NIL. Dr Chuks Ajaero FMCP FRACP Cardiologist QEH, NALHN, SA Heart & Central Districts. Approach. Approach. 06-Nov-14

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1 Stroke Prevention in Atrial Fibrillation: Commencing Non- Oral Anticoagulants in GP setting Dr Chuks Ajaero FMCP FRACP Cardiologist QEH, NALHN, SA Heart & Central Districts Disclosures NIL Classification of AFib Paroxysmal (usually 48hrs) Based on Duration Persistent ( 7days or requires CV) Long-standing Persistent ( year) Silent Permanent (accepted) Modified from: Cm AJ, et al. Heart J. 200;3(9): Based on anticoagulant type Valvular Non- Valvular Medical Importance 56 years old man with no PMH holidaying in Thailand with wife had a LMCA Stroke and incidentally found to be having paroxysms of AFib. TTE Showed no abormalities.

2 Medical Importance AFib is the most common arrhythmia in the elderly Estimated 2.3Million in the USA; with 45% in >75yrs Also 0.% in <55yrs to 9.0% in >80yrs Advancing age therefore is the most important risk factor for AFib More in males and whites Go, AS JAMA 200 AF in Australian General Practice Sple of 4,750 patients, > 30 y.o. from 32 GPs Prevalence of AF is 4% (men 6%, women 4%) Prevalence increases with age Age < Men <% <2% 6% 4% 6% Women <% <% 3% 9% 3% BEACH study: : Non-valvular AF managed at a rate of 0.6 per 00 encounters : Non-valvular AF managed at a rate of. per 00 encounters. Sturm JW, et al. MJA. 2002;76: Britt H, et al. 2008;General Practice series no. 23. Cat no. GEP 23 AIHW. Prevalence of Valvular and Non-valvular AF in Australia Diagnosed Undiagnosed Total n. n. n. Valvular AF 39, 627 9, , 534 Non-valvular AF 365, 209 9, , 5 Total 404, 836 0, , 045 The Causes of Ischaemic Stroke Causes of Ischaemic Stroke Small vessel disease Large artery atherosclerosis % 6 Cardio-embolic 42 83% of AF is Non-valvular AF In Australia 25,000 General Practitioners 2, each GP has 8 patients with Non-valvular AF Other causes 6 Undetermined 25 *Non-valvular AF will now be referred to as AF. Deloitte Access Economics, 20. Off beat: Atrial fibrillation and the cost of preventable strokes. Available at: 2. Australian Institute of Health and Welfare 203. Medical workforce 20. National health workforce series no. 3. Cat. no. HWL 49. Canberra: AIHW. 9 Leyden JM, et al. Stroke. 203;44(5): % of all CE stroke and 36% of all ISC Stroke 0 Medical Importance contd Strokes due to AF are associated with more disability more severe disability higher mortality Marini C, et al. Stroke. 2005;36:5-9. Lin HJ, et al. Stroke. 996;27: Risk Factors for Stroke: The CHADS 2 & CHA 2 DS 2 -VASc Stroke Risk Scores Risk factors for AF Congestive heart failure Stroke Risk Factors: CHADS 2 Congestive heart failure. Gage BF, et al. JAMA. 200;285: Lip GY, et al. CHEST. February 200;37(2): Risk Score CHADS 2 Stroke Risk Factors: Risk Score 2 Congestive heart failure Hypertension Hypertension Hypertension Age Age ( 75) Age ( 75) 2 Diabetes Diabetes Diabetes (previous MI, PAD or aortic plaque) Obesity/ sleep apnoea Stroke/TIA 2 Stroke/TIA/ Thromboembolism (TE) Risk Category Low CHADS 2 Score Sum Individual Risk Scores for Total Risk Score Medium 2 or 3 High 4 (previous MI, PAD or aortic plaque) Age (65-74) Sex category (female) Risk Category 2 Score Low 0 Intermediate High 2 2 2

