Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable CAD Post MI/TIA with Atrial Fibrillation on Concurrent DOAC Therapy

Transcription

1 Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable CAD Post MI/TIA with Atrial Fibrillation on Concurrent DOAC Therapy Erin R. Pilcher, Pharm.D. PGY1 Pharmacy Practice Resident Central Texas Veterans Healthcare System 01/06/2017 1

2 Objectives Provide an overview of the epidemiology, etiology, and pathophysiology of CAD Briefly review the evidence for benefit of aspirin therapy for patients with stable CAD Analyze the literature in order to provide a clinical recommendation on the use of aspirin + DOAC combination therapy for AF patients post MI/TIA with stable CAD 2

3 Abbreviations ACCP American College of Chest Physicians AF atrial fibrillation APT antiplatelet therapy ASA acetylsalicylic acid OR aspirin AWP average wholesale price BID twice daily administration CABG Coronary artery bypass graft CAD coronary artery disease CHD coronary heart disease CI confidence interval CRNM clinically relevant nonmajor DE drug exposure DOAC direct oral anticoagulant HDER higher dose edoxaban regimen HR hazard ratio INR international normalized ratio LDER lower dose edoxaban regimen MI myocardial infarction PCI percutaneous coronary intervention RCT randomized controlled trial SAPT single antiplatelet therapy SEE systemic embolic event SSE stroke and systemic embolism TIA transient ischemic attack VKAs vitamin K antagonists 3

4 CAD Epidemiology, Etiology, and Pathophysiology 4

5 CAD Definition One or more of the following Stable angina pectoris History of unstable angina pectoris History of PCI CABG Previous MI Stable disease 12 months since event 5 CHEST 2012; 141(2)(Suppl):e637S e668s

6 Epidemiology Major cause of death and disability in developed countries Responsible for 1/3 or more of all deaths in people over 35 years old The Global Burden of Disease Study in 2013 Estimated that deaths related to cardiovascular disease has increased 41% since

7 CAD in the US CAD in Middle aged Men CAD in Middle aged Women ~50% ~33% 7

8 CAD and AF On average, 30% of patients with AF have concomitant CAD 10 15% of patients with stable CAD have an indication for long term oral anticoagulation Little is known about AF prognosis in stable CAD outpatients AF + CHADS2 score of 3: 4.6% annual risk of stroke Schurtz G, Bauters C, Ducrocq G, et al. Panminerva Medica 2016 December;58(4):

9 Audience Response Question Which of the following is NOT a risk factor for CAD? 1. Hypertension 2. Depression 3. Obesity 4. Diabetes 5. All of the above are risk factors for CAD 9

10 Risk Factors Non Modifiable Increasing Age: Men >45yrs Post menopausal Women Male Sex Family History Race African Americans Mexican Americans American Indians Hawaiian Asian Americans Modifiable Hyperlipidemia Low HDL High LDL High Triglycerides Tobacco Smoke Hypertension Physical Inactivity Overweight / Obesity Diabetes Mellitus Excessive Alcohol Depression / Stress 10

11 Bleeding Risk Clinical characteristic* Points Hypertension (ie, uncontrolled blood H pressure) 1 Abnormal renal and liver function (1 point A each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 Drugs (concomitant aspirin or NSAIDs) or D excess alcohol use (1 point each) 1 or 2 HAS BLED Score Total Bleeds per 100 patientyears to 9 Insufficient data Other contributing factors Anemia Hx of GI bleed Recent bleed Diabetes mellitus Inherited disorders 11

12 Etiology 12 Image from:

13 Etiology 13 Image from:

14 Etiology 14 Image from:

15 Etiology 15 Image from:

16 Etiology 16 Image from:

17 Pathophysiology Rupture of the vulnerable plaque Complex inflammatory and coagulation cascade Image from: 1 Illustration of the blood clotting process showing the four mainsteps of.png 17

18 Primary Hemostasis Clopidogrel Prasugrel Ticlopidine (irreversible) Ticagrelor (reversible) Aspirin Image from: 1 Illustration of the blood clotting process showing the four mainsteps of.png 18

19 Clotting Cascade Kininogen Kallikrein Trauma Trauma 19 Cross linked Fibrin Clot

20 Clotting Cascade Kininogen Kallikrein Trauma Warfarin Warfarin Rivaroxaban Apixaban Edoxaban Dabigatran Trauma 20 Cross linked Fibrin Clot

