Triple Therapy Post-Percutaneous Coronary Intervention (PCI) and/or Acute Coronary Syndrome (ACS): How and When to Ditch the Third Wheel

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1 Triple Therapy Post-Percutaneous Coronary Intervention (PCI) and/or Acute Coronary Syndrome (ACS): How and When to Ditch the Third Wheel Elaine Lum (PharmD) Vancouver General Hospital April 19,

2 Presenter Disclosure Presenter s Name: Elaine Lum I have no current or past relationships with commercial entities Speaking Fees for current learning activity: I will be receiving a speaker s fee from CSHP for this learning activity

3 Commercial Support Disclosure This Learning Activity has received no financial or in-kind support from any commercial or other organization

4 Acknowledgement Some slides have been taken directly from the CCS educational slide deck following their guidelines I have cited the Canadian Journal of Cardiology and the Canadian Cardiovascular Society as references I have not used any Canadian Cardiovascular Society logos or trademarks on any slides I have not modified the slide content Wording of the recommendations from the published guidelines have not been modified 4

5 Learning Objectives By the end of this presentation you will be able to: 1. Describe practical considerations when determining the best antiplatelet and/or anticoagulation for your patient with atrial fibrillation (AF) presenting immediately post-percutaneous coronary intervention (PCI) to prevent stent thrombosis and embolic stroke. 2. Locate the most current and relevant clinical resources to assist in the choosing the best antiplatelet and anticoagulation therapy for patients post-pci with AF 3. Recognize landmark trials that support the recommendations in the new 2018 Canadian Cardiovascular Society (CCS) Anti-platelet guidelines around antiplatelet and anticoagulation in patients post-pci with AF 4. Apply new guideline recommendations to a specific patient based on his/her risk factors

Case Difficulty Ratings https://www.warn.

6 Case Difficulty Ratings 6

7 Case HB (Ms. High-risk Bleeder) ID: HB, 89 year old female (wt = 55kg; ht=5 1 ), presenting with STEMI treated with a single DES in the mid-rca. Post-PCI patient developed AF with rapid ventricular response (HR = 132bpm; irregularly irregular). Past Medical History: Long standing diverticulosis with chronic lower GI bleeding. Medications PTA: None Medications started in hospital: ASA 80mg po DAILY Ticagrelor 90mg po BID Metoprolol 50mg po BID Ramipril 5mg po DAILY Atorvastatin 80mg daily 7

8 Case HB (Ms. High-risk Bleeder) Echocardiogram: EF = 55%, severe atrial enlargement. Left atrial size = 4.7cm (normal = 3.9cm for females) Labs: Hg = 90g/dL; SCr = 60umol/L egfr = 80mL/min; all other bloodwork WNL Course in Hospital: - 3 days post-procedure, patient reports melena and Hg drops from 89 to 70g/dL - GI consulted, lower GI scope confirmed lower GI bleed secondary diverticulosis. No treatment planned. Surgical intervention in future if bleeding worsens and when patient off DAPT - AF persists, but rate controlled at 96bpm. No cardioversion planned as patient is asymptomatic. Unlikely to convert due large left atrial size 8

9 Case HB (Ms. High-risk Bleeder) What would you recommend for prevention of stroke and stent thrombosis for HB? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B. Rivaroxaban 15mg daily + Clopidogrel 75mg po daily C. Apixaban 2.5mg BID + Clopidogrel 75mg po daily + ASA EC 81mg po daily D. Dabigatran 110mg po BID + Clopidogrel 75mg daily E. ASA 80mg po daily + Clopidogrel 75mg po daily F. ASA 80mg po daily + Ticagrelor 90mg po BID 9

10 Case SR (Mr. Stroke Risk) ID: SR, 75 year old male (wt = 80kg; ht=5 9 ), presenting with NSTEMI treated with a 3 x DES in the proximal LAD (long lesion; >60mm full metal jacket Past Medical History: Long standing CAD, MI at age 60y; HFrEF (EF = 30%); diabetes, hypertension, cardioembolic stroke x 3 (last stroke 4 months ago) Medications PTA: Apixaban 5mg BID Carvedilol 25mg BID Ramipril 10mg daily Spironolactone 25mg daily Amlodipine 10mg daily Rosuvastatin 40mg daily Metformin 1000mg po BID 10

11 Case SR (Mr. Stroke Risk) Medications in hospital: IV Heparin protocol apixaban held ASA EC 80mg daily Ticagrelor 90mg po BID Carvedilol 25mg BID Ramipril 10mg daily Spironolactone 25mg daily Amlodipine 10mg daily Rosuvastatin 40mg daily Metformin 1000mg po BID Labs: CBC, Lytes WNL, SCr = 90 umol/l egfr = 75mL/min 11

12 Case SR (Mr. Stroke Risk) What would you recommend for prevention of stroke and stent thrombosis for SR? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B. Warfarin (INR 2-3) + Clopidogrel 75mg po daily + ASA EC 80mg daily C. Rivaroxaban 15mg daily + Clopidogrel 75mg daily D. Rivaroxaban 15mg daily + Clopidogrel 75mg daily + ASA EC 80mg daily (for up to 6 months) E. Rivaroxaban 2.5mg BID + Clopidogrel 75mg daily + ASA EC 80mg daily F. Rivaroxaban 20mg daily + Clopidogrel 75mg daily G. Rivaroxaban 20mg daily + Clopidogrel 75mg + ASA EC 80mg daily (up to 6 months) H. Apixaban 5mg BID + Clopidogrel 75mg daily I. Apixaban 5mg BID + Clopidogrel 75mg daily + ASA EC 80mg daily (up to 6 months) J. Dabigatran 110mg PO BID + Clopidogrel 75mg daily K. Dabigatran 150mg PO BID + Clopidogrel 75mg daily L. Any of the options above (but substitute clopidogrel with ticagrelor) 12

