Anticoagulant therapy in atrial fibrillation

Anticoagulant therapy in atrial fibrillation 

  • Anticoagulant terminology
    • Vitamin K antagonist anticoagulant
      • Warfarin
    • Non–vitamin K antagonist anticoagulant
      • The following terms are used interchangeably:
        • Non–vitamin K oral anticoagulant (NOAC)
          • Has also been used for the less precise terminology novel anticoagulant
        • Direct-acting oral anticoagulants (DOAC)
      • Options include dabigatran, apixaban, rivaroxaban, and edoxaban
  • Anticoagulant recommendations are based on classification of atrial fibrillation
    • Nonvalvular atrial fibrillation
      • Atrial fibrillation in absence of either a mechanical heart valve or moderate to severe mitral stenosis
      • Use CHA2DS2-VASc score to determine ischemic stroke risk and need for anticoagulation
      • Anticoagulation, when indicated, is done with a non–vitamin K oral anticoagulant or warfarin
    • Valvular atrial fibrillation
      • Atrial fibrillation in presence of a mechanical heart valve or moderate to severe mitral stenosis
      • Associated with high stroke risk; CHA2DS2-VASc score is not used to determine need for anticoagulation
      • Anticoagulation is done with warfarin; non–vitamin K oral anticoagulants are contraindicated in these patients

Risk Models and Risk Scores

CHA2DS2-VASc Score

  • Scoring system recommended by US and European clinical practice guidelines to assess stroke risk in patients with nonvalvular atrial fibrillation. Canadian guidelines use a similar, but modified, scoring system
  • Recommendation to prescribe anticoagulation is based on total score attained from the following patient characteristics:
    • Congestive heart failure: 1 point
    • Hypertension: 1 point
    • Age 65 to 74 years: 1 point
    • Age 75 years and older: 2 points
    • Diabetes: 1 point
    • Stroke or transient ischemic attack: 2 points
    • Vascular disease (prior myocardial infarction, peripheral vascular disease, or aortic plaque): 1 point
    • Female: 1 point
  • CHA2DS2-VASc score–based anticoagulation recommendation
    • Score 2 or higher in men, 3 or higher in women: anticoagulation recommended
    • Score 1 or higher in men, 2 or higher in women: can consider anticoagulation
    • Score 0 in men, 1 in women: reasonable to omit anticoagulation

HAS-BLED Score

  • Can use to assess bleeding risk
    • H: uncontrolled hypertension (higher than 160 mm Hg systolic): 1 point
    • A: abnormal renal and/or hepatic function: 1 point each of the following:
      • Dialysis
      • Transplant
      • Serum creatinine level higher than 200 μmol/L
      • Cirrhosis
      • Bilirubin level more than 2 times the upper limit of reference range
      • AST/ALT/alkaline phosphatase level more than 3 times upper limit of reference range
    • S: stroke or previous stroke: 1 point
    • B: bleeding history (prior major bleed, anemia, or thrombocytopenia): 1 point
    • L: labile INR (time in therapeutic range less than 60% for patient receiving warfarin): 1 point
    • E: elderly (older than 65 years) or extreme frailty: 1 point
    • D: drugs or excessive alcohol drinking (concomitant use of antiplatelet or NSAID and/or excessive alcohol): 1 point each
  • HAS-BLED score 3 or higher is considered high risk
    • Generally correlates with both bleeding risk and higher stroke risk
    • Mandates correcting or minimizing modifiable risk factors and planning closer follow-up of the patient
    • Not used as a reason to withhold anticoagulation owing to net clinical benefit of anticoagulation

