Is the loading dose period still required for Eliquis and Xarelto if a patient has been on treatment dosing of LMWH or UFH for a prolonged period of time prior to starting the DOAC?

Comment by InpharmD Researcher

Current guidelines do not specifically address whether the apixaban or rivaroxaban lead-in can be shortened or omitted after prolonged therapeutic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) and instead describe the standard full lead-in regimens when initiating these direct oral anticoagulants (DOACs). Available studies are predominantly retrospective and generally evaluate abbreviated, modified, or omitted oral lead-in regimens, with preceding parenteral anticoagulation typically lasting several days. Most studies reported comparable recurrent venous thromboembolism (VTE) outcomes, although some found higher bleeding or mortality with modified regimens, and one study found significantly higher bleeding and recurrent VTE with a parenteral-only lead-in followed by maintenance-dose DOAC therapy. Additionally, a pharmacokinetic study found that apixaban 5 mg twice daily on day 7 produced less than half the exposure (AUC) of apixaban 10 mg twice daily; however, this study involved healthy subjects and did not evaluate transitions from therapeutic LMWH or UFH, precluding conclusions regarding omission of the lead-in regimen. Overall, evidence remains insufficient to determine whether the DOAC lead-in can be safely omitted after prolonged therapeutic parenteral anticoagulation, highlighting the need for prospective studies.

PubMed and Google Scholar were searched for guidelines and clinical studies evaluating apixaban or rivaroxaban lead-in dosing after therapeutic LMWH or UFH for acute VTE. Search terms included “apixaban,” “rivaroxaban,” “lead-in,” “loading dose,” “parenteral anticoagulation,” “LMWH,” “UFH,” and “venous thromboembolism.”

Background

Current guidelines on the management of venous thromboembolism (VTE) describe the VTE anticoagulation process as an initiation phase followed by an initial treatment phase and, when indicated, an extended treatment phase. During initiation, the 2026 ACC/AHA guideline specifies an initial high dose regimen for apixaban (10 mg twice daily for 7 days) and rivaroxaban (15 mg twice daily for 21 days) followed by maintenance dose therapy. The 2024 CHEST guideline compendium similarly notes that initiation with apixaban or rivaroxaban involves a high dose regimen followed by the maintenance dose. Neither guideline specifically addresses whether an apixaban or rivaroxaban lead-in can be omitted in patients who have received prolonged parenteral anticoagulation before transitioning to a direct oral anticoagulant (DOAC). [1], [2]

A 2015 review highlighted the first seven days after a VTE event as the acute treatment phase since there is the highest risk for VTE recurrence and bleeding from anticoagulation during this period. Additionally, the authors noted the duration of acute treatment for apixaban 10 mg BID as 10 days. Regardless, there is no discussion of a specific time frame after which the loading dose can be omitted completely. [3]

A pharmacokinetic/pharmacodynamics study of multiple-dose apixaban was performed in healthy subjects over 7 days. On day 7, the apixaban 5 mg BID group (n=6) had lower Cmax, Cmin, and AUC compared to the apixaban 10 mg group (n=6). In particular, the AUC for apixaban 5 mg BID group was 1051.9 ng·h/mL versus 2424.9 ng·h/mL in the 10 mg BID group after 7 days which is less than half, indicating potential for being under-dosed if omitting the loading dose period. Overall, exposure to apixaban appears to increase in a dose-dependent manner as higher levels of clotting measures (e.g. INR, aPTT, mPT) are seen at higher doses. [4]

Background References: [1] Writing Committee Members, Creager MA, Barnes GD, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153(12):e977-e1051. doi:10.1161/CIR.0000000000001415
[2] Stevens SM, Woller SC, Baumann Kreuziger L, et al. Antithrombotic Therapy for VTE Disease: Compendium and Review of CHEST Guidelines 2012-2021. Chest. 2024;166(2):388-404. doi:10.1016/j.chest.2024.03.003
[3] Hillis C, Crowther MA. Acute phase treatment of VTE: Anticoagulation, including non-vitamin K antagonist oral anticoagulants [published correction appears in Thromb Haemost. 2015 Jul;114(1):210]. Thromb Haemost. 2015;113(6):1193-1202. doi:10.1160/TH14-12-1036
[4] Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76(5):776–786. doi:10.1111/bcp.12106
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

Is the loading dose period still required for Eliquis and Xarelto if a patient has been on treatment dosing of LMWH or UFH for a prolonged period of time prior to starting the DOAC?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

