 101 or "Lipo‐hepin" or M 118 or "M 118REH" or M118 or Octaparin or OP 386 or OP 622 or Pabyrin or Pularin or Subeparin or Sublingula or Thromboliquine or Triofiban or "UNII‐1K5KDI46KZ" or "UNII‐4QW4AN84NQ" or "UNII‐5R0L1D739E" or "UNII‐7UQ7X4Y489" or "UNII‐9816XA9004" or "UNII‐E47C0NF7LV" or "UNII‐M316WT19D8" or "UNII‐P776JQ4R2F" or "UNII‐S79O08V79F" or "UNII‐T2410KM04A" or "UNII‐V72OT3K19I" or "UNII‐VL0L558GCB" or Vetren or Vitrum AB or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or "Hep‐lock" or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Panheprin).mp. 4. (LMWH* or heparin* or nadroparin* or frixiparin* or enoxaparin* or clexane or klexane or lovenox or dalteparin or fragmin or ardeparin* or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin* or danaproid or danaparoid or orgaran or antixarin or bemiparin* or hibor or zibor or ivor or badyket or semuloparin or parnaparin or tedelparin or fluxum or lohepa or lowhepa or parvoparin or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or clivarine or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or Liquaemin or Liquemin or Multiparin or Novoheparin or Eparina or Hep‐lock or Heparinate or Heparinic acid or Panheprin or Hepalean or Heparin Leo or Heparin Lock).mp. 5. (FR‐860 or FR 860 or FR860 or PK‐10,169 or PK 10,169 or PK10,169 or PK‐10169 or PK 10169 or PK10169 or EMT‐967 or EMT 967 or EMT967 or EMT‐966 or EMT 966 or EMT966 or CY 216 or CY‐216 or CY216 or LMF CY‐216 or LMF CY 216 or LMF CY216).mp. 6. exp Coumarins/ 7. (coumarin* or chromonar or coumestrol or esculin or isocoumarin* or psoralens or pyranocoumarins or umbelliferones).tw. 8. (4‐Hydroxycoumarin* or warfarin* or acenocoumarol or nicoumalone or sinthrome or Sintrom or phenindione or dicoumarol or coumadin or phenprocoumon or phepromaron or ethyl‐biscoumacetate or phenindione or Diphenadione or Tioclomarol or Racumi or Marcoumar or Marcumar or Falithrom or Jantoven or vitamin K antagonist* or VKA or fluindione or difenacoum or coumatetralyl or coumadin* or warfant or marevan or aldocumar).mp. 9. (Dermatan Sulfate or (Chondroitin Sulfate adj B) or Dermatan Sulfphate or DS 435 or MF‐701 or OP‐370 or b‐Heparin or Mistral or Venorix).mp. 10. (thrombin adj inhibitor*).mp. 11. (factor Xa inhibitor* or antithrombin* or anticoagul*).mp. 12. (rivaroxaban or Xarelto or apixaban or Eliquis or dabigatran etexilate or Edoxaban or Savaysa or Betrixaban or ximelagatran or pradaxa or lixiana or exanta or Darexaban or Otamixaban* or Razaxaban or Bivalirudin or Desirudin or Lepirudin or Melagatran or YM 150 or Iprivask or argatrovan or pradax* or Xarelto or BIBR‐953 or BIBR‐953ZW or BAY 59‐7939 or BMS‐562247 or DU‐176 or DU‐176b).mp. 13. RIVAROXABAN/ 14. DABIGATRAN/ 15. (BIBR 953 or BIBR 953 ZW or Dabigatran or HSDB 8062 or Pradaxa or UNII‐I0VM4M70GC).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 16. (target specific oral anticoagulant* or target‐specific oral anticoagulant* or TSOAC* or new oral anticoagulant* or novel oral anticoagulant* or NOAC* or direct‐acting oral anticoagulant* or direct acting oral anticoagulant* or direct oral anticoagulant* or DOAC*).ti,ab,kw. 17. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 18. exp Neoplasms/ 19. (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor* or glioma* or myeloma* or lymphoma* or leukemia* or leukaemia* or epithelioma* or adenoma*).tw. 20. 18 or 19 21. 17 and 20 22. Meta‐Analysis as Topic/ 23. meta analy$.tw. 24. metaanaly$.tw. 25. Meta‐Analysis/ 26. (systematic adj (review$1 or overview$1)).tw. 27. exp Review Literature as Topic/ 28. 22 or 23 or 24 or 25 or 26 or 27 29. cochrane.ab. 30. embase.ab. 31. (psychlit or psyclit).ab. 32. (psychinfo or psycinfo).ab. 33. (cinahl or cinhal).ab. 34. science citation index.ab. 35. bids.ab. 36. cancerlit.ab. 37. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 38. reference list$.ab. 39. bibliograph$.ab. 40. hand‐search$.ab. 41. relevant journals.ab. 42. manual search$.ab. 43. 38 or 39 or 40 or 41 or 42 44. selection criteria.ab. 45. data extraction.ab. 46. 44 or 45 47. Review/ 48. 46 and 47 49. Comment/ 50. Letter/ 51. Editorial/ 52. animal/ 53. human/ 54. 52 not (52 and 53) 55. 49 or 50 or 51 or 54 56. 28 or 37 or 43 or 48 57. 56 not 55 58. 21 and 57
Embase	RCT search strategy: 1. exp anticoagulant agent/ 2. (anticoagulant* or anti‐coagulant*).tw. 3. (Heparin or Adomiparin or alpha‐Heparin or Arteven or "AVE‐5026" or CY 222 or "Depo‐Heparin" or "EINECS 232‐681‐7" or Fluxum or "Hed‐heparin" or Hepathrom or HSDB 3094 or KB 101 or "Lipo‐hepin" or M 118 or "M 118REH" or M118 or Octaparin or OP 386 or OP 622 or Pabyrin or Pularin or Subeparin or Sublingula or Thromboliquine or Triofiban or "UNII‐1K5KDI46KZ" or "UNII‐4QW4AN84NQ" or "UNII‐5R0L1D739E" or "UNII‐7UQ7X4Y489" or "UNII‐9816XA9004" or "UNII‐E47C0NF7LV" or "UNII‐M316WT19D8" or "UNII‐P776JQ4R2F" or "UNII‐S79O08V79F" or "UNII‐T2410KM04A" or "UNII‐V72OT3K19I" or "UNII‐VL0L558GCB" or Vetren or Vitrum AB or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or "Hep‐lock" or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Panheprin).mp. 4. (LMWH* or heparin* or nadroparin* or frixiparin* or enoxaparin* or clexane or klexane or lovenox or dalteparin or fragmin or