1

TITLE PAGE

Full title:

Direct oral anticoagulants compared with vitamin K antagonists for acute symptomatic

venous thromboembolism: evidence from phase 3 trials

Running title:

DOACs versus VKAs for treatment of acute VTE

Authors:

Nick van Es, MD1

Michiel Coppens, MD PhD1

Sam Schulman, MD PhD2

Saskia Middeldorp, MD PhD1

Harry R. Büller, MD PhD1

1 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

2 Department of Medicine, McMaster University and Thrombosis and Atherosclerosis

Research Institute, Hamilton, ON, Canada

Correspondence to:

Nick van Es

Academic Medical Center

Department of Vascular Medicine

Room F4-139

Meibergdreef 9

1105 AZ Amsterdam

2

The Netherlands

E-mail: n.vanes@amc.nl

Telephone: +31 20 56 66023

Fax: +31 20 566 9343

Word count (abstract): 191

Word count (main body of text): 2,863

Table count: 1

Figure count: 5

Reference count: 15

Primary scientific category: Thrombosis and Hemostasis

Secondary scientific category: Clinical Trials and Observations

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KEY POINTS

DOACs have similar efficacy as VKAs in the treatment of acute symptomatic VTE, but

significantly reduce the risk of major bleeding.

The efficacy and safety of DOACs in the treatment of acute VTE are consistent in

clinically important subgroups.

ABSTRACT

In the last four years, six phase 3 trials including a total of 27,023 patients with venous

thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K

antagonists (VKAs). To aid the clinician in assessing the amount of information, we address

frequently raised clinical questions in a review of combined trial results. We included the

phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with

VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of

DOAC recipients compared with 2.2% in VKA recipients (RR 0.90, 95%-CI 0.77-1.06).

Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95%-CI

0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor

bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs

were consistent in patients with pulmonary embolism, deep venous thrombosis, body weight

≥ 100 kg, moderate renal insufficiency, age ≥ 75 years, and cancer. In conclusion, DOACs

and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is

consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of

major bleeding.

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INTRODUCTION

The treatment of venous thromboembolism (VTE) traditionally consists of initial

unfractionated or low-molecular-weight heparin (LMWH) followed by vitamin K antagonists

(VKAs) for at least 3 months. Recently, oral factor Xa and IIa (thrombin) inhibitors,

collectively termed direct oral anticoagulants (DOACs), have proven to be an effective and

safe alternative. DOACs offer significant simplification of long-term anticoagulation as these

drugs, unlike VKAs, do not require frequent laboratory monitoring and subsequent dose

adjustments. Between 2009 and 2013, four different compounds were compared with

conventional therapy for the treatment of acute VTE. In total, 27,023 patients were enrolled in

six phase 3 randomized controlled trials.1–6 Rivaroxaban has been approved for VTE

treatment in most countries and approval for apixaban, dabigatran etexilate (hereafter:

dabigatran), and edoxaban is expected soon.

Clinicians will have to choose between these new anticoagulants and standard

treatment, and need clinically relevant information whether these agents are indeed suited

for all their patients with VTE. To aid the clinician in dealing with the overwhelming amount of

information, we here present a review of the combined results of the phase 3 trials and

address various frequently raised clinical questions:

(i) What is the overall efficacy of DOACs compared with VKAs on recurrent VTE?

(ii) What is the safety profile of DOACs compared with VKAs in terms of major bleeding,

intracranial bleeding, major gastrointestinal bleeding, and clinically relevant nonmajor

(CRNM) bleeding?

(iii) What is the efficacy and safety of DOACs compared with VKAs in specific subgroups, i.e.

patients with pulmonary embolism (PE), patients with deep venous thrombosis (DVT),

patients with cancer, elderly patients, obese patients, and patients with impaired renal

function?

(iv) What is the net clinical benefit in terms of patient-relevant outcomes (i.e. prevention of

recurrence with minimal risk of major bleeding) of DOACs compared with VKAs?

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METHODS

STUDY SELECTION AND DATA COLLECTION

We performed a meta-analysis of phase 3 randomized controlled trials comparing

DOACs with VKAs for treatment of acute symptomatic DVT, PE, or both. Six studies were

included, evaluating the direct thrombin inhibitor dabigatran (RE-COVER and RE-COVER II

studies 1,2), and the factor Xa inhibitors rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE

studies 5,6), apixaban (AMPLIFY study 4), and edoxaban (Hokusai-VTE study 3). Phase 2

dose-finding studies and studies evaluating extended anticoagulant treatment after the initial

treatment period were excluded. Studies on the thrombin inhibitor ximelagatran were also

excluded because this agent is unavailable for patient use.