Rethinking Lead-in Strategies: Evaluation of Full vs. Reduced Dose Factor Xa Inhibitors in Acute VTE
Design Multicenter, retrospective, observational cohort study

N= 1,424
Objective To evaluate bleeding and thrombotic events associated with reducing factor Xa inhibitor lead-in duration in patients who have received prior parenteral anticoagulation
Study Groups Full lead-in (n= 1,068)

Reduced lead-in (n= 356)
Inclusion Criteria Patients admitted for a new diagnosis of pulmonary embolism (PE) or deep vein thrombosis (DVT); received at least 24 hours of therapeutic parenteral anticoagulation; treated with apixaban or rivaroxaban for venous thromboembolism (VTE)
Exclusion Criteria Receipt of a lead-in dose reduction not corresponding to parenteral anticoagulation days, bleeding at index admission, mechanical valve replacement, moderate/severe mitral valve stenosis, antiphospholipid antibody syndrome, severe liver disease, pregnancy, incarceration, >1 hour overlap between parenteral anticoagulation and FXaI initiation, prior therapeutic anticoagulation, contraindicated interacting medications
Methods Patients received at least 24 h of therapeutic parenteral anticoagulation (heparin, enoxaparin, fondaparinux, bivalirudin, or argatroban) before starting apixaban or rivaroxaban.

Full lead-in dosing was 13–14 doses of apixaban 10 mg or 39–42 doses of rivaroxaban 15 mg. Reduced lead-in dosing was at least 7 or 21 days of sequential parenteral anticoagulation and lead-in dosing of apixaban or rivaroxaban, respectively. Two doses of apixaban or rivaroxaban lead-in dosing were substituted for each 24-hour period of therapeutic parenteral anticoagulation.

Data were collected from electronic records using ICD-9 and ICD-10 codes.
Duration January 2017 to March 2024
Outcome Measures Primary: Time to recurrent VTE within six months

Secondary: Major bleeding, clinically relevant non-major bleeding (CRNMB), re-hospitalization for VTE or anticoagulant related events, hospital length of stay, mortality within six months
Baseline Characteristics   Full Lead-In (n= 1,068) Reduced Lead-In (n= 356) p-value
Age, years 63.4 ± 15.6 67.9 ± 13.6 0.29
Female 560 (52.4%) 169 (47.5%) 0.04
Weight, kg 93.5 ± 29.4 86.5 ± 23.7 0.25
BMI, kg/m2 32.3 ± 9.8 29.8 ± 8.3 0.38
ICU Admission 309 (28.9%) 141 (39.6%) 0.1

Type of VTE

DVT
PE
DVT and PE

 

97 (9.1%)
664 (62.2%)
177 (16.6%)

 

70 (19.7%)
207 (58.1%)
57 (16.0%)

 

0.14
0.04
0.01
Duration of parenteral AC, median, h 44 192 <0.01

DOAC

Apixaban

Rivaroxaban

 

869 (81.4%)

199 (18.6%)

 

245 (68.8%)

111 (31.2%)

 -

Concomitant medications

Aspirin
P2Y12 Inhibitors
NSAIDs
Estrogen
SSRI
Non-DHP CCB
Amiodarone
SNRI
TCA

 

199 (18.6%)
48 (4.5%)
41 (3.8%)
16 (1.5%)
111 (10.4%)
33 (3.1%)
23 (2.2%)
36 (3.4%)
23 (2.2%)

 

92 (25.8%)
25 (9.8%)
4 (1.1%)
4 (1.1%)
36 (10.1%)
10 (2.8%)
16 (4.5%)
10 (2.8%)
14 (3.9%)

 

