ΔΙΑΧΕΙΡΙΣΗ ΑΣΘΕΝΩΝ ΜΕ ΣΤΕΦΑΝΙΑΙΑ ΚΑΡΔΙΟΠΑΘΕΙΑ ΚΑΙ ΚΟΛΠΙΚΗ ΜΑΡΜΑΡΥΓΗ:ΚΙΝΔΥΝΟΙ ΚΑΙ ΟΦΕΛΗ ΔΙΠΛΗΣ ΚΑΙ ΤΡΙΠΛΗΣ ΘΕΡΑΠΕΙΑΣ

Transcription

1 ΔΙΑΧΕΙΡΙΣΗ ΑΣΘΕΝΩΝ ΜΕ ΣΤΕΦΑΝΙΑΙΑ ΚΑΡΔΙΟΠΑΘΕΙΑ ΚΑΙ ΚΟΛΠΙΚΗ ΜΑΡΜΑΡΥΓΗ:ΚΙΝΔΥΝΟΙ ΚΑΙ ΟΦΕΛΗ ΔΙΠΛΗΣ ΚΑΙ ΤΡΙΠΛΗΣ ΘΕΡΑΠΕΙΑΣ Χρήστος Δ.Καλλιάνος Α Καρδιολογικό τμήμα και Ηλεκτροφυσιολογικό Εργαστήριο ΓΝΑ «Ο Ευαγγελισμός»

2 Epidemiology: AF and PCI Concomitant AF and CAD is common owing to the strong association of both conditions with ageing and overlapping risk factors CAD is estimated to occur in 2 4% of patients with AF 1,2 Owing to an aging population, patient numbers are set to increase globally over the coming decades The literature indicates that 2 4% of patients with AF and CAD require coronary revascularization by PCI or CABG 3,4 In a prospective study, 34% of patients with AF also had CAD, of whom 21% required PCI or CABG % of patients with AF enrolled in ARISTOTLE had prior PCI 4 ~1 2 million patients with AF indicated for anticoagulation in the US and Europe are candidates for coronary revascularization 2 1. The AFFIRM Investigators. Am Heart J 22;143:991 11; 2. Capodanno D et al, Circ Cardiovasc Interv 214;7: ; 3. Kralev S et al, PLoS One 211;6:e24964; 4. Bahit MC et al, Int J Cardiol 213;17:21 22

3 27 Guidelines Recommended Prolonged Triple Therapy ACC/AHA 27 Guidelines for management of patients with NSTE-ACS UA/NSTEMI patient groups at discharge with indication for anticoagulation Drug-eluting stent group Bare-metal stent group ASA* mg/day for at least 3 6 months, then mg/day indefinitely Clopidogrel # 7 mg/day for at least 1 year Warfarin When added to ASA plus clopidogrel an INR of is recommended ASA* mg/day for at least 1 month, then mg/day indefinitely Clopidogrel # 7 mg/day for at least 1 month and ideally up to 1 year Warfarin When added to ASA plus clopidogrel an INR of is recommended *For ASA allergic patients, use clopidogrel alone (indefinitely), or try desensitization; # for clopidogrel allergic patients, use ticlopidine 2 mg by mouth twice daily; continue ASA indefinitely and warfarin longer term as indicated for specific conditions such as AF Anderson JL et al, Circulation 27;116:e148 e34

4 Primary efficacy outcome* (%/year) Antiplatelet Therapy Alone Does Not Provide Adequate Protection from AF-Related Stroke A randomized trial for DAPT (n=3,33) vs VKA (n=3,371) for prevention of vascular events in patients with AF demonstrated superiority of OAC 6 RR=1.44 (9% CI ) p=.3,6 4 3, VKA (INR 2. 3.) DAPT (7 mg clopidogrel *Composite of stroke, non-cns embolus, MI and vascular death The ACTIVE Writing Group. Lancet 26;367:

5 ESC Guidelines for the Management of AF and PCI: Minimize Triple Therapy Duration Guidelines recommend the following in patients with AF after PCI: months 1 month 6 months 12 months Elective PCI with stent 1,2 Triple OAC+A+C Dual OAC+A or C OAC mono High bleeding risk/low atherothrombotic risk: shorten dual Urgent PCI after ACS 1 3 Triple OAC+A+C Dual OAC+A or C OAC mono High bleeding risk/low atherothrombotic risk: shorten triple High atherothrombotic risk/low bleeding risk: lengthen triple In selected patients, dual may be considered instead of triple 1 European guidelines suggest that NOACs may be used in triple/dual, 1 3 whereas US guidelines recommend a VKA 4, 1. Kirchhof P et al, Eur Heart J 216; doi:1.193/eurheartj/ehw21; 2. Heidbuchel H et al, Europace 21;17: ; 3. Windecker S et al, Eur Heart J 214;3: ; 4. Amsterdam EA et al, Circulation 214;13:e344 e426;. O Gara PT et al, J Am Coll Cardiol 213;61:e78 e14

