Anticoagulation Update Rhona Maclean Rhona.maclean@sth.nhs.uk

By the end of this session you will know: What anticoagulant therapies are currently available What anticoagulants can be used in particular clinical situations Practical tips in using anticoagulants Starting/ switching/ procedures Current STH pathway for management DVT/PE

Available Anticoagulant Therapies Heparins Vitamin K Antagonists NOACs Unfractionated Heparin Warfarin Dabigatran Low molecular weight heparin Sinthrome (Acenocoumarol) Rivaroxaban Fondaparinux Phenindione Apixaban

Heparin and Fondaparinux Immediate onset of anticoagulation

Warfarin Mode of Action Prothrombin Prothrombin precursor - - - - Carboxylase Reduced vitamin K Oxidised vitamin K Vitamin K epoxide reductase - Vit K dependent Coagulation factors FII FVII FIX FX Warfarin Onset of action- >5 days; not until INR >2 for 24hrs

Mode of Action NOACs

Novel Oral Anticoagulants (NOACs) Dabigatran Rivaroxaban Apixaban Half life 12-17h 5-13h 9-12h Administration Oral Renally excreted? +++ +/- Heparin Induced Thrombocytopenia - Osteoporosis Side effects Dyspepsia in 8-10% Monitoring? No Dietary/ drug interactions + Reversal agent? ?

Drug Interactions with NOACs Dabigatran Rivaroxaban Apixaban Increase anticoagulant effect Amiodarone (caution) Verapamil (caution) Azole antimycotics Tacrolimus Cyclosporin HIV protease inhibitors Dronaderone Azole Antimycotics HIV Protease Inhibitors Reduce anticoagulant effect Rifampicin Carbamazepine Phenytoin Phenobarbital St John’s wort

Licensed and NICE approved indications for NOACs Dabigatran: VTE prevention after elective hip or knee replacement surgery Stroke prevention in Atrial Fibrillation Rivaroxaban: Deep Vein Thrombosis treatment and secondary prevention Pulmonary Embolism treatment and secondary prevention Acute coronary syndromes Apixaban:

Risk of adverse events in patients with atrial fibrillation taking warfarin : Warfarin is an effective drug Background: Oral anticoagulant therapy is effective for the prevention of arterial thromboembolism in variouspatient groups. The increased risk of hemorrhage remains the major drawback to this therapy and is associated with the intensity of anticoagulation. Finding the optimal intensity at which the overall incidence rate of both bleeding and thromboembolic events is minimized represents a way to improve the safety of oral anticoagulant treatment. Methods: We evaluated all patients visiting the Leiden Anticoagulation Clinic with mechanical heart valve prostheses, atrial fibrillation, or myocardial infarction from 1994 to 1998. Untoward events were major thromboembolism and major hemorrhage. We calculated intensity-specific incidence rates of untoward events to assess the optimal intensity per indication of treatment. We enrolled 4202 patients for a total of 7788 patientyears. Results: A total of 3226 hospital admissions were reported, 306 owing to an untoward event. Incidence rates of untoward events were around 4% per year for all indications: 4.3 (95% confidence interval [CI], 3.1-5.6) for patients with mechanical heart valve prostheses, 4.3 (95% CI, 3.7-5.1) for patients with atrial fibrillation, and 3.6 per year (95% CI, 3.0-4.4) for patients treated after a myocardial infarction. The optimal intensity of anticoagulation for patients with mechanical heart valve prostheses was an international normalized ratio (INR) of 2.5 to 2.9; for patients with atrial fibrillation, an INR of 3.0 to 3.4; and for patients after myocardial infarction, an INR of 3.5 to 3.9. Conclusion: Our study suggests target INRs of 3.0 for patients with mechanical heart valve prostheses and atrial fibrillation Optimal level of oral anticoagulant therapy Torn M et al, Arch Int Med 2009; 169:203-1209

