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A CME-CERTIFIED CLINICAL TOPICS GRAND ROUNDS PROGRAM
Jointly provided by Potomac Center for Medical Education and Rockpointe
Supported by an educational grant from Daiichi Sankyo, Inc.
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Learning Objectives
• Identify AFib patients who are at risk for developing
ischemic stroke and comply with treatment guidelines for
their management
• Evaluate options to overcome the limitations of vitamin K
antagonists to reduce the risk of new and recurrent strokes
• Individualize antithrombotic treatments to find the right drug
at the right dose for the right patient
Polling Question 1
Activity Survey
How confident are you in your ability to adopt evidencebased treatment strategies to manage patients with atrial
fibrillation?
A. Not at all confident
B. Slightly confident
C. Confident
D. Very confident
E. Expert
Lecture Overview
• Prevalence and Incidence of Atrial Fibrillation (AF)
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
The ECG of Atrial Fibrillation
Normal
sinus
rhythm
Atrial
fibrillation
Stroke and Atrial Fibrillation Burden
 More
 AF
than 2.2 million individuals in the US have AF
increases risk of stroke about 5-fold
 Strokes
 Costly
30
in patients with AF strokes lead to worse outcomes
health care ~$16 billion/year
Framingham
AF prevalence
20
Strokes
attributable
to AF
%
10
0
50–59
Wolf PA et al. Stroke. 1991;22:983-988.
60–69
70–79
Age Range (years)
80–89
Atrial Fibrillation: An Epidemic
Age-adjusted
Global Incidence
AF-related
Mortality
Chugh SS et al. Circulation. 2014;129:837-847.
Lecture Overview
• Prevalence and Incidence of AF
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
Efficacy and Safety of Warfarin
20
Ischemic
Stroke
Odds Ratio
15
Intracranial
Hemorrhage
Target
10
5
1
1.0
2.0
3.0
4.0
5.0
International Normalized Ratio
Fang MC et al. Ann Intern Med. 2004;141:745.
Hylek EM et al. N Engl J Med. 1996;335:540.
6.0
7.0
8.0
Nonvalvular Atrial Fibrillation
Stroke Rates Without Anticoagulation
According to Isolated Risk Factors
15
12.5
10
7.5
5
2.5
0
Heart Failure Hypertension
Age
 LVEF
>75 years
C
Hart RG et al. Neurology. 2007;69:546-554.
H
A
Diabetes
Prior
Stroke/TIA
D
S
Female
Polling Question 2
Activity Survey
A patient who has atrial fibrillation and a CHA2DS2-VASc risk
score of 4.0 has an approximate annual risk of stroke of:
A. 1.3%
B. 2.2%
C. 4.0%
D. 6.7%
E. >7.0%
Redefining Risk: CHA2DS2-VASc
Points
CHA2DS2-VASc
Score
Stroke (% / yr)
CHF / LV Dysfunction
1
1
0%
Hypertension
1
2
1.3 %
Age ≥75
2
3
2.2 %
Diabetes Mellitus
1
4
4.0 %
Stroke / TIA / Embolism
2
5
6.7 %
Vascular Disease
1
6
9.8 %
Age 64-74
1
7
9.6 %
Sex Category (female)
1
8
6.7 %
Maximum Score
9
9
15.2 %
Risk Factor
ESC Guidelines. Eur Heart J. 2010;31:2369-2429.
CHA2DS2-VASc Refines Stroke Risk
Stratification in CHADS2=0 vs CHA2DS2VASc
A nationwide Danish cohort study in 47,576 non-warfarin treated non-valvular AF patients
with a CHADS2 score = 0-1 at baseline (1997-2008)
Proportion of patients free
of stroke / thromboembolism
100%
0.84%
1.59%
1.75%
2.69%
3.20%
98%
96%
CHADS2 = 0: n=17,327 person-years
94%
CHA2DS2VASc = 0: n=6,919 person-years
CHA2DS2VASc = 1: n=6,811 person-years
CHA2DS2VASc = 2: n=3,347 person-years
CHA2DS2VASc = 3: n=250 person-years
92%
0%
Stroke / thromboembolism
rate (% person-years)
0
100
Olesen et al. Thromb Haemost. 2012;107:1172-1179.
