controversies in anticoagulation: optimizing outcome for atrial fibrillation

Transcription

1 controversies in anticoagulation: optimizing outcome for atrial fibrillation SUNDAY, NOVEMBER 13, 2016 WESTIN HOTEL NEW ORLEANS CANAL PLACE COLLABORATE INVESTIGATE EDUCATE

2 PROVIDING PERSPECTIVE: CURRENT STATUS OF ANTICOAGULATION FOR ATRIAL FIBRILLATION Christopher B. Granger, MD Professor of Medicine, Division of Cardiology, Department of Medicine Director, Cardiac Care Unit Duke University Medical Center, Durham, NC

3 Disclosures Research contracts: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, FDA, Janssen, Novartis, GSK, Medtronic Foundation, Pfizer, The Medicines Company, FDA, NIH Consulting/Honoraria: AstraZeneca, Bayer, BMS, Boston Scientific, GSK, Pfizer, Lilly, Daiichi Sankyo, Novartis, Boehringer Ingelheim, Medtronic, Medtronic Foundation, The Medicines Company For full listing see

4 88 year old woman, paroxysmal AF, 48 kg, bioprosthetic aortic valve, creatinine 1.0 mg/dl (creat clearance 30), on warfarin for 5 years, INR generally in target range. Sometimes difficulty getting INR done. Some dyspepsia. Now on naproxen for knee arthritis. Tired of having INR checked. Continue warfarin Dabigatran 110 mg bid Rivaroxaban 15 mg/d Apixaban 2.5 mg bid Edoxaban 30 mg/d

5

6 Oral anticoagulation is very effective at preventing stroke

7 Oral Anticoagulation for stroke prevention Warfarin compared to control or placebo Trial AFASAK I (1990) SPAF I (1991) BAATAF (1990) CAFA (1991) SPINAF (1992) EAFT (1993) Combined Relative Risk Reduction (95% CI) NOAC compared to warfarin Trial RE-LY (2009) ROCKET AF (2011) ARISTOTLE (2011) ENGAGE AF-TIMI 48 (2013) Combined Relative Risk Reduction (95% CI) 100% 50% 0 50% 100% Favors warfarin Favors placebo or control Warfarin vs. Placebo or Control (6 trials, total n=2,900) Hart R, et al. Ann Intern Med. 2007;146: % 0 50% Favors NOAC RRR 64% RRR 19% Favors warfarin NOAC vs. Warfarin (4 trials, total n=71,683) Ruff C, et al. Lancet. 2014;383: These are not head-to-head comparisons between the new anticoagulants

8 Overview of 4 Trials of Novel Agents vs Warfarin in ~72,000 Patients (Lancet December 2013) Risk Ratio (95% CI) Hemorrhagic Stroke 0.49 ( ) p< All-Cause Mortality 0.90 ( ) p= Favors NOAC Favors Warfarin Heterogeneity p=ns for all outcomes Duke Clinical Research Institute Ruff CT, et al. Lancet 2014;383:

9 Duke Clinical Research Institute What do the guidelines say?

10 Atrial Fibrillation Guidelines Risk Recommended Therapy No risk factors CHA 2 DS 2 -VASc= 0 CHA 2 DS 2 -VASc= 1 ESC 2016 No antithrombotic therapy (III B) OAC (IIa B) (NOAC > VKA) AHA/ACC/HRS 2014 No antithrombotic therapy (IIa) None or OAC or ASA (IIb) Duke Clinical Research Institute CHA 2 DS 2 -VASc 2 Mechanical valve, mitral stenosis OAC (I) (NOAC > VKA (IA)) VKA OAC (I) (NOAC or VKA) ESC Guidelines. Eur Heart J 2016 AHA/ACC/HRS Guidelines. Circulation 2014

11 NT-proBNP is a powerful predictor of stroke and can be used as a tie breaker for patients with CHADS-VASc = 1 Duke Clinical Research Institute

12 Biomarkers and Risk in AF By Quartiles of NT-proBNP and CHADS-VASc Hijazi Z. J Am Coll Cardiol 2013;61: Hijazi Z. Eur Heart J 2016;37:

13 Important changes: Avoid the misleading term non valvular AF No recommendation to use bleeding scores to withhold oral anticoagulation (only to identify modifiable factors) NOACs preferred over warfarin for patients with history of stroke (IB) Aspirin is a class IIIA indication (harm) for stroke prevention in AFib Kirchhof P Eur Heart J 2016

14 Kirchhof P Eur Heart J 2016

15 Should patients with or at risk of falls receive anticoagulation? Duke Clinical Research Institute

16 Among older patients, falling is common (about 30% fall at least once a year), and subdural hematomas are uncommon persons taking warfarin must fall about 295 times in 1 year for warfarin to not be the optimal therapy. In ARISTOTLE, among patients with history of falls, there was an 80% lower rate of ICH with apixaban vs warfarin» Of 375 patients with falling on apixaban, 0 had subdural hematoma Arch Intern Med 1999;159: Rao M et al. ESC 2016

17 4.3% had fall risk. Edox vs warfarin, 3 vs 13 ICH Steffel J. J Am Coll Cardiol 2016;68:

18 Duke Clinical Research Institute How about patients at high risk of bleeding?

19 AVERROES Study: Bleeding Analysis Bleeding events ICH: 11 apix, 13 ASA Flaker G. Stroke. 2012;43:3291-7

20 Duke Clinical Research Institute What about ICH?

21 Predictors of ICH (of those on warfarin, 78% had prior INR <3.0) Effect Chi-Square HR (95% CI) Region Asia vs Europe Randomized treatment (apixaban vs warfarin) Age 3.19 ( ) ( ) ( ) (per 5 years increase) Prior stroke/tia ( ) Aspirin treatment ( ) Lopes RD, et al. Presented at AHA Data on file; Lopes RD, et al. (Manuscript under review).