Tips for achieving good warfarin control and avoid complications Patient education and engagement Encourage stable lifestyle Minimise other drug changes/ choose drugs less likely to interact with warfarin Use standardised induction regimen Adjust warfarin dose cautiously (+/- 10% of weekly dose) when outside therapeutic range Consider patient’s previous response Don’t blindly follow CCDS (INR star) Do INR if change of medication likely to interact or if unwell/ bleeding

Unstable Warfarin Anticoagulation INR Results 4 8 12 16 20 09/09/2006 08/10/2006 06/11/2006 05/12/2006 03/01/2007 01/02/2007 Dosage 40 60 80 100 68 year old woman on warfarin for recurrent VTE INR 3.5

Rivaroxaban Warfarin Event rate/100 patient years Major and non major clinically relevant bleeding 14.9 14.5 Major bleeding 3.6 3.4 Critical bleeding 0.8 1.2 Intracranial bleeding 0.5 0.7

Clinical Benefit of Anticoagulants in AF Banerjee et al, T&H 2012

What anticoagulant to use in AF? Warfarin Pros Experience Efficacious Long half life Reversal agent Use in renal failure Cons Requirement for monitoring Variable dosing requirements Not immediate onset of action Drug interactions/ lifestyle issues Bleeding Risk

What anticoagulant to use in AF NOACs Pros Immediate onset of action Once or twice daily medication- dosette boxes No (little) monitoring required Few drug interactions Risk major bleeding reduced, particularly intracranial Cons New- as yet relatively unfamiliar Shorter half life- compliance issues? Lack of specific reversal agent- as yet… Cannot use in renal failure

How to start NOAC in patient with AF Counsel patient- it is an anticoagulant Check baseline bloods (FBC, renal and liver biochem) Start NOAC (Rivaroxaban with food- in morning?) See patient for review in 3-4 weeks- any problems? Check FBC, biochemistry, 3-12 monthly dependent on patient factors Reinforce compliance whenever possible

Which anticoagulant to use for VTE? After a first VTE event, patients require minimum 3 months anticoagulation If idiopathic or ongoing risk factors, consider longer term anticoagulant treatment (NICE) Patients require immediate anticoagulation If start warfarin, usually entails 8-15 anticoagulation visits in first 3 months of treatment

EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome Methods of VTE treatment EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome 0.5 3.0 2.5 2.0 1.5 1.0 0.0 Rivaroxaban N = 4150 Enoxaparin/VKA N = 4131 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Cumulative event rate (%) HR=0.89; p non-inferiority <0.0001 Mean time in therapeutic range = 61.7% EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome Among patients with acute symptomatic DVT without PE or PE with or without DVT treated for 3, 6 or 12 months, the single-drug approach with oral rivaroxaban showed non-inferiority for the primary efficacy outcome of symptomatic recurrent VTE, compared with the current standard therapy (86 events [2.1%] vs 95 events [2.3%], respectively; HR=0.89; 95% CI 0.66–1.19; p<0.0001 for non-inferiority). Number of patients at risk Rivaroxaban 4150 4018 3969 3924 3604 3579 3283 1237 1163 1148 1102 1034 938 Enoxaparin/VKA 4131 3932 3876 3826 3523 3504 3236 1215 1149 1109 1071 1019 939 ITT population

EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding Methods of VTE treatment EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding First major bleeding 0.5 3.0 2.5 2.0 1.5 1.0 0.0 Rivaroxaban N=4130 Enoxaparin/VKA N=4116 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Cumulative event rate (%) Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 40/4130 (1.0) 72/4116 (1.7) 0.54 (0.37–0.79) p=0.002 EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding Major bleeding, a prespecified secondary outcome, was significantly lower in the rivaroxaban group compared with standard therapy (40 events [1.0%] vs 72 events [1.7%], respectively; HR=0.54; 95% CI 0.37–0.79; p=0.002). This included fewer critical-site bleeding events in the rivaroxaban compared with standard therapy group (9 vs 26, respectively) and fewer fatal major bleeding events (3 vs 8, respectively). Number of patients at risk Rivaroxaban 4130 3921 3862 3611 3479 3433 2074 1135 1095 1025 969 947 499 Enoxaparin/VKA 4116 3868 3784 3525 3394 3348 1835 1109 1065 990 950 916 409 Safety population