13 How to Choose the best Triple Therapy for your AF Patients Post-PCI 13

14 Questions to ask yourself What is your patient s stroke risk? What is your patient s risk of thrombotic events (ischemic event or stent thrombosis)? What your patient s bleed risk? What is the most-effective agent for stroke prevention in AF? What is the safest SPAF agent for this specific patient? What is the safest combination for your patient? 14

15 Stroke Prevention in AF: Basics 15

16 ENGAGE AF-TIMI 48 N Engl J Med 2013;369: DOI: /NEJMoa High dose edoxaban (60mg/day) was non-inferior to warfarin wrt stroke/systemic embolic events with less major bleeding (dose reduced by 50% if CrCl = 30 to 50 ml/min, wt 60 kg, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors). 16

17 ACTIVE-A Lancet 2006; 367: Design: Multi-centre, double-blind, RCT Population n=7554 Patients with AF plus 1 risk factor for stroke who were ineligible to take OAC Intervention Comparator Clopidogrel 75mg/day plus ASA mg/day Placebo plus ASA Outcome 1 : first occurrence of stroke, non-cns systemic embolism, MI or vascular death: 6.8% vs. 7.6%; p= 0.01 Time frame Safety: Major bleeding: 2% vs. 1.3% p < Enrollment period: June 2003 and May 2006 Median follow-up 3.6 years 17

18 Case EC (Mr. Elective Cath) ID: AF, 64 year old male, referred to cardiac cath lab for elective angiogram for new symptoms of chest pain on exertion. Patient was subsequently treated with PCI with single drug-eluting stent (DES) in the distal LAD Past Medical History: lone AF (diagnosed 10 years ago), CHADS2 score = 0, newly diagnosed coronary artery disease Medications PTA: Bisoprolol 5mg po daily for rate control, ASA started recently for new symptoms of angina on exertion. Post-procedure, patient was given a prescription for the following: ASA 80mg po DAILY Clopidogrel 75mg po DAILY Bisoprolol 5mg DAILY Atorvastatin 80mg daily Are there any drug-related problems? 26

19 Which reference would you look up to find the answer? A. CHEST Guidelines: Antithrombotic Therapy for Atrial Fibrillation? B. AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes? C. CCS Atrial Fibrillation Guidelines? D. CCS Antiplatelet Guidelines? 27

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25 Acknowledgement 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy Shamir R. Mehta, MD, MSc, Kevin R. Bainey, MD, Warren J. Cantor, MD, Marie Lordkipanidzé, BPharm, PhD, Guillaume Marquis- Gravel, MD, Simon D. Robinson, MBChB, MD, Matthew Sibbald, MD, PhD, Derek Y. So, MD, Graham C. Wong, MD, MPH, Joseph G. Abunassar, MD, Margaret L. Ackman, PharmD, Alan D. Bell, MD, Raymond Cartier, MD, James D. Douketis, MD, Patrick R. Lawler, MD, MPH, Michael S. McMurtry, MD, Jacob A. Udell, MD, Sean van Diepen, MD, Subodh Verma, MD, G.B. John Mancini, MD, John A. Cairns, MD, Jean-François Tanguay, MD Paul W. Armstrong, MD, Akshay Bagai, MD, MHS, Claudia Bucci, PharmD, Jean-Pierre Déry, MD, Jean Diodati, MD, Jocelyn Dupuis, MD, PhD, David Fitchett, MD, Michael P. Love, MB, ChB, MRCP, MD, Robert Welsh, MD Shamir R. Mehta, MD, MSc, Kevin R. Bainey, MD, Warren J. Cantor, MD, Marie Lordkipanidzé, BPharm, PhD, Guillaume Marquis-Gravel, MD, Simon D. Robinson, MBChB, MD, Matthew Sibbald, MD, PhD, Derek Y. So, MD, Graham C. Wong, MD, MPH, Joseph G. Abunassar, MD, Margaret L. Ackman, PharmD, Alan D. Bell, MD, Raymond Cartier, MD, James D. Douketis, MD, Patrick R. Lawler, MD, MPH, Michael S. McMurtry, MD, Jacob A. Udell, MD, Sean van Diepen, MD, Subodh Verma, MD, G.B. John Mancini, MD, John A. Cairns, MD, Jean-François Tanguay, MD Paul W. Armstrong, MD, Akshay Bagai, MD, MHS, Claudia Bucci, PharmD, Jean-Pierre Déry, MD, Jean Diodati, MD, Jocelyn Dupuis, MD, PhD, David Fitchett, MD, Michael P. Love, MB, ChB, MRCP, MD, Robert Welsh, MD Canadian Journal of Cardiology Volume 34, Issue 3, Pages (March 2018) DOI: /j.cjca Copyright 2018 Terms and Conditions

Back to Case EC (Mr. Elective Cath) ID: EC, 64 year old male, referred to cardiac cath lab for elective angiogram for new symptoms of chest pain on exertion.

