Dual anti platelet therapy- Comprehensive.pptx

Dual anti platelet therapy

1. Structure of Presentation 1 Background & Introduction 2 3 4 5 6 7 Antiplatelet agents - Duration of DAPT Anticoagulant Therapy  Individualizing Treatment Decisions  Future directions  Conclusion

2. Atherosclerosis, and its attendant complication of thrombosis (atherothrombosis), is the leading cause of CV mortality and morbidity. Antiplatelet therapy post PCI is a must. Aspirin is imperfect, relatively weak (COX-1 inhibitor), and associated with GI bleeding complications. For >10 years, the mainstay of antiplatelet therapy post PCI has been the combination of aspirin, and ADP-receptor antagonist clopidogrel, although newer P2Y12 antagonist has evolved. The 1 year duration of dual antiplatelet therapy (DAPT) post-PCI with drug eluting stents is based on “anecdotal historical data”. Miyazaki Y, Serruys PW et al. Nat Rev Cardiol. 2017 Feb 9. BACKGROUND

3. INITIAL CARE OF ACS 1. CAREFUL PATIENT SELECTION IS A MUST – 2. Based on -- Risk -- based Triaging for the timing of Invasive strategy. 3. “Risk Based Triage “ --Age , Gender , BP, HR,ECG-STEMI/NSTEMI, Lab, Imaging, Ischemic Vs Bleeding Risk ,Past History of Bleeding, Low Body Wt , Renal Insufficiency 4. An intensive approach to reduce thrombotic complications with aggressive use of antiplatelet and antithrombotic preferred. 5. Early Invasive approach favoured for high risk pts. N E J M – Feb 4, 2021 ACS is known to have a broad clinical spectrum with large variations in the incidence of in-hospital mortality.

4. Antiplatelet agents The ever-growing maze of oral antiplatelet therapy-- Current clinical practice of DAPT-- ASA , Clopidogrel, Ticagrelor , Prasugrel

5. Compared with ASA monotherapy, DAPT for 12 months reduces the risk of recurrent major ischemic events in patients with ACS. However, bleeding risk with DAPT is still a major concern.--- more important than ischemic risk in predicting clinical outcomes after PCI. Furthermore, with advanced DES and improved skills for optimal stent implantation, DAPT duration shortening is recommended. P2Y12 inhibitor monotherapy is suggested as an alternative antiplatelet strategy in patients undergoing PCI. Several clinical trials have been performed to compare the efficacy and safety of P2Y12 monotherapy with conventional DAPT after PCI. DAPT is a cornerstone of therapy for patients with ACS

6. Current clinical practice of DAPT Compelling evidence from RCT have confirmed the efficacy of DAPT , with aspirin and a P2Y12 inhibitor(clopidogrel*, Prasugrel# , ^Ticagrelor ), in reducing the risk of c ardiovascular events particularly among patients with ACS and/or those undergoing PCI. * CURE –CLOPIDOGREL; # TRITON-TIMI- PRASUGREL ;^ PLATO- TICAGRELOR Ref- Oxford Medicine ; European Society of Cardiology; date: 13 November 2019

7. DAPT- TRIAL DES PCI : MACCE for DAPT vs. placebo: 4.3% vs. 5.9%, p < 0.001; MI: 2.1% vs. 4.1%, p < 0.001; stent thrombosis: 0.4% vs. 1.4%, p < 0.001; all-cause mortality: 2.0% vs. 1.5%, p = 0.05; GUSTO moderate/severe bleeding: 2.5% vs. 1.6%, p = 0.001 BMS PCI : MACCE for DAPT vs. placebo: 4.0% vs. 4.7%, p = 0.72; MI: 2.7% vs. 3.1%, p = 0.74; stent thrombosis: 0.5% vs. 1.1%, p = 0.24; all-cause mortality: 1% vs. 1.2%, p = 0.83 Trial design: Patients undergoing DES/BMS PCI, no ischemic/bleeding complications, and with documented compliance at 1 year, were randomized to receive another 18 months of dual antiplatelet therapy (DAPT) or placebo. Patients were followed for 18 months. Results Conclusions Mauri L, et al. N Engl J Med 2014;371:2155-66 DAPT DES PCI (n = 5,020) MACCE Prolonged DAPT ~30 months following DES PCI results in lower stent thrombosis/recurrent MIs compared with 12-month DAPT, although bleeding and all-cause mortality were higher; BMS subset showed a less impressive treatment effect Unclear to what extent this trial will immediately impact clinical practice; further follow-up and data from other ongoing trials are awaited Placebo DES PCI (n = 4,941) % (p < 0.001) % (p = 0.72) DAPT BMS PCI (n = 842) Placebo BMS PCI (n = 845)

