ΔΟΡΥΦΟΡΙΚΟ ΣΥΜΠΟΣΙΟ. Αντιπηκτική αγωγή στη σύγχρονη κλινική πράξη το 2017

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Rolf Gibbs
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1 ΔΟΡΥΦΟΡΙΚΟ ΣΥΜΠΟΣΙΟ Αντιπηκτική αγωγή στη σύγχρονη κλινική πράξη το 2017 Διαχείριση του θρομβωτικού κινδύνου σε ασθενείς με μη βαλβιδική κολπική μαρμαρυγή και υψηλό καρδιαγγειακό κίνδυνο Γ.Ν.Α. «Ο Ευαγγελισμός» Ξυδώνας Σωτήριος, MD, PhD, FESC Β Καρδιολογικό Τμήμα, Γ.Ν.Α. «Ο Ευαγγελισμός»

2 Conflict of Interest Bayer, Boehringer-Ingelheim, Boston Scientific, Elpen, Medtronic, Merck, Novartis, Pfizer, Servier This presentation is intended for non-promotional scientific purposes only and may contain information on products or indications currently under investigation and/or that have not been approved by the regulatory authorities. This presentation is accurate at the time of presentation. Any data about non-novartis products are based on publicly available information at the time of presentation.

3 (An) Important Steps for Thrombocardiology

4 Διαχείριση θρομβωτικού κινδύνου Thrombocardiology Ortho Acute Indications Medically ill Chronic Indications VTE tx AF PCI CAD/PAD

5 Διαχείριση θρομβωτικού κινδύνου Ortho Acute Indications Medically ill Chronic Indications VTE tx AF PCI CAD/PAD

6 Atrial Fibrillation Europace 2011;13:

7 Proportion of patients (%) Ischemic stroke in AF results in persistent disability & death Outcomes of first ischemic stroke in high-risk patients with AF (n=597) % Persisting disability Modified Rankin scale 2 20% Death Stroke 2009;40:

8 Hemorrhagic stroke in AF What was the mortality rate in the DOAC phase III studies? % % % %

9 Hemorrhagic stroke in AF What was the mortality rate from Intracranial hemorrhage in the DOAC phase III studies? % % % %

10 Patients with non-valvular AF and high CV risk 1. Elderly 2. Chronic Kidney Disease 3. Coronary Artery Disease

11 ROCKET AF: Elderly subgroup analysis Stroke and Systemic Embolism (SSE) Circulation 2014;130:

12 ROCKET AF: Elderly subgroup analysis Circulation 2014;130:

13 Patients with non-valvular AF and high CV risk 1. Elderly 2. Chronic Kidney Disease 3. Coronary Artery Disease

14 AF and CKD CKD High Prevalence Important Predictor for SSE 28% have egfr <60% 10% have egfr <45% Circulation 2011;123: Circulation 2009;119: Circulation 2013;127:

15 Rivaroxaban and Renal Impairment Circulation 2017;135:

16 Rivaroxaban and Worsening Renal Function SSE Bleeding On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin Insights From ROCKET AF Circulation 2016;134:37-47.

17 Patients with non-valvular AF and high CV risk 1. Elderly 2. Chronic Kidney Disease 3. Coronary Artery Disease

18 ROCKET AF: Prior MI subgroup analysis CV death, MI and UA in patients with and without prior MI Eur Heart J 2014;35:

19 ROCKET AF: Prior MI subgroup analysis Eur Heart J 2014;35:

20 Διαχείριση θρομβωτικού κινδύνου Ortho Acute Indications Medically ill Chronic Indications VTE tx AF PCI CAD/PAD

21 What we know so far Monotherapy with low-dose Aspirin superior in efficacy to placebo or no antiplatelet therapy associated with a very low incidence of serious bleeding Low-dose Aspirin + PY 12 inhibitor enhances efficacy cost of additional bleeding Low-dose Aspirin + Warfarin reduces re-infarction increases serious bleeding substantially frequent monitoring and dose adjustment leads to poor adherence Low-dose Aspirin + PY 12 inhibitor + Warfarin high risk of serious bleeding unacceptable over the long term

22 ESC and ACC/AHA Guidelines assess CHA 2 DS 2 -VaSc, HAS-BLED anticoagulant doses adjusted radial approach PPIs when on DAPT with high risk of bleeding PCI without interruption of VKAs/NOACs no UFH, when on Warfarin with INR>2,5 to age, sex, BW, renal function, sex(?) add low-dose parenteral anticoagulation when on NOACs, irrespectively of last dose timing Clopidogrel preferred GPIIb/IIIb inhibitors only for bailout of periprocedural complications KEEP TRIPLE THERAPY AS SHORT AS POSSIBLE

