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Management of AF patients with ACS undergoing PCI.pptx

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Praveen Nagula

- The AUGUSTUS trial compared apixaban to vitamin K antagonist (VKA) for prevention of thromboembolic events in patients with atrial fibrillation undergoing percutaneous coronary intervention or experiencing acute coronary syndrome. - Over 4,600 patients were randomized to apixaban 5mg twice daily or adjusted-dose VKA plus a P2Y12 inhibitor with or without aspirin for 6 months. - The primary outcome was major or clinically relevant non-major bleeding. Apixaban resulted in a 31% relative risk reduction in the primary outcome compared to VKA.

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Management of AF patients with ACS/undergoing PCI Dr. Praveen Nagula MD,DM Associate Professor of Cardiology Osmania Medical College/General Hospital, Hyderabad
INTRODUCTION  Atrial fibrillation is the most common arrhythmia in patients undergoing PCI.  Presence of AF in ACS – increases in-hospital and 30 day mortality.  Managing the thrombotic risk and bleeding is an herculean task.  Individualizing the duration, number of antithrombotics and anticoagulants is of prime importance.  NOACs and single antiplatelet with trial evidence suggest effective outcomes with less bleeding in this subset of patients.
Case • A 54 year male, hypertensive, diabetes, had CVA 2 years ago. He had raised creatinine (2.2mg/dl) and haemoglobin of 9.6gm/dl. Now admitted with chest pain. ECG showed extensive anterior wall STEMI. Echo showed dilated LA,LV and severe LV dysfunction. He underwent PPCI Stent to LAD. During his hospital stay, he had AF with FVR reverted pharmacologically. At discharge, what drugs to be kept for prevention of thrombotic events in future as well as protect from bleeding complications? • A. Aspirin 150mg, Clopidogrel 75 mg, Rivaroxaban 20 mg OD for 3 months. • B. Aspirin 75mg, Clopidogrel75mg, Rivaroxaban 15 mg BID for 1 month • C. Aspirin 75mg, Clopidogrel 75mg, Apixaban 2.5 mg BD for 3 months • D. Aspirin 75mg, Clopidogrel 75mg, Apixaban 5mg BD for one month • E. None of the above.
AF and ACS – A DOUBLE EDGED SWORD • Patients with NVAF with a recent ACS and/or have undergone PCI:  Require anticoagulation for stroke risk reduction associated with NVAF.  Require add-on single or dual antiplatelet therapy for reducing the risk of ischemic events in ACS or PCI.  Combining these regimens increases the risk for bleeding.  The optimal combination of anticoagulation and antiplatelet therapy which balances bleeding risk and thrombotic risk is unknown. ACS, acute coronary syndrome; NVAF, non-valvular atrial fibrillation; PCI, percutaneous coronary intervention. Lopes RD, et al. N Engl J Med 2019;380:1509–24
• AGE 54 years • HYPERTENSION • DIABETES • DERANGED RFT • CVA • ACS • AF
Management of AF patients with ACS undergoing PCI.pptx
Coronary stenting in patient with AF and high risk of stroke Stent thrombosis Stroke Major bleeding DAPT OAC + You cannot simultaneously prevent all three Gibson et al. N Engl J Med 2016;375:2423-34.
How best these patients can be managed? What is the trial evidence?
Management of AF patients with ACS undergoing PCI.pptx
Management of AF patients with ACS undergoing PCI.pptx
Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF-PCI1  Primary endpoint: TIMI major + minor and bleeding requiring medical attention  Secondary endpoint: CV death, MI, stroke and stent thrombosis *Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min. †Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor. ‡Low-dose aspirin (75-100 mg/d). PCI- Percutaneous coronary Intervention; TIMI: Thrombolysis in Myocardial Infarction; CV: Cardiovascular; MI: Myocardial Infarction # Participants who received treatment for 1 to 6 months received this treatment for the remainder of 12-month treatment period  2100 patients with NVAF  PCI with stent placement  No prior stroke/TIA, GI bleeding 12 months before randomization, Hb<10g/dL, CrCl<30mL/min R A N D O M I Z E 1,6, or 12 months Rivaroxaban 15 mg qd* Clopidogrel 75 mg qd† Rivaroxaban 15mg qd# Aspirin 75-100 mg qd Rivaroxaban 2.5 mg bid Clopidogrel 75 mg qd† Aspirin 75-100 mg qd‡ VKA (target INR 2.0-3.0)# Aspirin 75-100 mg qd VKA (target INR 2.0-3.0) Clopidogrel 75 mg qd† Aspirin 75-100 mg qd ≤72 hours After Sheath removal 1,6, or 12 months End of treatment 12 months WOEST Like ATLAS Like Triple Therapy Pre randomization MD Choice Pre randomization MD Choice 1. Gibson CM, et al. N Engl J Med 2016;375:2423-34..
PIONEER AF-PCI: Summary of results Primary endpoint was a composite of major bleeding or minor bleeding according to TIMI criteria or bleeding requiring medical attention. MACE was a composite of death from cardiovascular causes, myocardial infarction or stroke. Rivaroxaban 15 mg + P2Y12 inhibitor vs. warfarin + DAPT Rivaroxaban 2.5 mg + DAPT vs. warfarin + DAPT Primary endpoint: clinically significant bleeding Major bleeding Minor bleeding Bleeding requiring medical attention Secondary endpoint: MACE Stent thrombosis Favours rivaroxaban 15 mg + P2Y12 inhibitor 0 0.5 1 1.5 2 HR (95% CI) 0 0.5 1 1.5 2 HR (95% CI) Favours warfarin + DAPT Favours rivaroxaban 2.5 mg + DAPT Favours warfarin + DAPT . Gibson CM, et al. N Engl J Med 2016;375:2423-34.
Interpretation of the PIONEER Results  Initial important evidence in a field where it has been lacking  Clear signal of less bleeding with both reduced antithrombotic regimens  No aspirin (riva 15 + P2Y12)  Very low-dose OAC (riva 2.5 + P2Y12 + aspirin)  Effects on ischemic events were imprecise with wide confidence intervals  Stroke: No Aspirin = HR 1.07, 95% CI 0.39-2.96 Low-dose OAC = HR 1.36, 95% CI 0.52-3.58  Stent thrombosis: No aspirin = HR 1.20, 95% CI 0.32-4.45 Low-dose OAC = HR 1.44, 95% CI 0.40-5.09 Gibson CM, et al. N Engl J Med 2016;375:2423-34.
