Comparative Effectiveness of Apixaban and Rivaroxaban Lead-in Dosing in VTE Treatment: Observational Multicenter Real-World Study

Design

Multicenter retrospective cohort study

N= 368

Objective

To assess the effectiveness and safety of two lead-in dosing regimens on the incidence of recurrent venous thromboembolism (rVTE), major bleeding (MB), and clinically relevant non-major bleeding (CRNMB) in patients with acute VTE events

Study Groups

Mixed lead-in (n= 72)

Recommended lead-in (n= 296)

Inclusion Criteria

Age ≥ 18 years, diagnosed with new VTE event, used either apixaban or rivaroxaban for treatment, not on therapeutic anticoagulants prior to index VTE

Exclusion Criteria

Patients switched to maintenance doses other than recommended (5 mg BID for apixaban and 20 mg daily for rivaroxaban), received lead-in therapy for more than the maximum duration of 9 days for apixaban or 23 days for rivaroxaban (i.e., the total duration for parenteral and oral anticoagulant)

Methods

Data were collected from patients treated at one of three hospitals in Riyadh, Saudi Arabia. Patients were included in one of two groups, based on treatment. The recommended-lead-in regimen included patients who received the recommended 7 days of apixaban 10 mg BID or 21 days of rivaroxaban 15 mg BID with no more than 2 days of prior parenteral anticoagulation. The mixed-lead-in group included patients who received a parenteral anticoagulant and then apixaban 10 mg BID or rivaroxaban 15 mg BID to complete a total duration of at least 6 or 19 days of combined lead-in therapy, respectively. 

Duration

January 2016 - December 2020

Follow-up: 90 days 

Outcome Measures

Efficacy: incidence of rVTE during hospitalization or within 30 or 90 days of the indexed VTE event, incidence of rehospitalization for VTE-related causes within 30 or 90 days of the indexed VTE event, all-cause death during hospitalization

Safety: incidence of MB and CRNMB during hospitalization or within 30 or 90 days of the indexed VTE event

Baseline Characteristics

Mixed (n= 72)

Recommended (n= 296)

Age, years

Female

BMI, kg/m²

Hospital length of stay, days*

Pre-existing conditions

Atrial fibrillation

Coronary artery disease

Hypertension

Valvular disease

Stroke

Transient ischemic attack

Diabetes mellitus

Chronic kidney disease

Active smoking

Thrombophilia

Active cancer

History of MB (within 12 months)

History of CRNMB (within 12 months)

History of any bleeding (within 12 months)

4 (4.2%)

6 (8.3%)

33 (45.8%)

1 (1.4%)

5 (6.9%)

0

27 (37.5%)

3 (4.2%)

5 (6.9%)

3 (4.2%)

5 (6.9%)

8 (11.1%)

1 (1.4%)

2 (2.8%)

5 (1.7%)

13 (4.4%)

104 (35.1%)

2 (0.7%)

28 (9.5%)

3 (1%)

97 (32.8%)

15 (5.1%)

23 (7.8%)

10 (3.4%)

7 (2.4%)

14 (4.7%)

10 (3.4%)

6 (2%)

Concomitant antithrombotic medications

Aspirin

P2Y12 inhibitors

9 (12.5%)

3 (4.2%)

45 (15.2%)

7 (2.4%)

Risk factors for VTE recurrence

History of previous VTE

Type of historical VTE**

DVT

PE

DVT plus PE

Time of historical VTE

Within 3 months

Within 12 months

Within > 12 months

Use of oral contraceptive or ERT

Obesity (BMI ≥ 30 kg/m²)

Immobility

Major general surgery within 1 year

Orthopedic surgery within 1 year

4 (5.6%)

0 of 4

4 of 4 (100%)

0 of 4

0

0

3 (75%)

5 (6.9%)

31 (43.1%)

18 (25%)

11 (15.3%)

8 (11.1%) 

35 (11.8%)

27 of 35 (77.1%) 

5 of 35 (14.3%)

3 of 35 (8.6%)

3 (8.6%)

2 (5.7%)

29 (82.9%)

38 (12.8%)

150 (50.7%)

65 (22%)

30 (10.1%)

21 (7.1%)

Type of current VTE event

DVT

PE

DVT plus PE

10 (13.9%)

54 (75%)

8 (11.1%)

141 (47.6%)

134 (45.3%)

21 (7.1%)

VTE etiology

Provoked

Unprovoked

Not reported

37 (51.4%)

16 (22.2%)

19 (26.4%)

166 (56.1%)

65 (22%)

65 (22%)

Bleeding risk

High risk

Intermediate risk

Low risk

4 (5.6%)

52 (72.2%)

16 (22.2%)

7 (2.4%)

231 (78%)

58 (19.6%)

Type of parenteral anticoagulant used

Enoxaparin

Unfractionated heparin

61 (84.7%)

