Stroke prevention in AF: Implementing the NICE guidelines

Stroke prevention in AF: Implementing the NICE guidelines Dr Hamsaraj Shetty, B.Sc, MBBS, FRCP (London & Edinburgh) Consultant Physician & Honorary Senior Lecturer, University Hospital of Wales & Cardiff University

Disclosures & acknowledgements I have been an advisor for BMS, Bayer, Boehringer Ingleheim,& Pfizer from whom I have received honoraria. I would like to thank Boehringer Ingleheim for supporting a Research Nurse, who has collected the primary care AF data I would also like to thank Bayer who have provided me some of the data

Key points The importance of AF as a risk factor Identification & Risk stratification The guidelines Choice of drugs Prescribing NOACs: practical aspects

AF& Stroke AF is the most common arrhythmia Incidence is increasing Prevalence of AF is high & rising ( Estimate 1.48-1.81% ) An important risk factor for stroke More likely to cause severe & fatal strokes

Atrial Fibrillation in Ischemic Stroke: Clinical Outcomes Risk of death at 30 days Stroke in AF patients Stroke in non-af patients 22.3% 10.2%; P<0.0001 Risk of death 1 year 37.1% 19.5%; P<0.0001) Death or disability at discharge 69.7% 54.7%; P<0.0001) Risk of intracranial hemorrhage (any type) with thrombolysis 16.5% 11.6%; relative risk, 1.42; 95% CI, 1.05 1.91) Saposnik et al, Stroke. 2013;44:99-104

AF & Ischemic Stroke: functional outcomes at discharge (Modified Rankin Scale) Saposnik et al, Stroke. 2013;44:99-104

Stroke prevention in AF: the problem 18% of AF remains undiagnosed 93% of AF are nonvalvular; 87% of whom are eligible for anticoagulation Anticoagulants are underused

AF Ischaemic Stroke Inpatients per 1000 AF QOF Patients 2012-13 (HES Intersect Analysis for Inpatients with a Primary or Secondary Diagnosis of Ischaemic Stroke with Atrial Fibrillation) Pre Stroke Diagnosis of AF At or Post Spell Diagnosis of AF All AF istroke per 1000 AF QOF English CCGs NHS Eastern Cheshire CCG 15.6 14.1 29.7 12.5 11.1 23.6 NHS Halton CCG 9.8 15.9 25.7 NHS Knowsley CCG 12.5 16.9 29.4 NHS Liverpool CCG 14.8 13.9 28.7 NHS South Cheshire CCG 11.4 12.3 23.7 NHS South Sefton CCG 10.0 13.7 23.7 NHS Southport and Formby CCG 11.5 16.4 27.9 NHS St Helens CCG 17.3 15.2 32.5 NHS Vale Royal CCG 13.6 13.0 26.6 NHS Warrington CCG 11.3 17.3 28.7 NHS West Cheshire CCG 15.0 13.4 28.4 NHS Wirral CCG 13.2 17.2 30.4 Job Bag: L.GB.01.2014.5158 Date of Prep: Jan 2014-5 10 15 20 25 30 35 Primary & Secondary Diagnosed AF-iStroke Patients per 1000 AF QOF Patients 9

Use of antithrombotics in AF GARFIELD registry, Adapted from Kakkar et al., Plos One 2013

Use of OAC for AF in South East Wales Total: 775 patients, 5 surgeries Anjum T, Welsh M, Shetty H, 2014

Use of OAC for AF in South East Wales Mean age: 76 years (range 47-95 years) 353/775 females (45.5%) 443/775 patients (57.2%) were on OAC The median time in therapeutic range (TTR): 79.6% (TTR range 73.4-85.5%) Anjum T, Welsh M, Shetty H, 2014

Use of OAC for AF in South East Wales Only 18 patients (4%) had TTR <60% 5/443 (1.1%) had major haemorrhages requiring hospitalisation No deaths on OACs Anjum T, Welsh M, Shetty H, 2014

Use of OAC for AF in South East Wales: Reasons for not prescribing OAC 332/775 (42.8%) patients in AF were not on OAC 169/332 (50.9%) of these patients were high-risk : CHADS2 score >2 OAC not used in eligible patients because: previous haemorrhages, malignancy, poor compliance, low platelets, erratic INR control or patient refusal 96/169 (57%) eligible patients were denied OAC due to falsely perceived contraindications e.g. old age, falls risk, dementia, active life style Anjum T, Welsh M, Shetty H, 2014

AF the challenge remains! Many patients remain undetected in the community Need to identify & risk stratify all AF patients All eligible patients should be anticoagulated unless there are genuine contraindications.

