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PekkaRaatikainen

Indications for and Implementation of Anticoagulant Therapy in Atrial Fibrillation

Essentials

  • Anticoagulant therapy is the only form of treatment that unquestionably has been shown to improve the prognosis of patients with atrial fibrillation (AF).
  • It is important in clinical practice to identify and treat patients who will benefit from long-term anticoagulant therapy.
  • A direct oral anticoagulant, i.e. DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) is a better alternative than warfarin for most patients. DOACs are, however, contraindicated in patients with severe mitral valve stenosis, mechanical prosthetic heart valve or severe renal insufficiency.

Background

  • AF is the most important factor that predisposes the patient to cardiogenic embolism.
    • Cardiogenic embolism causes mortality, morbidity and long-term disability.
    • On average, 15-20% of all strokes are associated with AF. Other forms of systemic emboli have been reported less frequently.
  • The pumping action of the atria becomes inefficient during AF and blood will pool in the atria, which predisposes the patient to cardiogenic embolism.
    • In AF, the aim is to prevent blood from clotting by influencing thrombin activation and fibrin formation, rather than platelet adhesiveness, which is the target in the prevention of arterial thrombi.
  • Without anticoagulation the annual incidence of embolic complications in patients with AF is about 5%.
    • Depending on the risk factors, AF carries a 2-7 times increased risk of cerebral infarction compared with age-matched controls in sinus rhythm. The risk of stroke is up to 17 times higher if the patient has rheumatic valvular disease.
    • The risk of thromboembolism is equally high in symptomatic and asymptomatic AF.
    • The treatment guidelines for paroxysmal AF and for atrial flutter are the same as for permanent AF, even though it seems that the risk of stroke is slightly lower.

Indications for anticoagulant therapy Anticoagulants for Non-Rheumatic Atrial Fibrillation and a History of Stroke or Transient Ischaemic Attacks, Warfarin or Antiplatelet Therapy for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation, Direct Oral Anticoagulants Versus Vitamin K Antangonists in Non-Valvular Atrial Fibrillation

  • The need for anticoagulation must always be assessed when a patient presents with AF. The assessment of the need for anticoagulation is based on the individual patient's risk of thromboembolism and bleeding.
  • It is recommended that the risk stratification for thromboembolism uses the modified CHA2DS2-VASc score (table T1) and that the risk of bleeding is assessed using the HAS-BLED score (table T2).
  • A recommendation on choosing antithrombotic medication based on the risk score is presented in picture .
    • Anticoagulation is always indicated for patients at high risk (CHA2DS2-VASc HASH(0x2f5d108) 2), even if the risk of bleeding were slightly elevated.
    • In patients with moderate risk (CHA2DS2-VASc = 1) the need for anticoagulation is evaluated individually
      • Anticoagulation is recommended if the patient has also other, lesser risk factors, such as smoking, dyslipidemia or renal insufficiency.
      • On the other hand, anticoagulation may be omitted according to patient's wish, particularly if the implementation of the treatment is difficult or if a single risk factor has been well taken care of (e.g. hypertension has minor significance if it is well managed).
      • Anticoagulation should not be used, if the risk of bleeding is high (HAS-BLED HASH(0x2f5d108) 3)
    • Anticoagulation is not indicated for patients at low risk (CHA2DS2-VASc = 0) since the benefit gained is inferior to the possible harms.
  • Very high risk factors for thromboembolic events not considered in the scoring are
    • mitral stenosis
    • valve prosthesis.

Assessment of the risk of thromboembolism by a modified1 CHA2DS2-VASc score. Source: Current Care Guideline on atrial fibrillation (Finland, 2021, modified).