RE DUAL PCI
Dabigatran etexilate 150 mg BID + P2Y12 inhibitor 1o End Point Time to first ISTH major bleeding or clinically relevant non-major bleeding event n~2,500 patients (approx. 834 patients per arm) Dabigatran etexilate 110 mg BID + P2Y12 inhibitor Warfarin (INR 2.0 – 3.0) + P2Y12 inhibitor + ASA Paroxysmal, persistent or permanent NVAF, PCI with stenting [BMS or DES] elective or ACS Screening R 0-120 hours post-PCI Trial design Patients >80 years living outside of the USA will be assigned to 110mg dabigatran etexilate (BID) or warfarin in a 1:1 ratio RE-DUAL PCI ACS: Acute Coronary Syndrome; ASA: Acetylsalicylic acid; BMS: Bare Metal Stent DES: Drug Eluting Stent; ISTH: International Society on Thrombosis and Haemostasis; INR: International Normalized Ratio; NVAF: Non Valvular Atrial Fibrillation; PCI: Percutaneous Coronary Intervention ClinicalTrials.gov: NCT02164864 Cannon, C, et al. N Engl J Med 2017;377:1513-24.
RE-DUAL PCI: Summary of results Cannon CP, et al. N Engl J Med 2017;377:1513–24. Time to first ISTH or CRNM bleeding event Time to first ISTH major bleeding event Time to first TIMI major bleeding event Time to first TIMI minor or major bleeding event Thromboembolic events, death or unplanned revascularization Thromboembolic event or death 0 0.5 1 1.5 2 HR (95% CI) Favours dabigatran + P2Y12 inhibitor Favours VKA + DAPT Dabigatran 110 mg Dabigatran 150 mg
Lessons from PIONEER and RE-DUAL  Only patients undergoing PCI included  NOAC + P2Y12 inhibitor appears to be associated with reduced bleeding versus triple therapy with VKA  PIONEER assessed doses of rivaroxaban not tested for stroke prevention  Due to the design of RE-DUAL, it is unclear whether the reductions in bleeding are due to use of dabigatran or the avoidance of aspirin  Neither trial powered for efficacy outcomes  In PIONEER, both doses of rivaroxaban were associated with numerical increases in CV death, stroke and stent thrombosis  In RE-DUAL, the lower dose of dabigatran (110 mg BID) was associated with a numerical increase in death, MI, stroke and stent thrombosis Gibson CM, et al. N Engl J Med 2016;375:2423-34 Valgimigli et al. European Heart Journal (2018) 39, 213–254  Cannon, C, et al. N Engl J Med 2017;377:1513-24. .
AUGUSTUS TRIAL
AUGUSTUS - Research Hypothesis Two Independent Hypotheses:  Apixaban is at least non-inferior or superior to VKA on the composite outcome of ISTH major bleeding or clinically relevant non-major (CRNM) bleeding in patients with NVAF who develop ACS and/or require PCI with concomitant antiplatelet therapy (P2Y12 inhibitor) with or without aspirin.  Single antiplatelet therapy with a P2Y12 inhibitor is superior to dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the combined outcome of ISTH major bleeding or CRNM bleeding in patients with NVAF with a recent ACS and/or require PCI with planned concomitant anticoagulant therapy. ACS, acute coronary syndrome; ISTH, International Society on Thrombosis and Haemostasis; NVAF, non-valvular atrial fibrillation; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist. 1. Lopes RD, et al. N Engl J Med 2019;380:1509–24; 2. Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 Coadministration of apixaban with antiplatelet agents increases the risk of bleeding.2 Please consult local marketing label for full information.
AUGUSTUS: Trial design Lopes RD, et al. Am Heart J 2018;200:17–23. Aspirin Placebo Double blind Aspirin Placebo Double blind Apixaban 5 mg BID Apixaban 2.5 mg BID in selected patients† Primary outcome: ISTH major/CRNM bleeding Secondary outcome(s): death/hospitalization, death/ischaemic events Randomise N=4,600 patients Aspirin for all on the day of ACS or PCI Aspirin vs placebo after randomisation Open label VKA (INR 2–3) EXCLUSION • Contraindication to DAPT • Other conditions that require OAC (such as prosthetic valves or moderate or severe mitral stenosis), severe renal insufficiency, and history of intracranial haemorrhage • Recent or planned CABG, coagulopathy or ongoing bleeding, contraindication to VKA, apixaban, all P2Y12 inhibitors, or aspirin INCLUSION • AF (prior, persistent, >6 hours); physician decision for OAC • ACS or PCI; planned P2Y12 inhibitor for ≥6 months A P2Y12 inhibitor for all patients x 6 months “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Dosing regimen of 2.5 mg BID in patients with 2 or more of the following criteria: –Serum Cr ≥1.5 mg/dL –Age ≥80 years –Body weight ≤60 kg P2Y12 inhibitor for all patients X 6 months Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021
AUGUSTUS: Baseline characteristics Total (N=4,614) Age, median (25th, 75th), years 70.7 (64.2, 77.2) Female, % 29.0 CHA2DS2-VASc score, mean (SD) 3.9 (1.6) HAS-BLED score, mean (SD) 2.9 (0.9) Prior OAC, % 49.0 P2Y12 inhibitor, % Clopidogrel 92.6 Prasugrel 1.1 Ticagrelor 6.2 Number of days from ACS/PCI to randomisation, mean (SD) 6.6 (4.2) Qualifying index event, % ACS and PCI 37.3 ACS and no PCI 23.9 Elective PCI 38.8 Lopes RD, et al. N Engl J Med 2019;380:1509–24. CHA2DS2-VASc score, mean (SD) 3.9 (1.6) HAS-BLED score, mean (SD) 2.9 (0.9) Prior OAC, % 49.0 P2Y12 inhibitor, % Clopidogrel 92.6 CHA2DS2-VASc score, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, female sex; HAS-BLED, hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol; SD, standard deviation.
