Tigullio Cardiologia 2018 Santa Margherita Ligure, 5-6 aprile Corso di Aggiornamento Multidisciplinare in Cardiologia

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1 Tigullio Cardiologia 2018 Santa Margherita Ligure, 5-6 aprile Corso di Aggiornamento Multidisciplinare in Cardiologia Sessione plenaria 7 Terapia anticoagulante ed antiaggregante 6 aprile :00-15:40 Stato dell arte: La gestione delle complicanze della terapia anticoagulante ed antiaggregante Raffaele De Caterina Università G. d Annunzio Chieti e Fondazione G. Monasterio Pisa, Italia 6 aprile 2018, 14:00-14:20-20 min min. disc.

2 Prof. Raffaele De Caterina Conflitti d interesse Co-author ESC Guidelines on Atrial Fibrillation Steering Committee member, National Coordinator for Italy, and Coauthor of APPRAISE-2, ARISTOTLE, AVERROES, ENGAGE AF- TIMI 38, Re-DUAL PCI Fees, honoraria and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi-Sankyo, Novartis, Merck, Portola

3 La gestione delle complicanze della terapia antitrombotica } = la gestione delle complicanze emorragiche } che è un compito soprattutto extra-cardiologico (Pronto Soccorso, Medicina Interna, Neurologia, Centri Trasfusionali ) } Ma è compito principalmente del cardiologo prevenirle } assicurare cioè la navigazione più sicura possibile tra la Scilla della trombosi e la Cariddi del sanguinamento

4 Le complicanze emorragiche della terapia antitrombotica }Come prevenirle }Come trattarle

5 Le complicanze emorragiche della terapia antitrombotica }Come prevenirle

6 Le complicanze emorragiche della terapia antitrombotica } Aspirina } Altri farmaci antipiastrinici } Warfarin e altri anti-vitamina K } Nuovi anticoagulanti orali } terapie antitrombotiche parenterali

7 Le complicanze emorragiche della terapia antitrombotica } Aspirina } Altri farmaci antipiastrinici } Warfarin e altri anti-vitamina K } Nuovi anticoagulanti orali } terapie antitrombotiche parenterali

8 Aspirina e altri farmaci antipiastrinici } In genere emorragie cutaneo-mucose: petecchie, ematomi, emorragie gastrointestinali, uterine } Molto più rare le emorragie intracraniche, stimate come aumentate (forse) del 25% con aspirina, rare anche con gli inibitori parenterali della GPIIB/IIIa, e con la DAPT

9 Aspirina: meccanismi del sanguinamento GI } Interferenza con l emostasi primaria } Interferenza con il meccanismo endogeno di gastroprotezione rappresentato dalla produzione gastrica di PGE 2 } Quest ultimo è dose-dipendente, e (quasi) del tutto assente con le basse dosi } Gli anti-ht 2 e i PPI riducono le emorragie gastriche da antipiastrinici riducendo le microlesioni della mucosa che facilitano il sanguinamento quando presente interferenza con l emostasi primaria

10 Blood coagulation a contemporary view INITIATION AMPLIFICATION PROPAGATION X Xa Xa Prothrombin (II) Free VWF Fibrinogen (I) TF-VIIa TF-VIIa IX Va IXa TF-expressing cell/ microparticle Thrombin (IIa) XI XIa Platelet V Va P-selectin VIII/VWF XIa VIIIa CD40L X IXa VIIIa Activated platelet PAR-1 Prothrombin Xa Xa Va P2Y 12 /ADP XIII Thrombin (IIa) XIIIa Gp IIb/IIIa Fibrin Clot De Caterina R. et al. Thromb Haemost 2013;109:

11 Blood coagulation the classical view Initiation TF/ VIIa VII X IX Amplification- Propagation VIIIa Va Xa IXa Targets of heparin Targets of VKA Thrombin activity II IIa Fibrinogen Fibrin Fig. Fig. 3 3 De Caterina R. et al. Thromb Haemost 2013;109:

12 Initiation TF/VIIa X IX Amplification- Propagation VIIIa IXa Va Xa Direct Rivaroxaban Apixaban Edoxaban Thrombin activity II IIa Direct Dabigatran Fibrinogen Fibrin De Caterina R. et al. Thromb Haemost 2013;109:

13 Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients DOACs vs. Warfarin 71,683 Patients 6 Trials of Warfarin vs. Placebo ROCKET AF (Rivaroxaban) 2010 ENGAGE AF-TIMI 48 (Edoxaban) 2013 RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) 2011

14 All NOACS: Stroke or SEE RE-LY [150 mg] ROCKET AF Risk Ratio (95% CI) 0.66 ( ) 0.88 ( ) ARISTOTLE 0.80 ( ) ENGAGE AF-TIMI 48 [60 mg] 0.88 ( ) Combined [Random Effects Model] 0.81 ( ) p=< N=58, Favors NOAC 1 Favors Warfarin 2 Heterogeneity p=0.13 Ruff CT, et al. Lancet 2014;383:

15 Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke Hemorrhagic Stroke MI All-Cause Mortality 0.92 ( ) p= ( ) p< ( ) p= ( ) p= Favors NOAC Favors Warfarin Heterogeneity p=ns for all outcomes Ruff CT, et al. Lancet 2014;383:

16 Secondary Safety Outcomes Risk Ratio (95% CI) ICH 0.48 ( ) p< GI Bleeding 1.25 ( ) p=0.043 Heterogeneity ICH, p=0.22 GI Bleeding, p= Favors NOAC Favors Warfarin Ruff CT, et al. Lancet 2014;383:

17 1. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during : findings from the Global Burden of Disease Study The Lancet Global health 2013;1:e Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. European heart journal 2012;33: Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Annals of internal medicine 2009;151: Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. Journal of the American College of Cardiology 2007;50: Annual incidence of ICH in untreated patients Study Year published Population characteristics Age Population (n) Intracranial bleeds (%/year) Krishnamurthi et al 2013 Friberg et al 2009 Singer et al 2009 Shen et al 2007 General population, high income AF swedish patients, never used warfarin AF patients not receiving warfarin AF patients not receiving warfarin % % % < % % % < (<75) 0.10% % % 3090(>75) % < % %

18 Intracranial hemorrhage among patients taking NOACs Drug and dosage Trial Population (n) Events Intracranial bleeds ITT (%/year) Dabigatran 150 mg bid RE-LY Dabigatran 110 mg bid RE-LY Rivaroxaban 20 mg od ROCKET-AF Apixaban 5/2.5 mg bid ARISTOTLE Edoxaban 60/30 mg od ENGAGE-AF Edoxaban 30/15 mg od ENGAGE-AF

19 Probability of clinical outcomes versus edoxaban concentration Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015;385:

20 REDUCED RISK OF ANY BLEEDING AND ICH WITH BOTH DOSES OF DABIGATRAN VS WARFARIN D110 vs W HR* (95% CI) Any 0.72 ( ) Major 0.93 ( ) Fatal 0.52 ( ) GI 0.50 ( ) ICH 0.30 ( ) D150 vs W Any 0.68 ( ) Major 0.67 ( ) Fatal 0.70 ( ) GI 1.45 ( ) ICH 0.33 ( ) Favours dabigatran Favours warfarin VKA-naïve stratum *HR adjusted for: age, components of CHA 2 DS 2 -VASc, HAS-BLED, months since August 2011 Larsen TB et al. Am J Med 2014;127:650 6

21 Combination therapy increases risk of fatal and nonfatal bleeding Hansen M et al. Arch Intern Med 2010;170:

22 RE-LY: the only phase III NOAC study to allow a combination of an OAC with dual antiplatelet therapy (270 patients in each arm received triple therapy) Major bleeding Warfarin Dabigatran 150 Dabigatran 110

23 Is the increased risk of bleeding by combining antiplatelet agents and a NOAC simply nuisance bleeding? }No!!!

24 Data from APPRAISE-2 Alexander JH et al. N Engl J Med 2011;365:

25 Major bleeding (TIMI definition) Apixaban Placebo Alexander JH et al. N Engl J Med 2011;365:

26 APPRAISE-2 - Clinical Outcomes About ¼ of all major bleeding were intracranial!!! Alexander JH et al. N Engl J Med 2011;365:

27 Thus (conclusion 1) } Adding antiplatelet agents to an anticoagulant at full dose as in APPRAISE-2 the same dose you would use in AF substantially increases major bleeding, and among these bleeds, intracranial hemorrhage (ICH) after an acute coronary syndrome } Thus the addition of antiplatelet therapy transforms an otherwise innocuous agent a NOAC which by per se does not apparently increase ICH (the AVERROES experience) into an intracranial bomb!

28 MACE Major bleeding Oldgren J. Et al, European Heart Journal (2013) 34,

29 } In this meta-analysis of patients with a recent ACS, the addition of a new oral anticoagulant to antiplatelet therapy led to a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced in patients receiving dual antiplatelet therapy. Oldgren J. Et al, European Heart Journal (2013) 34,

30 this is after an ACS } What do we now about adding an antiplatelet (e.g., aspirin) to a NOAC in a stable CAD patient?

31 Data from ARISTOTLE } Of the patients enrolled in ARISTOTLE, 5632 (31%) were using aspirin at baseline, and 4434 (24%) were using aspirin on Day 1. } Why? } And what were the outcomes? Alexander JH et al. Eur Heart J 2014;35:

32 Concomitant aspirin use over time overall and among patients with and without arterial vascular disease in ARISTOTLE Arterial vascular disease includes a history of coronary artery disease, stroke, or peripheral arterial disease Alexander JH et al. Eur Heart J 2014;35:

33 Event rates per year, adjusted hazard ratios, and 95% confidence intervals for the effect of apixaban vs. warfarin among patients using and not using aspirin in the overall population Alexander JH et al. Eur Heart J 2014;35:

34 Alexander JH et al. Eur Heart J 2014;35:

35 Antiplatelets + anticoagulation 2016 AF Guidelines Kirchhof, P et al, Eur Heart J 2016

36 Antiplatelets + anticoagulation 2016 AF Guidelines Kirchhof, P et al, Eur Heart J 2016

37 Conclusion 2 } Try to avoid combination of antithrombotic agents as much as possible } Specifically, do not combine anticoagulants even with a single antiplatelet agent in stable CAD patients } If you opt for drug combination after stenting, limit it to the essential minimum