ardeparin* or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin* or danaproid or danaparoid or orgaran or antixarin or bemiparin* or hibor or zibor or ivor or badyket or semuloparin or parnaparin or tedelparin or fluxum or lohepa or lowhepa or parvoparin or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or clivarine or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or Liquaemin or Liquemin or Multiparin or Novoheparin or Eparina or Hep‐lock or Heparinate or Heparinic acid or Panheprin or Hepalean or Heparin Leo or Heparin Lock).mp. 5. (FR‐860 or FR 860 or FR860 or PK‐10,169 or PK 10,169 or PK10,169 or PK‐10169 or PK 10169 or PK10169 or EMT‐967 or EMT 967 or EMT967 or EMT‐966 or EMT 966 or EMT966 or CY 216 or CY‐216 or CY216 or LMF CY‐216 or LMF CY 216 or LMF CY216).mp. 6. exp coumarin derivative/ 7. (coumarin* or chromonar or coumestrol or esculin or isocoumarin* or psoralens or pyranocoumarins or umbelliferones).tw. 8. (4‐Hydroxycoumarin* or warfarin* or acenocoumarol or nicoumalone or sinthrome or Sintrom or phenindione or dicoumarol or coumadin or phenprocoumon or phepromaron or ethyl‐biscoumacetate or phenindione or Diphenadione or Tioclomarol or Racumi or Marcoumar or Marcumar or Falithrom or Jantoven or vitamin K antagonist* or VKA or fluindione or difenacoum or coumatetralyl or coumadin* or warfant or marevan or aldocumar).mp. 9. (Dermatan Sulfate or (Chondroitin Sulfate adj B) or Dermatan Sulfphate or DS 435 or MF‐701 or OP‐370 or b‐Heparin or Mistral or Venorix).mp. 10. (thrombin adj inhibitor*).mp. 11. (factor Xa inhibitor* or antithrombin* or anticoagul*).mp. 12. (rivaroxaban or Xarelto or apixaban or Eliquis or dabigatran etexilate or Edoxaban or Savaysa or Betrixaban or ximelagatran or pradaxa or lixiana or exanta or Darexaban or Otamixaban* or Razaxaban or Bivalirudin or Desirudin or Lepirudin or Melagatran or YM 150 or Iprivask or argatrovan or pradax* or Xarelto or BIBR‐953 or BIBR‐953ZW or BAY 59‐7939 or BMS‐562247 or DU‐176 or DU‐176b).mp. 13. rivaroxaban/ 14. dabigatran/ 15. (BIBR 953 or BIBR 953 ZW or Dabigatran or HSDB 8062 or Pradaxa or UNII‐I0VM4M70GC).mp. 16. (target specific oral anticoagulant* or target‐specific oral anticoagulant* or TSOAC* or new oral anticoagulant* or novel oral anticoagulant* or NOAC* or direct‐acting oral anticoagulant* or direct acting oral anticoagulant* or direct oral anticoagulant* or DOAC*).ti,ab,kw. 17. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 18. exp neoplasm/ 19. (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor* or glioma* or myeloma* or lymphoma* or leukemia* or leukaemia* or epithelioma* or adenoma*).tw. 20. 18 or 19 21. 17 and 20 22. crossover procedure/ 23. double‐blind procedure/ 24. randomised controlled trial/ 25. single‐blind procedure/ 26. random*.mp. 27. factorial*.mp. 28. (crossover* or cross over* or cross‐over*).mp. 29. placebo*.mp. 30. (double* adj blind*).mp. 31. (singl* adj blind*).mp. 32. assign*.mp. 33. allocat*.mp. 34. volunteer*.mp. 35. 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. 21 and 35 Systematic Review search strategy: 1. exp anticoagulant agent/ 2. (anticoagulant* or anti‐coagulant*).tw. 3. (Heparin or Adomiparin or alpha‐Heparin or Arteven or "AVE‐5026" or CY 222 or "Depo‐Heparin" or "EINECS 232‐681‐7" or Fluxum or "Hed‐heparin" or Hepathrom or HSDB 3094 or KB 101 or "Lipo‐hepin" or M 118 or "M 118REH" or M118 or Octaparin or OP 386 or OP 622 or Pabyrin or Pularin or Subeparin or Sublingula or Thromboliquine or Triofiban or "UNII‐1K5KDI46KZ" or "UNII‐4QW4AN84NQ" or "UNII‐5R0L1D739E" or "UNII‐7UQ7X4Y489" or "UNII‐9816XA9004" or "UNII‐E47C0NF7LV" or "UNII‐M316WT19D8" or "UNII‐P776JQ4R2F" or "UNII‐S79O08V79F" or "UNII‐T2410KM04A" or "UNII‐V72OT3K19I" or "UNII‐VL0L558GCB" or Vetren or Vitrum AB or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or "Hep‐lock" or enoxaparin* or klexane or lovenox or fragmin* or normiflo or logiparin or innohep or danaproid or danaparoid or orgaran or antixarin or hibor or zibor or ivor or badyket or lohepa or lowhepa or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or fondaparinux or Arixtra or UFH or Hepalean or Panheprin).mp. 4. (LMWH* or heparin* or nadroparin* or frixiparin* or enoxaparin* or clexane or klexane or lovenox or dalteparin or fragmin or ardeparin* or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin* or danaproid or danaparoid or orgaran or antixarin or bemiparin* or hibor or zibor or ivor or badyket or semuloparin or parnaparin or tedelparin or fluxum or lohepa or lowhepa or parvoparin or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or clivarine or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or Liquaemin or Liquemin or Multiparin or Novoheparin or Eparina or Hep‐lock or Heparinate or Heparinic acid or Panheprin or Hepalean or Heparin Leo or Heparin Lock).mp. 5. (FR‐860 or FR 860 or FR860 or PK‐10,169 or PK 10,169 or PK10,169 or PK‐10169 or PK 10169 or PK10169 or EMT‐967 or EMT 967 or EMT967 or EMT‐966 or EMT 966 or EMT966 or CY 216 or CY‐216 or CY216 or LMF CY‐216 or LMF CY 216 or LMF CY216).mp. 6. exp coumarin derivative/ 7. (coumarin* or chromonar or coumestrol or esculin or isocoumarin* or psoralens or pyranocoumarins or umbelliferones).tw. 