8. JACC 2018; 72( 23):2915-31 "The DAPT prescribers is confronted with a number of challenges that essentially include, but are not limited to, selecting the P2Y12 inhibitor and determining the optimal duration of DAPT with the scope of minimizing the risk of ischemic and bleeding complications in light of each patient's clinical characteristic and circumstance Use of risk scores as guidance for the duration of DAPT JACC Guideline Comparison

9. www.escardio.org/guidelines 2017 ESC Focused Update on DAPT in Coronary Artery Disease, developed in collaboration with EACTS (European Heart Journal 2017 - doi:10.1093/eurheartj/ehx419) Risk scores validated for DAPT duration decision-making s PRECISE-DAPT score DAPT score Time of use At the time of coronary stenting After 12 months of uneventful DAPT DAPT duration strategies assessed Short DAPT (3–6 months) vs. Standard/long DAPT (12–24 months) Standard DAPT (12 months) vs. Long DAPT (30 months) Score calculation HB ≥211-5 11 10-5 ≤10 Age ≥75 65 to <75 <65 Cigarette smoking Diabetes mellitus MI at presentation Prior PCI or prior MI Paclitaxel-eluting stent Stent diameter <3 mm CHF or LVEF <30% Vein graft stent –2 pt WBC ≤5 8 1012141618 ≥20 –1 pt pt +1 pt Age ≤50 60 70 80 ≥90 +1 pt +1 pt CrCI ≥100 80 60 40 20 0 +1 pt +1 pt +1 pt Prior Bleeding No Yes +2 pt +2 pt Score 0 2 4 6 8 1012141618202224262830 Points Score range to 100 points – 2 to 10 points Decision making cut-off suggested Score ≥25  Short DAPT Score <25  Standard/long DAPT Score ≥2  Long DAPT Score <2  Standard DAPT Calculator www.precisedaptscore.com www.daptstudy.org

10. Absolute Risk Difference Effect of Long (12-24 mo.) vs. short (3-6 mo.) DAPT ACS subgroup 6% 6% 4% 4% 2% 0% 2% Benefit Harm 8% Net Effect 8% Very Low Ischemia (MI, Def. ST, Stroke, TVR) Bleeding (TIMI major or minor) Low PRECISE DAPT Moderate <25 High ≥ 25 NET HARM LONG DAPT Ischemia: +1.54% p= 0.61 Bleeding: +2.61% p=0.032 NNT=38 NET BENEFIT OF LONG DAPT Ischemia: – 4.13% p< 0.001 NNT=24 Bleeding: +0.14% p=0.80 Lancet. 2017 Mar 11;389(10073):1025-1034. doi: 10.1016/S0140-6736(17)30397-5.

11. Ischemia vs Bleeding 1. Current guidelines recommend at least 6-12 months of DAPT depending on indication of PCI. 2. Both ischemic and bleeding complications increase mortality post PCI. 3. With the advent of newer-generation stents with lower ischemic complications, a 1-3 months course of DAPT followed by P2Y12 inhibitor monotherapy was hypothesized to be as effective as standard of care therapy with the potential benefit of reducing bleeding complications. 1. Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. Journal of the American College of Cardiology. 2018;72(23, Part A):2915-31. Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA, Botelho RV, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. Jama. 2013;310(23):2510-22.

12. POST ACS MANAGEMENT – INCREASINGLY COMPLEX DUE TO RAPIDLY CHANGING GUIDELINES A Balancing Act CLINICAL BENEFIT OF ANTITHROMBOTICS- REDUCES MORTALITY BLEEDING COMPLICATIONS OF ANTITHROMBOTICS – INCREASES MORTALITY

13. www.escardio.org/guidelines 2017 ESC Focused Update on DAPT in Coronary Artery Disease, developed in collaboration with EACTS (European Heart Journal 2017 - doi:10.1093/eurheartj/ehx419) High-risk features of recurrent ischaemic events Prior stent thrombosis on adequate antiplatelet therapy. Stenting of the last remaining patent coronary artery. Diffuse multivessel disease especially in diabetic patients. Chronic kidney disease (i.e. creatinine clearance <60 mL/min). At least three stents implanted. At least three lesions treated. Bifurcation with two stents implanted. Total stent length >60 mm. Treatment of a chronic total occlusion. Patient - related Procedure - related

14. RISK HIGHER LOWER ACS Event In the first 30 days after an ACS event, the benefits of intensive antithrombotic therapy generally outweigh the increased risk of bleeding. However, this benefit dissipates with additional time after the ACS event, favoring a therapeutic approach that considers the risks of both bleeding and thrombosis. BLEEDING THROMBOSIS Risks of Thrombosis and Bleeding after an ACS Day 30

15. Clopidogrel and Ticagrelor: the Romulus and Remus of Antiplatelet Therapy?

16. Newer ADP blockers (Prasugrel & Ticagrelor ) address limitations of clopidogrel- Advantages – Faster onset of action M ore predictable and more potent platelet inhibition, fewer drug–drug interactions. Current clinical practice of DAPT