38 Despite all such precautions, bleeding occurs. So, what to do next?

39 Management of bleeding while on NOAC Bleeding while using a NOAC Inquire about last NOAC intake Blood sample to determine creatinine (clearance), hemoglobin and WBC Rapid coagulation assessment, incl. plasma drug levels (if available) Mild bleeding Delay or discontinue next dose Reconsider concomitant medication Reconsider choice of NOAC & dosing Non life-threatening major bleeding + + Supportive measures : Mechanical compression Endoscopic hemostasis if gastro-intestinal bleed Surgical hemostasis Fluid replacement RBC substitution if needed Platelet substitution (if platelet count <60x10 9 /L) Consider adjuvant tranexamic acid Maintain adequate diuresis For dabigatran: Consider idarucizumab / hemodialysis (if idarucizumab is not available) Life-threatening bleeding For dabigatran-treated patients: Idarucizumab 5g i.v. For FXa inhibitor -treated patients: Andexanet alpha (pending approval and availability) Otherwise, consider: PCC (e.g. Beriplex, CoFact ) 50 U/kg; +25 U/kg if indicated apcc (Feiba ) 50 U/kg; max 200 U/kg/day Steffel et al., EHRA Practical Guide, European Heart Journal 2018

40 Application of NOAC reversal agents Application of Idarucizumab Reversal of dabigatran: 5g i.v. in two doses at 2.5g i.v. no more than 15 minutes apart 015 Suppression of dtt t 24h Application of Andexanet Alpha (if approved and available)* Reversal of rivaroxaban (last intake >7h before) or apixaban: 400mg bolus, 480mg infusion at 4mg/min Reversal of rivaroxaban (last intake <7h before or unknown), enoxaparin or edoxaban: 800mg bolus, 960mg infusion at 8mg/min Infusion over 2 h 0 Suppression of FXa level 2h t 24h Steffel et al., EHRA Practical Guide, European Heart Journal 2018

41 RE-VERSE AD : IMMEDIATE REVERSAL OF DABIGATRAN IN PTS WITH BLEEDING OR REQUIRING SURGERY Group A: Uncontrolled bleeding Assay upper limit of normal Group B: Emergency surgery or procedure Assay upper limit of normal dtt (s) Idarucizumab g dtt (s) Idarucizumab g Baseline Between vials min Time post-idarucizumab 1 h 2 h 4 h 12 h 24 h Adapted from Pollack CV et al. N Engl J Med 2015 Baseline Between vials min Time post-idarucizumab 1 h 2 h 4 h 12 h 24 h

42 IDARUCIZUMAB IS EASY TO USE AND HAS NO CONTRAINDICATIONS Idarucizumab is indicated in patients treated with dabigatran when rapid reversal of the anticoagulant effects of dabigatran is required for emergency surgery/urgent procedures or in life-threatening bleeding No contraindications to use Administered as a fixed dose (5 g, 2.5 g per vial) Vials contain solution (2.5 g/50 ml) ready for infusion or injection No dose adjustment for age or renal impairment etc. Absence of antithrombotic therapy exposes pts to the thrombotic risk of their underlying disease or condition à dabigatran treatment can be re-initiated 24h after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved

43 time courses of anti factor xa activity before and after administration of andexanet Siegal DM et al. N Engl J Med 2015;373:

44 Time Courses of Thrombin Generation before and after the Administration of Andexanet Reduction in tissue factor pathway inhibitor (TFPI) activity, an endogenous, reversible FXaI Increase in prothrombin fragments F1 and F2 Siegal DM et al. N Engl J Med 2015;373:

45 Stroke prevention post GI bleeding ü ü ü ü ü ü ü Continuing / Restarting NOAC? Consider factors favouring withholding (ü) vs. (re-) starting anticoagulation Unidentifiable site of bleeding Multiple angiodysplasias in the GI tract No reversible / treatable cause? Bleeding during treatment interruption Chronic alcohol abuse Need for dual antiplatelet therapy after PCI Older age Net assessment in favour of withholding anticoagulation according to a multidisciplinary decision Yes Consider no anticoagulation vs. LAA occlusion # # Without evidence; ideally include patient in ongoing trial No (Re-) initiate (N)OAC as early as feasible (after 4-7 days) If >75 years old, consider NOAC other than dabigatran, rivaroxaban or higher-dose edoxaban as the first choice Steffel et al., EHRA Practical Guide, European Heart Journal 2018

46 Conclusions and take-home messages Prevention of bleeding during antithrombotic therapies is better than dealing with it Try to avoid combination of antithrombotic therapies as much as possible For irreversible antiplatelet agents the real antidote is platelet transfusion For warfarin, PCC, apcc, rfviia are viable options For dabigatran we have a specific and safe reversal agent For FXa inhibitors andexanet alfa is forthcoming, but with less experience In the meantime, PCC, apcc, rfviia are viable options