27 Back to Case EC (Mr. Elective Cath) ID: EC, 64 year old male, referred to cardiac cath lab for elective angiogram for new symptoms of chest pain on exertion. Patient was subsequently treated with PCI with single drug-eluting stent (DES) in the distal LAD Past Medical History: lone AF (diagnosed 10 years ago), CHADS2 score = 0, newly diagnosed coronary artery disease Medications PTA: Bisoprolol 5mg po daily for rate control, ASA started recently for new symptoms of angina on exertion. Post-procedure, patient was given a prescription for the following: ASA 80mg po DAILY Clopidogrel 75mg po DAILY Bisoprolol 5mg DAILY Atorvastatin 80mg daily Are there any drug-related problems? No. Patient is 64y. CHADS2 score = 0. Patient should be ASA + Clopidogrel. 37

28 QUESTION Why do we use DAPT post-pci? Why can t we use just use warfarin + ASA (or OAC + ASA)? 38

29 ISAR N Eng J Med 1996; Design: Prospective, Randomized, Single-centre trial Population Intervention Comparato r Outcome Time frame n=517 patients with successful PTCA Indications for stenting: extensive coronary artery dissection after PTCA, complete vessel closure, residual stenosis of 30%, lesions in venous bypass grafts Exclusion: cardiogenic shock, mechanical ventilation, stent was for bridging to aorto-coronary bypass grafting Heparin continued until 12h post PTCA + ASA 100mg BID plus TICLOPIDINE 250mg BID x 4 weeks Heparin continued until 5-10d post PTCA + ASA 100mg BID + Phenprocoumon (Target INR = ) x 4 weeks Primary Cardiac Outcome: Cardiac death, MI, CABG, repeat revascularization of stented vessel Primary Non-cardiac Outcome: Non-cardiac death, CVA, severe PVD, severe hemorrhagic event Secondary outcomes: combined cardiac and non-cardiac and occlusion in stented vessel Follow up: All patients hospitalized for 10 days for surveillance. Patients seen 1 month post procedure. Repeat angiogram done if suspected myocardial ischemia 40

30 ISAR N Eng J Med 1996; ARR = 4.6% NNT = 22 x 4 weeks 43

31 STARS N Eng J Med 1998; 339: Design: Prospective, Randomized, multi (50)-centre trial Population Intervention n=1965 patients with 1 or 2 target lesions with 60% stenosis in 3-4 mm native coronary artery (NOT involving left main or major coronary bifurcation) Exclusion: additional stenoses within the target vessel, recent acute MI (within 7 days), bleeding diathesis, current treatment with abciximab, planned angioplasty of another lesion within 30 days ASA 325mg DAILY + Ticlopidine 250mg po BID x 4 weeks Comparator Outcome Time frame 325mg po DAILY Vs. ASA 325mg po DAILY + Warfarin (INR = ) x 4 weeks Primary Endpoint: death, revascularization of target lesion, angiographic evidence of thrombosis or MI within 30 days Follow up: 30 days Enrollment period: February 1996 to November

32 STARS N Engl J Med 1998;339: ARR = 3.1% NNT = 33 x 4 weeks 3.6% 2.7% 0.5% Primary endpoint: death, revascularization of the target lesion, angiographically evident thrombosis, or myocardial infarction within 30 days 49

33 QUESTION Why do we use DAPT post-pci? Why can t we use just use warfarin + ASA (or OAC + ASA)? ANSWER: ISAR and STARS demonstrated that DAPT (ASA + ticlopidine) reduced major adverse cardiac events compared to ASA + VKA ASA is a relatively weak inhibitor of overall platelet activation compared to thienopyridines and warfarin is not useful in preventing platelet activation and thrombus formation in the setting of vessel wall damage Circulation. 2017;135:

35 What are High Risk Features? 55

36 56

Interpreting the Angiogram LM = left main (left coronary artery) LAD (left anterior descending) D1 and D2 = diagonal branches Septal branches Cx = circumflex M1 and M2 =

37 Interpreting the Angiogram LM = left main (left coronary artery) LAD (left anterior descending) D1 and D2 = diagonal branches Septal branches Cx = circumflex M1 and M2 = marginal branches RCA = right coronary artery AM = acute marginal branch AV node branch PDA = posterior descending artery 57

38 Resolute = 2 nd generation zotarolomus eluting stent 58

Journal of the American College of Cardiology May 2005, 45 (10) 1570-1573; DOI: 10.1016/j.jacc.2005.01.049 Figure 1. A. Diffuse disease of the left anterior descending coronary artery B.

39 Journal of the American College of Cardiology May 2005, 45 (10) ; DOI: /j.jacc Figure 1. A. Diffuse disease of the left anterior descending coronary artery B. treated with three sirolimus-eluting stents (lesion > 60mm) = FULL METAL JACKET C. Angiographic follow-up at six months with focal in-stent restenosis is shown 60

40 Chronic Total Occlusion (CTO) Circulation. 2011;123: CTO = heavy atherosclerotic plaque burden resulting in complete (or nearly complete) occlusion of the artery Total occlusion must be present for at least 3 months to be considered a true CTO (clinically distinct from ACS) Possible benefits of treating CTO with PCI Improvement in angina symptoms Improvement in LV Function Improvement in survival Figure A. Mustafa Zakkar et al. Circulation. 2016;133: Limitations of treating CTO with PCI Historically low PCI success rates (~70% vs. 97% in non-cto PCI) Increased complexity of CTO procedures Inability to see the course of the vessel at the site of occlusion Often longer length of lesions Difficult to deliver coronary balloons an stents into fibrotic, calcific lesions Potential for important complications Longer procedure time greater exposure to radiation and contrast increased risk of vessel dissection, perforation and tamponade 61

Bifurcation Treated with 2 Stents https://img.