8. (4‐Hydroxycoumarin* or warfarin* or acenocoumarol or nicoumalone or sinthrome or Sintrom or phenindione or dicoumarol or coumadin or phenprocoumon or phepromaron or ethyl‐biscoumacetate or phenindione or Diphenadione or Tioclomarol or Racumi or Marcoumar or Marcumar or Falithrom or Jantoven or vitamin K antagonist* or VKA or fluindione or difenacoum or coumatetralyl or coumadin* or warfant or marevan or aldocumar).mp. 9. (Dermatan Sulfate or (Chondroitin Sulfate adj B) or Dermatan Sulfphate or DS 435 or MF‐701 or OP‐370 or b‐Heparin or Mistral or Venorix).mp. 10. (thrombin adj inhibitor*).mp. 11. (factor Xa inhibitor* or antithrombin* or anticoagul*).mp. 12. (rivaroxaban or Xarelto or apixaban or Eliquis or dabigatran etexilate or Edoxaban or Savaysa or Betrixaban or ximelagatran or pradaxa or lixiana or exanta or Darexaban or Otamixaban* or Razaxaban or Bivalirudin or Desirudin or Lepirudin or Melagatran or YM 150 or Iprivask or argatrovan or pradax* or Xarelto or BIBR‐953 or BIBR‐953ZW or BAY 59‐7939 or BMS‐562247 or DU‐176 or DU‐176b).mp. 13. rivaroxaban/ 14. dabigatran/ 15. (BIBR 953 or BIBR 953 ZW or Dabigatran or HSDB 8062 or Pradaxa or UNII‐I0VM4M70GC).mp. 16. (target specific oral anticoagulant* or target‐specific oral anticoagulant* or TSOAC* or new oral anticoagulant* or novel oral anticoagulant* or NOAC* or direct‐acting oral anticoagulant* or direct acting oral anticoagulant* or direct oral anticoagulant* or DOAC*).ti,ab,kw. 17. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 18. exp neoplasm/ 19. (malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor* or glioma* or myeloma* or lymphoma* or leukemia* or leukaemia* or epithelioma* or adenoma*).tw. 20. 18 or 19 21. 17 and 20 22. exp Meta Analysis/ 23. ((meta adj analy$) or metaanalys$).tw. 24. (systematic adj (review$1 or overview$1)).tw. 25. 22 or 23 or 24 26. cancerlit.ab. 27. cochrane.ab. 28. embase.ab. 29. (psychinfo or psycinfo).ab. 30. (cinahl or cinhal).ab. 31. science citation index.ab. 32. bids.ab. 33. 26 or 27 or 28 or 29 or 30 or 31 or 32 34. reference lists.ab. 35. bibliograph$.ab. 36. hand‐search$.ab. 37. manual search$.ab. 38. relevant journals.ab. 39. 34 or 35 or 36 or 37 or 38 40. data extraction.ab. 41. selection criteria.ab. 42. 40 or 41 43. review.pt. 44. 42 and 43 45. letter.pt. 46. editorial.pt. 47. animal/ 48. human/ 49. 47 not (47 and 48) 50. 45 or 46 or 49 51. 25 or 33 or 39 or 44 52. 51 not 50 53. 21 and 52
CENTRAL (the Cochrane Library, latest issue)	#1 MeSH descriptor: [Anticoagulants] explode all trees #2 (LMWH* or heparin* or nadroparin* or frixiparin* or enoxaparin* or clexane or klexane or lovenox or dalteparin or fragmin or ardeparin* or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin* or danaproid or danaparoid or orgaran or antixarin or bemiparin* or hibor or zibor or ivor or badyket or semuloparin or parnaparin or tedelparin or fluxum or lohepa or lowhepa or parvoparin or seleparin* or tedelgliparin or lomoparan or orgaran or sulodexide or zivor or embolex or xaparin or clivarine or fondaparinux or Arixtra or UFH or Hepalean or Calcilean or Calciparine or Liquaemin or Liquemin or Multiparin or Novoheparin or Eparina or Hep‐lock or Heparinate or Heparinic acid or Panheprin or Hepalean or Heparin Leo or Heparin Lock) #3 FR‐860 or FR 860 or FR860 or PK‐10,169 or PK 10,169 or PK10,169 or PK‐10169 or PK 10169 or PK10169 or EMT‐967 or EMT 967 or EMT967 or EMT‐966 or EMT 966 or EMT966 or CY 216 or CY‐216 or CY216 or LMF CY‐216 or LMF CY 216 or LMF CY216 #4 MeSH descriptor: [Coumarins] explode all trees #5 (4‐Hydroxycoumarin* or warfarin* or acenocoumarol or nicoumalone or sinthrome or Sintrom or phenindione or dicoumarol or coumadin or phenprocoumon or phepromaron or ethyl‐biscoumacetate or phenindione or Diphenadione or Tioclomarol or Racumi or Marcoumar or Marcumar or Falithrom or Jantoven or vitamin K antagonist* or VKA or fluindione or difenacoum or coumatetralyl) #6 (Dermatan Sulfate or (Chondroitin Sulfate adj B) or Dermatan Sulfphate or DS 435 or MF‐701 or OP‐370 or b‐Heparin or Mistral or Venorix) #7 thrombin near inhibitor* #8 factor Xa inhibitor* or antithrombin* or anticoagul* #9 (rivaroxaban or Xarelto or apixaban or Eliquis or dabigatran etexilate or Edoxaban or Savaysa or Betrixaban or ximelagatran or pradaxa or lixiana or exanta or Darexaban or Otamixaban* or Razaxaban or Bivalirudin or Desirudin or Lepirudin or Melagatran or YM 150 or Iprivask or argatrovan or pradax* or Xarelto or BIBR‐953 or BIBR‐953ZW or BAY 59‐7939 or BMS‐562247 or DU‐176 or DU‐176b).mp. #10 MeSH descriptor: [Rivaroxaban] this term only #11 MeSH descriptor: [Dabigatran] this term only #12 target specific oral anticoagulant* or target‐specific oral anticoagulant* or TSOAC* or new oral anticoagulant* or novel oral anticoagulant* or NOAC* or direct‐acting oral anticoagulant* or direct acting oral anticoagulant* or direct oral anticoagulant* or DOAC* #13 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 #14 MeSH descriptor: [Neoplasms] explode all trees #15 malignan* or neoplasm* or cancer* or carcinoma* or adenocarcinoma* or tumour* or tumor* or glioma* or myeloma* or lymphoma* or leukemia* or leukaemia* or epithelioma* or adenoma* #16 #14 or #15 #17 #13 and #16