Major/CRNM bleeding Number at risk: Apixaban VKA Cumulative incidence of event (%) 0 0 2,290 2,259 Days since start of intervention 5 10 15 20 30 2,110 1,984 60 2,019 1,861 90 1,957 1,795 120 1,902 1,736 150 1,858 1,686 180 1,037 1,079 HR=0.69 (95% CI: 0.58, 0.81); p<0.001 for non-inferiority, p<0.001 for superiority; ARR=4.2%; NNT=24 VKA: 14.7% Apixaban: 10.5% Lopes RD, et al. N Engl J Med 2019;380:1509–24. Apixaban vs VKA Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
Major/CRNM bleeding ARI, absolute risk increase; NNH, number needed to harm. Lopes RD, et al. N Engl J Med 2019;380:1509–24. Number at risk: Aspirin Placebo Cumulative incidence of event (%) 0 0 Days since start of intervention 5 10 15 20 30 60 90 120 150 180 HR=1.89 (95% CI: 1.59, 2.24); p<0.001; ARI=7.1%; NNH=14 Aspirin: 16.1% Placebo: 9.0% Aspirin vs placebo 2,277 2,279 2,003 2,095 1,863 2,006 1,789 1,941 1,717 1,880 1,674 1,824 962 1,079 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
Major/CRNM bleeding1 1. Lopes RD, et al. N Engl J Med 2019;380:1509–24; 2. Lopes RD, et al. N Engl J Med 2019;380:1509–24. Suppl appendix. Number at risk: Apixaban and aspirin Apixaban and placebo VKA and aspirin VKA and placebo Cumulative incidence of event (%) 0 0 1,145 1,143 1,123 1,126 Days since start of intervention 5 10 15 20 30 1,036 1,075 962 1,007 60 975 1,044 881 947 90 937 1,007 838 917 120 903 975 800 883 150 880 947 776 851 180 485 536 467 528 Apixaban + aspirin: 13.8%2 VKA + aspirin: 18.7%2 VKA + placebo: 10.9%2 Apixaban + placebo: 7.3%2 Apixaban + placebo vs VKA + aspirin:2 11.4% absolute risk reduction (NNT =9) AUGUSTUS was not powered to compare individual primary outcomes for apixaban + placebo vs VKA + aspirin NNT: Number needed to treat Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
Secondary Outcomes 25
Secondary Outcomes: Death or Ischemic event Apixaban vs VKA and Aspirin vs Placebo Endpoint Apixaban (N=2306) VKA (N=2308) Hazard Ratio (95%CI) Aspirin (N=2307) Placebo (N=2307) Hazard Ratio (95%CI) Death / Ischemic Events (%) 6.7 7.1 0.93 (0.75-1.16) 6.5 7.3 0.89 (0.71-1.11) Death (%) 3.3 3.2 1.03 (0.75-1.42) 3.1 3.4 0.91 (0.66-1.26) CV Death (%) 2.5 2.3 1.05 (0.72-1.52) 2.3 2.5 0.92 (0.63-1.33) Stroke (%) 0.6 1.1 0.50 (0.26-0.97) 0.9 0.8 1.06 (0.56-1.98) Myocardial Infarction (%) 3.1 3.5 0.89 (0.65-1.23) 2.9 3.6 0.81 (0.59-1.12) Definite or Probable Stent Thrombosis (%) 0.6 0.8 0.77 (0.38-1.56) 0.5 0.9 0.52 (0.25-1.08) Urgent Revascularization (%) 1.7 1.9 0.90 (0.59-1.38) 1.6 2.0 0.79 (0.51-1.21) Hospitalization (%) 22.5 26.3 0.83 (0.74-0.93) 25.4 23.4 1.10 (0.98-1.24) All patients were concomitantly receiving P2Y12 therapy Lopes RD, et al. N Engl J Med 2019;380:1509–24
Death/hospitalization Lopes RD, et al. N Engl J Med 2019;380:1509–24. Number at risk: Apixaban VKA Cumulative incidence of event (%) 0 0 Days since randomisation 10 20 30 40 30 60 90 120 150 180 HR=0.83 (95% CI: 0.74, 0.93); p=0.002; ARR=3.9%; NNT=26 VKA: 27.4% Apixaban: 23.5% Apixaban vs VKA 2,306 2,308 2,090 2,035 1,965 1,885 1,881 1,805 1,821 1,732 1,772 1,673 947 1,001 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not Recommended”
Death/hospitalization NS, not significant. Lopes RD, et al. N Engl J Med 2019;380:1509–24. Number at risk: Aspirin Placebo Cumulative incidence of event (%) 0 0 Days since randomisation 10 20 30 40 30 60 90 120 150 180 HR=1.08 (95% CI: 0.96, 1.21); p=NS Placebo: 24.7% Aspirin: 26.2% Aspirin vs placebo 2,307 2,307 2,042 2,083 1,909 1,941 1,822 1,864 1,752 1,801 1,699 1,746 951 997 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
Death/hospitalisation1 AUGUSTUS was not powered to compare individual primary outcomes for apixaban + placebo vs VKA + aspirin 1. Lopes RD, et al. N Engl J Med 2019;380:1509–24; 2. Lopes RD, et al. N Engl J Med 2019; suppl appendix. Number at risk: Apixaban and aspirin Apixaban and placebo VKA and aspirin VKA and placebo Cumulative incidence of event (%) 0 0 Days since randomisation 10 20 30 40 30 60 90 120 150 180 Apixaban + aspirin: 24.9%2 VKA + aspirin: 27.5%2 VKA + placebo: 27.3%2 Apixaban + placebo: 22.0%2 Apixaban + placebo vs VKA + aspirin:2 5.5% absolute risk reduction (NNT=18) 1,153 1,153 1,154 1,154 1,026 1,064 1,016 1,019 970 995 939 946 923 958 899 906 888 933 864 868 863 909 836 837 459 488 492 509 NNT: Number needed to treat Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
Secondary End Point: Death & Hospitalization
31 Amit N. Vora et al. Circulation. 2019;140:1960–1963
32 All-cause hospitalization HR 0.83 (95% CI 0.74–0.93); p=0.002 Cardiovascular hospitalization HR 0.81 (95% CI 0.71–0.94); p=0.004 Bleeding-related hospitalization HR 0.65 (95% CI 0.50–0.86); p=0.003 Apixaban VKA Apixaban VKA Apixaban VKA Amit N. Vora et al. Circulation. 2019;140:1960–1963 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
33 All-cause hospitalization HR 1.10 (95% CI 0.98–1.24); p=0.104 Cardiovascular hospitalization HR 0.99 (95% CI 0.86–1.14); p=0.862 Bleeding-related hospitalization HR 2.11 (95% CI 1.58–2.81); p<0.001 Aspirin Placebo Aspirin Placebo Aspirin Placebo Amit N. Vora et al. Circulation. 2019;140:1960–1963 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
All-cause hospitalization p=0.0031 Cardiovascular hospitalization p=0.0180 Bleeding-related hospitalization p<0.0001 Amit N. Vora et al. Circulation 2019 Amit N. Vora et al. Circulation. 2019;140:1960–1963
Stent Thrombosis 35
Ischemic outcomes Endpoint Apixaban (N=2,306) VKA (N=2,308) HR (95% CI) Death/ischaemic events (%) 6.7 7.1 0.93 (0.75, 1.16) Death (%) 3.3 3.2 1.03 (0.75, 1.42) CV death (%) 2.5 2.3 1.05 (0.72, 1.52) Stroke (%) 0.6 1.1 0.50 (0.26, 0.97) Myocardial infarction (%) 3.1 3.5 0.89 (0.65, 1.23) Definite or probable stent thrombosis (%) 0.6 0.8 0.77 (0.38, 1.56) Urgent revascularisation (%) 1.7 1.9 0.90 (0.59, 1.38) Hospitalisation (%) 22.5 26.3 0.83 (0.74, 0.93) Lopes RD, et al. N Engl J Med 2019;380:1509–24. Apixaban vs VKA
