Should It Stay or Should It Go? - University Blog...
Transcript of Should It Stay or Should It Go? - University Blog...
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
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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
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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
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CADEpidemiology, Etiology, and Pathophysiology
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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
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CHEST 2012; 141(2)(Suppl):e637S–e668S
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
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CAD in the US
CAD in Middle‐aged Men
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CAD in Middle‐aged Women
~50% ~33%
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.
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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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
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Bleeding Risk
• Other contributing factors• Anemia• Hx of GI bleed• Recent bleed• Diabetes mellitus• Inherited disorders
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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
Etiology
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Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad
Etiology
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Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad
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Etiology
Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad
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Etiology
Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad
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Etiology
Image from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=chlcad
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
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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Clotting Cascade
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Kininogen Kallikrein
Trauma
Trauma
Cross‐linked Fibrin Clot
Clotting Cascade
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Kininogen Kallikrein
Trauma
Trauma
Cross‐linked Fibrin Clot
Warfarin
Warfarin
RivaroxabanApixabanEdoxaban Dabigatran
ASPIRIN FOR SECONDARY PREVENTION OF CAD
Per ACCP Guidelines21
CHEST Guideline EvidenceAspirin ‐ Table 3
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“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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CHEST Guideline EvidenceClopidogrel ‐ Table 4
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“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
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
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ASA 81mg, EC CLOPIDOGREL 75mg
AWP (120 tabs) $6.40 (90 tabs) $626.40
VA price (120 tabs) $0.60 (90 tabs) $7.74
DOACS AND ASPIRIN
Evaluating Their Role in Patients with Both AF and CAD
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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
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• Apixaban• ARISTOTLE
• Dabigatran• RE‐LY
• Edoxaban• ENGAGE
• Rivaroxaban• ROCKET AF
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.
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Insights from the ARISTOTLE Trial
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• 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
• 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
Subgroup Breakdown
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Apixaban Warfarin
ASA added
N= 2233 N= 2201
No ASA
N= 6852 N=6847
Baseline Characteristics
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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
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
Results (cont.)
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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
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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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
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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• 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
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.
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Insights from the RE‐LY Trial
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• 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
• 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
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Insights from the RE‐LY Trial
Subgroup Breakdown
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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
Antiplatelet Use
Aspirin32%
Clopidogrel2%
Both Aspirin and Clopidogrel
4%
No APT62%
Antiplatelet Use in RE‐LY
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• 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%
Baseline Characteristics
45ASA users and non‐users were seemingly well balanced. No p values provided for statistically significant differences
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Benefits attenuated with ASA use}Results
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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”
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)
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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
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)
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Insights from the ENGAGE Trial
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• Objective• Study the concomitant use of SAPT on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation
• 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
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Insights from the ENGAGE trial
Subgroup Breakdown
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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
Antiplatelet Use
Aspirin23%
Clopidogrel2%
No APT75%
Antiplatelet Use in ENGAGE
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• 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
Baseline Characteristics
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Results ‐HDER
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Results – HDER (cont.)
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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
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
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
Insights from the ROCKET AF Trial
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• 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.
• 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
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Insights from the ROCKET AF Trial
Antiplatelet Use
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• Mean baseline daily dose of aspirin was 99.2mg
Baseline Characteristics
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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
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
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Results
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Results (cont.)
Results (cont.)
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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
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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.
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
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
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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
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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