Appendix 3. Sensitivity analysis related to missing outcome data

Sensitivity analyses using the a priori plausible assumptions for the outcome symptomatic DVT under the comparison DOAC vs no prophylaxis:

• RI_LTFU/FU = 1.5 (RR 0.47. 95% CI 0.24 to 0.90)

• RI_LTFU/FU = 2 (RR 0.47. 95% CI 0.24 to 0.91)

• RI_LTFU/FU = 3 (RR 0.49. 95% CI 0.25 to 0.95)

• RI_LTFU/FU = 5 (RR 0.52. 95% CI 0.27 to 1.01)

Data and analyses

Comparison 1. Vitamin K antagonist (VKA) versus no prophylaxis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mortality at 6 months (main analysis)	3	946	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.77, 1.13]
1.2 Mortality at 6 months (subgroup analysis‐lung cancer)	3	946	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.77, 1.14]
1.2.1 Lung cancer (small cell and non‐small cell)	3	813	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.72, 1.06]
1.2.2 Non‐lung cancer	1	133	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.82, 1.82]
1.3 Mortality at 12 months (main analysis)	5	1281	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.87, 1.03]
1.4 Mortality at 12 months (subgroup analysis‐lung cancer)	5	1281	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.87, 1.03]
1.4.1 Lung cancer (small cell and non‐small cell)	4	837	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.85, 1.05]
1.4.2 Non‐lung cancer	2	444	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.81, 1.10]
1.5 Pulmonary embolism at 12 months	1	311	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.07, 16.58]
1.6 Symptomatic deep vein thrombosis at 12 months	1	311	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.00, 1.42]
1.7 Major bleeding at 12 months (main analysis)	5	1281	Risk Ratio (M‐H, Random, 95% CI)	2.93 [1.86, 4.62]
1.8 Major bleeding at 12 months: sensitivity analysis	6	1372	Risk Ratio (M‐H, Random, 95% CI)	2.89 [2.07, 4.04]
1.9 Major bleeding at 12 months (subgroup analysis‐lung cancer)	5	1281	Risk Ratio (M‐H, Random, 95% CI)	2.85 [1.76, 4.62]
1.9.1 Lung cancer (small cell and non‐small cell)	4	837	Risk Ratio (M‐H, Random, 95% CI)	3.95 [2.38, 6.55]
1.9.2 Non‐lung cancer	2	444	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.63, 4.89]
1.10 Minor bleeding at 12 months (main analysis)	4	863	Risk Ratio (M‐H, Random, 95% CI)	3.14 [1.85, 5.32]
1.11 Minor bleeding at 12 months (subgroup analysis‐lung cancer)	4	865	Risk Ratio (M‐H, Random, 95% CI)	3.19 [1.83, 5.55]
1.11.1 Lung cancer (small cell and non‐small cell)	3	554	Risk Ratio (M‐H, Random, 95% CI)	3.79 [1.55, 9.24]
1.11.2 Non‐lung cancer	1	311	Risk Ratio (M‐H, Random, 95% CI)	2.44 [0.64, 9.27]

Comparison 2. Direct oral anticoagulants (DOAC) versus no prophylaxis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mortality at 3 to6 months (main analysis)	3	1440	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.64, 1.38]
2.2 Mortality at 3 to6 months (sensitivity analysis)	4	1562	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.64, 1.38]
2.3 Pulmonary embolism at 3 to6 months (main analysis)	3	1440	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.24, 0.98]
2.4 Pulmonary embolism at 3 to6 months (sensitivity analysis)	4	1562	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.23, 0.88]
2.5 Symptomatic deep vein thrombosis at 3 to6 months	3	1440	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.30, 1.15]
2.6 Major bleeding at 3 to6 months (main analysis)	3	1440	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.72, 3.80]
2.7 Major bleeding at 3 to6 months (sensitivity analysis)	4	1562	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.37, 3.40]
2.8 Minor bleeding at 3 to 6 months	3	1440	Risk Ratio (M‐H, Random, 95% CI)	3.58 [0.55, 23.44]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Carrier 2019 (AVERT).

