Ischemic stroke

Anticoagulant therapy in acute stroke

  • 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   Aortic arch thrombus (on CTA and echocardiography)
    • thrombotic stenosis or occlusion of the CCA and ICA –  safety and efficacy are unknown (AHA/ASA 2019 IIb/C-LD)  Thrombus in the CCA in a patient with polycytemia veraTrombotic ICA occlusion
      • 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:
Bridging in stroke patients


  • 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
  • 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)   Cortical cerebral microbleeds and lobar hematomas in patient with cerebral amyloid angiopathy
    • ↑ 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  RETRACE trial - functional outcome at 1 year, stratified by anticoagulation resumption and intracerebral hemorrhage (ICH) location
  • 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

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Timing of anticoagulant therapy