Classification of anticoagulant drugs

Direct anticoagulants
They inactivate the clotting factors present in the plasma
Indirect anticoagulants
They affect clotting factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs bind to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs activate antithrombin
  • vitamin K antagonists (VKAs)
  • hirudin (direct thrombin inhibitor – DTI)


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

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

Anticoagulant therapy
risk of bleeding
CHA2DS2-VASc score
ABC score
  • in addition to clinical factors, the ABC-bleeding risk score also incorporates the biomarkers: high-sensitivity troponin T, growth differentiation factor–15, and hemoglobin

ABC-stroke score

ABC-stroke score

ABC-bleeding score

ABC-bleeding score
HAS-BLED score
  • a tool to guide the decision to initiate anticoagulation in patients with Afib
  • always compare the risk for major bleeding (calculated by the HAS-BLED score) with the risk of thromboembolic events (calculated by the CHA2DS2-VASc score) ⇒  does the benefit of anticoagulation outweigh the risk of bleeding?
  • a study comparing HEMORR2HAGES, ATRIA, and HAS-BLED showed superior performance of the HAS-BLED score compared to the other two scores
HAS-BLED score
uncontrolled BP (SBP >160 mmHg)
Abnormal liver/renal function
renal disease – dialysis, transplant, Cr >2.26 mg/dL or >200 µmol/L
liver disease – cirrhosis or bilirubin >2x normal or AST/ALT/AP >3x normal
Stroke previous stroke
prior major bleeding or predisposition to bleeding
Labile INR unstable INR, time in therapeutic range <60% 1
Elderly age ≥ 65 years
medication predisposing to bleeding –  aspirin, clopidogrel, NSAIDs
heavy alcohol use
HAS-BLED score
Pisters et al. annual ICH risk
Lip et al. annual ICH risk
0 1.1% 0.9%
1 1% 3.4%
2 1.9% 4.1%
3 3.7% 5.8%
4 8.7% 8.9%
5 12.5% 9.1 %
Not enough data for higher scores; risk is most likely > 10%

A score ≥ 3 is associated with an increased risk of major bleeding.
Frequent monitoring, DOAC use, or alternatives to anticoagulation (such as
LAA occlusion) are recommended.

ORBIT score
  • The ORBIT bleeding risk score has a superior predictive ability for major bleeding in AFib patients compared to the HAS-BLED and ATRIA risk scores. The ORBIT risk score may provide a simple, easy-to-remember tool to assist in clinical decision-making [O´Brian,  2015]  [Hilkens, 2017]
Older age ( >75 y) 1
Reduced hemoglobin/Hct/anemia  (men <13 g/dL and Hct < 40%, women < 12 g/dL and Hct < 36% ) 2
Bleeding 2
Insufficient kidney function (GFR < 60 mL/min/1.73 m2) 1
Treatment with antiplatelets 1
Maximum score 7
score 0–2 – low risk ~ 2.4% / y
score 3 –  medium risk ~ 4.7% / y
score ≥ 4 – high risk ~ 8.1% / y
  • older age and hemorrhagic transformation of ischemia are not absolute contraindications to subsequent anticoagulation
  • approx. risk of ICH on AC therapy
    • VKA – 0.3-0.6% /year
    • DOAC – 0.1-0.2% /year
  • concerning risk/benefit, the increased risk of falls in elderly patients is not 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 anticoagulants
    • apixaban is preferred in patients at increased risk of GI bleeding
  • 20-30% of ischemic strokes are caused by cardiac embolism  more about cardioembolic strokes here
  • emboli are most commonly associated with:
    • atrial fibrillation (50%)
    • non-rheumatic and rheumatic valvular defects
    • CAD
  • anticoagulation is indicated in patients with proven cardioembolic etiology
Selected indications and contraindications for anticoagulants in patients with atrial fibrillation and associated comorbidities (according to ESC guidelines 2018)
nonvalvular atrial fibrillation (NVAF)
  • DOAC
  • warfarin
intracardiac thrombus
mechanical valve
  • warfarin
  • DOAC contraindicated
    • dabigatran was inferior compared to warfarin in RE-ALIGN)
    • no other data
moderate to severe mitral stenosis
  • warfarin
  • DOAC contraindicated
other valvular defects, mild to moderate
  • DOAC
  • warfarin
severe aortal stenosis
  • warfarin
  • DOAC – limited data (excl. criterium in RELY trial)
bioprosthetic valves (>3 months after implantation)
  • warfarin
  • DOAC
    • rivaroxaban is non-inferior to warfarin even in bioprosthetic MI valves ( RIVER trial)
    • no strong data for the other DOACS
    • do not administer in rheumatic etiology
hypertrophic cardiomyopathy (HCM)
  • warfarin
  • limited data for DOACs, but can be considered (ESC 2018)
PTAV (percutaneous transluminal aortic valvuloplasty)
TAVI (transcatheter aortic valve implantation)
  • warfarin
  • no data for DOAC
  • trials, including the only randomized trial CADISS (Cervical Artery Dissection In Stroke, showed no difference in the risk of stroke recurrence with antiplatelet and anticoagulant therapy
  • if anticoagulation is indicated, warfarin should be preferred; data on the safety and efficacy of DOACs in this indication are not available
  • start parenteral anticoagulation (heparin, LMWH) in the acute phase, followed by oral medications (warfarin, DOACs)