Risk factorPoints
Congestive heart failure 1
Hypertension 1
A2ge HASH(0x2f5d108) 75 years 2
Diabetes 1
Earlier S2troke or TIA 2
Vascular disease* 1
Age 65-74 years 1
Sex category female, when age HASH(0x2f5d108) 75 years 1
Maximum score is 9, since the age provides 1 or 2 points. The recommendation on selecting antithrombotic therapy based on the score is displayed in image . The risk factors marked with red colour cannot be affected, but the risk associated with other factors can be reduced by good management of these.
* Earlier myocardial infarction, coronary artery disease, aortic arch plaque or severe periferal arterial disease
1 In this modified version of the score, female sex gives one point only if age is HASH(0x2f5d108) 75 years, allowing the use of identical cut-off values for both men and women.
Assessment of bleeding risk by HAS-BLED score. Each item provides 1 point. Bleeding risk is high if the total score is at least 3. Source: Current Care Guideline on atrial fibrillation (Finland, 2021, modified).
Risk factorPoints
Hypertensionover 160 mmHg1
Abnormal liver or kidney functionSevere failure of liver or kidneys1 for each
StrokeEarlier stroke1
BleedingBleeding diathesis *1
Labile INRFluctuation of INR values1
ElderlyAge over 65 years1
Drugs or alcoholMedication that increases bleeding risk or abundant use of alcohol1 for each
The risk factors marked with red colour cannot be affected, but the risk associated with other factors can be reduced in most cases by good management of these. Bleeding risk is increased if the total score is at least 3.
* Cancer, anaemia, thrombocytopenia, platelet dysfunction, earlier bleeding
Implementation of anticoagulant therapy
  • Before anticoagulant therapy is introduced
    • ensure that the patient has no contraindications to anticoagulation or to the specific agent
    • investigate whether the bleeding risk is increased, and check blood pressure as well as renal and hepatic function.
  • Recommended laboratory tests are: basic blood count (Hb, platelet count), creatinine (eGFR Gfr Calculator), ALT and INR.
  • Anticoagulant therapy may be contraindicated or its implementation may require special attention, if any of the following apply:
    • the risk of significant bleeding is greater than that of thromboembolism
    • forgetfulness and non-adherence to medication in situations where the medicine use cannot be monitored (e.g. by a district nurse)
    • alcohol abuse
    • a history of cerebral haemorrhage
    • a recent or recurrent bleeding peptic ulcer
    • gastrointestinal or urinary tract neoplasm
    • other conditions predisposing the patient to bleeding
    • clinically significant drug interaction
    • allergy or other specific contraindication to the medicine (another medicine can often be used instead).
  • Advanced age is not a contraindication to anticoagulation - on the contrary, it increases the risk of thrombosis. Special care must however be exercised when treating elderly patients already using several medicines (NSAIDs!).
  • In stable coronary artery disease, the use of direct anticoagulant or warfarin only is sufficient to prevent events related to both atrial fibrillation and arterial disease, and combined use with ASA and clopidogrel or other P2Y12 receptor antagonists is usually not indicated.
    • Combined use increases risk of bleeding, but does not reduce occlusions.
    • Temporary combined use is indicated, however, in acute coronary syndrome and after coronary balloon angioplasty.
  • In emergencies (e.g. severe bleeding, urgent surgery), the effect of apixaban, edoxaban and rivaroxaban can be reversed with andexanet alpha and that of dabigatran with idarucizumab.
  • Prothrombin complex concentrate (PCC) is effective in reversing the effect of warfarin and factor X inhibitors, but not that of dabigatran.

Dosage of anticoagulants

  • When using direct anticoagulants, routine tests for monitoring blood coagulation are not needed (cf. warfarin), but renal function (eGFR) and basic blood count should be regularly checked.
  • Typical dosage of direct anticoagulants is presented below. Depending on the product used, some factors, such as the patient's advanced age, weight, renal function and certain drugs, may necessitate a reduction of the dose of a direct anticoagulant (see locally available drug information for further details).
  • The dose of warfarin is adjusted based on regular INR monitoring (INR target = 2-3).

Apixaban Factor Xa Inhibitors Versus Vitamin K Antagonists for Preventing Embolism in Patients with Atrial Fibrillation

  • Apixaban is a factor X inhibitor. Its effect is at least equal to that of warfarin in terms of stroke prevention.
  • The recommended dose in prevention of AF-induced thromboembolism is 5 mg twice daily.

Dabigatran Dabigatran Versus Vitamin K Antagonists in Non-Valvular Atrial Fibrillation

  • Dabigatran is a direct thrombin inhibitor. Its effect is at least equal to that of warfarin in terms of prevention of AF related thromboembolic events.
  • The recommended dose in the prevention of thromboembolic events in AF is 150 mg twice daily.

Edoxaban

  • Edoxaban is a factor X inhibitor. Its effect is at least equal to that of warfarin in terms of stroke prevention.
  • The recommended dose in prevention of AF-induced thromboembolism is 60 mg once daily.

Rivaroxaban Factor Xa Inhibitors Versus Vitamin K Antagonists for Preventing Embolism in Patients with Atrial Fibrillation

  • Rivaroxaban is a direct factor X inhibitor. Its effect is equal to that of warfarin in terms of stroke prevention.
  • The recommended dose in the prevention of thromboembolic events in AF is 20 mg once daily.

Warfarin Warfarin for Preventing Stroke in Patients with Non-Valvular Atrial Fibrillation and No History of Cerebral Ischaemia

  • Warfarin reduces the risk of stroke by more than 60%, compared with placebo.
  • Regular monitoring of the INR values is essential during warfarin therapy.
    • The target INR is 2-3. The therapeutic effect is not sufficient if the INR values are lower, and higher values will increase the bleeding risk.
    • INR is checked frequently when treatment is started, but after the therapeutic level has been stabilised the readings are usually checked about once a month. More frequent checks are indicated if the patient's other medication or condition changes.
    • The aim is that the INR values are in the therapeutic range at least 80% of the time (time in therapeutic range, TTR > 80%).