6 Canadian Cardiovascular Society Guidelines Recommend OAC + single AP after Elective PCI For patients with AF and recent elective PCI Age <6 and CHADS 2 = Age 6 or CHADS 2 1 ASA plus clopidogrel for 12 months OAC* plus clopidogrel for 12 months ASA alone after 12 months OAC* alone after 12 months *A NOAC is preferred over warfarin for patients with NVAF Macle L et al, Can J Cardiol 216;32:

7 Crude incidence rates (events per 1 person-years ± SE) Triple Therapy with a VKA Reduces Thromboembolic Events but Increases Bleeding after PCI in AF Patients Danish registry data (2 29; N=11,48 patients) Triple (VKA plus ASA plus clopidogrel) VKA plus single antiplatelet DAPT (ASA plus clopidogrel) VKA mono Single antiplatelet 1 CV death plus MI plus ischaemic stroke Fatal and non-fatal bleeding Lamberts M et al, Circulation 212;126:

8 Treating AF with Concomitant ACS Is a Balancing Act Thromboembolic risk Patients with ACS and AF are at risk of both a second myocardial infarction 1 and a stroke 2 Bleeding risk Risk of bleeding increases with the number of antithrombotic agents 3 1. Clessen BE et al, Neth Heart J 21;23: ; 2. Wolf P et al, Stroke 1991;21: ; 3. Lamberts M et al, Circulation 212;126:

9 Cumulative incidence (%) Cumulative incidence (%) The WOEST trial: Is ASA Necessary in Triple Therapy? Small-scale, open-label WOEST study (N=73) compared safety outcomes with triple (VKA plus clopidogrel plus ASA) vs dual (VKA plus clopidogrel): 69% of WOEST patients had AF Safety outcomes 4 3 Efficacy outcomes 4 3 VKA plus clopidogrel (dual ) (n=279) VKA plus clopidogrel plus ASA (triple ) (n=284) 2 1 * * 2 1 Power 23% 14% 31% * Any bleeding TIMI major TIMI major + minor Death MI Stroke Use of dual was associated with significantly lower rates of bleeding and overall mortality vs triple, with similar rates of thrombotic events *p<. Dewilde WJ et al, Lancet 213;381:

10 PIONEER AF-PCI: First Prospective Study in Patients with AF Undergoing PCI Taking a NOAC In an area of limited evidence, rivaroxaban is the first and currently only NOAC (versus VKA) to provide data from a dedicated RCT for patients with AF undergoing PCI

11 PIONEER AF-PCI Study Objective Study objective: To assess the safety of two rivaroxaban treatment strategies compared with the current standard of care in patients with paroxysmal, persistent or permanent NVAF undergoing PCI with stent placement Gibson CM et al, Am Heart J 21;169: e

12 Rivaroxaban is the First & Currently Only NOAC to Provide Data From a Dedicated RCT in AF-PCI Design: An open-label, randomized, controlled phase IIIb safety study Population: patients with 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 1 mg OD* # plus single antiplatelet Rivaroxaban 2. mg BID # plus DAPT VKA (INR 2. 3.) plus DAPT Rivaroxaban 1 mg OD* plus low-dose ASA VKA plus low-dose ASA DAPT duration (1 or 6 months) End of treatment (12 months) *CrCl 3 49 ml/min: 1 mg OD; # first dose hours after sheath removal; clopidogrel (7 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 1%); ASA (7 1 mg daily) plus clopidogrel (7 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 1%); first dose hours after sheath removal 1. Janssen Scientific Affairs, LLC [accessed 1 Oct 216]; 2. Gibson CM et al, Am Heart J 21;169: e; 3. Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

13 PIONEER AF-PCI Rationale for Dual and Triple Therapy Arms Study group 1 Study group 2 Study group 3 12 months 1, 6 or 12 months Up to 12 months 1, 6 or 12 months Up to 12 months Rivaroxaban 1 mg OD plus P2Y 12 Rivaroxaban 2. mg BID plus ASA plus P2Y 12 Rivaroxaban 1 mg OD plus ASA VKA plus ASA plus P2Y 12 VKA plus ASA The WOEST study showed oral anticoagulation in combination with clopidogrel was associated with significantly lower bleeding than triple with no increase in thrombotic events 1 This strategy has not yet been tested in a large study Where US guidelines recommend triple with a VKA, 2,3 recent European guidelines suggest that a NOAC may be used in triple and dual after PCI 4, Triple with a VKA plus DAPT followed by dual with VKA plus ASA is the standard of care for patients with AF and ACS, as recommended by US guidelines 2,3 1. Dewilde WJ et al, Lancet 213;381: ; 2. Amsterdam EA et al, Circulation 214;13:e344 e426; 3. O Gara PT et al, J Am Coll Cardiol 213;61:e78 e14; 4. Kirchhof P et al, Eur Heart J 216; doi:1.193/eurheartj/ehw21;. Heidbuchel H et al, Europace 21;17:

14 PIONEER AF-PCI Rationale for Anticoagulant Dose Selection Study group 1 Study group 2 Study group 3 12 months 1, 6 or 12 months Up to 12 months 1, 6 or 12 months Up to 12 months Rivaroxaban 1 mg OD plus P2Y 12 Rivaroxaban 2. mg BID plus ASA plus P2Y 12 Rivaroxaban 1 mg OD plus ASA VKA plus ASA plus P2Y 12 VKA plus ASA ATLAS ACS TIMI 46: rivaroxaban 1 mg OD was associated with lower bleeding rates than 2 mg OD when taken in combination with antiplatelets 1 J-ROCKET AF: rivaroxaban 1 mg OD showed similar efficacy and safety compared with warfarin, with a trend towards a lower incidence of stroke/se 2 The safety of the rivaroxaban 2. mg BID dose in combination with DAPT was demonstrated in the ATLAS ACS 2 TIMI 1 trial 3 A target INR of was selected because this is the recommended INR for stroke prevention in patients with AF 4 1. Mega JL et al, Lancet 29;374:29 38; 2. Hori M et al, Circ J 212;76: ; 3. Mega JL et al, N Engl J Med 212;366:9 19; 4. Kirchhof P et al, Eur Heart J 216; doi:1.193/eurheartj/ehw21

15 PIONEER AF-PCI Rationale for Selection of ASA or P2Y 12 Inhibitor Study group 1 Study group 2 Study group 3 12 months 1, 6 or 12 months Up to 12 months 1, 6 or 12 months Up to 12 months Rivaroxaban 1 mg OD plus P2Y 12 Rivaroxaban 2. mg BID plus ASA plus P2Y 12 Rivaroxaban 1 mg OD plus ASA VKA plus ASA plus P2Y 12 VKA plus ASA WOEST showed that combining an OAC (VKA) and clopidogrel was safe and effective 1 Prasugrel and ticagrelor were permitted at the discretion of the investigator as they are recommended in ACS guidelines 2,3 In Groups 2 and 3, a period of triple was followed by dual using an OAC plus low-dose ASA. ASA was selected over clopidogrel because it is used for longterm after PCI (guidelines from the ACCF/AHA/SCAI for the management of PCI recommend continuing with ASA indefinitely) 4 1. Dewilde WJ et al, Lancet 213;381: ; 2. Steg PG et al, Eur Heart J 212;33: ; 3. Roffi M et al, Eur Heart J 216;37:267 31; 4. Levine GN et al, Circulation 211;124:e74 e61

16 PIONEER AF-PCI Primary Outcomes Primary safety outcomes TIMI clinically significant bleeding: Composite of TIMI major bleeding, TIMI minor bleeding and bleeding requiring medical attention Time to the first event in the composite outcome Gibson CM et al, Am Heart J 21;169: e

17 PIONEER AF-PCI Secondary Outcomes Secondary safety and efficacy outcomes Components of the clinically significant bleeding outcome TIMI major TIMI minor Bleeding requiring medical attention Composite and components of major adverse CV events: CV death MI Stroke Stent thrombosis Time to the first event in the composite outcome or components Gibson CM et al, Am Heart J 21;169: e

18 PIONEER AF-PCI Key Inclusion and Exclusion Criteria Key inclusion criteria Medical history of paroxysmal, persistent or permanent NVAF Undergone PCI with stent placement for primary atherosclerotic disease INR 2. at randomization Key exclusion criteria Contraindication for anticoagulant or antiplatelet or unacceptable risk of bleeding* History of stroke or TIA CrCl <3 ml/min at screening *Including, but not limited to, platelet count <9,/µl at screening, history of ICH, 12-month history of clinically significant GI bleeding, non-vka-induced elevated PT at screening, anaemia of unknown cause with a haemoglobin level <1 g/dl (<6.21 mmol/l) or significant liver disease or liver function test abnormalities Janssen Scientific Affairs, LLC [accessed 14 Oct 216]

19 Early discontinuations (n) More Patients in the VKA Group Discontinued Treatment Early than in Either Rivaroxaban Group Primary reason for early discontinuation from treatment period Group 3 (VKA plus DAPT) (n=697) Group 2 (rivaroxaban 2. mg BID plus DAPT) (n=76) Group 1 (rivaroxaban 1 mg OD plus single antiplatelet) (n=696) ** ** 1 1 *p=.16; **p<.1 Early discontinuations (all-cause) Adverse event Bleeding adverse event Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194] Death * Non-compliance with study drug Cause of early discontinuation Physician decision ** ** Patient decision Early discontinuations were highest in the VKA plus DAPT group; discontinuation due to patient decision was significantly higher in this group vs both rivaroxaban groups. There were no patients lost to follow up.

