Feb 25, 2016
Stroke Prevention in Atrial Fibrillation
Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and
Anticoagulation-Based Management for SPAF
New Frontiers and Treatment Paradigms for
Program ChairmanSamuel Z. Goldhaber, MD
Cardiovascular DivisionBrigham and Women’s Hospital
Professor of MedicineHarvard Medical School
CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC
Commercial Support: This National Initiative is Sponsored by an Independent Educational Grant from Boehringer-Ingelheim
Welcome and Program Overview
Program FacultyPROGRAM CHAIRMANSAMUEL Z. GOLDHABER, MDCardiovascular DivisionBrigham and Women’s HospitalProfessor of MedicineHarvard Medical School
CHRISTIAN T. RUFF, MD, MPHTIMI Study GroupBrigham and Women’s HospitalHarvard Medical SchoolBoston, MA
CHRISTOPHER B. GRANGER, MD Professor of MedicineDuke University Medical CenterDirectory, Cardiac Care UnitDuke University Medical CenterDurham, NC
Conflict of Interest DisclosuresProgram ChairmanSAMUEL Z. GOLDHABER, MDResearch Support: Eisai; EKOS; Johnson and Johnson; sanofi-aventisConsultant: Baxter, Boehringer-Ingelheim; BMS; Daiichi; Eisai; Janssen; Merck; Pfizer; Portola, sanofi-aventis
CHRISTIAN T. RUFF, MD, MPHResearch Support: Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, Sanofi-Aventis Consultant: Alere and Beckman Coulter
CHRISTOPHER GRANGER, MDResearch Support: Boehring Ingelheim, Bristol Myers Squibb, GSK, Medtronic Foundation, Merck & Co., Pfizer, Sanofi-aventis, Takeda, The Medicines Company Consultant: Boehringer Ingelheim, Bristol Myers Squibb, GSK, Hoffmann-LaRoche, Lilly, Pfizer, Sanofi-aventis, Takeda, The Medicines Company, Astra Zeneca, Daiichi Sankyo, Ross Medical Corporation
Epidemiology and OverviewRisk, Disease Burden, and Deciphering the Maze of Risk-Specific Interventions for AF
Focus on Non-Monitored Oral Anticoagulation and the Unmet Need for Safer and More Effective Stroke
Prevention in NVAF
Samuel Z. Goldhaber, MDProgram Chairman
Director, Thrombosis Research GroupCardiovascular Division
Brigham and Women’s HospitalProfessor of Medicine
Harvard Medical School
New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation
Faculty COI Disclosures
Research SupportBristol-Myers Squibb, Daiichi, EKOS, NHLBI, Thrombosis Research Institute
Consultant
Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Merck, Pfizer, Portola, sanofi-aventis
Formal Definition: Atrial Fibrillation
AF is an arrhythmia characterized by uncoordinated
atrial activation, with consequent deterioration of atrial mechanical function
Circulation 2011; 121: e269-e367
Normal sinus
rhythm
Atrial fibrillati
on
The ECG of Atrial Fibrillation
ParoxysmalSelf-Terminating
PersistentLasts > 7 Days
PermanentCardioversion Failed or Not
Attempted
Normal Sinus Rhythm
Atrial Fibrillation
The “3 Ps” and Natural History of Atrial Fibrillation
Paroxysmal AF is as likely to cause stroke as
persistent or permanent AF
Atrial Fibrillation: Epidemiology
► The No. 1 preventable cause of stroke
► In the United States, up to 16 million individuals will be affected by the year 2050
► Increasing survival from heart attack and increasing age (“the ‘graying’ of America”) help explain rise in incidence of atrial fibrillation
0
2
4
6
8
10
12
14
16
18
20002005
20102015
20202025
20302035
20402045
2050Year
Proj
ecte
d Nu
mbe
r of P
eopl
e wi
th A
F (m
illion
s)
Miyakasa Y, et al. Circulation. 2006; 114:119-125.
Atrial Fibrillation: An Epidemic
16 millionUS Prevalence
1 in 4 lifetime risk in men and women ≥ 40 years old
Obesity
CVDDiabetes
Hypertension
OSA
AtrialFibrillation
Magnani J W et al. Circulation 2013;128:401-405
Atrial Fibrillation: An Epidemic
Age, years
Prev
alen
ce, p
erce
ntRelationship Between
Atrial Fibrillation and Age
Go AS, et al. JAMA. 2001; 285:2370-2375.
Atrial Fibrillation Causes Stroke Left Atrial Appendage Thrombus
Chimowitz. Stroke 1993; 24: 1015Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622
Stroke and Atrial Fibrillation Burden
Wolf PA, et al. Stroke 1991; 22: 983-988
%AF prevalence Strokes attributable to AF
Age Range (years)0
10
20
30
50–59 60–69 70–79 80–89
Framingham
Approximately 5-fold increased risk of stroke
Quantify stroke risk: CHADS2/ CHA2DS2-VASc
AF strokes have worse outcomes Costly health care ~ $16 billion/year
Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling
73
33
58
16
36
1630
11
Framingham Heart Study
Lin HJ, et al. Stroke. 1996;27:1760-1764.
More Patients are Vulnerable to Stroke than Previously Realized
Fuster V, Chinitz JS. Circulation 2012; 125:2285-2287
2012 Focused Update: ESC Guidelines
Assess stroke risk using CHA2DS2VASc, instead of CHADS2 Recommend anticoagulation for stroke prevention with CHA2DS2-VASc score ≥ 1
Favor novel, non-monitored anticoagulants (apixaban, rivaroxaban, and dabigatran)
Camm AJ, et al. European Heart Journal 2012; 33: 2719
Anticoagulation in Atrial Fibrillation Effects on Stroke Risk Reduction
Warfarin better Control better
AFASAKSPAF
BAATAFCAFA
SPINAF
EAFT
100% 50% 0 -50% -100%
Aggregate
RRR of stroke: 62%
RRR All-cause mortality: 26%
RRR, relative risk reduction.
Hart RG, et al. Ann Intern Med. 1999;131:492-501.
