Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials.

Annals of Medicine, 2014; Early Online: 1–8 © 2014 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2014.982064

Original article

Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials

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Matteo Nicola Dario Di Minno1,2, Roberta Lupoli1, Alessandro Di Minno1, Pasquale Ambrosino1, Antonella Scalera1 & Francesco Dentali3 1Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy, 2Unit of Cell and Molecular Biology in Cardiovascular

Diseases, Centro Cardiologico Monzino, IRCCS, Milan, Italy, and 3Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy

Objective. To evaluate the effect of body weight (BW) on safety and efficacy of direct oral anticoagulants (DOACs). Methods. We performed a meta-analysis of randomized controlled trials (RCTs) comparing DOACs with vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Efficacy (prevention of recurrent VTE or VTE-related death) and safety (occurrence of major or clinically relevant non-major bleeding) outcomes were stratified according to patients’ BW (low, normal, and high). Results. Six RCTs with a total of 27,023 patients were included. DOACs showed a similar efficacy to VKA in patients with high BW, normal BW, and low BW (RR 0.98, 95% CI 0.72, 1.35; RR 0.91, 95% CI 0.75, 1.09; and RR 0.84, 95% CI 0.57, 1.24, respectively). Safety was comparable among DOACs and VKA in patients with high BW and low BW (RR 0.93, 95% CI 0.65, 1.32; and RR 0.80, 95% CI 0.54, 1.20), whereas DOACs were marginally safer than VKA in normalBW subjects (RR 0.82, 95% CI 0.67, 1.00). However, the difference among DOACs and VKA in the rate of bleeding episodes appeared similar in the three BW groups. Conclusions. Results of our meta-analysis suggested that DOACs might be a safe and effective therapeutic option for the treatment of acute VTE even in the patients with extreme body weights. However, other studies with larger study populations are warranted to confirm our findings. Key words: Direct oral anticoagulants, obesity, venous thrombosis

Introduction In patients with venous thromboembolism (VTE), anticoagulation is mandatory to prevent thrombus extension and/or VTE recurrence, and low-molecular-weight heparin (LMWH) followed by oral anticoagulation with vitamin K antagonists (VKA) has been considered the gold standard of treatment until a few years ago (1). In recent years, new direct oral anticoagulants (DOACs) have been developed, including factor IIa (thrombin) and factor Xa (FXa) inhibitors, and a number of trials in patients

Key messages ••This is the first meta-analysis evaluating the impact of body weight on safety and efficacy of direct oral anticoagulants (DOACs) as compared with vitamin K antagonists (VKA) for the treatment of acute venous thromboembolism (VTE). ••The efficacy and safety of DOACs is comparable with that of VKA in different weight categories.

with acute VTE have shown a comparable efficacy in the prevention of VTE recurrence and a significantly lower bleeding risk for DOACs as compared to VKA (2). Among their potential advantages, DOACs include a wider therapeutic window at fixed dosing regimens and minimal and manageable food and drug interactions with no requirement for routine monitoring (3). Patients with extreme body weight are frequently encountered in clinical practice (4). Extremes of body weight (obesity or low body weight) may alter the exposure profile of an anticoagulant and its benefit/risk ratio (5). Obesity is associated with an increased risk of first and recurrent VTE (6–10), and low body weight is often associated with a higher risk of bleeding in patients treated for cardiovascular diseases (11). Laboratory studies on a small number of healthy subjects demonstrate that extremes of body weight have modest effects on DOAC exposure that are unlikely to be clinically meaningful (12,13). However, limited clinical information exists on the safety and efficacy of these new drugs in patients with extreme body weights, and there is no clinical study that specifically evaluated these populations. Thus, the aim of our meta-analysis was to evaluate the effect of extreme body weight (BW) on safety and efficacy of DOACs using data from randomized controlled trials (RCTs) that included patients treated for acute VTE.

Correspondence: Matteo Nicola Dario Di Minno, MD, Department of Clinical Medicine and Surgery, Federico II University, Via S. Pansini 5, 80131 Napoli, Italy. Fax:  39.081.7462060. E-mail: [email protected] (Received 21 May 2014; accepted 23 October 2014)

2 M. N. D. Di Minno et al.

Methods A protocol for this review was prospectively developed, detailing the specific objectives, the criteria for study selection, the approach to assess study quality, the outcomes, and the statistical methods.