Rivaroxaban for VTE Currently in patients with a first DVT without contraindications Eg pregnancy, breastfeeding, renal failure, interacting drugs 15mg bd for 3 weeks then 20mg od for 10 weeks ?Reduce dose in renal impairment A reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE Consider duration of treatment Reassess after 3 months Idiopathic/ recurrent events Long term rivaroxaban? Renal impairment Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2). In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15 - 29 ml/min) renal impairment the following dosage recommendations apply: - For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2). - For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2). No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) (see section 5.2).

LMWH for patients with VTE and cancer Lee A et al, NEJM 2003

LMWH for treatment VTE Dalteparin 200iu/kg once daily In pregnancy currently use bd dosing. SPC caps dose at 18,000iu od if >83kg- good evidence that need to increase dose in those with high body weight- STH guideline After 30 days reduce dose (as per BNF/ STH guideline) Patients with cancer- watch weight and renal function- may need to adjust dose

Summary: Anticoagulation for VTE Patient choice Rivaroxaban after a first VTE event (unless contraindicated), if unstable, side effects or contraindications to warfarin LMWH if cancer, pregnant, interacting drugs with rivaroxaban Once chemotherapy finished, consider switching from LMWH to alternative anticoagulant Warfarin if renal failure, if recurrent events

Mechanical Heart Valves Do not use NOACs Study of dabigatran terminated as excess bleeding and thrombosis in dabigatran groups compared with warfarin. No other studies underway at present

Converting from Warfarin to Rivaroxaban Discuss with patient Check that patient is not on interacting drugs Baseline bloods- FBC, renal and liver biochemistry, INR Make switch Review in a couple of weeks for side-effects and to reinforce compliance FBC and biochemistry every 3-12 months

Converting from Warfarin to Rivaroxaban VTE treatment INR < 2.5 Stop VKA VKA Monitor INR Commence Xarelto at appropriate dose SPAF INR < 3.0 VTE INR ≤ 2.5 Xarelto SmPC SmPC for rivaroxaban L.GB.12.2012.1370 Date of preparation Jan 2013 28 28 28

(dose according to indication) Converting from Rivaroxaban to Warfarin Standard VKA dose INR adapted VKA dose Xarelto (dose according to indication) Xarelto can be stopped once INR > 2.0 INR testing before Xarelto administration Days Once Rivaroxaban is discontinued, INR testing may be done reliably at least 24hrs after the last dose Xarelto SmPC 29

Preoperative management of Rivaroxaban anticoagulation Major surgery Minor surgery

Postoperative Management of Rivaroxaban Anticoagulation Major surgery Surgery D +1 D+2 D+3 D+4 D+5 D + 6 Prophylactic dalteparin once daily starting 6 – 8 hrs post op Stop dalteparin the day before restarting therapeutic rivaroxaban (at day 3 – 5, at earliest on day 3, depending on bleeding tendency). Check U&E/LFT. Do not restart therapeutic anticoagulation with epidural in situ. Minor surgery Start Rivaroxaban 24 hours after the procedure. Patients admitted on prophylactic doses of rivaroxaban (10 mg OD) may be re-started 6 - 8 hours post op.

Patient pathway for VTE Diagnosed in A&E or as an inpatient Seen by thrombosis nurse specialist for assessment MDT Malignancy suspected 2 weeks O.P.A with consultant Unprovoked DVT 4 to 6 weeks O.P.A with consultant Provoked DVT Nurse-led pathway

Conclusion Warfarin and NOACs both efficacious in prevention stroke in AF and treatment VTE Most important issue is patients who require anticoagulation have access to anticoagulant treatment