DOAC the story so far... Dr GM Benson Director NI Haemophilia and Thrombosis Centre BHSCT

DOAC the story so far... Dr GM Benson Director NI Haemophilia and Thrombosis Centre BHSCT

A rose by any other name.. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH The term NOAC has been used the longest, and, recently, some have argued for use of the term non-vka oral antagonists (NOACs), to take advantage of the commonly used abbreviation without using the terms novel and new. However, identifying a class of drugs by what they are not is scientifically unappealing. Perhaps more importantly, there is at least one reported account where the term NOAC written in the medical record was interpreted as meaning No AntiCoagulation, potentially resulting in the patient not receiving the critical therapy that was intended DOAC, 58.4%; TSOAC, 49.4%; and NOAC, 39.0%. TSOAC (target-specific oral anticoagulant), ODI (oral direct inhibitor), and SODA (specific oral direct anticoagulant)

Risk factors Score CHA 2 DS 2 - VASc scoring for AF Eur Heart J (2013) doi: 10.1093/eurheartj/eht291 Congestive Heart Failure +1 Hypertension +1 Age > 75 years +2 Diabetes Mellitus +1 Stroke/ TIA/TE +2 Vascular Disease +1 Age 65-74 years +1 Sex Category (female) +1

Risk factors Score HAS-BLED score in AF Eur Heart J (2013) doi: 10.1093/eurheartj/eht291 Hypertension +1 Abnormal liver function +1 Abnormal renal function +1 Previous Stroke +1 Prior Major Bleeding or Predisposition Labile INR (<60% of time in therapeutic range) +1 +1 Age >65 years (Elderly) +1 Drugs Predisposing to Bleeding +1 Alcohol use (>8 drinks/week) +1

Real-world variability in dabigatran levels in patients with atrial fibrillation. Volume 13, Issue 6, June 2015, J. Douxfils, Bleeding risk in real world patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort. Volume 9, Issue 8, August 2011,J. B. OLESEN Journal of Thrombosis and Haemostasis Dabigatran adherence in atrial fibrillation patients during the first year after diagnosis: a nationwide cohort study. Volume 13, Issue 4, April 2015, A. Gorst- Rasmussen, Adherence to anticoagulant treatment with dabigatran in a real-world setting. Volume 11, Issue 7, July 2013, S. Schulman Reasons for and consequences of vitamin K antagonist discontinuation in very elderly patients with nonvalvular atrial fibrillation. Volume 14, Issue 11, November 2016, G. Bertozzo

Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with vitamin K antagonists. J. Carmo (1), 2016 116 4: 754-763 Unreal world or real world data in oral anticoagulant treatment of atrial fibrillation. B. Freedman, 2016 116 4: 587-589 Dabigatran in real-world clinical practice for stroke prevention in patients with non-valvular atrial fibrillation. T. S. Potpara, 2015 114 6: 1093-1098 Thrombosis Haemostasis Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice. J. Beyer-Westendorf, 2016 116 Suppl. 2: S13-S23 Ischaemic stroke and bleeding rates in real-world atrial fibrillation patients. I. M. Ogilvie, 2011 106 1: 34-44 Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis. G. Y. H. Lip 2016 116 5: 975-986 Effectiveness and safety of apixaban versus warfarin in nonvalvular atrial fibrillation patients in real-world clinical practice. A propensity-matched analysis of 76,940 patients. X. Li 2017 117 6: 1072-1082 Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a real world atrial fibrillation population: A modelling analysis based on a nationwide cohort study. A. Banerjee 2012 107 3: 584-589

Licensing Time in therapeutic range INR testing Efficacy Patient education/choice Frequency of dosing Key factors influencing choice of anticoagulant Renal function Extremes of BMI GI adverse effects Bleeding Stability in compliance aids Reversal Monitoring Food/drug interactions Missed dose Contraindications Pregnancy/breastfeeding Bridging

Assessing anticoagulation control with vitamin K antagonists NICE CG180, 2014 Calculate time in therapeutic range (TTR) at each visit Reassess anticoagulation for a person with poor anticoagulation control: 2 INR values > 5 or 1 INR value > 8 within the past 6 months 2 INR values < 1.5 within the past 6 months TTR < 65%.

Patient Safety Alerts

The prescription of a DOAC must be preceded by a thorough evaluation of patient characteristics, including age, body weight, history of renal or liver disease, history of bleeding, other co-morbidities and use of concomitant drugs. The results of laboratory tests, including full blood count, PT and aptt, serum creatinine, transaminases and bilirubin, should be available and carefully evaluated. CrCl should always be calculated using a commonly available formula This information will not only guide correct prescription, but will also identify patients requiring dose adjustments, which are recommended in fragile patients such as elderly patients defined at increased risk of bleeding and patients with moderated to severe renal impairment.

