Three new/novel oral anticoagulants (NOAC) have been licensed in Ireland since 2008:

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1 Key Points to consider when prescribing NOACs Introduction Three new/novel oral anticoagulants (NOAC) have been licensed in Ireland since 2008: Dabigatran Etexilate (Pradaxa ) 75mg, 110mg, 150mg. Rivaroxaban (Xarelto ) 10mg, 15mg, 20mg. Apixaban (Eliquis ) 2.5mg, 5mg. They differ in their mode of action: Dabigatran Etexilate is a direct thrombin inhibitor while Rivaroxaban and Apixaban are direct factor Xa inhibitors. NOACS are licensed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and primary prevention of venous thromboembolic events (VTE) following total hip (THR) and knee (TKR) replacement surgery. Rivaroxaban has an additional license for the treatment of DVT and PE and the prevention of recurrent DVT and PE. They are not licensed for anticoagulation in patients with prosthetic valves. Warfarin remains the only oral anticoagulant for patients with prosthetic valves. NOAC prescribing requires substantial knowledge of posology, contraindications, special precautions for use and interactions with other drugs to avoid increased bleeding risk. Each patient will require careful individualised risk-benefit assessment prior to treatment to minimise bleeding risk and maximise anticoagulation. Prior to prescribing, knowledge of renal and liver function is imperative to allow correct dosing regime and avoid excessive bleeding risk. There are reduced dose options available for each NOAC. During treatment patients require regular renal function monitoring and clinical and/or diagnostic monitoring for bleeding. Strict compliance is required to avoid lapses in anticoagulation leading to a prothrombotic state. Currently in the case of excessive coagulation there is no antidote available for any NOAC. Dialysis may be used to treat Dabigatran Etexilate over coagulation but it is not used to treat Rivaroxaban or apixaban overcoagulation. Using NOACs in the Consultation NOACs versus Warfarin For those taking Warfarin the potential risks and benefits of switching to NOACs should be considered in light of the INR control. Advantages of NOAC: No routine monitoring required. Broader therapeutic window. Fixed dosing regimen. No interactions with food. Fewer drug interactions. Better patient compliance if less monitoring and less food/drug interactions. 1

2 Disadvantages of NOAC: No antidote currently available. Lack of experience of long-term use compared with warfarin and aspirin. Limited data on use in patients at extremes of body weight and hepatic impairment. Limited clinical experience dealing with overdose and reversal of NOAC effects in the case of major bleeding events. Short half-life requires strict compliance to avoid a pro-thrombotic state. The necessity for BD dosing could compromise compliance. Inability to monitor anticoagulation or to validate patient compliance. Costly. Age is an additional risk factor for haemorrhage. Integrity of Dabigatran Etexilate capsules is imperative as capsule pellets consumed without the shell have an increased oral bioavailability of 75% resulting in a potential increased risk of bleeding. Contraindicated in prosthetic heart valves. Advantages of Warfarin: Well established efficacy Adequate efficacy/ safety ratio. Antidote available. Low cost. Established bridging criteria where discontinuation of Warfarin is essential but anticoagulation still required. Disadvantages of Warfarin: Narrow therapeutic window Long half life Requires frequent monitoring to maintain INR within therapeutic range for given indication. Complicated dosing regimes with no standardised doses. Onset of action slow and takes 2-6 days to get to therapeutic range Multiple interactions with food and drugs Polymorphisms exist which could determine increased sensitivity or resistance to Warfarin. Age is an additional factor in the risk of bleeding. Therapeutic Indications The therapeutic indication for each NOAC varies and should be considered prior to commencement of these agents. Dabigatran Etexilate 1. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with 1 of the following risk factors: Previous CVA, TIA or systemic embolism Left Ventricular Ejection Fraction < 40% Symptomatic heart failure NYHA Class II. Age 75 years Age 65 years associated with one of the following: diabetes mellitus, coronary artery disease or hypertension. 2

3 2. Primary prevention of VTE events in adult patients who have undergone elective total hip replacement or total knee replacement surgery. Rivaroxaban 1. Prevention of stroke and systemic embolism in adults with NVAF and 1 of the following factors: Hypertension DM CCF Age 75 years Prior CVA or TIA 2. Treatment of DVT and PE. 3. Prevention of recurrent DVT and PE. 4. Prevention of VTE following elective THR and TKR. Apixaban 1. Prevention of stroke and systemic embolism in adults with NVAF with 1 of following risk factors: Prior CVA or TIA Age 75 years Hypertension DM Symptomatic CCF (NYHA Class II) 2. Prevention of VTE in patients following elective THR and TKR. Non-valvular Atrial Fibrillation: atrial fibrillation without the presence of haemodynamically relevant mitral valve stenosis or prosthetic heart valve (mechanical or biological). Commencing therapy All patients should have Creatinine Clearance assessed (CrCl) **. All patients should have LFT s undertaken. Hb/ Hct should be undertaken as a baseline reference level in the event of bleeding incidents. All patients should have an individualized assessment of their suitability for treatment with NOAC and an assessment of their bleeding versus thromboembolic risk. The risk-benefit of NOAC versus Warfarin should be considered. All patients need to have their current medications assessed for potential interactions with NOAC All patients need to be educated with regard to common side effects, missed dose procedures and warnings with regard to managing bleeding events and symptoms of covert bleeding. All patients need to be furnished with written information and PIL/FAQ/ self help documentation/ website address to familiarize them with the new medication. 3

4 has up to date PIL for each of the NOAC. Importance of compliance to avoid pro-thrombotic states needs to be stressed. Patient education with regard to Dabigatran Etexilate capsule handling/removal from packaging/storage is essential to product integrity and effectiveness. Contraindications, special precautions and dosage regimes differ with each NOAC and with individual patient characteristics **Calculating Creatinine Clearance (CrCl) 12 This is calculated using the Cockgroft-Gault Equation. For creatinine in μmol/l 1.23 x (140 age [years]) X weight [kg]( x0.85 if female) Serum creatinine in μmol/l For creatinine in mg/dl (140 age [years]) X weight [kg] (x 0.85 if female) 72 x serum creatinine [mg/dl] Maintenance Treatment with NOAC Patients over 75 years treated with Dabigatran Etexilate should have renal function assessed at least once a year. Renal function should ideally be monitored on patients treated with Rivaroxaban and Apixaban also. Patients with impaired renal function treated with Dabigatran Etexilate should have renal function assessed at least once a year Renal function should be checked when it is suspected that it could deteriorate e.g. Hypovolaemia, dehydration or with concomitant use of medicinal products that affect renal function. All patients should be monitored for signs of bleeding. Any unexplained fall in Haemoglobin and/or Haematocrit or BP should lead to a search for a bleeding site. When commencing new medications a careful assessment needs to be made to ensure that there is no contraindication to its use with NOAC or any special precautions attached to its concomitant use with the NOAC. Reiteration regarding the need for strict compliance. References available on request Authors: Dr Philippa Kildea- Shine and Dr Margaret O'Riordan ICGP 4

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