Two authors (NvE and MC) independently extracted information about the following

outcomes from the main trial publications and supplemental data: symptomatic recurrent

VTE or VTE-related death, major bleeding, intracranial bleeding, fatal bleeding, major

gastrointestinal bleeding, CRNM bleeding, all-cause mortality, and net clinical benefit defined

as the composite of first occurrence of symptomatic recurrent VTE, VTE-related death, or

major bleeding. The definitions of recurrent VTE and bleeding were similar across all

included studies and in accordance with the criteria proposed by the International Society on

Thrombosis and Haemostasis.7 Therein, major bleeding was defined as fatal bleeding,

bleeding in a critical area or organ, or bleeding causing a fall in haemoglobin of 2 mg/dL (or

1.24 mmol/L). CRNM bleeding was defined as overt bleeding not meeting the criteria for

major bleeding, but associated with a medical intervention, an unscheduled contact with a

physician, (temporary) cessation of study treatment, or associated with discomfort for the

patient such as pain, or impairment of activities of daily life.

We performed additional analyses for subgroups of patients with symptomatic PE with

or without concomitant DVT, DVT of the leg only, cancer at baseline, age ≥ 75 years,

creatinine clearance of 30-49 ml/min, and body weight ≥ 100 kg. Furthermore, we performed

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a sensitivity analysis of studies evaluating a factor Xa inhibitor only, i.e. AMPLIFY,

EINSTEIN-DVT, EINSTEIN-PE, and Hokusai-VTE.

When data could not be retrieved from the trial publications, we approached the

corresponding authors and sponsors for additional information.

STATISTICAL ANALYSIS

Analyses were performed with data as provided by the trial publications in which the

intention-to-treat population was used for efficacy outcomes and the safety population for

bleeding outcomes. We calculated relative risks (RRs) and corresponding 95% confidence

intervals (CI) for each outcome. Outcomes across the studies were combined using the

Mantel-Haenszel method and compared with the DerSimonian and Laird random-effects

model. We assessed and quantified statistical heterogeneity across the studies using the

Cochran Q statistic and I2 test. All analyses were performed with Review Manager version

5.2 (Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012).

RESULTS

CHARACTERISTICS

Overall, 13,512 patients were randomized to a DOAC and 13,511 patients to a VKA with

a target INR of 2.0-3.0. Patient characteristics and study details are shown in the Table. The

overall mean age was 56 years and 57% were men. Risk factors for recurrent VTE were

evenly distributed. The index event was DVT of the leg in 57% of patients and PE with or

without concomitant DVT in 43%. The majority of patients (72%) received anticoagulant

treatment for 6 months. The overall time in the therapeutic INR range (TTR) in patients on

VKAs ranged from 57% to 64% in the studies. Patients and physicians were blinded for

treatment allocation, except for both EINSTEIN studies which had an open-label design. All

suspected outcomes were adjudicated by the same blinded independent central adjudication

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committee in all studies. In the RE-COVER, RE-COVER II and Hokusai-VTE studies,

dabigatran and edoxaban were started after an initial course of parenteral anticoagulants for

a minimum of 5 days. Rivaroxaban (EINSTEIN studies) and apixaban (AMPLIFY) were given

as monotherapy during the entire treatment period with a higher dose in the first one to three

weeks. In EINSTEIN-DVT, EINSTEIN-PE, and Hokusai-VTE patients were treated for three,

six, or twelve months as determined by the treating physician, whereas the treatment

duration was six months in the other studies (Table).

OVERALL EFFICACY

In total, 26,872 patients were included in the efficacy analysis. Recurrent VTE, including

VTE-related death, occurred in 271 of 13,430 (2.0%) patients randomized to a DOAC versus

301 of 13,442 (2.2%) patients randomized to a VKA (RR 0.90, 95% CI 0.77-1.06; Figure 1).

This is in line with the findings of the individual studies in which DOACs were consistently

shown to be non-inferior to VKAs. There was no evidence for heterogeneity (I2=0%).