Ischemic outcomes Endpoint Aspirin (N=2,307) Placebo (N=2,307) HR (95% CI) Death/ischaemic events (%) 6.5 7.3 0.89 (0.71, 1.11) Death (%) 3.1 3.4 0.91 (0.66, 1.26) CV death (%) 2.3 2.5 0.92 (0.63, 1.33) Stroke (%) 0.9 0.8 1.06 (0.56, 1.98) Myocardial infarction (%) 2.9 3.6 0.81 (0.59, 1.12) Definite or probable stent thrombosis (%) 0.5 0.9 0.52 (0.25, 1.08) Urgent revascularisation (%) 1.6 2.0 0.79 (0.51, 1.21) Hospitalisation (%) 25.4 23.4 1.10 (0.98, 1.24) Lopes RD, et al. N Engl J Med 2019;380:1509–24. Aspirin vs placebo “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2
Rate of Stent Thrombosis at 6 Months According to Different Definitions 0 0.25 0.5 0.75 1 Definite stent thrombosis Definite/probable stent thrombosis KM Rate at 6 Months n=20 n=30 Lopes et al. Circulation. 2020;141:781–783
Definite/Probable Stent Thrombosis According to Antithrombotic Regimen — VKA + Aspirin — Apixaban + Aspirin — VKA + No Aspirin — Apixaban + No Aspirin Lopes et al. Circulation. 2020;141:781–783 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021
Endpoint Aspirin (N=2,277) Placebo (N=2,279) HR (95% CI) ISTH major or CRNM bleeding, n (%) 367 (16.1) 204 (9.0) 1.89 (1.59, 2.24) Definite or probable stent thrombosis, n (%) 11 (0.63) 19 (1.08) 0.58 (0.28, 1.22) AUGUSTUS: Bleeding Events vs Stent Thrombosis Events Bleeding events are much more common than stent thrombosis events in AUGUSTUS NNT at 6 months: 222 NNH at 6 months: 41 (major bleeding) NNT at 1 month: 176 NNH at 1 month: 100 (major bleeding) NNT: Number needed to treat NNH: Number needed to harm Lopes et al. Circulation. 2020;141:781–783 Lopes RD, et al. N Engl J Med 2019;380:1509–24. “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021
TILL WHAT TIME PERIOD DOES THE REMOVAL OF ASPIRIN INFLUENCE ISCHEMIC OUTCOMES? How early we can stop? Or To continue indefinitely? Is there an Answer?
Ischemic Events With Placebo vs. Aspirin • Though not statistically significant, there were numerically more of some ischemic events in patients assigned placebo than aspirin: Aspirin Placebo • Death 72 (3.1%) vs. 79 (3.4%) • Cardiovascular Death 53 (2.3%) vs. 58 (2.5%) • Stroke 20 (0.9%) vs. 19 (0.8%) • Stent thrombosis (definite or probable) 11 (0.5%) vs. 21 (0.9%) • Myocardial infarction 68 (2.9%) vs. 84 (3.6%) • Urgent revascularization 37 (1.6%) vs. 47 (2.0%) Adapted from: Lopes RD, et al. N Engl J Med 2019;380:1509-24 • Analysis of the stent thrombosis events suggested that most of the increased risk was early, within 30 days of randomization Lopes RD, et al. Circulation 2020; 141:781-783
Tradeoff Between Bleeding and Ischemic Events There is a temporal component to the balance of bleeding and ischemic risk • Recurrent ischemic events (specifically stent thrombosis) tend to occur early after PCI • Bleeding risk is cumulative and is higher with long-term, potent antithrombotic therapy Schomig A, et al. Heart 2009;95:1280–1285
Severe Bleeding and Ischemic Outcomes Randomization to 30 Days Fatal, ICH, Major Bleeding CV Death, Stroke, MI, Stent Thrombosis Alexander et a Circulation. 2020;141:1618–1627
Severe Bleeding and Ischemic Outcomes 30 Days to 6 Months Fatal, ICH, Major Bleeding CV Death, Stroke, MI, Stent Thrombosis Alexander et a Circulation. 2020;141:1618–1627
Conclusion “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 Lopes RD, et al. N Engl J Med 2019;380:1509–24 • Among patients with AF and recent PCI including current generation of drug- eluting stent, definite or probable stent thrombosis is rare and occurs more frequently early after PCI. • These data support the use of Apixaban and a P2Y12 inhibitor without aspirin during the first 6 months for most patients, considering the almost 2-fold increase in bleeding with aspirin use. • In patients with a high risk of stent thrombosis and an acceptable risk of bleeding, using aspirin up to 30 days after PCI should be considered. Further studies to identify patients who might benefit the most from this strategy are warranted.
Finding the Antithrombotic Sweet Spot Antithrombotic Sweet Spot Risk of Ischemic Events Risk of Bleeding Events The right combination of antithrombotic agents at the right dose and duration to reduce ischemic events as much as possible at a minimal cost of bleeding Lopes RD et.al. Eur Heart J 2019 Dec 7;40(46):3768-3770
What do Guidelines say?
2019 ESC Guidelines-management of chronic coronary syndromes CCS - Chronic Coronary Syndrome AF - Atrial Fibrillation Knuuti et al. Eur Heart J 2020 Jan
2019 AHA/ACC/HRS Focused Update January CT et al; J Am Coll Cardiol 2019 Jul 9;74(1):104-132 Dropping ASA is recommended for AF/ACS patients …but, the strength of recommendation and quality of evidence are both only moderate.
2020 ESC AF Guideline AF and ACS/PCI CAD – Coronary Artery Disease Hindricks et al. European Heart Journal, Volume 42, Issue 5, 1 February 2021, Pages 373–498
2020 ESC AF Guideline AF and ACS/PCI: Recommendations for patients with AF and an ACS, PCI, or CCS Hindricks et al. European Heart Journal, Volume 42, Issue 5, 1 February 2021, Pages 373–498
Patient • Aspirin 75mg OD • Clopidogrel 75mg OD • Apixaban 5mg BD for a month Thereafter • Clopidogrel 75mg OD • Apixaban 5mg BD
TAKE HOME MESSAGE • 1.AF with PCI is a double edged sword, most of the patients have multiple comorbidities keeping them at risk of bleeding events as same as thrombotic events. • 2.These patients should be given Dual Inhibition for duration depending on their risk and thereafter to continue single antiplatelet and NOACs. • 3.NOACs are proven to be noninferior to warfarin in AF and PCS cases and are more useful conventionally with no monitoring. • 4.Cost factor and Availability of Ideal reversal agent is the issue with NOACs. • 5.Subset of patients with VHD, Prosthetic valve and having ACS to be evaluated in trials..