17. Issues with Clopidogrel Onset: 4-6 hours (after loading dose with 8 x maintenance dose) Offset: 5-7 days . Variable response: 25-30% of patients achieve less than 25% inhibition of platelet activity. Binds irreversibly to P2Y 12 receptor Clopidogrel requires hepatic conversion to its active form through a pathway that is inefficient in 25% of white and 60% of Asian patients , and efficacy is uncertain in these patients. Clopidogrel and Ticagrelor: the Romulus and Remus of Antiplatelet Therapy? ( N Engl J Med 2020; 383:207-217) Gurbel, PA, et al, Circulation 2003; 107:2908-2913;Laine L, Hennekens CH: Am J Gastro. Published online 11/13/09

18. 1. G uidelines(US & EUROPE) favor more potent, next-generation P2Y12 inhibitors( ticagrelor and prasugrel). 2. I n head-to-head comparisons, clinical trials have shown the superiority of these next-generation inhibitors over clopidogrel in reducing ischemic events. Current clinical practice of DAPT

19. 1. Ticagrelor was ranked as possibly the most effective strategy for the prevention of CV mortality or all- cause mortality. 2. Prasugrel ranked the most effective intervention for definite or probable Stent Thrombosis . 3. Conversely, for major bleeding, clopidogrel was ranked as the safest strategy. Ranking of Treatment Strategies Circulation. 2020;142:150–160. DOI: 10.1161/CIRCULATIONAHA.120.046786 Network Meta-Analysis of 52816 Patients From 12 Randomized Trials-

20. Problem with ASA + P2Y12 inhibitor R ecent RCTs -- ASA has limited additional clinical benefits when associated with P2Y12 inhibitors. T he safety and efficacy of early ASA discontinuation with P2Y12 inhibitor as single antiplatelet therapy continuation, as compared to a strategy of sustained DAPT following ACS or PCI in a meta-analysis( 40,621 patients ), demonstrated that the early discontinuation of aspirin, with or without concomitant OAC treatment, was associated with a significant reduction in bleeding events without detectable impacts on mortality or ischemic risk. J. Clin. Med. 2021, 10, 177. https://doi.org/10.3390/jcm10020177

21. >18,000 PATIENTS WITH ACS STUDIED IN PLATO 1 >45,000 PATIENTS WITH ACS STUDIED IN REAL-WORLD REGISTRY (SWEDHEART )THAT CONFIRMED PLATO OUTCOMES 2,3 >21,000 PATIENTS WITH PRIOR MI STUDIED IN PEGASUS 4 >19,000 HIGH-RISK PATIENTS WITH CAD+T2D WITHOUT HISTORY OF MI OR STROKE STUDIED IN THEMIS 5 R ecent meta-analysis of 12 trials found that of the three P2Y12 receptor inhibitors, only ticagrelor was associated with decreased mortality. ( Circulation 2020;142:150–160. ) Why Ticagrelor- Evaluated in > 100000 Pts References: 1.  (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. .  N Engl J Med.  2009;361(11):1045-1057 and Supplementary Appendix. 3. Sahlén A, Varenhorst C, Lagerqvist B, et al.: experiences from SWEDEHEART registry.  Eur Heart J.  2016;37(44):3335-3342. 4. Bonaca MP, Bhatt DL, Cohen M, et al, for the PEGASUS-TIMI 54 .  N Engl J Med.  2015;372(19):1791-1800. 5. Steg PG, Bhatt DL, Simon T, et al; N Engl J Med.  2019;381(14):1309-1320.

22. Ticagrelor Is the Right Choice! 10 YEARS SINCE PLATO! 6-12 MONTH EXPOSURE Ticagrelor 180 mg LD, then 90 mg BID maintenance; (additional 90 mg pre-PCI) Clopidogrel If pretreated, no additional LD; if naive, standard 300 mg LD, then 75 mg qd maintenance; (additional 300 mg allowed pre-PCI NSTEMI-ACS (moderate-to-high risk), STEMI (if primary PCI) ; Clopidogrel-treated or -naive; randomized within 24 hours of index event (N = 18,624) Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding The treatment groups were well balanced with regard to baseline characteristics as well as non study medications and procedures. ACS diagnoses included 37.5% of STEMI, 42.9% with NSTEMI, and 16.6% with unstable angina.

