New Anticoagulants. Stroke Prevention in AF Commencing Novel Oral Anticoagulants (NOACs) in the GP Setting. 30-Oct-14

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1 Stroke Prevention in AF Commencing Novel Oral Anticoagulants (NOACs) in the GP Setting A/Prof Michael Nguyen Fremantle Hospital Access Cardiology General Practice Education Day Oct 2014 ORAL TTP889 Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 442 Dabigatran New Anticoagulants X Fibrinogen TF/VIIa Xa Adapted from Weitz & Bates, J Thromb Haemost 2007 IXa VIIIa II IIa Va IX AT Fibrin PARENTERAL TFPI (tifacogin) APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux DX-9065a STROKE IS THE LEADING COMPLICATION OF ATRIAL FIBRILLATION AF is associated with a 5-fold higher stroke risk overall 1 AF doubles the risk of stroke when adjusted for other risk factors 2 AF is responsible for nearly a third of all strokes, 3 and the leading cause of embolic stroke 4 Without prevention, approximately 1 in 20 patients will have a stroke each year 5 Approximately 1 in 3 people with a first-time stroke will die within the first 12 months 6 1. Savelieva I et al. Ann Med 2007; 39: ACC/AHA/HRS focused update guidelines: Fuster V et al. Circulation 2011; 123: e Hannon N et al. Cerebrovasc Dis 2010; 29: Emmerich J et al. Eur Heart J 2005; 7(Suppl C): C Atrial Fibrillation Investigators. Arch Intern Med 1994; 154: Thrift et al. Stroke 2000; 31:

2 GUIDELINES RECOMMEND USING NOACs INSTEAD OF WARFARIN 1 ACCORDING TO THE 2012 ESC GUIDELINES: this guideline now recommends [novel oral anticoagulants (NOACs)] as broadly preferable to VKA in the vast majority of patients with non-valvular AF, when used as studied in the clinical trials performed so far. 1. Camm AJ et al. Eur Heart J 2012; 33:

3 New Options - Anticoagulants Dabigatran Pradaxa Direct Thrombin Inhibitor Approved to prevent stroke and systemic embolism nonvalvular atrial fibrillation Rivaroxaban Xarelto Factor Xa Inhibitor Approved to prevent stroke and systemic embolism nonvalvular atrial fibrillation and Postoperative thromboprophylaxis Apixaban Factor Xa Inhibitor Approved to prevent stroke and system embolism nonvalvular atrial fibrillation Rivaroxaban, Package Insert Dabigatran, Package Insert XARELTO (rivaroxaban): EFFICACY AND SAFETY VS. WARFARIN 1-3 Outcome measure Stroke or systemic embolism (primary endpoint)* Ischaemic stroke Major and clinically relevant non-major bleeding Intracranial haemorrhage Xarelto 20 mg/15 mg OD (RRR vs. warfarin; n=7,131) 1,2 Non-inferior (p<0.001 for noninferiority; NS for superiority) NS NS 33% (p=0.02) *Analysis for non-inferiority performed using the per-protocol population. Analysis for superiority performed using the ITT population. Analysis performed using the safety on-treatment population. A pre-specified analysis of patients taking Xarelto 15 mg reported results consistent with the overall trial. 3 ELIQUIS (apixaban): EFFICACY AND SAFETY VS. WARFARIN 1 Outcome measure Stroke or systemic embolism (primary endpoint)* Ischaemic or uncertain type of stroke* Major bleeding Intracranial haemorrhage *Analysis performed using the ITT population. Analysis performed using the safety on-treatment population. Eliquis 5 mg/2.5 mg BD (RRR vs. warfarin; n=9,120) 21% (p=0.01) NS 31% (p<0.001) 58% (p<0.001) ITT=intent-to-treat; RRR=relative risk reduction; NS=not statistically significant. 1. Patel MR et al. N Engl J Med 2011; 365: Patel MR et al. N Engl J Med 2011; 365: (supplementary appendix). 3. Fox KA et al. Eur Heart J 2011; 32: ITT=intent-to-treat; RRR=relative risk reduction; NS=not statistically significant. 1. Granger CB et al. New Engl J Med 2011; 365: PRADAXA (dabigatran): EFFICACY AND SAFETY VS. WARFARIN 1,2 Outcome measure (ITT population) Stroke or systemic embolism (primary endpoint) Ischaemic stroke PRADAXA 150 mg BD (RRR vs. warfarin; n=6,076) 35% (p=0.001 for superiority) 24% (p=0.003) PRADAXA 110 mg BD (RRR vs. warfarin; n=6,015) Non-inferior (p=0.001 for non-inferiority; NS for superiority) Major bleeding NS* 20% (p=0.003) Intracranial haemorrhage 59% (p<0.001) 70% (p<0.001) In patients aged <75 years, PRADAXA 150 mg BD reduced the risk of major bleeding by 30% vs. warfarin (p<0.001; post hoc analysis).* 3 NS ITT=intent-to-treat; RRR=relative risk reduction; NS=not statistically significant. 1. Connolly SJ et al. N Engl J Med 2009; 361: Connolly SJ et al. N Engl J Med 2010; 363: Eikelboom JW et al. Circulation 2011; 123:

4 Managing Bleeding with NOACs Common Themes Across NOAC Trials Compared with warfarin All NOACS are non-inferior for stroke prevention NOACS have similar or lower rates of major bleeding but still substantial (2%-4% per year) All NOACS have have significantly reduced risk of intracranial hemorrhage All trials had relatively short duration follow-up and high discontinuation rates (1/5 to 1/4 over 2 years) Disadvantages / Limitations of NOACS Limited experience/familiarity Lack of long-term data No antidote Short half-life (greater risk of missed doses) No INR to monitor / lack of reliable coagulation assay how to monitor therapy? less frequent contact with clinicians cannot titrate dose Disadvantages / Limitations of NOACS Contraindicated in renal failure; caution with renal impairment (need to monitor renal function) Fixed dose extremes of body weight? extremes of age? Expensive Advantages of Warfarin Familiarity (>50 years of experience) In expert clinician hands, TTR can be high INR monitoring Ability to assess good/poor adherence Ability to assess treatment failures PO and IV antidotes available Non-renal clearance; can use in patients with renal failure 4

5 Advantages of Warfarin Slow onset of action can be desirable (e.g. post acute stroke) Long half-life (36 hours) Known benefits in AMI, CAD, mechanical valves Inexpensive Practical Prescribing Tips 10/18/12 NOACS: Patient Selection All 3 NOACs approved for the prevention of stroke/se in patients with non-valvular AF in whom anticoagulation is appropriate Patients should be able to reliably take daily medication o.d. for rivaroxaban b.i.d. for dabigatran and apixaban NOACS are Not Appropriate For Mechanical heart valves Eikelboom et al. RE-ALIGN trial NEJM Sep 2013 Rheumatic heart disease Severe renal dysfunction or dialysis CrCL<30 for dabigatran and rivaroxaban; CrCL<25 for apixaban Severe liver dysfunction Pregnancy Active bleeding/very high bleeding risk/?active cancer Likely poor compliance NOACS: Choosing the Right Dose Before prescribing, check egfr, CBC, INR/PTT, LFT All NOACs require dose reduction for renal dysfunction Dabigatran: 150mg bid for patients aged <75, CrCL >50, average bleeding risk 110mg bid for patients aged 75, CrCL 30-50, increased bleeding risk Rivaroxaban: 20mg od standard dose 15mg od for patients with CrCL Apixaban: 5mg bid standard dose 2.5mg bid for patients with 2 of 3 (age 80, <60kg, or creatinine >133) NOACs: Patient Instructions Indication (stroke prevention) Potential side effects Bleeding (minor/major/fatal/ich) dyspepsia with dabigatran Adherence (and risks of nonadherence/discontinuation) Importance of taking every day on time (patients missing 1-2 consecutive doses will be subtherapeutic) 5