OVERALL BLEEDING

In total, 26,958 patients were included in the safety analysis. Treatment with a DOAC

was associated with a 39% relative reduction in major bleeding (RR 0.61, 95% CI 0.45-0.83;

Figure 2). In parallel, intracranial bleeding and fatal bleeding occurred significantly less in

patients in the DOAC group (RR 0.37 [95% CI 0.21-0.68] and 0.36 [95% CI 0.15-0.84],

respectively; Figure 3). In this VTE setting, DOACs were associated with a 22% non-

significant relative reduction in major gastrointestinal bleeding (RR 0.78, 95% CI 0.47-1.31),

and a relative reduction of 27% in CRNM bleeding (RR 0.73, 95% CI 0.58-0.93; Figure 3).

Heterogeneity was substantial in the analyses of major bleeding, major gastrointestinal

bleeding, and CRNM bleeding (I2=51-85%). Forest plots with individual study data are

provided in the supplemental data.

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PATIENT-RELEVANT OUTCOMES

Net clinical benefit, defined as the composite of a first episode of a patient-relevant

outcome, i.e. recurrent VTE, VTE-related death, or major bleeding, occurred in 424 of 13,430

(3.2%) DOAC recipients and in 537 of 13,442 (4.0%) patients treated with VKAs (RR 0.79,

95% CI 0.70-0.90). The all-cause mortality rate was similar in both groups (RR 0.98, 95% CI

0.84-1.14). There was no evidence for heterogeneity in the patient-relevant outcome

analyses (I2=0%).

SUBGROUPS

The efficacy of DOACs was consistent across the subgroups of patients with PE,

patients with DVT only, patients with a body weight ≥ 100 kg, and patients with a moderately

impaired renal function (creatinine clearance 30-49 ml/min) (Figure 4A). In elderly patients

(age ≥ 75 years) and patients with cancer, we observed significantly less recurrent VTE in

the DOAC group than in the VKA group (RR 0.56 [95% CI 0.38-0.82] and RR 0.57 [95% CI

0.36-0.91], respectively; Figure 4A).

The significant reduction in major bleeding associated with DOAC treatment was

maintained in patients with a creatinine clearance 30-49 ml/min and in patients aged 75 or

over (RR 0.51 [95% CI 0.26-0.99] and RR 0.49 [95% CI 0.25-0.96], respectively; Figure 4B).

In cancer patients, we observed no difference in the risk of major bleeding (RR 0.77, 95% CI

0.44-1.33; Figure 4B). The absolute major bleeding rate in the DOAC and VKA groups was

considerable in patients with impaired renal function, elderly patients, and cancer patients,

indicating a higher bleeding risk in these subgroups. There was no evidence for

heterogeneity in the subgroup analyses for efficacy (I2=0%). For major bleeding,

heterogeneity was substantial in the subgroup analysis of elderly patients (I2=60%). Forest

plots with individual study data are provided in the supplemental data.

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FACTOR XA-INHIBITORS ONLY

In the sensitivity analysis of the four studies evaluating a factor Xa inhibitor, factor Xa

inhibitors were as effective as VKAs in the prevention of recurrent VTE with a significant

relative reduction of 44% in major bleeding (RR 0.56, 95% CI 0.36-0.88; Figure 5). Point

estimates for intracranial bleeding, major gastrointestinal bleeding, fatal bleeding, CRNM

bleeding, net clinical benefit, and all-cause mortality were comparable to the overall analysis,

although the benefit in CRNM bleeding did not reach statistical significance.

DISCUSSION

The present clinical review of all phase 3 trials reveals that DOACs are clearly non-

inferior to VKA therapy with respect to overall efficacy in the treatment of acute symptomatic

VTE. This effect is consistent in patients with PE, DVT, body weight ≥ 100 kg, and moderate

renal insufficiency. An interesting observation is a possibly better efficacy of DOACs versus

VKAs in elderly patients and cancer patients. It should be realized that the regimen of LMWH

followed by VKAs is very effective with a relative reduction in recurrent VTE of 80% to 90%

compared to no or inadequate treatment.8,9 As a consequence all phase 3 trials were

designed as non-inferior studies for efficacy. Taken together, the observed comparable

efficacy of DOACs should reassure the clinician that these agents are effective in all

subgroups analysed.