200
300
Days from discharge
Initiation of OAC to Reduce Stroke Risk in Patients with AF
• The CHA2DS2-VASc scoring system helps clinicians determine stroke risk and to choose
oral anticoagulation (OAC) therapy
• OAC therapy options: New direct oral anticoagulants (DOAC) or vitamin K antagonists
(VKA); The most commonly used VKA is warfarin
• Drug interactions should also be considered when prescribing
Risk Factor
C
H
A2
D
S2
V
A
Sc
Points
Congestive heart failure (or left ventricular systolic dysfunction)
Hypertension (blood pressure consistently above 140/90 mmHg)
Age ≥75 years
Diabetes mellitus
Prior stroke or TIA or thromboembolism
Vascular disease (peripheral artery disease, MI, aortic plaque)
Age 65-74 years
Sex category (i.e. female sex)
Total Score
Anticoagulation Stroke Option
0 Low stroke risk
1 Moderate
≥2 High
No antithrombotic therapy (or aspirin 75-325 daily)
1
1
2
1
2
1
1
1
Either DOAC or warfarin at an internationalized ratio (INR) of 2.0-3.0
Either DOAC or warfarin at INR 2.0-3.0
Kovacs RJ et al. J Am Coll Cardiol. 2015;65:1340-1360.
Bleeding Risk: HAS-BLED
16
Letter
Clinical
Characteristic
Points
H
Hypertension
1
A
Abnormal Liver or
Renal Function
1 or 2
S
Stroke
1
B
Bleeding
1
6
L
Labile INR
1
4
E
Elderly (age >65)
1
2
D
Drugs or Alcohol
1 or 2
0
Maximum Score
9
ESC Guidelines. Eur Heart J . 2010;31:2369-2429.
High
Risk
14
12
Bleeds 10
per
100 pt 8
years
Moderate
Risk
Low
Risk
0
1
2
3
4
HAS-BLED Score
5
Net Clinical Benefit of Warfarin
All-cause Mortality, Ischemic Stroke, and ICH
Friberg L et al. Circulation. 2012;125:2298-2307.
Lecture Overview
• Prevalence and Incidence of AF
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
Stroke Prevention in AF
Warfarin vs Placebo (pooled analysis of 2900 participants)
AFASAK-1 (671)
SPAF (421)
BAATAF (420)
CAFA (378)
SPINAF (571)
EAFT (439)
All Trials (n=6)
64%
100%
50%
Warfarin Better
Hart RG et al. Ann Intern Med. 2007;146:857-867.
0%
-50%
-100%
Warfarin Worse
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; continual dose titration needed
• Increases risk of intracerebral hemorrhage and fatal
bleeding
Polling Question 3
Activity Survey
In a recent survey of patients with atrial fibrillation who were
at high risk for stroke (CHA2DS2VASc ≥2) and are eligible
for warfarin anticoagulation, what percentage actually
received such treatment?
A. Greater than 80%
B. 70%-80%
C. 50%-70%
D. Less than 50%
Modest Use of Vitamin K Antagonists
Even in High-risk Patients
European Heart Survey
100
5333 AF patients in 35 countries: 2003–2004
OAC therapy (%)
80
60
58
59
1
2
64
61
3
4
40
20
0
OAC = oral anticoagulant
Nieuwlaat R et al. Eur Heart J. 2006;27:3018-3026.
Gage BF et al. JAMA. 2001;285:2864-2870.
