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Direct Oral Anticoagulants

Essentials

  • Direct oral anticoagulants (DOAC) are an alternative to warfarin in the prevention and treatment of thromboses in certain groups of patients. The choice of patients should follow the guidelines confirmed by research evidence.
  • DOACs include dabigatran, rivaroxaban, apixaban and edoxaban.
  • Due to their short elimination half-life, it is important to use DOACs regularly to ensure effective treatment. Making decisions together with the patient, patient guidance, and commitment to treatment are key factors.
  • Regular clinical and laboratory monitoring (including liver and kidney function tests) at least every 6 months is necessary. Good treatment and monitoring of hypertension, and diagnosis and appropriate investigation and treatment of any anaemia are important to minimize the risk of severe (e.g. intracranial or gastrointestinal) haemorrhage associated with the treatment.
  • The doctor starting the treatment should record the most important data on a patient card 1 always carried by the patient for any accident or acute illness.

Mechanism of action

  • Slowing down of blood coagulation by inhibiting either thrombin (dabigatran) or coagulation factor Xa (rivaroxaban, apixaban, edoxaban)
  • The elimination half-lives of these drugs are rather short (approx. 9-15 h) but longer in patients with renal failure. The effects of the drugs cannot be measured by routine laboratory tests.

Indications 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, Oral Direct Thrombin Inhibitors or Oral Factor Xa Inhibitors for the Treatment of Deep Vein Thrombosis, Dabigatran Versus Vitamin K Antagonists in Non-Valvular Atrial Fibrillation, Dabigatran Versus Lmwhs for Thromboprophylaxis after Total Hip or Knee Replacement

  • Management of risk of thrombosis associated with atrial fibrillation
    • The European Heart Rhythm Association (EHRA) has published a treatment guide dealing with the use of DOACs in non-valvular atrial fibrillation. See the up-to-date English website of EHRA at www.noacforaf.eu http://www.noacforaf.eu.
  • Treatment and prevention of recurrence of deep venous thromboembolism or uncomplicated pulmonary embolism
    • Insufficient data are available about the efficacy of the drugs in the treatment of other types of venous thromboembolism, such as sinus thrombosis in cerebral veins, mesenteric or renal thrombosis, or venous thrombosis in patients with liver disease.
  • If the patient has severe phospholipid antibody syndrome or is triple-positive (lupus anticoagulant, beta-2-glycoprotein 1 antibodies and cardiolipin antibodies all positive) Evaluation of Thrombophilia Systemic Lupus Erythematosus (Sle), direct oral anticoagulants are contraindicated. In particular, if the blockage is arterial, the only anticoagulants recommended in antiphospholipid antibody syndrome are either warfarin or LMWH, depending on the indication, often in combination with a platelet inhibitor.
  • Treatment of patients with cancer can be carried out with a DOAC, as long as there are no drug interactions and haemostasis is secured. DOACs should not be used in cancer patients during their active treatment phase (bleeding risk). DOACs are not suitable in gastrointestinal cancers and pancreatic cancer, and when there is metastatic spread to the brain or liver.
  • DOACs are unsuitable for patients with mechanical valve prosthesis or mitral valve stenosis because their efficacy in preventing thromboses in these patients is insufficient.
  • Apixaban, dabigatran and rivaroxaban are only suitable for prophylactic treatment of venous thrombosis in association with elective hip or knee arthroplasty, not in other operations. The indications for edoxaban do not include post-operative prophylactic treatment of venous thrombosis.
  • DOACs are unsuitable for prophylactic treatment of venous thromboses in acutely ill medical patients because they increase haemorrhagic complications in this patient group.
  • They are contraindicated in the treatment of paediatric or pregnant patients, at least for the time being.
  • They are contraindicated in the treatment of patients with severe renal failure or liver disease.