23. PLATO : Conclusion In patients with an ACS with or without ST-segment elevation, treatment with ticagrelor compared with clopidogrel •Reduced the primary endpoint of death form vascular causes, MI or stroke. •Reduced the rate of all cause mortality. •Without an increase in the rate of overall major bleeding (increase in non CABG related major bleeding with ticagrelor) – SIMILAR RESULTS WERE ALSO OBSERVED ---- •in patients identified by the investigator at randomization as requiring invasive management via PCI/CABG (72% of the whole study cohort). •In patients with a diagnosis of STEMI (41% of the whole study cohort). •In patients identified by the investigator at randomization as requiring non-invasive, medical management (28% of the whole study cohort). Wallentin et al . New EngJ Med 2009; 361(11): 1045-1057

24. Ticagrelor More Effective Than Clopidogrel in ACS-With No Extra Bleeding PLATO CONCLUSION -- 1. At 12 months, the primary efficacy endpoint, (composite of CV death, MI, or stroke) occurred significantly less often in the ticagrelor group compared with the clopidogrel group. 2. The reduction was driven by decreased rates of CV death and MI; Stroke rates for the 2 treatments were similar. 3. In addition, ticagrelor reduced the incidence of definite or probable stent thrombosis in patients who received stents. 4. Rates of major bleeding as well as life-threatening and fatal bleeding were similar between the ticagrelor and clopidogrel groups.   SUPERIOR TO CLOPIDOGREL: 18,000 PATIENTS PROVE IT Wallentin et al . New EngJ Med 2009; 361(11): 1045-1057

25. 5. For every 1,000 ACS patients treated, switching 54 from clopidogrel to ticagrelor for 1 year would prevent 1 CV death, MI, or stroke.  6. T he finding of a reduction in all-cause mortality (22% relative reduction, 1.4% absolute reduction) is unique to this study. 7 . A dvantage of ticagrelor was seen across a wide range of subgroups and regardless of whether patients received invasive or medical management or whether PCI patients were given the currently recommended higher loading dose of clopidogrel. 8 . Reversibility may make any bleeding that does occur easier to treat as well as facilitate management of patients on antiplatelet therapy who will be undergoing subsequent procedures. Ticagrelor More Effective Than Clopidogrel in ACS-With No Extra Bleeding PLATO CONCLUSION -- SUPERIOR TO CLOPIDOGREL: 18,000 PATIENTS PROVE IT

26. Background: Global Leaders – CLINICAL TRIAL 1. Ticagrelor, a potent and consistent antiplatelet drug, may be a better foundation as monotherapy for long term antiplatelet therapy compared to ASA in at-risk patients 2. Avoid the higher risk of bleeding potentially associated with adding ASA (even low dose) to Ticagrelor 3. Maintain the clinical benefits of potent platelet inhibition after PCI, beyond the initial period of high stent thrombosis risk (30 days) 4. The trial may pave the way for future studies of Ticagrelor as a single foundation therapy

27. 30 d 90 d 120 d 1 year 1.5 years 2 years ECG discharge ECG 90D ECG 2Y ASA 75-100 mg/d Ticagrelor 90 mg bid Clopidogrel 75 mg/d “All-comers” PCI population N = 15,991 1:1 Randomization, open-label design, 130 centers worldwide Ticagrelor 90 mg bid ASA 75-100 mg/d ASA 75-100 mg/d Bivalirudin -supported BioMatrix DES by default ⦁Any type of lesions: Left main, SVG, CTO bifurcation, ISR, etc. ⦁Unrestricted use of DES ( number,length ) 4 Experimental strategy ACS + Stable CAD Reference strategy ACS: UA+NSTEMI+STEMI Stable CAD

28. GLOBAL LEADERS - CONCLUSION GLOBAL LEADERS - 1-month ASA plus ticagrelor followed by 23 months ticagrelor monotherapy vs. 12 months DAPT followed by 12 months ASA monotherapy was associated with similar death or Q wave MI at 2 years and no difference in BARC 3–5 bleeding. B enefit s of ASA withdrawal at 1-month from the PCI seen also in the acute setting of STEMI. Despite the high ischemic burden, this strategy allowed to reduce by half the bleeding, without an increase of ischemic complications. European Heart Journal (2021) 00, 1–2

29. Ticagrelor with or without ASA in high-risk patients after PCI ( TWILIGHT trial) Why this study – the rationale/objective? Monotherapy with a P2Y 12  inhibitor after a short period of (DAPT) is an emerging approach to reduce the risk of bleeding after (PCI). ACS Pts or who have undergone PCI, the risk of thrombotic events is lower with DAPT than with aspirin alone. The use of more potent P2Y 12  inhibitors or extension of the duration of DAPT lowers residual ischemic risk among such Pts but increases bleeding. Hence, the TWILIGHT was designed to test the hypothesis that in Pts undergoing PCI who are at high risk for ischemic or hemorrhagic complications & who have completed a 3-month course of DAPT with ticagrelor plus aspirin, continued treatment with ticagrelor monotherapy(90MG bd) would be superior to ticagrelor plus aspirin (81-100mg /d )with respect to clinically relevant bleeding and would not lead to ischemic harm.

30. Adherence to ticagrelor treatment at 1 year was similar in both group The incidence of BARC type 3 or 5 bleeding was 1.0% in the ticagrelor/placebo group and 2.0% in the group the ticagrelor/aspirin group . The incidence of death from any cause was similar in both groups as were the incidences of MI  and definite or probable stent thrombosis . Ischemic stroke was found in 0.5% of patients in the ticagrelor/placebo group and in 0.2% in the ticagrelor/aspirin group. TWILIGHT - What is the main result?

