Switching of antithrombotic therapy

David Goldemund M.D.
Updated on 03/10/2024, published on 24/01/2024

switching antithrombotic medications must be carefully managed to ensure the patient’s safety and efficacy (risk of temporary under- or overdosing)
factors such as the type of antithrombotic medication, its indication, the patient’s medical history, and the reason for switching are crucial in determining the appropriate strategy
common reasons for switching include:
- perioperative management
- new-onset contraindication to the current anticoagulant
- need for a short-acting or parenteral anticoagulant
in general, a new drug is started when the next scheduled dose of the previous drug is due, with exceptions in cases where higher plasma concentrations are expected, such as in patients with renal insufficiency
close monitoring and evaluation of the patient’s clinical status and laboratory results are essential during this transition to minimize the risk of both thrombotic and bleeding complications

start VKA while continuing LMWH (see notes on bridging)
treatment usually starts with a dose of 1.5-5 mg/day of warfarin to allow a gradual onset of effect
- high initial doses may lead to a rapid depletion of protein C and S ⇒ ↑ risk of hypercoagulable state with warfarin-induced skin necrosis
monitor INR regularly
discontinue LMWH if INR >2 for at least 24 hours
adjust VKA dose based on measured and target INR values

stop VKA and monitor INR
LMWH should be started when INR is < 2
- adjust LMWH dose based on renal function and weight
- in selected cases (e.g., active thrombosis), LMWH can be started as soon as warfarin is discontinued, with overlap until the INR falls below 2
monitor for efficacy and safety

all DOACs can be started immediately if the INR < 2
official recommendation:
- rivaroxaban – INR < 3
- edoxaban – INR ≤ 2.5
- apixaban/dabigatran – INR < 2
if the INR is > 2.5, check the INR the next day, or you can start using rivaroxaban if the INR < 3
once starting with rivaroxaban, apixaban, or dabigatran, INR measurement becomes unreliable and may be falsely elevated

DOAC and VKA (vitamin K antagonist) can be administered simultaneously until INR is >2
DOACs may affect INR (falsely elevated values) – always measure INR before taking another DOAC during concomitant administration and measure again 24-48h after discontinuing DOACs
it is recommended to reduce the dose when starting VKAs while using edoxaban
- for patients taking the 60 mg dose, administer edoxaban at 30 mg once daily along with an appropriate dose of a VKA
- for patients taking the 30 mg dose, administer edoxaban at 15 mg once daily with a proper dose of a VKA
close monitoring of INR is recommended during the first month until stable INR values are achieved
if intermediate concomitant DOAC + VKA is not applicable, consider switching from DOAC to LMWH and then from LMWH to VKA (especially in patients at high risk of thromboembolism)

no need for overlap or bridging
from heparin: start DOAC 2 hours after discontinuing IV heparin
from LMWH: DOACs should be administered at the time of the next scheduled LMWH dose (some authors recommend starting DOACs 2 hours earlier)
- in patients with renal insufficiency, beware of prolonged LMWH elimination

calculate the appropriate dose of LMWH based on the patient’s weight, renal function, and indication
heparin/LMWH can be started at the time of the next scheduled DOAC dose
- dabigatran in patients with CrCl <50 mL/min has prolonged clearance; initiate LMWH 12-24 hours after the last dose of dabigatran
consider checking anti-Xa levels for LMWH to ensure therapeutic anticoagulation
if switching to IV UFH, do not start with a heparin bolus → unfractionated IV heparin protocol

start the new DOAC at the time when the next dose of the original DOAC was scheduled to be given
except in situations where a higher than therapeutic plasma concentration is expected (e.g., in patients with renal insufficiency)

start DOACs immediately and discontinue antiplatelet therapy (SAPT or DAPT) unless combination therapy is indicated (recent stenting + AFib, etc.)
short overlap of both drugs poses a very low risk

discontinue DOACs and start antiplatelet therapy immediately (antiplatelets needs time to reach full effect)
a short overlap of DOAC and antiplatelet effects is associated with relatively low bleeding risk (AFib patients with recent stenting safely receive prolonged combination of DOAC+antiplatelet drug)

LMWH bridging

bridging anticoagulation involves the administration of a short-acting anticoagulant (usually LMWH) in the following situations:
- initiation of anticoagulant therapy
- periprocedural bridging → see separate chapter

Bridging in stroke patients

WARFARIN

there is a short-term procoagulant effect of warfarin at the beginning of treatment, and this period is associated with a higher risk of ischemic stroke [Diener, 2014]
- this effect is attributed to warfarin’s influence not only on coagulation factors but also on proteins C and S
- both proteins have a shorter biological half-life than clotting factors, and when warfarin treatment is initiated, their deficiency occurs before clotting factor levels decrease
- this results in a short-term increase in plasma thrombogenic activity
this brief hypercoagulable state can be bridged by the administration of LMWH/heparin
- the efficacy of bridging has been demonstrated in treatment of DVT
- no trial data is available in stroke prevention

patients without acute stroke – bridging is recommended for patients with a high risk of thromboembolism (e.g., history of stroke, bioprosthetic valve, intracardiac thrombus, or mitral stenosis) with a low risk of bleeding (according to American College of Chest Physicians guidelines from 2012)

acute stroke patients – bridging is generally not recommended; full-dose LMWH is associated with an increased risk of bleeding that outweighs its prophylactic effect [Hallevi, 2008]
an alternative approach involves administering of a prophylactic dose of LMWH + slow titration of warfarin to prevent the initial hypercoagulable state

DOACs – LMWH bridging is not recommended!

no increased risk of recurrent stroke was observed with DOACs
the RAF-NOACs trial found the risk of bleeding 7.3% (with LMWH bridging) vs. 1.9% (without LMWH bridging), and the combined outcome was 12% vs. 4.4% (with LMWH vs. without LMWH)
data analysis from both the RAF and RAF-NOACs trials also showed no benefit from bridging therapy [Altavilla, 2019]
according to the IAC trial, bridging is associated with a higher risk of sICH (HR 2.74) [Yaghi, 2020]

Bridging in patients with VTE

warfarin	LMWH twice daily for ≥ 5 days; meanwhile, start warfarin discontinue LMWH when INR> 2 on two consecutive days
dabigatran (PRADAXA) edoxaban (LIXIANA)	LMWH bridging for 5 days
apixaban (ELIQUIS) rivaroxaban (XARELTO)	no bridging; start DOAC immediately