21 ASPIRIN FOR SECONDARY PREVENTION OF CAD Per ACCP Guidelines 21

22 CHEST Guideline Evidence Aspirin Table 3 22

23 The number of vascular events and total deaths prevented is far greater than the number of bleeding events that resulted from aspirin. 23

24 CHEST Guideline Evidence Clopidogrel Table 4 24

25 After a mean follow up of 1.9 years, clopidogrel was associated with a possible reduction in nonfatal MI and nonfatal extracranial bleeding and little or no effect on total mortality. 25

26 CHEST Guidelines Recommendation Long term single APT with aspirin (75 100mg) OR clopidogrel 75mg daily for patients with stable CAD Considering difference in cost and mortality benefits, many patients are placed on daily aspirin 81mg Clopidogrel reasonable alternative for patients with ASA allergy ASA 81mg, EC CLOPIDOGREL 75mg AWP (120 tabs) $6.40 (90 tabs) $ VA price (120 tabs) $0.60 (90 tabs) $

27 DOACS AND ASPIRIN Evaluating Their Role in Patients with Both AF and CAD 27

28 CHEST Guidelines on DOACs and ASA Mostly discusses ASA + VKAs RE LY trial Rates of major bleeding were roughly 2x higher for patients receiving aspirin in conjunction with either warfarin (INR 2 3) or dabigatran Recommendation For patients with AF and stable CAD who choose oral anticoagulation, we suggest VKA therapy alone (INR 2 3) rather than combination of VKA therapy and aspirin. 28

29 Trials Evaluating DOACs and Antiplatelet Use Apixaban ARISTOTLE Dabigatran RE LY Edoxaban ENGAGE Rivaroxaban ROCKET AF 29

30 Apixaban vs. Warfarin with Concomitant Aspirin in Patients with Atrial Fibrillation: Insights from the ARISTOTLE Trial Alexander JH, et al. Eur Heart J. 2014;35(4):

31 Insights from the ARISTOTLE Trial Objectives Describe the use over time and dose of concomitant aspirin in patients with AF overall and in the subgroups of patients with and without arterial vascular disease Evaluate the efficacy and safety of apixaban compared with warfarin in patients receiving and not receiving aspirin overall and in the subgroups of patients with and without arterial vascular disease 31

32 Insights from the ARISTOTLE Trial Design Treatment Groups Double blind, double dummy RCT of patients with AF and at least one additional risk factor for stroke or systemic embolism >=75yrs, HTN, diabetes, HF, or reduced ventricular systolic function, and prior stroke or systemic embolism Apixaban 5mg BID + warfarin placebo (N=9120) Dose adjusted to 2.5mg BID where appropriate Apixaban placebo + warfarin (N=9081) with INR of 2 3 Defined as those using aspirin on Day 1 Considered to be taking aspirin in a particular week if they received aspirin for at least 50% of the days of the week Aspirin Users 32

33 Subgroup Breakdown ASA added No ASA Apixaban Warfarin N= 2233 N= 2201 N= 6852 N=

34 Baseline Characteristics Baseline Characteristics Aspirin Users (n=4434) Non user (n=13699) P value Age, median (25th, 75th) 70 (64,76) 70 (62,75) Male Sex (%) 3029 (68.3) 8709 (63.6) < Diabetes (%) 1282 (28.9) 3249 (23.7) < HTN (%) 3940 (88.9) (87.0) Hx of CAD (%) 2264 (51.1) 4354 (31.8) < Hx of MI (%) 1046 (23.6) 1529 (11.2) < Hx of PCI (%) 744 (16.8) 903 (6.6) < >12 months from most recent PCI 618 (83.4) 706 (78.5) Proportion with Stent Placed (%) 518 (70.7) 562 (63.4) Hx of CABG (%) 582 (13.1) 620 (4.5) < Hx of Stroke (%) 501 (11.3) 1624 (11.9) CHADS2 Score (31.4) 4763 (34.8) (36.4) 4882 (35.6) < (32.2) 4054 (29.2) Aspirin users were more likely to be male, have diabetes, HTN, have a Hx of CAD, MI, PCI, CABG and have higher CHADS2 scores 34

35 Results Reduction in Ischemic Events: Apixaban vs. Warfarin Stroke or Systemic Embolism ASA Status HR CI ASA without ASA Interaction P value Ischemic Stroke ASA without ASA MI ASA without ASA Death ASA without ASA Patients on ASA had statistically significant improvements in SSE 35

36 Results (cont.) Reductions in Bleeding: Apixaban vs. Warfarin Major Bleeding Hemorrhagic Stroke Major or CRNM Bleeding Any Bleeding ASA Status HR CI ASA without ASA ASA without ASA ASA without ASA ASA without ASA Statistically Significant Interaction P value Compared to non users, ASA users had similar rates of bleeding 36