20 Rivaroxaban is the First & Currently Only NOAC to Provide Data From a Dedicated RCT in AF-PCI Design: An open-label, randomized, controlled phase IIIb safety study Population: patients with 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 1 mg OD* # plus single antiplatelet Rivaroxaban 2. mg BID # plus DAPT VKA (INR 2. 3.) plus DAPT Rivaroxaban 1 mg OD* plus low-dose ASA VKA plus low-dose ASA 12 mos: 1% 1 mo: 16% 6 mos: 3% 12 mos: 49% 1 mo: 16% 6 mos: 3% 12 mos: 49% DAPT duration (1 or 6 months) End of treatment (12 months) *CrCl 3 49 ml/min: 1 mg OD; # first dose hours after sheath removal; clopidogrel (7 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 1%); ASA (7 1 mg daily) plus clopidogrel (7 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 1%); first dose hours after sheath removal 1. Janssen Scientific Affairs, LLC [accessed 1 Oct 216]; 2. Gibson CM et al, Am Heart J 21;169: e; 3. Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

21 TTR (%) Time in Therapeutic Range When Receiving VKA plus DAPT Was High Across All Participating Regions Average TTR (INR 2. 3.) was 6% TTR by region (safety analysis set) ,9 1, 7, 1,3 7,9 8,2 3,9 3,7 3,3 4, 4,4 4,1 6, 6,7 9,6 64,4 9, 8,1 12,7 1,9 16,9 All regions (N=61) North America (N=6) Latin America (N=43) Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa ,4 1,4 66,6 63,6 9,2 9,9 1, 13,1 14,2 Western Europe (N=237) Eastern Europe (N=276) Asia-Pacific (N=3) INR 3.2 INR 3. <3.2 INR 2. <3. INR 1.8 <2. INR <1.8

22 TIMI major, TIMI minor or bleeding requiring medical attention (%) Both Rivaroxaban Strategies was Associated With Significantly Improved Safety Rivaroxaban 1 mg OD plus single antiplatelet vs VKA plus DAPT: HR=.9; (9% CI.47.76); p<.1 Rivaroxaban 2. mg BID plus DAPT vs VKA plus DAPT: HR=.63 (9% CI..8); p< % 18.% 16.8% ARR 8.7% NNT= 12 ARR 9.9% NNT= Time (days) Group 3 (VKA plus DAPT) Group 2 (Rivaroxaban 2. mg BID plus DAPT) Group 1 (Rivaroxaban 1 mg OD plus single antiplatelet) Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194]

23 36-day Kaplan Meier estimate (%) Primary Safety Endpoint: Reduced with Rivaroxaban Strategies vs VKA 3 2 Group 3 (VKA plus DAPT) (n=697) Group 2 (rivaroxaban 2. mg BID plus DAPT) (n=76) Group 1 (rivaroxaban 1 mg OD plus single antiplatelet) (n=696) RRR RRR RRR 37% RRR 41% 33% 39% 2 1 ** ** * ** 1 Clinically significant # bleeding Composite endpoint TIMI major TIMI minor Bleeding requiring medical attention Components of composite endpoint Both rivaroxaban strategies associated with significant reduction in incidence of clinically significant bleeding vs the VKA plus DAPT strategy *p=.2 vs Group 3; **p<.1 vs Group 3; # composite of TIMI major bleeding, TIMI minor bleeding and bleeding requiring medical attention Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

24 Incidence (%) ISTH Major Bleeding Significantly Reduced with Rivaroxaban Strategies vs VKA 2 Group 3 (VKA plus DAPT) (n=697) Group 2 (rivaroxaban 2. mg BID plus DAPT (n=76) Group 1 (rivaroxaban 1 mg OD plus single antiplatelet) (n=696) * * * * * Major bleeding Clinically relevant non-major bleeding Minimal bleeding Incidence of fatal bleeding:.3% in group 1,.3% in group 2,.9% in group 3 Both rivaroxaban strategies associated with significant reduction in ISTH major and clinically relevant non-major bleeding vs the VKA plus DAPT strategy *p<. vs Group 3 Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194]