Known Problems With Warfarin
1) Delayed onset/offset
2) Unpredictable dose response
3) Narrow therapeutic index
4) Drug-drug, drug-food interactions
5) Problematic monitoring
6) High bleeding rate
7) Slow reversibility
1) Established efficacy 2) Low cost ($4/month; $10/3 mos)3) Long track record (1954)4) Centralized anticoagulation clinics that
maintain TTRs > 60%5) Rapid, turnaround genetic testing6) Point-of-care self-testing7) INR testing q 12 weeks if stable
Warfarin Will Likely Survive: Why?
CoumaGen-II. Circ 2012; March 19ACCP Chest Guidelines 2012
Sites of Action in Coagulation System
Novel Factor Xa and DT Inhibitors
Hankey GJ and Eikelboom JW. Circulation 2011;123:1436-1450
RivaroxabanApixabanEdoxabanBetrixaban
Xa
IIa
TF/VIIa
X IX
IXaVIIIaVa
II
FibrinFibrinogen
Dabigatran
Initiation
Propagation
Fibrin formation
Steps in Coagulation Pathway Drugs
Comparison Overview of New Anticoagulants with Warfarin
Features Warfarin New AgentsOnset Slow Rapid
Dosing Variable Fixed
Food effect Yes No
Drug interactions Many Few
Monitoring Yes No
Half-life Long Short
Antidote Yes No
Novel Oral AnticoagulantsImportant Comparative Features
• Oral direct thrombin inhibitor• Twice daily dosing• Renal clearance
Dabigatran
• Direct factor Xa inhibitor• Once daily (maintenance), twice daily (loading)• Renal clearance
Rivaroxaban
• Direct factor Xa inhibitor• Twice daily dosing• Hepatic clearance
Apixaban
• Direct factor Xa inhibitor• Once daily dosing• Hepatic clearance
Edoxaban
Circulation 2010;121:1523
Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Base
Rivaroxaban Apixaban EdoxabanOpen LabelTwo DosesTwice Daily
RE-LY
Double BlindTwo DosesOnce Daily
ROCKET-AF
Double BlindTwo DosesTwice Daily
ARISTOTLE
Double BlindTwo DosesOnce Daily
ENGAGE
Dabigatran
Novel Anticoagulants
FIIa Inhibitor Fxa Inhibitor
A “Failure to Prophylax” Syndrome
Over the past decade, about 40% of patients with atrial fibrillation are unprotected from the risk of stroke because of failure to prescribe anticoagulation.
Because criteria for anticoagulation have expanded in 2012, the problem has intensified.
Heightened awareness of the disconnect between guidelines/evidence and suboptimal intervention for SPAF. Anticoagulation is necessary as a first step.
Only 60% Use of Anticoagulation for SPAF: Euro Heart Survey
Nieuwlaat R, et al. Eur Heart J 2006; 27: 3018
% R
ecei
ving
Ant
icoag
ulat
ion
CHADS2 Score
5,333 AF Patients; 35 Countries: 2003–2004
58 59 64 61
Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479
Only 60% Use of Anticoagulation: Minimal Variation by CHA2DS2-VASc
Score
(n=10,607) (n=305) (n=1,345) (n=2,903) (n=2,471) (n=2,180) (n=1,311) (n=902)
Patie
nts,
N (%
)
Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479
Reasons Why VKAs Were Not Given: Patients with CHADS2 Score ≥ 2
Reasons for Failing to AnticoagulatePatients with CHADS2>2 [n=2,302] (n, %)
Alcohol misuse 11 (0.5)Already taking antiplatelet drug for another condition 117 (5.1)
Patient refusal 165 (7.2)Previous bleeding event 55 (2.4)Taking medication contraindicated/cautioned for use with vitamin K antagonists 16 (0.7)
Other 239 (10.4)Physicians choice 1,112 (48.3) Bleeding risk 170 (7.4) Concern over patient compliance 121 (5.3) Guideline recommendation 32 (1.4) Fall risk 150 (6.5) Low risk of stroke 95 (4.1) Other 544 (23.6)
Changing MD Behavior
► Guidelines alone do not suffice.► Physician champions► Individual hospital protocols► Registries (GARFIELD)► Coalitions (“Stop AF”)► Public awareness/ advocacy
(North American Thrombosis Forum) ► Litigation► Electronic alerts
Computerized Support:Tricks of the Trade
Piazza G, Goldhaber SZ. Circulation 2009;120:113
Integrate support into quality improvement. Link to an incentive system. Foster acceptance of computer guidance. Couple support with order entry software. Limit to key decisions to avoid alert fatigue. Use automatic, not user-initiated, systems. Measure outcomes and provider behavior.
The SPAF Landscape 2012: Conclusions
► The frequency of atrial fibrillation is increasing, so risk of devastating stroke is increasing as well.
► Anticoagulants can effectively reduce stroke risk, but they are underutilized.
► NOACs have less ICH bleeding risk than warfarin and are superior—or at least noninferior—for stroke prevention.
► We must overcome the failure-to-prophylax syndrome.
State-of-the-Art Risk Stratification of Patients with
Atrial Fibrillation Anticoagulation Strategies Based on Established and Evolving Atrial Fibrillation Scoring Systems
for Thrombosis and Hemorrhagic Risk
New Paradigms in the Science and Medicine of Heart Disease
CHRISTOPHER B. GRANGER, MD Professor of Medicine
Duke University Medical CenterDirectory, Cardiac Care Unit
Duke University Medical CenterDurham, NC
Stroke
Systemic Embolism
Embolic Hemodynamic
Fatigue
Shortness of Breath
Palpitations
CHF
Complications of AF
Antithrombotic Therapy
Rate ControlRhythm Control
Treatment of AF
Rate N:Rhythm N:
20272033
19251932
18251807
13281316
774780
236255
0
5
10
15
20
25
30
0 1 2 3 4 5
Mor
talit
y,
%RateRhythmp=0.078 unadjusted
Time (years)
p=0.068 adjusted
The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.
AFFIRM: Rate vs. Rhythm Control
Nearly ¾ of all strokes were related to discontinuation or inadequate anticoagulation
Only 42% of strokes during documented AF
Al-Khatib SM, et al. EHJ 2013; 34: 2464-2471
Outcomes by AF Type - ARISTOTLE
Adjusted HR 0.70, 95% CI 0.51-0.93 P=0.015
Subclinical AF and Risk of Stroke
Healey JS, et al. NEJM 2012; 366:120-129
Stro
ke o
r Sys
tem
ic Em
bolis
m
Years
Atrial Tachyarrhythmia > 6 min ≤ 3 Months After Pacemaker or Defibrillator Implantation
Van Gelder IC et al. N Engl J Med. 2010;362:1363-1373.