37 Authors Conclusions If there is a strong indication for combination aspirin and oral anticoagulation, apixaban seems to be safer than warfarin in patients with AF irrespective of ASA use In ARISTOTLE, concomitant aspirin was used in 20 25% of patients with AF treated with an anticoagulant (apixaban or warfarin) and was associated with a higher risk of bleeding 37

38 Authors Conclusions (cont.) Similar effects of apixaban, compared with warfarin, on stroke or systemic embolism, major bleeding, or mortality irrespective of concomitant aspirin use Adequately powered RCT are needed to better define optimal antithrombotic regimen and its duration in patients with both AF and atherosclerotic CAD, especially those with ACS or recent stenting 38

39 Critical Appraisal Strengths One of very few trials looking at the effects of concomitant aspirin and DOAC use Large sample size Conclusions matched data presented Clinically useful Limitations Patients receiving ASA were different, with higher risk for both ischemic and bleeding events Though adjustments for confounders were made, more likely exist Aspirin use was not blinded Subgroup analysis limited power Generalizability Bristol Myers Squibb and Pfizer participated in trial design and data collection Conclusion: Apixaban + ASA still carries improved bleeding risk over warfarin +/ ASA and may have benefits on SSE 39

40 Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long Term Anticoagulation Therapy (RE LY) Trial Dans AL, et al. Circulation. 2013;127(5):

41 Insights from the RE LY Trial Objective Determine the efficacy and safety of two doses of dabigatran versus warfarin in relation to whether concomitant antiplatelet treatment was used during the RE LY study 41

42 Insights from the RE LY Trial Design Treatment Groups Antiplatelet Users 18,113 patients with AF and additional risk factors for stroke recruited to receive one of two blinded doses of dabigatran (110mg BID or 150mg BID) or open label warfarin (INR 2 3) Main efficacy outcome = stroke or systemic embolism Safety outcome = major bleeding Dabigatran 110mg BID Dabigatran 150mg BID Warfarin (INR2 3) +/ antiplatelet agent Use of anti platelet agents was allowed at the discretion of the attending physicians and recorded at every visit Aspirin or clopidogrel 42

43 Subgroup Breakdown Antiplatelet Therapy No Antiplatelet Agent Dabigatran 110mg BID Dabigatran 150mg BID Warfarin (INR 2 3) N=2322 N=2304 N=2326 N=3693 N=3772 N=

44 Antiplatelet Use Only 27% of patients were on concomitant antiplatelet therapy at any one time during the study ASA Dose N % <100mg % Antiplatelet Use in RE LY No APT 62% Aspirin 32% Clopidogrel 2% mg % 300mg % Both Aspirin and Clopidogrel 4% 44

45 Baseline Characteristics ASA users and non users were seemingly well balanced. No p values provided for statistically significant differences 45

46 Results }Benefits attenuated with ASA use 46

47 Results (cont.) CHEST: Rates of major bleeding were roughly 2x higher for patients receiving aspirin in conjunction with either warfarin (INR 2 3) or dabigatran 47

48 Authors Conclusions Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE LY without affecting the advantages of dabigatran over warfarin Dabigatran 150mg BID reduced the primary outcome of stroke and systemic embolism compared to warfarin However, this effect seemed attenuated among patients who used anti platelets (HR 0.80, 95% CI ) in comparison to those who did not (HR 0.52, 95% CI ) 48

49 Critical Appraisal Strengths One of very few trials looking at the effects of concomitant aspirin and DOAC use Large sample size Conclusions matched data presented Aspirin doses defined Mean duration of use was 66% of total study duration similar to real adherence rates Limitations Patients receiving APT were different, with higher risk for both ischemic and bleeding events Though adjustments for confounders were made, more likely exist Aspirin and Clopidogrel used, not randomized Only 16% of Aspirin users used 81mg Subgroup analysis limited power Generalizability Conclusion: Dabigatran + ASA increases major bleeding risk similar to warfarin + ASA but may NOT exhibit benefits on SSE 49

50 Concomitant Use of Single Antiplatelet Therapy with Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF TIMI48 Trial Xu H, Ruff CT, Giugliano RP, et al. J Am Heart Assoc. 2016;5(2) 50

51 Insights from the ENGAGE Trial Objective Study the concomitant use of SAPT on the efficacy and safety of the anti Xa agent edoxaban in patients with atrial fibrillation 51