41 Bifurcation Treated with 2 Stents 62

42 Canadian Journal of Cardiology 34 (2018)

43 Mr. EC Returns 1 year later with UA ID: EC, now 65 years old, presents with unstable angina and is treated with PCI to the proximal LAD Past Medical History: AF, CHADS2 score = 0, CAD treated with PCI 1 year ago Medications PTA: ASA 80mg po DAILY Clopidogrel 75mg po DAILY Bisoprolol 5mg DAILY Atorvastatin 80mg daily Progress in Hospital: Post-PCI, EC is chest pain free. BP = 100/60, HR = 63 (irregularly, irregular). Otherwise normal physical exam. Medications in hospital: ASA 80mg DAILY Ticagrelor 90mg po BID Bisoprolol 5mg DAILY Ramipril 5mg DAILY Atorvastatin 80mg daily Are there any drug-related problems? 64

44 What would you recommend for EC? A. No change. Patient s CHADS2 score is 0. ASA + Ticagrelor is adequate. B. OAC + ASA + ticagrelor C. OAC + ASA + clopidogrel D. OAC + clopidogrel E. OAC + ticagrelor 65

45 Ditching the third wheel: How and Why 66

47 Canadian Journal of Cardiology , DOI: ( /j.cjca ) 68

48 WOEST Lancet 2013; 381: Design: Multi-centre, open-label RCT (Belgium and Netherlands) Population n=573 Adults receiving OAC for long-term indication ( 1y after study) and undergoing PCI Intervention Comparator Clopidogrel + OAC (Clopidogrel LD [300mg if > 24h or 600mg > 4h pre-pci, ASA mg/day, INR target = 2.0) Triple therapy (ASA/clopidogrel/OAC) Outcome Time frame 1 : Bleeding episode within 1 year 2 : Composite of MI, CVA, target vessel revascularization, stent thrombosis Follow up: up to 1 yr Randomization period: November 2009 to November

49 Lancet 2013; 381:

50 WOEST: Primary Endpoint (Any Bleeding) Lancet 2013; 381:

51 Ten%20Berg_ESC%20WOEST% ppt 77

52 Ten%20Berg_ESC%20WOEST% ppt 78

53 WOEST Lancet 2013; 381:

54 WOEST: Secondary Endpoint (death, MI, CVA, target vessel revascularization and stent thrombosis) Lancet 2013; 381:

55 WOEST Lancet 2013; 381:

56 WOEST: Limitations Small, open-label design Study powered to show superiority on the primary bleeding endpoint of any bleeding, but not powered to show non-inferiority on the secondary endpoints Underpowered to resolve with confidence that there is no excess of stent thrombosis when ASA omitted TIMI major bleeding similar in both groups. Reduction in bleeding driven by minor bleeding PPI s only used in ~ 40% patients (lower than expected)? Reason for high incidence of bleeding Cannot extrapolate to newer, higher-potency antiplatelet agents

57 QUESTION: If you decide to use triple therapy, how long should you continue the clopidogrel? 98

58 ISAR Triple J Am Coll Cardiol 2015;65: Design: 3-centre, open-label RCT (Europe) Population n=614 Patients receiving OAC who underwent DES implantation Intervention ASA + OAC + 6 week clopidogrel Comparator ASA + OAC + 6 month clopidogrel Outcome 1 : composite of death, MI, definite stent thrombosis, CVA or TIMI major bleed at 9 months 2 : Composite of MI, CVA, target vessel revasc, stent thrombosis Time frame Follow up: 9 months Randomization period: Sep 2008 to Dec

59 ISAR Triple J Am Coll Cardiol 2015;65:

60 ISAR Triple J Am Coll Cardiol 2015;65:

61 ISAR Triple: Primary Endpoint J Am Coll Cardiol 2015;65: Primary endpoint (cumulative incidence of death, myocardial infarction, stent thrombosis, stroke or Thrombolysis In Myocardial Infarction [TIMI] major bleeding), 103

62 ISAR Triple: Bleeding Endpoint J Am Coll Cardiol 2015;65: bleeding endpoint (TIMI major bleeding) at 9 months 104

63 ISAR Triple: Limitations and Conclusion J Am Coll Cardiol 2015;65: Open-label design Not specifically powered to detect differences of individual components of composite endpoint Role of new oral anticoagulants or new antiplatelet agents not investigated Conclusion: 6 weeks of TT was not superior to 6 months with respect to net clinical outcomes Bottom-line: Weigh patient s individual ischemic and bleeding risk when choosing shorter or longer duration triple therapy 105

64 QUESTION: If you decide to use triple therapy, how long should you continue the clopidogrel? ANSWER: Short course (6 weeks) was not superior to longer course (6 months) in ISAR Triple In the setting of AF, current guidelines recommend - 12 months of clopidogrel post-pci in ACS months of clopidogrel in elective PCI with DES (up to 12 months in high risk patients) - 1 month in elective PCI with BMS (up to 12 months in high risk patients) 106

65 QUESTION Can you use NOACs as OAC combined with SAPT in patients undergoing PCI who require stroke prevention in atrial fibrillation? If so, which one would you use? A. Apixaban? B. Dabigatran? C. Edoxaban? D. Rivaroxaban? 119

66 PIONEER-AF N Engl J Med 2016;375: DOI: /NEJMoa Open-label, randomized, controlled, international multicentre trial Population Intervention Comparator Outcome Time frame n=2024 patients with non-valvular AF who had undergone PCI with stenting Exclusion: history of CVA or TIA, clinically significant GI bleed within 12 months before randomization, CrCl < 30mL/min, anemia with unknown cause, or condition known to increase risk of bleed Group 1: Rivaroxaban 15mg po DAILY (reduced to 10mg/day if they had CrCl =30-50mL/min) + P2Y12 inhibitor (clopidogrel 75mg/day; prasugrel 10mg/day or ticagrelor 90mg po BID 15% of participants) x 12 months Group 2: Rivaroxaban 2.5mg PO BID + DAPT x 1, 6 or 12 months. Those receiving 1 or 6 months, switched to rivaroxaban 15mg daily (or 10mg/day if CrCL 30-50mL/min) + ASA mg/day for remainder of 12 month period VKA (INR target = 2-3)+ DAPT x 1, 6, 12 months + DAPT (DAPT = ASA mg + P2Y12 inhibitor as above) 1 safety outcome: clinically significant bleeding (composite of TIMI major + minor bleeding or bleeding requiring medical attention) 2 outcomes: major adverse CV event (CV death, MI, CVA), stent thrombosis Enrollment period: May 2013 to July 2015 Follow-up: 12 months 120