The most striking finding is the significant almost 40% relative reduction in major

bleeding. Consistent with this observation are the reductions in important components of

major bleeding, such as fatal bleeding (64% relative reduction) and intracranial bleeding

(63% relative reduction). Although rare they are the most feared complications of

anticoagulant treatment. In line with these reductions, DOAC recipients have significantly

less CRNM bleeding, and there are no indications that the risk of major gastrointestinal

bleeding is increased in this setting of VTE. The benefit of DOACs with respect to major

bleeding was maintained in patients with moderate renal insufficiency and elderly patients,

10

whereas in cancer patients the risk of major bleeding was add least comparable to that in the

standard treatment group and possibly better. Taken together, our results indicate that

DOACs can be prescribed safely to patients with VTE.

Our findings with respect to major bleeding are very similar to the results seen in the

atrial fibrillation (AF) trials where DOACs reduced intracranial haemorrhage by a significant

52% compared to VKAs.10 In contrast, DOACs were associated with a significant 25%

relative increase in major gastrointestinal bleeding in the AF trials whereas, in the treatment

of VTE no difference in major gastrointestinal bleeding rates was seen.10 The reasons for this

discrepancy are at present unclear, but may include differences in patient characteristics

(e.g. use of concomitant antiplatelet drugs) and treatment duration.

The above discussed conclusions are strengthened by the superiority of DOACs with

respect to the composite measurement of patient-relevant outcomes, i.e. recurrent VTE,

VTE-related death, and major bleeding. Based on the sensitivity analysis of factor Xa

inhibitors and the previously published pooled analysis of the thrombin inhibitor dabigatran,

efficacy and safety are maintained across the two drug classes.2

Other meta-analyses of acute VTE trials have been published previously.11,12

Although the overall conclusions are similar, the present analysis include all phase 3 data

and, additionally, provides the treating physician with important safety and efficacy

information for clinically relevant and frequently encountered subgroups. Furthermore, as a

result of the larger number of patients included, the point estimates and the confidence

intervals are more robust both for conclusions regarding non-inferiority and superiority.

Our study has potential limitations. By combining results of six trials, we presume that

all DOACs are the same, which they are not. We have pooled data of four different

compounds, and the included studies were different in follow-up durations and treatment

regimens. Three studies used initial heparin, but the need for this, particularly in clinically

significant thrombosis, remains to be determined. Nevertheless, most combined results were

quite homogeneous, hence it seems that the similarities between these compounds are

larger than the differences. This is further supported by the results of the analyses of factor

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Xa inhibitors only. Of note, the observed heterogeneity for major, major gastrointestinal, and

CRNM bleeding was statistically significant across the studies at an alpha level of 0.10.

Potential explanations, apart from differences between drugs, include variability in patient

characteristics and study design.

Treatment with a DOAC has clear practical advantages over treatment with a VKA.

Frequent treatment monitoring and individualized dose adjustments, as is usual in VKA

treatment, are no longer required. Moreover, apixaban and rivaroxaban can be given as oral

monotherapy without the need for cumbersome daily injections with LMWH or continuous

infusion of unfractionated heparin during the initial phase. A potential downside is that patient

adherence to DOACs may be worse than to VKAs due to the absence of regular contact with

anticoagulation clinics. Occasionally missing a dose may lead to subtherapeutic drug levels

more quickly due to the shorter half-life of DOACs. Nevertheless, it is impossible to predict

how this will affect the relative efficacy and safety of DOACs versus VKAs in the real world,

as the quality of INR control of VKA therapy is also lower in real world patients compared

with patients enrolled in randomized trials.13 Other concerns include the lack of a specific

reversal agent for DOACs and the lack of DOAC specific laboratory assays in most hospitals,

complicating the management of DOAC-related bleeding episodes. This has to be balanced

against the significant numerical reduction in major and CRNM bleeding associated with

treatment with DOACs. Furthermore, emerging evidence suggests that major bleeding on

DOACs tends to have a less severe presentation and take a less severe clinical course than

VKA-related bleeding.14

The uptake of DOACs for treatment of acute VTE in clinical practice will also depend

on regulatory and reimbursement approval. Some have raised concerns that relatively high

numbers needed to treat will not justify more costly drugs for a relatively short duration.12

However, this is not in line with the recent analyses of the financial consequences of VTE

treatment with rivaroxaban presented by the British National Institute for Health Care and

Excellence (NICE).15,16 They conclude that rivaroxaban represents a clinical and cost-

effective option for treatment of DVT or PE for all treatment durations, and even dominates

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LMWH and VKA therapy in the 3-month treatment group. It is likely that with the more robust

findings in efficacy and safety in the present analysis the cost-effectiveness conclusions will

be reinforced for this group of drugs.

