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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
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Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

May 11, 2020

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Page 1: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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 ResidentCentral Texas Veterans Healthcare System01/06/2017

1

Page 2: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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

Page 3: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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 non‐major

• 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

Page 4: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

CADEpidemiology, Etiology, and Pathophysiology 

4

Page 5: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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

Page 6: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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 1990

6

Page 7: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

CAD in the US

CAD in Middle‐aged Men

7

CAD in Middle‐aged Women

~50% ~33%

Page 8: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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 

8Schurtz G, Bauters C, Ducrocq G, et al. Panminerva Medica 2016 December;58(4):271‐85.

Page 9: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Audience Response Question• Which of the following is NOT a risk factor for CAD? 

1. Hypertension2. Depression3. Obesity4. Diabetes5. All of the above are risk factors for CAD

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Page 10: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Risk FactorsNon‐Modifiable Modifiable

Increasing Age: Men >45yrsPost‐menopausal Women

HyperlipidemiaLow HDLHigh LDLHigh Triglycerides

Male Sex Tobacco Smoke

Family History  Hypertension

Race African AmericansMexican AmericansAmerican IndiansHawaiianAsian Americans

Physical Inactivity

Overweight / Obesity

Diabetes Mellitus

Excessive Alcohol

Depression / Stress

10

Page 11: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Bleeding Risk

• Other contributing factors• Anemia• Hx of GI bleed• Recent bleed• Diabetes mellitus• Inherited disorders

11

Clinical characteristic* Points

H Hypertension (ie, uncontrolled blood pressure) 1

A Abnormal renal and liver function (1 point each) 1 or 2

S Stroke 1B Bleeding tendency or predisposition 1L Labile INRs (for patients taking warfarin) 1E Elderly (age greater than 65 years) 1

D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2

HAS‐BLED Score Total

Bleeds per 100 patient‐years

0 1.13

1 1.022 1.883 3.74

4 8.7

5 to 9 Insufficient data

Page 12: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Etiology

12

Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad

Page 13: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Etiology

13

Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad

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14

Etiology

Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad

Page 15: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

15

Etiology

Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad

Page 16: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

16

Etiology

Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad

Page 17: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

PathophysiologyRupture of the vulnerable plaque 

Complex inflammatory and coagulation cascade

17Image from: 

https://www.researchgate.net/profile/Salvatore_Cito/publication/233973730/figure/fig1/AS:300049700540419@1448548831866/Fig‐1‐Illustration‐of‐the‐blood‐clotting‐process‐showing‐the‐four‐main‐

steps‐of.png

Page 18: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Primary Hemostasis

Aspirin

ClopidogrelPrasugrelTiclopidine(irreversible)

Ticagrelor(reversible)

Image from: https://www.researchgate.net/profile/Salvatore_Cito/publication/233

973730/figure/fig1/AS:300049700540419@1448548831866/Fig‐1‐Illustration‐of‐the‐blood‐clotting‐process‐showing‐the‐four‐main‐

steps‐of.png

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Page 19: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Clotting Cascade

19

Kininogen Kallikrein

Trauma

Trauma

Cross‐linked Fibrin Clot

Page 20: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Clotting Cascade

20

Kininogen Kallikrein

Trauma

Trauma

Cross‐linked Fibrin Clot

Warfarin

Warfarin

RivaroxabanApixabanEdoxaban Dabigatran

Page 21: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

ASPIRIN FOR SECONDARY PREVENTION OF CAD

Per ACCP Guidelines21

Page 22: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

CHEST Guideline EvidenceAspirin ‐ Table 3

22

Page 23: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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

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Page 24: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

CHEST Guideline EvidenceClopidogrel ‐ Table 4

24

Page 25: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

“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

Page 26: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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

26

ASA 81mg, EC CLOPIDOGREL 75mg

AWP (120 tabs) $6.40 (90 tabs) $626.40

VA price (120 tabs) $0.60 (90 tabs) $7.74

Page 27: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

DOACS AND ASPIRIN

Evaluating Their Role in Patients with Both AF and CAD

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Page 28: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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.”

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Trials Evaluating DOACs and Antiplatelet Use

29

• Apixaban• ARISTOTLE

• Dabigatran• RE‐LY

• Edoxaban• ENGAGE

• Rivaroxaban• ROCKET AF

Page 30: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Apixaban vs. Warfarin with Concomitant Aspirin in Patients with Atrial Fibrillation: Insights from the ARISTOTLE TrialAlexander JH, et al. Eur Heart J. 2014;35(4):224‐32.