67 PIONEER-AF N Engl J Med 2016;375: DOI: /NEJMoa

68 PIONEER-AF N Engl J Med 2016;375: DOI: /NEJMoa

69 PIONEER-AF N Engl J Med 2016;375: DOI: /NEJMoa

70 01/Atrial_Fib_March2 015_PrintLocked.pdf 125

71 PIONEER-AF: Primary Safety Endpoint N Engl J Med 2016;375: DOI: /NEJMoa Hazard ratio for group 1 vs. group 3, 0.59 (95% CI, ) P<0.001 Hazard ratio for group 2 vs. group 3, 0.63 (95% CI, ) P<

72 PIONEER-AF: Secondary Efficacy Endpoint N Engl J Med 2016;375: DOI: /NEJMoa Hazard ratio for group 1 vs. group 3, 1.08 (95% CI, ) P=0.75 Hazard ratio for group 2 vs. group 3, 0.93 (95% CI, ) P=

73 PIONEER-AF: Limitations N Engl J Med 2016;375: DOI: /NEJMoa Open-label design Small sample size Not powered to establish superiority or non-inferiority for efficacy endpoints Wide confidence intervals for efficacy endpoints Unconventional dosing 2.5mg BID not available in North America 15mg DAILY not approved for SPAF or ACS Duration of DAPT based on physician preference (non-randomized) Imbalanced groups across DAPT durations within each strata Little ethnic diversity (<7% non-white) Limited presentation of adverse events Short follow-up period (1 year) 129

74 RE-DUAL N Engl J Med 2017;377: DOI: /NEJMoa Randomized, open-label, multi-centre controlled trial Population Intervention Comparator Outcome Time frame n=2725 patients with non-valvular AF who had undergone PCI (for stable angina or ACS); age 18y Exclusion: bioprosthetic or mechanical valve, CrCl <30mL/min Dabigatran 110mg BID + clopidogrel or ticagrelor (for at least 12 months) or Dabigatran 150mg BID + clopidogrel or ticagrelor (for at least 12 months) Outside the US, patients 80y were given 110mg BID Warfarin (INR 2-3) + clopidogrel or ticagrelor (for at least 12 months) + ASA ( 100mg/day for 1 to 3 months; ASA x 1 month in BMS; 3 mos in DES) 1 : Major or clinically relevant nonmajor bleeding (ISTH definition) 2 : Non-inferiority of dual therapy with dabigatran to TT with warfarin with respect to composite thromboembolic endpoints (MI, CVA, systemic embolism or unplanned revascularization) Enrollment period: July 21, 2014 to October 31, 2016 Median follow-up: 14 months 130

75 RE-DUAL N Engl J Med 2017;377: DOI: /NEJMoa

76 RE-DUAL N Engl J Med 2017;377: DOI: /NEJMoa

77 RE-DUAL: Bleeding Endpoints N Engl J Med 2017;377: DOI: /NEJMoa

78 RE-DUAL: Bleeding Endpoints N Engl J Med 2017;377: DOI: /NEJMoa

79 RE-DUAL: Thromboembolic Endpoints N Engl J Med 2017;377: DOI: /NEJMoa

80 RE-DUAL: Limitations N Engl J Med 2017;377: DOI: /NEJMoa Open-label design Protocol amended to enrol a smaller number of patients limited power to assess thrombotic events Hard to discern relative contributions of the omission of ASA and the type of oral anticoagulant in the dual-therapy groups and the triple-therapy group Not a 2 x 2 factorial design Less than 12% patients on ticagrelor (limited generalizability) 137

81 Ongoing Trials Dual antiplatelet therapy versus oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation and low-to-moderate thromboembolic risk undergoing coronary stenting (MUSICA-2) An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention (AUGUSTUS) Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI) 143

82 QUESTION Can you use NOACs as OAC combined with SAPT in patients undergoing PCI who require stroke prevention in atrial fibrillation? If so, which one would you use? ANSWER: A. Apixaban no RCTs published evaluating safety and efficacy B. Dabigatran YES (RE-DUAL demonstrated 110mg BID dosing + clopidogrel had least bleeding with similar rates of MACE compared to TT with warfarin) C. Edoxaban No RCTs published evaluation safety and efficacy D. Rivaroxaban YES (PIONEER-AF demonstrated 15mg DAILY dosing [reduced to 10mg/day if CrCl = 30 50mL/min] + clopidogrel or 2.5mg BID + ASA + clopidogrel had lower rates of bleeding compared to TT with warfarin with similar rates of MACE 146

83 Question Can you use NOACs in a TRIPLE THERAPY regimen for stroke prevention in AF post-pci? Is it safe? Is it effective? 147

84 APPRAISE-2 N Engl J Med 2011;365: Design: Multi-centre, double-blind, placebo-controlled RT Population n=7392 Patients with recent ACS plus 2 risk factors for recurrent ischemic events Intervention Apixaban 5mg BID Comparator Placebo Outcome Time frame 1 : CV death, MI or ischemic CVA (7.5% vs. 7.9% p=0.51) Safety: TIMI major bleeding 1.3% vs. 0.5% p=0.001 (greater number of intracranial and fatal bleeding with apixaban) Enrollment period: June 2003 and May 2006 Median follow-up 241 days (stopped early due to increased risk of major bleeding and lack of benefit) 148

