Classification of anticoagulant drugs

Direct anticoagulants
They inactivate the coagulation factors present in the plasma
Indirect anticoagulants
They affect coagulation factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs are bound to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs act through the activation of antithrombin
  • vitamin K antagonists (VKAs)
    • warfarin (coumadin)
  • xabans (free and clot-bound factor Xa inhibitors)
    • apixaban
    • rivaroxaban
    • edoxaban
    • betrixaban
  • hirudin (direct thrombin inhibitor – DTI)

Indications

  • the decision to start anticoagulant therapy should be based on the individual assessment of the risk of thromboembolism and the risk of bleeding

risk of ischemic stroke
CHA2DS2VAsc score
spontaneous echo contrast in the left atrium
intra-atrial thrombus

Anticoagulant therapy
risk of bleeding
HAS-BLED
ABC
ORBIS
HEMORR2HAGES
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  • older age and hemorrhagic transformation of ischemia are not absolute contraindications to subsequent anticoagulation
  • risk of ICH on AC therapy
    • VKA – 0.3-0.6% /year
    • DOAC – 0.1-0.2% /year
  • concerning risk/benefit, neither the increased risk of falls in elderly patients is a contraindication to anticoagulation (AAN guidelines 2014)
    • in patients with CHADS2 ≥2, warfarin is safer than ASA or no therapy, even with an increased risk of falls
    • elderly patients with a risk of stroke >2%/year would need to fall more than 300 times/year for warfarin not to be considered optimal therapy  [Garwood, 2008]
  • direct oral anticoagulants (DOACs) are currently preferred to warfarin (if possible)
    • aspirin is not an adequate alternative to anticoagulant drugs
    • in patients at increased risk of GI bleeding, apixaban is preferred among the DOACs
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  • WARSS trial  (Warfarin Aspirin Recurrent Stroke Study) compared the efficacy of warfarin with a target INR of 1.4-2.8 versus ASA at a dose of 325 mg. 2206 patients with non-cardioembolic stroke were randomized. This study did not demonstrate superior efficacy of warfarin compared with aspirin in preventing stroke recurrence and death (17.8% vs. 16%), nor was the incidence of hemorrhagic complications significantly different in the two groups (2.2% warfarin vs. 1.5% aspirin). The effect was also not demonstrated in the subgroup of patients with evidence of stenosis or occlusion of a major artery
  • WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease Study)  tested the efficacy of warfarin with a target INR of 2-3 versus aspirin in patients with angiographically proven symptomatic intracranial stenosis >50%. The study was terminated early for safety reasons due to a high incidence of bleeding complications in the anticoagulated group. The primary outcome criterion was achieved in approximately 22% of patients in both arms
  • ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial)  trial compared the efficacy of warfarin with INR 2-3 (n=536) versus 30-325 mg aspirin (n=532) in secondary prevention in patients with TIA or cerebral infarction with presumed arterial origin. The primary outcome criteria were death from vascular causes, non-fatal stroke, non-fatal myocardial infarction, and major bleeding complications. The mean follow-up time was 4.6 years. 19% of patients on warfarin and 18% on aspirin achieved the primary outcome criterium. The efficacy of anticoagulation therapy compared with aspirin in preventing ischemic events (major ischemic events 62 vs. 84) was neutralized by a higher incidence of major bleeding events (45 vs. 18)

Timing of anticoagulant therapy

Monitoring

In a patient on anticoagulant therapy, check at each visit:

Adherence – check compliance + repeat education

    • switch from warfarin to DOAC (if possible) when INR fluctuates, but good adherence is essential (missing a single dose of DOAC has a greater impact than missing a single dose of warfarin)
    • repeatedly educate the patient on the correct use of the medication
    • advise the patient to carry a medication chart and the anticoagulant therapy card in his/her pocket

Bleeding risk assessment

    • search for bleeding complications
    • repeatedly check hemorrhage risk scales –  HAS-BLED score
    • use PPIs if necessary
    • assess the need for dose reduction or drug switching

Creatinine clearance (according to Cockcroft-Gault) – monitor renal function, adjust the dose of DOACs if needed

    • every 12 months in healthy patients < 75 years of age
    • every 6 months in patients ≥ 75 years of age or fragile individuals
    • CrCl/10-months interval in patients with CrCl < 60 mL/min

Drug interaction

    • verify drug interactions – may increase bleeding risk or reduce the anticoagulant effect  (e.g., antirheumatic drugs, verapamil in patients on dabigatran, etc.) → see the chapter on DOACs

Examination and other

    • monitor blood pressure and weight
    • any signs of thromboembolism or bleeding?
    • any adverse reactions?
    • laboratory tests, besides CrCl, may include:
      • blood count, kidney and liver tests (at least once a year, more frequently in individual cases)
      • specific tests to verify anticoagulant effect in selected patients

→ Direct Oral Anticoagulants (DOACs)

Recanalization therapy in anticoagulated patients

Anticoagulant therapy and renal functions

  • patients with renal insufficiency require special attention, and renal functions should be monitored regularly in patients on anticoagulant therapy
  • The Chronic Kidney Disease (CKD) classification divides patients into five groups based on glomerular filtration rate
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Anticoagulant therapy and malignancy

  • tumors and their treatment are associated with a higher risk of both thrombosis and bleeding
  • LMWH is the optimal treatment for patients with cancer-related VTE and VTE prophylaxis  (Mullard, 2014)
    • some reports demonstrated better efficacy of DOACs compared to VKAs and LMWHs, but a meta-analysis of randomized trials suggests a higher risk of bleeding (O´Connell, 2020)
  • there is little experience with DOACs in preventing stroke in patients with malignancy (as malignancy was an exclusion criterion in most trials)   → see more
    • data analysis of the ARISTOTLE trial demonstrated superior efficacy and safety of apixaban compared to VKAs
    • evidence for the effectiveness of long-term LMWHs in preventing stroke in Afib patients is lacking
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Anticoagulant therapy
link: https://www.stroke-manual.com/anticoagulant-therapy/