ADD-ONS / MEDICATION

Timing of anticoagulant therapy

David Goldemund M.D.
Updated on 11/12/2023, published on 23/02/2022

Ischemic stroke

Anticoagulant therapy in acute stroke

→ recanalization therapy in anticoagulated patients

in general, immediate anticoagulant therapy is not recommended for patients with acute ischemic stroke (AHA/ASA 2019 III/A)
- heparin and low molecular weight heparins (LMWH) in the acute phase either do not reduce the risk of early stroke recurrence, or their subtle effect is counteracted by a higher incidence of bleeding ( FISS-tris) [Wong, 2007]
- this is also applies to patients with AFib (IST trial) [Saxena, 2001]
- the risk of bleeding is highest:
  - during the first 10-14 days after the stroke
  - in large infarct and severe deficit
  - in patients with poorly compensated hypertension
management of acute stroke patients already on anticoagulant therapy is discussed here

acute anticoagulation may be considered in the following scenarios (although clinical trials have not shown efficacy):
- intracardiac or aortic thrombosis
- thrombotic stenosis or occlusion of the CCA and ICA – safety and efficacy are unknown (AHA/ASA 2019 IIb/C-LD)
  - dual antiplatelet therapy (DAPT) may be an alternative to anticoagulation in this setting
- TIA patients with AFib (as early secondary prevention)

what to do:
- studies have shown no significant difference in efficacy between LMWH and heparin
- start with
  - HEPARIN (preferably without bolus administration)
  - LMWH with an anti-Xa target of 0.5-1 IU/mL
  - DOACs (for TIA with Afib)
- then switch to DOACs / warfarin (VKA)

Initiation of anticoagulant therapy in the subacute phase of stroke

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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

Intracerebral hemorrhage

general risk of ICH recurrence is ~2-4%/year (without anticoagulation)
risk of ICH recurrence with anticoagulation therapy is increased and depends on the cause of bleeding and the type of drug used ( DOAC vs. low-dose DOAC vs. warfarin)
- ↑ risk in patients with proven cerebral microbleeds (CMBs) on GRE (if amyloid angiopathy is suspected ⇒ the risk of ICH is increased 7-fold)
- ↑ risk in lobar hematomas (> 4%/year)
- ↑ risk in patients with apolipoprotein E4 (ApoE4)
according to meta-analyses (mainly from warfarin trials), reintroducing anticoagulation therapy reduces the risk of ischemic stroke without significantly increasing the risk of ICH (Sembill, 2019) [Murthy, 2017]
the RETRACE trial (meta-analysis) indicates that the resumption of anticoagulation therapy improves outcome regardless of the type of hematoma

clinical decision-making regarding the use of antithrombotic medications after ICH remains challenging
when determining the indication/timing of anticoagulation after ICH, the risk of thromboembolism and bleeding should be assessed in the context of multiple factors
- in patients with Afib who suffered an ICH while on anticoagulant therapy, resuming anticoagulation was associated with a lower risk of stroke and a similar risk of recurrent ICH compared to the control group [Murthy, 2017]
- no other randomized trials are available; only case series data are available
- the 30-day risk of ischemic stroke is ~2-3% (including patients with Afib and mechanical valve)

if bleeding has stabilized (according to CT), heparinization with a prophylactic dose (e.g., CLEXANE 0.4 mL SC once daily) for VTE prophylaxis can be initiated within 3-4 days
the timing of anticoagulation restart should be decided on a case-by-case basis after individual risk assessments of thromboembolism, recurrent ICH, and late ICH expansion
in cases of subcortical hematomas with well-compensated hypertension, full anticoagulation can be started within 10-14 days
- in Afib patients, EUSI recommends an interval of 10-14 days; AHA/ASA 2022 guidelines do not specify the type of ICH and suggest 7-8 weeks (AHA/ASA 2022 2b/C-LD)
- for patients with spontaneous ICH and high-risk thromboembolic condition (e.g., a mechanical valve or LVAD), early resumption of anticoagulation is reasonable
  - > 14 days after the index event seems appropriate for patients with a mechanical valve [Kuramatsu, 2018]
- prefer DOAC; if VKA is used, careful dose titration is essential (as INR fluctuations increase the ICH risk)
in cases of lobar hematoma, the high risk of bleeding recurrence with anticoagulation therapy (>4%/year) may neutralize the benefit in preventing thromboembolism ⇒ consider DOAC at a reduced dose (antiplatelet therapy is ineffective and also increases bleeding risk)
- restart anticoagulation in 7-8 weeks (AHA/ASA 2022 2b/C-LD)
- according to the RETRACE trial, there is a benefit of continued AC therapy even in lobar hematomas
ESC guidelines 2016 specifically recommend using anticoagulants with a low risk of IC bleeding (DOACs)

LAA occlusion may be considered to reduce the risk of thromboembolic events in patients with Afib and spontaneous ICH who are considered ineligible for anticoagulation (AHA/ASA 2022 2b/C-LD)

Factor	for	against
Etiology of bleeding
hypertensive bleeding, proper blood pressure control is essential
amyloid angiopathy, particularly associated with large lobar hematoma
high HAS-BLED score
bleeding occurred while taking a VKA (or due to a VKA overdose)
bleeding occurred while taking the correct dose of DOAC
traumatic bleeding
alcohol/drug abuse
another cause of bleeding that cannot be eliminated
SAH with secured aneurysm (embolization/clipping)

Microvascular risks
*cerebral microbleeds*
no or mild leukoencephalopathy (→ FAZEKAS scale)
Indication for anticoagulant therapy
secondary stroke prevention
primary stroke prevention
Afib with a high CHA₂DS₂Vasc score
Afib with a low CHA₂DS₂Vasc score
mechanical valve
hypercoagulable state
assumption of complicated INR controls (VKA)

Timing of anticoagulant therapy (ESC 2016)

Perioperative and periprocedural management of anticoagulant therapy

→ see separate chapter