0.08
0.10
0.07
0.01
<0.01
0.01
0.06
0.01
0.05
Abbreviations: AC= anticoagulant. BMI= body mass index. CCB= calcium channel blocker. DHP= dihydropyridine. DOAC= direct oral anticoagulant. DVT= deep vein thrombosis. ICU= intensive care unit. NSAIDs= nonsteroidal anti-inflammatory drugs. PE= pulmonary embolism. SSRI= selective serotonin reuptake inhibitor. TCA= tricyclic antidepressant. VTE= venous thromboembolism.
Results   Full Lead-In (n= 1068) Reduced Lead-In (n= 356) p-value
Recurrent VTE 29 (2.7%) 5 (1.4%) 0.16
Major Bleeding 26 (2.4%) 8 (2.2%) 0.84
CRNMB  24 (2.2%) 6 (1.7%) 0.52
Re-hospitalization  44 (4.1%) 11 (3.15) 0.38
Hospital length of stay, days  6.9 ± 6.7  13.9 ± 9.3  <0.01
All-cause Mortality 16 (1.5%) 22 (6.2%) <0.01
Time to recurrence was not different between groups (p= 0.18).
Adverse Events Higher all-cause mortality in the reduced lead-in group (p<0.01); however, the propensity-matched cohorts (n= 316 in each group) demonstrated no difference in all-cause mortality (5.7% vs. 3.5%; p= 0.18).
Study Author Conclusions Among patients transitioning from parenteral anticoagulation to oral factor Xa inhibitors, a reduced lead-in duration was not associated with increased VTE recurrence or major bleeding.
Critique The study is strengthened by its large sample size and multicenter design, providing adequate power to detect differences in clinical outcomes. However, as a retrospective observational study, it may be subject to biases related to documentation accuracy and selection. Additionally, the study's findings may not be generalizable to shorter durations of anticoagulation or different patient populations.

 

Table 1 References:
[5] Jolakoski N, Grazia S, Brewster C, et al. Rethinking lead-in strategies: evaluation of full vs. reduced dose factor Xa inhibitors in acute VTE. J Thromb Thrombolysis. 2026;59(3):708-717. doi:10.1007/s11239-025-03199-8
Modified vs Full Lead-in Dose Apixaban and Rivaroxaban for Treatment of Acute Venous Thromboembolism
Design Single-center, retrospective cohort study

N= 101
Objective To evaluate the effectiveness and safety of a modified lead-in strategy, where parenteral anticoagulation (AC) counts toward shortening or eliminating the direct oral anticoagulant (DOAC) lead-in period, compared to a full lead-in strategy, where a 7-day apixaban or 21-day rivaroxaban lead-in is prescribed irrespective of parenteral anticoagulation received
Study Groups Modified lead-in (n= 47)

Full lead-in (n= 54)
Inclusion Criteria Patients ≥18 yo; diagnosed with acute venous thromboembolism (VTE) during hospitalization; received continuous infusion unfractionated heparin (UFH) or therapeutic enoxaparin for at least 24 hours before transitioning to apixaban or rivaroxaban
Exclusion Criteria Patients on AC prior to admission; received thrombolytics during current hospitalization; diagnosed solely with left ventricular thrombus or cerebral venous sinus thrombus; pregnant; incarcerated
Methods

Patients were grouped based on a modified versus full lead-in DOAC treatment strategy.

A modified lead-in strategy was defined as any regimen in which the duration of parenteral anticoagulation counted toward shortening or eliminating the oral lead-in period.

A full lead-in strategy was defined as completion of the full oral high-dose lead-in, regardless of prior parenteral anticoagulation received.

Total anticoagulation exposure was determined using dispense histories documented in the institution’s electronic health record.

Recurrent VTE and mortality were evaluated through 90 days after the index VTE; bleeding outcomes were evaluated from the first day of parenteral anticoagulation.
Duration January 2022 to September 2024
Outcome Measures Primary: Incidence of recurrent VTE (rVTE)

Secondary: Composite of major bleeding and clinically relevant non-major bleeding (CRNMB) at 90 days, individual incidence of major bleeding and CRNMB, time to bleeding event, mortality
Baseline Characteristics   Modified lead-in (n = 47) Full lead-in (n = 54) p-value
Age, years 58.4 ± 12.4 56.5 ± 17 0.6750
Female 24 (51%) 21 (39%) 0.2191
Weight, median (IQR), kg 80 (68-93) 88.1 (68.8-98.8) 0.2498
BMI, median (IQR), kg/m2 29.6 (24.1-32.4) 28.7 (24.55-35) 0.6048
Hypertension 30 (64%) 30 (56%) 0.3976
Diabetes 21 (45%) 12 (22%) 0.0160
Active cancer 17 (36%) 17 (31%)  0.6191
History of VTE 7(15%) 6 (11%) 0.7979
Liver disease 4 (9%) 3 (6%) 0.7019
Chronic kidney disease 10 (21%) 1 (2%) 0.0025
CrCl, median (IQR), mL/min 95.9 (63.2-120) 116.1 (89.4-120) 0.0155
Hospital length of stay, median (IQR), days 9 (6.8-16.2) 4.9 (3.1-8.1) <0.0001
Bleeding within prior 12 months 19 (40%) 7 (13%) 0.0018

