PROBLEMES COURANTS D ANTICOAGULATION EN POST-CHIRURGIE CARDIAQUE LA FIBRILLATION ATRIALE J.Y. LE HEUZEY Hopital Georges Pompidou, Université René Descartes, Paris Rennes, 30 Septembre 2016
Disclosures Fees for boards and conferences from : Astra-Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb/Pfizer, Daiichi-Sankyo, Meda, Sanofi, Servier, Novartis
Quelle chirurgie? Valvulaire ou non? Quelle prothèse si valvulaire? Echo : quelle taille d oreillette, contraste spontané? La vraie difficulté : patient ne justifiant pas d une anticoagulation du fait de sa cardiopathie en elle même, typiquement le coronarien jeune (en fait coronarien = CHA 2 DS 2 VASc = 1, si 65 ans = 2)
Circulation, 2008; 118: 1612-8
Am. J. Cardiol. 2012; 109: 219-25
Eur. J. Cardiothorac. Surg. 2015; 48: 817-24
Clin. Lab. Med. 2014; 34:537-61
18 Clinical risk factors for stroke, transient ischaemic attack, and systemic embolism CHA 2 DS 2 -VASc risk factor Congestive heart failure Signs/symptoms of heart failure or objective evidence of reduced left-ventricular ejection fraction Hypertension Resting blood pressure >140/90 mmhg on at least two occasions or current antihypertensive treatment Points 1 1 Age 75 years or older 2 Diabetes mellitus Fasting glucose >125 mg/dl (7 mmol/l) or treatment with oral hypoglycaemic agent and/or insulin 1 Previous stroke, transient ischaemic attack, or thromboembolism 2 Vascular disease Previous myocardial infarction, peripheral artery disease, or aortic plaque 1 Age 65 74 years 1 Sex category (female) 1 2016 www.escardio.org/guidelines European Heart Journal - doi:10.1093/eurheartj/ehw 210
19 Modifiable and non-modifiable risk factors for bleeding in anticoagulated patients with AF Modifiable bleeding risk factors: Hypertension (especially when systolic blood pressure is >160 mmhg) Labile INR or time in therapeutic range <60% in patients on vitamin K antagonists Medication predisposing to bleeding, such as antiplatelet drugs and non-steroidal antiinflammatory drugs Excess alcohol ( 8 drinks/week) Potentially modifiable bleeding risk factors: Anaemia Impaired renal function Impaired liver function Non-modifiable bleeding risk factors: Age (>65 years) ( 75 years) History of major bleeding Previous stroke Dialysis-dependent kidney disease or renal transplant Cirrhotic liver disease Malignancy Genetic factors Biomarker-based bleeding risk factors: High-sensitivity troponin Growth differentiation factor-15 Reduced platelet count or function 2016 Serum creatinine/estimated CrCl www.escardio.org/guidelines European Heart Journal - doi:10.1093/eurheartj/ehw 210
20 Stroke prevention in atrial fibrillation Mechanical heart valves or moderate or severe mitral stenosis Yes No Estimate stroke risk based on number of CHA 2 DS 2 -VASc risk factors 0 a 1 2 No antiplatelet or anticoagulant treatment (IIIB) OAC should be considered (IIaB) Oral anticoagulation indicated Assess for contra-indications Correct reversible bleeding risk factors LAA occluding devices may be considered in patients with clear contra-indications for OAC (IIbC) NOAC (IA) b VKA (IA) c a Includes women without other stroke risk factors b IIaB for women with only one additional stroke risk factor c IB for patients with mechanical heart valves or mitral stenosis 2016 www.escardio.org/guidelines European Heart Journal - doi:10.1093/eurheartj/ehw 210
Are all CHA 2 DS 2 VASc 1 the same? 40 years with hypertension vs 64 years with ejection fraction 15%?? Circulation 2014; 130: 2071-104
RE-LY: Time to first intracranial bleed Cumulative hazard rates 0.02 0.01 0.0 Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR 0.40 (95% CI: 0.27 0.60) p<0.001 (Sup) RR 0.31 (95% CI: 0.20 0.47) p<0.001 (Sup) RRR 60% RRR 69% 0 0.5 1.0 1.5 2.0 2.5 Years RR, relative risk; RRR, relative risk reduction; CI, confidence interval; Sup, superior Connolly et al.,esc meeting, Barcelona 2009