Treatment

Approach to Treatment

  • Long-term (lifelong) anticoagulation is recommended for patients with atrial fibrillation, based on embolic stroke risk stratification
    • Anticoagulation has been shown to reduce stroke risk by more than 50% in patients with atrial fibrillation
    • Patients with valvular atrial fibrillation and patients with hypertrophic cardiomyopathy and atrial fibrillation are at high risk of stroke and require anticoagulation without regard to CHA2DS2-VASc score
    • For patients with nonvalvular atrial fibrillation, assess stroke risk using the CHA2DS2-VASc score to determine need for anticoagulation
      • Annual stroke risk varies from less than 1% (for CHA2DS2-VASc score of 0) to more than 10% (for CHA2DS2-VASc score of 9). A CHA2DS2-VASc score of 2 is associated with an annual stroke risk of approximately 2%
      • Anticoagulation is based on patient’s CHA2DS2-VASc score, irrespective of atrial fibrillation type (paroxysmal, persistent, long-standing persistent)
        • Anticoagulation is recommended for patients with CHA2DS2-VASc score:
          • Men, score 2 or higher
          • Women, score 3 or higher
        • Consider anticoagulation, based on individual risk-benefit and shared decision-making, in patients with CHA2DS2-VASc score:
          • Men, score 1
          • Women, score 2
        • Reasonable to omit anticoagulation in patients with CHA2DS2-VASc score:
          • Men, score 0
          • Women, score 1
        • Platelet inhibitors are not recommended to reduce stroke risk
    • Consider bleeding risk
      • HAS-BLED score (0-9) can be used to assess bleeding risk, but do not use this score as a reason to withhold anticoagulation because strokes related to atrial fibrillation are often fatal or disabling, whereas most bleeding events can be controlled and do not cause death or permanent disability
        • There are few absolute contraindications to oral anticoagulants. These contraindications include:
          • Serious active bleeding
          • Recent high-risk bleeding (eg, intracranial hemorrhage)
          • Some associated comorbid conditions (eg, severe thrombocytopenia with platelet counts lower than 50/μL)
      • If HAS-BLED score is 3 or higher, address modifiable bleeding risk factors:
        • Hypertension (higher than 160 mm Hg systolic)
        • Excessive alcohol consumption
        • Concomitant use of aspirin
        • Concomitant use of an NSAID
    • After reviewing patient’s stroke and bleeding risks, base decision to anticoagulate (and choice of anticoagulant) on shared decision-making, considering patient’s preferences and values
    • Can consider percutaneous left atrial appendage occlusion for patients with atrial fibrillation who have increased stroke risk and contraindications for long-term anticoagulation
  • Anticoagulation recommendations in patients undergoing pharmacologic or electrical cardioversion
    • Cardioversion is associated with a brief and transient increase in stroke risk during and immediately after the cardioversion procedure
    • Anticoagulation recommendations vary by duration of atrial fibrillation (48 hours or longer versus fewer than 48 hours)
    • Except in the setting of hemodynamic instability, atrial fibrillation duration 48 hours or longer requires precardioversion anticoagulation for 3 weeks