11 (15.3%)

168 (56.8%)

29 (9.8%)

Duration of received lead-in dose of DOAC, days

Duration of received parenteral anticoagulant, days

Duration of received parenteral anticoagulant and DOAC, days

4 (apixaban); 15 (rivaroxaban)

2.2 (apixaban; 5.6 (rivaroxaban)

6.2 (apixaban); 20.7 (rivaroxaban)

7 (apixaban); 21 (rivaroxaban)

1.3 (apixaban); 1.2 (rivaroxaban)

8.3 (apixaban); 22.2 (rivaroxaban)

*p< 0.0001

**p= 0.0006

BMI: body mass index; VTE: venous thromboembolism; DVT: deep-vein thrombosis; PE: pulmonary embolism; ERT: estrogen-replacement therapy; MB: major bleeding; CRNMB: clinically relevant non-major bleeding

Results

Endpoint

Mixed (n= 72)

Recommended (n= 296)

p-Value

rVTE event

During hospitalization

Within 30 days

Cumulative within 90 days

Patients with ≥ 1 rVTE within 90 days

0

0

1 (1.4%)

1 (1.4%) 

2 (0.7%)

2 (0.7%)

2 (0.7%)

4 (1.4%) 

NS

NS

NS

NS

MB event

During hospitalization

Within 30 days

Cumulative within 90 days

Patients with ≥ 1 MB within 90 days

7 (9.7%)

0

1 (1.4%)

7 (9.7%) 

11 (3.7%)

4 (1.4%)

5 (1.7%)

14 (4.7%) 

NS

NS

NS

NS

CRNMB event

During hospitalization

Within 30 days

Cumulative within 90 days

Patients with ≥ 1 CRNMB within 90 days

3 (4.2%)

4 (5.6%)

4 (5.6%)

7 (9.7%) 

9 (3%)

23 (7.8%)

23 (7.8%)

29 (9.8%) 

NS

NS

NS

NS 

Rehospitalization

Within 30 days

Cumulative within 90 days

0

2 (2.8%)

7 (2.4%)

13 (4.4%)

NS

NS 

Death during hospitalization

NS: not significant

Adverse Events

Study Author Conclusions

The lead-in therapy with the recommended or mixed regimens showed comparable effectiveness and safety outcomes. Subtracting parenteral-anticoagulation days from the total lead-in regimen for both apixaban and rivaroxaban might be a reasonable strategy. However, large and prospective studies are required to verify these findings.

InpharmD Researcher Critique

Evaluation of Lead-in Direct Oral Anticoagulant Prescribing Practices in Newly Diagnosed Venous Thromboembolism

Design

Single-center, retrospective cohort

N= 192

Objective

To identify if full lead-in dosing duration surrounding parenteral anticoagulation affects thrombotic and bleeding outcomes

Study Groups

Full lead-in (n= 93)

Reduced lead-in (n= 99)

Inclusion Criteria

Patients hospitalized with newly diagnosed venous thromboembolism (VTE) and treated with apixaban or rivaroxaban; newly started on anticoagulation and have received parenteral therapy for at least 24 hours prior to transitioning to apixaban or rivaroxaban

Exclusion Criteria

Age < 18 years; received therapeutic anticoagulation prior to admission 

Methods

Patients were grouped based on duration of lead-in dosing. The full-lead in dosing group included patients who were considered to have received the appropriate duration of direct oral anticoagulants (DOAC), defined as apixaban 10 mg twice daily for seven days or rivaroxaban 15 mg twice daily for 21 days during the initial treatment phase. Reduced lead-in dosing was defined as apixaban 10 mg twice daily for less than seven days or rivaroxaban 15 mg twice daily for less than 21 days during the initial treatment phase. 

Duration

August 1, 2021 - July 31, 2022

Follow-up: up to six months 

Outcome Measures

Primary: recurrence of VTE (new and/or worsening VTE) within index admission to six months

Secondary: recurrence of VTE within the index admission or within six months; major bleeding; clinically-relevant minor bleeding; mortality within six months 

Baseline Characteristics

Full lead-in (n= 93)

Reduced lead-in (n= 99)

Age, years, median (IQR)

Female

White

African American

Hispanic

48%

38%

12%

53%

27%

16%

BMI, median (IQR)

CrCl, median (IQR)

Comorbidities

Atrial fibrillation

Acute kidney injury

Chronic kidney disease

Liver disease

Cancer

Congestive heart failure

Diabetes mellitus

Hypertension

Myocardial infarction

Stroke

Transient ischemic attack

Surgery within 5 weeks

Thrombophilias

Prolonged immobility ≥ 5 days

6%

18%

25%

5%

25%

19%

23%

49%

5%

12%

2%

17%

0

6%

16%

24%

29%

7%

25%

18%

23%

45%

1%

10%

1%

23%

1%

4%

Prior NSAID therapy

Prior antiplatelet therapy

5%

34%

12%

19%

Type of VTE

DVT

PE

Both DVT and PE

26%

48%

26%

45%

38%

16%

Modified HAS-BLED score, median (IQR)