Stroke or systemic embolism (ITT) Cumulative hazard rates No at risk Warfarin Dab 110 mg Dab 150 mg No at risk Apixaban Warfarin Percent with event 0.05 0.04 0.03 0.02 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 Years 5862 RE-LY 2009 5862 6022 6015 6076 4 3 2 1 0 Warfarin Dabigatran 110 mg Dabigatran 150 mg 5939 Warfarin Apixaban RE-LY 1 2009 ROCKET AF 2 2011 5718 5710 5779 4593 4593 4682 ARISTOTLE 3 2011 2890 2945 3044 1322 1385 1429 21% RRR A: 212 patients, 1.27% per year W: 265 patients, 1.60% per year p<0.001 (non-inferiority) p=0.011 (superiority) 0 6 12 18 24 30 Months 9120 8726 8440 6051 3464 1754 9081 8620 8301 5972 3405 1768 1. Connolly et al. N Eng J Med 2009;361:1139 1151 AVERROES 2011 2. Patel et al. N Eng J Med 2011;365:883 891 ARISTOTLE 2011 Cumulative rate (%) No at risk Rivaroxaban Warfarin Stroke or Systemic Embolism (%) No at risk Warfarin High-dose edoxaban Low-dose edoxaban 6 5 4 3 2 1 0 8 6 4 2 Warfarin Rivaroxaban HR 0.88 (0.75, 1.03) p<0.001 (non-inferiority) p=0.12 (superiority) 0 120 240 360 480 600 720 840 Days since randomisation 7081 6879 6683 6470 5264 4105 2951 1785 7090 6871 6656 6440 5225 4087 2944 1783 ENGAGE AF-TIMI 48 4 2013 Warfarin High-dose edoxaban Low-dose edoxaban 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years 7036 6798 6615 6406 6225 4593 2333 536 7035 RE-LY 6816 6650 20096480 6283 4659 2401 551 7034 6815 6631 6461 6277 4608 2358 534 3. Granger et al. N Eng J Med 2011;365:981 992 4. Giugliano et al. N Eng J Med 2013;369:2093 2104
All NOACs: Stroke or SEE Risk Ratio (95% CI) RE-LY [Dabigatran 150 mg] 0.66 (0.53 0.82) ROCKET AF 0.88 (0.75 1.03) ARISTOTLE 0.80 (0.67 0.95) ENGAGE AF-TIMI 48 [Edoxaban 60 mg] 0.88 (0.75 1.02) Combined 0.81 (0.73 0.91) [Random Effects Model] N=58,541 p<0.0001 0.5 1 2 Favours NOAC Favours Warfarin Heterogeneity p=0.13 Ruff et al. Lancet 2014;383:955 962
All NOACs: Major bleeding Risk Ratio (95% CI) RE-LY [Dabigatran 150 mg] 0.94 (0.82 1.07) ROCKET AF 1.03 (0.90 1.18) ARISTOTLE 0.71 (0.61 0.81) ENGAGE AF-TIMI 48 [Edoxaban 60 mg] 0.80 (0.71 0.90) Combined [Random Effects Model] 0.86 (0.73 1.00) N=58,498 p=0.06 0.5 1 2 Favours NOAC Favours Warfarin Heterogeneity p=0.001 Ruff et al. Lancet 2014;383:955 962
Advantages of Direct Oral Anticoagulants No routine coagulation monitoring Less intracranial hemorrhages in the trials At least as effective as Warfarine Short half lifes Less inter and intraindividual variability of the effect Simplification or suppression of bridging No major interaction with food Fixed doses and more predictable response
Limitations of Direct Oral Anticoagulants Specific antidote only for Dabigatran at that time, difficulties in bleeding management Drug-drug interactions (PgP and CYP) Precaution +++ in patients with moderate renal failure (elderly), contraindication if more severe failure (creatinine clearance less than 30 ml/min with the Cockroft method) Therapeutics schemes to redefine in specific situations (for example coronary heart disease) Cost ++++++++
Which is the best direct oral anticoagulant? NO HEAD TO HEAD COMPARISON Slightly different populations in the trials: higher CHADS 2 score and more secondary prevention patients in ROCKET AF Ischaemic stroke reduction only with dabigatran 150 mg In the trials increase in gastrointestinal bleeding with dabigatran, rivaroxaban and high-dose edoxaban, not with apixaban and low-dose edoxaban Decrease in total mortality with apixaban and low-dose edoxaban
Which is the best direct oral anticoagulant? Discussion on dabigatran and myocardial infarction increased risk Lower discontinuation rate with apixaban in ARISTOTLE and edoxaban in ENGAGE AF Different rates of renal excretion (dabigatran > edoxaban > rivaroxaban > apixaban) Higher difficulty in switching QD vitamin K antagonist for a BID new oral anticoagulant than for a QD one