RACE II: Lenient vs. Strict Rate Control
Noninferior
Strict control
Lenient control
Months
Cum
ulat
ive
Incid
ence
of
Prim
ary
Outc
ome
(%)
0 6 12 18 24 30 36
20
15
10
5
0
14.9
12.9
No. at RiskStrict control 303 282 273 262 246 212 131Lenient control 311 298 290 285 255 218 138
Balancing the Risks of Thrombosis and Bleeding
Ris
k of
Any
Eve
nt
Adapted from Ferreiro JL et al. Thromb Haemost. 2010;103:1-8.
High risk of Thrombotic events
Ris
k of
Any
Eve
nt
Potency of Antithrombotic Therapy
“Sweet spot”High risk of
bleeding events
– +Thrombotic risk Bleeding risk
Risk Factor Points
Congestive Heart Failure 1
Hypertension 1
Age ≥ 75 1
Diabetes Mellitus 1
Stroke or TIA 2
Maximum Score 6
CHADS2 Risk Score
Gage BF, et al. JAMA. 2001;285:2864-2870.VanWalraven C, et al. Arch Intern Med 2003; 163:936.Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.
CHADS2 Stroke (% / yr)0 1.91 2.8
2 4.0
3 5.9
4 8.5
5 12.5
6 18.2
3% / year
Risk Factor Recommended Therapy
No risk factorsCHADS2 = 0 Aspirin, 81-325 mg
One moderate risk factorCHADS2 = 1
Aspirin, 81-325 mg orWarfarin
(INR 2.0-3.0, target 2.5)
Any high risk factor or>1 moderate risk factorCHADS2 >2
Warfarin(INR 2.0-3.0, target 2.5)
Prosthetic valve Warfarin(INR 2.5-3.5, target 3.0)
Prior ACC/AHA/ESC Guidelines
Risk Factor PointsCHF / LV Dysfunction 1Hypertension 1
Age ≥ 75 2
Diabetes Mellitus 1
Stroke / TIA / Embolism 2
Vascular Disease 1
Age 64-74 1
Sex Category (female) 1
Maximum Score 9
ESC Guidelines: Eur Heart J . 2010;31:2369-2429.
CHA2DS2-VASc Score Stroke (% / yr)1 0 %2 1.3 %
3 2.2 %
4 4.0 %
5 6.7 %
6 9.8 %
7 9.6 %
8 6.7 %
9 15.2 %
Redefining Risk: CHA2DS2-VASc
CHA2DS2VASc Refines Stroke Risk Stratification in CHADS2=0
A nationwide Danish cohort study in 47,576 non-warfarin treated NVAF patients with a CHADS2 score = 0-1 at baseline (1997-2008)
100%
CHADS2=0: n=17,327 person-yearsCHA2DS2VASc=0: n=6,919 person-yearsCHA2DS2VASc=1: n=6,811 person-yearsCHA2DS2VASc=2: n=3,347 person-yearsCHA2DS2VASc=3: n=250 person-years
Stroke / thromboembolism
rate (% person-years)
Prop
ortio
n of
pat
ient
s fre
e of
stro
ke /
thro
mbo
embo
lism
0%
92%
94%
96%
98%
0.84%
Days from discharge0 100 200 300
1.59%1.75%2.69%3.20%
Olesen et al. Thromb Haemost 2012; 107:1172-1179
Danish Hospital Registry Data 1997-200614,572 patients CHADS-VASc 0 or 1
Olesen J. BMJ 2011;342:d124
A nationwide Danish cohort study in 47,576 non-warfarin treated NVAF patients with a CHADS2 score = 0-1 at baseline (1997-2008)
CHADS2=1: n=22,945 person-yearsCHA2DS2VASc=1: n=2,069 person-
yearsCHA2DS2VASc=2: n=8,516 person-yearsCHA2DS2VASc=3: n=11,223 person-yearsCHA2DS2VASc=4: n=1,137 person-years
Prop
ortio
n of
pat
ient
s fre
e of
stro
ke /
thro
mbo
embo
lism
0%
92%
94%
96%
98%
100%
1.93%
Days from discharge0 100 200 300
4.05%
4.92%5.81%
8.18%
Stroke / thromboembolism
rate (% person-years)
Olesen et al. Thromb Haemost 2012; 107:1172-1179
CHA2DS2VASc Refines Stroke Risk Stratification in CHADS2=1
ESC Guidelines: Eur Heart J . 2010;31:2369-2429
Redefining Risk: HAS-BLED
Letter Clinical Characteristic Points
H Hypertension 1
A Abnormal Liver or Renal Function 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age > 65) 1
D Drugs or Alcohol 1 or 2
Maximum Score 9 Pisters R, et al. Chest 2010; 138(5): 1093-1100
The Problem with Risk Scores (ARISTOTLE)
Lopes RD, et al. Lancet 2012; 380:1749-1758 Apixaban Better Warfarin Better
Stroke or SEE
Major Bleeding
ESC Guidelines: Eur Heart J . 2010;31:2369-2429
HAS-BLED
Letter Clinical Characteristic Points
H Hypertension 1
A Abnormal Liver or Renal Function 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age > 65) 1
D Drugs or Alcohol 1 or 2
Maximum Score 9 Pisters R, et al. Chest 2010; 138(5): 1093-1100
Reasons for Withholding OAC in Patients with AF and Stroke Risk
Patient Provider System
Appropriate: Refusal after complete understanding
Recent intracranial hemorrhage
Lack of access to INR monitoring and can not afford novel drug
Inappropriate: Desire to avoid monitoring (and can afford NOAC)
Old age; CHADS score = 1
Lack of time to address issues
Uncertain appropriateness:
Desire to avoid bruising
Substantial fall risk
Unable to afford cost of monitoring
Anticoagulation in Patients at Risk For Falls
“…persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin
not to be the optimal therapy…”
ACTIVE - Major Bleeding
The ACTIVE Writing Group. Lancet 2006;367:1903-1912
0.0
0.01
0.02
0.03
0.04
0.0 0.5 1.0 1.5
OAC
Clopidogrel+ASACum
ulat
ive
Haza
rd R
ates
Years
# at RiskC+A 3335 3172 2403 914OAC 3371 3212 2423 901
2.4 %/year
2.2 %/year
RR = 1.06P = 0.67
OAC
Clopidogrel+ASA
Bleeding According to Antiplatelet Therapy in RE-LY Trial
Series of no, single, and dual antiplatelet therapy
HRs adjusted for age, gender, warfarin experience, SBP, CAD, HF, hypertension, diabetes, TIA, CrCl and statin use.