25 CV death, MI or stroke (%) Efficacy was Comparable Between All Three Treatment Strategies* Rivaroxaban 1 mg OD plus single antiplatelet vs VKA plus DAPT: HR=1.8; (9% CI ); p=.7 Rivaroxaban 2. mg BID plus DAPT vs VKA plus DAPT: HR=.93 (9% CI ); p= % 6.%.6% 4 Group 3 (VKA plus DAPT) Time (days) Group 2 (Rivaroxaban 2. mg BID plus DAPT) Group 1 (Rivaroxaban 1 mg OD plus single antiplatelet) *Trial not powered to definitively demonstrate either superiority or non-inferiority for efficacy endpoints Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

26 36-day Kaplan Meier estimate (%) Comparable Efficacy with Rivaroxaban Strategies vs VKA plus DAPT 7 Group 3 (VKA plus DAPT) (n=69) Group 2 (rivaroxaban 2. mg BID plus DAPT) (n=74) Group 1 (rivaroxaban 1 mg OD plus single antiplatelet) (n=694) Major adverse CV events* Composite endpoint CV death MI Stroke Stent thrombosis Components of composite endpoint and stent thrombosis Incidence of major adverse CV events was comparable between all three treatment strategies; however, the trial was not powered for efficacy *Composite of CV death, MI and stroke Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194]

27 (%)1 TIMI major, TIMI minor or bleeding requiring medical attention CV death, MI or stroke (%) Rivaroxaban Strategies Show Significantly Improved Safety and Comparable Efficacy vs VKA plus DAPT Clinically significant bleeding Time (days) 26.7% 18.% 16.8% Major adverse CV events Time (days) 6.% 6.%.6% Group 1 (Rivaroxaban 1 mg OD plus single antiplatelet) Group 2 (Rivaroxaban 2. mg BID plus DAPT) Group 3 (VKA plus DAPT) Both rivaroxaban strategies were associated with a significant reduction in incidence of the primary safety endpoint with comparable incidence of major adverse CV events vs the VKA plus DAPT strategy (trial not powered for efficacy) Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194]

28 Significantly Reduced Bleeding* with Rivaroxaban 1 mg Strategy Across Subgroups vs VKA plus DAPT Subgroup HR 9% CI HR (9% CI) p-value Age Sex <7 years <.1 7 years Male Female Type of stent Drug-eluting Bare metal Both Type of P2Y 12 inhibitor Clopidogrel <.1 Prasugrel Ticagrelor *Composite of TIMI major bleeding, TIMI minor bleeding and bleeding requiring medical attention Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194] No significant p-value for interaction,12,2, Favours 1 2 Favours rivaroxaban VKA

29 CV Bleeding Proportion of patients who were rehospitalized (%) Re-hospitalization Due to CV Events and Bleeding Were Both Reduced with the Rivaroxaban Strategies 3 2 Group 3 (VKA plus DAPT) Group 2 (Rivaroxaban 2. mg BID plus DAPT) Group 1 (Rivaroxaban 1 mg OD plus single antiplatelet) 28.4% 2.3% 2.3% CV 1 1.% 6.%.4% Bleeding Time (days) Group 1 vs Group 3: HR=.68; (9% CI.4.8); p<.1 ARR=8.1%; NNT=13 Group 2 vs Group 3: HR=.73 (9% CI.8.91); p=. ARR=8.1%; NNT=13 Group 1 vs Group 3: HR=.61; (9% CI.41.9); p=.12 ARR=4.%; NNT=2 Group 2 vs Group 3: HR=.1 (9% CI.34.77); p=.1 ARR=.1%; NNT=2 Adverse events leading to hospitalization were classified by consensus panel blinded to treatment group as potentially related to either bleeding, CV or other causes; Rehospitalizations do not include the index event and include the first rehospitalization after the index event. Gibson CM et al, Circulation 216; doi:1.1161/circulationaha

30 PIONEER AF-PCI Limitations Power Trial was not powered to definitively demonstrate either superiority or non-inferiority for efficacy endpoints Power to detect a 1% risk reduction for major adverse CV events was 11.4% Assuming a 9% power to detect a 1% relative difference between the treatment groups, a superiority trial would require 13,98 participants/arm DAPT stratification Stratification of patients in Groups 2 and 3 according to duration of DAPT (1, 6 or 12 months) was determined by the attending physician This resulted in imbalances in patient characteristics between treatment strategies within each stratum Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

31 PIONEER AF-PCI Summary of Study Results Both rivaroxaban dose strategies significantly reduced rates of clinically significant bleeding vs the VKA strategy Rivaroxaban 1 mg OD plus single antiplatelet: RRR=41% Rivaroxaban 2. mg BID plus DAPT: RRR=37% Rates of CV death, MI and stroke were comparable between all three groups; however, the trial was not powered to definitively demonstrate either superiority or non-inferiority for efficacy 36-day Kaplan Meier estimates for the composite endpoint were 6.% (Group 1),.6% (Group 2) and 6.% (Group 3) Post hoc analysis showed a reduction in mortality or recurrent hospitalization with both rivaroxaban strategies vs the VKA strategy Rivaroxaban 1 mg OD plus single antiplatelet: RRR=21% Rivaroxaban 2. mg BID plus DAPT: RRR=2% Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194]