23 PIONEER AF-PCI Design: Open-label, RCT IIIb SAFETY study Population: paroxysmal, persistent or permanent NVAF undergoing PCI (with stent placement) N=2,124 Decision for DAPT duration: 1, 6 or 12 months 1:1:1 R Rivaroxaban 15 mg od * # plus single antiplatelet Rivaroxaban 2.5 mg bd # plus DAPT VKA (INR ) plus DAPT Rivaroxaban 15 mg od * plus low-dose ASA VKA plus low-dose ASA 12 mos: 100% 1 mo: 16% 6 mos: 35% 12 mos: 49% 1 mo: 16% 6 mos: 35% 12 mos: 49% DAPT duration (1 or 6 months) End of treatment (12 months) *CrCl ml/min: 10 mg OD; # first dose hours after sheath removal; clopidogrel (75 mg daily)(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); ASA ( mg daily) plus clopidogrel (75 mg daily)(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); first dose hours after sheath removal N Engl J Med 2016; 375:

24 PIONEER AF-PCI Characteristic Group 1 Rivaroxaban 15 mg OD plus single antiplatelet (N=709) Group 2 Rivaroxaban 2.5 mg BID plus DAPT (N=709) Group 3 VKA plus DAPT (N=706) Age, years, mean ± SD 70.4± ± ±8.7 Female sex, n (%) 181 (25.5) 174 (24.5) 188 (26.6) CrCl, ml/min, mean ± SD 78.3± ± ± <60 ml/min, n (%) 194 (28.8) 196 (28.8) 175 (26.2) <30 ml/min, n (%) 8 (1.2) 7 (1.0) 2 (0.3) CHA 2 DS 2 -VASc score, mean ± SD 3.73± ± ± , n (%) 77 (10.9) 75 (10.6) 51 (7.2) 2, n (%) 632 (89.1) 634 (89.4) 655 (92.8) HAS-BLED score, mean ± SD* 3.00± ± ± , n (%) 196 (27.6) 227 (32.0) 208 (29.3) 3, n (%) 513 (72.4) 482 (68.0) 498 (70.5) Type of AF, n (%) Persistent 146 (20.6) 146 (20.6) 149 (21.1) Permanent 262 (37.0) 238 (33.6) 243 (34.5) Paroxysmal 300 (42.4) 325 (45.8) 313 (44.4) N Engl J Med 2016; 375:

25 PIONEER AF-PCI Characteristic Group 1 Rivaroxaban 15 mg OD plus single antiplatelet (N=709) P2Y 12 inhibitor at baseline, n (%) Group 2 Rivaroxaban 2.5 mg BID plus DAPT (N=709) Group 3 VKA plus DAPT (N=706) Clopidogrel 660 (93.1) 664 (93.7) 680 (96.3) Prasugrel 12 (1.7) 11 (1.6) 5 (0.7) Ticagrelor 37 (5.2) 34 (4.8) 21 (3.0) Urgency of revascularization, n (%) Elective 428 (60.4) 430 (60.6) 449 (63.6) Urgent 281 (39.6) 279 (39.4) 257 (36.4) Type of index event, n (%) NSTEMI 130 (18.5) 129 (18.4) 123 (17.8) STEMI 86 (12.3) 97 (13.8) 74 (10.7) Unstable angina 145 (20.7) 148 (21.1) 164 (23.7) Type of stent, n (%) Drug-eluting stent 464 (65.4) 471 (66.8) 468 (66.5) Bare metal stent 231 (32.6) 220 (31.2) 224 (31.8) Both 14 (2.0) 14 (2.0) 12 (1.7) N Engl J Med 2016; 375:

26 TTR (%) PIONEER AF-PCI Average TTR: 65% TTR by region (safety analysis set) ,9 10,0 7,0 10,3 7,9 8,2 3,9 3,7 3,3 4,5 4,4 4,1 65,0 60,7 64,4 64,4 66,6 63,6 INR 3.2 INR 3.0 <3.2 INR 2.0 <3.0 INR 1.8 <2.0 INR < ,6 9,0 8,1 12,7 15,9 16,9 All regions (N=651) North America (N=60) Latin America (N=43) 10,4 9,2 9,9 10,5 13,1 14,2 Western Europe (N=237) Eastern Europe (N=276) Asia-Pacific (N=35) N Engl J Med 2016; 375:

TIMI major, TIMI minor or bleeding requiring medical attention (%) PIONEER AF-PCI Safety in both Rivaroxaban groups Rivaroxaban 15 mg od + SAPT vs. VKA + DAPT HR=0.59; (95% CI 0.47 0.76); p<0.