6 NOACs: Patient Instructions Switching from warfarin: Stop warfarin and start NOAC when INR <2.0 Switching to warfarin: Stop NOAC 1-3 days after starting warfarin, depending on renal function Annual Bleeding Risks with Single, Dual, Triple Therapy Warfarin 3.9% ASA 3.7% Clopidogrel 5.6% ASA + clopidogrel 7.4% Warfarin + ASA 6.9% Warfarin + clopidogrel 13.9% Warfarin + ASA + clopidogrel 15.7% Hansen et al. Arch Intern Med 2010;170(16): Drug Interactions - Dabigatran Drug Interactions - Rivaroxaban Dronedarone Ketoconazole/azoles Cyclosporine/tacrolimus HIV protease inhibitors Amiodarone Quinidine (take 2h after dabi) Verapamil (reduce dose of dabi; take 2h after dabi) Clarithromycin Rifampin St. John s Wort Carbamazepine/Phenyt oin/phenobarb Antacids/PPIs (take 2h after dabi) Ketoconazole/azoles HIV protease inhibitors Dronedarone Clarithromycin/erythro mycin Cyclosporine/tacrolimus Quinidine 10/18/12 Carbamazepine/Phenytoin /Phenobarb Rifampin St. John s Wort Drug Interactions - Apixaban Ketoconazole/azoles HIV protease inhibitors 10/18/12 Carbamazepine/Phenytoin /Phenobarb Rifampin St. John s Wort Peri-Procedural Management Very minor procedures (e.g. dental/cataract) May be performed at trough concentration (not peak concentration), i.e. just before the next scheduled dose Or skip one dose of dabigatran/apixaban Minor surgery/low bleeding risk Stop NOAC 1 day before; longer if renal dysfunction Major surgery/high bleeding risk/spinal anesthesia Stop NOAC 2 days before (2-3 days for dabigatran); longer if renal dysfunction Restart NOAC 24h post-op for minor surgery; 48h post-op for major surgery 6

7 Laboratory Assays Dabigatran If aptt is normal, reasonable to assume there is unlikely to be a significant dabigatran bleeding risk Thrombin time Rivaroxaban/Apixaban Cannot use aptt as a guide Prothrombin time (not INR) may help, but may be unreliable Anti-Factor Xa assay better Summary AF is a major preventable cause of stroke We have entered a new era of anticoagulation for stroke prevention Aim for safe and appropriate use of the new agents Careful patient selection Regular patient follow-up Assessing and reinforcing medication adherence Ongoing patient and physician education Dabigatran controversy RELY substudy 9183 patients plasma levels analysed 7

8 US Medicare data patients Summary for treatment of AF Rate vs Rhythm control Anticogulation vs no Anticoagulation hemorrhage Major GI bleeding ( ) Acute MI ( ) Mortality ( ) * Primary findings for Pradaxa are based on analysis of both 75 and 150 mg together without stratification by dose. This study included adjustments for many potential confounding variables; however, confounding from other unmeasured factors may be present. Outcomes were largely based on previously validated algorithms with high positive predictive values but were not validated by medical record review. The results for major GI bleeding differ from those of our previous Mini Sentinel Modular Program analysis which found lower rates of GI and intracranial hemorrhages among new users of Pradaxa, compared to new users of warfarin. Approximately 10,600 new users of Pradaxa were included in this analysis, RATE two-thirds (64%) vs of RHYTHM whom were over age 65. The Modular Program analysis did not allow for rigorous adjustment of confounding variables as was possible with the Medicare data. Rate control is default option unless: The larger Medicare study, which assessed a relatively older population (all over 65 years of age) found that Pradaxa was associated with an increased risk of major GI bleeding compared to warfarin. This finding is consistent with the RE-LY trial which showed that the risk of GI bleeding with Pradaxa compared to warfarin increased with age. The disparity between the results of the Medicare study and the prior Mini Sentinel Modular Program analysis may reflect the age AF that is symptomatic (usually young patients differences in the two patient populations. with paroxysmal AF) FDA plans to publish the study of Medicare patients. FDA also continues to investigate the reasons for differences in major GI bleeding rates for Pradaxa and warfarin observed in the Mini-Sentinel and Medicare analyses. Left ventricular impairment We are continuing to review anticoagulant use and the risk of bleeding and will communicate any relevant information that becomes available. Anticoagulation vs No Anticoagulation CHADS2 - >/= 1 > Anticogulation CHADS2 0 then check CHADS2VASC CHADS2VASC - >/= 1 consider Anticoagulation References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: