Safety and efficacy of apixaban and rivaroxaban in obese patients with acute venous thrombosis/embolism

Design

Retrospective, observational, single-center study

N= 499

Objective

To retrospectively analyze the use and 60-day outcomes of two direct-acting oral anticoagulants (DOACs), apixaban and rivaroxaban, prescribed to severely obese patients after venous thromboembolism (VTE)

Study Groups

Apixaban (n= 203)

Rivaroxaban (n= 296)

Inclusion Criteria

Exclusion Criteria

Chronic VTE diagnosis; received anticoagulation other than DOACs

Methods

This was a retrospective chart review of severely obese patients treated for VTE with apixaban or rivaroxaban at a single health system in Michigan. Data abstracted from electronic medical records included age, sex, race, BMI, and post-admission diagnoses of VTE or bleeding. 

Duration

January 2013 to January 2020

Outcome Measures

Primary: development of new VTE or progression of prior VTE within 60 days of DOAC initiation

Secondary: bleeding events, length of stay, mortality within 60 days

Baseline Characteristics

Apixaban (n= 203)

Rivaroxaban (n= 296)

Age, years

Female

BMI, kg/m² (range)

Race

Caucasian

Black

Other

63%

35%

2%

81.6%

17.7%

0.7%

-

Results

Apixaban (n= 203)

Rivaroxaban (n= 296)

p-value

VTE recurrence

Mortality

Length of stay, days (range)

Bleeding

Vaginal/uterine

Gastrointestinal

Hematuria

Hematoma

Epistaxis

12 (5.9%)

5/12 (41.7%)

3/12 (25%)

0

3/12 (25%)

1/12 (8.3%)

23 (7.8%)

6/23 (26.1%)

7/23 (30.4%)

6/23 (26.1%)

2/23 (8.7%)

2/23 (8.7%)

Adverse Events

There were two clotting events in the rivaroxaban arm (0.7%) compared to one in the apixaban arm (0.5%), which was not a statistically significant difference (p= 1.000).

Study Author Conclusions

This study indicates that apixaban and rivaroxaban are not associated with an increase in VTE recurrence. Bleeding rates were slightly higher in the rivaroxaban group compared to the apixaban group in severely obese patients, though not significantly different.

InpharmD Researcher Critique

This study is limited by its retrospective, single-center design which is susceptible to confounding. This study only included patients who presented to the hospital and at a 60-day follow-up with physicians in the same health system, which may present a selection bias in this population. The short follow-up period of 60 days presents a possibility of recurrent VTE beyond that time frame. Dosing of the DOACs (i.e., standard dose vs. adjusted dose) was not discussed in this study.

Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data

Design

Single-center, retrospective chart review

N=795

Objective

To investigate the efficacy and safety of the direct oral anticoagulants apixaban and rivaroxaban in comparison with warfarin in morbidly obese patients

Study Groups

Apixaban (n=150)

Rivaroxaban (n=326)

Warfarin (n=319)

Inclusion Criteria

Aged ≥18 years; BMI ≥40 kg/m²; started on oral anticoagulation with apixaban, rivaroxaban, or warfarin for atrial fibrillation or venous thromboembolism; had at least one follow-up visit after anticoagulation initiation

Exclusion Criteria

Methods

This was a retrospective analysis of chart data from a single center in New York. Outcomes of recurrent venous thromboembolism, stroke, and bleeding were measured from the first prescription date to the earliest of a thrombotic event, medication discontinuation, death, or end of the study on June 30, 2017.

Patients were stratified based on anticoagulation indication: atrial fibrillation (Afib) or venous thromboembolism (VTE).

Duration

March 2013 to March 2017

Median follow-up: 359.4 days (Afib); 196 (VTE)

Outcome Measures

Baseline Characteristics

Apixaban (n=150)

Rivaroxaban (n=326)

Warfarin (n=319)

Age, years

VTE (n=366)

AFib (n=429)

53.3 ± 13.9

65.9 ± 10.7

52.4 ± 14.7

60.9 ± 12.6

52.6 ± 14.5

66.8 ± 13.6

Female

BMI, kg/m² (IQR)

VTE (n=366)

AFib (n=429)

43.3 (41.2-49.4)

43.8 (41.0-48.1)

43.7 (41.1-48.8)

44.6 (41.8-48.6)

45.3 (41.3-50.1)

44.5 (41.7-52.3)

BMI ≥50 kg/m²

Follow-up, days (IQR)

VTE (n=366)

AFib (n=429)

163.3 (90.0–233.3)

331.5 (181.5–577.0)

217.4 (94.4–514.1)

412.9 (187.3–675.2)

206.3 (64.4–540.3)

293.6 (81.6–671.8)

Results

Apixaban (n=150)

Rivaroxaban (n=326)

Warfarin (n=319)

Recurrent VTE

VTE group (n=366)

1/47 (2.1%)

3/152 (2.0%)

2/167 (1.2%)

Stroke

AFib (n=429)

1/103 (1.0%)

4/174 (2.3%)

2/152 (1.3%)

Major bleeding

VTE (n=366)

AFib (n=429)

4 (2.7%)

1/47 (2.1%)

3/103 (2.9%)

7 (2.1%)

2/152 (1.3%)

5/174 (2.9%)

16 (5.0%)

4/167 (2.4%)

12/152 (7.9%)

Adverse Events

Composite bleeding

VTE: apixaban 4%; rivaroxaban 9%; warfarin 10%

AFib: apixaban 11%; rivaroxaban 10%; warfarin 16%

Study Author Conclusions

This study provides further evidence of similar efficacy and safety between the direct oral anticoagulants apixaban and rivaroxaban, and warfarin in morbidly obese patients with atrial fibrillation and venous thromboembolism. 

InpharmD Researcher Critique

Limitations of this study include the retrospective and single-center design. The low number of events also limited the ability of this study to conduct additional statistical analyses. This study (the Bronx, NY) also had a high proportion of Black and Hispanic patients.

Although patients could have had unrecorded events if they were treated at another clinic, this center covers most of the study population so it was likely any events were documented within the system. 

Evaluation of the Efficacy of Direct Oral Anticoagulants (DOACs) in Comparison to Warfarin in Morbidly Obese Patients

Design

Retrospective cohort study

N= 180

Objective

To evaluate the efficacy of the DOACs apixaban, rivaroxaban, and dabigatran in comparison to warfarin in preventing a composite of stroke and systemic emboli in morbidly obese patients

Study Groups

DOAC group (n= 90)

Warfarin group (n= 90)

Inclusion Criteria

Adults 18 years or older; body mass index (BMI) >40 kg/m²; weight >120 kg

Exclusion Criteria

Patients on ritonavir, itraconazole, ketoconazole, clarithromycin, dronedarone, edoxaban, or betrixaban; CrCl <30 mL/min; recent diagnosis of atrial fibrillation or atrial flutter within 30 days with no evidence of transmural thrombi; history of head trauma; hepatic disease with coagulopathy

Methods

This was a retrospective study from a single-center in Texas assessing the use of DOACs in morbidly obese patients. Rates of ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), myocardial infarction (MI), and major bleeding were analyzed in morbidly obese patients receiving apixaban, rivaroxaban, or dabigatran in comparison to warfarin for anticoagulation due to nonvalvular atrial fibrillation, postoperative thrombus prophylaxis, or DVT/PE treatment and/or reduction in risk for recurrence.

Duration

October 2012 to October 2017

Outcome Measures

Primary: composite of stroke, transient ischemic attack (TIA), DVT, or PE

Secondary: frequency of each composite, major and non-major bleeding events (defined by Internation Society of Thrombosis and Hemostasis [ISTH] criteria for major bleeding), all-cause mortality

Baseline Characteristics

DOACs (n= 90)

Warfarin (n= 90)

61 (24-89)

63 (18-89)

33 (36.7%)

42 (46.7%)

100%

100%

46 (51.1%) apixaban
11 (12.2%) dabigatran
33 (36.7%) rivaroxaban

INR goal 2-3
(68% of the time within goal)

18 (20.0%)

21 (23.7%)

Mean BMI, kg/m²

Mean weight, kg

Anticoagulation indication

Atrial fibrillation

DVT/PE treatment

Postoperative prophylaxis

64 (71.1%)

23 (25.6%)

1 (3.3%)

56 (62.2%)

26 (28.9%)

8 (8.9%)

IQR: interquartile range

Results

DOACs (n= 90)

Warfarin (n= 90)

Odds Ratio (95% CI)

Composite stroke and systemic emboli

Ischemic Stroke

DVT

PE

MI

11 (12.2%)

3 (3.3%)

3 (3.3%)

1 (1.1%)

4 (4.4%)

10 (11.1%)

3 (3.3%)

2 (2.2%)

2 (2.2%)

3 (3.3%)

0.82 (-8.6 to 10.8)

N/A

0.65 (-4.8 to 7.3)

0.56 (-4.1 to 6.7)

0.70 (-5.5 to 7.9)