1 Pointers towards which NOAC to choose Previous stroke (secondary prevention) Consider best investigated agent or greatest reduction of 2 nd stroke Rivaroxaban Apixaban Previous GI bleeding or high risk Consider agent with the lowest reported incidence of GI bleed Apixaban [Edoxaban] Specific patient characteristics High risk of ischaemic stroke, low bleeding risk High risk of bleeding, e.g. HAS-BLED 3 CAD, previous MI or high-risk for ACS/MI Renal impairment Consider agent / dose with the best reduction of ischaemic stroke Consider agent / dose with the lowest incidence of bleeding Consider agent with a positive effect in ACS Consider agent least dependent on renal function Dabigatran 150 Dabigatran 110 Apixaban [Edoxaban] Rivaroxaban Apixaban Rivaroxaban GI upset / disorders Consider agent / dose with no reported GI effects Apixaban Rivaroxaban [Edoxaban] Patient preference Consider once-daily formulation Rivaroxaban [Edoxaban] Adapted from Savelieva and Camm. Clin Cardiol 2014;37:32 47
Diapositive 30 CH1 We request that this slide be deleted due to legal purposes Claudia Henn; 29/10/2014 1 No, I refuse, this discussion is the most interesting of the presentation for the cardiologists Do not publish it but I will present it JEAN-YVES LE HEUZEY; 04/11/2014
RE-ALIGN Study design Population A Population B Start warfarin up to day 7 Start DE day 3-7 Study treatment Warfarin (INR according to guidelines) CrCI <70 ml/min: DE 150 mg bid CrCI 70 <110 ml/min: DE 220 mg bid CrCI 110 ml/min: DE 300 mg bid 1 week follow-up or transition to RE-ALIGN extension trial B: Surgery (>3 months) A: Surgery *Increased dose of dabigatran when trough plasma level <50 ng/ml (by Hemoclot ) 12 weeks Composite of a first thromboembolic event or death 1.0 1.0 First bleeding event (any bleeding) Probability of no event No at risk Dabigatran Warfarin 0.8 0.6 p=0.24 for comparison of treatment 0.6 p=0.01 for comparison of treatment groups (Wald χ 2 test) groups (Wald χ 2 test) 0.4 «Valvular» atrial fibrillation : vitamine 0.4 K antagonists 0.2 0.0 0 50 100 150 200 250 300 350 400 Time to first event (days) 156 126 108 RE-LY 2009 82 66 55 168 84 Start of RE-ALIGN extension trial 73 40 44 22 15 9 Warfarin Dabigatran First thromboembolic event includes stroke, systemic embolism, TIA, myocardial infarction 7 4 Probability of no event No at risk Dabigatran Warfarin 0.8 0.2 0.0 0 50 100 150 200 250 300 350 400 Time to first event (days) 129 103 86 RE-LY 2009 73 56 50 168 84 Start of RE-ALIGN extension trial 58 38 32 22 11 11 Warfarin Dabigatran Van de Werf ESC 2013; Eikelboom et al. N Eng J Med 2013;369:1206 14 6 4
DOACs Exclusion criteria in the studies Study Drug Exclusion criteria RE-LY ROCKET-AF ARISTOTLE Dabigatran Rivaroxaban Apixaban History of heart valve disorder (i.e., prosthetic valve or hemodinamically relevant valve disease) Hemodynamically significant mitral valve stenosis, prosthetic heart valves (annuloplasty with or without prosthetic ring, commisurotomy and/or valvuloplasty are permitted) Conditions other than AF that require anticoagulation (i.e. prosthetic heart valves ) ENGAGE AF Edoxaban Adapted from Mabo P. Moderate-to-severe mitral stenosis, other indication for anticoagulation (subjects with bioprosthetic heart valves and/or valve repair could be included) Connolly SJ, NEJM 2009 Patel MR, NEJM 2011 Connolly SJ, NEJM 2011 Giugliano RP, NEJM 2013
To be or not to be valvular? - aortic stenosis - aortic regurgitation - mild mitral stenosis - mitral regurgitation - tricuspid stenosis - tricuspid regurgitation - valve repair - bioprosthetic valve replacement Avezum A. et al. Circulation 2015; 132 : 624-32
CONCLUSIONS 1- La survenue d une fibrillation atriale en post chirurgie cardiaque est liée à un plus mauvais pronostic (mortalité, accidents thromboemboliques) 2- On manque d essais randomisés sur l interet à long terme de l anticoagulation dans cette population spécifique 3- Ceci dit la majeure partie de ces patients opérés ont un score de CHA 2 DS 2 VASC supérieur ou égal à 2 et donc justifent d une anticoagulation (mais que faire à distance s il n y a pas de récidive?) 4- Si l anticoagulation est décidée, les dernières recommandations européennes 2016 privilégient les anticoagulants oraux directs, les autorités de santé françaises non