Beginning treatment

  • After confirming the indication and contraindications, check blood pressure, kidney and liver function and any anaemia.
    • Basic blood count with platelet count, creatinine, eGFR Gfr Calculator, ALT, INR or prothrombin time; APTT testing to screen for any coagulation disorder is also recommended.
  • Consider the patient's age, any known bleeding tendency, other factors increasing the risk of bleeding, and kidney and liver function.
  • Individual risks of thrombosis and bleeding can be screened by using rough risk scoring (CHA2DS2-VASc and HAS-BLED).
  • Note any other medication, use of natural products, and the possibility of harmful interactions. Consult locally available drug database and each anticoagulant's Summary of Product Characteristics (SPC) for current knowledge on drug interactions.
  • Aspirin should be withdrawn when anticoagulant therapy is started unless there is a clear indication for its concomitant use.
  • Due to the short elimination half-life, the anticoagulant effect rapidly wears off during the period of withdrawal.
    • High commitment to the treatment (taking the drug regularly) is important. If this cannot be achieved, patient guidance should be intensified or alternative medication considered.
  • The doctor starting the treatment should record in the patient card the indication and planned duration of the treatment, the results of laboratory tests, and the anticoagulant and dosage prescribed. The doctor is also responsible for arranging monitoring of treatment.

Monitoring of treatment

  • Regular monitoring is necessary to ensure commitment to the treatment and to assess the efficacy of the medication, bleeding risk and kidney and liver function.
  • Basic blood count with platelet count, creatinine, eGFR Gfr Calculator, ALT, depending on the patient's primary disease and other medication 1-4 times a year
    • eGFR 30-60 ml/min/1.73 m2 , patient over 75 years or fragile: laboratory tests no less frequently than every 3-6 months
    • eGFR 15-30 ml/min/1.73 m2 : laboratory tests every 1-3 months
    • More frequent laboratory monitoring if the patient has some other disease (such as anaemia or a disease affecting liver or kidney function, some cancers in their stable phase)
  • Laboratory tests should also be done in association with any acute disease or injury and whenever surgical or invasive procedures are being planned.
  • In addition, the following should be examined and recorded:
    • implementation and regularity of treatment
    • any thromboembolic events
    • whether there are any bleeding episodes
    • blood pressure level
    • adverse effects
    • changes in health or habits (smoking, obesity), other diseases, changes in medication, drug interactions.

Factors increasing the risk of bleeding

  • Many primary diseases and their medication, renal failure, anaemia and traumas are associated with an increased bleeding risk.
  • Anticoagulants may accumulate in patients with renal, hepatic (Bil > 2 ×, aminotransferases > 3 × upper limit of reference range) or cardiac failure.
  • Anaemia increases the bleeding risk in patients on anticoagulants.
    • The most common cause of anaemia is iron deficiency causing lack of oxygen in the peripheral circulation, cardiac and renal failure, and irritation of the vascular endothelium, increasing the number of platelets and possibly making patients more susceptible to both thrombosis and bleedings.
    • The cause of iron deficiency must always be investigated and the treatment chosen accordingly.
    • The risk of bleeding is high in aged people with anaemia taking non-steroidal anti-inflammatory analgesics (NSAIDs).
  • A history of bleeding or bleeding tendency, thrombocytopenia or platelet dysfunction, advanced age (> 75 years), active cancer (especially in the gastrointestinal tract and in a metastatic disease), untreated hypertension (systolic blood pressure > 160 mmHg), alcoholism (especially in the elderly), developing cirrhosis of the liver and oesophageal varices increase the risk of bleeding.
    • In the treatment of hypertension, it is important to keep to the target levels.
  • Other medication affecting haemostasis increases the risk of bleeding significantly.
  • Uncontrolled alcohol consumption will predispose patients to the adverse effects of any anticoagulant treatment.