THANK YOU

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Management of AF patients with ACS undergoing PCI.pptx

  • 1. Management of AF patients with ACS/undergoing PCI Dr. Praveen Nagula MD,DM Associate Professor of Cardiology Osmania Medical College/General Hospital, Hyderabad
  • 2. INTRODUCTION  Atrial fibrillation is the most common arrhythmia in patients undergoing PCI.  Presence of AF in ACS – increases in-hospital and 30 day mortality.  Managing the thrombotic risk and bleeding is an herculean task.  Individualizing the duration, number of antithrombotics and anticoagulants is of prime importance.  NOACs and single antiplatelet with trial evidence suggest effective outcomes with less bleeding in this subset of patients.
  • 3. Case • A 54 year male, hypertensive, diabetes, had CVA 2 years ago. He had raised creatinine (2.2mg/dl) and haemoglobin of 9.6gm/dl. Now admitted with chest pain. ECG showed extensive anterior wall STEMI. Echo showed dilated LA,LV and severe LV dysfunction. He underwent PPCI Stent to LAD. During his hospital stay, he had AF with FVR reverted pharmacologically. At discharge, what drugs to be kept for prevention of thrombotic events in future as well as protect from bleeding complications? • A. Aspirin 150mg, Clopidogrel 75 mg, Rivaroxaban 20 mg OD for 3 months. • B. Aspirin 75mg, Clopidogrel75mg, Rivaroxaban 15 mg BID for 1 month • C. Aspirin 75mg, Clopidogrel 75mg, Apixaban 2.5 mg BD for 3 months • D. Aspirin 75mg, Clopidogrel 75mg, Apixaban 5mg BD for one month • E. None of the above.
  • 4. AF and ACS – A DOUBLE EDGED SWORD • Patients with NVAF with a recent ACS and/or have undergone PCI:  Require anticoagulation for stroke risk reduction associated with NVAF.  Require add-on single or dual antiplatelet therapy for reducing the risk of ischemic events in ACS or PCI.  Combining these regimens increases the risk for bleeding.  The optimal combination of anticoagulation and antiplatelet therapy which balances bleeding risk and thrombotic risk is unknown. ACS, acute coronary syndrome; NVAF, non-valvular atrial fibrillation; PCI, percutaneous coronary intervention. Lopes RD, et al. N Engl J Med 2019;380:1509–24
  • 5. • AGE 54 years • HYPERTENSION • DIABETES • DERANGED RFT • CVA • ACS • AF
  • 7. Coronary stenting in patient with AF and high risk of stroke Stent thrombosis Stroke Major bleeding DAPT OAC + You cannot simultaneously prevent all three Gibson et al. N Engl J Med 2016;375:2423-34.
  • 8. How best these patients can be managed? What is the trial evidence?
  • 11. Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF-PCI1  Primary endpoint: TIMI major + minor and bleeding requiring medical attention  Secondary endpoint: CV death, MI, stroke and stent thrombosis *Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min. †Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor. ‡Low-dose aspirin (75-100 mg/d). PCI- Percutaneous coronary Intervention; TIMI: Thrombolysis in Myocardial Infarction; CV: Cardiovascular; MI: Myocardial Infarction # Participants who received treatment for 1 to 6 months received this treatment for the remainder of 12-month treatment period  2100 patients with NVAF  PCI with stent placement  No prior stroke/TIA, GI bleeding 12 months before randomization, Hb<10g/dL, CrCl<30mL/min R A N D O M I Z E 1,6, or 12 months Rivaroxaban 15 mg qd* Clopidogrel 75 mg qd† Rivaroxaban 15mg qd# Aspirin 75-100 mg qd Rivaroxaban 2.5 mg bid Clopidogrel 75 mg qd† Aspirin 75-100 mg qd‡ VKA (target INR 2.0-3.0)# Aspirin 75-100 mg qd VKA (target INR 2.0-3.0) Clopidogrel 75 mg qd† Aspirin 75-100 mg qd ≤72 hours After Sheath removal 1,6, or 12 months End of treatment 12 months WOEST Like ATLAS Like Triple Therapy Pre randomization MD Choice Pre randomization MD Choice 1. Gibson CM, et al. N Engl J Med 2016;375:2423-34..
  • 12. PIONEER AF-PCI: Summary of results Primary endpoint was a composite of major bleeding or minor bleeding according to TIMI criteria or bleeding requiring medical attention. MACE was a composite of death from cardiovascular causes, myocardial infarction or stroke. Rivaroxaban 15 mg + P2Y12 inhibitor vs. warfarin + DAPT Rivaroxaban 2.5 mg + DAPT vs. warfarin + DAPT Primary endpoint: clinically significant bleeding Major bleeding Minor bleeding Bleeding requiring medical attention Secondary endpoint: MACE Stent thrombosis Favours rivaroxaban 15 mg + P2Y12 inhibitor 0 0.5 1 1.5 2 HR (95% CI) 0 0.5 1 1.5 2 HR (95% CI) Favours warfarin + DAPT Favours rivaroxaban 2.5 mg + DAPT Favours warfarin + DAPT . Gibson CM, et al. N Engl J Med 2016;375:2423-34.
  • 13. Interpretation of the PIONEER Results  Initial important evidence in a field where it has been lacking  Clear signal of less bleeding with both reduced antithrombotic regimens  No aspirin (riva 15 + P2Y12)  Very low-dose OAC (riva 2.5 + P2Y12 + aspirin)  Effects on ischemic events were imprecise with wide confidence intervals  Stroke: No Aspirin = HR 1.07, 95% CI 0.39-2.96 Low-dose OAC = HR 1.36, 95% CI 0.52-3.58  Stent thrombosis: No aspirin = HR 1.20, 95% CI 0.32-4.45 Low-dose OAC = HR 1.44, 95% CI 0.40-5.09 Gibson CM, et al. N Engl J Med 2016;375:2423-34.
  • 15. Dabigatran etexilate 150 mg BID + P2Y12 inhibitor 1o End Point Time to first ISTH major bleeding or clinically relevant non-major bleeding event n~2,500 patients (approx. 834 patients per arm) Dabigatran etexilate 110 mg BID + P2Y12 inhibitor Warfarin (INR 2.0 – 3.0) + P2Y12 inhibitor + ASA Paroxysmal, persistent or permanent NVAF, PCI with stenting [BMS or DES] elective or ACS Screening R 0-120 hours post-PCI Trial design Patients >80 years living outside of the USA will be assigned to 110mg dabigatran etexilate (BID) or warfarin in a 1:1 ratio RE-DUAL PCI ACS: Acute Coronary Syndrome; ASA: Acetylsalicylic acid; BMS: Bare Metal Stent DES: Drug Eluting Stent; ISTH: International Society on Thrombosis and Haemostasis; INR: International Normalized Ratio; NVAF: Non Valvular Atrial Fibrillation; PCI: Percutaneous Coronary Intervention ClinicalTrials.gov: NCT02164864 Cannon, C, et al. N Engl J Med 2017;377:1513-24.