W
D 150
D 110
Circulation. published online December 27, 2012
ORBIT-AF Registry (N=7,347): 6-month Major Bleeding
Steinberg B et al. Circulation 2013;128:721-728
* Compared to control35 more minor bleeds occurred with warfarinPooled data from AFASAK, SPAF, and BAATAFIntention-to-treat analysis
For every 1000 patients with AF in clinical trials treated with warfarin for 1 year
Benefit Risk35 fewer thromboembolic
events*1 more intracranial or major bleed*
Adapted from Alberts et al. Ann Neurol 1991;30:511-518.
Anticoagulation in AFBenefit vs. Risk
Registry cohort study of all Danish pts surviving first-time hosp for AF between 1997 and 2006
82,854 of 118,606 pts had prescription filled for warfarin, ASA, or clopidogrel after discharge.
During follow-up of 3.3 yrs, 13,573 pts (11.4%) had nonfatal or fatal bleeding.
Arch Intern Med. 2010;170:1433-1441
Risk of Bleeding with Single, Dual, or Triple Therapy in Patients with AF
3 to 4 fold risk of bleeding with triple therapy
What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing
(WOEST)
N = 563
Days
Bleeding Events
(OAC + clopidogrel)
Dewilde W, et al. Lancet 2013; 381:1107-1115
What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing
(WOEST)
Dewilde W, et al. Lancet 2013; 381:1107-1115
P = 0.027 0.38 0.88 0.13 0.17
Risk Profile Class / Level
CHA2DS2-VASc = 0 No antithrombotic therapyI B
CHA2DS2-VASc = 1VKA (INR 2-3)
OrDabigatran / Rivaroxaban / Apixaban
IIa A (Favored)
CHA2DS2-VASc ≥ 2VKA (INR 2-3)
OrDabigatran / Rivaroxaban / Apixaban
I A (Favored)
ESC 2012 AF Guidelines Update
Quartiles of NT-proBNP
Patton et al., Circulation 2009; 120:1768-74
Biomarkers and Risk PredictionNT-proBNP Predicts AF
Biomarkers & Risk Prediction – RE-LY
Hijazi Z, et al. Circulation 2012; 125:1605-1616
Troponin
NTproBNP
Troponin
NTproBNP
Stroke & SEE Vascular Death
Hijazi Z, et al. Circulation 2012; 125:1605-1616
Stroke, SEE, PE, MI, & Vascular Death
CHAD
S 2
CHAD
S 2
Trop NTproBNP
TropNTproBNP
Multimarker & Risk PredictionRE-LY
65
Enhanced Risk Prediction - ARISTOTLE
Hijazi Z, et al. JACC 2013;61:2274-2284
CHA2DS2VASc NTproBNP
CHA2DS2VASc
NTproBNP
Stroke or SEE
Cardiac Death
Summary
► Risk stratification is improving► Most patients with AF have at least one
risk factor for stroke and should be anticoagulated
► Now the focus is on identifying the low risk patient (who does not need anticoagulation)
► Biomarkers (BNP, hsTn) provide powerful prognostic information
► We need prospective studies of “multimarker” risk assessment tools
► Better understanding of how burden of AF relates to risk is needed
Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-
Monitored, Oral Anticoagulants (NOACs) for SPAF
Christian T. Ruff, MD, MPHTIMI Study Group
Brigham and Women’s HospitalHarvard Medical School
Boston, MA
New Paradigms in the Science and Medicine of Heart Disease
History of Warfarin
Limitations of Warfarin
Delayed onset/offset
Multiple food and drug interactions
Genetic variability in metabolism (VKORC1 and CYP2C9)
Requires frequent monitoring of INR due to limited therapeutic index
Subtherapeutic INR 29%
INR in range10%
No warfarin61%
Preventable Strokes
AF Patients with Stroke with no Known Contraindication to
Anticoagulation
Gladston, DJ, et al. Stroke 2009;40:235-40
Properties BenefitOral, once-daily dosing Ease of administration
Rapid onset of action No need for overlapping parenteral anticoagulant
Minimal food or drug interactions Simplified dosing
Predictable anticoagulant effect No coagulation monitoring
Extra renal clearance Safe in patients with renal disease
Rapid offset in action Simplifies management in case of bleeding or intervention
Antidote For emergencies
Properties of an Ideal Anticoagulant
Major Advances In Oral Anticoagulation for SPAF
6 Trial of Warfarin vs. Placebo1989-1993
RE-LY(Dabigatran)
2009
ROCKET AF (Rivaroxaban)
2010
ARISTOTLE (Apixaban)
2011
ENGAGE AF (Edoxaban)
2013
Dabigatran Rivaroxaban Apixaban Edoxaban
Target IIa (thrombin) Xa Xa Xa
Hrs to Cmax 2 2-4 1-3 1-2CYP metabolism None 32% 15% NRBioavailability 7% 80% 66% > 45%Transporters P-gp P-gp/BCRP P-gp P-gpProtein binding 35% >90% 87% 55%Half-life 12-14h 9-13h 8-15h 8-10hRenal elimination 80% 33% 25% 35%Linear PK Yes No Yes Yes
Comparative PK/PD of Novel Agents
Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22
BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported; P-gp = P-glycoprotein
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 vs Warfarin
Dabigatran 150 vs Warfarin
Non-inferiorityP-value< 0.001
< 0.001
SuperiorityP-value 0.34
< 0.001
Margin = 1.46
HR (95% CI)
RE-LY Efficacy - DabigatranStroke/Systemic Embolic Event
Connolly, et al. N Engl J Med 2009;361:1139-51
0.1 0.3 0.5 1.0 2.0
Dabigatran 110 mgDabigatran 150 mg