Opportunistic screening Palpate pulse in people presenting with breathlessness/dyspnoea palpitations syncope/dizziness chest discomfort An irregular pulse sensitive to the presence of AF PPV greatest in those over 75 years old The NPV of a regular pulse very high (>96%)

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. TE = thromboembolism DBG2919 September 2011

Treatment guidelines European Cardiology Society Guidelines 2012 NICE guidelines June 2014 AWMSG guidelines September 2014

Anticoagulation for AF Risk category One major risk factor or 2 clinically relevant non-major risk factors One clinically relevant non-major risk factor CHA 2 DS 2 -VASc score 2 Recommended antithrombotic therapy Oral anticoagulant (OAC) 1 Oral anticoagulant No risk factors 0 No antithrombotic therapy European Heart Journal (2012) 33, 2719 2747

European Heart Journal (2012) 33, 2719 2747

Warfarin is highly effective Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% *, ARR 2.7% (95% CI: 49 74%) 100 50 0 50 100 RRR (%) Random effects model; Error bars = 95% CI; * p>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Compared to a 19% RRR, 0.7% ARR for aspirin Hart RG et al. Ann Intern Med 2007;146:857 67. DBG2919 September 2011

Disadvantages of warfarin Narrow therapeutic index Slow onset of action Inter-individual (genetic) variabilty Need for regular monitoring Poor anticoagulation control in up to 45% Potentially dangerous interactions Poor compliance

% of patients without stroke IMPACT OF POOR INR CONTROL Stroke survival in 37,907 AF patients UK General Practice Research Database (27,458 warfarin users and 10,449 not treated with an antithrombotic) 100 95 90 85 80 75 No warfarin I I I I I I 0 20 40 Months 60 80 100 %TTR > 70 61 70 51 60 41 50 31 40 < 30 Adapted from Gallagher et al. Thromb Haemost 2011;106:968 77.

New anticoagulants: modes of action TF / VIIa x IX IXa VIIIa Va Xa Apixaban Edoxaban Rivaroxaban II IIa Dabigatran Fibrinogen Fibrin

Warfarin vs New oral anticoagulants Features Warfarin New drugs Onset Slow Rapid Dosing Variable Fixed Interaction with food Yes No Drug interaction Many Few Monitoring Yes No Half life Long Short Antidotes Yes Under evaluation

Features of new oral anticoagulants Features Rivaroxaban Apixaban Edoxaban Dabigatran Target Xa Xa Xa IIa Molecular weight (Daltons) 436 460 720 628 Prodrug No No No Yes Bioavailability (%) Time to peak (hrs) 80 50 62 6 3 3 1-2 2 Half life (hrs) 9 9-14 9-11 12-17 Renal excretion(%) 65 25 50 80

Efficacy of NOACs vs Warfarin: Meta-analysis Ruff et al, Lancet 2014, 383: 955-62

NOACs vs Warfarin: Secondary efficacy & safety outcomes Ruff et al, Lancet 2014, 383: 955-62

Need for regular follow up NOACs can cause serious bleeding Older people are more susceptible for ADRs Drug-interactions do occur & can be dangerous www.escardio.org/ehra

What to check? Adherence Thrombo-embolic events Bleeding & other ADRs Concomitant drugs including over the counter

AF oral anticoagulation card Card can be downloaded in a printer-ready form from www.noacforaf.eu

What to check? Check UE, FBC, LFT Consider stopping or changing the drug, if problems Arrange date for next follow up (1, 3 or 6 months)

Choosing a NOVAC Consider: Risk vs benefit Age Renal function Body weight Co-medications taken by patient PPI to reduce risk for GI bleeding Educate patient on importance of strict adherence

C. Everett Koop 13th Surgeon General of the United States under President Ronald Reagan from 1982 to 1989 Drugs don t work in patients who don t take them