Prescribed DOAC therapy

Apixaban

Rivaroxaban

96%

4%

93%

7%

Prescribing service

ICU

Acute care

11%

89%

22%

78%

Hospital length of stay, days, median (IQR)

Received thrombolytics

Received thrombectomy

17%

10%

8%

7%

BMI: body mass index; CrCl: creatinine clearance; DVT: deep vein thrombus; ICU: intensive care unit; IQR: interquartile range; NSAID: nonsteroidal anti-inflammatory drugs; PE: pulmonary embolism 

Patients on apixaban and rivaroxaban received less lead-in dosing in reduced lead-in group (apixaban: 0 days vs. 7 days; p< 0.01; rivaroxaban: 3 days vs. 21 days; p= 0.01)

Combined duration of parenteral anticoagulation followed by DOAC lead-in dosing: apixaban (7 days in reduced-in lead group compared to 9 days in full lead-in group; p< 0.01); rivaroxaban (9 days in reduced lead-in group compared to 23.5 days in full lead-in group; p= 0.19)

Results

Endpoint

Full lead-in (n= 93)

Reduced lead-in (n= 99)

p-Value

Recurrent VTE within index admission to 6 months

Within index admission

Within readmission in 6 months

2.2%

0

2.2%

3%

1%

2%

1.0

1.0

1.0

Major bleeding

Within index admission

Within readmission in 6 months

Clinically-relevant minor bleeding

Within index admission

Within readmission in 6 months

2.2%

3.2%

9.6%

4.3%

11.1%

3%

16.2%

5.1%

0.02

1.0

0.1

1.0

Mortality in 6 months

Univariate analysis of factors predicting recurrent VTE found that patients on oral contraceptive use were more likely to experience a thrombotic event (odds ratio [OR] 46.5; 95% confidence interval [CI] 1.65 to 1,334; p= 0.01). 

Analysis of factors predicting bleeding found lower BMI < 25 were three-fold more likely to have a major bleeding event within index admission to six months (OR 3.808; 95% CI 1.42 to 10.57; p= 0.01)

Adverse Events

See results section 

Study Author Conclusions

Reduced lead-in dosing was not associated with an increased rate of thrombotic and mortality events among patients with newly diagnosed VTE. This study provides evidence to support reduced lead-in dosing duration in high-risk patients without compromising efficacy outcomes. The results demonstrate that reduced lead-in dosing may be safely used for VTE treatment among patients at an increased risk for bleeding, including those in the ICU, patients with renal dysfunction, and patients who experienced a bleed prior to anticoagulation. However, larger studies are needed to further support these findings. 

InpharmD Researcher Critique

The single-center retrospective design limits the comparison between the two groups due to the risk for bias and confounding variables that were not controlled for. Adherence could not be assessed, and follow-up was limited to available records, possibly missing instances of thrombosis or bleeding. 

Real-World Evaluation of the Safety and Effectiveness of Apixaban & Rivaroxaban Lead-in Dosing Compared to Parenteral Lead-in Dosing in the Treatment of Venous Thromboembolism: A Multi-Center Retrospective Cohort Study

Design

Multi-center, retrospective observational cohort 

N= 389

Objective

To compare the safety and effectiveness of lead-in parenteral anticoagulation to lead-in apixaban or rivaroxaban in patients who received apixaban or rivaroxaban for venous thromboembolism (VTE) treatment 

Study Groups

Direct oral anticoagulants (DOAC) lead-in (n= 296)

Parenteral lead-in (n= 93)

Inclusion Criteria

Age ≥ 18 years; admitted to the hospital with newly diagnosed VTE; received either apixaban or rivaroxaban for VTE treatment 

Exclusion Criteria

Received rivaroxaban or apixaban for non-VTE treatment indications; received other oral anticoagulation therapy for VTE treatment (i.e., edoxaban, dabigatran, or warfarin); received inappropriate lead-in or maintenance dosing or duration of apixaban or rivaroxaban; already on a treatment dose of oral or injectable anticoagulants before the indexed VTE event date 

Methods

Included patients were divided into two groups based on the lead-in anticoagulation administered for acute VTE treatment. The DOAC lead-in group consisted of patients who received apixaban 10 mg twice daily for seven days or rivaroxaban 15 mg twice daily for 21 days for lead-in therapy, with or without prior parenteral anticoagulation (maximum of 48 hours). Patients then transitioned to recommended maintenance doses (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily). The parenteral lead-in group patients only received treatment dose of parenteral anticoagulant prior to being transitioned to the recommended maintenance doses of apixaban or rivaroxaban. 