  • 16. RE-DUAL PCI: Summary of results Cannon CP, et al. N Engl J Med 2017;377:1513–24. Time to first ISTH or CRNM bleeding event Time to first ISTH major bleeding event Time to first TIMI major bleeding event Time to first TIMI minor or major bleeding event Thromboembolic events, death or unplanned revascularization Thromboembolic event or death 0 0.5 1 1.5 2 HR (95% CI) Favours dabigatran + P2Y12 inhibitor Favours VKA + DAPT Dabigatran 110 mg Dabigatran 150 mg
  • 17. Lessons from PIONEER and RE-DUAL  Only patients undergoing PCI included  NOAC + P2Y12 inhibitor appears to be associated with reduced bleeding versus triple therapy with VKA  PIONEER assessed doses of rivaroxaban not tested for stroke prevention  Due to the design of RE-DUAL, it is unclear whether the reductions in bleeding are due to use of dabigatran or the avoidance of aspirin  Neither trial powered for efficacy outcomes  In PIONEER, both doses of rivaroxaban were associated with numerical increases in CV death, stroke and stent thrombosis  In RE-DUAL, the lower dose of dabigatran (110 mg BID) was associated with a numerical increase in death, MI, stroke and stent thrombosis Gibson CM, et al. N Engl J Med 2016;375:2423-34 Valgimigli et al. European Heart Journal (2018) 39, 213–254  Cannon, C, et al. N Engl J Med 2017;377:1513-24. .
  • 19. AUGUSTUS - Research Hypothesis Two Independent Hypotheses:  Apixaban is at least non-inferior or superior to VKA on the composite outcome of ISTH major bleeding or clinically relevant non-major (CRNM) bleeding in patients with NVAF who develop ACS and/or require PCI with concomitant antiplatelet therapy (P2Y12 inhibitor) with or without aspirin.  Single antiplatelet therapy with a P2Y12 inhibitor is superior to dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the combined outcome of ISTH major bleeding or CRNM bleeding in patients with NVAF with a recent ACS and/or require PCI with planned concomitant anticoagulant therapy. ACS, acute coronary syndrome; ISTH, International Society on Thrombosis and Haemostasis; NVAF, non-valvular atrial fibrillation; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist. 1. Lopes RD, et al. N Engl J Med 2019;380:1509–24; 2. Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 Coadministration of apixaban with antiplatelet agents increases the risk of bleeding.2 Please consult local marketing label for full information.
  • 20. AUGUSTUS: Trial design Lopes RD, et al. Am Heart J 2018;200:17–23. Aspirin Placebo Double blind Aspirin Placebo Double blind Apixaban 5 mg BID Apixaban 2.5 mg BID in selected patients† Primary outcome: ISTH major/CRNM bleeding Secondary outcome(s): death/hospitalization, death/ischaemic events Randomise N=4,600 patients Aspirin for all on the day of ACS or PCI Aspirin vs placebo after randomisation Open label VKA (INR 2–3) EXCLUSION • Contraindication to DAPT • Other conditions that require OAC (such as prosthetic valves or moderate or severe mitral stenosis), severe renal insufficiency, and history of intracranial haemorrhage • Recent or planned CABG, coagulopathy or ongoing bleeding, contraindication to VKA, apixaban, all P2Y12 inhibitors, or aspirin INCLUSION • AF (prior, persistent, >6 hours); physician decision for OAC • ACS or PCI; planned P2Y12 inhibitor for ≥6 months A P2Y12 inhibitor for all patients x 6 months “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Dosing regimen of 2.5 mg BID in patients with 2 or more of the following criteria: –Serum Cr ≥1.5 mg/dL –Age ≥80 years –Body weight ≤60 kg P2Y12 inhibitor for all patients X 6 months Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021
  • 21. AUGUSTUS: Baseline characteristics Total (N=4,614) Age, median (25th, 75th), years 70.7 (64.2, 77.2) Female, % 29.0 CHA2DS2-VASc score, mean (SD) 3.9 (1.6) HAS-BLED score, mean (SD) 2.9 (0.9) Prior OAC, % 49.0 P2Y12 inhibitor, % Clopidogrel 92.6 Prasugrel 1.1 Ticagrelor 6.2 Number of days from ACS/PCI to randomisation, mean (SD) 6.6 (4.2) Qualifying index event, % ACS and PCI 37.3 ACS and no PCI 23.9 Elective PCI 38.8 Lopes RD, et al. N Engl J Med 2019;380:1509–24. CHA2DS2-VASc score, mean (SD) 3.9 (1.6) HAS-BLED score, mean (SD) 2.9 (0.9) Prior OAC, % 49.0 P2Y12 inhibitor, % Clopidogrel 92.6 CHA2DS2-VASc score, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, female sex; HAS-BLED, hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol; SD, standard deviation.
