Does apixaban require a loading dose when transitioning from Lovenox for patients with acute DVT/PE?

Comment by InpharmD Researcher

There is a paucity of data evaluating the omission or reduced duration of an apixaban loading dose in patients who have already received parenteral treatment for DVT/PE. Per the 2020 American Society of Hematology guidelines, direct oral anticoagulants can be given at a standard- or low-dose after primary treatment for VTE, especially if bleeding is a risk. However, a pharmacokinetic study of apixaban shows the AUC of 5 mg BID is less than half of 10 mg BID after 7 days, potentially underdosing a patient if not given the loading regimen.

Background

Per the 2020 American Society of Hematology guidelines for the management of venous thromboembolism (VTE), patients who have completed primary treatment and will transition to a direct oral anticoagulant (DOAC) for secondary prevention are recommended to receive a standard- or low-dose DOAC. The guidelines have only identified two agents studied at a reduced dose: apixaban 2.5 mg BID (from 5 mg BID) and rivaroxaban 10 mg daily (from 20 mg daily). Use of a lower dose may be prompted by the desire to reduce the risk of bleeding. When compared to standard doses, lower doses of DOACs are associated with a nonsignificant increase in the risk of nonfatal pulmonary embolism. [1]

A pharmacokinetic/pharmacodynamics study of multiple-dose apixaban was performed in healthy subjects over 7 days (see Table 1). 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 1,051.9 ng·h/mL versus 2,424.9 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 dose. [2]

In the AMPLIFY trial studying apixaban for venous thromboembolism treatment, patients were started with a loading dose of 10 mg BID x7 days then 5 mg BID for six months. In this study, nearly two-thirds of patients had previous treatment with heparin (unfractionated or low-molecular-weight) before the study medication was administered. However, patients who had more than 36 hours of continuous intravenous heparin were excluded. [3]

The manufacturer of apixaban, Bristol-Myers Squibb, does not provide any guidance on starting apixaban in patients who have received > 48 hours of low molecular weight heparin (LMWH) therapy for the treatment of venous thromboembolism (VTE). No clinical studies have evaluated dosing strategies for this clinical situation. Patients who received more than 2 doses of LMWH or a heparin drip for >36 hours were excluded from the phase III AMPLIFY study. [4]

References:

[1] Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738.
[2] 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
[3] Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
[4] Bristol-Myers Squibb. Apixaban dose for the treatment of DVT or PE in patients who have received over 48h of LMWH. Medical Communications.
Relevant Prescribing Information

ELIQUIS [5]

Treatment of DVT and PE
The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.

Converting from or to ELIQUIS
Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual time of the next dose of the anticoagulant other than warfarin.

References:

[5] Eliquis [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2021.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Does apixaban require a loading dose when transitioning from Lovenox for patients with acute DVT/PE?

Level of evidence

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Please see Tables 1-2 for your response.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

Design

Randomized, double-blind, placebo-controlled, parallel-group trial

N=48

Objective

This study examined the safety, pharmacokinetics, and pharmacodynamics of multiple-dose apixaban

Study Groups

Apixaban (n=36)

Placebo (n=12)

Inclusion Criteria

Age 18 to 45 years, body mass index between 18-30 kg/m2

Exclusion Criteria

Previous history of coagulopathy or adverse reaction to anticoagulant or antiplatelet agents; significant head injury within the previous 2 years; gastrointestinal disease within the previous 3 months; blood transfusion or donation of blood or plasma within 4 weeks before the study; inability to tolerate venipuncture or venous access

Methods

Participants were randomized 3:1 to receive apixaban or placebo. The apixaban patients received 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily (n= 6 for each). 