Drug Therapy

First Line Therapy

  • Choice of long-term oral anticoagulant
    • Valvular atrial fibrillation
      • Treat with warfarin
        • Clinical trials have either not been performed to determine efficacy of non–vitamin K oral anticoagulants to prevent stroke in patients with valvular atrial fibrillation or have shown (in the case of dabigatran) to be associated with increased rates of thromboembolic and bleeding complication compared with warfarin
    • Nonvalvular atrial fibrillation
      • Non–vitamin K oral anticoagulants are recommended over warfarin owing to ease of use (no routine laboratory monitoring) combined with equivalent or superior efficacy and safety
        • Cochrane review of factor Xa inhibitors found significantly reduced risk of stroke, systemic embolic events, and intracranial hemorrhage compared with warfarin in patients with atrial fibrillation. Risk of major bleeding was also decreased, but the evidence was less robust
        • Meta-analysis of data from clinical trials of all 4 non–vitamin K oral anticoagulants (dabigatran, apixaban, rivaroxaban, and edoxaban) used to prevent stroke or systemic embolic events in patients with atrial fibrillation revealed significant reductions in stroke, intracranial hemorrhage, and mortality, with major bleeding similar to that seen with use of warfarin
        • Choice of non–vitamin K oral anticoagulant
          • There are no head to head randomized controlled trials of the relative safety and effectiveness of individual non–vitamin K oral anticoagulants
          • Decisions regarding which drug to prescribe are based largely on patient preference for once a day versus twice a day administration and differences in drug cost based on insurance contracts
          • Check renal function before initiating non–vitamin K oral anticoagulant as these medications have exclusions and dose recommendations based on renal function
      • Deviating from FDA-approved dosing for non–vitamin K oral anticoagulants in stroke prevention for atrial fibrillation has been associated with worse clinical outcomes
      • Warfarin may be the most appropriate anticoagulant for some patients with nonvalvular atrial fibrillation
        • If warfarin is used, INR goal is between 2 and 3
      • Platelet inhibitors are not recommended for stroke reduction in patients with atrial fibrillation,
  • Anticoagulation recommendation for patients undergoing cardioversion
    • If atrial fibrillation is 48 hours or longer or is of unknown duration:
      • Anticoagulate for 3 weeks before and at least 4 weeks post cardioversion, regardless of CHA2DS2-VASc score or cardioversion method
      • It is reasonable to perform transesophageal echocardiography and proceed with immediate cardioversion if no clot is seen in left atrial appendage. Then continue anticoagulation for a minimum of 4 weeks post cardioversion
      • If a clot is observed at the time of transesophageal echocardiogram, reschedule cardioversion for at least 3 weeks later while patient is maintained on an appropriate anticoagulant
      • If patient requires immediate cardioversion to treat hemodynamic instability, initiate anticoagulation as soon as possible after cardioversion and maintain for at least 4 weeks
    • If atrial fibrillation is fewer than 48 hours duration:
      • If CHA2DS2-VASc score is 2 or higher (in men) or 3 or higher (in women), initiate anticoagulation as soon as possible before cardioversion and continue long term
      • Anticoagulation in this setting is most efficiently and commonly accomplished with a non–vitamin K oral anticoagulant
      • If CHA2DS2-VASc score is 0 (in men) or 1 or (in women), it is reasonable to omit anticoagulation before and after cardioversion

Drug Therapy: Anticoagulant therapy in atrial fibrillation.

MedicationTherapeutic useDosageSafety concernsNotable adverse reactions
Non–vitamin K oral anticoagulants* (NOAC)
Direct thrombin inhibitors
DabigatranPreferred over warfarin

May be preferred in Asian patients†

150 mg dose may be preferred in patients at high stroke risk or recurrent stroke
110 mg dose (where available) may be preferred in patients with high bleed risk (HAS-BLED ≥3) or high GI bleed risk
Usual dose: 150 mg PO twice daily

Low dose: 110 mg PO twice daily

Adjust dose for patients with CrCl 15-30 mL/min
BOXED WARNING: risk for thrombotic events with premature discontinuation and spinal or epidural hematoma

Contraindicated in patients with mechanical prosthetic heart valve

Not recommended for use in patients with severe mitral stenosis, triple-positive APS, or CrCl <15 mL/min

Drug interactions: may need to avoid or adjust dosage of certain drugs

Routine therapeutic drug monitoring not necessary

Reversal strategy: idarucizumab, PCC or aPCC, or hemodialysis
Major bleeding‡:

150 mg vs. warfarin: no difference

110 mg vs. warfarin: lower
Factor Xa inhibitors
ApixabanPreferred over warfarin
May be preferred in patients with high bleed risk (HAS-BLED ≥3), high GI bleed risk, ESRD, or Asian patients†
5 mg PO twice daily 

Adjust dose if 2 of the following: age ≥80 years, body weight ≤60 kg, or SCr ≥1.5 mg/dL
BOXED WARNING: risk for thrombotic events with premature discontinuation and spinal or epidural hematoma

Not recommended for use in patients with prosthetic mechanical heart valve, severe mitral stenosis, triple-positive APS, or Child-Pugh Class C hepatic impairment

Drug interactions: may need to avoid or adjust dosage of certain drugs

Routine therapeutic drug monitoring not necessary

Reversal strategy: andexanet alfa, aPCC or PCC
Major bleeding‡ vs. warfarin: lower
EdoxabanPreferred over warfarin

