What is the best strategy for initiating a heparin infusion for acute or worsening venous thromboembolism (VTE) in a patient who is actively taking a direct oral anticoagulant (DOAC)?

What is the best strategy for initiating a heparin infusion for acute/worsening venous thromboembolism (VTE) in a patient who is actively taking a direct oral anticoagulant (DOAC)?

Comment by InpharmD Researcher

Data on the optimal strategy for initiating a heparin infusion in patients with acute or worsening venous thromboembolism (VTE) who are actively taking a direct oral anticoagulant (DOAC) is limited and mainly focuses on laboratory monitoring considerations and assay interference during anticoagulant transitions. Approaches suggested in the literature include timing unfractionated heparin (UFH) initiation based on the last DOAC dose, avoiding an initial bolus, and using activated partial thromboplastin time (aPTT) for early monitoring due to potential interference with anti-factor Xa assays. Despite concern for potential interference, one retrospective analysis assessing the transition from apixaban or rivaroxaban to UFH utilized a standardized anti-factor Xa-guided UFH titration protocol with an initial weight-based infusion and dose adjustments based on anti-factor Xa levels checked every 6 hours until therapeutic (see Tables 1 and 2). Overall, in the absence of direct outcome-based data, recommendations are primarily based on pharmacologic principles and laboratory assay behavior rather than validated clinical protocols specifically addressing acute VTE deterioration in patients actively receiving a DOAC. An additional search did not yield further information.

Background

A 2016 guidance article on the practical management of direct oral anticoagulants (DOACs) in venous thromboembolism (VTE) treatment describes transition strategies between parenteral anticoagulation and oral factor Xa inhibitors in the context of VTE therapy. While the guidance details approaches to transitioning from unfractionated heparin (UFH) to DOACs, the reverse scenario of initiating UFH in patients already taking a DOAC is not specifically addressed, making the optimal strategy for this situation unclear. [1]

There appears to be limited guidance on the optimal strategy for initiating a heparin infusion in patients with acute or worsening VTE who are actively taking an oral factor Xa inhibitor; however, another 2016 review suggests potential approaches when transitioning from a factor Xa inhibitor to UFH. The recommended strategy is to first determine the time of the last DOAC (factor Xa inhibitor) dose, then initiate UFH infusion without a bolus approximately 2 hours before the time when the next scheduled DOAC dose would have been due. During the initial 48 hours of UFH therapy (extended to 72 hours in patients with significant renal or hepatic impairment), anticoagulation should be monitored using aPTT every 6-8 hours due to potential assay interference from the DOAC. After this period, transition to anti-Xa monitoring may be considered, though if anti-Xa levels are >1.10 IU/mL on two consecutive measurements, reverting back to aPTT monitoring is suggested. In addition, experts recommend considering aPTT assay monitoring over anti-Xa monitoring during the first 28 to 72 hours of UFH infusion due to potential assay interference, and emphasizes careful monitoring during this transition period. It is important to note that these recommendations are not specific to acute or worsening VTE itself, but rather apply to the pharmacologic and laboratory considerations involved in transitioning from an oral factor Xa inhibitor to unfractionated heparin. [2]

Literature Review

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

What is the best strategy for initiating a heparin infusion for acute/worsening venous thromboembolism (VTE) in a patient who is actively taking a direct oral anticoagulant (DOAC)?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-2 for your response.

Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: A retrospective review
Design	Retrospective chart review N= 76
Objective	To determine a patient’s clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin (UFH) infusion.
Study Groups	Heparin anti-Xa (n= 69) aPTT (n= 7)
Inclusion Criteria	Patients at least 18 years of age with administration of rivaroxaban or apixaban within 72 hours prior to an order for a continuous UFH infusion
Exclusion Criteria	Child-Pugh score “C”; administration of UFH, low-molecular-weight heparin, direct thrombin inhibitors, fondaparinux, or thrombolytics within 48 hours prior to an order for continuous UFH; and warfarin or edoxaban administration within 5 days prior to an order for continuous UFH
Methods	Retrospective chart review of patients' electronic medical records. Patients were separated into cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. Data collected included bleeding and thrombotic events, UFH infusion holds, and rate changes. Heparin titration protocols were based on actual body weight, with units rounded to the nearest 100-unit intervals (see dosing protocol in Table 2).
Duration	Data collection from November 2017 through February 2018
Outcome Measures	Primary: Total number of bleeding and thrombotic events Secondary: Average incidence of heparin infusion holds and rate changes per patient
Baseline Characteristics		Heparin Anti-Xa Cohort (n= 69)
	DOAC use - Apixaban	24 (34.8%)
	DOAC use - Rivaroxaban	45 (65.2%)
	Age, years (IQR)	68 (59-73)
	Body mass index, kg/m2 (IQR)	30.2 (27.5-34.7)
	Indication for UFH infusion - Treatment of DVT/PE	21 (30.4%)
	Indication for UFH infusion - Acute coronary syndrome	19 (27.5%)
	Indication for UFH infusion - Nonvalvular atrial fibrillation	17 (24.6%)
	Indication for UFH infusion - History of DVT/PE	4 (5.8%)
	Indication for UFH infusion - Nonischemic cardiomyopathy	4 (5.8%)
	Indication for UFH infusion - Critical limb ischemia	2 (2.9%)
	Indication for UFH infusion - Treatment embolic stroke/arterial clot	2 (2.9%)
	Indication for UFH infusion - History embolic stroke/arterial clot	0 (0%)
	Abbreviations: DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; IQR, interquartile range; PE, pulmonary embolism.
Results	Due to the small number of patients in the aPTT group, outcome data for that cohort were not reported. Among 69 patients monitored using a heparin anti-Xa protocol, the mean number of unplanned UFH infusion holds due to supratherapeutic anti-Xa levels was 0.84 per patient, and UFH infusion rates were adjusted a mean of 2.65 times per patient. Mean up-titrations and down-titrations were similar (1.30 and 1.35 per patient, respectively). Most UFH dose reductions occurred within the first 6 hours after UFH initiation, while most dose increases occurred after 36 hours.
Adverse Events	In the heparin anti-Xa cohort, there were 10 bleeding events (4 major, 5 clinically relevant nonmajor, and 1 minor) and 1 thrombotic event (a peripherally inserted central catheter line–associated deep vein thrombosis).
Study Author Conclusions	In the presence of a recently administered oral factor Xa inhibitor, more down-titrations occur in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, whereas more up-titrations occur after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.
Critique	The study was limited by the small sample size of the aPTT cohort, which prevented meaningful comparisons between groups. The retrospective design may have introduced confounding, and identification of bleeding and thrombotic events relied on chart documentation. Additionally, although patients receiving UFH for DVT and PE were included, outcomes were not stratified by indication for UFH initiation, limiting interpretation in patients with acute or worsening venous thromboembolism.

References:
[1] [1] Smith AR, Dager WE, Gulseth MP. Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: a retrospective review. Am J Health Syst Pharm. 2020;77(Suppl 3):S59-s65. doi:10.1093/ajhp/zxaa143

Unfractionated Heparin Titration Nomogram by Indication and Anti-Xa Level
	Venous Thromboembolism		Cardiac, Stroke, Other Nonvenous Thromboembolism
Regimen	Standard-Intensity	Low-Intensity	Standard-Intensity	Low-Intensity
Initial bolus	80 units/kg maximum: 10,000 units optional—provider discretion	None	60 units/kg maximum: 4,000 units optional—provider discretion	None
Initial maintenance rate	18 units/kg/h maximum: 2,000 units/h	18 units/kg/h maximum: 2,000 units/h	12 units/kg/h maximum: 1,000 units/h	12 units/kg/h maximum: 1,000 units/h
Adjustments for heparin anti-Xa levels (drawn every 6 hours until 2 consecutive levels within goal range, then drawn every 24 hours)	<0.20 Increase rate 2 units/kg/h + 30 unit/kg bolus	<0.20 Increase rate 2 units/kg/h	<0.20 Increase rate 2 units/kg/h + 30 unit/kg bolus	<0.20 Increase rate 2 units/kg/h
	0.20–0.29 Increase rate 1 units/kg/h + 15 unit/kg bolus	0.20–0.29 Increase rate 1 units/kg/h	0.20–0.29 Increase rate 1 units/kg/h + 15 unit/kg bolus	0.20–0.29 Increase rate 1 units/kg/h
	0.30–0.70 No change	0.30–0.50 No change	0.30–0.70 No change	0.30–0.50 No change
	0.71–0.85 Decrease rate 1 unit/kg/h	0.51–0.64 Decrease rate 1 unit/kg/h	0.71–0.85 Decrease rate 1 unit/kg/h	0.51–0.64 Decrease rate 1 unit/kg/h
	0.85–0.99 Decrease rate 2 units/kg/h	0.65–0.79 Hold infusion for 30 min Decrease rate 2 units/kg/h	0.85–0.99 Decrease rate 2 units/kg/h	0.65–0.79 Hold infusion for 30 min Decrease rate 2 units/kg/h
	≥1.00 Hold infusion for 1 hr, and Decrease rate 3 units/kg/h	≥0.80 Hold infusion for 1 hr, and Decrease rate 3 units/kg/h	≥1.00 Hold infusion for 1 h, and Decrease rate 3 units/kg/h	≥0.80 Hold infusion for 1 h, and Decrease rate 3 units/kg/h