Antiplatelet agents

Aspirin

Clopidogrel

Scheduled NSAID

 

12 (26%)

1 (2%)

0 (0%)

 

12 (22%)

0 (0%)

1 (2%)

 

-

-

-
DOAC score ≥8 (high/very high bleed risk) 12 (25%) 3 (6%) 0.0049

Parenteral AC agent

UFH

Enoxaparin

 

34 (72%)

13 (28%)

 

47 (87%)

7 (13%)

 

-

-
Length of parenteral AC, median (IQR), days 5.3 (3.0-7.7)  2.3 (1.7-3.9)  <0.0001

Oral AC agent

Apixaban

Rivaroxaban

 

40 (85%)

7 (15%)

 

41 (76%)

13 (24%)

 

-

-

VTE event type

PE

DVT

Both

 

17 (36%)

16 (34%) 

14 (30%)

 

29 (54%)

6 (11%)

19 (35%)

 

0.0776

0.0054

0.5640
Results   Modified lead-in (n = 47) Full lead-in (n = 54) p-value
rVTE events at 90 days 4 (9%) 2 (4%) 0.4129
Composite major bleeding or CRNMB at 90 days 10 (21%) 3 (6%) 0.0167
Time to bleeding events, median (IQR), days 50.6 (29.4-63.25)  72 (44-82)  0.2049
Mortality at 90 days 5 (11%) 3 (6%) 0.4671
Adverse Events Of 13 total bleeding events, 5 were classified as major bleeding (3 [6%] vs 2 [4%]) and 8 as CRNMB (7 vs 1); the publication reported the corresponding CRNMB percentages as 19% and 2%, respectively.
Study Author Conclusions No significant difference in recurrent VTE was observed between groups. The modified lead-in group had a higher incidence of bleeding, possibly reflecting greater baseline risk and clinical complexity rather than the modification itself. Modified lead-in strategies may be reasonable in select patients, particularly those at high risk for bleeding; however, larger studies are needed to confirm safety and efficacy.
Critique The study provides valuable insights into real-world prescribing practices and highlights the potential for modified lead-in strategies in high-risk patients. However, the small sample size and retrospective design limit the ability to detect statistically significant differences in outcomes. The study's findings may not be generalizable due to the higher prevalence of active cancer and longer parenteral AC exposure in the modified lead-in group. Additionally, the reliance on outpatient follow-up for outcome evaluation may have led to underrepresentation of events. Larger, prospective studies are needed to validate these findings.

 

Table 2 References:
[6] Lahoud J, Jacobs J, Ratrut L, Kitten A, Franco-Martinez C. Modified vs Full Lead-in Dose Apixaban and Rivaroxaban for Treatment of Acute Venous Thromboembolism. Ann Pharmacother. Published online June 28, 2026. doi:10.1177/10600280261456308
Comparing the Safety and Effectiveness of Apixaban Lead-In Dosing Strategies in Hospitalized Adults With Venous Thromboembolism
Design

Retrospective, single-center, observational study

N= 68
Objective To evaluate the effectiveness and safety of different apixaban lead-in durations for hospitalized adults with newly diagnosed VTE
Study Groups

Parenteral + abbreviated lead-in apixaban (n= 11)

Parenteral + full lead-in apixaban (n= 25)

Apixaban-only full lead-in (n= 32)
Inclusion Criteria Patients ≥18 yo with a new incidence of VTE (DVT or PE) that received apixaban 5 mg twice daily
Exclusion Criteria Patients that received parenteral anticoagulation for ≥8 days before transitioning to apixaban, had left ventricular thrombus, were pregnant, had underlying hemophilia or thrombophilia, had severe hepatic dysfunction (Child Pugh Class C), switched to a different anticoagulant during the 6-month treatment period, had <6 months of follow-up data, were on chronic anticoagulation leading up to admission, or had active bleeding or malignancy at time of admission
Methods

Retrospective analysis of patients with one of the following lead-in regimens: (1) parenteral anticoagulation ≥48 hours with abbreviated course of apixaban lead-in, (2) parenteral anticoagulation ≥48 hours with full apixaban lead-in, or (3) no parenteral anticoagulation with full apixaban lead-in.