31. a ) Ticagrelor monotherapy was associated with a 44% lower risk of BARC type 2, 3, or 5 bleeding over 1 year than ticagrelor plus aspirin. b) There was no evidence of a higher risk of death, MI, or stroke among patients who received ticagrelor monotherapy than among those who received ticagrelor plus aspirin. c) The treatment effect with respect to both bleeding and ischemic endpoints was consistent across subgroups. d) This means that a transition to an antiplatelet strategy of treatment with ticagrelor alone after a 3- month course of DAPT in high-risk patients who had undergone PCI provided a clinical benefit of less bleeding without ischemic harm T he relevance for clinical practice– TWILIGHT

32. Twilight --Drop ASA? Mehran et al. NEJM 2019 HR 0.56 (0.45 – 0.68) HR 0.99 (0.78 – 1.25) Dropping aspirin from a DAPT regimen and continuing with ticagrelor therapy alone is effective in reducing bleeding after PCI.

33. Comment – TWILIGHT –ACS The salient finding consists in the halving of the composite bleeding outcome in ACS patients (3.6% vs. 7.6%, P< 0.001), without negative impact on the composite ischemic event (4.3% vs. 4.4%, P=0.84).

34. Recent trials ( GLOBAL LEADERS and TWILIGHT for Ticagrelor )- P2Y12 inhibitor monotherapy is noninferior or superior to conventional DAPT for ischemic events at 1-year follow-up after PCI, and the risk of major bleeding was similar or lower in the P2Y12 inhibitor monotherapy group. These clinical trials showed that early aspirin-free strategy with P2Y12 inhibitor monotherapy might be an alternative after PCI. Early Aspirin free strategy in Post – PCI J. Clin. Med. 2020, 9, 1657

35. 12-month outcomes of the SIDNEY (Single Versus Dual Antiplatelet Therapy) collaboration 1. T icagrelor monotherapy was compared with DAPT after coronary stenting. 2. The dataset available for the present analysis stemmed from the GLASSY and the TWILIGHT trials. 3. Individual data from approx. 15,000 patients were pooled. 4. The analysis of the primary endpoint revealed a 44% relative risk reduction in terms of BARC type 3 or 5 bleeding with ticagrelor monotherapy versus DAPT. 5. The analysis of the coprimary efficacy endpoint, a composite of all-cause death, myocardial infarction, and stroke, displayed no excess of ischemic events with ticagrelor monotherapy; 6. O n the contrary, ticagrelor monotherapy was associated with significantly lower mortality compared with DAPT. J A C C : C A R D I O V A S C U L A R I N T E R V E N T IO N S V O L . 1 4 , N O . 4 , FEB 22, 2 0 2 1

36. Risk for BARC Type 3 to 5 Bleeding and All-Cause Death After 12 Months With Ticagrelor Monotherapy Versus DAPT J A C C : C A R D I O V A S C U L A R I N T E R V E N T IO N S V O L . 1 4 , N O . 4 , FEB 22, 2 0 2 1

37. SIDNEY- CONCLUSION 1. The reduction of bleeding events without a corresponding increase of ischemic events with a strategy of Ticagrelor monotherapy compared with DAPT represents a finding of utmost importance. 2. SIDNEY collaboration lends support to superior safety and comparable efficacy of ticagrelor monotherapy compared with ticagrelor or clopidogrel plus aspirin after coronary stenting . 3. C oncerns exist about the application of an aspirin-free regimen for clopidogrel, because of the relevant proportion of patients with low response to clopidogrel and the risk of exposing them to insufficient protection if aspirin is omitted from therapy. J A C C : C A R D I O V A S C U L A R I N T E R V E N T IO N S V O L . 1 4 , N O . 4 , FEB 22, 2 0 2 1

38. THEMIS &POST – THEMIS The FDA has approved a new indication for Ticagrelor 90 mg, following the results of the THALES trial, in patients with acute ischemic stroke or high-risk TIA: ---- Ticagrelor is indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤5) or high risk transient ischemic attack (TIA). THALES suggests patients with high risk transient ischemic attack or mild-to-moderate ischemic stroke have a lower risk of death and subsequent stroke when treated with combination ticagrelor and aspirin than with aspirin alone. THEMIS - By enrolling 19,271 patients with diabetes and established coronary artery disease but no history of myocardial infarction or stroke, ticagrelor has been shown to reduce MACE as compared to placebo.