May be preferred in patients with high bleed risk (HAS-BLED ≥3), Asian patients,† and those who want a reduced pill burden

60-mg dose may be preferred in patients with high stroke risk
Usual dose: 60 mg PO once daily

Low dose: 30 mg PO once daily
Adjust dose in patients with CrCl 15-50 mL/min
BOXED WARNING: risk for thrombotic events with premature discontinuation and spinal or epidural hematoma; reduced efficacy in patients with CrCl >95 mL/min

Not recommended for use in patients with prosthetic mechanical heart valve, severe mitral stenosis, triple-positive APS, CrCl >95 mL/min or <15 mL/min, or Child-Pugh Class B or C hepatic impairment

Drug interactions: may need to avoid or adjust dosage of certain drugs

Routine therapeutic drug monitoring not necessary

Reversal strategy: andexanet alfa, aPCC, or PCC
Major bleeding‡ 30 or 60 mg vs. warfarin: lower
RivaroxabanPreferred over warfarin

May be preferred in patients with ESRD or those who want a lower pill burden
20 mg PO once daily with food

Adjust dose in patients with CrCl <50 mL/min
BOXED WARNING: risk for thrombotic events with premature discontinuation and spinal or epidural hematoma

Not recommended for use in patients with prosthetic mechanical heart valve, severe mitral stenosis, triple-positive APS, or Child-Pugh Class B or C hepatic impairment

Drug interactions: may need to avoid or adjust dosage of certain drugs

Routine therapeutic drug monitoring not necessary

Reversal strategy: andexanet alfa, aPCC or PCC
Major bleeding§ vs. warfarin: no difference
Vitamin K antagonists (VKA)
WarfarinPreferred in patients with ESRD, mechanical heart valve, or mitral stenosis

To aid in determining if a patient will do well on warfarin therapy, a score of 0-2 on the SAMe-TT2R2 is recommended; for score >2, non–vitamin K oral anticoagulant preferred or more frequent INR monitoring necessary¶
Initial dose: 2.5-10 mg PO once daily#BOXED WARNING: bleeding risk

Monitor INR at least weekly until stable, then monthly; adjust dose to INR 2-3

Genetic polymorphisms, changes in diet and concomitant drugs affect therapeutic efficacy and safety

Reversal strategy: vitamin K, PCC, FFP
Bleeding

Skin necrosis

Systemic atheroemboli

Caption: aPCC = activated prothrombin complex concentrates, APS = antiphospholipid syndrome, ESRD = end-stage renal disease, FFP = fresh frozen plasma, INR = international normalized ratio, PCC = activated prothrombin complex concentrates.

*Non–vitamin K oral anticoagulants include dabigatran, apixaban, edoxaban, and rivaroxaban.D1-D3

†Incidence of intracranial hemorrhage was significantly lower compared to warfarin in clinical trials; Asian patients with atrial fibrillation are at higher risk for intracranial hemorrhage vs. White patients.D1

‡Major bleeding is defined as reduction in the hemoglobin level of at least 20 g/L, transfusion of at least 2 units of blood, symptomatic bleeding in a critical area or organ, or fatal bleeding.D6,D12,D15

§Major bleeding is defined as decrease in hemoglobin >2 g/dL, requiring transfusion, critical or fatal bleeding.D17

¶The SAMeTT2R2 score predicts success on warfarin therapy.D1,D3

#Initial dose is very individualized and based on expected maintenance dose; consideration and testing of genotypes may help determining initial dosing.D20

Treatment Procedures

Left Atrial Appendage Occlusion

  • Procedure types
    • Surgical ligation or resection of the left atrial appendage
    • Percutaneous insertion of a plug into the appendage, which effectively occludes the appendage and prevents thrombus formation
  • Current guidelines from American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society state that percutaneous left atrial appendage occlusion can be considered for patients with atrial fibrillation who have increased stroke risk and who have contraindications for long-term anticoagulation
  • Current European and Canadian guidelines state that these procedures “can be considered” for patients with increased risk of stroke who have contraindications to long-term anticoagulation
  • Base decisions about anticoagulation more than 2 months after an atrial fibrillation ablation procedure on patient’s stroke risk profile not on perceived success or failure of the procedure