Study characteristics
Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	563 participants who had a newly diagnosed cancer or progression of known cancer after complete or partial remission and who were initiating a new course of chemotherapy with a minimum treatment intent of 3 months Mean age 61 years, 58.2% were women, most common types of primary cancer were gynaecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). Khorana score of 2 or higher Participants were excluded if they had a cancer diagnosis consisting solely of basal‐cell or squamous‐cell skin carcinoma, acute leukaemia,or myeloproliferative neoplasm; a planned stem cell transplantation; a life expectancy of less than 6 months; renal insufficiency with a glomerular filtration rate of less than 30 mL per minute per 1.73 m2 of body‐surface area; or a platelet count of less than 50,000 per cubic millimetre.
Interventions	Intervention: apixaban at a dose of 2.5 mg twice daily Control: identical placebo tablets twice daily Duration of treatment: 180 days
Outcomes	Participants were followed for up to 210 days or death, regardless of the duration of the treatment period Overall survival Objectively‐documented major venous thromboembolism (proximal deep‐vein thrombosis or pulmonary embolism) within the first 180 days (symptomatic or incidentally detected) Major bleeding Clinically relevant non‐major bleeding
Notes	Funded by the Canadian Institutes of Health Research and Bristol‐Myers Squibb–Pfizer Alliance Ethical approval: "The institutional review board at each of the 13 participating sites approved the protocol" Conflict of interest: at least one author disclosed financial conflict of interest NCT02048865
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization by means of a centralized, Web‐based randomizations system"
Allocation concealment (selection bias)	Low risk	Quote: "randomizations by means of a centralized, Web‐based randomization system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "placebo‐controlled, double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "placebo‐controlled, double‐blind"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The primary analysis was performed in the modified intention‐to‐treat population, which included all the participants who had undergone randomisation and received at least one dose of apixaban or placebo on or before day 180 (±3 days)." Comment: judgement based on comparison in the intervention arm between rate of participants with missing data (13/288 (4.5%)) and event rate (35/278 (12.7%)) for the main outcome ‐ mortality at 3‐6 months. Similary for the control arm: rate of participants with missing data (11/275 (4%)) and event rate (27/264 (10.2%)).
Selective reporting (reporting bias)	Low risk	All outcomes listed in the methods section and protocol were reported on. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early.

Chahinian 1989.

Study characteristics
Methods	Randomised controlled trial
Participants	189 participants with small cell lung cancer undergoing chemotherapy (CALBG 0‐3). Mean age 60 years, 70% male.
Interventions	Intervention: warfarin (PT 1.5‐2) Control: no intervention Co‐intervention: both arms received chemotherapy Discontinued treatment: none
Outcomes	Duration of follow‐up: not reported Major bleeding Mortality (6 months, 1 year, 2 years and 5 years) Screening test for DVT/PE: none Diagnostic test for DVT/PE: none
Notes	Funding: TJ Martell Foundation Ethical approval: not reported Conflict of interest: not reported Intention‐to‐treat analysis: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomized controlled trial."
Allocation concealment (selection bias)	High risk	Not reported. Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo used. Comment: probably not blinded; knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of co‐interventions.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No placebo used. Comment: probably not blinded; knowledge of the assigned intervention is unlikely to have impacted on the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: judgement based on comparison in the intervention arm between rate of participants with missing data (3/103 (2.9%)) and event rate (74/100 (74%)) for the main outcome ‐ mortality at 12 months. Similarly for the control arm: rate of participants with missing data (2/86 (2.3%)) and event rate (68/84 (80.9%)).
Selective reporting (reporting bias)	Low risk	Study not registered. No published protocol. All outcomes listed in the methods section were reported on. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early.

Ciftci 2012.

Study characteristics
Methods	Randomised controlled trial
Participants	91 participants with lung cancer undergoing chemotherapy
Interventions	Intervention: warfarin starting day 1 of chemotherapy at a dose of 5 mg daily to achieve a target INR of 1.5 to 2.5 Control: no warfarin Co‐intervention: both arms received chemotherapy Discontinued treatment: not reported
Outcomes	Duration of follow‐up: 6 months Mortality Bleeding Diagnostic test for DVT/PE: not reported
Notes	Funding: not reported Ethical approval: not reported Conflict of interest: "No significant relationship." Intention‐to‐treat analysis: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients with lung cancer were randomly assigned."
Allocation concealment (selection bias)	High risk	Not reported. Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not reported. No placebo used. Comment: not blinded; knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention, or differential administration of co‐interventions.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not reported. Comment: probably not blinded; knowledge of the assigned intervention is unlikely to have impacted on the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported (data available only from abstract)
Selective reporting (reporting bias)	Unclear risk	Not reported (data available only from abstract)
Other bias	Low risk	Study not stopped early for benefit

Khorana 2019 (CASSINI).