Duration

Patients admitted between January 1, 2016 - December 31, 2021

Outcome Measures

Primary: recurrent VTE (rVTE) during hospitalization and within 30- and 90-day follow-ups (defined as deep vein thromboembolism [DVT], pulmonary embolism [PE], or both DVT and PE)

Safety: major bleeding (MB) and clinically relevant non-major bleeding (CRNMB); rehospitalization due to VTE-related causes within 90 days of VTE diagnosis; death from any cause during hospitalization 

Baseline Characteristics

Parenteral lead-in (n= 93)

DOAC lead-in (n= 296)

Age, years

Female

BMI, kg/m²

Hospital length of stay, days

Pre-existing conditions

Atrial fibrillation

Coronary artery disease

Hypertension

Valvular disease

Stroke

Transient ischemic attack

Diabetes mellitus

Chronic kidney disease

Active smoking

Active cancer

Thrombophilia

History of MB (within 12 months)

History of CRNMB (within 12 months)

History of any bleeding (within 12 months)

3.2%

17.2%

48.4%

1.1%

17.2%

4.3%

44.1%

6.5%

4.3%

9.7%

4.3%

3.2%

2.2%

2.2%

1.7%

4.4%

35.1%

0.7%

9.5%

1%

32.8%

5.1%

7.8%

2.4%

3.4%

4.7%

3.4%

2%

Concomitant medications

Aspirin

Clopidogrel

Ticagrelor

36.6%

10.8%

1.1%

15.2%

2.4%

0.3%

Risk factors for VTE recurrence

History of previous VTE

DVT

PE

DVT + PE

Time of historical VTE

Within 3 months

Within 6 months

Within 12 months

> 12 months

Use of oral contraceptives or ERT

Obesity (BMI > 30 kg/m²)

Immobility

Major general surgery (within one year)

Orthopedic surgery (within one year)

8.6%

75%

25%

0

0

12.5%

0

50%

6.5%

54.8%

35.5%

7.5%

14%

11.8%

77.1%

14.3%

8.6%

8.6%

0

5.7%

82.9%

12.8%

50.7%

22%

10.1%

7.1%

Type of current VTE

DVT

PE

DVT + PE

VTE etiology

Provoked

Unprovoked

Not reported

Bleeding risk

High risk

Intermediate risk

Low risk

34.4%

59.1%

6.5%

64.5%

16.1%

19.4%

7.5%

72%

20.4%

47.6%

45.3%

7.1%

56.1%

22%

22%

2.4%

78%

19.6%

Type of parenteral anticoagulant used

LMWH

UFH

Fondaparinux

None

Duration for lead-in dose of DOAC, days

Duration for received parenteral anticoagulation, days

72%

25.8%

2.2%

NA

N/A

3.7 ± 2.4

56.8%

9.8%

0.3%

33.1%

7 (apixaban); 21 (rivaroxaban)

1.3 (apixaban); 1.2 (rivaroxaban)

BMI, body mass index; ERT, estrogen replacement therapy; LMWH, low molecular weight heparin; UFH, unfractionated heparin 

Results

Endpoint

Parenteral lead-in (n= 93)

DOAC lead-in (n= 296)

p-Value

rVTE event

During hospitalization

Within 30 days

Within 90 days

Total within 90 days

3.3%

1.1%

2.2%

5.4%

0.6%

0.7%

0.7%

1.4%

0.091

0.560

0.243

0.039

MB Event

During hospitalization

Within 30 days

Within 90 days

Total within 90 days

CRNMB event

During hospitalization

Within 30 days

Within 90 days

Total within 90 days

14%

0

2.2%

14%

10.8%

7.5%

7.5%

16.1%

3.7%

1.4%

1.7%

4.7%

3%

7.8%

7.8%

9.8%

< 0.001

0.576

0.674

0.004

0.006

0.938

0.938

0.092

Rehospitalization

Within 30 days

Within 90 days

1.1%

2.2%

2.4%

4.4%

0.686

0.537

Death during hospitalization 

Adverse Events

See results section

Study Author Conclusions

Parenteral anticoagulation lead-in before starting maintenance of apixaban and rivaroxaban showed a significantly higher risk of bleeding and a trend toward higher VTE recurrence than the DOAC lead-in. This study adds to the evidence supporting the utilization of the DOAC lead-in regimen in treating patients with VTE. Still, larger studies with robust designs are needed to confirm these findings. 

InpharmD Researcher Critique

The retrospective design limits the ability to control for confounding variables and introduces the risk for selection bias. Additionally, the small sample size in the parenteral lead-in group limits the ability to make comparisons between groups. Also, due to the retrospective nature of the study data for outcomes was reliant on available records, which may not be complete and does not account for patient adherence once discharged from the hospital.