Stroke Prevention in Atrial Fibrillation NICE guidelines 2014 and their local implementation Craig Barr Consultant Cardiologist Prescribing information available at this meeting L.GB.09.2014.7880c Date of Preparation: October 2014 This session has been sponsored by an unrestricted grant from Bayer HealthCare
Disclosures Consultancy work: Bayer Boston Scientific Cameron Health GE Medtronic Research funding: Biotronik Medtronic
Anti-platelet therapy Do not offer aspirin monotherapy solely for stroke prevention to patients with atrial fibrillation.
Personalised package of care Assessing stroke risk Measures to prevent stroke Rate or rhythm control Psychological support Up-to-date and comprehensive education and information
Stroke risk Use CHA2DS2VASc to assess risk in AF, atrial flutter and in patients after cardioversion (or other interventions) Bleeding risk Use HASBLED to highlight and monitor reversible causes of bleeding
Risk factor Congestive heart failure/lv dysfunction Points +1 Hypertension +1 Age 75 years +2 Diabetes mellitus +1 Stroke/TIA/TE +2 Vascular disease (MI, aortic plaque, PAD)* +1 Age 65 74 years +1 Sex category (female) +1 Cumulative score http://www.improvement.nhs.uk/graspaf/- accessed 07/09/2012 Range 0 9
Interventions to reduce stroke risk Offer anticoagulation to people if CHA2DS2VASc 2 or more Consider anticoagulation for men with a CHA2DS2VASc of 1 Continue to assess bleeding risk Allow identification and correction of modifiable risk factors Assess VKA control at each visit for marker of poor control Considering cognitive function, illness, con meds and lifestyle Review stroke risk
Anticoagulation Apixaban Dabigatran Rivaroxaban NVAF with 1 or more risk factors NICE TA 275, 249 and 256 respectively VKA LAA occlusion
VKAs are effective for stroke prevention in AF Reduction of risk of thromboembolism in AF 1 Study, year Relative risk reduction (95% CI) Absolute risk reduction AFASAK I, 1989; 1990 SPAF I, 1991 BAATAF, 1991 CAFA, 1991 SPINAF, 1992 EAFT, 1993 2.6% 4.7% 2.4% 1.2% 3.3% 8.4% All trials (n=6) Primary prevention 2.7, Secondary prevention 8.4 100% 50% 0 50% 100% Favours VKA Favours placebo 1. Hart RG et al. Ann Intern Med 2007;146:857 867
Age, years Oral anti-coagulation: benefit risk improves with increasing age Net clinical benefit: events prevented per 100 person-years 1 85 1.29 2.34 3.30 75 84 0.44 1.00 1.40 65 74 0.37 0.11 0.40 <65 0.65 0.25 0.08 1 0.5 0 0.5 1 1.5 2 2.5 3 3.5 Worse with warfarin Better with warfarin 1. Singer DE et al. Ann Intern Med 2009;151:297 305
Odds ratio for event VKAs have a narrow therapeutic window Adjusted odds ratios for ischaemic stroke and intracranial bleeding in relation to intensity of anticoagulation 20 15 Data on bleeding and stroke risk support recommendation for narrow INR target range of 2.0 3.0 10 Ischaemic stroke Intracranial bleeding 5 Target INR 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 International normalized ratio 11
Many factors elevate AF stroke risk CHADS 2 score Risk factor Points Congestive heart failure/lv +1 dysfunction Hypertension +1 Age 75 years +1 Diabetes mellitus +1 Stroke/TIA/TE +2 Cumulative score Range 0 6 Annual Risk of Stroke CHADS2 Score Stroke Risk % 95% CI 0 1.9 1.2 3.0 1 2.8 2.0 3.8 2 4.0 3.1 5.1 3 5.9 4.6 7.3 4 8.5 6.3 11.1 5 12.5 8.2 17.5 6 18.2 10.5 27.4 1. Gage Bet al. Circulation 2004; 110:2287-2292
Risk factor Congestive heart failure/lv dysfunction Points +1 Hypertension +1 Age 75 years +2 Diabetes mellitus +1 Stroke/TIA/TE +2 Vascular disease (MI, aortic plaque, PAD)* +1 Age 65 74 years +1 Sex category (female) +1 Cumulative score Range 0 9 http://www.improvement.nhs.uk/graspaf/- accessed 07/09/2012