Stephen Wilkins 2014

Initiation of the treatment Adherence: components Implementation of the dosing regimen Discontinuation marks the end of therapy Persistence: the length of time between initiation & discontinuation

Persistence better with NOACs Patients newly initiated on rivaroxaban or warfarin Treatment persistence was significantly better with rivaroxaban than with warfarin (hazard ratio (HR) 0.66; 95% confidence interval: 0.60 0.72, P, 0.0001) Laliberte et al Curr Med Res Opin 2014;30:1317 25

Od vs Bd Dosing: predicted biological impact

Analyse the reason before switching! Simply switching to a NOAC will not necessarily improve adherence! Medication adherence is not solely a patient problem Reliable quantification of dosing errors can reveal patient-specific causes of non-adherence and point to individualized solutions

Methods to monitor adherence Self-report Pill counts Direct methods (Pharmacokinetics & Pharmacodynamics) Prescription and refill databases Electronic monitoring: gold standard

Smart packages ( eg; MEMS ) MEMS is a smart package in the form of a cap containing an electronic chip registering the time & date of each pill bottle opening Safe, un-intrusive (easy use), long lasting (battery) Adherence data are reliable and detailed Can easily be adapted to blister packs, inhalers, injectable,etc or for poly medication. Arnet et al Front Pharmacol 2013;4:26.

Significant interactions Dronedarone Avoid Dabigatran Ketoconazole, Itraconazole, Voriconazole, Posaconazole Avoid Dabigatran, Apixaban & Rivaroxaban HIV protease inhibitors Avoid Rivaroxaban Rifampicin, St John s wort, Carbamezepine, Phenytoin, Phenobarbital Avoid Dabigatran, Apixaban

Potential care models

A model for long term NOVAC management

Do NOACs need drug level monitoring? Drug levels monitoring may be clinically helpful: To ensure clearance of the drug in an emergency procedure To ensure compliance. In the cases of overdoses, renal impairment & bleeding, drug levels are unlikely to be helpful

Dabigatran: measuring coagulant effect aptt: At trough >2x ULN suggests excess bleeding risk dtt: at trough >200ng/ml 65s: excess bleeding risk Ecarin clotting time: at trough >2x ULN: excess bleeding risk

Prothrombin time as a predictor of bleeding Edoxaban: prolonged but no known relation with bleeding risk Rivaroxaban: prolonged & may indicate excess bleeding risk but local calibration required Apixaban & Dabigatran: cannot be used

Van Ryn et al Am J Med 2012;125:417

Idarucizumab for Dabigatran Reversal A monoclonal antibody fragment Binds dabigatran with an affinity 350 times as high as that observed with thrombin Binds free and thrombin-bound dabigatran and neutralizes its activity. Immediate and complete reversal of the anticoagulant effects of dabigatran without procoagulant effects in volunteers Pollack et al DOI: 10.1056/NEJMoa1502000

Idarucizumab for Dabigatran Reversal 5 g of intravenous idarucizumab Patients who had serious bleeding (51 group A) or required an urgent procedure (39 group B) Primary end point: the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours (DTT/ECT) Pollack et al DOI: 10.1056/NEJMoa1502000

Idarucizumab for Dabigatran Reversal Among 68 patients with DTT and 81 with ECT at baseline, the median maximum percentage reversal was 100% (95% CI, 100 to 100) Normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes Pollack et al DOI: 10.1056/NEJMoa1502000

Idarucizumab for Dabigatran Reversal Pollack et al DOI: 10.1056/NEJMoa1502000

Idarucizumab for Dabigatran Reversal Among 35 patients in group A who could be assessed, hemostasis, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated Pollack et al DOI: 10.1056/NEJMoa1502000

Anti-Xa reversal agents under development Andexanet alfa, a recombinant factor Xa variant that specifically binds all the oral factor Xa inhibitors but lacks coagulant activity. PER977, a nonspecific reversal agent, which binds to several of the direct oral anticoagulants by means of electrostatic interactions

Perioperative dosing of NOACs

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Conclusions AF is an important risk factor for stroke & leads to severe strokes It is still under recognized & under treated Anticoagulation is highly effective in stroke prevention New anticoagulants offer a number of advantages over warfarin