3 Risk Factors for AF, Stroke and Bleeding Risk factors for AF Stroke Risk Risk Score Bleeding Risk HAS-BLED Risk Score HAS-BLED CHF CHF Hypertension Hypertension Hypertension (uncontrolled, > 60 mmhg systolic), Age Age ( 75) 2 Diabetes Diabetes (previous MI, PAD or aortic plaque) Obesity/Sleep Apnoea Abnormal Hepatic or Renal Function Stroke/ TIA/ TE 2 Stroke (previous MI, PAD or aortic plaque) + Bleeding Labile INR Age (65-74) Elderly (>65) Sex category (female) Drugs and/or alcohol + Action points of the oral anticoagulants Apixaban, Rivaroxaban Dabigatran The Approved 3 NOACs ARISTOTLE RELY ROCKET-AF Trial drug Apixaban 5 mg bd vs Dabigatran 0 mg bd Dabigatran 50 mg bd Rivaroxaban 20 mg od Inclusion criteria AF within 2 months prior randomisation + risk factor AF within 6 months prior randomisation + risk factor AF within 6 months prior randomisation + 2 risk factors 3

4 ARISTOTLE RELY ROCKET AF Apixaban superior to warfarin: -In preventing stroke or -In causing less bleeding including ICH -In reducing mortality Dabigatran 50mg superior to warfarin: In preventing stroke or In reducing ischaemic stroke In causing less ICH Major bleeding rates are similar Rivaroxaban non-inferior to warfarin: (superiority with on-treatment analysis) In preventing stroke or Similar rate of bleeding Causes less ICH All cause stroke and Ischaemic and unspecified stroke Haemorrhagic stroke Dabigatran 0mg noninferior to warfarin: In preventing stroke or Causes less major bleeding Causes less ICH Miller et al. American Journal of Cardiology, Epub 202 Properties of the New Oral Anticoagulants Major Bleeding Intracranial Bleeding GI Bleeding Property Apixaban Dabigatran 2 (as etexilate) Rivaroxaban 3 Target Factor Xa Factor IIa (Thrombin) Factor Xa Bioavailability 50% 6.5% 66% Cmax (hrs) t ½ (hrs) Dosing B.I.D B.I.D Q.D Renal Excretion 27% 85% 66% CrCl >80 CrCl >50 to 80 CrCl 30 to 50 CrCl <30 t ½ (hrs) AUC* t ½ (hrs) AUC* t ½ (hrs) AUC* AUC = Area under the curve. *Relative to Creatinine Clearance (CrCl) >80.. Product information, Eliquis (apixaban). 2. Product information, Pradaxa (dabigatran etexilate). 3. Product information, Xarelto (rivaroxaban). 22 Practical Management issues 4