85 ATLAS ACS-2-TIMI-51 J Am Coll Cardiol 2013;61: Design: Multi-centre, double-blind, placebo-controlled RT Population n=15,526 Patients with recent ACS Intervention Comparator Rivaroxaban 2.5mg BID vs. Rivaroxaban 5mg BID (On top of usual therapy ASA + clopidogrel) Placebo Outcome Time frame 1 : CV death, MI or CVA (ARR=1.6% with 2.5mg BID) Safety: TIMI major bleeding (non-cabg related) (ARI=1.2% with 2.5mg BID dose) Enrollment period: November 2008 to September 2011 Mean follow-up: 13 months (up to 31 months) 150

86 RE-DEEM Eur Heart J Nov;32(22): doi: /eurheartj/ehr113 Design: Prospective, double-blind, multi-centre, placebo-controlled dose-escalation Phase 2 Trial Population Intervention Comparator n=1861 Patients hospitalized with NSTEMI or STEMI within last 14 days receiving DAPT (ASA + clopidogrel or other thienopyridine) Exclusion: ongoing or planned VKA, severe disabling CVA in last 6 mos or any CVA in last 14d, increased risk of bleeding, history of severe bleeding, GI hemorrhage, lytic within 48h, uncontrolled HTN, Hg < 100, Plt 100, CrCl < 30mL/min Dabigatran 50mg BID or 75mg BID or 110mg BID or 150mg BID Vs. Placebo Outcome Time frame 1 : Major or clinically relevant minor bleeding CV ischemic endpoints: CV death, Non-fatal MI, non-hemorrhagic CVA Mean exposure to study drugs: Dabigatran (159 to 165 days) and Placebo (165 days) 154

87 RE-DEEM Eur Heart J Nov;32(22): doi: /eurheartj/ehr113 ARI = 5.7% NNH =

88 RE-DEEM Eur Heart J Nov;32(22): doi: /eurheartj/ehr

89 Question Can you use NOACs in a TRIPLE THERAPY regimen for stroke prevention in AF post-pci? Is it safe? Is it effective? ANSWER: Triple therapy with NOACs in the setting of AF has only been evaluated with very low dose rivaroxaban (2.5mg BID) in PIONEER-AF, demonstrating 8.6% ARR in clinically significant bleeding compared to TT with warfarin No difference in major adverse CV events Controversies Efficacy of Rivaroxaban 2.5mg BID dose not studied in SPAF Study not powered to evaluate MACE Triple therapy with NOAC in the setting of ACS has been evaluated using rivaroxaban, apixaban and dabigatran (Phase 2 trial) rivaroxaban 2.5mg BID increased TIMI major bleeding (ARI 1.2%) and reduced CV death/mi/cva (ARR=1.6%) when compared to DAPT (ATLAS ACS-2-TIMI-51) Apixaban 2.5mg BID increased risk of major bleed (ARI 0.8%) with no reduction in MACE (APPRAISE- 2) Dabigatran demonstrated dose-related bleeding. Questionable benefit in reducing MACE Safety: NOAC s increase risk of major bleeding when used in conjunction with ASA + clopidogrel compared to DAPT. Rivaroxaban 2.5mg BID + ASA + clopidogrel had less bleeding than TT with warfarin Efficacy: In ACS, NOACs + DAPT have little to no benefit in reducing MACE. In AF + PCI, Rivaroxaban 2.5mg BID + ASA + clopidogrel had similar rates of MACE compared to TT with warfarin 158

90 Question Can you use novel antiplatelet agents (prasugrel or ticagrelor) in a triple therapy regimen? ANSWER: NOT YET In Pioneer-AF: Prasugrel usage: % Ticagrelor usage: 3-5.2% In RE-DUAL, ticagrelor usage was % at 90 days Due to higher bleeding risk with novel antiplatelet agents and limited data, CCS 2018 guidelines recommend using clopidogrel in triple therapy regimens 159

91 Switching 161

92 Canadian Journal of Cardiology 34 (2018)

93 Switching Recommendations Clopidogrel to Ticagrelor Clopidogrel to Prasugrel Prasugrel to Ticagrelor Ticagrelor to Prasugrel Ticagrelor or Prasugrel to clopidogrel Ticagrelor to Clopidogrel Prasugrel to clopidogrel Ticagrelor 180mg x 1, then 90mg BID (regardless of timing of last clopidogrel dose) Prasugrel 60mg x 1, then 10mg DAILY (regardless of timing of last clopidogrel dose) NO load. Ticagrelor 90mg BID, starting at time of the next scheduled prasugrel dose Prasugrel 60mg x 1, then 10mg DAILY, starting at the time of the next scheduled ticagrelor dose In the setting of clinically significant bleeding complication that has resolved, de-escalate to clopidogrel 75mg DAILY In the setting of non-bleeding side-effects: Clopidogrel 600mg x 1 followed by 75mg daily (start at time of next scheduled ticagrelor dose) In the setting of non-bleeding side-effects: No loading dose. Clopidogrel 75mg daily at time of next scheduled prasugrel dose. Canadian Journal of Cardiology 34 (2018) Strong rec; Modquality evidence Strong rec; Modquality evidence Weak rec; very low quality evidence Weak rec; very low-quality evidence Weak rec; very low-quality evidence Weak rec; very low quality evidence Weak rec; modquality evidence 163

Mr. EC Returns 1 year later with UA ID: EC, now 65 years old, presents with unstable angina and is treated with PCI to the proximal LAD Past Medical History: AF, CHADS2 score = 0, CAD treated with