Score Risk Considerations 0 Low No antithrombotic therapy preferred although usually VKA / ODI required for DCCV / AF ablation 1 Moderate Oral anticoagulant 2 or more Moderate/ High Oral anticoagulant (e.g. VKA or ODI) 1. Camm et al, Eur Heart J 2010
Drivers to switch to NOAC Once daily No Food Interactions Predictable response No routine coagulation monitoring Fixed dosing Wide therapeutic window Easily adaptable for compliance aids Ideal Warfarin Xarelto* *To be taken with food
% Patients ROCKET AF: Studied across a wide range of patients, including those of older age, with co-morbidities or with high CHADS score 42.9 44.3 Mean CHADS 2 score = 3.5 29.3 28.0 Rivaroxaban (n=7131) Warfarin (n=7133) 13.0 13.1 13.1 12.4 1.7 2.2 Patel MR et al. NEJM 2011; 365: 883-891 CHADS 2 score
ROCKET AF: Significantly fewer haemorrhagic strokes with Rivaroxaban Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Intention-to-Treat Population Event Rate Event Rate HR (95% CI) P-value Vascular Death, Stroke, Embolism 4.51 4.81 0.94 (0.84, 1.05) 0.265 Stroke Type Hemorrhagic Ischemic Unknown Type 0.26 1.62 0.15 0.44 1.64 0.14 0.58 (0.38, 0.89) 0.99 (0.82, 1.20 1.05 (0.55, 2.01) 0.012 0.916 0.871 Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308 Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464 Data on file: ROCKET All Cause Mortality Vascular Non-vascular Unknown Cause 4.52 2.91 1.15 0.46 4.91 3.11 1.22 0.57 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 0.152 0.350 0.611 0.195
Bleeding risks Parameter Rivaroxaban (n=7111) Warfarin (n=7125) n (% per year) n (% per year) Hazard ratio (95% CI) Hazard ratio and 95% CIs Principal safety endpoint 1475 (14.9) 1449 (14.5) 1.03 (0.96,1.11) Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Haemoglobin drop ( 2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* Intracranial haemorrhage 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding Major bleeding from gastrointestinal site ** (upper, lower and rectal) 1185 (11.8) 1151 (11.4) 1.04 (0.96,1.13) 224 (3.2%) 154 (2.2%) p<0.001 0.2 0.5 1 2 5 Favours rivaroxaban Favours warfarin Patel MR et al. NEJM 2011; 365: 883-891
Process NICE guidance Multi-specialty interest PCT (CCG) MMC support Pre-implementation training Nurse-led clinic for all referrals Primary care follow up (renal function)
Simplified protocol Choice of rivaroxaban Multiple indications Once daily Dosing regime Lack of drug interactions Use in pre-packed medication trays Absorption limit in overdose
Renal function and dosing Creatinine clearance 50 + ml/min 20mg Once daily 150mg BD or 110mg BD Creatinine clearance 50 + ml/min Creatinine clearance 30-49 ml/min Creatinine clearance 15-29 ml/min Creatinine clearance <15 ml/min 15mg Once daily 15mg Once daily with caution Not recommended 150mg BD with caution. Consider using 110mg BD if high bleeding risk Dose adjust based on age, weight and concomitant medications Not recommended Creatinine clearance 30 50 ml/min Creatinine clearance <30 ml/min Rivaroxaban Dabigatran
Importance of renal function Patients with renal impairment were excluded from the ROCKET-AF and EINSTEIN studies if they had a CrCl of <30ml/min Patients with a CrCl of <50ml/min only represented a small proportion (<10%) of patients studied in ROCKET- AF Similarly in ARISTOTLE patients with a CrCl of <25ml/min were excluded Similarly in ARISTOTLE patients with a CrCl of <50ml/min only represented 17% of patients studied
Need for testing Peak plasma levels are reached 2 to 3 h after ingestion Rivaroxaban is 33% renally excreted and has a half-life of 9 h in patients with normal renal function There is a dose-dependent effect of rivaroxaban on laboratory clotting tests (Samama et al,2010; Freyburger et al, 2011; Hillarp et al, 2011)
