NOACs in AF. Dr Colin Edwards Auckland Heart Group and Waitemata DHB. Dr Fiona Stewart Auckland Heart Group and Auckland DHB

Transcription

1 NOACs in AF Dr Colin Edwards Auckland Heart Group and Waitemata DHB Dr Fiona Stewart Auckland Heart Group and Auckland DHB

2 Conflict of Interest Dr Fiona Stewart received funding from Pfizer to attend the 2015 American College of Cardiology Meeting Dr Colin Edwards AF Master class series - Pfizer

3 CHA 2 DS 2 VASc Scoring CHA2DS2-VASc Risk Score CHF or LVEF < 40% 1 Hypertension 1 Age > 75 2 Diabetes 1 Stroke/TIA/ Thromboembolism 2 Vascular Disease 1 From ESC AF Guidelines Age Female 1

4 CHA 2 DS 2 VASc - Stroke Risk CHA2DS2-VASc score Patients (n = 7329) Adjusted stroke rate (%/year) From ESC AF Guidelines:

5 NOACs vs Warfarin Reduced rates of Stroke (19%) Haemorrhagic stroke (51%) Death (10%) Intracranial haemorrhage (52%) Increased rate of GI bleed (25%) 42,411 on NOACS, 29,272 on warfarin Lancet 2014;383:955-62

6 The NOACs Dabigatran Rivaroxaban Apixaban Factor targeted IIa Xa Xa Dose Indications for dose 150mg bd 110mg bd 20mg die 15mg die 5mg bd 2.5mg bd >80 egfr<50 2 of >80, <60kg, creat >133 Renal clearance 80% 35% 25% Hours to max concentration Dyspepsia 5-10% no no Blister packed no yes yes

7 Mrs M aged 84 Persistent AF Hypertension Diabetes On aspirin Won t take warfarin

8 Mrs M CHA 2 DS 2 - VASc Score = 5 Risk of stroke 6.7%/y Swedish AF cohort study Stroke risk 7.2%/y Stroke/TIA/Systemic embolism 15.3%/y Anticoagulation will reduce this risk by 67%

9 Aspirin vs Apixaban AVERROES Trial Apixaban Aspirin Stroke or systemic embolism 1.6%/y 3.7%/y Disabling or fatal stroke 1% 2.3% Death 3.5%/y 4.4%/y Major bleeding 1.4%/y 1.2%/y Intracranial bleeding 11 13

10 Aspirin is not appropriate treatment for stroke prevention with AF in the elderly

11 NOACs in Over 80s Dabigatran 110mg bd (watch renal function 3-6/12) Rivaroxaban 15mg/d GFR < 50 Apixaban 2.5mg bd 2 of age >80, weight < 60kg, creat >133

12 Drugs to avoid with NOACs Avoid Imidazoles (Ketaconazole etc) Extreme caution with phenytoin, carbamazepine, St John s wort Rivaroxaban with Protease inhibitors

13 Consider reduced NOAC dose with: Dabigatran Verapamil Amiodarone Apixaban Diltiazem (if other risk factors) Take care with erythromycin, clarithromycin

14 Consider Mr N needs surgery How to manage the NOAC Type of surgery Renal function (Dabigatran)

15 Continue NOAC (and Warfarin) Dental procedures Cataract surgery Minor skin excision

16 Perioperative anticoagulation with NOACs Low risk surgery 24 hours (apixaban and rivaroxaban) Dabigatran (depends on renal function) High risk surgery Includes regional anaesthesia 48 hours (apixaban and rivaroxaban) 48 - >96 hours dabigatran (check renal function) Restart when haemostasis secure Bridging anticoagulation should not be needed

17 Drug level monitoring Coagulation Testing Reversal agents Combination Therapy - case Colin Edwards Cardiologist WDHB, Auckland Heart group JUNE 2015

18 Drug related and Emergency Department Visits Anti-coagulants and aspirin associated with relatively frequent complications requiring ED visits. Complications take the form of bleeding, thrombosis, overdose etc. NOACS/DOACS Desire to monitor anti-coagulant therapy in order to prevent morbidity and mortality

19 Theoretical Framework for monitoring Dabigratran plasma levels

20 Theoretical framework for monitoring Dabigratran plasma levels A level of <10 ng/ml should be safe for most types of surgery.

21 Monitoring Drug Levels Monitoring drug levels is complex what is the ideal drug level? Should levels vary with age? Should levels vary in different in clinical situations e.g. patients on Amiodarone No data to back up that there is better clinical outcome with monitoring levels Large variation (inter-patient and intra-patient) in trough plasma Dabigatran levels Should the level be a little on the high side- no data to say the patients will do better with a change in dose.