Stroke/SEE
Ischemic Stroke
Hemorrhagic Stroke
0.91 (0.74-1.11)
0.66 (0.53-0.82)
1.11 (0.89-1.40)
0.76 (0.60-0.98)
0.31 (0.17-0.56)
0.26 (0.14-0.49)
Dabigatran Better Warfarin Better
RE-LY Efficacy
Connolly, et al. N Engl J Med 2009;361:1139-51
0.1 0.3 0.5 1.0 2.0
Major Bleed
ICH
GI Bleed
0.80 (0.69-0.93)0.93 (0.81-1.07)
0.31 (0.20-0.47)0.40 (0.27-0.60)
1.10 (0.86-1.41)1.50 (1.19-1.89)
MI 1.29 (0.96-1.75)1.27 (0.94-1.71)
Dabigatran Better Warfarin Better
RE-LY Safety Results
Connolly, et al. N Engl J Med 2009;361:1139-51
Dabigatran 110 mgDabigatran 150 mg
Rivaroxaban Warfarin
Event Rate
Event Rate
HR(95% CI) P-value
On Treatment
N = 14,1431.70 2.15 0.79
(0.65, 0.95) 0.015
ITTN = 14,171 2.12 2.42 0.88
(0.74, 1.03) 0.117
Rivaroxabanbetter
Warfarinbetter
Event Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat through
Site Notification populations
0.5 1 2
Patel, et al. N Engl J Med 2011;365(10);883-891
ROCKET AF Efficacy - RivaroxabanStroke/Systemic Embolic Event
ROCKET AF Key Secondary Efficacy
Event Rivaroxaban(%/yr)
Warfarin(%/yr)
Hazard Ratio(95% CI)
P-value
Ischemic Stroke 1.34 1.42 0.94 (0.75-1.17) 0.581
Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-0.93) 0.024
MI 0.91 1.12 0.81 (0.63-1.06) 0.121
Total Mortality 1.87 2.21 0.85 (0.70-1.02) 0.073
Vascular Mortality 1.53 1.71 0.89 (0.73-1.10) 0.289
Patel, et al. N Engl J Med 2011; 365(10);883-891
ROCKET AF Safety
Event Rivaroxaban(%/yr)
Warfarin(%/yr)
Hazard Ratio(95% CI)
P-value
Major and Clinically Relevant Bleed 14.9 14.5 1.03 (0.96-
1.11) 0.44
Major Bleed 3.6 3.4 1.04 (0.90-1.20) 0.58
Fatal Bleed 0.2 0.5 0.50 (0.31-0.79) 0.003
ICH 0.5 0.7 0.67 (0.47-0.93) 0.02
Patel, et al. N Engl J Med 2011; 365(10);883-891
ARISTOTLE Efficacy - Apixaban
Granger CB, et al. NEJM 2011; 365:981-992
HR 0.79 (0.66–0.95)
P (non-inferiority) < 0.001
21% RRR(1.27 %/yr )
(1.60 %/yr)
P (superiority) = 0.011
ARISTOTLE Efficacy Outcomes
Granger CB, et al. NEJM 2011; 365:981-992
Outcome
Apixaban(N = 9120)
Warfarin(N = 9081)
HR (95% CI) P ValueEvent
Rate(%/yr)
Event Rate
(%/yr)Stroke or systemic embolism* 1.27 1.60 0.79 (0.66,
0.95) 0.011
Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012
Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42
Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75)
< 0.001
Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70
All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047
Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81,
0.98) 0.019
Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37
ARISTOTLE Safety End Points
Event Apixaban(%/yr)
Warfarin(%/yr)
Hazard Ratio(95% CI)
P-value
ISTH Major Bleeding 2.13 3.09 0.69 (0.60-0.80) < 0.001
ICH 0.33 0.80 0.42 (0.30-0.58) < 0.001
GUSTO Severe 0.52 1.13 0.46 (0.35-0.60) < 0.001
Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) 0.37
Granger CB, et al. NEJM 2011; 365:981-992
AF Trials – Dose Comparison
RE-LY ROCKET-AF ARISTOTLEENGAGE
AF-TIMI 48Drug Dabigatran Rivaroxaban Apixaban Edoxaban
N 18,113 14,266 18,201 21,105Dose (mg)Frequency
150, 110BID
20 QD
5BID
60, 30QD
Initial Dose adj* No 20 → 15 mg 5 → 2.5 mg 60 → 30 mg
30 → 15 mgDose adj (%) 0 21 4.7 >25Dose adj* after randomization No No No Yes
Design PROBE 2x blind 2x blind 2x blind
*Dose adjusted in patients with ↓drug clearance. PROBE = prospective, randomized,
open-label, blinded end point evaluation
Connolly SJ et al. N Engl J Med 2009; 361:1139-51Patel MR et al. N Engl J Med 2011; 365:883-91
Granger CB et al. N Engl J Med 2011; 365:981-92Ruff CR et al. Am Heart J 2010; 160:635-41
Baseline Characteristics in AF Trials
RE-LY(Dabigatran)
ARISTOTLE(Apixaban)
ENGAGE AF-TIMI 48*(Edoxaban)
ROCKET-AF(Rivaroxaban)
# Enrolled 18,113 18,201 21,105 14,264
Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78]
Female 36% 35% 38% 40%
CHADS2 score ≥3 32% 30% 52% 87%
VKA naive 50% 43% 41% 38%
Paroxysmal AF 33% 15% 25% 18%
Prior stroke/TIA 20% 19% 18% / 12% 55%**
Diabetes 23% 25% 36% 40%
Prior CHF 32% 35% 56% 62%
Hypertension 79% 87% 90% 91%
*Preliminary data**includes prior systemic embolism
Connolly SJ et al. N Engl J Med 2009; 361:1139-51Patel MR et al. N Engl J Med 2011; 365:883-91
Granger CB et al. N Engl J Med 2011; 365:981-92Ruff CR et al. Am Heart J 2010; 160:635-41
AF Trials: Results To Date
Outcomes vs. Warfarin Dabigatran 110 mg
Dabigatran150 mg Rivaroxaban Apixaban
Stroke or Systemic Embolism Non-inferiority Superiority Non-
inferiority Superiority
Stroke No Yes No Yes
Ischemic Stroke No Yes No No
Hemorrhagic Stroke Yes Yes Yes Yes
Fatal / Disabling Stroke No Yes No Yes
Vascular Death No Yes No No
All-Cause Death No No No Yes
Major Bleeding Yes No No Yes
ICH Yes Yes Yes Yes
GI Bleeding No Yes Yes No
88
Efficacy of New Oral Anticoagulants
Stroke & SEE
Ischemic & Unsp.