94 Mr. EC Returns 1 year later with UA ID: EC, now 65 years old, presents with unstable angina and is treated with PCI to the proximal LAD Past Medical History: AF, CHADS2 score = 0, CAD treated with PCI 1 year ago Medications PTA: ASA 80mg po DAILY Clopidogrel 75mg po DAILY Bisoprolol 5mg DAILY Atorvastatin 80mg daily Progress in Hospital: Post-PCI, EC is chest pain free. BP = 100/60, HR = 63 (irregularly, irregular). Otherwise normal physical exam. Medications in hospital: ASA 80mg DAILY Ticagrelor 90mg po BID Bisoprolol 5mg DAILY Ramipril 5mg DAILY Atorvastatin 80mg daily Are there any drug-related problems? 164

95 What would you recommend for EC? A. No change. Patient s CHADS2 score is 0. ASA + Ticagrelor is adequate. B. Warfarin + Clopidogrel 75mg daily C. Warfarin + Clopidogrel 75mg daily + ASA (up to 6 months) D. Dabigatran 110mg BID + Clopidogrel 75mg daily E. Rivaroxban 15mg daily + Clopidogrel 75mg daily F. Rivaroxaban 2.5mg BID + ASA EC 80mg daily + Clopidogrel 75mg daily G. Rivaroxaban 15mg daily + clopidogrel 5mg daily + ASA (up to 6 months) ***REMEMBER to increase to full dose OAC when complete course of DAPT 165

96 Case HB (Ms. High-risk Bleeder) ID: HB, 89 year old female (wt = 55kg; ht=5 1 ), presenting with STEMI treated with a single DES in the mid-rca. Post-PCI patient developed AF with rapid ventricular response (HR = 132bpm; irregularly irregular). Past Medical History: Long standing diverticulosis with chronic lower GI bleeding. Medications PTA: None Medications started in hospital: ASA 80mg po DAILY Ticagrelor 90mg po BID Metoprolol 50mg po BID Ramipril 5mg po DAILY Atorvastatin 80mg daily 166

97 Case HB (Ms. High-risk Bleeder) Echocardiogram: EF = 55%, severe atrial enlargement. Left atrial size = 4.7cm (normal = 3.9cm for females) Labs: Hg = 90g/dL; SCr = 60umol/L egfr = 80mL/min; all other bloodwork WNL Course in Hospital: - 3 days post-procedure, patient reports melena and Hg drops from 89 to 70g/dL - GI consulted, lower GI scope confirmed lower GI bleed secondary diverticulosis. No treatment planned. Surgical intervention in future if bleeding worsens and when patient off DAPT - AF persists, but rate controlled at 96bpm. No cardioversion planned as patient is asymptomatic. Unlikely to convert due large left atrial size 167

98 Case HB (Ms. High-risk Bleeder) What would you recommend for prevention of stroke and stent thrombosis for HB? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B. Rivaroxaban 15mg daily + Clopidogrel 75mg po daily C. Rivaroxaban 2.5mg BID + Clopidogrel 75mg po daily + ASA EC 80mg daily D. Apixaban 2.5mg BID + Clopidogrel 75mg po daily E. Dabigatran 110mg po BID + Clopidogrel 75mg daily F. ASA 80mg po daily + Clopidogrel 75mg po daily G. ASA 80mg po daily + Ticagrelor 90mg po BID 168

99 Case HB (Ms. High-risk Bleeder) What would you recommend for prevention of stroke and stent thrombosis for HB? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B. Rivaroxaban 15mg daily + Clopidogrel 75mg po daily C. Rivaroxaban 2.5mg BID + Clopidogrel 75mg po daily + ASA EC 80mg daily D. Apixaban 2.5mg BID + Clopidogrel 75mg po daily E. Dabigatran 110mg po BID + Clopidogrel 75mg daily F. ASA 80mg po daily + Clopidogrel 75mg po daily G. ASA 80mg po daily + Ticagrelor 90mg po BID Consider anticoagulation in future, once course of DAPT completed and diverticular bleed repaired 169

100 Case SR (Mr. Stroke Risk) ID: SR, 75 year old male (wt = 80kg; ht=5 9 ), presenting with NSTEMI treated with a 3 x DES in the proximal LAD (long lesion; >60mm full metal jacket Past Medical History: Long standing CAD, MI at age 60y; HFrEF (EF = 30%); diabetes, hypertension, cardioembolic stroke x 3 (last stroke 4 months ago) Medications PTA: Apixaban 5mg BID Carvedilol 25mg BID Ramipril 10mg daily Spironolactone 25mg daily Amlodipine 10mg daily Rosuvastatin 40mg daily Metformin 1000mg po BID 170

101 Case SR (Mr. Stroke Risk) Medications in hospital: IV Heparin protocol apixaban held ASA EC 80mg daily Ticagrelor 90mg po BID Carvedilol 25mg BID Ramipril 10mg daily Spironolactone 25mg daily Amlodipine 10mg daily Rosuvastatin 40mg daily Metformin 1000mg po BID Labs: CBC, Lytes WNL, SCr = 90 umol/l egfr = 75mL/min 171

102 Case SR (Mr. Stroke Risk) What would you recommend for prevention of stroke and stent thrombosis for SR? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B. Warfarin (INR 2-3) + Clopidogrel 75mg po daily + ASA EC 80mg daily C. Rivaroxaban 15mg daily + Clopidogrel 75mg daily D. Rivaroxaban 15mg daily + Clopidogrel 75mg daily + ASA EC 80mg daily (for up to 6 months) E. Rivaroxaban 2.5mg BID + Clopidogrel 75mg daily + ASA EC 80mg daily F. Rivaroxaban 20mg daily + Clopidogrel 75mg daily G. Rivaroxaban 20mg daily + Clopidogrel 75mg + ASA EC 80mg daily (up to 6 months) H. Apixaban 5mg BID + Clopidogrel 75mg daily I. Apixaban 5mg BID + Clopidogrel 75mg daily + ASA EC 80mg daily (up to 6 months) J. Dabigatran 110mg PO BID + Clopidogrel 75mg daily K. Dabigatran 150mg PO BID + Clopidogrel 75mg daily L. Any of the options above (but substitute clopidogrel with ticagrelor) 172

Case SR (Mr. Stroke Risk) What would you recommend for prevention of stroke and stent thrombosis for SR? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B.