27 TIMI major, TIMI minor or bleeding requiring medical attention (%) PIONEER AF-PCI Safety in both Rivaroxaban groups Rivaroxaban 15 mg od + SAPT vs. VKA + DAPT HR=0.59; (95% CI ); p<0.001 Rivaroxaban 2.5 mg bd + DAPT vs. VKA + DAPT HR=0.63; (95% CI ); p< % 18.0% 16.8% ARR 8.7% ARR 9.9% NNT = 12 NNT = Group 3 (VKA + DAPT) Time (days) Group 2 (Rivaroxaban 2.5 mg bd + DAPT) Group 1 (Rivaroxaban 15 mg od + SAPT)

28 360-day Kaplan Meier estimate (%) *p<0.01 vs VKA plus DAPT PIONEER AF-PCI Clinically significant bleeding according to DAPT duration Groups 2 and 3 were stratified according to the intended duration of triple therapy (decided by the physician before randomization) Group 3 (VKA + DAPT) Group 2 (Rivaroxaban 2.5 mg bd + DAPT) * * n=113 n=108 n=243 n=248 n=341 n=350 1 month 6 months 12 months Rivaroxaban 2.5 mg bd + DAPT followed by 15 mg od + ASA reduced bleeding risk irrespective of DAPT duration VKA + DAPT

CV death, MI or stroke (%) PIONEER AF-PCI Efficacy Rivaroxaban 15 mg od + single antiplatelet vs. VKA + DAPT HR=1.08; (95% CI 0.69 1.68); p=0.750 Rivaroxaban 2.5 mg bd +DAPT vs. VKA + DAPT HR=0.

29 CV death, MI or stroke (%) PIONEER AF-PCI Efficacy Rivaroxaban 15 mg od + single antiplatelet vs. VKA + DAPT HR=1.08; (95% CI ); p=0.750 Rivaroxaban 2.5 mg bd +DAPT vs. VKA + DAPT HR=0.93 (95% CI ); p= % 6.0% 5.6% 4 2 Group 3 (VKA + DAPT) Group 2 (Rivaroxaban 2.5 mg bd + DAPT) Group 1 (Rivaroxaban 15 mg od + single antiplatelet) Time (days) *Trial not powered to definitively demonstrate either superiority or non-inferiority for efficacy endpoints

30 360-day Kaplan Meier estimate (%) PIONEER AF-PCI Efficacy Group 3 (VKA + DAPT) (n=695) Group 2 (Rivaroxaban 2.5 mg bd + DAPT) (n=704) Group 1 (Rivaroxaban 15 mg od + single antiplatelet) (n=694) 0 Major adverse CV events* Composite endpoint CV death, MI and stroke CV death MI Stroke Stent thrombosis Components of composite endpoint and stent thrombosis Incidence of major adverse CV events was comparable between all treatment strategies; however, the trial was not powered for efficacy N Engl J Med 2016; 375:

31 PIONEER AF-PCI Rehospitalizations Circulation 2016;134:00 00.

32 PIONEER AF-PCI Rehospitalizations Circulation 2016;134:00 00.

33 SPC Rivaroxaban (24/8/2017) Περίληψη Χαρακτηριστικών Προϊόντος Παράγραφος 4.2: Ασθενείς με μη βαλβιδική κολπική μαρμαρυγή που υποβάλλονται σε PCI (διαδερμική στεφανιαία παρέμβαση) με τοποθέτηση stent. Υπάρχει περιορισμένη εμπειρία με τη μειωμένη δόση του Xarelto 15 mg άπαξ ημερησίως (ή Xarelto 10 mg άπαξ ημερησίως σε ασθενείς με μέτρια νεφρική δυσλειτουργία [κάθαρση κρεατινίνης ml/min] χορηγούμενου επιπροσθέτως ενός αναστολέα του P2Y12 για μέγιστο διάστημα 12 μηνών σε ασθενείς με μη βαλβιδική κολπική μαρμαρυγή που χρήζουν από του στόματος αντιπηκτική αγωγή και υποβάλλονται σε PCI με τοποθέτηση stent (δείτε παραγράφους 4.4 και 5.1).