Aspirin (ASA) and other antiplatelet drugs Antiplatelet Therapy for Patients with Non-Valvular Atrial Fibrillation, Warfarin or Antiplatelet Therapy for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation

  • ASA, clopidogrel and other P2Y12 receptor antagonists should not be used alone to prevent thrombosis in patients with attrial fibrillation.
    • In patients at high or moderate risk, the effectiveness is not sufficient, and the risk of bleeding is approximately the same as with oral anticoagulant therapy.
    • In patients at low risk, the risk of bleeding and other adverse effects exceed the benefits gained.
  • Concomitant use of antiplatelet drugs and anticoagulants should be avoided, since it it increases the risk of bleeding, but will not reduced the incidence of thrombosis.
    • Antiplatelet drugs should usually be stopped when warfarin or direct anticoagulant is introduced.
    • The presence of a mitral valve prosthesis is an exception (permanent use of warfarin and ASA).
    • Temporary concomitant use (so-called dual or triple therapy) is indicated in acute coronary syndrome and in the context of balloon dilatation of coronary arteries.

Choosing between direct anticoagulants and warfarin Direct Oral Anticoagulants Versus Vitamin K Antangonists in Non-Valvular Atrial Fibrillation, Factor Xa Inhibitors Versus Vitamin K Antagonists for Preventing Embolism in Patients with Atrial Fibrillation, Dabigatran Versus Vitamin K Antagonists in Non-Valvular Atrial Fibrillation, Direct Oral Anticoagulants Versus Warfarin Among Atrial Fibrillation Patients with Chronic Kidney Disease, Noac Versus Warfarin Postpci in Atrial Fibrillation

  • Direct anticoagulant is the primary choice due to the better treatment compliance, safety and the convenience benefit for
    • most new patients with atrial fibrillation
    • short-term therapy in association with, for example, cardioversion or AF catheter ablation therapy (reaching therapeutic control and effective degree of anticoagulation with warfarin is slow)
    • patients with increased risk of intracranial bleeding (DOACs cause fewer intracranial haemorrhages than warfarin).
  • An overview of the benefits and disadvantages of DOACS and warfarin is presented in table T3.
    • Direct anticoagulants have not been compared between each other, which is why clinical guidelines do not take a stand on their superiority to each other.

The benefits and disadvantages of direct anticoagulants compared with warfarin. Source: Current Care Guideline on atrial fibrillation (Finland, 2021).

Benefits
Fewer intracranial haemorrhages
Constant dosage and easier to predict dose-effect relationship
Variation in vitamin K intake (nutrition) does not change the effect
Fewer drug interactions
No need for routine monitoring of drug effect (easier and more convenient to implement)
Significant disadvantages
Contraindicated in patients with mitral stenosis and in patients with mechanical prosthetic valve
Contraindicated in patients with severe renal failure (dosage can be reduced in milder cases)
Other aspects to consider
Poorer availability of monitoring methods (follow-up of drug effect and compliance is more challenging when it is needed)
Patient's age and weight influence the dosage of some preparations
Other adverse effects than bleeding are more common (e.g. dyspepsia)
Price
Shorter experience of use
  • The most significant advantage of warfarin is that it can be used also in patients with a mechanical prosthetic valve, mitral stenosis or severe renal failure.
  • In long-term treatment a well-balanced warfarin therapy may be continued, but changing it to a direct anticoagulant is indicated if
    • warfarin causes allergy or is otherwise not suitable
    • INR monitoring is not feasible
  • If TTR (time in therapeutic range) is < 80%, the reason for poor treatment balance should be investigated and it should be evaluated whether the situation may be corrected by changing to a direct anticoagulant or by intensifying the warfarin therapy.

Occlusion of atrial appendage

  • In high-risk patients, percutaneous transcatheter occlusion of the atrial appendage may be considered if, owing to haemorrhagic complications, anticoagulant therapy is not an option.
    • In selected patients, the efficacy of the percutaneously inserted device is equal to that of warfarin therapy in terms of prevention of thromboembolic cerebral events.
  • Surgical closure or removal of the atrial appendage may be considered in conjunction with other heart surgery.

Anticoagulation during cardioversion for acute AF

  • Anticoagulant therapy is also essential in the treatment of an acute AF attack (duration less than 48 hours); see article Management of acute atrial fibrillation Management of Acute Atrial Fibrillation for details.
    • Sinus rhythm can be restored without anticoagulation in low- to moderate-risk patients (CHA2DS2-VASc HASH(0x2f62220) 1) if the arrhythmia has lasted less than 12 hours.
    • In other cases, either a DOAC or LMWH+warfarin is started already before cardioversion and the therapy is continued uninterrupted for, depending on thrombosis risk factors, at least one month or permanently. When using warfarin, therapy with LMWH is continued at a dose adjusted to the patient's body weight until INR is in the therapeutic range.
  • If the duration of AF is > 48 hours or it is not known, cardioversion must not be carried out unless
    • warfarin therapy has been on the therapeutic level (INR HASH(0x2f5d108) 2.0) for at least 3 weeks or
    • the patient has been using a direct anticoagulant with the recommended doses continuously for at least 3 weeks or
    • intracardiac thrombi are excluded with transoesophageal echocardiography (see Management of Acute Atrial Fibrillation).

    References

    • Kirchhof P, Benussi S, Kotecha D et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37(38):2893-2962. [PubMed]
    • Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17(10):1467-507. [PubMed]
    • Hindricks G, Potpara T, Dagres N ym. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42(5):373-498. [PubMed]
    • Steffel J, Collins R, Antz M ym. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace 2021;23(10):1612-1676. [PubMed]