Statistical analysis and risk of bias assessment

To identify all available studies, a detailed search of RCTs comparing DOACs to VKA in the treatment of acute VTE was conducted according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines (14). A systematic search was performed in major electronic databases (PubMed, Web of Science, Scopus, EMBASE), using the following search terms in all possible combinations: venous thrombosis, deep-vein thrombosis, pulmonary embolism, venous thromboembolism, NOACs, DOACs, new oral anticoagulants, new direct oral anticoagulants, rivaroxaban, dabigatran, apixaban, and edoxaban. The latest search was performed in May 2014. The search strategy was developed without any language restriction. In addition, the reference lists of all retrieved articles were manually reviewed. In case of missing data, study authors were contacted by e-mail to try to retrieve original data. Two authors (M.N.D.D.M. and R.L.) independently analyzed each article and performed the data extraction. In case of disagreement, a third investigator was consulted (F.D.). Discrepancies were resolved by consensus. Selection results have been reported according to the PRISMA flow chart (Supplementary Appendix 1, to be found online at http://informahealthcare.com/doi/abs/ 10.3109/07853890.2014.982064).

Statistical analysis was carried out using Review Manager (Version 5.2, The Cochrane Collaboration, Copenhagen, Denmark) provided by The Cochrane Collaboration. Differences among DOAC and VKA groups in the efficacy and safety outcomes were expressed as risk ratios (RR) with pertinent 95% confidence intervals (95% CI). The overall effect was tested using Z scores, and significance was set at P  0.05. Furthermore, meta-regression analysis was performed to evaluate the safety and efficacy of DOACs compared to warfarin according to different cut-off for low, normal, and high body weight used in original studies. Statistical heterogeneity between studies was assessed with chi-square, Cochran’s Q test, and with I2 statistic, which measures the inconsistency across study results and describes the proportion of total variation in study estimates that is due to heterogeneity rather than sampling error. In detail, I2 values of 0% indicate no heterogeneity, 25% low, 25%–50% moderate, and 50% high heterogeneity (16). Publication bias was represented graphically by funnel plots of the standard difference in means versus the standard error. Visual inspection of funnel plot asymmetry was performed to address possible small-study effects (17). In order to be as conservative as possible, the random-effect method was used to take into account the variability among included studies.

Data extraction and quality assessment

Subgroup analyses

According to the pre-specified protocol, all RCTs comparing DOACs with VKA in the treatment of patients with acute VTE were included. Case-reports, cross-sectional and observational studies, and reviews were excluded. To be included in the analysis, a study had to provide data on safety and/or efficacy outcome separately for different BW categories (low BW, normal BW, and high BW). Cut-offs to define BW categories have been decided based on data reported in included studies. Efficacy and safety data of DOACs versus VKA have been analyzed separately for different BW categories, and a separate analysis stratifying data based on BMI ( or  30 kg/m2) was also performed. The efficacy outcome was defined as the prevention of recurrent VTE or death related to VTE; the safety outcome was defined as the occurrence of major or clinically relevant non-major bleeding. In each study, data regarding sample size, major clinical and demographic variables, and data about efficacy outcome and safety outcome were extracted. The evaluation of methodological quality of each study was performed by two reviewers (M.N.D.D.M. and R.L.) using a validated scale (15) based on three major domains (methods used to generate the randomization sequence, method of double blinding, and description of patient withdrawals and dropouts). A score of 1 point was given for each criterion satisfied, and 1 additional point was given in the presence of appropriateness of randomization and double blinding methods used, with a resulting score ranging between 0 and 5, a higher score representing a higher methodological quality. In particular, studies with a score  2 were considered high quality, and studies with a score  2 were considered low quality.

We also planned to perform subgroup analyses of results according to the type of DOAC used (anti-FIIa or anti-FXa).

Search strategy


Results of the quality assessment are reported in Supplementary Appendix 2 (to be found online at http://informahealthcare. com/doi/abs/10.3109/07853890.2014.982064).

Results As reported in Supplementary Appendix 1, to be found online at http://informahealthcare.com/doi/abs/10.3109/07853890.2014. 982064 of the 842 retrieved studies, 828 were excluded because they were reviews, case-reports, or judged off the topic after scanning the title and/or the abstract. Other 8 studies were excluded after full-length paper evaluation. Thus, 6 randomized controlled trials (18–23) on a total of 27,023 patients (13,512 receiving DOACs and 13,511 VKA) with acute VTE were included in the analysis. Of them, 2 studies (18,19) evaluated dabigatran as experimental drug, 2 rivaroxaban (20,21), 1 edoxaban (22), and 1 apixaban (23).