52 Insights from the ENGAGE trial Design Treatment Groups Antiplatelet Users Multinational, double blind, RCT comparing two dosing regimens of edoxaban with warfarin 21,105 patients with AF and a CHADS2 score 2 enrolled Exclusion Criteria: CrCl <30 ml/min, high bleeding risk, receiving or anticipated DAPT, Hx of stroke, ACS or coronary revascularization within 30 days of randomization Primary efficacy endpoint: SSE Primary safety endpoint: major bleeding Net clinical outcome: composite of SSE, all cause death, or major bleeding HDER: Edoxaban 60mg/day Edoxaban 30mg/day, if expected increased DE LDER: Edoxaban 30mg/day Edoxaban 15mg/day, if expected increased DE Warfarin (INR2 3) +/ ASA beginning 3 months after randomization Physician discretion Aspirin 100mg daily strongly encouraged Clopidogrel used in small subset of patients 52

53 Subgroup Breakdown Antiplatelet Therapy at 3 Months No Antiplatelet Agent at 3 Months HDER LDER Warfarin (INR 2 3) N=1642 N=1625 N=1645 N=4953 N=5046 N=

54 Antiplatelet Use 24.6% of patients were on concomitant antiplatelet therapy during the study, after the 3 month point 25% of patients on APT at randomization discontinued within 3 months 1196 subjects with death/sse/major bleed prior to 3 months OR missing APT data at 3 months were excluded No APT 75% Antiplatelet Use in ENGAGE Aspirin 23% Clopidogrel 2% 54

55 Baseline Characteristics 55

56 Results HDER 56

57 Results HDER (cont.) 57

58 Authors Conclusions Patients with AF who were selected by their physicians to receive APT in addition to an anticoagulant had similar risk of stroke/see and higher rates of bleeding than those not receiving SAPT Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT Patients with AF who are deemed to require the addition of a SAPT should receive a Xa inhibitor for anticoagulation whenever possible 58

59 Critical Appraisal Strengths Limitations One of very few trials looking at the effects of concomitant aspirin and DOAC use Large sample size Consistent 24 25% of patients were on APT throughout the study Very little other APT used other than ASA 100mg Patients receiving APT were different, with higher risk for both ischemic and bleeding events Though adjustments for confounders were made, more likely exist APT use not randomized 25% of patients on APT at study randomization discontinued within first 3 months Subgroup analysis limited power Generalizability Daiichi Sankyo funded the trial, provided the study drug, and some authors are Daiichi Sankyo employees Conclusion: Edoxaban + ASA has favorable bleeding risk over warfarin +/ ASA and may exhibit benefits on SSE 59

60 Use of Concomitant Aspirin In Patients With Atrial Fibrillation: Findings From the ROCKET AF Trial Shah R, Hellkamp A, Lokhnygina Y, et al. Am Heart J. 2016;179:

61 Insights from the ROCKET AF Trial Objective Understand the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known CAD. 61

62 Insights from the ROCKET AF Trial Design Treatment Groups Antiplatelet Users Multicenter, double blind, double dummy, eventdriven trial to assess non inferiority of rivaroxaban vs. warfarin Exclusion Criteria: CrCl <30 ml/min, bleeding risk, recent stroke or SEE, prosthetic heart valves, or had significant mitral stenosis Primary efficacy endpoint: stroke or non central nervous system embolism Secondary efficacy endpoints: MI, vascular death, and all cause death Primary safety endpoint: major or non major clinically relevant bleeding Secondary safety endpoints of major fatal bleeding, intracranial hemorrhage and hemorrhagic stroke Rivaroxaban 20mg daily (15mg daily if CrCl 30 49mL/min) Warfarin (INR 2 3) +/ ASA at baseline Analysis performed using baseline aspirin use 62

63 Antiplatelet Use 63 Mean baseline daily dose of aspirin was 99.2mg

64 Baseline Characteristics ASA patients were more likely to be Female Slightly younger Paroxysmal AF Mean CHADS2 score of 3.5 CAD HTN Prior MI CHF and COPD Prior VKA use ACE/ARB at baseline Digoxin at baseline 64

65 Statistical Methods Chi square test for categorical variables Presented using percentage (count) Wilcoxon rank sum test for continuous variables Presented using median (2th 75 th percentiles) Cox proportional hazard method used to calculate hazard ratios All endpoints were generated as events per 100 patient years and total events 65