Each laboratory should be aware of the sensitivity of their own PT and APTT assays to dabigataran and rivaroxaban; this can be achieved using commercially available dabigatran and rivaroxaban calibrants With an appropriate reagent, the PT (or APTT) can be used for the urgent determination of the relative intensity of anticoagulation due to rivaroxaban. The PT is usually more sensitive. It cannot be used to determine the drug level
Analogy with therapeutic LMWH We very rarely ask for an anti-xa assay And what is the clinical significance of a Xa assay? (Cut off values are largely arbitrary) Importance of when the last dose was taken? Importance of what is the renal function? If bleeding What is the nature of the bleeding? Compression, surgery, reversal
Bleeding risks Parameter Rivaroxaban (n=7111) Warfarin (n=7125) n (% per year) n (% per year) Hazard ratio (95% CI) Hazard ratio and 95% CIs Principal safety endpoint 1475 (14.9) 1449 (14.5) 1.03 (0.96,1.11) Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Haemoglobin drop ( 2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* Intracranial haemorrhage 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding Major bleeding from gastrointestinal site ** (upper, lower and rectal) 1185 (11.8) 1151 (11.4) 1.04 (0.96,1.13) 224 (3.2%) 154 (2.2%) p<0.001 0.2 0.5 1 2 5 Favours rivaroxaban Favours warfarin Patel MR et al. NEJM 2011; 365: 883-891
If major bleeding Withhold the NOAC If ongoing and life threatening bleeding we recommend flat dose PCC (Octaplex) to be given at a dose of 25IU/kg Please note little clinical data to support the use of PCC or any other blood product to reverse the effects of NOACs, though an emerging consensus regarding PCC
How is warfarin reversal currently managed? Major bleeding: limb or life threatening bleeding that requires complete reversal in 6-8 hours Emergency anticoagulation reversal in patients with major bleeding: 25 50 u/kg four-factor prothrombin complex concentrate (PCC) and 5 mg intravenous vitamin K (1B level of evidence) Recombinant factor VIIa: not recommended (1B) Fresh frozen plasma: only if PCC unavailable (1C)
PCC for NOAC reversal 12 healthy volunteers: reversal of Rivaroxaban and Dabigatran with PCC investigated in double-blind, crossover study 50 IU/kg Cofact administered IV Rivaroxaban significantly prolonged PT time and completely reversed by PCC Rivaroxaban significantly inhibited endogenous thrombin potential normalised with PCC Dabigatran increased activated partial thromboplastin time, ecarin clotting time and thrombin time these were not reversed by PCC
Recombinant Xa antidote PRT064445 Reversal of rivaroxaban mediated anticoagulation in animal models by a recombinant antidote protein: PRT064445 reversed anti-fxa activity in ASA + rivaroxaban treated mice PRT064445 produced >80% reduction of blood loss in mice treated with ASA + rivaroxaban Lu G et al. Abstract 3715 presented as slides at Eu Soc Card 2011
egfr (ml/min/1.73m 2 ) > 100 80 60 40 20 0 Distribution by age and egfr of rivaroxaban patient group Rivaroxaban 20mg OD Rivaroxaban 15mg OD 0 10 20 30 40 50 60 70 80 90 100110 AGE (Years)
Site and outcome of major bleeding in patients on rivaroxaban n = 11 1 1 Intracranial 5 3 1 Fatal GU Bleeding GI Bleed - PCC Administered
Cardiac procedures Perioperative management Overdose Managing bleeding complications (antidote) Coagulation testing
A prospective, randomized, open-label, parallel-group, active- controlled, multicenter study exploring the efficacy and safety of once-daily oral rivaroxaban compared with that of dose-adjusted oral vitamin K antagonists (VKA) for the prevention of cardiovascular events in subjects with non-valvular atrial fibrillation scheduled for cardioversion.