Now that the clinical development programs of all DOACs for the treatment of acute

VTE have been completed, several relevant questions are left unanswered. Post-marketing

registries will need to assess whether the favorable trial results also apply to “real-world”

patients that have more co-morbidities, more co-medication, and are less adherent than a

standard trial population. Patients with severe renal impairment (creatinine clearance less

than 30 ml/min) were excluded from the trials, hence the results do not apply to this group of

patients. Furthermore, the optimal therapy of VTE in cancer patients is uncertain. LMWH

monotherapy is suggested over VKAs according to current clinical guidelines because of a

better efficacy.8 DOACs could become an attractive alternative to daily LMWH injections for

patients with active cancer, who frequently require indefinite anticoagulant treatment.

However, it should be realized that patients with a life expectancy of less than the duration of

the trial were excluded from the DOAC trials, as were patients for whom long-term treatment

with LMWH was anticipated. Still, our results in the subgroup of cancer patients indicate a

possibly better efficacy of DOACs over VKAs without increasing the risk of major bleeding,

which is in line with the findings of trials comparing LMWH with VKAs. Direct comparisons of

DOACs versus LMWH in randomized controlled trials are urgently needed to address the

efficacy and safety of DOACs in cancer patients.

In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute

symptomatic deep venous thrombosis and pulmonary embolism, a finding that is consistent

in key clinical subgroups. Treatment with a DOAC is associated with a significant reduction in

the risk of major bleeding, intracranial bleeding, fatal, and clinically relevant nonmajor

bleeding.

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AUTHORSHIP CONTRIBUTIONS

All authors made a substantial contribution to the concept and design of the study,

interpreted the data, and reviewed the manuscript. N. van Es and M. Coppens performed the

data extraction. N. van Es performed the analyses. N. van Es and M. Coppens drafted the

paper. S. Schulman, S. Middeldorp and H.R. Büller critically revised the paper for important

intellectual content.

DISCLOSURE OF CONFLICTS OF INTEREST:

There was no funding source for this study. Nick van Es declares that he has no conflicts of

interest. Michiel Coppens has received research support, lecturing and consultancy fees for

Boehringer Ingelheim, Bayer, Daiichi-Sankyo and Bristol-Myers Squibb. Sam Schulman has

received honoraria from Boehringer Ingelheim. Saskia Middeldorp has received consulting

fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and

Daiichi-Sankyo and research support from Bayer, Bristol-Meyers Squibb/Pfizer,

GlaxoSmithKline, and Sanquin. Harry Büller has received consulting fees and research

support from Bayer, Bristol-Meyers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Isis, Pfizer,

Roche, Sanofi-Aventis, and ThromboGenics.

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Suppl):e419S–94S.

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new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis

of randomised trials. Lancet. 2014;383(9921):955–62.

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15. National Institute for Health and Care Excellence. Rivaroxaban for the treatment of

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16. National Institute for Health and Care Excellence. Rivaroxaban for treating pulmonary

embolism and preventing recurrent venous thromboembolism. TA287. London:

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TABLE: STUDY DETAILS AND BASELINE PATIENT CHARACTERISTICS

Hokusai-VTE RE-COVER RE-COVER II AMPLIFY EINSTEIN-DVT EINSTEIN-PE Combined

edoxaban

(n=4118)

VKA

(n=4122)

dabigatran

(n=1273)

VKA

(n=1266)

dabigatran

(n=1280)

VKA

(n=1288)

apixaban

(n=2691)

VKA

(n=2704)

rivaroxaban

(n=1731)

VKA

(n=1718)

rivaroxaban

(n=2419)

VKA

(n=2413)

DOAC

(n=13512)

VKA

(n=13511)

Treatment duration 3, 6 or 12 months¶ 6 months 6 months 6 months 3, 6 or 12 months¶ 3, 6 or 12 months¶ - -

Design Double blinded Double blinded Double blinded Double blinded Open-label Open-label - -