32 PIONEER AF-PCI Conclusions Administration of either rivaroxaban 1 mg OD plus a single antiplatelet for 1 year, or rivaroxaban 2. mg BID plus 1, 6 or 12 months of DAPT reduced the risk of clinically significant bleeding compared with a standard VKA plus DAPT strategy Although the study was not powered to detect differences in efficacy endpoints, both rivaroxaban strategies demonstrated similar efficacy compared with a standard VKA plus DAPT strategy Both rivaroxaban strategies showed a reduced risk of recurrent hospitalization Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

33 Comparable Efficacy with Rivaroxaban Strategies vs VKA plus DAPT Endpoints HR 9% CI HR (9% CI) p-value Rivaroxaban 1 mg OD plus single antiplatelet vs VKA plus DAPT Major adverse CV events* CV death MI Stroke Stent thrombosis Rivaroxaban 2. mg BID plus DAPT vs VKA plus DAPT Major adverse CV events* CV death MI Stroke Stent thrombosis ,1 1 1 Incidence of major adverse CV events was Favours comparable between Favours all three rivaroxaban VKA treatment strategies; however the trial was not powered for efficacy *Composite of CV death, MI and stroke Gibson CM et al, New Engl J Med 216; doi: 1.16/NEJMoa161194

34 RE-DUAL PCI: dual antithrombotic with dabigatran after percutaneous coronary intervention in patients with atrial fibrillation Christopher P. Cannon Deepak L Bhatt, Jonas Oldgren, Gregory YH Lip, Stephen G Ellis, Takeshi Kimura, Michael Maeng, Bela Merkely, Uwe Zeymer, Savion Gropper, Matias Nordaby, Eva Kleine, Ruth Harper, Jenny Manassie, James L Januzzi, Jurrien M ten Berg, Philippe Gabriel Steg and Stefan H Hohnloser On behalf of the steering committee and RE-DUAL PCI investigators

35 Antithrombotic for atrial fibrillation and PCI NVAF PCI NVAF and PCI Anticoagulant Low shear stress thrombosis in left Anticoagulation atrium superior to antiplatelet ASA, acetylsalicylic acid; PCI, percutaneous coronary intervention Antiplatelet High shear stress thrombosis platelet mediated in the arteries Dual antiplatelet superior to ASA alone BOTH anticoagulant and dual antiplatelet triple = High bleeding risk?

36 Study Design: Multicenter, randomized, open-label trial following a PROBE design Patients with AF undergoing PCI with stenting R Dabigatran 1 mg BID + P2Y12 inhibitor Dabigatran 11 mg BID + P2Y12 inhibitor Mean duration of follow-up: ~14 months N=272 Randomiza tion 12 hours post-pci* Warfarin (INR 2. 3.) + P2Y12 inhibitor + ASA 6-month minimum treatment duration with visits every 3 months for the first year, then visits and telephone contact alternating every 3 months and a 1-month post-treatment visit Dabigatran (11 or 1 mg) P2Y12 inhibitor Warfarin P2Y12 inhibitor 1 month of ASA (BMS) 3 months of ASA (DES) *Study drug should be administered 6 hours after sheath removal and no later than 12 hrs post- PCI ( 72 hrs is preferable). PROBE, prospective, randomized, open, blinded end-point; R, randomization; BMS, bare metal stent; DES, drugeluting stent. ClinicalTrials.gov: NCT ; Cannon et al. Clin Cardiol 216

37 Patients were randomized based on age group and location Patients aged <8 years worldwide (<7 years in Japan), and patients aged 8 years in the USA Patients aged 8 years outside the USA ( 7 years in Japan) Dabigatran 1 mg dual n=763 Dabigatran 11 mg dual n=769 Warfarin triple Warfarin triple n=766 Dabigatran 11 mg dual n=212 n=21

38 Inclusion and exclusion criteria Key inclusion criteria Key exclusion criteria opatients aged 18 years with paroxysmal, persistent or permanent NVAF oacs successfully treated by PCI and stenting (BMS or DES) ostable CAD with 1 lesion eligible for PCI that was successfully treated by elective PCI and stenting (BMS or DES) ocardiogenic shock during current hospitalization ouse of fibrinolytics within 24 hrs of randomization that, in the investigator s opinion, will put patient at high risk of bleeding ostroke or major bleeding event within 1 month prior to screening visit osevere renal impairment (CrCl <3mL/min) ACS, acute coronary syndrome; CAD, coronary artery disease; CrCl, creatinine clearance