5 Transition from to NOACs Transition from LMWH to NOACs or Vice Versa Beware of doubling up check INR first as may need to cease warfarin Delay start of NOAC until INR in lower therapeutic range e.g. <2.5 Start NOAC the following day Similar half-life and rapid onset give alternate drug at time of next scheduled dose e.g. twice daily dosing e.g. once daily dosing INR NOAC (exple shown for a NOAC utilising a twice daily dosing regimen) N.B some sources recommend switching to NOAC once INR <3.0 consider in those at high risk of stroke. Check Product Information for each drug, as advice may vary Transition from NOACs to warfarin Perioperative Management of NOACs Remember delayed onset of warfarin effect (3-5 days to reach therapeutic range) Use NOAC similarly to Low Molecular Weight Heparin (LMWH) at initiation overlap with warfarin until INR >2.0. Avoid large loading doses of warfarin NOAC (exple shown for a NOAC utilising a twice daily dosing regimen) INR Patients should be monitored closely at initiation of warfarin therapy Some Factor Xa inhibitors (especially rivaroxaban) will prolong the INR Check Product Information for each drug, as advice may vary. Product information, Xarelto (rivaroxaban). 27 Bleeding Risk Surgical Exple Suggested Measure (normal renal function) Minimal Low High Cataract surgery Single tooth extraction Percutaneous biopsies Dental surgery Major surgery Spinal surgery Continue anticoagulant therapy Stop NOAC 24 hrs before procedure Stop NOAC 48 hrs before surgery Patient features determine the risk of thrombosis while anticoagulants withheld If renal function is impaired, longer periods (72 hrs) may be necessary to clear drug Caution when restarting NOAC if high-risk procedure, may be safer to recommence anticoagulation with prophylactic dose LMWH for hrs Check Product Information for each drug, as advice may vary 28 Drug Interactions Contraindications to the NOACs CCBs, Artovarstatin, Amiodarone, Macrolides, can mild to moderately increase the AUC Ketoconazole etc significantly increase AUC St John,s worth, Rifpicin, Phenytoin, Carbazepine significantly decrease AUC Valvular Afib: Rheumatic valve disease Mechanical heart valve prosthesis Pregnancy,, Severe Hepatic or renal disease, recent stroke, surgery, GI bleed or ulcer ICH< 6months 5

6 Assessment of Renal Function is Essential Renal Dose Reduction in Renal Impairment Renal Function Excretion Contraindication Apixaban 27% Lower dose - 2.5mg B.I.D if 2 or more of: age 80 years, body weight 60 kg, or serum Cr of 33 μmol /L CrCl < 25 ml/min Dabigatran 2 85% Lower dose - 0mg B.I.D if CrCl ml/min CrCl < 30 ml/min Rivaroxaban 3 66% Lower dose - 5mg Q.D if CrCl ml/min CrCl < 30 ml/min Is your Patient compliant? Thrombin Time and APTT should not be normal with dabigatran CrCl egfr Estimate Creatinine Clearance (CrCl) using the Cockcroft-Gault equation estimated CrCl = (40-age) x (weight [kg]) x [constant]/serum creatinine [μmol/l]) (Constant is.23 for men and.04 for women). Product information, Eliquis (apixaban). 2. Product information, Pradaxa (dabigatran etexilate). 3. Product information, Xarelto (rivaroxaban). 3 PT should not be normal with Rivaroxaban Antidotes??? Concerns over blood thinning drug Pradaxa RE-VERSE AD ongoing phase 3 study of Idarucizumab for Dabigatran ANNEXA-A phase 3 study of IV andexanert alfa for Apixaban met its primary endpoint Presently, dialysis for Dabigatran or wait it out for all three. Dabigatran stands out as The only Pro drug Low Bioavailabilty Poor Protein binding- hence dialyzable Marked Renal excretion Significantly reduced ischemic stroke comp to warfarin It is important for patients to continue their Dabigatran An 82-year-old man with permanent atrial fibrillation on rate control therapy with a history of diabetes, hypertension, and ischemic cardiomyopathy is being treated with rivaroxaban 20 mg once daily. The patient is slightly overweight. He has no history of bleeding but has had difficulty maintaining his international normalized ratio (INR) in the target range in the past. A routine laboratory test showed an increase in his plasma creatinine level with a clearance of 40 ml/min. What would be the preferable antithrombotic therapy for this patient?. Continue current rivaroxaban dose 2. Reduce his rivaroxaban dose to 5 mg once daily 3. Stop rivaroxaban and start dose-adjusted warfarin 4. Antiplatelet agents are preferable to oral anticoagulation in this patient in view of his history of ischemic cardiomyopathy 6

7 Conclusion All the NOACs are at least non inferior to in preventing ischemic stroke ICH is less with all the NOACs compared to warfarin Renal function monitoring is obligatory with the NOACs especially in the elderly Dose reduction is required in the underweight, the elderly and mild to moderate renal impairment NOACs are only for Non-Valvular AF Specific antidotes are on the way Thank you 7