103 Case SR (Mr. Stroke Risk) What would you recommend for prevention of stroke and stent thrombosis for SR? A. Warfarin (INR 2-3) + Clopidogrel 75mg po daily B. Warfarin (INR 2-3) + Clopidogrel 75mg po daily + ASA EC 80mg daily C. Rivaroxaban 15mg daily + Clopidogrel 75mg daily D. Rivaroxaban 15mg daily + Clopidogrel 75mg daily + ASA EC 80mg daily (for up to 6 months) E. Rivaroxaban 2.5mg BID + Clopidogrel 75mg daily + ASA EC 80mg daily F. Rivaroxaban 20mg daily + Clopidogrel 75mg daily G. Rivaroxaban 20mg daily + Clopidogrel 75mg + ASA EC 80mg daily (up to 6 months) H. Apixaban 5mg BID + Clopidogrel 75mg daily??? (no evidence yet) I. Apixaban 5mg BID + Clopidogrel 75mg daily + ASA EC 80mg daily (up to 6 months)??? (no evidence yet) J. Dabigatran 110mg PO BID + Clopidogrel 75mg daily K. Dabigatran 150mg PO BID + Clopidogrel 75mg daily L. Any of the options above (but substitute clopidogrel with ticagrelor) 173

104 NOAC Underdosing Cohort data (Yao et al), suggest underdosing of apixaban associated with: higher risk of stroke (HR 4.87; 9% CI ) no difference in major bleeding Under dosing of rivaroxaban and dabigatran showed no relationships J Am Coll Cardiol;69(23): doi: /j.jacc Registry data (ORBIT-AF Investigators) Underdosing associated with increased CV hospitalization (adjusted HR: 1.26; p=0.007) J Am Coll Cardiol 2016;68:

105 PROTON PUMP INHIBITORS Practical Tip. Consider using a proton pump inhibitor for protection against gastrointestinal bleeding while patients are receiving a triple therapy regimen Canadian Journal of Cardiology 34 (2018)

106 OTHER REASONS FOR ANTICOAGULATION POST-PCI Mechanical Valve Surgical Bioprosthetic Valve Transcatheter Aortic Valve Replacement (TAVR implanted < 6 months) Venous Thromboembolism ***Treat according to DVT/PE Guideline Recommendations Left Ventricular Thrombus (LVT) Formation Canadian Journal of Cardiology 34 (2018) VKA + clopidogrel + ASA (ASA may be stopped on the day of PCI or at 6 months) ASA (for life) + clopidogrel (6 to 12 months) ASA (for life) + clopidogrel (3-6 months) Parenteral or OAC + ASA (can be stopped post PCI or up to 6 months) + clopidogrel (up to 12 months) OAC + ASA (can be stopped post-pci or up to 6 months) + clopidogrel (for up to 12 months) ***If LVT resolved after 3 months, d/c OAC and treat with DAPT for up to 1y Weak Rec; Low quality evidence? Restart ASA when complete course of clopidogrel? Weak Rec; Low quality evidence Weak Rec; Low quality evidence Weak Rec; Very Low quality evidence Weak Rec; Very Low quality evidence ***Warfarin is the only OAC evaluated for treatment 178 of established in LVT

107 SESSION RE-CAP 180

Figure 3 Canadian Journal of Cardiology 2018 34, 214-233DOI:

109 ??? Canadian Journal of Cardiology , DOI: ( /j.cjca ) 182

Figure 4 Canadian Journal of Cardiology 2018 34, 214-233DOI:

111 Questions to ask yourself What is your patient s stroke risk? What is your patient s risk of thrombotic events (ischemic event or stent thrombosis)? What type of stent does patient have Does patient have high risk clinical or angiographic features? What your patient s bleed risk? What is the most-effective agent for stroke prevention in AF? What is the safest SPAF agent for this specific patient? What is the safest dose? What is the safest combination for your patient? What is the duration of therapy For DAPT? For anticoagulation? Does patient have clear understanding of stop dates? Have reversible risk factors for bleeding been eliminated? NSAID use, omega-3 fatty acids, blood thinning herbal products/supplements Does patient need GI protection with PPI? Can Fam Physician May; 63(5):

112 Summary Refer to the RIGHT guidelines Correct indication Most recent version Consider all risk factors Stroke risk (CHADS2) Thrombotic Risk (Clinical and Angiographic) Bleed risk (HAS-BLED) Be familiar with the guidelines and (lack of) evidence OAC + SAPT vs. TT trials Not powered to show efficacy Short duration of follow-up (1 year vs. ~2h in stroke trials) Don tfollow guidelinesblindly. Use your clinicaljudgment Choose the safest and/or most effective regimen for your patient Protect against GI bleed with PPI Educate the patient about duration of the therapy and signs and symptoms of bleed/stroke/stent thrombosis/cardiovascular event Remember to increase to full-dose OAC when DAPT complete 185

ANTIPLATELET THERAPY ANTIPLATELET THERAPY ANTIPLATELET THERAPY

ANTIPLATELET THERAPY 2018 UPDATE ANTIPLATELET THERAPY ANTIPLATELET THERAPY About this Pocket Guide This pocket guide is a quick-reference tool that features diagnostic and management recommendations based