Study characteristics
Methods	Multinational, multicenter, randomised, double‐blind, placebo‐controlled phase IIIb superiority study
Participants	841 participants with various solid tumours/lymphomas initiating new systemic regimen and at high risk of VTE (Khorana score ≥2) Mean age 62%, almost 50% were males, 68% had a Khorana score of 2, 32% with pancreatic cancer
Interventions	Intervention: rivaroxaban 10 mg once daily Control: placebo once daily Duration of treatment: 180 +\‐ 3 days Discontinued treatment: 50% in placebo arm and 44% in the intervention arm discontinued treatment prematurely.The characteristics of the participants were well‐balanced at baseline, except that more participants with a history of venous thromboembolism were randomly assigned to the rivaroxaban group than to the placebo group (Table 1)".
Outcomes	Duration of follow‐up: follow‐up visits every 8 weeks (±7 days) during the 180 ± 3 days treatment period and additional 30 day follow‐up Symptomatic or asymptomatic lower extremity proximal DVT Symptomatic upper‐ or lower‐extremity distal DVT Symptomatic or incidental pulmonary embolism VTE‐related death Confirmed arterial thromboembolism Confirmed visceral thrombosis All‐cause mortality Major bleeding Clinically relevant non‐major bleeding Screening for DVT/PE: spiral computed tomography; compression ultrasonography
Notes	Funding: co‐sponsored by Janssen and Bayer Ethical approval: "the study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and applicable regulatory and country‐specific requirements. This study will be undertaken at each location only after the independent ethics committee/institutional review board (local/central) has given full approval." Conflict of interest: at least one author disclosed financial conflict of interest Intention‐to‐treat analysis: "The primary efficacy analysis was based on the intention‐to‐treat analysis population, which comprised all the participants who had undergone randomisation".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients...were randomly assigned ...according to a computer generated randomisation schedule."
Allocation concealment (selection bias)	High risk	Not reported Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Suspected DVT and non‐fatal PE occurring during the double‐blind treatment phase and the 30‐day follow‐up phase will be centrally adjudicated by an independent, blinded clinical end‐point committee whose members."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Patients who discontinued the trial regimen were still followed up for efficacy, and 39% of all the primary endpoint events occurred in these patients".
Selective reporting (reporting bias)	Low risk	All outcomes listed in the methods section and protocol were reported on. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early

Levine 1994.

Study characteristics
Methods	Randomised controlled trial
Participants	315 participants with breast cancer undergoing chemotherapy; minimum life expectancy 3 months; good performance status (ECOG < 3).
Interventions	Intervention: very‐low‐dose warfarin 1 mg daily for 6 weeks (INR 1.3 to 1.9) started within 4 weeks of chemotherapy until 1 week after termination of chemotherapy Control: placebo Co‐intervention: both arms received chemotherapy Discontinued treatment: 2 participants in the warfarin group and 2 in the control group did not receive chemotherapy and they were not considered in the analysis. 27 participants in each arm discontinued treatment.
Outcomes	Duration of follow‐up: not reported Thromboembolic events Mortality (1 year) Bleeding Diagnostic test for DVT: venography, impedance plethysmography or Doppler Diagnostic test for PE: ventilation/perfusion scan or angiography
Notes	Funding: National Cancer Institute, Canada. Ethical approval: "The protocol was approved by the institutional review boards for the participating centres." Conflict of interest: ML is a scientist of the Medical Research Council of Canada, JH is a distinguished professor of the Heart & Stroke Foundation of Ontario and PG is a career scientist of the Ontario Ministry of Health. Intention‐to‐treat analysis: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were assigned warfarin or placebo according to a computer‐generated random arrangement."
Allocation concealment (selection bias)	High risk	Not reported Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Neither patients nor doctors were aware of treatment allocation." Comment: definitely blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The manager relayed the INR (actual value for patients on active drug, sham value for patients on placebo) to the study nurse and investigator." Comment: Definitely blinded; knowledge of the assigned intervention is unlikely to have impacted on the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: judgement based on comparison in the intervention arm between rate of participants with missing data (2/154 (1.3%)) and event rate (87/152 (57.2%)) for the main outcome ‐ mortality at 12 months. Similarly for the control arm: rate of participants with missing data (1/161 (1.2%)) and event rate (99/159 (62.2%)).
Selective reporting (reporting bias)	Low risk	Study not registered. No published protocol. All outcomes listed in the methods section were reported on. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early for benefit

Levine 2012.

Study characteristics
Methods	Randomised, phase II, double‐blind trial.
Participants	125 participants with advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian or prostate cancers; cancer of unknown origin; myeloma; or selected lymphomas from 6 sites in Canada and 8 in the USA. Mean age 60 years, 50% male, ECOG 0 50%, with central venous catheter (VTE risk factor) 30%
Interventions	Intervention: apixaban 5 mg, 10 mg or 20 mg once daily for 12 weeks beginning within 4 weeks of the date on which the first‐line or second‐line chemotherapy was begun Control: placebo Co‐intervention: either first‐line or second‐line chemotherapy (expected course ≥ 90 days) Discontinued treatment: none
Outcomes	Duration of follow‐up: 30 days after completion of the 12‐week treatment period (114‐121 days) or premature discontinuation of study medication or of the study Mortality Major bleeding Clinically relevant non‐major bleeding Higher adverse events (≥ grade 3) VTE Symptomatic DVT Symptomatic PE Diagnostic tests for bleeding: "In the absence of visible bleeding, confirmatory imaging techniques that can detect the presence of bleeding (e.g. ultrasound [US], computed tomography [CT], and magnetic resonance imaging) could be used." Diagnostic tests for DVT: compression ultrasound or venography Diagnostic tests for PE: spiral computed tomography or ventilation/perfusion lung scan
Notes	Funding: Bristol‐Myers Squibb and Pfizer Inc. Ethical approval: "The study protocol was approved by the Institutional Review Board of each participating centre." Conflict of interest: not reported Intention‐to‐treat analysis: not reported Quote: "In September 2008, a decision was made by the Steering Committee and BMS [Bristol‐Myers Squibb] to close the trial because of the slow rate of accrual. It was felt that the main study objectives could be met despite not reaching the intended sample size."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed centrally by contacting a computerized telephone voice response system provided by Bristol Myers Squibb (BMS)." "Treatment assignments were implemented with a randomisation schedule with blocks of size four; blocks were stratified by the presence (or not) of metastatic liver disease and clinical centre."
Allocation concealment (selection bias)	High risk	Not reported. Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Subjects received blister packs containing a combination of apixaban (2.5‐mg or 10‐mg tablets) and matching placebo tablets supplied by BMS. All subjects took four tablets orally once daily; these consisted of a combination of apixaban and matching placebo tablets for the apixaban treatment groups, or all placebo tablets for the placebo treatment group, such that the study supplies for subjects in all treatment groups were identical in appearance." Comment: blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All bleeding and VTE events were adjudicated by a committee unaware of treatment allocation." Comment: blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up
Selective reporting (reporting bias)	Low risk	Study not registered. No published protocol. All outcomes listed in the methods section were reported on. Quote: "Study protocol approved by Institutional Review Board of each participating centre." Comment: probably free of selective reporting
Other bias	Low risk	Study not stopped early for benefit

Maurer 1997.