Death

Major Bleeding

Events with the DOACs   

Events

Ischemic Stroke

DVT

PE

MI

Major bleeding

0

0

0

1 (2.4%)

1 (2.4%)

1 (3.0%)

2 (6.1%)

1 (3.0%)

2 (6.1%)

1 (3.0%)

2 (18.2%)

1 (9.1%)

0

1 (9.1%)

0

Adverse Events

N/A

Study Author Conclusions

This study found that rivaroxaban, apixaban, and dabigatran were not associated with an increase in stroke or systemic emboli in morbidly obese patients in comparison to warfarin. However, due to the small sample size and retrospective design, this conclusion can only be hypothesis-generating.

InpharmD Researcher Critique

Due to the study's retrospective design, causation cannot be implied between DOACs and stroke and systemic emboli risks. Additionally, retrospective datasets are poor choices for comparative analyses between therapies. There is also limited generalizability due to the small size and single-center design.

Treatment of venous thromboembolism with rivaroxaban in relation to body weight: A sub-analysis of the EINSTEIN DVT/PE studies 

Design

Post-hoc, sub-analysis of the EINSTEIN DVT/PE studies (open-label, randomized, multicenter, event-driven, non-inferiority studies)

N=8230 (for the analysis per BMI) 

Objective

To determine the incidence of major bleeding in patients with a low body weight and recurrent venous thromboembolism (VTE) in patients with a high body weight during rivaroxaban or enoxaparin/vitamin K antagonist (VKA) therapy

Study Groups

BMI <25 (n=2,481)

BMI ≥25-30 (n =3,258)

BMI ≥30-35 (n=1,630)

BMI ≥35 (n=861)

Inclusion Criteria

Patients with acute symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE)

Exclusion Criteria

Methods

Patients from the EINSTEIN DVT and EINSTEIN PE trials received either fixed-dose rivaroxaban 15 mg PO BID for 21 days, followed by 20 mg once daily or bodyweight-adjusted enoxaparin followed by a VKA (either warfarin or acenocoumarol; target INR: 2.0-3.0) for 3, 6, or 12 months of therapy. Follow-up assessed for signs and symptoms of bleeding or VTE recurrence.   

Duration

359 days 

Outcome Measures

Primary outcome: percentage of patients with symptomatic recurrent venous thromboembolism (EINSTEIN DVT/PE)

Secondary outcomes:

EINSTEIN DVT: percentage of patients with the composite variable comprising recurrent DVT, Non-fatal PE and all cause mortality

EINSTEIN PE: major bleeding, death from any cause, vascular events (acute coronary syndrome, ischemic stroke, transient ischemic attack, systemic embolism)  

Baseline Characteristics

BMI<25

(n=2,481)

BMI ≥ 25-30

(n=3,258)

BMI ≥ 30-35

(n=1,630)

BMI ≥ 35

(n=861)

Median age, years (range)

Men

Index event

DVT

PE+DVT

PE

No confirmed event

43.9%

11.6%

43.3%

0.9%

40.0%

15.8%

43.4%

0.8%

40.1%

16.0%

42.8%

1.1%

37.0%

16.6%

45.4%

1.0%

Unprovoked VTE

Known thrombophilia

Treatment duration, median days

Rivaroxaban

Enoxaparin/VKAs

182 (1-359)

181 (1-359)

183 (1-359)

182 (1-359)

184 (1-359)

183 (1-359)

184 (1-359)

183 (1-359)

Proportion of patients with INR

> 3.0

< 2.0

2.0 to 3.0

20.6%

17.3%

62.1%

19.5%

17.8%

62.6%

17.7%

17.0%

65.3%

17.6%

19.3%

63.1%

Results

BMI<25

(n=2,481)

BMI ≥ 25-30

(n=3,258)

BMI ≥ 30-35

(n=1,630)

BMI ≥ 35

(n=861)

Recurrent VTE

Rivaroxaban

Enoxaparin/VKA

28/1,266 (2.2%)

30/1,215 (2.5%)

35/1,608 (2.2%)

41/1,650 (2.5%) 

10/825 (1.2%)

14/805 (1.7%)

13/427 (3.0%)

9/434 (2.1%)

Hazard ratio (95% CI)

0.92 (0.54 to 1.57)

0.82 (0.52 to 1.29)

0.70 (0.31 to 1.57)

1.45 (0.62 to 3.39)

Major bleeding

Rivaroxaban

Enoxaparin/VKA

15/1,257 (1.2%)

25/1,214 (2.1%)

18/1,603 (1.1%)

30/1,643 (1.8%)

2/822 (0.2%)

8/803 (1.0%)

5/426 (1.2%)

7/432 (1.6%)

Hazard ratio (95% CI)

0.56 (0.30 to 1.06)

0.60 (0.34 to 1.08)

0.27 (0.06 to 1.28)

0.71 (0.22 to 2.24)

No association between BMI and recurrent VTE was found for rivaroxaban group or enoxaparin/VKA group. 