30

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Insights from the ARISTOTLE Trial

31

• 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

Page 32: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

• Double blind, double dummy RCT of 18201 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

DesignDesign

• 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

Treatment Groups 

Treatment Groups 

• 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 UsersAspirin Users 32

Insights from the ARISTOTLE Trial

Page 33: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Subgroup Breakdown

33

Apixaban Warfarin

ASA added

N= 2233 N= 2201

No ASA

N= 6852 N=6847

Page 34: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Baseline Characteristics

34

Baseline CharacteristicsAspirin Users (n=4434) Non‐user (n=13699) P‐value

Age, median (25th, 75th) 70 (64,76) 70 (62,75) 0.0058

Male Sex (%) 3029 (68.3) 8709 (63.6) <0.0001Diabetes (%) 1282 (28.9) 3249 (23.7) <0.0001HTN (%) 3940 (88.9) 11914 (87.0) 0.001Hx of CAD (%) 2264 (51.1) 4354 (31.8) <0.0001Hx of MI (%) 1046 (23.6) 1529 (11.2) <0.0001Hx of PCI (%) 744 (16.8) 903 (6.6) <0.0001>12 months from most 

recent PCI 618 (83.4) 706 (78.5) 0.0452

Proportion with Stent Placed (%) 518 (70.7) 562 (63.4) 0.0019

Hx of CABG (%) 582 (13.1) 620 (4.5) <0.0001Hx of Stroke (%) 501 (11.3) 1624 (11.9) 0.3172CHADS2 Score

<0.00011 1391 (31.4) 4763 (34.8)2 1616 (36.4) 4882 (35.6)3 1472 (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

Page 35: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

ResultsReduction in Ischemic Events: Apixaban vs. 

WarfarinASA Status HR CI Interaction P‐

value

Stroke or Systemic Embolism

ASA 0.59 0.40‐0.870.1114

without ASA 0.85 0.67‐1.08

Ischemic StrokeASA 0.72 0.45‐1.88

0.2685without ASA 0.99 0.74‐1.32

MIASA 1.15 0.70‐1.88

0.2144without ASA 0.77 0.51‐1.14

DeathASA 1.03 0.72‐1.46

0.3727without ASA 0.85 0.70‐1.03 35

Patients on ASA had statistically significant improvements in SSE

Page 36: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Results (cont.)

36

Reductions in Bleeding: Apixaban vs. Warfarin

ASA Status HR CI Interaction P‐value

Major Bleeding

ASA 0.77 0.6‐0.990.29

without ASA 0.65 0.55‐0.78

Hemorrhagic Stroke

ASA 0.43 0.21‐0.870.6332

without ASA 0.53 0.32‐0.87

Major or CRNM Bleeding

ASA 0.73 0.6‐0.890.4623

without ASA 0.67 0.59‐0.76

Any BleedingASA 0.69 0.62‐0.77

0.4857without ASA 0.72 0.68‐0.77

Statistically Significant

Compared to non‐users, ASA users had similar rates of bleeding 

Page 37: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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

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Page 38: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

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

Page 39: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Critical Appraisal Strengths Limitations

• One of very few trials looking at the effects of concomitant aspirin and DOAC use

• Large sample size• Conclusions matched data 

presented• Clinically useful 

• Patients receiving ASA were different, with higher risk for both ischemic and bleedingevents

• 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

39Conclusion: Apixaban + ASA still carries improved bleeding risk over warfarin +/‐ ASA and may have benefits on SSE

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Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) TrialDans AL, et al. Circulation. 2013;127(5):634‐40.