Study characteristics
Methods	Randomised controlled study.
Participants	369 participants aged > 18 years with small cell lung cancer undergoing chemotherapy and radiotherapy from 27 CALBG main member institutions and their affiliates Mean age 48 years, 65% male, 55% performance status 0, minimum life expectancy 2 months; CALGB < 3
Interventions	Intervention: warfarin (PT 1.4 to 1.6) started with chemotherapy at 10 mg daily for 3 days and continued for 3 weeks after last cycle of chemotherapy and radiotherapy Control: no warfarin Co‐intervention: both arms received 3 cycles of chemotherapy Discontinued treatment: 3 participants were randomised but excluded pretreatment because they did not receive protocol treatment (unclear in which group)
Outcomes	Duration of follow‐up: not reported Mortality (6 months, 1 year, 2 years, 5 years) Bleeding Diagnostic tests for PE: not reported Diagnostic tests for DVT: not reported
Notes	Funding: National Cancer Institute, USA Ethical approval: "Each patient provided signed informed consent, which included a discussion of alternative therapies and which was approved by the institutional review board." Conflict of interest: not reported Intention‐to‐treat analysis: "Ineligible patients and patients who did not receive protocol treatment are excluded from subsequent analyses."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomised to receive warfarin or no warfarin." Communication with author: "allocation by central office." Comment: probably yes given this was done by a central office.
Allocation concealment (selection bias)	Low risk	Communication with author: "allocation by central office." Comment: yes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo used Comment: not blinded; knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of co‐interventions.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No placebo used Comment: probably not blinded; knowledge of the assigned intervention is unlikely to have impacted on the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Follow‐up rate: not reported
Selective reporting (reporting bias)	Low risk	Study not registered. No published protocol. All outcomes listed in the methods section were reported on. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early for benefit

NCT00320255.

Study characteristics
Methods	Phase 2 pilot study, randomised, double‐blind, placebo‐controlled
Participants	130 participants with advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian, or prostate cancer or myeloma, selected lymphomas, or cancer of unknown origin receiving first‐ or second‐line chemotherapy Almost half were older than 65 years, 47% were women Per Protocol Amendment 5, participants receiving Bevacizumab were eligible to participate, provided that Bevacizumab was used for indications approved by local country law
Interventions	Intervention: apixaban as tablet, 5 mg (32 participants), 10 mg (30 participants), and 20 mg (33 participants), once daily Control: placebo tablets once daily Co‐intervention: both arms received chemotherapy Discontinued treatment: 32 participants did not complete the treatment
Outcomes	Composite of venous thromboembolism (VTE) and all‐cause death (VTE includes symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE)) (time frame: first dose to 2 days following last dose of study drug) Major bleeding (time frame: first dose to 2 days following last dose of study drug) Clinically relevant non‐major (CRNM) bleeding (time frame: first dose to 2 days following last dose of study drug) Deep vein thrombosis (DVT) (time frame: first dose to 30 days following last dose of study drug) Pulmonary embolism (PE) (time frame: first dose to 30 days following last dose of study drug) All‐cause death (time frame: first dose to 30 days following last dose of study drug) Adverse events (AEs), serious adverse events (SAEs) (time frame: first dose to 2 days following last dose of study drug) Screening test for DVT: compression US, contrast venography Screening test for PE: pulmonary angiography, ventilaiton perfusion lung scan, spiral computed tomography scan
Notes	Funding: Bristol‐Myers Squibb Ethical approval: not reported Conflict of interest: not reported Intention‐to‐treat analysis: not reported First posted: 3 May 2006 Results first posted: 16 August 2016 Last update posted: 16 August 2016
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomized"
Allocation concealment (selection bias)	High risk	Quote: "Not reported" Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Double (Participant, Investigator)"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Double (Participant, Investigator)"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported in published table on ClinicalTrials.gov
Selective reporting (reporting bias)	Low risk	All outcomes listed in the methods section were reported on. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early for benefit

Stanford 1979.

Study characteristics
Methods	Randomised controlled trial.
Participants	24 participants with a small cell carcinoma (at least stage T3 disease) of the bronchus receiving chemotherapy. 75% male, 79% extrathoracic metastases
Interventions	Intervention: 48 hours before each induction course of cytotoxic drugs, a loading dose of heparin 5000 IU and then heparin 20,000 IU daily for 6 days. During the first 24 hours of anticoagulants, participants also received 1 L of dextran (Rheomacrodex). A loading dose of warfarin 25 mg was given on the 4th day of heparin treatment. On the day of the intravenous maintenance chemotherapy, each participant of the anticoagulant group also received heparin 5000 IU contained in 500 mL of dextran over 4 hours. Control: no anticoagulant Co‐intervention: "Both groups received two induction courses of chemotherapy at the weekly intervals followed by maintenance drugs given three times weekly." Discontinued treatment: none
Outcomes	Duration of follow‐up: 16 months Mortality (12 months) Minor bleeding (4 months) Diagnostic tests for PE: not reported Diagnostic tests for DVT: not reported
Notes	Funding: not reported Ethical approval: not reported Conflict of interest: not reported Intention‐to‐treat analysis: not reported. "All the 24 patients enrolled in the study completed the follow‐up and their data had been analysed."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "They were assigned to either the anticoagulant or control treatment groups according to a table of random numbers."
Allocation concealment (selection bias)	High risk	Not reported. Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo used Comment: not blinded; knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of co‐interventions)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No placebo used Comment: probably not blinded; knowledge of the assigned intervention is unlikely to have impacted on the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up
Selective reporting (reporting bias)	Unclear risk	Study not registered. No published protocol. No listing of outcomes in the methods section.
Other bias	Low risk	Study not reported as stopped early for benefit No other bias suspected

Zacharski 1984.