Anticoagulation use in AF DCCV Dudley 2013 n=130 Wafarin 45% n=160 NOAC 55%
Anticoagulation use in DCCV Anticoagulant Age Male Female CHADSVasc HAS-BLED NOAC 64±11 106 54 2.5±1.3 1.5±0.7 Warfarin 67±10 80 50 2.7±1.5 1.6±0.82
Procedural cancellations
Anticoagulant Procedural waiting time duration (days) NOAC 65±53 Warfarin 90±71 p=0.002
Peri-procedural management If the patient is taking either rivaroxaban, dabigatran or apixaban exclusively for AF there is no need to specifically bridge the short period of interruption for elective procedures with low molecular weight heparin In patients with normal renal function who are to undergo a procedure with a low risk of bleeding (i.e. those procedures that would be safe with an INR of 1.5), rivaroxaban, dabigatran and apixaban should be interrupted for 24 hours
Restarting post major elective procedures For major with incomplete haemostasis, the drugs should not be started if there is evidence of active bleeding For procedures with good haemostasis the first dose should be given at least 4-6 hours post procedure For dabigatran, the first dose should be halved (i.e. 75mg), and a similar approach is reasonable for rivaroxaban (i.e. 10mg) Normal dosing can be resumed from the second dose In practice prophylactic LMWH is administered the evening post procedure and recommence NOACs at the standard dose the day after
New onset AF: warfarin naïve Clinical profile: 83 male, nonvalvular AF diagnosed 1 month ago Hypertensive IHD DM Drugs: aspirin; furosemide; ramipril; beta blocker; statin Other considerations Patient lives alone No transport 28 units of alcohol Clinical evaluation and next steps Stroke risk factor(s):htn, DM CHADS2= 3 Annual stroke risk is 2.2%( 9 times greater than a patient without AF) Oral anticoagulation is recommended Rivaroxaban Highly effective, predictable anticoagulation No dietary restrictions Fast onset of action No need for routine coagulation monitoring
Patient with existing AF- warfarin discontinuer Clinical profile: 68, non-valvular AF diagnosed 3 years ago at annual check-up; Diabetes mellitus, hypertension Current management plan: amiodarone; metformin; atenolol; Discontinued warfarin Other considerations Farmer who lives with wife in the country Spends a few months a year in Spain where he has limited access to INR clinics Discontinued warfarin due to his inability to attend the INR clinic frequently given personal and working situation Clinical evaluation and next steps Stroke risk factor(s):hypertension, diabetes CHADS 2 = 2 Annual stroke risk is 2.2%( 9 times greater than a patient without AF) Oral anticoagulation is recommended Rivaroxaban Highly effective, predictable anticoagulation No dietary restrictions Fast onset of action No need for routine coagulation monitoring No increase in MI
Echocardiography In whose in whom long term management will be affected Refine risk stratification Patients for rhythm control strategy
Anti-platelet therapy Do not offer aspirin monotherapy solely for stroke prevention to patients with atrial fibrillation DAPT only if anticoagulation is contra-indicated or not tolerated
Diagnosis Pulse checking ECG confirmation Holter Cardiomemo AliveECG ILR Cardiac device analysis
The more we monitor the more AF we find
Rate or rhythm control Rate control as initial strategy Rhythm control AF with reversible cause Tachycardiomyopathy New onset AF
Beta blocker or CCB Rate control Digoxin in sedentary elderly Combination of the above Amiodarone not for long term rate control
Rhythm control Where symptoms persists after rate control or if rate control has failed DCCV preferred Consider amiodarone pre-treatment TOE-guided DCCV or conventional DCCV acceptable
Rhythm control Beta blocker preferable (avoid sotalol) Dronedarone rarely Amiodarone LA ablation for the highly symptomatic
Rhythm Acute management of AF DCCV for haemodynamic compromise in new onset AF Optimise rate control in compromised patients selected for a rate control strategy Chemical CV : flecainide / amiodarone Anticoagulation Anticoagulate and risk stratify Continue anticoagulation in most
New and improved? Catching up with evidence Risk stratification Avoid aspirin (rarely use DAPT) Use any anticoagulant NOACs are our destiny Preference for rate control strategy DCCV should be mainly amiodarone-facilitated AF ablation for highly symptomatic AF