All regimens were followed by maintenance apixaban for at least 6 months. Data were collected from electronic medical records using ICD-10 codes.
Duration March 1, 2014, to September 1, 2019, with data collected through March 1, 2020
Outcome Measures

Primary: Incidence of recurrent VTE (rVTE) and bleeding events within 6 months

Secondary: Type of rVTE (DVT or PE) or bleeding event (MB or CRNMB), time to first occurrence of rVTE or bleeding event, all-cause mortality within 180 days after admission
Baseline Characteristics   Parenteral + abbreviated lead-in apixaban (n= 11) Parenteral + full lead-in apixaban (n= 25) Apixaban-only full lead-in (n= 32) p-value
Age, median (IQR), years  70 (54-80) 66 (49-78) 52.5 (39.5-61) <0.01
Female 6 (54.5%) 13 (52%) 18 (56.3%)  0.95

Race

White

Black or African American

 

9 (81.8%)

2 (18.2%)

 

20 (80%)

3 (12%)

 

20 (62.5%)

9 (28.1%)

0.67

 

 
Weight, median (IQR), kg  61.6 (50.1-70.7) 61.6 (56.9-70.7) 62.8 (55.8-74) 0.59
BMI, median (IQR), kg/m2 29.8 (25.6-38.7) 30.1 (27-35.5) 31 (27.2-36.5) 0.99

Comorbidities

Hypertension
Obesity
Diabetes mellitus
Hyperlipidemia
Coronary artery disease
Chronic kidney disease
Atrial fibrillation
Previous stroke/TIA
None

 

10 (90.9%)
4 (36.4%)
4 (36.4%)
4 (36.4%)
3 (27.3%)
1 (9.1%)
1 (9.1%)
0 (0%)
1 (9.1%)

 

14 (56%)
7 (28%)
5 (20%)
4 (16%)
2 (8%)
2 (8%)
1 (4%)
4 (16%)
7 (28%)

 

12 (37.5%)
12 (37.5%)
4 (12.5%)
4 (12.5%)
1 (3.1%)
1 (3.1%)
0 (0%)
1 (3.1%)
12 (37.5%)

 

<0.01
0.78
0.24
0.21
0.18
0.50
0.15
0.18
0.23

Type of VTE

DVT
PE
DVT + PE

 

1 (9.1%)
9 (81.8%)
1 (9.1%)

 

2 (8%)
23 (92%)
0 (0%)

 

20 (62.5%)
12 (37.5%)
0 (0%)

 <0.01

 

 

Laboratory Value, median (IQR)

CrCl, mL/min
Hemoglobin, g/dL
Hematocrit, %
Platelets, THOU/uL

 

68.3 (52.6–115)
11.8 (10.4–14.6)
37 (33–46)
223 (168–277)

 

71.6 (52.3–93.1)
13.7 (12.1–14.5)
42 (37–45)
226 (196–252)

 

90 (67–108)
13.8 (12.3–14.4)a
40 (38–43)a
246.5 (197–293)b

 

0.28
0.54
0.70
0.87

Medications after admission

Aspirin
P2Y12 inhibitor
Aspirin + P2Y12 inhibitor + AC

 

7 (63.6%)
1 (9.1%)
1 (9.1%)

 

9 (36%)
1 (4%)
0 (0%)

 

3 (9.4%)
0 (0%)
0 (0%)

 

<0.01
0.15
0.16

Parenteral anticoagulation

Enoxaparin
IV unfractionated heparin

 

11 (100%)
1 (9.1%)

 

20 (80%)
7 (28%) 

 

0 (0%)
0 (0%)

 

0.30
0.39

Time from parenteral AC to apixaban

Started at the same time
48 hours
49–72 hours
73–96 hours
97–120 hours
121–144 hours
145–168 hours

 

—
4 (36.4%)
3 (27.3%)
3 (27.3%)
0 (0%)
0 (0%)
1 (9.1%)

 

—
5 (20%)
11 (44%)
5 (20%)
1 (4%)
2 (8%)
1 (4%)

 

32 (100%)
—
—
—
—
—
—

 

—
0.41
0.47
0.68
0.99
0.99
0.52

Apixaban lead-in dose is full duration

0 (0%)

25 (100%)

32 (100%)

<0.01

Number of apixaban days if not full lead-in, median (IQR)

5 (4-6)