Study characteristics
Methods	Randomised controlled trial
Participants	431 participants with different types of cancer undergoing chemotherapy; minimum life expectancy of 2 months from 13 different Veterans Affairs Medical Centers over a 4‐year period and were followed for an additional 12 months.
Interventions	Intervention: warfarin (therapeutic range) Control: no intervention Co‐intervention: not reported Discontinued treatment: 0 participants. 13 randomised participants were excluded from survival analyses (unclear in which group)
Outcomes	Duration of follow‐up: 4 years followed for an additional 12 months Major bleeding Mortality (6 months, 1 year) Diagnostic tests for PE: not reported Diagnostic tests for DVT: not reported
Notes	Funding: Department of Veterans Affairs Medical Research Service Ethical approval: not reported Conflict of interest: not reported Intention‐to‐treat analysis: probably not. "patients randomised to receive warfarin were excluded if they did not receive at least 2 weeks of anticoagulant therapy following randomisation."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients admitted to the study were subjected to computer randomisation by hospital, performance status and tumour category to receive standard therapy either with or without warfarin anticoagulation."
Allocation concealment (selection bias)	High risk	Not reported Comment: probably not concealed
Blinding of participants and personnel (performance bias) All outcomes	High risk	No placebo used Comment: not blinded; knowledge of the assigned intervention may have led to differential behaviours across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of co‐interventions)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No placebo used Comment: probably not blinded; knowledge of the assigned intervention is unlikely to have impacted on the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (5/215 (2.3%)) and event rate (138/210 (65.7%)) for the main outcome ‐ mortality at 12 months. Similarly for the control arm: rate of participants with missing data (8/216 (3.7%)) and event rate (141/208 (67.7%))
Selective reporting (reporting bias)	Low risk	Study not registered. No published protocol. All outcomes listed in the methods section were not reported. Probably free of selective reporting.
Other bias	Low risk	Study not stopped early for benefit

DVT: deep vein thrombosis; ECOG: Eastern Cooperative Oncology Group; INR: international normalised ratio; IU: international unit; PE: pulmonary embolism; PT: prothrombin time; VKA: vitamin K antagonist; VTE: venous thromboembolism

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Agnelli 2005	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Alikhan 2003 (MEDENOX)	Not population of interest (people with cancer without VTE undergoing a surgical procedure); included 2 reports
Auer 2011	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Cohen 2006 (ARTEMIS)	Not population of interest (hospitalised)
Cohen 2007 (PREVENT)	Not population of interest (hospitalised people with cancer); included 3 reports
Couban 2005	Not population of interest (people with cancer with CVC without VTE); included 3 reports
Dong 2018	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Ek 2017	Not comparison of interest (parenteral anticoagulant)
Goldhaber 2002	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Haas 2011	Not population of interest (hospitalised people with cancer); included 3 reports
Harenberg 1996	Not population of interest (hospitalised people with cancer); included 2 reports
Hata 2016	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Hata 2019	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Jung 2018	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Kakkar 2014	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Khorana 2017	Not comparison of interest (parenteral anticoagulant); included 2 reports
Macbeth 2016 (FRAGMATIC)	Not comparison of interest (parenteral anticoagulant); included 4 reports
Murakami 2002	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Nagata 2015	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Pelzer 2015 (CONKO‐004)	Not intervention of interest (parenteral anticoagulant); included 10 reports
Sakon 2010	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Song 2014	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Song 2018	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Tanaka 2019	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Vadhan‐Raj 2013	Not intervention of interest (parenteral anticoagulant)
Vedovati 2014	Not population of interest (people with cancer who had a surgical procedure); included 5 reports
Verso 2008	Not population of interest (people with cancer with CVC without VTE); included 4 reports
Young 2018	Not population of interest (people with cancer with VTE)
Zheng 2014	Not population of interest (people with cancer without VTE undergoing a surgical procedure)
Zwicker 2013 (MICRO TEC)	Not intervention of interest (parenteral anticoagulant); included 2 reports

CVC: central venous catheter; LMWH: low‐molecular‐weight heparin; VTE: venous thromboembolism

Differences between protocol and review

• We previously reported using the 'related citation' feature in PubMed and 'citation tracking' of included studies in Web of Science Core Collection to identify additional articles. We stopped applying this method in February 2018, as over two years (February 2016 until February 2018), it did not retrieve any additional reference compared to the findings of the database automated search.

• We have updated our search strategy (Appendix 2).

• For feasibility reasons, we will be updating the status of this systematic review every six months instead of every month.

• In this review, we do not report on outcomes assessed at two and five years as we did in the previous version, due to lack of new outcome data for these time points.

Contributions of authors

LAK: searching for trials, full‐text retrieval, screening, data extraction, data analysis, data interpretation, manuscript drafting, review co‐ordination.
CFM: screening, data extraction.
IGT: screening, data extraction, manuscript drafting.
MBH: full‐text retrieval, screening, data extraction, manuscript drafting.
MB, VY, IT, FS: screening.
HJS: protocol development, data interpretation, methodological expertise.
EAA: protocol development, data analysis, data interpretation, manuscript drafting, methodological expertise, review co‐ordination.

Sources of support

Internal sources

• None, Other

External sources

• NIHR, UK

  This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group

• American Society of Hematology, USA

  This project was supported by the American Society of Hematology

Declarations of interest

LAK: none known. MBH: none known. IGT: none known. CFM: none known. MB: none known. VY: none known. IT: none known. FS: none known. HJS: no personal payments from for‐profit sponsors related to the subject matter since 2014. EAA: served on the executive committee of the American College of Clinical Pharmacy Antithrombotic Therapy Guidelines published in 2016.

Edited (no change to conclusions)