Study characteristics The major characteristics of included studies are shown in Table I. In the RECOVER-II (19) study the stratification according to BW was provided in the frame of a pooled analysis that included data from the RECOVER-I study (18). Thus, these two studies have been analyzed as a unique data set. The number of patients varied from 3449 to 8240, the mean age from 54 to 58 years, the prevalence of male gender from 42% to 59%, and the treatment duration from 6 to 12 months. The cut-off to define high BW was 100 kg in 4 studies (18,19,22,23) and 90 kg in 2 (20,21). The cut-off for low BW was 50 kg in 2 studies (18,19), 60 kg in 2 studies (22,23), and 70 in 2 studies (20,21). Furthermore, a pooled analysis of the EINSTEINDVT and EINSTEIN-PE studies providing data of patients with body weight  50 kg has been recently published (24). Thus,

DOACs for VTE in extreme body weight patients 3 Table I. Characteristics of included studies. Study (ref.)

Drug

Dosage

RECOVER I & II Dabigatran 150 mg/BID (18,19) (anti-FIIa)

Duration 6 months

Study population

Age (mean) Males

DOAC group: 2553; VKA group: 2554

54 years

59%

EINSTEIN-DVT Rivaroxaban 15 mg/BID (3 wks) 12 months (20) (anti-FXa)  20 mg/OD


56 years

57%

EINSTEIN-PE (21)

Rivaroxaban 15 mg/BID (3 wks) 12 months (anti-FXa)  20 mg/OD


58 years

53%

HOKUSAI (22)

Edoxaban 60 mg/OD (anti-FXa)


56 years

57%

AMPLIFY (23)

Apixaban 10 mg/BID (7 days) 6 months (anti-FXa)  5 mg/BID


57 years

59%

12 months

Patients with high BW, n (%)

Patients with low BW, n (%)

DOAC group: 438 (17.1%); VKA group: 394 (15.4%) DOAC group: 491 (28.4%); VKA group: 486 (28.3%) DOAC group: 683 (28.2%); VKA group: 672 (27.8%) DOAC group: 611 (14.8%); VKA group: 654 (15.9%) DOAC group: 509 (18.9%); VKA group: 508 (18.8%)

DOAC group: 26 (1.0%); VKA group: 31(1.2%) DOAC group: 494 (28.5%); VKA group: 524(30.5%) DOAC group: 653 (27.0%); VKA group: 621(25.7%) DOAC group: 524 (12.7%); VKA group: 519(12.6%) DOAC group: 225 (8.4%); VKA group: 232(8.6%)


BID  twice daily; BW  body weight; DOAC  direct oral anticoagulant; OD  once daily; VKA  vitamin K antagonist; wks  weeks.

analyses regarding the low-body-weight groups were repeated using these data. The prevalence of high BW ranged from 15.3% to 28.3% and of low BW from 1.1% to 29.5%. Overall, a total of 5446 out of 27,023 enrolled patients (20.1%) had high BW, and 3849 (14.2%) had low BW at randomization. The prevalence of patients with high BW and of those with low BW was similar in DOACs and VKA groups (20.2% versus 20.1%, P  0.78 and 14.2% versus 14.3%, P  0.92). All the 6 studies (18–23) provided efficacy outcome data stratified according to BW, and 4 (20–23) also provided data on safety. The study quality assessment showed that all studies were of high quality (score  2) (Supplementary Appendix 2, to be found online at http://informahealthcare.com/doi/abs/10.3109/07853890.2014. 982064) and used methodologically adequate tools for the assessment of study outcomes (Supplementary Appendix 3, to be found online at http://informahealthcare.com/doi/abs/10.3109/ 07853890.2014.982064)

Body weight Efficacy outcome

All the 6 RCTs (18–23) provided data about the efficacy outcome (see Methods section) stratified according to BW. As shown in Figure 1, DOACs were comparable to VKA in the prevention of VTE recurrence/VTE-related death in patients with high BW (2.7% versus 2.8%, RR 0.98, 95% CI 0.72, 1.35, P  0.92; I2 0%, P  0.69), in those with normal BW (2.4% versus 2.6%, RR 0.91, 95% CI 0.75, 1.09, P  0.30; I2 0%, P  0.82), and in those with low BW (2.6% versus 3.11%, RR 0.84, 95% CI 0.57, 1.24, P  0.38; I2 4%, P  0.38). When we repeated the analysis using data derived from the pooled analysis of the two EINSTEIN studies (24) in which low BW is defined with a cut-off of 50 kg, we obtained similar results for this group (RR 0.82, 95% CI 0.49, 1.39, P  0.46).