22 Duke Clinical Research Institute GI Bleeding

23 GI Bleeding: Consider PPI in Patients at High Risk 2.5 % /year with major GI bleed HR 1.49* HR 1.61* HR.89 HR 1.23* NOAC Warfarin 0 dabigatran 150 rivaroxaban apixaban edoxaban *statistically significant GI = gastrointestinal; HR 1. = hazard Connolly ratio; S, NOAC et al. NEJM. = novel oral anticoagulant; 2. Patel M, et PPI al. NEJM. = proton pump 3. inhibitors Granger CB, et al. NEJM Giugliano RP et al. NEJM 2013.

24 Duke Clinical Research Institute Do not add aspirin to oral anticoagulation without a clear indication.

25 Bleeding According to Antiplatelet Rx W none ASA ASA + clopi D 150 D 110 Series of no, single, and dual antiplatelet therapy HRs adjusted for age, gender, warfarin experience, SBP, CAD, HF, hypertension, diabetes, TIA, CrCl and statin use. Circulation. published online December 27, 2012

26 Are NOACs safe in the elderly? Duke Clinical Research Institute

27 Apixaban vs. warfarin in patients 80 vs. < 80 years Age < 80 Event Rate (%/year) Age 80 Interaction Apixaban Warfarin HR (95% CI) P-value Stroke/Systemic Embolism 0.91 Age < (0.65, 0.96) Age (0.51, 1.29) Major Bleeding 0.74 Age < (0.60, 0.82) Age (0.48, 0.90) All Bleeding 0.83 Age < (0.67, 0.76) Age (0.64, 0.83) Intracranial Bleeding 0.67 Age < (0.30, 0.62) Age (0.17, 0.77) All-cause Mortality 0.73 Age < (0.78, 1.00) Age (0.74, 1.16) 0.25 Apixaban better Warfarin better Halvorsen S, et al. Eur Heart 2014

28 What about use of NOACs in chronic kidney disease? Duke Clinical Research Institute

29 Safety outcomes Clinical endpoint (% per year) Rivaroxaban (N=7111) Warfarin (N=7116) CrCl 50 ml/min CrCl ml/min HR (95% CI) Rivaroxaban vs warfarin P (interaction) Principal safety outcome* ( ) 0.98 ( ) 0.45 Major bleeding ( ) 0.95 ( ) 0.48 Hct or Hb drop ( ) 1.14 ( ) 0.65 Transfusion ( ) 1.17 ( ) 0.71 Critical organ ( ) 0.55 ( ) 0.39 Fatal bleeding ( ) 0.39 ( ) 0.53 Intracranial haemorrhage ( ) 0.81 ( ) Based on safety population on treatment *Composite of major plus non-major clinically relevant bleeding. Rivaroxaban 20 mg od. Rivaroxaban 15 mg od Fox KAA Eur Hear J 2011

30 Can NOACs be used in AF patients with valvular heart disease? Duke Clinical Research Institute

31 non-valvular AF is a misnomer 26% of patients in ARISTOTLE had a history of mod or severe valvular abnormalities at baseline Any VHD* 4, % Any mitral valve disease 3, % Any aortic valve disease 1, % Tricuspid regurgitation 2, % Prior valve surgery % *Patients may be included in more than one category. Avezum A, et al. Eur Heart J 2013;34(Abst_Suppl):809.

32 Who should we treat with NOACs? Duke Clinical Research Institute

33 Compared to NOACs, warfarin results in: 10 to 50% increased risk of stroke 2 3 fold times rate of ICH As much as one third higher rate of major bleeding (versus apixaban) Requirement for monthly monitoring to adjust dose Falls out of target anticoagulation one third of the time in highly controlled trials and nearly one half the time in general practice Many food and drug interactions 10% significant increase in mortality Diener HC et al. Int J Stroke. 2012;7: Ruff CT, et al. Lancet 2014;383: Hylek EM, et al. Circulation 2007;115:

34 Which Agent? Largest RRR of ischemic stroke: dabigatran Largest renal elimination: dabigatran One daily dosing: rivaroxaban, edoxaban Well established dosing for modest renal insufficiency: rivaroxaban, apixaban, edoxaban Safe including for GI bleeding: apixaban, low dose dabi Reduction in stroke and reduction in major bleeding: apixaban Severe renal insufficiency, mechanical prosthetic valves, rheumatic mitral stenosis: warfarin Least expensive: warfarin

35 Unanswered questions being addressed in trials What should you do with patients needing anticoagulation for AF who have coronary stents placed? (PIONEER, RE DUAL, AUGUSTUS) Is there a role for NOACs for patients with cryptogenic stroke? (NAVIGATE ESUS, RESPECT ESUS) How much asymptomatic AF detected on a pacemaker/icd should prompt starting an anticoagulant? (ARTESiA) Is it safe to treat patients with AF on hemodialysis with apixaban (vs warfarin)? (RENAL AF) How can we increase the proportion of patients treated with oral anticoagulants? (IMPACT AF, Premier Project, Sentinel Initiative)