DIRECT ORAL ANTICOAGULANTS: WHEN TO USE, WHICH TO CHOOSE AND MANAGEMENT OF BLEEDING

Transcription

1 DIRECT ORAL ANTICOAGULANTS: WHEN TO USE, WHICH TO CHOOSE AND MANAGEMENT OF BLEEDING KATHERINE STIRLING CONSULTANT PHARMACIST ANTICOAGULATION AND THROMBOSIS DR LISHEL HORN CONSULTANT HAEMATOLOGIST HAEMOSTASIS AND THROMBOSIS LEEDS TEACHING HOSPITALS NHS TRUST NOVEMBER 2017

2 AIMS The first aim of this session is for delegates to understand what are appropriate uses for the direct oral anticoagulants (DOACs) based on trial and licensing information and how to choose the right DOAC for individual patients. The second aim is to understand how to manage bleeding in patients on DOACs.

3 DOACS WHEN TO USE -AF Stroke and systemic embolism prevention for patients with nonvalvular AF Is the patient in AF? What is their Chadsvasc? What is non-valvular AF? Exclusions from trials prosthetic valves, clinically significant mitral stenosis, < 18, pregnancy, liver disease, clearance < 30ml/min

4 ALGORITHM: STROKE PREVENTION OF PEOPLE WITH NONVALVULAR AF UK/CVS Date of prep: June 2014 National Clinical Guideline Centre. Atrial fibrillation: the management of atrial fibrillation. June Available at: (accessed June 2014).

5 CHA2DS2VASC FOR PATIENTS IN AF 1 point for CCF 1 point for Hypertension 2 points for age > 75 1 point for diabetes 2 points for stroke/tia 1 point for vascular disease i.e. MI, PVD 1 point for age point for being female

6 NICE AF GUIDANCE Discuss the options for anticoagulation with the person and base the choice on their clinical features and preferences Assess anticoagulation control with warfarin, TTR over at least 6 months Do not offer aspirin monotherapy solely for stroke prevention NICE CKD 2014 apixaban for AF with CrCl 30-50ml/min

7 HASBLED 1 point for BP > 160 systolic uncontrolled 1 point for Renal disease, Dialysis, transplant, >200 µmol/l 1 point for liver disease cirrhosis or bilirubin >2x normal with AST/ALT/AP >3x normal 1 point for stroke 1 point for prior major bleeding or predisposition to bleeding 1 point for labile INR TTR < 60% 1 point for age > 65 1 point for medication predisposing to bleeding 1 point for alcohol > 8 drinks per week

8 BLEEDING RISK Falls risk Baseline bloods clotting check at baseline, if INR 1.3 or more refer to haematology platelets > 100 and not on downward trend anticoagulate platelets <100 investigate cause, refer to haematology Hb low check haematinics, ensure investigated Renal function - poor renal function increases bleeding risk Liver function

9 EVIDENCE BASED Only dabigatran 150mg bd showed superiority to well controlled warfarin in terms of reduction in stroke and systemic embolus in trials Warfarin TTR in trials varied from 52% to 64% All trials excluded patients with a clearance < 30ml/min All trials excluded patients with metallic heart valves, pregnant patients, patients < 18, Very few patients of very low (<50kg )or very high weight (>100kg) Trials excluded patients with liver disease LFTs 2x ULN

10 DOACS WHAT TO CHOOSE -AF Dosing Compliance aids Food Interactions Renal function Liver function Bleeding Side effects

11 DOAC DOSING IN AF Dabigatran Rivaroxaban Apixaban Edoxaban Dose 150mg bd or 110mg bd if >80 or on verapamil. Consider 110mg bd if or moderate renal impairment or gastritis/duo denitis/oeso phagitis or high bleeding risk. 20mg od or 15mg od if CrCl 15-49ml/min (AF only) 5mg bd or 2.5mg bd if 2 of > 80, weight < 60, >133 (AF only) 60mg od or 30mg od if CrCl 15-49ml/min or <60kg or on dronedarone, ciclosporin, ketoconazole or erythromycin

12 WHICH NOAC Dabigatran Rivaroxaban Apixaban Edoxaban Frequency BD OD with a meal BD OD Can go in a compliance aid NO own compliance aid available YES YES YES Swallow whole YES bioavailability increased by opening capsule NO can be crushed NO can be crushed YES

13 Dabigatran Rivaroxaban Apixaban Edoxaban Renal function Contraindicated clearance <30ml/min Consider dose reduction if clearance <50ml/min and high risk of bleeding Contraindicated clearance < 15ml/min Caution clearance 15-29ml/min Contraindicated clearance < 15ml/min Caution clearance 15-29ml/min Contraindicated clearance < 15ml/min Caution clearance 15-29ml/min

14 NEW ORAL ANTICOAGULANTS Dabigatran Rivaroxaban Apixaban Edoxaban Side effects Bleeding GI abdo pain, diarrhoea, dyspepsia Bleeding GI, dizziness, light-headedness, pruritus, peripheral oedema Bleeding Nausea Bleeding Nausea, rash, pruritus Interactions Strong P-gp inhibitors/ inducers cautioned or contra-indicated Verapamil, clarithromycin, amiodarone Rifampicin, carbamazepine phenytoin CYP3A4 inhibitors/ inducers Azole antifungals, HIV protease inhibitors Rifampicin, carbamazepine, phenytoin, phenobarbitone, St Johns wort P-gp inhibitors/ inducers CYP3A4 inhibitors/ inducers Azole antifungals, HIV protease inhibitors Rifampicin, carbamazepine, phenytoin, phenobarbitone, St Johns wort P-gp inhibitors/ inducers P-gp inhibitors/ inducers ciclosporin, clarithromycin, ketoconazole Rifampicin, carbamazepineph enytoin

15 DOACS WHEN TO USE - ACUTE VTE TREATMENT DOACs non-inferior to LMWH and warfarin for acute VTE with less bleeding Exclusions pregnancy or breast feeding, clearance < 30ml/min, clinically significant liver disease, Mean age 55 < 10% of patients with active cancer in trials

16 EXCLUSION CRITERIA FOR DOAC VTE STUDIES Apixaban Dabigatran Edoxaban Rivaroxaban Renal function Liver disease Active cancer Others CrCl < 25ml/min CrCl< 30ml/min CrCl < 30ml/min CrCl < 30ml/min excluded excluded excluded excluded Life expectancy < 3 months and LMWH indicated Provoked event so treatment < 3 months Life expectancy < 6 months Symptoms > 14/7, PE requiring urgent intervention, IVC filter, thrombolytic therapy Life expectancy < 3 months and LMWH indicated Thrombectomy, IVC filter, fibrinolytic agent Life expectancy < 3 months Thrombectomy, IVC filter or fibrinolytic agent administered

17 OBESITY DOACs equivalent to warfarin in highest weight category Non-inferior compared with normal weight Guidance statements from ISTH Patients < 120kg normal dosing Consider avoiding if >120kg Could check levels if > 120kg and if in range suggest OK.

18 DOACS WHAT TO CHOOSE ACUTE VTE TREATMENT 5 day LMWH lead in - dabigatran and edoxaban 3 weeks high dose rivaroxaban 1 week high dose apixaban Dose reduction for Creatinine clearance < 50ml/min edoxaban LMWH still gold standard for cancer associated thrombosis and thrombosis in pregnancy

19 Dabigatran Rivaroxaban Apixaban Edoxaban Dose 150mg bd or 110mg bd if >80 or on verapamil. Consider 110mg bd if or moderate renal impairment or gastritis/duo denitis/oeso phagitis or high bleeding risk. Acute VTE 15mg bd for 3 weeks then 20mg od for 6 months then 10mg or 20mg od. Acute VTE 10mg bd for 7 days then 5mg bd for 6 months then 2.5mg bd 60mg od or 30mg od if CrCl 15-49ml/min or <60kg or on dronedarone, ciclosporin, ketoconazole or erythromycin

20 DOACS WHEN TO USE PREVENTION OF RECURRENT VTE AFTER ACUTE EVENT Full or reduced dose Trials AMPLIFY extend, EINSTEIN extend, EINSTEIN Choice, REMEDY, RESONATE Looked at dose, vs. warfarin, placebo or aspirin Consider if high, medium or low risk for recurrence

21 DOACS WHAT TO USE PREVENTION OF RECURRENT VTE High risk for recurrence continue full dose, warfarin, dabigatran, edoxaban, rivaroxaban Medium risk for recurrence as above or reduce rivaroxaban to 10mg as per EINSTEIN choice or apixaban to 2.5mg bd as in AMPLIFY extend

22 DOACS WHEN NOT TO USE Metallic valves The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. Poor renal and liver function Arterial disease Stroke not due to AF Anti-phospholipid syndrome? VTE in patients with active cancer?

23 Dabigatran Rivaroxaban Apixaban Edoxaban Switching from a VKA Start when INR < 2 AF start when INR < 3 VTE start when INR < 2.5 Start when INR < 2 Start when INR < 2.5 Renal function Contraindicated clearance <30ml/min Consider dose reduction if clearance <50ml/min and high risk of bleeding Contraindicated clearance < 15ml/min Caution clearance 15-29ml/min Contraindicated clearance < 15ml/min Caution clearance 15-29ml/min Contraindicated clearance < 15ml/min Caution clearance 15-29ml/min

24 SUMMARY There are a number of advantages to using DOACs rather than warfarin for stroke prevention in AF and for VTE treatment but consider renal function weight liver function lack of reversal agent for some interactions There is not yet sufficient evidence to for DOACs to completely replace warfarin for all indications.