40

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Insights from the RE‐LY Trial

41

• 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

Page 42: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

• 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

DesignDesign

• Dabigatran 110mg BID• Dabigatran 150mg BID• Warfarin (INR2‐3)• +/‐ antiplatelet agent

Treatment Groups 

Treatment Groups 

• Use of anti‐platelet agents was allowed at the discretion of the attending physicians and recorded at every visit

• Aspirin or clopidogrel

Antiplatelet Users

Antiplatelet Users

42

Insights from the RE‐LY Trial

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Subgroup Breakdown

43

Dabigatran 110mg BID

Dabigatran 150mg BID

Warfarin (INR 2‐3)

AntiplateletTherapy

N=2322 N=2304 N=2326

No Antiplatelet Agent

N=3693 N=3772 N=3696

Page 44: Should It Stay or Should It Go? - University Blog …sites.utexas.edu/phr-residencies/files/2015/07/ShouldASA...Should It Stay or Should It Go? Aspirin Therapy for Patients with Stable

Antiplatelet Use

Aspirin32%

Clopidogrel2%

Both Aspirin and Clopidogrel

4%

No APT62%

Antiplatelet Use in RE‐LY

44

• Only 27% of patients were on concomitant antiplatelet therapy at any one time during the study

ASA Dose N %

<100mg 2908 16%

100‐299mg

1621 8.9%

≥300mg 293 1.6%

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Baseline Characteristics

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

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46

Benefits attenuated with ASA use}Results

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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”

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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 0.59‐1.08) in comparison to those who did not (HR 0.52, 95% CI 0.38‐0.72)

48

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Critical Appraisal Strengths Limitations

• 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

• 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

49Conclusion: Dabigatran + ASA increases major bleeding risk similar to warfarin + ASA but may NOT exhibit benefits on SSE

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

50

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Insights from the ENGAGE Trial

51

• Objective• Study the concomitant use of SAPT on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation

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• 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

DesignDesign

• 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

Treatment Groups 

Treatment Groups 

• Physician discretion• Aspirin ≤ 100mg daily strongly encouraged• Clopidogrel used in small subset of patients

Antiplatelet Users

Antiplatelet Users

52

Insights from the ENGAGE trial

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Subgroup Breakdown

53

HDER LDER Warfarin (INR 2‐3)

AntiplateletTherapy at 3 Months

N=1642 N=1625 N=1645

No Antiplatelet Agent at 3 Months

N=4953 N=5046 N=4998

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Antiplatelet Use

Aspirin23%

Clopidogrel2%

No APT75%

Antiplatelet Use in ENGAGE

54

• 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

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Baseline Characteristics

55

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Results ‐HDER 

56

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Results – HDER (cont.)

57

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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

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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

59Conclusion: Edoxaban + ASA has favorable bleeding risk over warfarin +/‐ ASA and may exhibit benefits on SSE

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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;179:77‐86. 60

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Insights from the ROCKET AF Trial

61

• 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.

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• Multicenter, double‐blind, double‐dummy, event‐driven 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

DesignDesign

• Rivaroxaban 20mg daily (15mg daily if CrCl 30‐49mL/min)

• Warfarin (INR 2‐3)• +/‐ ASA at baseline

Treatment Groups 

Treatment Groups 

• Analysis performed using baseline aspirin use

Antiplatelet Users

Antiplatelet Users

62

Insights from the ROCKET AF Trial

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Antiplatelet Use

63

• Mean baseline daily dose of aspirin was 99.2mg

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Baseline Characteristics

64

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

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Statistical Methods• Chi‐square test for categorical variables• Presented using percentage (count)

• Wilcoxon rank‐sum test for continuous variables• Presented using median (2th‐75th percentiles)

• Cox proportional hazard method used to calculate hazard ratios

• All endpoints were generated as events per 100 patient‐years and total events

65

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Results

66

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67

Results (cont.)

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Results (cont.)

68

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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

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Critical Appraisal Strengths Limitations

• One of very few trials looking at the effects of concomitant aspirin and DOAC use

• Large sample size

• 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

70Conclusion: Rivaroxaban + ASA may have favorable benefits for CAD secondary prevention and may have less bleeding events than warfarin + ASA. More data needed.

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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

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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

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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

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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 ResidentCentral Texas Veterans Healthcare System01/06/2017

74

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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

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Questions

76

Email: [email protected]

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Resources1) 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;130:390‐5

2) 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):224‐32

3) Behnes M, Fastner C, Ansari U and Akin I. New oral anticoagulants in coronary artery disease. Cardiovascular and Haematological Disorders‐Drug Targets. 2015(15)101‐105.

4) 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):634‐40.

5) Wilson P, Douglas PS, et al. Epidemiology of coronary heart disease. UpToDate. Topic updated Jan 23, 2015. Updated Dec 2016. https://www.uptodate.com/contents/epidemiology‐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):1577‐85.

7) 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):271‐85.

8) 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;179:77‐86.

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Resources9) 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):1390–1396.10) 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.

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