39 Study objective and design RE-DUAL PCI tests the safety and efficacy of two regimens of dual with dabigatran without aspirin vs triple with warfarin The primary endpoint was time to first ISTH major or clinically relevant non-major bleeding Formally tested and powered endpoints included: Non-inferiority of 11 mg and 1 mg dual groups on time to first ISTH major or clinically relevant non-major bleeding event. Non-inferiority of both dual groups combined on time to first event of death, thromboembolic event (MI, stroke, systemic embolism) or unplanned revascularization Superiority testing of the bleeding endpoints 1% of outcome events were independently adjudicated by blinded external committee ISTH, International Society of Thrombosis and Haemostasis; MI, myocardial infarction Noninferiority testing (margin 1.38)

40 Baseline characteristics Dabiga tran 11 mg dual (n=981 ) Warfarin triple (n=981) Dabigatran 1 mg dual (n=763) Age, years, mean Corresponding Warfarin triple (n=764) 8 (US, ROW), 7 (Japan), % <8 (US, ROW), <7 (Japan), % Male, % Baseline CrCl, ml/min, mean Diabetes mellitus, % CHA 2 DS 2 VASc score (mean) Modified HAS-BLED score at baseline (mean) ACS indication for PCI, % DES only, % ROW, rest of world

41 Probability of event (%) Primary Endpoint: Time to first ISTH major or clinically relevant non-major bleeding event 34 3 HR:.2 (9% CI:.42.63) Non-inferiority P<.1 P<.1 Warfarin triple 34 3 HR:.72 (9% CI:.8.88) Non-inferiority P<.1 P=.2 Warfarin triple Dabigatran 11 mg dual Dabigatran 1 mg dual Time to first event (days) Time to first event (days)

42 Primary endpoint: ISTH major or clinically relevant non-major bleeding event Patients with outcome event (%) HR:.2 (9% CI:.42.63) P<.1 ARR: 11.% 1.4 % 26.9 % HR:.72 (9% CI:.8.88) P=.2 ARR:.% 2.2 % 2.7 % Dabigatran 11 mg dual (n=981) Warfarin triple (n=981) Dabigatran 1 mg dual (n=763) Warfarin triple (n=764) Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=.). ARR, absolute risk reduction

43 Patients with outcome event (%) Rates of ISTH major bleeding HR:.2 (9% CI:.37.74) P=.3 ARR: 4.2%.% 9.2% ARR: 2.8% HR:.64 (9% CI:.43.94) P=.22.6% 8.4 % Dabigatran 11 mg dual (n=981) Warfarin triple (n=981) Dabigatran 1 mg dual (n=763) Warfarin triple (n=764) Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=.). ISTH major bleeding definition: fatal, critical organ (including intracranial haemorrhage), clinically overt bleeding with fall in Hb 2 g/dl. Hb, haemoglobin

44 Patients with outcome event (%) Rates of TIMI major or minor bleeding HR:.41 (9% CI:.26.63) P<.1 ARR: 4% 3. % 7. % HR:.3 (9% CI:.33.8) P=.9 ARR: 2.8% 3. % 6.3 % 1 Dabigatran 11 mg dual (n=981) Warfarin triple (n=981) Dabigatran 1 mg dual (n=763) Warfarin triple (n=764) Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=.). TIMI major bleeding definition: fatal, intracranial haemorrhage, clinically overt bleeding with fall in Hb g/dl; TIMI minor bleeding definition: clinically overt bleeding (including imaging), resulting in Hb drop of 3 to > g/dl. TIMI, thrombolysis in

45 Patients with outcome event (%) Rates of TIMI major bleeding HR:.37 (9% CI:.2.68) P=.1 HR:.1 (9% CI:.28.93) P= ARR: 2.4% 1.4% 3.8% ARR: 1.8% 2.1% 3.9 % Dabigatran 11 mg dual (n=981) Warfarin triple (n=981) Dabigatran 1 mg dual (n=763) Warfarin triple (n=764) Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=.). TIMI major bleeding definition: fatal, intracranial haemorrhage, clinically overt bleeding with fall in Hb g/dl.

46 Patients with outcome event (%) Rate of intracranial haemorrhage 1. 1 HR:.3 (9% CI:.8 1.7) P= % HR:.12 (9% CI:.2.98) P= %. ARR:.7%.3 % Dabigatran 11 mg dual (n=981) Warfarin triple (n=981) ARR:.9%.1 % Dabigatran 1 mg dual (n=763) Warfarin triple (n=764) Wald two-sided P value from (stratified) Cox proportionalhazard model (alpha=.)