Stroke
Hemorraghic Stroke
Miller CS, et al. Am J Cardiol 2012;110(3):453-460.Favors NOACs Favors Warfarin
13%
55%
89
Safety of New Oral Anticoagulants
Major
ICH
GI
Bleeding
Miller CS, et al. Am J Cardiol 2012;110(3):453-460.
51%
Favors NOACs Favors Warfarin
12%
Mortality Benefit ofNew Oral Anticoagulants
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011
Apixaban 5 m b.i.d.
ivaroxaban 20 mg
abigatran 110 mg b.i.d.
bigatran 150 mg b.i.d.
0.5 1 2
Dabigatran 150 mg BID
Dabigatran 110 mg BID
Rivaroxaban 20 mg
Apixaban 5 mg BID
► 150 mg twice daily if CrCL > 30 mL/min
► 75 mg twice daily if CrCL 15-30 mL/min
Dabigatran
► 20 mg if CrCl > 50 mL/min
► 15 mg if CrCL 15-50 mL/min
Rivaroxaban
► 5 mg twice daily
► 2.5 mg twice daily if at least 2 of the following: Age ≥ 80 years Weight ≤ 60 kg Cr ≥ 1.5 mg/dL
Apixaban
Low dose regimenEdoxaban 30 mg QD
(n≈7000)
Active ControlWarfarin(n≈7000)
High dose regimenEdoxaban 60 mg QD
(n≈7000)
AF on Electrical Recording <12 moIntended oral A/C
CHADS2 >2
N = 21,105
RRandomization Stratified By
1. CHADS2 2-3 vs 4-62. Drug Clearance
Median Duration of Follow-up 24 months
Primary ObjectiveEdoxaban: Therapeutically as Good as Warfarin
DOUBLE BLINDDOUBLE DUMMY
SEE = systemic embolic event
1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)2º EP = Stroke or SEE or CV mortality
Safety EP’s = Major Bleeding, Hepatic Function
EVENT DRIVEN
Ruff CR et al. Am Heart J 2010; 160:635-41
Phase III: Protocol Schema
Connolly SJ, et al. Circulation 2008;118:2029-2037
OAC
OAC
C+A
C+A
Years Years
Even
t Rat
e (%
)
Even
t Rat
e (%
)
TTR < 65% TTR ≥ 65%RR=0.93 (0.70-1.24)
p=0.61RR=2.14 (1.61-2.85)
P=0.0001
0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5
12
10
8
6
4
2
0
12
10
8
6
4
2
0
ACTIVE-W: Risk of Stroke / SEE / MI / Vascular Death by cTTR
Does INR Matter?
RE-LY (Dabigatran 150 mg) 0.20<57.1% 1.1 1.9257.1–65.5% 1.04 2.0665.5–72.6% 1.04 1.51>72.6% 1.27 1.34
Treatment GroupEvent Rate / Year
WarfarinEvent Rate / Year
p-value(interaction)
ROCKET AF 0.740.00-50.62% 1.77 2.53 50.71-58.54% 1.94 2.18 58.63-65.71% 1.90 2.14 65.74-100.0% 1.33 1.80
ARISTOTLE 0.29< 58.0% 1.75 2.28 58.0–65.7% 1.30 1.61 65.7–72.2 % 1.21 1.55 > 72.2 % 0.83 1.02
0.2 21 5
Hazard Ratio (95% CI)Study Drug WarfarinFavors
Wallentin L, et al. Lancet 2010;376:975-983Patel, et al. NEJM 2011;365(10);883-891Granger CB, et al. NEJM 2011; 365:981-992
Efficacy Stratified by Prior VKA (RE-LY)
Ezekowitz MD, et al. Circulation 2010;122:2246-2253
Al-Khatib SM, et al. EHJ 2013 (published on-line April 17, 2013)
Outcomes by AF Type - ARISTOTLE
ARISTOTLE: Efficacy & SafetyAcross Baseline Risk
Lopes RD, et al. Lancet 2012; 380:1749-1758 Apixaban Better Warfarin Better
Stroke or SEE
Major Bleeding
ARISTOTLE: ApixabanRenal Function
Hohnloser SH, et al. EHJ 2012; 33:2821-2830
Baseline Cockcroft-Gault eGFR mL/min
Annu
alize
d Ev
ent R
ate
Stroke or SEE Major Bleeding
(N=647)
Cardioversion
(N=672) (N=664)Nagarakanti R, et al. Circulation 2011;123:131-136
RE-LY
%
ROCKET AF
%
Cardioversion & Catheter Ablation
Piccini JP, et al. JACC 2013;61:1998-2006
Kim JS, et al. Heart Rhythm 2013; 10:483-489
Catheter Ablation with NOACs
Case-control: 763 consecutive patients undergoing AF ablationP=0.8
5
P=1.0
P=1.0
%P=0.81
Periprocedural Major Bleeding
%
Healey JS, et al. Circulation 2012; 126:343-348
RE-LY
Discontinuing NOACs Prior to Procedures
Heidbuchel H, et al. Eurospace 2013;15:625-651.
www.NOACfor AF.eu
Dabigatran Apixaban Edoxaban Rivaroxaban No important bleeding risk and/or adequate local haemostasis possible:
perform at trough level (i.e. ≥12h or 24h after last intake) Low risk High risk Low risk High risk Low risk High risk Low risk High risk
CrCl ≥80 ml/min ≥24h ≥48h ≥24h ≥48h no data no data ≥24h ≥48h
CrCl 50-80 ml/min ≥36h ≥72h ≥24h ≥48h no data no data ≥24h ≥48h
CrCl 30-50 ml/min ≥48h ≥96h ≥24h ≥48h no data no data ≥24h ≥48h
CrCl 15-30 ml/min
not indicate
d
not indicated ≥36h ≥48h no data no data ≥36h ≥48h
CrCl <15 ml/min no official indication for use
Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127
Dabigatran (FIIa) Monitoring
aPTT Hemoclot Test
Van Ryn J, et al. Thromb Hemost. 2010; 103:1116-1127
Rivaroxaban (Fxa) Monitoring
PT
Rivaroxaban (µg L-1)0 100 200 300 400 500 600
Prot
hrom
bin
time
(s)
0
10
20
30
40
Rotachrom Anti-Xa
Managing Bleeding with NOACs
Heidbuchel H, et al. Eurospace 2013;15:625-651.
www.NOACfor AF.eu
Granger CB, et al. European Heart Journal 2012;33 (Supplement):685-686
Pattern mirrored the first 30 days of the trial where warfarin-naïve patients starting warfarin had a higher rate of stroke or systemic
embolism (5.41%/year) than warfarin-experienced patients (1.41%/year).