Treatment regimen - -

Initial treatment LWMH or UFH

for ≥ 5 days

LWMH or UFH

for ≥ 5 days

LWMH or UFH

for ≥ 5 days

apixaban

10 mg bid

for 7 days

LMWH† or UFH

for ≥ 5 days

rivaroxaban

15 mg bid

for 3 weeks

LMWH†

for ≥ 5 days

rivaroxaban

15 mg bid

for 3 weeks

LMWH†

for ≥ 5 days

- -

Long-term

treatment

edoxaban

60mg od*

warfarin

(INR 2-3)

dabigatran

150 mg bid

warfarin

(INR 2-3)

dabigatran

150 mg bid

warfarin

(INR 2-3)

apixaban

5 mg bid

warfarin

(INR 2-3)

rivaroxaban

20 mg od

any VKA

(INR 2-3)

rivaroxaban

20 mg od

any VKA

(INR 2-3)

- -

Mean age (years) 55.7 55.9 55.0 54.4 54.7 55.1 57.2 56.7 55.8 56.4 57.9 57.5 56.2 56.2

Men 57% 57% 58% 59% 61% 60% 58% 59% 57% 56% 54% 52% 7750 (57%) 7690 (57%)

Index event

DVT only 60% 60% 69% 69% 69% 68% 65% 66% 99% 99% 0% 0% 7682 (57%) 7675 (57%)

PE ± DVT 40% 40% 31% 31% 31% 32% 35% 34% 0% 0% 100% 100% 5792 (43%) 5797 (43%)

Risk factors

Unprovoked 66% 65% NR NR NR NR 90% 90% 61% 63% 65% 64% 7750 (71%) 7760 (71%)

Malignancy

(at baseline)

9% 10% 5% 5% 4% 4% 2% 3% 7% 5% 5% 5% 790 (6%) 775 (6%)

Previous VTE 19% 18% 26% 25% 19% 16% 17% 15% 19% 19% 19% 20% 2612 (19%) 2489 (18%)

TTR in VKA group - 64% - 60% - 57% - 60% - 58% - 63% - -

Intended treatment duration

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3 months 12% 13% 0% 0% 0% 0% 0% 0% 12% 12% 5% 5% 820 (6%) 853 (9%)

6 months 48% 47% 100% 100% 100% 100% 100% 100% 63% 63% 57% 57% 9686 (72%) 9663 (72%)

12 months 40% 40% 0% 0% 0% 0% 0% 0% 25% 25% 37% 37% 3006 (22%) 2995 (22%)

VKA: vitamin K antagonist; DOAC: direct oral anticoagulant; LMWH: low-molecular-weight-heparin; UFH: unfractionated heparin; od: once daily;

bid: twice daily; INR: international normalized ratio; DVT: deep venous thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism;

TTR: time in therapeutic range.

¶ treatment duration was left to the discretion of the physician

† enoxaparin 1mg/kg bid

* An edoxaban dose of 30 mg once daily was administered to patients with a creatinine clearance of 30 to 50 mL/min, a body weight of 60 kg or

less, and in those receiving concomitant treatment with potent P-glycoprotein inhibitors.

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FIGURES

Figure 1: First recurrent VTE or VTE-related death

VTE: venous thromboembolism; DOAC: direct oral anticoagulant; VKAs: vitamin K antagonist.

For Hokusai-VTE, we used event data for the on-treatment period.

Heterogeneity: I2 = 0%; P = 0.53.

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Figure 2: Major bleeding

DOAC: direct oral anticoagulant; VKA: vitamin K antagonist; RR: risk ratio; CI: confidence interval; ARR: absolute risk reduction.

The sums of numbers of events from RE-COVER and RE-COVER II with respect to major bleeding slightly differ from those in the pooled

analysis. We used data from the pooled analysis as these were most accurate.

Heterogeneity: I2 51%, P = 0.07.

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Figure 3: Intracranial, major gastrointestinal, fatal, and clinically relevant nonmajor bleeding

DOAC: direct anticoagulant; VKA: vitamin K antagonist; GI: gastrointestinal; CRNM: clinically relevant nonmajor; RR: relative risk; CI:

confidence interval; ARR: absolute risk reduction.

Intracranial bleeding numbers comprise fatal and non-fatal events. Since CRNM bleeding was not a predefined outcome on its own in both RE-

COVER studies, we obtained these numbers by subtracting major bleeding numbers from the composite of major and CRNM bleeding.