34 Strategies to avoid bleeding complications in patients on OACs 2017 ESC focused update on dual antiplatelet therapy in CAD Eur Heart J 2017);0:1 48.

35 DAPT duration in patients with indication for OACs Recommendations Class Level Discontinuation of antiplatelet treatment in patients treated with OAC should be considered at 12 months. IIa B In patients with an indication for VKA in combination with aspirin and/or clopidogrel, the dose intensity of VKA should be carefully regulated with a target INR in the lower part of the recommended target range and a time in the therapeutic range >65 70%. IIa B When a NOAC is used in combination with aspirin and/or clopidogrel, the lowest approved dose effective for stroke prevention tested in AFib trials should be considered. When Rivaroxaban is used in combination with aspirin and/ or clopidogrel, Rivaroxaban 15 mg q.d. may be used instead of rivaroxaban 20 mg q.d. IIa IIb C B The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and OAC. III C 2017 ESC focused update on dual antiplatelet therapy in CAD Eur Heart J 2017);0:

36 DAPT duration in patients with indication for OACs 2017 ESC focused update on dual antiplatelet therapy in CAD Eur Heart J 2017;0:1 48.

37 Διαχείριση θρομβωτικού κινδύνου Ortho Acute Indications Medically ill Chronic Indications VTE tx AF PCI CAD/PAD

COMPASS trial Objective: Efficacy and safety of Rivaroxaban for reducing the risk of MI, stroke and CV death in CAD/PAD Population: Chronic CAD (91%) PAD (27%) N=27,395 Average follow-up: 23 months

38 COMPASS trial Objective: Efficacy and safety of Rivaroxaban for reducing the risk of MI, stroke and CV death in CAD/PAD Population: Chronic CAD (91%) PAD (27%) N=27,395 Average follow-up: 23 months at early termination of study Antithrombotic investigations were stopped 1 year ahead of expectations in Feb 2017 due to overwhelming efficacy in Rivaroxaban 2.5 mg bid + Aspirin arm N Engl J Med 2017 Aug 27. doi: /NEJMoa [Epub ahead of print]

39 COMPASS trial Characteristic Riva 2.5 mg bd + aspirin 100 mg Riva 5 mg bd Aspirin 100 mg Age, years BP, mmhg 136/77 136/78 136/78 Total Chol, mmol/l CAD, % PAD, % DM, % ACEi / ARB 19,518 (71.2) CCB 7269 (26.5) Diuretic 8139 (29.7) β-blocker 19,184 (70.0) Lipid-lowering agent 24,601 (89.8) NSAID 1470 (5.4) Non-study PPI 9798 (35.8)

40 COMPASS trial Composite end-point: CV death, Stroke, MI N Engl J Med 2017 Aug 27. doi: /NEJMoa [Epub ahead of print]

41 COMPASS trial Primary components: CV death, Stroke, MI Secondary end-point: All cause death N Engl J Med 2017 Aug 27. doi: /NEJMoa [Epub ahead of print]

42 COMPASS trial Bleeding events Net Clinical Benefit N Engl J Med 2017 Aug 27. doi: /NEJMoa [Epub ahead of print]

43 Conclusions Elderly patients with CKD and CAD have increased risk for CV events Rivaroxaban has shown both efficacy and safety when used in these patients in preventing CV events Use of combinations post PCI: Rivaroxaban 15mg od + SAPT for 12m or Rivaroxaban 2,5mg bd + DAPT initially and 15mg od + SAPT till 12m significantly reduced bleeding risk remaining equally efficient with VKA + DAPT Indication included in drug s SPC Use of combination in chronic CAD / PAD: Rivaroxaban 2,5mg bd + Aspirin significantly reduced Stroke, CV death and All cause mortality compared with Aspirin

44 Γ.Ν.Α. «Ο Ευαγγελισμός»

45 Primary efficacy outcome Composite of MI, stroke or CV death Secondary efficacy outcomes Composite of major thrombotic events CAD death, MI, ischaemic stroke, acute limb ischaemia CV death, MI, ischaemic stroke, acute limb ischaemia Mortality (all cause) Primary safety outcome Modified ISTH major bleeding Fatal bleeding, and/or Symptomatic bleeding in a critical area or organ, such as intracranial, or Bleeding into the surgical site requiring re-operation, Bleeding leading to hospitalization