CHADS2 score
Lecture Overview
• Prevalence and Incidence of AF
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
Properties of an Ideal Anticoagulant
Properties
Benefit
Oral, 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
Non-Vitamin K Oral Anticoagulants
TF/VIIa
X
IX
VIIIa
IXa
Rivaroxaban
Apixaban
Edoxaban
Va
Xa
II
Dabigatran
IIa
Fibrinogen
Adapted from: Weitz JI, Bates SM. J Thromb Haemost. 2005;3:1843-1853.
Fibrin
Polling Question 4
Activity Survey
Which of the direct oral anticoagulant agents are approved
for once-daily dosing?
A. apixaban and edoxaban
B. apixaban and rivaroxaban
C. dabigatran and edoxaban
D. edoxaban and rivaroxaban
Comparison Overview of Non-vitamin K Oral
Anticoagulants (NOACs) with Warfarin
Features
Warfarin
NOACs
Onset
Slow
Rapid
Dosing
Variable
Fixed
Yes
No
Many
Few
Yes
No
Half-life
Long
Short
Antidote
Yes
No
Food effect
Drug interactions
Monitoring
Comparative PK/PD
Novel Oral Anticoagulants
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
IIa (thrombin)
Xa
Xa
Xa
Hours to Cmax
1-3
2-4
3-4
1-2
Half-life, hours
12-17
5-13
12
10-14
80
33*
27
50
Transporters
P-gp
P-gp
P-gp
P-gp
CYP Metabolism, %
None
32
~25
<4
Target
Renal Clearance, %
CYP = cytochrome P450; P-gp = P-glycoprotein
*33% renally cleared; 33% excreted unchanged in urine
Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013.
Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011.
Weinz et al. Drug Dispos Metab. 2009;37:1056-1064.
ELIQUIS Summary of Product Characteristics. Bristol-Myers Squibb/Pfizer EEIG, UK.
Matsushima et al. Am Assoc Pharm Sci. 2011; abstract.
Ogata et al. J Clin Pharmacol. 2010;50:743-753.
Mendell et al. Am J Cardiovasc Drugs. 2013;13:331-342.
Bathala et al. Drug Metab Dispos. 2012;40:2250-2255.
Stroke Prevention in Atrial Fibrillation Trials
Novel Oral Anticoagulants
RE-LY[a]
ROCKET-AF[b]
ARISTOTLE[c]
ENGAGE AF[d]
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
18,113
14,266
18,201
21,105
Dose (mg)
150, 110
20
5
60, 30
Frequency
Twice Daily
Once Daily
Twice Daily
Once Daily
No
20 → 15
5 → 2.5
60 → 30
30 → 15
0
21
5
25
No
No
No
8%
2.0-3.0
2.0-3.0
2.0-3.0
2.0-3.0
PROBE*
2x blind
2x blind
2x blind
Drug
# Randomized
Dose Adjustment
At Baseline
After Randomization
Target INR (Warfarin)
Design
*PROBE = prospective, randomized, open-label, blinded, end-point evaluation
a. Connolly SJ et al. N Engl J Med. 2009;361:1139-1151.
b. Patel MR et al. N Engl J Med. 2011;365:883-891.
c. Granger CB et al. N Engl J Med. 2011;365:981-992.
d. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.
Meta-analysis of All NOACs vs Warwfarin
Stroke or Systemic Embolic Events
Risk Ratio (95% CI)
RE-LY
0.66 (0.53 - 0.82)
ROCKET
AF
0.88 (0.75 - 1.03)
ARISTOTLE
0.80 (0.67 - 0.95)
ENGAGE AF-TIMI 48
0.88 (0.75 - 1.02)
Combined
0.81 (0.73 - 0.91)
n=58,541
P=<0.0001
[150 mg]
[60 mg]
[Random Effects Model]
0.5
Favors NOAC
Heterogeneity P=0.13
Ruff CT et al. Lancet. 2014;383:955-962.