Heterogeneity: intracranial bleeding I2 0%, P = 0.66; major GI bleeding I2 51%, P = 0.07; fatal bleeding I2 0%, P = 0.86; CRNM bleeding I2 85%,

P < 0.00001.

22

Figure 4A: First recurrent VTE or VTE-related death in specific subgroups

VTE: venous thromboembolism; DOAC: direct oral anticoagulant; VKA: vitamin K antagonist; RR: relative risk; CI: confidence interval; PE:

pulmonary embolism; DVT: deep venous thrombosis.

23

For Hokusai-VTE, we used event data for the overall study period.3 The group of patients with impaired renal function includes 28 DOAC

recipients and 32 VKA recipients with a creatinine clearance < 30 ml/min (protocol violations).

Heterogeneity: patients with index PE I2 0%, P = 0.65; patients with index DVT I2 0%, P = 0.41; patients with body weight < 100 kg I2 3%, P =

0.40; patients with body weight ≥ 100 kg I2 0%, P = 0.71; patients with creatinine clearance 30-49 ml/min I2 0%, P = 0.61; patients with

creatinine clearance ≥ 50 ml/min I2 0%, P = 0.59; patients < 75 years I2 0%, P = 0.71; patients ≥ 75 years I2 0%, P = 0.95; patients without

cancer I2 0%, P = 0.57; patients with cancer I2 0%, P = 0.99.

24

Figure 4B: Major bleeding in specific subgroups

VTE: venous thromboembolism; DOAC: direct oral anticoagulant; VKA: vitamin K antagonist; RR: relative risk; CI: confidence interval.

For the subgroup analyses of patients > 75 years and patients with a creatinine clearance of 30-49 ml/min we used the pooled RE-COVER data

from the double-dummy period only. For Hokusai-VTE, we used event data for the overall study period.3 The group of patients with impaired

renal function includes 28 DOAC recipients and 32 VKA recipients with a creatinine clearance < 30 ml/min (protocol violations).

25

Heterogeneity: patients with creatinine clearance 30-49 ml/min I2 11%, P = 0.35; patients with creatinine clearance ≥ 50 ml/min I2 63%, P =

0.03; patients < 75 years I2 28%, P = 0.24; patients ≥ 75 years I2 60%, P = 0.04; patients without cancer I2 54%, P = 0.06; patients with cancer I2

0%, P = 0.73.

26

Figure 5: Efficacy and safety of factor Xa inhibitors

Xa-inhibitor: oral direct factor Xa inhibitor; VKA: vitamin K antagonist; PE: pulmonary embolism; DVT: deep venous thrombosis; RR: relative

risk; CI: confidence interval.

Heterogeneity: overall I2 0%, P = 0.43; major bleeding I2 69%, P = 0.02; intracranial bleeding I2 0%, P = 0.60; major gastrointestinal bleeding I2

62%, P = 0.05; fatal bleeding I2 0%, P = 0.72; CRNM bleeding I2 89%, P = 0.13; net clinical benefit I2 11%, P = 0.34, all-cause mortality I2 10%,

P = 0.34.

Supplementary data “DOACs vs. VKAs for acute VTE”

Table of contents

Figure S1: Recurrent VTE or VTE-related death (overall) ...................................................... 3

Figure S2A: Major bleeding (risk ratio; overall) ...................................................................... 3

Figure S2B: Major bleeding (risk difference; overall) ............................................................. 3

Figure S3A: Fatal or non-fatal intracranial bleeding (risk ratio; overall) ................................. 4

Figure S3B: Fatal or non-fatal intracranial bleeding (risk difference; overall) ........................ 4

Figure S4A: Fatal bleeding (risk ratio; overall) ....................................................................... 4

Figure S4B: Fatal bleeding (risk difference; overall) .............................................................. 5

Figure S5A: Major gastrointestinal bleeding (risk ratio; overall) ............................................ 5

Figure S5B: Major gastrointestinal bleeding (risk difference; overall) .................................... 5

Figure S6A: Clinically relevant nonmajor bleeding (risk ratio; overall) ................................... 6

Figure S6B: Clinically relevant nonmajor bleeding (risk difference; overall) .......................... 6

Figure S7: Net clinical benefit (overall) .................................................................................. 6