Dose reduction for DOACs CrCl (ml/min) 50 Dabigatran Rivaroxaban Apixaban Edoxaban Usual dose is 150mg twice daily Consider 110mg twice daily in 75-80 year olds, or with moderate renal impairment, gastritis/ GORD or at increased risk of bleeding 110mg twice daily in patients >80 years or if taking verapamil 20mg once daily with food 5mg twice daily Reduce to 2.5mg twice daily in patients with two or more of the following: o Age 80 years o Body weight 60kg o Serum creatinine 1.5mg/dL (133 micromoles/l) 60mg once daily Reduce to 30mg once daily in patients with one or more of the following clinical factors: Low body weight <60kg Concomitant use of ciclosporin, dronedarone, erythromycin or ketoconazole 30 49 110-150 mg twice daily Reduce dose to Use normal dose 15 29 Do not use 15mg daily Reduce dose to 2.5mg twice daily < 15 Do not use Reduce dose to 30mg daily

When prescribing a DOAC, the presence of concomitant drugs potentially interfering with its bioavailability should be carefully ascertained. Some of these drugs (in particular verapamil for dabigatran and clarithromycin or erythromycin for rivaroxaban) may increase the risk of bleeding, and their co-administration must be carefully evaluated, also taking into account the individual risk profile. Other drugs such as phenobarbital, carbamazepine or phenytoin may decrease efficacy. Finally, as for the vitamin K antagonists, the concomitant administration of a DOAC with an antiplatelet agent will increase the risk of bleeding and the need for combined treatment should be reviewed.

Adequate counselling information must be provided when the DOAC is prescribed. The patient should be clearly informed about treatment indication, dosing schemes, dosing instructions if one or more doses are missed, risks associated with non-adherence and risks associated with drug intake Although patients treated with DOACs do not require regular laboratory monitoring, a clinical monitoring schedule should be planned with the patient, with regular review of adherence and concomitant medications. More frequent visits should be considered for fragile patients based on their age, body weight, presence of co-morbidities and concomitant treatments. Laboratory monitoring of renal function should be planned at least yearly, but possibly more often in some high-risk patient categories such as the elderly, patients with impaired renal function at baseline, or patients with concomitant medications or diseases potentially affecting renal function

Extremes of BMI International Society on Thrombosis & Haemostasis Standard dosing of DOACs in patients with BMI 40kg/m 2 and weight 120kg for VTE treatment, VTE prevention, and prevention of ischaemic stroke and systemic arterial embolism in non-valvular AF DOAcs should not be used in patients with BMI> 40kg/m 2 or a weight >120kg because there are limited clinical data available for patients at the extreme of weight available PK/PD evidence suggests that decreased drug exposures, reduced peak concentrations and shorter halflives occur with increasing weight, which raises concerns about underdosing at extremes of weight

Bleeding and reversibility

Indication for reversibility (Suspected) Bleed into a critical organ Head Eye Spinal cord Limb with compartment syndrome Drop in Hb of greater than 20g/l Need for surgery within 4 hours

January to June 2016 VKA reversal 62 patients received PCC for reversing an anticoagulant. 44 VKA, 13 DOAC Outcome at 24 hrs: Alive 55 Deceased 2 Outcome at 30 days: Alive 46 Deceased 11

DTI reversal

Xa inhibitior reversal

Prescribing trends/ challenges

Antiplatelet treatment NICE CG180, 2014 Do not offer aspirin monotherapy solely for stroke prevention to people with AF. No clear evidence of clinical benefit of aspirin in reducing mortality and systemic emboli. Modest benefit in reducing ischaemic stroke was partially offset by a modest harm in increased bleeding and haemorrhagic stroke. heavily dependent on results from the SPAF1 study, which used 325 mg aspirin/day

Items Trends in prescribing of DOACs in NI 50,000 45,000 40,000 Edoxaban Rivaroxaban Dabigatran Apixaban 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 Quarter ending Jun 2009 Sep 2009 Dec 2009 Mar 2010 Jun 2010 Sep 2010 Dec 2010 Mar 2011 Jun 2011 Sep 2011 Dec 2011 Mar 2012 Jun 2012 Sep 2012 Dec 2012 Mar 2013 Jun 2013 Sep 2013 Dec 2013 Mar 2014 Jun 2014 Sep 2014 Dec 2014 Mar 2015 Jun 2015 Sep 2015 Dec 2015 Mar 2016 Jun 2016 Sep 2016 Dec 2016

Increasing usage of OAC Appropriate? Need for safer patient selection and education Need for safer clinician selection and education Appropriate dosage selection for maximal stroke prevention benefit Anticoagulants reduce risk of clotting but with an increased risk of bleeding. Challenging choice of anticoagulant may lead to challenging choice of reversal agents.