Follow-up

Monitoring

  • For patients taking warfarin, monitor INR at least weekly during initial therapy and at least monthly once anticoagulation is stable. Goal INR is 2 to 3
  • Patients taking non–vitamin K oral anticoagulants do not require monitoring of anticoagulant effect
    • Routine coagulation tests (prothrombin time and activated partial thromboplastin time) do not provide an accurate assessment of their anticoagulant effects
  • Assess renal and hepatic function at least annually in patients taking a non–vitamin K oral anticoagulant
  • Periodically reevaluate:
    • Need for anticoagulation in low-risk patients who are not currently anticoagulated. Onset of stroke risk factors (including hypertension and diabetes), as well as aging itself, increases CHA2DS2-VASc score
    • Bleeding and fall risks. Focus attention on modifiable risk factors
    • Choice of anticoagulant, as it relates to patient compliance and renal and hepatic function

Complications

  • Anticoagulants increase bleeding risk
    • HAS-BLED score (range 0-9) can be used to assess bleeding risk. Do not use HAS-BLED score as a reason to withhold anticoagulation owing to the net clinical benefit of anticoagulation
    • If HAS-BLED score is 3 or higher, address modifiable bleeding risk factors
  • Approach to active bleeding
    • All patients
      • For moderate to severe bleeding, treat by replacing fluids, transfusing blood, and identifying and treating cause of bleeding (eg, endoscopic techniques for gastrointestinal bleeding)
    • Patients taking non–vitamin K oral anticoagulants
      • For minor bleeding, delay or hold next dose
      • For moderate to severe bleeding, treat by replacing fluids, transfusing blood, and identifying and treating cause of bleeding (eg, endoscopic techniques for gastrointestinal bleeding)
      • For life-threatening bleeding (or need for urgent surgery), consider administering a reversal agent
        • Reversal strategy is dependent on the specific non–vitamin K oral anticoagulant
    • Patients taking warfarin
      • Delay further doses until INR is lower than 2
      • For more severe bleeding, replace fluids, transfuse blood, and identify and treat bleeding source (eg, endoscopy); consider administering a reversal agent

Summary

Key Points

  • Prescribe long-term anticoagulation for all patients with atrial fibrillation who are at high risk for embolic stroke
    • For patients with nonvalvular atrial fibrillation, risk stratification and anticoagulation decision is based on the CHA2DS2-VASc score
      • If CHA2DS2-VASc score is greater 2 or higher (in men) or 3 or higher (in women), anticoagulation is recommended
      • If CHA2DS2-VASc score is 1 (in men) or 2 (in women), consider anticoagulation based on individual risk-benefit and shared decision-making
      • If CHA2DS2-VASc score is 0 (in men) or 1 (in women), it is reasonable to omit anticoagulation
    • All patients with valvular atrial fibrillation are considered at high risk for stroke and should receive anticoagulation
  • Anticoagulation is indicated irrespective of atrial fibrillation type (paroxysmal, persistent, long-standing persistent) and should not be based on apparent degree of atrial fibrillation control
  • Non–vitamin K oral anticoagulants are recommended over warfarin to treat nonvalvular atrial fibrillation owing to ease of use combined with equivalent or superior efficacy and safety
  • Use warfarin to treat patients with valvular atrial fibrillation, as clinical trials regarding the efficacy of most non–vitamin K oral anticoagulants in this population either have not been performed or, in the case of dabigatran, have been shown to be associated with increased rates of thromboembolic and bleeding complication compared with warfarin
  • Cardioversion (electrical, pharmacologic, ablative) increases stroke risk during and immediately after the procedure. Base anticoagulation decisions surrounding cardioversion on duration of atrial fibrillation (48 hours longer or fewer than 48 hours) and modified by CHA2DS2-VASc score

References

January CT et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2019;16(8):e66-e93.

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