No association between BMI and major bleeding was found for rivaroxaban group or enoxaparin/VKA group. 

Study Author Conclusions

The fixed-dose regimen of rivaroxaban 15 mg twice daily for the first 21 days, followed by 20 mg once daily without any dose adjustments, was not associated with either an increased risk of major bleeding in patients with a low BMI or an increased risk of recurrent VTE in patients with a high BMI. 

InpharmD Researcher Critique

The study did not measure any changes of BMI during the intervention. Also, other co-morbidities may have masked the effects of BMI on the risk of major bleeding and recurrent VTE. This study was a post-hoc analysis of two trials and did not attempt to adjust for confounders when merging groups. Attempts to stratify based on the treatment period of 3, 6, or 12 months was also not mentioned meaning the results represent quite a number of different individual therapeutic strategies. 

Investigation of Direct-Acting Oral Anticoagulants and the Incidence of Venous Thromboembolism in Patients Weighing 120 kg Compared to Patients Weighing

Design

Retrospective database analysis and chart review of patients receiving a DOAC within Veterans Integrated Service Network (VISN)

N=1,196

Objective

To identify if a difference exists in incidence of recurrent thromboembolic events in patients receiving a direct oral anticoagulant (DOAC) for the indication of venous thromboembolism (VTE) weighing ≥ 120 kg compared to patients weighing <120 kg

Study Groups

Patients Weighing ≥ 120 kg (n=133)

Patients Weighing <120 kg (n=1,063)

Inclusion Criteria

All adult Veterans older than the age of 18 who were treated with rivaroxaban, dabigatran, or apixaban for the treatment of a VTE within VISN 8 of the VHA system

Exclusion Criteria

Patients who received edoxaban; patients non-compliant with DOAC therapy (noncompliance was defined as more than 30 days past where refills were due)

Methods

A retrospective database analysis was conducted on patients taking either apixaban, dabigatran, or rivaroxaban for treatment of VTE from the Veterans Integrated Service Network 8, which consists of seven healthcare systems in Florida, Georgia, and Puerto Rico. Fisher’s exact tests were used to evaluate differences in VTEs between patients weighing ≥ 120 kg compared to patients <120 kg.

Duration

January 2012 and June 2017

Outcome Measures

Primary: incidence of recurrent VTE

Secondary: differences among DOACs (dabigatran, rivaroxaban, apixaban) in the incidence of VTE recurrence

Baseline Characteristics

≥120 kg (n=133)

<120 kg (n=1,063)

Age, years

Male

BMI, kg/m² 

Weight, kg 

White

DOAC agent prescribed

Apixaban

Dabigatran

Rivaroxaban

17 (12.8%)

39 (29.3%)

77 (57.9%)

210 (19.8%)

314 (29.5%)

539 (50.7%)

Duration on DOAC, days

Results

≥120 kg (n=133)

<120 kg (n=1,063)

P-value

Overall VTE recurrences

With apixaban

With dabigatran

With rivaroxaban

1 (0.8%)

0

1/39 (2.6%)

0

12 (1.1%)

3/210 (1.4%)

3/314 (0.9%)

6/539 (1.1%)

0.69

1.00

0.38

1.00

Upon chart review of primary outcome events, 3 patients (all <120 kg) with a documented recurrent VTE were noted to have recently missed doses of DOAC therapy at the time of VTE. If these events are excluded, the incidence of VTE between the weight groups would both be 0.8% (odds ratio 0.89; 95% confidence interval 0.11 to 7.06; P=0.91)

Adverse Events

Not studied

Study Author Conclusions

This study found no difference in VTE recurrence in patients weighing ≥ 120 kg compared to patients <120 kg with few events in either group.

InpharmD Researcher Critique

Limitations include the differences in the baseline characteristics between the study groups; patients weighing ≥ 120 kg were younger than patients weighing < 120 kg (mean age: 62 vs 69 years, respectively), and increasing age is a risk factor for VTE. The low incidence of VTE recurrence requires a large sample size that could not be met with the current Veterans Affairs patient pool; therefore, the study was underpowered.