-

-

-

a. n= 27. b. n= 26

Abbreviations: AC= anticoagulant. BMI= body mass index. CrCl= creatinine clearance. DVT= deep vein thrombosis. IQR= interquartile range. PE= pulmonary embolism. TIA= transient ischemic attack. VTE= venous thromboembolism.
Results   Parenteral + abbreviated lead-in apixaban (n = 11) Parenteral + full lead-in apixaban (n = 25) Apixaban-only full lead-in (n= 32) p-value
Recurrent VTE within 6-months 0 (0%) 1 (4%) 1 (3.1%) 0.99

Type of recurrent VTE

DVT
PE

 

-

-

 

1 (100%)
0 (0%)

 

1 (100%)
0 (0%)

 

-

-
Bleeding event within 6-months 0 (0%) 1 (4%) 2 (6.3%) 0.99

Type of bleeding event

CRNMB
Major bleed

 

-

-

 

1 (100%)
0 (0%)

 

2 (100%)
0 (0%)

 

-

-
Time to recurrent VTE, days - 47 45 -
Time to bleed, days - 167 149-150 -
All-cause mortality at 6 months 0 (0%)  0 (0%) 0 (0%) -
Adverse Events All bleeding events were clinically relevant non-major bleeding (CRNMB).
Study Author Conclusions Similar safety and effectiveness were noted between the 3 apixaban lead-in regimens. These findings suggest that all 3 regimens provide similar outcomes, warranting further investigation to optimize lead-in strategies.
Critique The low event rate and retrospective design limit definitive conclusions. Generalizability may also be limited by exclusion of patients with major clotting or bleeding risk factors and those who received ≥8 days of parenteral anticoagulation, limiting applicability to patients receiving prolonged parenteral therapy before apixaban initiation.

 

Table 3 References:
[7] Spencer J, Buchanan T, Heacock S, et al. Comparing the Safety and Effectiveness of Apixaban Lead-In Dosing Strategies in Hospitalized Adults With Venous Thromboembolism. J Pharm Technol. 2025;41(3):108-115. doi:10.1177/87551225251326436

 

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)

 62 (53-71) 68 (48.5-75)  

Female

55% 53%  

White

African American

Hispanic

48%

38%

12%

53%

27%

16%

  

BMI, median (IQR)

 28.5 (25.3-36) 27 (23.2-30.35)  

CrCl, median (IQR)

 87 (61-109) 69 (49.5-101.5)  

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)

 1 (0-2) 1 (1-2)  

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)

 5 (3-9) 12 (6-23.5)  

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

 3.2% 5.1% 0.7

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. 



Table 4 References:
[8] Cho SS, Yin E, Dalton K. Evaluation of Lead-In Direct Oral Anticoagulant Prescribing Practices in Newly Diagnosed Venous Thromboembolism [published online ahead of print, 2023 Sep 23]. J Clin Pharmacol. 2023;10.1002/jcph.2350. doi:10.1002/jcph.2350

 

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

 60.5 ± 20.3 52.6 ± 19.7  

Female

50.5% 65.5%  

BMI, kg/m2

 30.2 ± 7.4 31.1 ± 6.9  

Hospital length of stay, days

 15.2 ± 28.1 4.6 ± 7.4  

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 

 2.2% 0 0.032
 

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. 



Table 5 References:
[9] Korayem GB, Alshaya OA, Alnajjar N, et al. 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. Int J Gen Med. 2023;16:129-140. Published 2023 Jan 7. doi:10.2147/IJGM.S392505

 

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

 55.2 ± 19.2 52.6 ± 19.7  

Female

 59.7% 65.5%  

BMI, kg/m2

 29.3 ± 7.1 31.1 ± 6.9  

Hospital length of stay, days*

 12.2 ± 25.3  4.6 ± 7.4   

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

 0 0 --

NS: not significant

Adverse Events

 See above. 

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

 The retrospective nature and small sample size of this study are inherent limitations. The overall patient population was relatively young, with low bleeding risk and adequate renal function, hindering generalizability of results to other patient populations. 



Table 6 References:
[10] Alshaya OA, Korayem GB, Al Yami MS, et al. Comparative Effectiveness of Apixaban and Rivaroxaban Lead-in Dosing in VTE Treatment: Observational Multicenter Real-World Study. J Clin Med. 2022;12(1):199. Published 2022 Dec 27. doi:10.3390/jcm12010199