Preparing for surgical and other procedures

  • The clinic should be informed about the patient's anticoagulant medication. Any other medication affecting blood coagulation should also be taken into consideration.
  • Before the procedure, do at least basic blood count with platelet count, creatinine, eGFR Gfr Calculator, ALT
    • Prothrombin time and APTT are necessary for screening but do not reflect the efficacy of DOAC therapy.
  • The situation should be assessed taking into consideration the patient's individual risk of bleeding and thrombosis, the indication for surgery and the associated bleeding risk.
  • The clinic will provide instructions for interruption of medication.
    • Some minor procedures do not require interruption of anticoagulant therapy.
    • Depending on the procedure, patients with a high risk of thrombosis may benefit from individual thromboprophylaxis with LMWH.
  • Summary of Product Characteristics (SPC) of each drug and the EHRA guide http://www.noacforaf.eu provide further information on the theme.

Low bleeding risk procedures

  • Low bleeding risk procedures which do not require a DOAC pause include
    • cataract surgery
    • extraction of a single tooth
    • excision of a naevus or a lump
    • arthrocenteses or biopsies under direct vision or under ultrasound guidance and when compression is possible.
  • The procedure should be performed at least 4-6 hours after the peak drug level (3-4 h), that is, 8-12 hours after the drug has been taken.
  • If a drug is taken twice a day, one dose may be skipped as necessary.
  • Supporting local haemostasis is the most important way to control the bleeding risk.
  • The patient's bleeding risk is low if there is no anaemia (Hb < 100 g/l), thrombocytopenia (platelet count < 100 × 109 /l), uncontrolled hypertension, or severe renal or liver failure.
  • Haemostasis is usually reached in 6 hours after the procedure, but if the patient is considered to have bleeding risks, starting the anticoagulant should be postponed until 12 hours (drug administered twice a day) to 24 hours (drug administered once a day) after the procedure.
  • See the DOACs: Perioperative Management instructions by Thrombosis Canada http://thrombosiscanada.ca/clinicalguides/.

Bleeding episodes and emergency procedures

  • Patients should be hospitalized if, during treatment, they develop any more significant bleeding or need an emergency procedure.
    • Administration of DOACs should be interrupted immediately.
    • The anticoagulant effect of dabigatran can be reversed in case of emergency by administering the specific antidote (idarucizumab)
      • in association with a severe bleeding episode (e.g. intracranial, retroperitoneal or intraocular bleeding)
      • for emergency surgery or urgent procedures.
    • The effect of rivaroxaban and apixaban can be diminished with prothrombin complex concentrate (PCC), or it can be reversed in the above-mentioned emergencies with andexanet alfa which is a very expensive preparation.
      • The anti-FXa method which is in routine use is not suitable for detecting the reversal of the effect.
      • The recovery of haemostasis and coagulation status should be monitored with clinical assessments and laboratory tests (Hb, platelets, prothrombin time, APTT and, as necessary, fibrinogen, antithrombin, F VIII and D-dimer, renal function).
  • Guidance on potential emergencies may be available through local professional associations or health care providers. Find out about local information. See also guidance by EHRAhttp://www.noacforaf.eu.
  • To find out the frequency of bleeding episodes associated with anticoagulants, adverse effects should be entered in patient records in a uniform fashion, using the ICD-10 code D68.3 (haemorrhagic disorder due to circulating anticoagulants). In addition, the causative drug with its ATC code should be recorded.
  • Prepare and send a locally appropriate report of adverse drug reactions to the relevant authorities.

    References

    • Steffel J, Verhamme P, Potpara TS ym. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39(16):1330-1393. [PubMed]
    • Goodman SG, Wojdyla DM, Piccini JP et al. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol 2014;63(9):891-900. [PubMed]
    • Heidbuchel H, Berti D, Campos M et al. Implementation of non-vitamin K antagonist oral anticoagulants in daily practice: the need for comprehensive education for professionals and patients. Thromb J 2015;13:22. [PubMed]
    • Raskob GE, van Es N, Verhamme P ym. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med 2018;378(7):615-624. [PubMed]
    • Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019;380(8):720-728. [PubMed]