Safety outcome

Four studies (20–23) reported data on the safety outcome (see Methods section) in 21,809 VTE patients: 4626 with high BW, 13,386 with normal BW, and 3797 with low BW (Figure 2). The rate of major or clinically relevant non-major bleeding was comparable among DOACs and VKA groups in patients with high BW (6.7% versus 7.1%, RR 0.93, 95% CI 0.65, 1.32, P  0.67; I2 54%, P  0.09) and low BW (8.4% versus 10.1%, RR 0.80, 95% CI 0.54, 1.20, P  0.29; I2 66%, P  0.03). DOACs appeared to be marginally significantly safer than VKA in those with normal BW

(6.5% versus 7.9%, RR 0.82, 95% CI 0.67, 1.00, P  0.05; I2 49%, P  0.12). The analysis performed using data from the pooled analysis of the two EINSTEIN studies (24) showed in the low BW group a significantly lower incidence of major or clinically relevant non-major bleeding events in patients randomized to DOACs compared to patients randomized to VKA (RR 0.54, 95% CI 0.33, 0.90, P  0.02).

Subgroup analyses

As shown in Table II, all the results regarding efficacy were confirmed when the data were stratified according to the type of DOAC (anti-FIIa or anti-FXa). Since all drugs included in the safety analysis were anti-FXa drugs (2 studies on rivaroxaban, 1 on edoxaban, and 1 on apixaban), no stratification for type of DOAC was possible. Considering that in the HOKUSAI trial an adjustment of DOAC dosage has been performed according to body weight, all the analyses have been repeated after excluding this study. All the results have been confirmed both for high BW and for low BW (data not shown).

BMI An attempt was made to stratify efficacy and safety data according to BMI. Interestingly, 4 studies reporting on 4973 patients with a BMI  30 kg/m2 and 10,144 with BMI  30 kg/m2 (18,19,21,23) consistently confirmed a comparable efficacy for DOACs and VKA both in obese subjects (RR 0.87, 95% CI 0.54, 1.40, P  0.57; I2 36%, P  0.21) and in those with a BMI  30 kg/m2 (RR 1.08, 95% CI 0.84, 1.41, P  0.54; I2 0%, P  0.87). However, only 1 study (23) provided data on safety stratified according to BMI. In that report, it was shown that apixaban was associated with a better safety profile both in patients with a BMI  30 (0.3% versus 2.1%, RR 0.15, 95% CI 0.04, 0.50, P  0.002; I2 NA) and in those with a BMI  30 (0.7% versus 1.7%, RR 0.42, 95% CI 0.21, 0.82, P  0.01; I2 NA).

Publication bias Funnel plots of effect size versus standard error for studies evaluating the association of BW with the efficacy of DOACs were quite symmetrical, suggesting the absence of publication bias and of small-study effect (Supplementary Appendix 4, to be found online at http://informahealthcare.com/doi/abs/10.3109/0785389 0.2014.982064). In contrast, given the low number of studies, no funnel plot assessment was possible to evaluate the publication bias for the safety outcome.


4 M. N. D. Di Minno et al.

Figure 1. Forest plot of the primary efficacy outcome (recurrent VTE or VTE-related death) of DOACs versus VKA in patients with high BW (Panel A), normal BW (Panel B), and low BW (Panel C).

Meta-regression analysis To assess further the impact of BW on efficacy and safety of DOACs, a meta-regression analysis was performed which showed that BW did not affect the efficacy (P  0.83) and safety (P  0.27) of DOACs as compared to VKA in the treatment of acute VTE (Figure 3).