  • 22. Major/CRNM bleeding Number at risk: Apixaban VKA Cumulative incidence of event (%) 0 0 2,290 2,259 Days since start of intervention 5 10 15 20 30 2,110 1,984 60 2,019 1,861 90 1,957 1,795 120 1,902 1,736 150 1,858 1,686 180 1,037 1,079 HR=0.69 (95% CI: 0.58, 0.81); p<0.001 for non-inferiority, p<0.001 for superiority; ARR=4.2%; NNT=24 VKA: 14.7% Apixaban: 10.5% Lopes RD, et al. N Engl J Med 2019;380:1509–24. Apixaban vs VKA Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 23. Major/CRNM bleeding ARI, absolute risk increase; NNH, number needed to harm. Lopes RD, et al. N Engl J Med 2019;380:1509–24. Number at risk: Aspirin Placebo Cumulative incidence of event (%) 0 0 Days since start of intervention 5 10 15 20 30 60 90 120 150 180 HR=1.89 (95% CI: 1.59, 2.24); p<0.001; ARI=7.1%; NNH=14 Aspirin: 16.1% Placebo: 9.0% Aspirin vs placebo 2,277 2,279 2,003 2,095 1,863 2,006 1,789 1,941 1,717 1,880 1,674 1,824 962 1,079 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 24. Major/CRNM bleeding1 1. Lopes RD, et al. N Engl J Med 2019;380:1509–24; 2. Lopes RD, et al. N Engl J Med 2019;380:1509–24. Suppl appendix. Number at risk: Apixaban and aspirin Apixaban and placebo VKA and aspirin VKA and placebo Cumulative incidence of event (%) 0 0 1,145 1,143 1,123 1,126 Days since start of intervention 5 10 15 20 30 1,036 1,075 962 1,007 60 975 1,044 881 947 90 937 1,007 838 917 120 903 975 800 883 150 880 947 776 851 180 485 536 467 528 Apixaban + aspirin: 13.8%2 VKA + aspirin: 18.7%2 VKA + placebo: 10.9%2 Apixaban + placebo: 7.3%2 Apixaban + placebo vs VKA + aspirin:2 11.4% absolute risk reduction (NNT =9) AUGUSTUS was not powered to compare individual primary outcomes for apixaban + placebo vs VKA + aspirin NNT: Number needed to treat Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 26. Secondary Outcomes: Death or Ischemic event Apixaban vs VKA and Aspirin vs Placebo Endpoint Apixaban (N=2306) VKA (N=2308) Hazard Ratio (95%CI) Aspirin (N=2307) Placebo (N=2307) Hazard Ratio (95%CI) Death / Ischemic Events (%) 6.7 7.1 0.93 (0.75-1.16) 6.5 7.3 0.89 (0.71-1.11) Death (%) 3.3 3.2 1.03 (0.75-1.42) 3.1 3.4 0.91 (0.66-1.26) CV Death (%) 2.5 2.3 1.05 (0.72-1.52) 2.3 2.5 0.92 (0.63-1.33) Stroke (%) 0.6 1.1 0.50 (0.26-0.97) 0.9 0.8 1.06 (0.56-1.98) Myocardial Infarction (%) 3.1 3.5 0.89 (0.65-1.23) 2.9 3.6 0.81 (0.59-1.12) Definite or Probable Stent Thrombosis (%) 0.6 0.8 0.77 (0.38-1.56) 0.5 0.9 0.52 (0.25-1.08) Urgent Revascularization (%) 1.7 1.9 0.90 (0.59-1.38) 1.6 2.0 0.79 (0.51-1.21) Hospitalization (%) 22.5 26.3 0.83 (0.74-0.93) 25.4 23.4 1.10 (0.98-1.24) All patients were concomitantly receiving P2Y12 therapy Lopes RD, et al. N Engl J Med 2019;380:1509–24
  • 27. Death/hospitalization Lopes RD, et al. N Engl J Med 2019;380:1509–24. Number at risk: Apixaban VKA Cumulative incidence of event (%) 0 0 Days since randomisation 10 20 30 40 30 60 90 120 150 180 HR=0.83 (95% CI: 0.74, 0.93); p=0.002; ARR=3.9%; NNT=26 VKA: 27.4% Apixaban: 23.5% Apixaban vs VKA 2,306 2,308 2,090 2,035 1,965 1,885 1,881 1,805 1,821 1,732 1,772 1,673 947 1,001 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not Recommended”
  • 28. Death/hospitalization NS, not significant. Lopes RD, et al. N Engl J Med 2019;380:1509–24. Number at risk: Aspirin Placebo Cumulative incidence of event (%) 0 0 Days since randomisation 10 20 30 40 30 60 90 120 150 180 HR=1.08 (95% CI: 0.96, 1.21); p=NS Placebo: 24.7% Aspirin: 26.2% Aspirin vs placebo 2,307 2,307 2,042 2,083 1,909 1,941 1,822 1,864 1,752 1,801 1,699 1,746 951 997 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 29. Death/hospitalisation1 AUGUSTUS was not powered to compare individual primary outcomes for apixaban + placebo vs VKA + aspirin 1. Lopes RD, et al. N Engl J Med 2019;380:1509–24; 2. Lopes RD, et al. N Engl J Med 2019; suppl appendix. Number at risk: Apixaban and aspirin Apixaban and placebo VKA and aspirin VKA and placebo Cumulative incidence of event (%) 0 0 Days since randomisation 10 20 30 40 30 60 90 120 150 180 Apixaban + aspirin: 24.9%2 VKA + aspirin: 27.5%2 VKA + placebo: 27.3%2 Apixaban + placebo: 22.0%2 Apixaban + placebo vs VKA + aspirin:2 5.5% absolute risk reduction (NNT=18) 1,153 1,153 1,154 1,154 1,026 1,064 1,016 1,019 970 995 939 946 923 958 899 906 888 933 864 868 863 909 836 837 459 488 492 509 NNT: Number needed to treat Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 30. Secondary End Point: Death & Hospitalization
  • 31. 31 Amit N. Vora et al. Circulation. 2019;140:1960–1963
  • 32. 32 All-cause hospitalization HR 0.83 (95% CI 0.74–0.93); p=0.002 Cardiovascular hospitalization HR 0.81 (95% CI 0.71–0.94); p=0.004 Bleeding-related hospitalization HR 0.65 (95% CI 0.50–0.86); p=0.003 Apixaban VKA Apixaban VKA Apixaban VKA Amit N. Vora et al. Circulation. 2019;140:1960–1963 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 33. 33 All-cause hospitalization HR 1.10 (95% CI 0.98–1.24); p=0.104 Cardiovascular hospitalization HR 0.99 (95% CI 0.86–1.14); p=0.862 Bleeding-related hospitalization HR 2.11 (95% CI 1.58–2.81); p<0.001 Aspirin Placebo Aspirin Placebo Aspirin Placebo Amit N. Vora et al. Circulation. 2019;140:1960–1963 Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended
  • 36. Ischemic outcomes Endpoint Apixaban (N=2,306) VKA (N=2,308) HR (95% CI) Death/ischaemic events (%) 6.7 7.1 0.93 (0.75, 1.16) Death (%) 3.3 3.2 1.03 (0.75, 1.42) CV death (%) 2.5 2.3 1.05 (0.72, 1.52) Stroke (%) 0.6 1.1 0.50 (0.26, 0.97) Myocardial infarction (%) 3.1 3.5 0.89 (0.65, 1.23) Definite or probable stent thrombosis (%) 0.6 0.8 0.77 (0.38, 1.56) Urgent revascularisation (%) 1.7 1.9 0.90 (0.59, 1.38) Hospitalisation (%) 22.5 26.3 0.83 (0.74, 0.93) Lopes RD, et al. N Engl J Med 2019;380:1509–24. Apixaban vs VKA