Duration

7 days

Outcome Measures

Pharmacokinetics parameters

Baseline Characteristics

  

Apixaban 5 mg BID (n=6)

Apixaban 10 mg BID (n=6)

Placebo (n=12)

Age, years

 31 30 34

Men

 6 (100%) 6 (100%) 12 (100%)

White

 4 (67%) 4 (67%) 7 (58%)

BMI, kg/m2

 25.1 23.2 23.7

Results

 

Cmax, ng/mL

Cmin, ng/mL

AUC, ng·h/mL

Day 1

5 mg BID

10 mg BID

 

81.9

226.2

 

25.3

72.7

 

600.6

1,608.3

Day 7

5 mg BID

10 mg BID

 

128.5

329.8

 

49.6

103.8

 

1,051.9

2,424.9
AUC= area under the curve; Cmax= maximum concentration; Cmin= minimum concentration

Study Author Conclusions

Multiple oral doses of apixaban were safe and well-tolerated, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.

InpharmD Researcher Critique

 The study population was small and consisted of all healthy males. This could have influenced the data that was obtained and thus, the application of it to the general population.
References:

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

 

Transforming and Simplifying the Treatment of Pulmonary Embolism (PE): ‘‘Safe Dose’’ Thrombolysis Plus New Oral Anticoagulants

Design

Retrospective, open-label, non-controlled, single-arm, cohort study

N= 159

Objective

To describe the experience in patients with moderate or severe PE who underwent safe dose thrombolysis (SDT) plus new oral anticoagulant (NOAC), and if substantiated by larger trials, to propose a transformational change in the treatment of symptomatic PE from an ‘‘anticoagulation first’’ to an ‘‘SDT first’’ approach.

Study Groups

All patients (n= 159)

Inclusion Criteria

Patients with moderate and severe PE; had at least a moderate thrombotic burden on computed tomographic angiography or ventilation/perfusion scanning; had a minimum of three or more of the following symptoms: chest pain, tachypnea (resting respiratory rate ≥20/min), tachycardia (resting heart rate ≥90/min), dyspnea, oxygen desaturation (ambient O2 saturation <95 %), or elevated jugular venous pressure (≥10 cm H2O); had undergone treatment with SDT and NOAC

Exclusion Criteria

Not specified (no patient was excluded for previous VTE or chronicity of disease)

Methods

Eligible patients with moderate and severe PE were prospectively followed to evaluate their clinical and echocardiographic outcome. The patients were evaluated at least daily while in the hospital, within 3 weeks of discharge, and every 6-month thereafter. All patients received heparin at a modified dose for 24 hours. Heparin was given at 70 U/kg as a bolus, but not to exceed 6000 U, with subsequent dose adjustment to keep the activated partial thromboplastin time (PTT) at 60–100 s. While tPA was being infused and for 3 hours thereafter, the maintenance dose of heparin was kept at 8–10 U/kg/h, not to exceed 1000 U/h. It was subsequently adjusted to reach the target PTT at 60–100 s but with no bolus injections.

After 24 hours of infusion, heparin was completely stopped and patients received rivaroxaban at 15 or 20 mg daily, or apixaban at 2.5 or 5 mg twice daily, 2 h after termination of heparin infusion. Patients with creatinine clearance of >30 mL/min and a weight ≥50 kg received 20 mg of rivaroxaban daily, and those with a creatinine clearance of 15–30 mL/min or a weight <50 kg received 15 mg daily. Patients with creatinine clearance of <15 mL/min, dialysis patients, or those with gastrointestinal symptoms, recent surgical procedures, and bleeding tendencies received apixaban. In these patients, if the weight was <50 kg the lower apixaban dose was utilized. Aspirin at 81 mg was given to patients with no contraindication to its use for a minimum of one month at the time initiation of NOAC and for those who were already on it and if at higher dose, the dose was reduced to 81 mg daily.