39. How should the ticagrelor be used? The point after the TWILIGHT and THEMIS-PCI studies The TWILIGHT study--- in high-risk patients who completed 3 months of DAPT after coronary angioplasty, ticagrelor monotherapy is associated with a 44% reduction in the risk of clinically relevant bleeding in the absence of an increase in the ischaemic risk. THEMIS – PCI -Subgroup of diabetic patients, with no history of heart attack or stroke, but with history of percutaneous revascularization, the addition of ticagrelor to the ASA is associated with a 15% reduction in the risk of a new ischaemic event with an improvement of the net clinical benefit and therefore may be an advisable strategy in this category of patient The use of ticagrelor was associated with a reduced number of strokes and myocardial infarctions including those with STEMI on which had an incidence of 0.3% and 0.9%, respectively in the ticagrelor group and in the placebo group after the first 3 months After 3 months , a ticagrelor-based monotherapy strategy that provides for the suspension of the ASA may represent a valid option, especially in those patients in whom there is fear that the bleeding risk is prevalent. European Heart Journal Supplements (2020) 22 (Supplement L), L72–L76

40. In the TICO trial, 3056 patients with ACS undergoing PCI were randomized 1:1 to Ticagrelor monotherapy after 3 months of DAPT vs. standard DAPT (aspirin + ticagrelor for 12 months). Ticagrelor monotherapy after 3 months was associated with a significant reduction in the composite primary endpoint of 1- year net adverse clinical events (2% absolute reduction). Randomized Evaluation Of Ticagrelor Monotherapy After 3- month Dual-antiplatelet Therapy In ACS -The TICO trial European Heart Journal (2021) 00, 1–2

41. Conclusions- TICO STEMI This is the first report assessing the feasibility of the ticagrelor monotherapy after short-term DAPT for STEMI patients with DES. Among patients with STEMI treated with ultrathin bioresorbable polymer sirolimus-eluting stents , Ticagrelor monotherapy after 3-month DAPT , compared with ticagrelor-based 12-month DAPT, resulted in a reduced risk of major bleeding. As for MACCE, there were no significant differences between the two treatment groups, without significant interaction with clinical presentation in this study. However, care should be taken in applying these results to the overall STEMI population, especially those at high risk for ischemia.

42. Short DAPT studies followed by P2Y 12 inhibitor monotherapy

43. There is short DAPT and short DAPT… To be offered to ACS patients at HBR as they do not benefit from prolonged (>6 month) DAPT and bleed more frequently if exposed to a prolonged DAPT regimen Associated to bleeding benefit and no apparent increase of ischemic events. Current evidence is highly promising but more data is needed: Class effect or P2Y12 inhibitor-dependent (does clopidogrel poor response matter?) Are there patients who do still benefit from concomitant ASA? Short DAPT followed by ASA monotherapy Very short DAPT followed by P2Y 12 inhibitor monotherapy

44. Comparison between ticagrelor versus clopidogrel in long term outcomes of Taiwanese diabetic subjects with ACS undergoing successful revascularization -From TSOC ACS-DM registry Ticagrelor versus clopidogrel treatment at discharge in diabetic patients with ACS after PCI was associated with a lower adjusted risk of death without an increase in the rate of overall re-hospitalization during 24-months follow-up. This study in real-world circumstance provided important complementary data to externally validate PLATO finding especially in the high-risk Asian diabetic population. Medicine (Baltimore).  2020 May; 99(19):

45. B leeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%)

46. Choice of Antiplatelet Therapy After PCI- clinical Algorithm YES NO Low Intermediate or High None or one High risk feature Multiple High risk Features and /ACS In Intermediate or High thrombotic risk, Use of clopidogrel alone in this context is confounded by the substantial pharmacodynamic variability in clopidogrel response and prasugrel has not been examined adequately in this manner . . Ref- J A C C : C A R D I O V A S C U L A R I N T E R V E N T IO N S V O L . 1 3 , N O . 1 9 , October 2 0 2 0 HIGH BLEEDING RISK >4% rate of major bleeding /year 1 month of DAPT followed by SAPT Ischemic risk (Based upon clinical/angiographic features) 3 - 6 mon t h s D APT fo l l o wed b y a s p i rin M onotherapy 12 mo n t hs of DAPT w i th a p o t e nt P 2 Y 1 2 in h i b i t o r, or 1- 3 m o nt h s of D A PT WITH t i c a g r e l o r f o l l o w ed b y ti c ag r e l o r a l o ne

47. POST –PCI ADJUNCT THERAPY STANDARD CHOICE - DAPT ( ASA + P2Y12 INHIBITOR- Clopidogrel, prasugrel, and ticagrel or) for a period of from 6 -12 months after the procedure and a SAPT (mostly aspirin) lifelong . Antithrombotic regimens other than standard DAPT have been the subject of a series of randomized trials, studying the risk/benefit ratio of intensifying, prolonging, shortening, or de-escalating platelet inhibition in patients with ACS and chronic coronary syndrome treated with contemporary PCI and stenting. J A C C : CARDIOVASCULAR INTE VENTIONS V O L . 1 4 , NO . 4 , 2 0 2 1

48. Antithrombotic therapy for atrial fibrillation and PCI NVAF NVAF + PCI PCI Anticoagulant therapy –Low shear stress thrombosis in left atrium. Anticoagulation superior to antiplatelet therapy Antiplatelet therapy-- High shear stress thrombosis – Platelet mediated in the arteries . DAPT superior to ASA alone + = BOTH anticoagulant and DAPT = ‘triple therapy’ High bleeding risk ?

