Anticoagulation - which patients should be on Novel Oral Anticoagulants (NOAC)?

Anticoagulation - which patients should be on Novel Oral Anticoagulants (NOAC)? Welsh Primary Cardiovascular Conference Abertawe, Mai 2014 Gethin Ellis Cardiologist Cwm Taf UHB

Declaration (?conflicts) of interest... Advisory boards: Boehringer, Pfizer, Bayer My personal experiences.. Many free pens, sandwiches, crisps, USB sticks, laser pens, car accessories, key rings, My clinical experience as a warfarin prescriber.

VKA NOAC/ODI/DOA/NVKA V. Novel Oral Anticoagulants Oral Direct Inhibitors Direct Oral Anticoagulants Non-vitamin K anticoagulants

Narrow therapeutic range with VKA Events / 1000 patient years 80 60 40 20 Target INR (2.0-3.0) Ischaemic stroke Intracranial haemorrhage The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range 0 <1.5 1.5 1.9 2.0 2.5 2.6 3.0 3.1 3.5 3.6-4.0 4.1-4.5 >4.5 1. Hylek EM, et al. N Eng J Med 2003; 349:1019-1026. International Normalised Ratio (INR)

Novel oral anticoagulants - NOAC Direct thrombin inhibitors dabigatran 1, ximelagatran Factor Xa inhibitors rivaroxaban 2, apixaban 3, edoxaban 4, betrixaban, idraparinux Factor IXa inhibitor TTP889 Glycosaminoglycan enhancer - odiparcil 1.RELY. 2.ROCKET-AF. 3.ARISTOTLE. 4.ENGAGE. www.nice.org

Licensed indications for NOAC NOAC Stroke prevention in nonvalvular AF DVT treatment PE treatment Prevention of recurrent DVT/PE Dabigatran Y N N N Y Rivaroxaban Y Y Y Y Y Apixiban Y N N N Y Prophylaxis VTE following knee and hip surgery

AF increases the risk of stroke AF is associated with a pro-thrombotic state ~5 fold increase in stroke risk 1 Risk of stroke is the same in AF patients regardless of whether they have paroxysmal or sustained AF 2,3 Cardioembolic stroke has a 30-day mortality of 25% 4 AF-related stroke has a 1-year mortality of ~50% 5 1. Wolf PA, et al. Stroke 1991;22:983-988; 2. Rosamond W et al. Circulation. 2008;117:e25 146; 3.Hart RG, et al. J Am Coll Cardiol 2000;35:183-187; 4. Lin H-J, et al. Stroke 1996; 27:1760-1764; 5. Marini C, et al. Stroke 2005;36:1115-1119.

Stroke risk assessment with CHADS 2 CHADS 2 criteria Congestive heart failure Score Hypertension 1 Age >75 yrs 1 Diabetes mellitus 1 Stroke / transient ischaemic attack 1 2 NRAF adjusted stroke rate per 100 patient years, without aspirin 20 16 12 8 4 0 Adjusted stroke risk 0 1 2 3 4 5 6 CHADS 2 score 1 Gage BF et al. JAMA 2001;285:2864 70. 2 Based on data from Gage BF et al. JAMA 2001;285:2864 70.

Car Parking at the Liberty Stadium

Stroke risk assessment with CHA 2 DS 2 -VASc CHA 2 DS 2 -VASc criteria Congestive heart failure/ left ventricular dysfunction Score Hypertension 1 Age 75 yrs 2 Diabetes mellitus 1 Stroke/transient ischaemic attack/te Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque) Age 65 74 yrs 1 Sex category (i.e. female gender) 1 2 1 1 CHA 2 DS 2 -VASc total score Rate of stroke/other TE (%/year)* 0 0.0 1 1.3 2 2.2 3 3.2 4 4.0 5 6.7 6 9.8 7 9.6 8 6.7 9 15.2 * Theoretical rates without therapy: assuming that warfarin provides a 64% relative reduction in TE risk (2.7% ARR), based on Hart et al. TE = thromboembolism 1 Lip GYH et al. Stroke 2010;41:2731 2738. 2 Hart RG et al. Ann Intern Med 2007;146:857 67. DBG2919 September 2011