Duration

Treatment: January 2012 to December 2013

Follow up: 18 ± 3 months

Outcome Measures

Primary outcomes: change in RV/LV ratio, PASP, heart rate, respiratory rate, subjective improvement before and shortly after SDT

Secondary outcomes: bleeding, mortality, and recurrent venous thromboembolism (VTE) during hospitalization and at follow-up

Baseline Characteristics

  

All patients (n= 159)

      

Age, years

 67 ± 7      

Male

82 (52%)      

Previous or concomitant disease

Hypertension

Diabetes mellitus

Cardiovascular

Hypercholesterolemia

Pulmonary

Renal

Current smoker

Surgery or trauma (within previous 3 m)

Estrogen/testosterone therapy

 

64 (40%)

45 (28%)

52 (33%)

33 (21%)

26 (16%)

10 (6%)

18 (11%)

14 (9%)

24 (15%)

      

Cancer

Active

History

 

23 (14%)

10 (6%)

      

Known prothrombotic state

 11 (7%)       

Evidence for thrombotic risk

Previous venous thromboembolism (VTE)

Bilateral pulmonary embolism (PE)

Concomitant deep venous thrombosis (DVT)

D-dimer elevation

Troponin I elevation

Brain natriuretic peptide (BNP) elevation

Right ventricle (RV) enlargement

 

29 (18%)

132 (83%)

92 (58%)

159 (100%)

113/146 (77%)

120/141 (85%)

105/151 (70%)

      

Thrombotic burden

Moderate PE*

Severe PE**

Mild

Massive

Submassive

 

136 (85.5%)

23 (14.5%)

0

13 (8.2%)

146 (92%)

      

*Moderate PE was defined as ≥70 % involvement of the right or left pulmonary artery (PA) or two lobar branches. PE was said to be moderate if the patient was symptomatic, had moderate thrombotic burden and was normotensive.

**Severe PE was defined as systolic blood pressure was ≤100 mmHg plus all other features of moderate PE; saddle pulmonary embolism; or involvement of >70 % of the main PA with thrombus, irrespective of blood pressure.

Results

Endpoint

All patients (n= 159)

Before SDT

All patients (n= 159)

Within 36 h after

All patients (n= 159)

6 months

p-value

Changes in echocardiographic and clinical parameters

PASP (mmHg)

RV/LV

Heart rate

Respiratory rate

Symptoms severity

 

53.12 ± 3.85

1.29 ± 0.28

103.78 ± 9.25

23.13 ± 3.60

6.35 ± 1.46

 

32.34 ± 3.66

0.93 ± 0.05

79.42 ± 5.13

16.55 ± 1.34

1.51 ± 0.71

 

30.39 ± 3.93

0.89 ± 0.03

--

--

-- 

 

p< 0.001

p< 0.001

p< 0.001

p< 0.001

p< 0.001

The duration of hospitalization was very short at 1.8 ± 0.3 days.

At the last follow-up, 112 patients (70 %) were still on anticoagulation.

At hospital discharge 132 patients were on aspirin. Indefinite anticoagulation was recommended to 103 patients (65 %).

Adverse Events

Adverse Events: One patient (0.6%) developed hematoma in the psoas muscle while being bridged with enoxaparin to warfarin 2 months after discharge, One patient (0.6%) who was on rivaroxaban at 20 mg daily developed gross hematuria after being started on high-dose amiodarone. He was also on aspirin and clopidogrel. No patient experienced major or minor in-hospital bleeding.

Percentage that Discontinued due to Adverse Events: there was no in-hospital mortality. Three patients died of cancer (8–17 months after discharge).

Study Author Conclusions

With combination of SDT and NOAC, treatment of massive and submassive PE becomes identical and is transformed from an ‘‘anticoagulation first’’ to a ‘‘thrombolysis first’’ approach, thereby making treatment streamlined, simple, safe and effective, accessible and inexpensive.

InpharmD Researcher Critique

 The study is limited based on retrospective, open-label, non-controlled, lack of exclusion criteria and relatively small sample size nature. There was a lack of control group to gauge the magnitude of therapy. The majority of patients consist of those with moderate to severe submassive pulmonary embolism



References:

Sharifi M, Vajo Z, Freeman W, Bay C, Sharifi M, Schwartz F. Transforming and simplifying the treatment of pulmonary embolism: "safe dose" thrombolysis plus new oral anticoagulants. Lung. 2015;193(3):369-374. doi:10.1007/s00408-015-9702-1