49. Trials of dual vs triple therapy with NOAC or VKA after PCI for stable CAD or ACS, or medically managed ACS, in patients with AF P I ONEER AF-PCP RE-DUAL PC l 2 AUGUSTUS3 ENTRUST-AF PC l 4 Trial size and design N=2, 124; multicentre, randomised, open-label N=2,725; multicentre, randomised, open-label N=4,614; multicentre, randomised, open-label N=-1,500; multicentre, randomised, open-label (EU + Asia) Formal hypothesis testing Pr i mary endpoint Safety (b l eeding) ; not powered for efficacy ( i schaemic endpo i nts ) Eligibility AF, PCI + stent for ACS or stable CAD NVAF; PCI + stent for ACS or stable CAD NVAF, ACS and/or PCI AF, PCI + stent for ACS or stable CAD Within 72 hours of sheath removal Within 120 hours of stent placement Within 14 days of index event Between 4 hours and 5 days after sheath removal Yes, riva 2.5mg BID vs VKA No Yes No No; 2.5 mg BID and 15 mg OD* Yes Yes Yes 1, 6 or 12 months (investigator discretion) 1 (BMS) or 3 (DES) months 6 months 1 to 12 months (investigator discretion) Enrolment window NOAC vs VKA comparison Approved SPAF dose DAPT duration *15 mg OD: approved dose only for the prevention of stroke and systemic embolism in patients with AF and moderate ( CrCI 30-49 ml/min) or severe ( CrCI 15-29 ml/min) renal impairment6. Gibson CM, et al. N Engl J Med 2016;375:2423-34 Cannon CP, et al. N Engl J Med 2017;377:1513 - 24 Lopes RD, et al. N Engl J Med 2019;380: 1509 - 24 Vranckx P, et al. Am Heart J 2018;196:105- 12

50. Trial Description: In a 2 x 2 factorial design, patients with atrial fibrillation undergoing coronary revascularization were randomized to either apixaban 5 mg BID or VKA with an INR goal of 2-3, or aspirin 81 mg daily or matching placebo. Patients were followed for 180 days RESULTS Apixaban vs. VKA: Primary safety outcome, ISTH major or clinically relevant non major bleeding: 10.5% vs. 14.7%, p < 0.0001 Aspirin vs. placebo: Primary safety endpoint: 16.1% vs. 9.0%, p < 0.0001 CONCLUSIONS Among patients with atrial fibrillation with recent ACS or PCI, adding apixaban to P2Y12inhibitor resulted in lower bleeding compared with VKA with a lower rate of death or rehospitalization, driven by a lower rate of rehospitalization In both arms, addition of aspirin resulted in greater bleeding without any difference in efficacy AUGUSTUS Lopes RD, et al. N EnglJ Med 2019;380:1509-24

51. Conclusions- RE-DUAL PCI In patients with AF who have undergone PCI---- Dual therapy with dabigatran and a P2Y12 antagonist significantly reduced the risk of bleeding versus warfarin triple therapy, with non-inferiority for overall thromboembolic events. Absolute risk reductions with dabigatran dual therapy were 11.5% and 5.5% in ISTH major or clinically relevant non-major bleeding at the 110 mg and 150 mg doses, respectively, compared with warfarin triple therapy. These dabigatran dual therapy regimens, using doses approved worldwide for stroke prevention, offer clinicians two additional options for managing Afib patients post-PCI.

52. Conclusions NOAC should be prioritized over VKA in all patients with AF undergoing PCI without contra-indications. The optimal timing for the transition from triple to dual AT (i.e. dropping ASA) should be probably individualized given the clear trade-off between bleeding benefit and ischemic risk. Many claimed triple therapy to be dead … after the WOEST … PIONEER AF PCI, RE-DUAL … . Triple is here to stay … it simply gets shrinked .