66 Results 66

67 Results (cont.) 67

68 Results (cont.) 68

69 Authors Conclusions Aspirin use at baseline was associated with an increased risk of bleeding and all cause death in ROCKET AF, a risk most pronounced in patients without known CAD No significant differences in treatment effect for rivaroxaban or warfarin were detected between patients with and without baseline aspirin use for any of the efficacy outcomes or the safety outcomes Baseline ASA + Rivaroxaban vs Baseline ASA + Warfarin was significant for reducing all cause death and less intracranial and fatal bleeds 69

70 Critical Appraisal Strengths One of very few trials looking at the effects of concomitant aspirin and DOAC use Large sample size Limitations Post hoc analysis Study not powered to show a difference Author s conclusions ASA not randomized, started and stopped during the trial Generalizability high baseline CHADS2 score almost 3.5 Jansen grant funded the study Conclusion: Rivaroxaban + ASA may have favorable benefits for CAD secondary prevention and may have less bleeding events than warfarin + ASA. More data needed. 70

71 Summary Apixaban Apixaban + ASA still carries improved bleeding risk over warfarin +/ ASA and may have benefits on SSE Dabigatran Dabigatran + ASA increases major bleeding risk similar to warfarin + ASA but may NOT exhibit benefits on SSE Edoxaban Edoxaban + ASA has favorable bleeding risk over warfarin +/ ASA and may exhibit benefits on SSE Rivaroxaban Conclusion: Rivaroxaban + ASA may have favorable benefits for CAD secondary prevention and may have less bleeding events than warfarin + ASA. More data needed. 71

72 Overall Conclusions ASA 81mg + DOAC therapy (apixaban, edoxaban) has so far been shown to be consistently safer in regards to bleeding events than warfarin therapy +/ ASA therapy Use of ASA with dabigatran 150mg BID may attenuate beneficial effects of ASA therapy while still carrying an increased risk of bleeding More data are needed to make recommendations on rivaroxaban s place in AF + CAD management 72

73 Clinical Recommendations Careful consideration should be made when recommending ASA + DOAC therapy Increases bleeding risk from baseline, regardless of DOAC chosen May have benefits on overall SSE Monotherapy with a DOAC is likely best for most patients CHEST Guideline recommendation If your patient has AF and a strong clinical indication for secondary CAD event prevention, recommend edoxaban or apixaban as preferred DOAC options Not enough data to conclude rivaroxaban s role Dabigatran may have attenuated SSE benefits with concomitant APT and still carries increased bleeding risk similar to warfarin + ASA 73

74 Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable CAD Post MI/TIA with Atrial Fibrillation on Concurrent DOAC Therapy Erin R. Pilcher, Pharm.D. PGY1 Pharmacy Practice Resident Central Texas Veterans Healthcare System 01/06/

75 Acknowledgements Dr. Erin Pilcher would like to thank the following people for their assistance and guidance in this presentation: Dr. Christine Wicke, Pharm.D., BCACP, CDE Dr. Katerine Getchell, Pharm.D., BCACP My Co Residents: Dr. Sarah Cho Dr. Diana Loffgren Dr. Steven Braun 75

76 Questions 76

77 Resources 1) Aguilar E, Garcia Diaz AM, Sanchez Munoz Torrero JF, Alvarez LR, Piedecausa M, Arnedo G, et al. Clinical outcome of stable outpatients with coronary, cerebrovascular or peripheral artery disease, and atrial fibrillation. Thromb Res 2012;130: ) Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2014;35(4): ) Behnes M, Fastner C, Ansari U and Akin I. New oral anticoagulants in coronary artery disease. Cardiovascular and Haematological Disorders Drug Targets. 2015(15) ) Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long Term Anticoagulation Therapy (RE LY) trial. Circulation. 2013;127(5): ) Wilson P, Douglas PS, et al. Epidemiology of coronary heart disease. UpToDate. Topic updated Jan 23, Updated Dec of coronary heart disease 6) Lamberts M, Gislason GH, Lip GY, et al. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. Circulation. 2014;129(15): ) Schurtz G, Bauters C, Ducrocq G, et al. Effect of aspirin in addition to oral anticoagulants in stable coronary artery disease outpatients with an indication for anticoagulation. Panminerva Medica 2016 December;58(4): ) Shah R, Hellkamp A, Lokhnygina Y, et al. Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial. Am Heart J. 2016;179:

78 Resources 9) Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest. 2006;130(5): ) Vandvik O., Lincoff AM., Gore JM., et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e637s e668s. 11) Xu H, Ruff CT, Giugliano RP, et al. Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF TIMI48 Trial. J Am Heart Assoc. 2016;5(2) 12) You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e531S 75S. 78