22 Context Metanalysis of NOACS-> patients NOACS were more effective and safer than Warfarin despite no monitoring Lancet 2014;383:

23 Coagulation Indices may be useful in patients on NOACS Eg acute bleeding, overdoses, or emergency surgery. Quantitative Assays (correlation with drug level) Qualitative Assays (exposure) INR MONITORING Dabigatran Dilute thrombin time aptt Escarin clotting time IS USELESS! Apixaban Specific anti-factor Xa Rivaroxaban assays Prothrombin time

24 No monitoring required but dose selection is necessary! DABIGATRAN: <80 years with normal renal function 150mg bd Cr Cl 30-50ml/min: 110mg bd >80 years 110mg bd RIVAROXABAN All age groups: 20mg/d Cr Cl 30-49mls/min 15mg/d APIXABAN: Standard dose is 5mg bd If >2 of the following dose reduce 2.5mg bd - (Age > 80 years, Creatinine >133umol/l, Weight <60kg)

25 No Longer Require Warfarin clinics but.. Baseline: hemoglobin/hematocrit, liver function, renal function, PT/INR 3-6 monthly assessments: If CrCl ml/min, >75 years of age, or fragile: Annual laboratory assessment: hemoglobin/hematocrit, renal function, liver function At every visit: adherence, signs/symptoms of bleeding or thromboembolism, side effects, concomitant medications (including over-the-counter)

26 BLEEDING on NOACS Contains FACTORS II, VII, IX, X Measure a level and consider a REVERSAL AGENT if levels are elevated

27 Reversal Agents for DOACs 31

28 Dabigatran Reversal (direct thrombin agents inhibitor) Rivaroxaban Apixaban Name IDARUCIZUMAB ANDEXANET-A ANDEXANET-R Mechanism Binds Dabigatran with great affinity IVI administration- rapid onset of action Factor Xa look alike that binds Apixaban or Rivaroxaban Status Trials underway Approval lodged with FDA and EMA

29

30 CASE combination therapy PAF and Coronary Disease

31 George visits the emergency department with acute chest pain George 75 years old. Mild hypertension PAF Dabigatran 150mg bd Admitted with chest pain NSTEMI CHA 2 DS 2 -VASc = 3-4 HAS-BLED = 2 George is taken to the cardiac catheterization laboratory PCI to RCA.

32 AF and requirement for PCI commonly co-exist ~30% of patients with AF and an indication for continuous OAC have co-existing CAD and may require PCI

33 How do we provide optimal protection for patients with NVAF and PCI/ACS? NVAF PCI/ACS NVAF and PCI/ACS Anticoagulant therapy Dabigatran Antiplatelet therapy Aspirin + P2Y12 inhibitor BOTH anticoagulant and dual antiplatelet therapy = triple therapy?

34 Triple therapy is associated with the greatest increase in bleeding risk with all OAC/antiplatelet combinations 1 5 Warfarin Dabigatran 150 mg BID Dabigatran 110 mg BID Antiplatelet therapy None (n=3478) Single (n=2312) Dual (n=232) None (n=3613) Single (n=2251) Dual (n=212) None (n=3510) Single (n=2288) Dual (n=217) Major bleeding (%/year) RE-LY was the only Phase III trial of a NOAC vs VKA to allow concomitant treatment with both ASA and clopidogrel 1. Dans et al. Circulation 2013; 2. Dewilde et al. Lancet 2013; 3. Lip et al. Thromb Haemost 2010; 4. Nikolsky et al. Am J Cardiol 2012; 5. Lamberts et al. Circulation

35 2014 European guidance recommends a step-wise approach to individualize care STEP 1: Stroke risk CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc 2 STEP 2: Bleeding risk Low to intermediate High Low to intermediate High STEP 3: Clinical setting Stable CAD ACS Stable CAD ACS Stable CAD ACS Stable CAD ACS If PCI is performed If PCI is performed If PCI is performed If PCI is performed STEP 4: Antithrombotic therapy Triple or double* (OAC + clopidogrel) Triple Double** (OAC + ASA or clopidogrel) 0 4 weeks 6 months or DAPT Double (OAC + clopidogrel) Monotherapy*** 12 months Lifelong or DAPT or DAPT Monotherapy*** Monotherapy*** Time from PCI/ACS OAC, oral coagulation: either warfarin (INR: ) or non-vka OAC at lower tested dose in AF (dabigatran 110 mg BID, rivaroxaban 15 mg OD or apixaban 2.5 mg BID) *Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients; **ASA as an alternative to clopidogrel may be considered in patients on dual therapy (i.e. oral anticoagulation plus single antiplatelet); ***Dual therapy with oral anticoagulation and an antiplatelet agent (ASA or clopidogrel) may be considered in patients at very high risk of coronary events. DAPT, dual antiplatelet therapy (ASA 75 mg/day + clopidogrel 75 mg/day) Lip et al. Eur Heart J

36 DOACs in Stable CAD?NOAC instead of Warfarin Low dose Dabigatran (110mg bd) or Apixaban (2.5mg bd) may be a good alternative to Warfarin BUT WE NEED DATA

37 RE-DUAL PCI addresses the need for innovative new treatment regimens and is the largest ongoing OAC study in this setting

38 CONCLUSION NOAC PROVIDE RAPID AND RELIABLE ANTICOAGULATION, MINIMAL DRUG:DRUG INTERACTIONS AND DRUG LEVEL MONITORING IS NOT REQUIRED. ESC GUIDELINES-In patients with non-valvular AF and an estimated stroke risk exceeding 1% per year CHA 2 DS 2 VASC 1 males, CHA 2 DS 2 VASC 2 females consider anticoagulation with DOAC. Aspirin is no longer appropriate. Aspirin is 1/3 as effective as OAC in preventing AF related stroke and with similar bleeding risk (BAFTA and AVERROES) Elderly patients ¼ of strokes are AF mediated emphasizing the importance of accurate anticoagulation in this age group. Risk of intracranial haemorrhage is lower with NOAC vs VKA (OR.46) this benefit was even larger in the elderly (0R 0.36) Reduce dose in elderly patients monitor renal function function 3 x per year Can be safely stopped and restarted for elective surgery will be reversal agents available to facilitate emergent surgery