Discussion The present meta-analysis is the first, to our best knowledge, evaluating the safety and efficacy of DOACs as compared with VKA for the treatment of acute VTE in patients with different weights. Our results suggest a comparable efficacy of DOACs compared to VKA in obese, normal-weight, and low-body-weight patients. Moreover, the incidence of VTE recurrence and of VTE-related death appeared similar in the two treatment groups also when patients were categorized according to different BMI and to different classes of DOACs (anti-FIIa and anti-FXa). Furthermore, since the raw weight may not be an adequate surrogate of person’s actual status, we repeated the analyses using

data on BMI, obtaining similar results and confirming the findings of the principal analysis. However, results of this secondary analysis should be interpreted with caution since data on this parameter were not available for all the included studies. Interestingly, the risk of major and of clinically relevant nonmajor bleeding appeared marginally significantly lower in patients treated with DOACs in normal-weight patients, whereas DOACs did not appear to reduce significantly the incidence of these complications in low-body-weight and obese patients. However, the level of reduction of major and clinically relevant non-major bleeding complications in comparison to VKA appeared similar, and different results, in terms of statistical significance, may be due to the different sample of the three groups of patients. Thus, in summary, the pooled results of the six major RCTs evaluating DOACs in acute VTE did not seem to find important clinical differences in the safety and efficacy of these compounds according to different body weights. Several studies suggest a higher risk of VTE in obese patients, and these patients may be exposed to an increased risk of VTE recurrence if not adequately treated. An increasing body fat mass, especially abdominal fat, might limit venous return, leading to a


DOACs for VTE in extreme body weight patients 5

Figure 2. Forest plot of the primary safety outcome (major or clinically relevant non-major bleeding) of DOACs versus VKA in patients with high BW (Panel A), normal BW (Panel B), and low BW (Panel C).

persistently raised intra-abdominal pressure and venous stasis in the femoral veins. Moreover, inactivity and poor gait may contribute to this phenomenon (25). In addition to these mechanical events, a series of molecular mechanisms appear to be responsible for the obesity-related hypercoagulable state. Obesity is associated with a hyper-expression of tumor necrosis factor-a (TNF-a) and transforming growth factor-b (TGF-b), which leads to a chronic pro-inflammatory state (26) and to an impaired endothelial function (27). Moreover, obesity might cause an increased expression of clotting factors and impaired fibrinolysis (28). BMI and waistto-hip ratio have been shown to correlate positively with levels of factor VII, factor VIIIc, and fibrinogen (29), as well as von

Willebrand factor (30), and obese subjects exhibited an increased expression of plasminogen activator inhibitor-1 (PAI-1). Furthermore, visceral adipose tissue is metabolically active and may overproduce some adipokines such as leptin, which may induce platelet aggregation and an overtranslation of PAI-1 (31,32). Two previous laboratory studies have evaluated the effect of extreme body weights on the pharmacokinetics, pharmacodynamics, safety, and tolerability of apixaban and rivaroxaban in healthy subjects (12,13). In the first of these studies, healthy female subjects weighing 50 kg, 70–80 kg, or  120 kg were given a single 10 mg dose of rivaroxaban. In this population, the Cmax was unaffected in subjects weighing  120 kg, but

Table II. Risk ratio (RR) of recurrent VTE or death related to VTE in patients with or without a body weight  100 kg receiving direct oral anticoagulants or vitamin K antagonists stratified according to the type of drug. High BW Type of drug Anti-FIIa (dabigatran) Anti-FXa (rivaroxaban, apixaban and edoxaban)

Studies, n 2 4

Population

Normal BW RR (95% CI)

DOAC group: 438; 1.16 (0.58, 2.29) VKA group: 394 DOAC group: 2294; 0.94 (0.66, 1.35) VKA group: 2320

Studies, n 2 4

Population

Low BW RR (95% CI)


BW  body weight; DOAC  direct oral anticoagulant; VKA  vitamin K antagonist.

Studies, n 2 4

Population

RR (95% CI)


6 M. N. D. Di Minno et al. Regression of BW on MH log odds ratio

(A) 0.60 0.44

MH log odds ratio

0.28 0.12 –0.04 –0.20 –0.36 –0.52 –0.68 –0.84 –1.00 45,00

51,00

57,00

63,00

69,00

75,00

81,00

87,00

93,00

99,00

105,00

94,40

99,20

104,00

Regression of BW on Log odds ratio

(B) 0.40 0.06 –0.28 –0.62 Log odds ratio


BW

–0.96 –1.30 –1.64 –1.98 –2.32 –2.66 –3.00 56,00

60,80

65,60

70,40

75,20

80,00

84,80

89,60

BW

Figure 3. Meta-regression of the effect of body weight (BW) on efficacy (Panel A) and safety (Panel B) of DOACs versus VKA in the treatment of venous thromboembolism.