53. 1. T riple therapy with an OAC , P2Y 12  inhibitor, and ASA for 1 to 6 months, followed by a transition to dual therapy with an OAC and either ASA or a P2Y 12  inhibitor until 1 year, after which antiplatelet therapy should be discontinued.  2. E arly transition from triple therapy to dual therapy whenever possible to reduce the risk of bleeding. 3. NOACs should be used at the lowest dose that has been proven to be effective for stroke prevention . AHC/ACC/HRS GUIDELINES RECOMMENDATIONS Ref- New engl J med 384;5 nejm.org February 4, 2021

54. Individualizing Treatment Decisions 1. GDMT reflects population- level data. 2. Many Pts do not perfectly meet trial inclusion criteria and have sociodemographic, clinical, or other characteristics that require special consideration. 3. Patients may not weigh bleeding, ischemic, or thromboembolic risks equally or in the same way that clinicians do. WHY ? n engl j med 384;5 nejm.org February 4, 2021

55. Tools to determine whether continuing DAPT beyond 12 months would provide a favorable risk–benefit profile Clinicians might weigh the risks of ischemia versus bleeding by balancing individual bleeding characteristics ---- 1. Advanced age 2. Low Body weight 3. Noncardiac coexisting conditions (e.g., cancer and kidney or liver disease) A gainst characteristics associated with high ischemic risk -- 1. D iabetes 2. Diffuse atherosclerotic coronary disease on angiography. Ref- New engl J med 384;5 nejm.org February 4, 2021

56. www.escardio.org/guidelines 2017 ESC Focused Update on DAPT in Coronary Artery Disease, developed in collaboration with EACTS (European Heart Journal 2017 - doi:10.1093/eurheartj/ehx419) Risk scores validated for DAPT duration decision-making PRECISE-DAPT score DAPT score Time of use At the time of coronary stenting After 12 months of uneventful DAPT DAPT duration strategies assessed Short DAPT (3–6 months) vs. Standard/long DAPT (12–24 months) Standard DAPT (12 months) vs. Long DAPT (30 months) Score calculation HB ≥211-5 11 10-5 ≤10 Age ≥75 65 to <75 <65 Cigarette smoking Diabetes mellitus MI at presentation Prior PCI or prior MI Paclitaxel-eluting stent Stent diameter <3 mm CHF or LVEF <30% Vein graft stent –2 pt WBC ≤5 8 1012141618 ≥20 –1 pt pt +1 pt Age ≤50 60 70 80 ≥90 +1 pt +1 pt CrCI ≥100 80 60 40 20 0 +1 pt +1 pt +1 pt Prior Bleeding No Yes +2 pt +2 pt Score 0 2 4 6 8 1012141618202224262830 Points Score range to 100 points –2 to 10 points Decision making cut-off suggested Score ≥25  Short DAPT Score <25  Standard/long DAPT Score ≥2  Long DAPT Score <2  Standard DAPT Calculator www.precisedaptscore.com www.daptstudy.org

57. Suggested Approaches to Antithrombotic Treatment after an ACS Event* Time after ACS Event Default Strategy Pts with High Ischemic Risk Pts with high Bleeding Risk Pts with concomitant Atrial Fibrillation # <= 1 month ASA+Newer Generation P2Y12 inhibitor ASA+Newer Generation P2Y12 Inhibitor ASA +Newer generation P2Y12 inhibitor ASA, CLOPIDOGREL & DOAC@ > 1 month – 12 month ASA +Newer Generation P2y!2 Inhibitor ASA+ Newer Generation P2Y12 Inhibitor Any P2Y12 INHIBITOR CLOPIDOGREL + DOAC > 12 Month ANY P2Y12 Inhibitor ASA + NEWER generation P2Y12 inhibitor OR Switch to ASA + Low Dose Rivaroxaban Any P2Y12 Inhibitor or Aspirin DOAC ASA- < 100 mg . PRASUGREL and TICAGRELOR – Newer Generation P2Y12 inhibitor ; DOAC – Direct Oral Anticoagulant # Recommendations for Non Valvular AF @- Consider withdrawing ASA before Hospital discharge for Pts of High Bleeding Risk . A one-size-fits-all approach is not suited to the management of antithrombotic therapies after an ACS Ref- New engl J med 384;5 nejm.org February 4, 2021

58. The North American P erspective – 2018 Update Angiolillo DJ et al. Circulation 2018; 138:527–536. Management of antiplatelet therapy in patients with AF undergoing PCI treated with an OAC

59. Reasons for Discontinuing Antiplatelet Therapy A lmost a quarter of patients discontinue antiplatelet therapy prematurely after an acute coronary syndrome due to--- Side effects of drugs Treatment complexity Cost and Drug interruption for noncardiac procedures Ref- New engl J med 384;5 nejm.org February 4, 2021

60. Future directions --- Several areas are under active investigation---- 1. Adequate duration of DAPT with more potent, newer-generation P2Y12 inhibitors. 2. Newer-generation stents that will require less potent platelet inhibition. 3. Newer trials with investigational agents that might improve the risk– benefit balance of current antithrombotic strategies. 4. C linical trials that recruit diverse populations with broad representation of race or ethnic group, sex, coexisting conditions, age, and sociocultural characteristics. Ref- New engl J med 384;5 nejm.org February 4, 2021

61. A careful assessment of thrombotic risk versus bleeding risk is required for each patient as part of a tailored, potentially dynamic treatment plan that uses the tools of risk stratification in the context of the patient’s values and preferences . CONCLUSION