1-2 3-7 8-14 15-300
5
10
15
20
25
21
5
Apixaban to VKA Group Warfarin to VKA Group Apixaban to VKA Total Events Warfarin to VKA Total Events
Days after last dose
Stro
ke o
r sy
stem
ic
embo
lism
(n)
ARISTOTLEApixaban: Increased Events at End of Trial
Rivaroxaban
Warfarin
48.8
81.3
# Pr
imar
y Ev
ents P =
0.008
Patel MR, et al. NEJM 2011; 365:883-891Patel MR, et al. JACC 2013;61:651-658
Safety/Days 3 to 30 after the last dose
# Primary Events during first 30 days of transition
ROCKET AFRivaroxaban: Increased Events at End of Trial
Rivaroxaban Warfarin
Outcomes Following Discontinuation of Anticoagulation
P=0.35
Patel MR, et al. JACC 2013;61:651-658
Stro
ke +
SEE
(%
/yea
r)
P=0.62
P=0.66
P=0.004
P=0.03
Efficacy and Safety of NOACs in the“Real World”
Larsen TB, et al. JACC 2013;61:2264-2273
RELY-ABLE
Connolly SJ, et al. Circulation 2013;128:237-243
Stroke or SEE Major Bleeding
Dabigatran 150 mg: 3.74% / year Dabigatran 110 mg: 2.99% / year
HR 1.26 (1.04-1.53)
Dabigatran 150 mg: 1.46 % / year Dabigatran 110 mg: 1.60 % / year
HR 0.91 (0.69-1.20)
New therapies provide the promise of providing safer and more convenient anticoagulation.
There are important differences in the half-life, metabolism, & renal elimination across the NOACs that will alter the risk/benefit profile in specific populations.
Persistent concern with lack of ability to monitor the level of anticoagulation.
Further experience and guidance needed in managing anticoagulation peri-procedure.
Desire for reversal agent and strategies to manage serious bleeding.
Conclusions
Stroke Prevention In AF:Vision Statement
Samuel Z. Goldhaber, MDProgram Chairman
Director, Thrombosis Research GroupCardiovascular Division
Brigham and Women’s HospitalProfessor of Medicine
Harvard Medical School
New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation
Faculty COI Disclosures
Research SupportBristol-Myers Squibb, Daiichi, EKOS, NHLBI, Thrombosis Research Institute
Consultant
Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Merck, Pfizer, Portola, sanofi-aventis
Themes
1. NOACs provide us with a potent pharmacological strategy to prevent stroke due to AF, and to treat PE/ DVT.
2. Appropriate uptake of NOACs will require sustained educational campaigns focusing on indication for therapy, appropriate patient profiles, and drug pharmacology.
Themes (Continued)
3. Electronic decision support can serve as an educational tool. More widespread availability of electronic medical records will facilitate decision support.
4. Anticoagulation therapy alone will not prevent stroke from AF. Our patients need intensified risk factor modification (e.g., quit cigarettes, treat hypertension) and transition to heart-healthy lifestyles re: exercise and nutrition.
NOACS vs. Warfarin: Cochrane Database
Efficacy and Safety Meta-Analysis
Bruins Slot KM, Berge E. Cochrane Database Syst Rev. 2013 Aug 8;8:CD008980.
Factor Xa Inhibitors Compared with Vitamin K Antagonists for the Prevention of Stroke and other Systemic Embolic Events in Patients with Atrial Fibrillation
Clinical OutcomesIllustrative Comparative Risks* (95%
CI)Assumed Risk Corresponding Risk
Warfarin Factor Xa InhibitorsStroke and other systemic embolic events (Follow-up: 12 weeks to 1.9 years)
32 per 1000 25 per 1000(0 to 38)
All strokes(Follow-up: 12 weeks to 1.9 years) 27 per 1000 20 per 1000
(0 to 26)Major bleeding(Follow-up: 12 weeks to 1.9 years) 46 per 1000 39 per 1000
(0 to 55)Intracranial hemorrhages(Follow-up: 12 weeks to 1.9 years) 11 per 1000 6 per 1000
(0 to 8)All-cause deaths(Follow-up: 12 weeks to 1.9 years) 51 per 1000 45 per 1000
(0 to 66)
Emergence of a New Safety and Efficacy
Paradigm
“Drugs don’t work in patients who don’t take them.”
C. Everett Koop, M.D.
Surgeon General 1981-1989
New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation
New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation
Failure To Anticoagulate Patients At High Risk For Stroke:
Scope Of Problem,
Strategic Tips
ONLY 60% USE of Anticoagulation: Minimal Variation by CHA2DS2-VASc Score
Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479
(n=10,607) (n=305) (n=1,345) (n=2,903) (n=2,471) (n=2,180) (n=1,311) (n=902)
Patie
nts,
N (%
)
Changing MD Behavior
► Guidelines alone do not suffice.► Physician champions► Individual hospital protocols► Registries (GARFIELD)► Coalitions (“Stop AF”)► Public awareness/ Advocacy
(North American Thrombosis Forum) ► Litigation► Electronic alerts
Unresolved Issues
► No established methods of monitoring ► No known therapeutic ranges► Lack of an established antidote► Uncertain management of bleeding► Long term safety► No head to head comparisons of new agents
Novel Anticoagulants: New Opportunities
Immediate onset of actionFixed dosing, with “low-dose” optionNo laboratory coagulation monitoringMinimal drug-food interactionsShort half-life; therefore, no “bridging” Improved efficacy, fewer catastrophic head
bleeds, trend toward lower all-cause mortality
1. NOACs for SPAF show: superiority or at least noninferiority to warfarin, reduction in ICH, more convenience for patients and clinicians.