New agents: Intracranial bleeding vs warfarin Intracranial bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg 0.32 0.76 0.41 (0.28-0.60) Dabigatran 110 mg 0.23 0.76 0.30 (0.19-0.45) Rivaroxaban 0.5 0.7 0.67 (0.47-0.93) Apixaban 0.33 0.80 0.42 (0.30-0.58) 0 1 2.0 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981-92.

www.escardio.org/guidelines

European Society of Cardiology www.escardio.org/ehra

AWMSG -NOAC for SPAF 2012

AF patients with previous TIA or ischaemic stroke, considered to be suitable for anticoagulation and admitted with acute ischaemic stroke (Ontario 2003 2007) No antithrombotics, 15% Warfarin therapeutic, 18% Dual antiplatelet therapy, 3% Single antiplatelet agent, 25% Warfarin Sub-therapeutic, 39% n=323 Adapted from Gladstone et al. Stroke 2009;40:235 40.

Antiplatelet/antcoagulants in stroke patients with AF (Wales)

2014 Practice in Cardiff (Dr Armon Daniels) Patients on the practice register with AF - nurse triaged and 47 reviewed by Cardiologist (Dr Richard Anderson) Therapeutic warfarin - 32 No antithrombotic - 12 Dual antiplatelet therapy -2 Single antiplatelet agent -20 Sub- therapeutic warfarin - 12

Changes. 6 switches from Warfarin to NOAC 7 switches from ASA/nil to Warfarin 2 switches from ASA/nil to NOAC

Dabigatran 1-3 Rivaroxaban 4,5 Apixaban 6,7 Mode of action Factor II Factor X Factor X Half life 12-14 hrs 7-11 hrs 12 hrs Dosing (in atrial fibrillation) B.D. O.D. B.D. Metabolism Esterase catalysed hydrolysis CYP P450dependantand independent mechanisms CYP P450 Excretion 85% Renal 1/3 Renal 2/3 Hepatic 1/4 Renal 3/4 Non Renal Form Capsule Tablet Tablet Dose 150 mg 110 mg (>80 yrs,verapamil or increased bleeding risk) 20 mg 15 mg (CrCL 30-49 ml/min) 5 mg 2.5 mg (2or more: >80yr; weight <60 kg; Cr >1.5 mg/dl) B.D. = twice daily; O.D. = once daily 1. Ezekowitz MD et al. Am Heart J 2009;157:805 10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 4. Rocket Investigators. Am Heart J 2010;159:340-347; 5. Patel MR et al. NEJM 2011;365:883 91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med 2011;365:981-92.

Drug interactions effect on NOAC plasma levels Dabigatran Apixiban Rivaroxaban Atorvastatin +18% No data yet No effect Verapamil +12-180% No data yet Minor effect Diltiazem No effect +40% Minor effect Amiodarone +12-60% No data yet Minor effect Clari/erythromycin +15-20% No data yet +30-54% CBZ, Rifampicin -66% -54% -50%

Warfarin vs. NOAC Consideration Valvular heart disease Recommendation Warfarin Severe hepatic impairment with associated coagulopathy Warfarin or LMWH Extremes of weight Warfarin CrCl<15ml/min Warfarin Needs triple therapy (AC+DAPT) Patient requires high level of AC (eg antiphospholipid Sx) Warfarin Warfarin (studies with NOAC underway) Adapted from Thachil, J Clin Med 201414;165-75.

Warfarin vs. NOAC Consideration Recommendation CrCl >15 - <30ml/min Warfarin or R. or A. History of MI Warfarin or R. or A. Recent ischaemic stroke on Warfarin Dabigatran 150mg bd DVT or PE Rivoraxaban Adapted from Thachil, J Clin Med 201414;165-75.

Warfarin vs. NOAC Consideration Pregnancy Recommendation Warfarin/LMWH Malignancy LMWH?!!!! Compliance concerns Nothing or Warfarin/LMWH Adapted from Thachil, J Clin Med 201414;165-75.

Predicting warfarin response in AF - SAMe-TT 2 R 2 Acronym Definitions Points S Sex (female) 1 A Age (<60 years) 1 Me Medical history* 1 T Treatment 1 T Tobacco use 2 R Race (non-caucasian) 2 *Two of following: HT, DM, CAD/PVD/CVD, CHF, pulmonary disease, hepatic or renal disease 0-1 Likely to do well on Warfarin 2 More likely to have poor INR control Chest 2013;144: 1555-1563.

?!!!