  • 37. Ischemic outcomes Endpoint Aspirin (N=2,307) Placebo (N=2,307) HR (95% CI) Death/ischaemic events (%) 6.5 7.3 0.89 (0.71, 1.11) Death (%) 3.1 3.4 0.91 (0.66, 1.26) CV death (%) 2.3 2.5 0.92 (0.63, 1.33) Stroke (%) 0.9 0.8 1.06 (0.56, 1.98) Myocardial infarction (%) 2.9 3.6 0.81 (0.59, 1.12) Definite or probable stent thrombosis (%) 0.5 0.9 0.52 (0.25, 1.08) Urgent revascularisation (%) 1.6 2.0 0.79 (0.51, 1.21) Hospitalisation (%) 25.4 23.4 1.10 (0.98, 1.24) Lopes RD, et al. N Engl J Med 2019;380:1509–24. Aspirin vs placebo “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2
  • 38. Rate of Stent Thrombosis at 6 Months According to Different Definitions 0 0.25 0.5 0.75 1 Definite stent thrombosis Definite/probable stent thrombosis KM Rate at 6 Months n=20 n=30 Lopes et al. Circulation. 2020;141:781–783
  • 39. Definite/Probable Stent Thrombosis According to Antithrombotic Regimen — VKA + Aspirin — Apixaban + Aspirin — VKA + No Aspirin — Apixaban + No Aspirin Lopes et al. Circulation. 2020;141:781–783 “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021
  • 40. Endpoint Aspirin (N=2,277) Placebo (N=2,279) HR (95% CI) ISTH major or CRNM bleeding, n (%) 367 (16.1) 204 (9.0) 1.89 (1.59, 2.24) Definite or probable stent thrombosis, n (%) 11 (0.63) 19 (1.08) 0.58 (0.28, 1.22) AUGUSTUS: Bleeding Events vs Stent Thrombosis Events Bleeding events are much more common than stent thrombosis events in AUGUSTUS NNT at 6 months: 222 NNH at 6 months: 41 (major bleeding) NNT at 1 month: 176 NNH at 1 month: 100 (major bleeding) NNT: Number needed to treat NNH: Number needed to harm Lopes et al. Circulation. 2020;141:781–783 Lopes RD, et al. N Engl J Med 2019;380:1509–24. “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021
  • 41. TILL WHAT TIME PERIOD DOES THE REMOVAL OF ASPIRIN INFLUENCE ISCHEMIC OUTCOMES? How early we can stop? Or To continue indefinitely? Is there an Answer?
  • 42. Ischemic Events With Placebo vs. Aspirin • Though not statistically significant, there were numerically more of some ischemic events in patients assigned placebo than aspirin: Aspirin Placebo • Death 72 (3.1%) vs. 79 (3.4%) • Cardiovascular Death 53 (2.3%) vs. 58 (2.5%) • Stroke 20 (0.9%) vs. 19 (0.8%) • Stent thrombosis (definite or probable) 11 (0.5%) vs. 21 (0.9%) • Myocardial infarction 68 (2.9%) vs. 84 (3.6%) • Urgent revascularization 37 (1.6%) vs. 47 (2.0%) Adapted from: Lopes RD, et al. N Engl J Med 2019;380:1509-24 • Analysis of the stent thrombosis events suggested that most of the increased risk was early, within 30 days of randomization Lopes RD, et al. Circulation 2020; 141:781-783
  • 43. Tradeoff Between Bleeding and Ischemic Events There is a temporal component to the balance of bleeding and ischemic risk • Recurrent ischemic events (specifically stent thrombosis) tend to occur early after PCI • Bleeding risk is cumulative and is higher with long-term, potent antithrombotic therapy Schomig A, et al. Heart 2009;95:1280–1285
  • 44. Severe Bleeding and Ischemic Outcomes Randomization to 30 Days Fatal, ICH, Major Bleeding CV Death, Stroke, MI, Stent Thrombosis Alexander et a Circulation. 2020;141:1618–1627
  • 45. Severe Bleeding and Ischemic Outcomes 30 Days to 6 Months Fatal, ICH, Major Bleeding CV Death, Stroke, MI, Stent Thrombosis Alexander et a Circulation. 2020;141:1618–1627
  • 46. Conclusion “There is limited experience of coadministration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, coadministration of these products with apixaban is not recommended Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 Lopes RD, et al. N Engl J Med 2019;380:1509–24 • Among patients with AF and recent PCI including current generation of drug- eluting stent, definite or probable stent thrombosis is rare and occurs more frequently early after PCI. • These data support the use of Apixaban and a P2Y12 inhibitor without aspirin during the first 6 months for most patients, considering the almost 2-fold increase in bleeding with aspirin use. • In patients with a high risk of stent thrombosis and an acceptable risk of bleeding, using aspirin up to 30 days after PCI should be considered. Further studies to identify patients who might benefit the most from this strategy are warranted.
  • 47. Finding the Antithrombotic Sweet Spot Antithrombotic Sweet Spot Risk of Ischemic Events Risk of Bleeding Events The right combination of antithrombotic agents at the right dose and duration to reduce ischemic events as much as possible at a minimal cost of bleeding Lopes RD et.al. Eur Heart J 2019 Dec 7;40(46):3768-3770
  • 49. 2019 ESC Guidelines-management of chronic coronary syndromes CCS - Chronic Coronary Syndrome AF - Atrial Fibrillation Knuuti et al. Eur Heart J 2020 Jan
  • 50. 2019 AHA/ACC/HRS Focused Update January CT et al; J Am Coll Cardiol 2019 Jul 9;74(1):104-132 Dropping ASA is recommended for AF/ACS patients …but, the strength of recommendation and quality of evidence are both only moderate.
  • 51. 2020 ESC AF Guideline AF and ACS/PCI CAD – Coronary Artery Disease Hindricks et al. European Heart Journal, Volume 42, Issue 5, 1 February 2021, Pages 373–498
  • 52. 2020 ESC AF Guideline AF and ACS/PCI: Recommendations for patients with AF and an ACS, PCI, or CCS Hindricks et al. European Heart Journal, Volume 42, Issue 5, 1 February 2021, Pages 373–498
  • 53. Patient • Aspirin 75mg OD • Clopidogrel 75mg OD • Apixaban 5mg BD for a month Thereafter • Clopidogrel 75mg OD • Apixaban 5mg BD
  • 54. TAKE HOME MESSAGE • 1.AF with PCI is a double edged sword, most of the patients have multiple comorbidities keeping them at risk of bleeding events as same as thrombotic events. • 2.These patients should be given Dual Inhibition for duration depending on their risk and thereafter to continue single antiplatelet and NOACs. • 3.NOACs are proven to be noninferior to warfarin in AF and PCS cases and are more useful conventionally with no monitoring. • 4.Cost factor and Availability of Ideal reversal agent is the issue with NOACs. • 5.Subset of patients with VHD, Prosthetic valve and having ACS to be evaluated in trials..