47 Patients with outcome event (%) Time to death or thromboembolic event, or unplanned revascularization Probability of event (%) HR: 1.4 (9% CI: ) Non-inferiority P=.47 Dabigatran (combined dose) dual (n=1744) Warfarin triple (n=981) Non-inferiority P value is one sided (alpha=.2). Results presented are Step 3 of hierarchical testing procedure, testing non-inferiority of dabigatran dual (combined doses) to warfarin triple in death or thromboembolic event and unplanned revascularization Dabigatran (combined doses) dual Time to first event (days) Warfari n triple

48 Additional individual thromboembolic endpoints Dabigatran 11 mg dual (n=981) n (%) Warfarin triple (n=981) n (%) D11 DT vs warfarin TT HR (9% CI) P value Dabigatran 1 mg dual (n=763) n (%) Warfarin triple (n=764) n (%) D1 DT vs warfarin TT HR (9% CI) P value All-cause death (.6) 48 (4.9) 1.12 ( ).6 3 (3.9) 3 (4.6).83 ( ).44 Stroke 17 (1.7) 13 (1.3) Unplanned 76 (7.7) 69 revascularizati (7.) on 1.3 ( ) 1.9 ( ).48 9 (1.2).61 1 (6.7) 8 (1.) 1.9 ( ) 2 (6.8).96 ( ).8.83 MI 44 (4.) 29 (3.) 1.1 ( ).9 26 (3.4) 22 (2.9) 1.16 ( ).61 Stent thrombosis 1 (1.) 8 (.8) 1.86 ( ).1 7 (.9) 7 (.9).99 ( ).98

49 Subgroup analysis: age and ticagrelor use at baseline Time to first ISTH MBE or CRNMBE Pts with Ticagrelor use at baseline (12% Pts) Age Interaction Pts with Interaction P value Pts (n) event (n) P value HR (9% CI) Pts (n) event (%) HR (9% CI) Elderly No D11-DT Not. eval* P=.69 Warfarin- TT 76 D1- DT Warfarin- TT D11- DT Nonelderly Warfarin-TT D1-DT P= P=.3 Warfarin TT Favours dabigatran dual Favours warfarin triple 1 1 Missing/not applicable categories.1not shown and.1 removed prior to calculation of interaction P values..1 *Not evaluable:.1 for age-stratified model, the interaction P value is not derived. For the comparison 1. with D1-DT, elderly patients outside the USA are excluded. 1.Age category is determined IVRS, interactive voice response system; MBE, major bleeding event; CRNMBE, clinically relevant non-major bleeding event; Pts, patients Ye s Favours dabigatran dual Favours warfarin triple 1 1

50 Conclusions In patients with AF who have undergone PCI: Dual with dabigatran and a P2Y12 antagonist significantly reduced the risk of bleeding versus warfarin triple, with noninferiority for overall thromboembolic events Absolute risk reductions with dabigatran dual were 11.% and.% in ISTH major or clinically relevant non-major bleeding at the 11 mg and 1 mg doses, respectively, compared with warfarin triple These dabigatran dual regimens, using doses approved worldwide for stroke prevention, offer clinicians two additional options for managing Afib patients post-pci

51 Dual antiplatelet duration in patients with indication for oral anticoagulation 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 >6 7%. 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 1 mg q.d. may be used instead of rivaroxaban 2 mg q.d. The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic with aspirin and OAC. IIa IIb III C B C ESC Focused Update on DAPT in Coronary Artery Disease, developed in collaboration with EACTS (European Heart Journal doi:1.193/eurheartj/ehx419)

52 Algorithm for dual antiplatelet (DAPT) in patients with an indication for oral anticoagulation undergoing percutaneous coronary intervention (PCI) ESC Focused Update on DAPT in Coronary Artery Disease, developed in collaboration with EACTS (European Heart Journal doi:1.193/eurheartj/ehx419)

53 Strategies to avoid bleeding complications in patients treated with oral anticoagulant Assess ischaemic and bleeding risks using validated risk predictors (e.g. CHA 2 DS 2 - VASc, ABC, HAS-BLED) with a focus on modifiable risk factors. Keep triple duration as short as possible; dual after PCI (oral anticoagulant and clopidogrel) to be considered instead of triple. Consider the use of NOACs instead of VKA when NOACs are not contraindicated. Consider a target INR in the lower part of the recommended target range and maximize time in therapeutic range (i.e. >6 7%) when VKA is used. Consider the lower NOAC regimen tested in approval studies and apply other NOAC regimens based on drug-specific criteria for drug accumulation. Clopidogrel is the P2Y 12 inhibitor of choice. Use low-dose ( 1 mg daily) aspirin. Routine use of PPIs ESC Focused Update on DAPT in Coronary Artery Disease, developed in collaboration with EACTS (European Heart Journal doi:1.193/eurheartj/ehx419)

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