Warfarin vs. NOAC chat 60 years vs. 6 years Long term effects - MI signal? Monitoring Weekly-monthly vs. 1-3 times/year Bleeding riskintracranial/gi bleeds Reversal strategies Drug/lifestyle interactions

Compliance..!!

Diolch

New agents: Ischaemic stroke vs warfarin Ischaemic stroke vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg 0.86 1.14 0.75 (0.58-0.97) Dabigatran 110 mg 1.28 1.14 1.13 (0.89-1.42) Rivaroxaban 1.34 1.42 0.94 (0.75-1.17) Apixaban* 0.97 1.05 0.92 (0.74-1.13) *Ischaemic or uncertain type of stroke 0.5 1 1.5 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981-92.

New agents: Major bleeding vs warfarin Major bleeding vs warfarin %/yr Warf %/yr HR (95% CI) Dabigatran 150 mg 3.32 3.57 0.93 (0.81-1.07) Dabigatran 110 mg 2.87 3.57 0.80 (0.70-0.93) Rivaroxaban 3.6 3.4 1.04 (0.90-1.20 Apixaban 2.13 3.09 0.69 (0.60-0.80) 0.5 1 1.5 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981-92.

Factors which may increase the haemorrhagic risk Pharmacodynamic and kinetic factors Factors increasing dabigatran plasma levels Pharmacodynamic interactions Diseases / procedures with special haemorrhagic risks Age 75 years Major: Moderate renal impairment (30 50 ml/min CrCL) P-gp inhibitor co-medication Minor: Low body weight (<50 kg) ASA NSAID Clopidogrel Congenital or acquired coagulation disorders Thrombocytopenia or functional platelet defects Active ulcerative GI disease Recent gastro-intestinal bleeding Recent biopsy or major trauma Recent ICH Brain, spinal or ophthalmic surgery Bacterial endocarditis DBG2919 September 2011

Practical points re. NOAC Patient selection and information/discussion Renal function-baseline ~ 1-3x year Dose decision Switching Concurrent medication

Bleeding advice using NOAC for SPAF Minor bleeding Omit 1dose of drug Restart once bleeding settled Consider lower dose

Warfarin vs. NOAC in SPAF Not licensed with prosthetic valves/valvular HD Dabigatran may cause dyspepsia/ increase GI bleeding risk Stopping abruptly relies predominantly on short half-life (currently) Long term effects unknown Warfarin may be protective post-acs Fewer drug/food interactions Little/no monitoring May be better May have lower major bleeding risk

Practical considerations when initiating Pradaxa Initiation for new patients Initiate Pradaxa Onset of effect starts shortly after dosing with peak plasma concentrations and maximal anticoagulant effects achieved within 0.5 2 hours No need to give an interim dose of low molecular weight heparin Defined process to switch patients from warfarin Discontinue warfarin Initiate Pradaxa once the patient s INR is below 2.0 The time this takes will vary from patient to patient Switching patients taking aspirin for SPAF Discontinue aspirin Initiate Pradaxa An educational pack has been developed to support the prescribing of Pradaxa for stroke prevention in atrial fibrillation DBG2919 September 2011

New agents: Myocardial infarction vs warfarin Myocardial infarction vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg 0.81 0.64 1.27 (0.94-1.71) Dabigatran 110 mg 0.82 0.64 1.29 (0.96-1.75) Rivaroxaban 0.91 1.12 0.81 (0.63-1.06) Apixaban 0.53 0.61 0.88 (0.66-1.17) 0.2 1 1.8 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981-92.

New agents: All cause mortality vs warfarin All cause mortality vs warfarin %/yr Warf %/yr HR (95% CI) Dabigatran 150 mg 3.64 4.13 0.88 (0.77-1.00) Dabigatran 110 mg 3.75 4.13 0.91 (0.80-1.03) Rivaroxaban 1.87 2.21 0.85 (0.70-1.02) Apixaban 3.52 3.94 0.89 (0.80-0.99) 0.5 1 1.5 Favours new orals Favours warfarin Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information. 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981-92.

Why time in therapeutic range (TTR) matters Cumulative survival 1.0 0.9 0.8 0.7 Warfarin group 71 100% 61 70% 51 60% 41 50% 31 40% <30% Non warfarin 0.6 0 500 1000 1500 2000 Survival to stroke (days) Morgan CL et al. Thrombosis Research 2009;124:37 41. DBG2919 September 2011