→ see separate chapter

  • start with LMWH in the acute phase
  • then switch to DOACs or warfarin
  • effect not proven (IST trial)


  • based on the results of the WARSS, WASID, and ESPRIT trials, anticoagulation therapy with warfarin is not recommended in patients with a stroke of arterial origin (except for dissection and hypercoagulable states)


    • dabigatran 110/150mg vs. ASA, therapy initiated within 72h after TIA/minor stroke onset
    • a phase II prospective, randomized, open-label, blinded endpoint trial
    • asymptomatic ICH 7.8 vs. 3.5% (ASA), sICH (primary endpoint) was 0% in both groups
    • there was insufficient power to show an effect, but there was a trend toward fewer recurrences on dabigatran, according to MRI findings (6.3% vs. 9.9%)

Combination of DOAC + antiplatelet therapy

Low-dose rivaroxaban + ASA

  • COMPASS trial
    • inclusion criteria: patients with coronary artery disease who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate (GFR) <60 ml per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier
    • n=27,395
    • primary endpoint: a combination of CV death, stroke, myocardial infarction
    • rivaroxaban 2×2.5mg + ASA 100mg is superior to ASA 100mg

      • primary endpoint: 4.1% vs. 5.4%
      • major bleeding: 3.1% vs. 1.9% (but there was no difference in fatal and intracranial bleeding)
      • mortality 3.4% vs. 4.1%
      • net benefit 4.7% vs 5.9% (HR 0.8)
    • rivaroxaban 2x 5mg alone is not superior to ASA  (there were fewer ischemic events and more bleeding)
  • 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 trial did not demonstrate the superior efficacy of warfarin over aspirin in preventing stroke recurrence and death (17.8% vs. 16%). The incidence of hemorrhagic complications was also not significantly different between 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)  evaluated 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 anticoagulation group. The primary endpoint 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 of presumed arterial origin. The primary endpoint was 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 endpoint. 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


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 anticoagulant therapy card in their pocket

Bleeding risk assessment

    • search for bleeding complications
    • review bleeding 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 DOAC dose if needed

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

Drug interaction

    • check for 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, renal and liver tests (at least annually, more frequently in individual cases)
      • specific tests to monitor the 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 function 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 an increased 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 the superior 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 stroke prevention 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 efficacy of long-term LMWHs in preventing stroke in Afib patients is lacking

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Anticoagulant therapy