Figure S8: All-cause mortality (overall) .................................................................................. 7

Figure S9: Recurrent VTE by index event.............................................................................. 7

Figure S10: Recurrent VTE by body weight ........................................................................... 8

Figure S11: Recurrent VTE by renal function ........................................................................ 9

Figure S12: Recurrent VTE in by age ...................................................................................10

Figure S13: Recurrent VTE by cancer status ........................................................................11

Figure S14: Major bleeding by renal function ........................................................................12

Figure S15: Major bleeding by age .......................................................................................13

Figure S16: Major bleeding by cancer status ........................................................................14

Figure S17: Recurrent VTE or VTE-related death (factor Xa inhibitors) ...............................14

Figure S18: Major bleeding (factor Xa inhibitors) ..................................................................15

Figure S19: Fatal or non-fatal intracranial bleeding (factor Xa inhibitors) .............................15

Figure S20: Fatal bleeding (factor Xa inhibitors) ...................................................................15

Figure S21: Major gastrointestinal bleeding (factor Xa inhibitors) ........................................16

Figure S22: Clinically relevant nonmajor bleeding (factor Xa inhibitors) ...............................16

Figure S23: Net clinical benefit (factor Xa inhibitors) ............................................................16

Figure S24: All-cause mortality (factor Xa inhibitors) ............................................................17

FIGURE S1: RECURRENT VTE OR VTE-RELATED DEATH (OVERALL)

FIGURE S2A: MAJOR BLEEDING (RISK RATIO; OVERALL)

FIGURE S2B: MAJOR BLEEDING (RISK DIFFERENCE; OVERALL)

FIGURE S3A: FATAL OR NON-FATAL INTRACRANIAL BLEEDING

(RISK RATIO; OVERALL)

FIGURE S3B: FATAL OR NON-FATAL INTRACRANIAL BLEEDING

(RISK DIFFERENCE; OVERALL)

FIGURE S4A: FATAL BLEEDING (RISK RATIO; OVERALL)

FIGURE S4B: FATAL BLEEDING (RISK DIFFERENCE; OVERALL)

FIGURE S5A: MAJOR GASTROINTESTINAL BLEEDING

(RISK RATIO; OVERALL)

FIGURE S5B: MAJOR GASTROINTESTINAL BLEEDING

(RISK DIFFERENCE; OVERALL)

FIGURE S6A: CLINICALLY RELEVANT NONMAJOR BLEEDING

(RISK RATIO; OVERALL)

FIGURE S6B: CLINICALLY RELEVANT NONMAJOR BLEEDING

(RISK DIFFERENCE; OVERALL)

FIGURE S7: NET CLINICAL BENEFIT (OVERALL)

FIGURE S8: ALL-CAUSE MORTALITY (OVERALL)

FIGURE S9: RECURRENT VTE BY INDEX EVENT

FIGURE S10: RECURRENT VTE BY BODY WEIGHT

FIGURE S11: RECURRENT VTE BY RENAL FUNCTION

FIGURE S12: RECURRENT VTE IN BY AGE

FIGURE S13: RECURRENT VTE BY CANCER STATUS

FIGURE S14: MAJOR BLEEDING BY RENAL FUNCTION

Note: RE-COVER pooled data is from double-dummy period only.

FIGURE S15: MAJOR BLEEDING BY AGE

Note: RE-COVER pooled data is from double-dummy period only.

FIGURE S16: MAJOR BLEEDING BY CANCER STATUS

FIGURE S17: RECURRENT VTE OR VTE-RELATED DEATH

(FACTOR XA INHIBITORS)

FIGURE S18: MAJOR BLEEDING (FACTOR XA INHIBITORS)

FIGURE S19: FATAL OR NON-FATAL INTRACRANIAL BLEEDING

(FACTOR XA INHIBITORS)

FIGURE S20: FATAL BLEEDING (FACTOR XA INHIBITORS)

FIGURE S21: MAJOR GASTROINTESTINAL BLEEDING

(FACTOR XA INHIBITORS)

FIGURE S22: CLINICALLY RELEVANT NONMAJOR BLEEDING

(FACTOR XA INHIBITORS)

FIGURE S23: NET CLINICAL BENEFIT (FACTOR XA INHIBITORS)

FIGURE S24: ALL-CAUSE MORTALITY (FACTOR XA INHIBITORS)