Page 59 - Retail Pharmacy March 2021

WARFARIN USE IN OLDER PEOPLE: AN OVERVIEW CPD ACTIVITY 57 Ann Winkle BPharm, BArts, AACP Ann is an accredited pharmacist and clinical writer with experience as an NPS MedicineWise facilitator and hospital pharmacist. LEARNING OBJECTIVES After completing this CPD activity, pharmacists should be able to: • Identifytheindicationsforwarfarinand other oral anticoagulants, including in older people. • Describehowwarfariniscommenced, monitored and dose adjusted using the international normalised ratio. • Describetherisksandprecautionsfor older people on warfarin therapy. • Explaintheroleofthepharmacist in warfarin management, including counselling patients. 2016 Competency Standards: 3.2, 3.3 3.6 Accreditation Number: A2103RP3 (exp: 21/03/2023). Introduction In 1940, researchers in the US state of Wisconsin discovered the anticoagulant coumarin in the sweet clover plant. Further work led to the synthesis of warfarin, which was initially approved as a rodenticide in the early 1950s before being approved for human use in 1954. The name warfarin was derived from WARF (Wisconsin Alumni Research Foundation) and –arin from coumarin.1 With a clinical history of more than 60 years, warfarin remains a widely used anticoagulant for prevention and treatment of thromboembolism and prevention of stroke in patients with atrial fibrillation (AF) or valvular heart disease. It has demonstrated effectiveness in a range of populations, including older people.2 Evidence suggests warfarin is underused in older people. This is likely due to concern over the risk of bleeding, particularly intracranial haemorrhage in those with AF. However, increasing age and AF are risk factors themselves for stroke and intracranial haemorrhage – commonly referred to as the ‘warfarin dilemma’. Increasing age alone is not a contraindication to warfarin use.3 Warfarin has a narrow therapeutic index with a well-established adverse effect profile. Management of warfarin to minimise bleeding includes starting with a low dose in older people, frequent laboratory monitoring to guide dose adjustment, and the availability of a reversal agent.2 Pharmacists are becoming more involved in the management of patients taking warfarin, including monitoring and dose alteration in dose administration aids. Therefore, it’s important for pharmacists to know the concepts that govern warfarin therapy, to minimise the risk of harm to patients. Background Warfarin characteristics Warfarin is the oldest oral anticoagulant available, with its clinical use beginning in the 1950s. It achieves anticoagulation by inhibiting the synthesis of vitamin K-dependent clotting factors II, VII, IX and X, and the antithrombotic factors protein C and protein S.4,5 Synthesis of these clotting and antithrombotic factors depend on vitamin K for carboxylation to become active.6 Vitamin K administration may be used to reverse over-anticoagulation with warfarin.2 Warfarin is well absorbed, almost 100 per cent bioavailable, and highly protein bound. It’s present in a racemic mixture of two enantiomers (S-warfarin and R-warfarin). S-warfarin is about three times more potent than R-warfarin, and they are metabolised by different enzymes. S-warfarin is metabolised by cytochrome P450 (CYP) 2C9 and R-warfarin is metabolised by CYP 1A1, 1A2 and 3A4. Warfarin has a half- life of 36-42 hours (R-warfarin 45 hours, S-warfarin 29 hours).6 Characteristics of other oral anticoagulants Newer oral anticoagulants (NOACs) are also known as non-vitamin K antagonists and are alternatives to warfarin in some long-term indications. They have shorter half-lives than warfarin and most lack an antidote, so good adherence and regular clinical monitoring is needed.7 Agents include a direct thrombin inhibitor (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban).2 Dabigatran and rivaroxaban came onto the Australian market for antithrombotic use in 2008 and apixaban joined them in 2011.8,9 All three NOACs were listed on the PBS in 2012.7 Dabigatran prevents thrombus formation by reversibly inhibiting both free and fibrin- bound thrombin, preventing conversion of fibrinogen to fibrin. Thrombin-induced platelet aggregation is also inhibited.5,6 The prodrug dabigatran requires bioconversion to an active form. It has a peak plasma concentration within two hours of dosing and an elimination half-life of seven to nine hours, or 12-14 hours in older people. About 20 per cent of the dose is excreted via the biliary system, with the rest excreted unchanged via the kidneys. Cytochrome P450 (CYP) enzymes are not involved in its metabolism.6 Rivaroxaban and apixaban selectively inhibit coagulation Factor Xa, thereby blocking thrombin production, conversion of fibrinogen to fibrin, and thrombus development. They don’t directly affect platelet aggregation.5,8,9 Apixaban and rivaroxaban have a rapid onset of action and a half-life of about 12 hours. However, apixaban is taken twice daily while rivaroxaban is usually taken once daily in the long-term. Caution is needed in patients treated with potent inhibitors of CYP 3A4 and P-glycoprotein (P-gp) concurrently with apixaban or rivaroxaban.5,10 Indications for oral anticoagulants Warfarin is highly effective in a range of thromboembolic disorders, including: • Stroke prevention in patients with AF. • Thrombus formation in those with prosthetic heart valves. • Prevention and treatment of venous thromboembolism.11 However, its narrow therapeutic index and adverse effect profile have been challenging clinically, particularly in older people. This has led to the development and PBS listing of the NOACs, although their bleeding risk, cautions and contraindications also require clinical monitoring and careful use in different patient groups.11 Indications for warfarin and NOACs differ slightly. Warfarin is indicated for:2,4 • Primary and secondary prevention of stroke in patients with AF or valvular heart disease. • Prevention of thromboembolism in patients with prosthetic heart valves. • Prevention of stroke in those with previous myocardial infarction and increased embolic risk. • Prevention and treatment of thromboembolism (deep venous thrombosis and pulmonary embolism). NOACs are indicated for prevention of venous thromboembolism (VTE) following elective hip or knee replacement, treatment TO PAGE 58 RETAIL PHARMACY •MAR 2021 2 CPD CREDITS