was marginally increased in those weighing 50 kg, compared with those of normal weight. This resulted in a small, not clinically relevant, increase in the pharmacodynamics effect, and the area under the plasma concentration–time curve (AUC) was not significantly affected by body weight (12). In the second study, 54 healthy subjects were enrolled, 18 for the each of the following groups: low ( 50 kg), reference (65–85 kg), and high ( 120 kg) body weight (13). A single dose of apixaban 10 mg was administered. Patients with low body weight had approximately 27% and 20% higher maximum plasma concentration (Cmax) and AUC, respectively, and patients with high body weight had approximately 31% and 23% lower Cmax and AUC, respectively. The renal clearance of apixaban was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Thus, body weight seems to have limited influence on the pharmacokinetics of these new compounds, and DOACs appeared to have a similar efficacy and safety, in comparison to VKA, among different body weight groups. Thus, the results of the present meta-analysis have some relevant clinical implications, since they suggest the reliability of a standard therapeutic approach with DOACs, with a fixed dose for patients with different body weights. This may overcome some potential limitations of traditional antithrombotic therapies: retrospective data suggest

that obese patients require significantly higher doses of warfarin and longer times to achieve a therapeutic International Normalized Ratios (INR) compared to non-obese patients (33), and there is also uncertainty about the adequate dose of LMWH in obese and low-weight patients. Our study has some potential limitations. First, we performed a meta-analysis of aggregate data, and differences in the baseline characteristics in patients treated with VKA and DOACs could not be definitively excluded since patients were not randomized according to different body weights. Second, definition of low body weight is highly variable among the studies and is defined as a body weight of  70 kg in two EINSTEIN studies (20,21). However, when we repeated the analyses using data derived from the recent pooled analysis of the two EINSTEIN studies (24) in which low BW is defined with a cut-off of 50 kg, results on the efficacy outcome were entirely confirmed, whereas a better safety profile was found for DOACs compared to VKA in this group of patients. Nevertheless, the sample of patients with a BW of  50 kg reported in the two EINSTEIN studies and in the AMPLIFY study was very limited, and results of this analysis were driven by the results of the HOKUSAI study (22). Thus, evidence on the safety and efficacy of these new compounds in patients with very low body weight ( 50 kg) remains very limited. Third, the original studies on direct thrombin inhibitors did not provide separate data for major and clinically relevant non-


DOACs for VTE in extreme body weight patients 7 major bleedings according to different body weights. Therefore, we have no further information on the safety of this class of drugs in obese and low-body-weight patients. Furthermore, heterogeneity among the studies for this end-point is not negligible. Thus, although we pooled the results of single studies using a random effect model, an approach that takes into consideration potential heterogeneity among the studies, results of this study should be interpreted with extreme caution. Last, due to limitations of study-level meta-analyses we were not able to adjust our results for potential confounders (e.g. cancer, older age, ethnicity). However, since only large randomized trials were included, it is extremely unlikely that differences in the two groups (DOACs and VKAs) would affect the validity of our results (34). In conclusion, the present meta-analysis of RCTs suggests that DOACs are a safe and effective therapeutic option for the treatment of acute VTE even in the patients with extreme body weights. However, other studies specifically including these populations are warranted to confirm our findings.

Acknowledgements Matteo Nicola Dario Di Minno conceived and designed the study, performed the analysis, interpreted results, and drafted the manuscript; Roberta Lupoli performed literature search, data extraction, and manuscript drafting; Pasquale Ambrosino, Antonella Scalera, and Alessandro Di Minno performed literature revision and acquired data. Francesco Dentali drafted the manuscript and performed critical revisions to the study. All authors read and approved the final version of the manuscript. Funding: No funds were received for this study. Declaration of interest: Dr Matteo Nicola Dario Di Minno and Dr Francesco Dentali received grants and honoraria for researches unrelated to the present studies. All the other authors have nothing to declare.

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Supplementary material available online Supplementary Appendix 1: PRISMA flow diagram. Supplementary Appendix 2: Quality of studies assessment according to Jadad scale for randomized controlled trials. Supplementary Appendix 3: Additional characteristics of included studies. Supplementary Appendix 4: Funnel plots of effect size versus standard error for studies evaluating the effect of high BW (Panel A), normal BW (Panel B), and low BW (Panel C) on the efficacy of DOACs.

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