2. Lower stroke and bleeding complication rates: not anticipated.
3. Many AF patients remain at risk and receive no anticoagulation.
Take Home Points
Take Home Points4. The rapid expansion of anticoagulation
options places clinician education at a premium. Focus must be on correct selection of patients, drugs, and doses.
5. Combining optimal anticoagulation with intensive lifestyle modification provide the best strategy for lowering cardiovascular disease burden.
So What Now? Trials in Translation
Applying Evidence-Driven Strategies to AF Patients at the Front Lines of Clinical
Practice
Samuel Z. Goldhaber, MDProgram Chairman
Director, VTE Research GroupCardiovascular Division
Brigham and Women’s HospitalProfessor of Medicine
Harvard Medical School
Advances in the Science and Medicine of Stroke Prevention in AF
Atrial Fibrillation Case Study #1
A patient with AF has a CHA2DS2-VASc score of 3 and and a HAS-BLED score of 4. What would you do for stroke prevention?
1) Anticoagulate the patient because risk of stroke outweighs risk of bleeding
2) Prescribe aspirin as the risk of bleeding with anticoagulation outweighs the risk of stroke
Please Enter Your Response On Your Keypad
Atrial Fibrillation Case Study #2 A 67-year-old female with a history of mitral
stenosis with subsequent mechanical mitral valve replacement has AF. Which of the following anticoagulants can be used for stroke prevention in this patient?
1) Warfarin2) Dabigatran 3) Rivaroxaban 4) Apixaban 5) All of the above
Please Enter Your Response On Your Keypad
Atrial Fibrillation Case Study #3Question #1
A 78-year-old woman with symptomatic AF, heart failure, and hypertension undergoes successful cardioversion and is now in sinus rhythm. She has been treated with warfarin. What would you do regarding her antithrombotic regimen?
1) She does not need any now that she is in sinus rhythm
2) Switch to aspirin3) Continue anticoagulation
Please Enter Your Response On Your Keypad
Our patient has recurrent AF and is continued on warfarin. She has had very labile INRs despite careful management. The best step in her management is?
1) Switch to aspirin and clopidogrel 2) Switch to a factor Xa or IIa inhibitor3) Continue warfarin
Atrial Fibrillation Case Study #3Question #2
Please Enter Your Response On Your Keypad
What about if her INR has been stable 2.0-3.0 on warfarin. Is there any benefit from to switching to a novel anticoagulant?
1) Yes
2) No
Atrial Fibrillation Case Study #3Question #3
Please Enter Your Response On Your Keypad
She wants to start a NOAC. Her weight is 70 kg (154 lbs) and her creatinine clearance (CrCl) is currently 20 mL/min but frequently fluctuates to 10-15 mL/min. What are her options?
1) Dabigatran 150 mg twice daily2) Dabigatran 75 mg twice daily3) Rivaroxaban 20 mg once daily4) Rivaroxaban 15 mg once daily5) Apixaban 5 mg twice daily6) Apixaban 2.5 mg twice daily7) She should continue on warfarin
Atrial Fibrillation Case Study #3Question #4
Please Enter Your Response On Your Keypad
What NOAC would be dose adjusted if her CrCl was stable at 40 mL/min (Cr 1.3)?
1) Dabigatran 2) Rivaroxaban 3) Apixaban
Atrial Fibrillation Case Study #3Question #5
Please Enter Your Response On Your Keypad
You decide to start dabigatran. Which of the following is true regarding transitioning a patient from warfarin to dabigatran?
1) Start dabigatran when INR < 32) Start dabigatran when INR < 23) Start dabigatran 24 hours after last dose of
warfarin
Atrial Fibrillation Case Study #3Question #5
Please Enter Your Response On Your Keypad
What about if you decide to start rivaroxaban instead?
1) Start rivaroxaban when INR < 32) Start rivaroxaban when INR < 23) Start rivaroxaban 24 hours after last dose of
warfarin
Atrial Fibrillation Case Study #3Question #6
Please Enter Your Response On Your Keypad
A man taking dabigatran for AF is in a motor vehicle accident and needs emergency surgery. It is unclear when he last took his dabigatran. Which of the following tests, if normal, would reassure surgeon that he is not anticoagulated?
1) INR (international normalized ratio)2) aPTT (activated partial thromboplastin time)3) PT (prothrombin time)4) Bleeding time
Atrial Fibrillation Case Study #4Question #1
Please Enter Your Response On Your Keypad
What if he had been on rivaroxaban or apixaban?
1) INR (international normalized ratio)2) aPTT (activated partial thromboplastin time)3) PT (prothrombin time)4) Bleeding time
Atrial Fibrillation Case Study #4Question #2
Please Enter Your Response On Your Keypad
Atrial Fibrillation Case Study #5 A patient on a NOAC is having life-threatening
bleeding. What reversal agent(s) can be considered?
1) Protamine sulfate2) Vitamin K3) Fresh frozen plasma (FFP)4) Activated prothrombin complex concentrate
(aPCC)5) Factor VIIa 6) All of the above7) 1, 2, and 38) 4 and 5Please Enter Your Response On Your Keypad
Atrial Fibrillation Case Study #6 A patient with atrial fibrillation on anticoagulation is
admitted to the hospital with NSTEMI and is found to have a lesion amenable to PCI. What is the best management option?
1) Placement of a DES with 1 year of aspirin, clopidogrel, and an anticoagulant and then anticoagulant and aspirin alone.
2) Placement of BMS with 1 month of aspirin, clopidogrel, and an anticoagulant and then anticoagulant and aspirin alone.
3) Placement of DES with 1 year of aspirin, prasugrel/ticagrelor, and an anticoagulant and then anticoagulant and aspirin alone.
4) Placement of a BMS with 1 month of aspirin, prasugrel/ticagrelor, and an anticoagulant and then anticoagulant and aspirin alone.
5) Placement of either a BMS/DES with initial treatment of clopidogrel and an anticoagulant.
Please Enter Your Response On Your Keypad
Atrial Fibrillation Case Study #7 A patient on a NOAC is having an elective
surgical procedure. When should he stop his NOAC prior to surgery?
1) 24 hours before2) 36 hours before3) 48 hours before4) Depends on renal function
Please Enter Your Response On Your Keypad