46 Inclusion and Exclusion Criteria Ensure That Patients Are Chronic CAD and PAD Patients CAD PAD Key inclusion criteria* PAD CAD with 1 of: Age 65 years Age <65 years plus atherosclerosis in 2 vascular beds or 2 additional risk factors Current smoker Diabetes mellitus Renal dysfunction (egfr<60 ml/min) Heart failure Non-lacunar ischemic stroke 1 month ago Key exclusion criteria Stroke 1 month or any haemorrhagic or lacunar stroke Severe HF with known ejection fraction <30% or NYHA class III or IV symptoms Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy egfr <15 ml/min # Including but not limited to; any other exclusion criteria in conjunction with the local Product Information and any other contraindication listed in the local labelling for rivaroxaban or the comparator have to be considered [accessed 21 Mar 2017]; Bosch J et al, Can J Cardiol 2017;33:

47 Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin Demonstrated a Clear Benefit Across All Subgroups Subgroup Rivaroxaban 2.5 mg bid + aspirin n/n (%) Aspirin alone n/n (%) HR (95% CI) HR (95% CI) p-value All participants 379/9152 (4.1) 496/9126 (5.4) 0.76 ( ) Age 0.20 <65 years 79/2150 (3.7) 126/2184 (5.8) 0.63 ( ) years 179/5078 (3.5) 238/5045 (4.7) 0.74 ( ) 75 years 121/1924 (6.3) 132/1897 (7) 0.89 ( ) Sex 0.75 Male 300/7093 (4.2) 393/7137 (5.5) 0.76 ( ) Female 79/2059 (3.8) 103/1989 (5.2) 0.72 ( ) Body weight kg 41/901 (4.6) 45/836 (5.4) 0.83 ( ) >60 kg 335/8241 (4.1) 448/8285 (5.4) 0.75 ( ) Estimated GFR 0.95 <60 ml/min 132/2054 (6.4) 177/2114 (8.4) 0.75 ( ) 60 ml/min 247/7094 (3.5) 319/7012 (4.5) 0.76 ( ) CAD 0.47 Yes 347/8313 (4.2) 460/8261 (5.6) 0.74 ( ) No 32/839 (3.8) 36/865 (4.2) 0.89 ( ) PAD 0.61 Yes 126/2492 (5.1) 174/2504 (6.9) 0.72 ( ) No 253/6660 (3.8) 322/6622 (4.9) 0.77 ( ) 0, Favours rivaroxaban 2.5 mg bid + aspirin Favours aspirin alone Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa

48 Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin Demonstrated a Clear Benefit Across All Subgroups Subgroup Rivaroxaban 2.5 mg bid + aspirin n/n (%) Aspirin alone n/n (%) HR (95% CI) HR (95% CI) p-value Geographic Region 0.56 North America 63/1304 (4.8) 80/1309 (6.1) 0.78 ( ) South America 93/2054 (4.5) 111/2054 (5.4) 0.84 ( ) Western Europe 117/2855 (4.1) 141/2855 (4.9) 0.82 ( ) Eastern Europe 59/1607 (3.7) 90/1604 (5.6) 0.65 ( ) Asia-Pacific 47/1332 (3.5) 74/1304 (5.7) 0.62 ( ) Race or ethnic group 0.37 White 235/5673 (4.1) 306/5682 (5.4) 0.76 ( ) Black 2/76 (2.6) 8/92 (8.7) 0.30 ( ) Asian 54/1451 (3.7) 81/1397 (5.8) 0.64 ( ) Other 88/1952 (4.5) 101/1955 (5.2) 0.87 ( ) Tobacco use 0.29 Yes 80/1944 (4.1) 122/1972 (6.2) 0.66 ( ) No 299/7208 (4.1) 374/7154 (5.2) 0.79 ( ) Diabetes 0.77 Yes 179/3448 (5.2) 239/3474 (6.9) 0.74 ( ) No 200/5704 (3.5) 257/5652 (4.5) 0.77 ( ) Hypertension 0.68 Yes 317/6907 (4.6) 409/6877 (5.9) 0.76 ( ) No 62/2245 (2.8) 87/2249 (3.9) 0.71 ( ) Dyslipidemia 0.47 Yes 325/8239 (3.9) 428/8158 (5.2) 0.74 ( ) No 54/913 (5.9) 68/968 (7) 0.85 ( ) 0,1 1,0 10,0 Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa Favours rivaroxaban 2.5 mg bid + aspirin Favours aspirin alone

PCI in Patients with AF Optimizing Oral Anticoagulation Regimen

PCI in Patients with AF Optimizing Oral Anticoagulation Regimen Walid I. Saliba, MD Director, Atrial Fibrillation Center Heart and Vascular Institute Cleveland Clinic 1 Epidemiology and AF and PCI AF and