1
Favors Warfarin
2
Polling Question 5
Activity Survey
Results from meta-analyses of existing NOAC data reveal
that NOACs offer greatest protection for prevention of:
A. All-cause mortality
B. Hemorrhagic stroke
C. Ischemic stroke
D. Myocardial infarction
E. All of the above
Meta-analysis of All NOACs vs Warfarin
Secondary Efficacy Outcomes
Risk Ratio (95% CI)
Ischemic Stroke
0.92 (0.83 - 1.02)
Hemorrhagic Stroke
0.49 (0.38 - 0.64)
MI
0.97 (0.78 - 1.20)
All-cause Mortality
0.90 (0.85 - 0.95)
P=0.10
P<0.0001
P=0.77
0.2
Heterogeneity P=NS for all outcomes
Ruff CT et al. Lancet. 2014;383:955-962.
P=0.0003
0.5
Favors NOAC
1
2
Favors Warfarin
Polling Question 6
Activity Survey
Meta-analyses of existing NOAC data reveal that risk of
gastrointestinal or intracranial bleeding is:
A. Less with NOACs than with warfarin
B. Comparable with NOACs and warfarin
C. Less with warfarin than with NOACs
D. There are insufficient data to draw conclusions
How Frequent is Bleeding with NOACs?
71,683 Patients: 4 Phase III AF NOAC Trials
P = 0.06
5.00
P = 0.04
4.00
% / Year
P < 0.01
3.00
Major Bleeding
GI Bleeding
2.80
2.39
ICH
2.00
1.17
0.92
1.00
0.66
0.32
0.00
NOACs
Ruff CT et al. Lancet. 2014;383:955-962.
Warfarin
AHA, ACC, and HRS Guidelines for the
Management of Patients with AF
• Use CHA2DS2-VASc instead of CHADS2 for patients with
non-valvular AF
• A CHA2DS2-VASc score of 1 in patients with non-valvular AF should
be treated with either no anti-coagulation therapy, aspirin, or an oral
anticoagulant
• A CHA2DS2-VASc score of ≥2 warrants use of an oral anticoagulant,
if there are no contraindications
• A CHA2DS2-VASc score of ≥2 warrants use of an oral anticoagulant,
either warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban
Updated from January CT et al. Circulation. 2014;130:2071-2104.
Is Aspirin as Effective and Safe as NOACs?
Data from Apixaban in the AVERROES Trial
Stroke or Systemic
Embolic Event
Major Bleeding
0.020
0.05
0.04
Aspirin
0.03
0.015
P<0.001
0.010
0.02
Apixaban
0.01
0.00
0
3
6
Apixaban
P<0.001
Aspirin
0.005
0.000
9
12
18
0
3
Aspirin
is less
efficacious
and6 has9 12
similar bleeding to apixaban.
HR 0.45 (0.32-0.62)
HR 1.13 (0.74-1.75)
Connolly SJ et al. N Engl J Med. 2011;364:806-817.
18
Lecture Overview
• Prevalence and Incidence of AF
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
Choice of Anticoagulant in Patients with AF
European Society of Cardiology Guidelines
Camm AJ et al. Eur Heart J. 2012;33:2719-2747.
Japanese Circulation Society 2014 Guidelines
Antithrombotic Therapy in AF
NVAF
CHADS2 score
Heart failure
Hypertension
Age ≥75
Diabetes
History of cerebral infarction/TIA
1
1
1
1
2
≥2 points
1 point
Recommended
Recommended
Dabigatran
Apixaban
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Warfarin*
Considered
Rivaroxaban
Edoxaban
Warfarin*
Other risk factors
Cardiomyopathy
65 to 74 years old
Vessel disease
Considered
Recommended
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Warfarin*
Warfarin*
*<70% TTR: INR 2.0–3.0, ≥70% TTR: INR 1.6–2.6
JCS Joint Working Group. Circ J. 2014;78:1997-2021.
Mitral stenosis
or
mechanical valve
When there is
adaptation of an
equivalent level, an
NOAC is more
desirable than warfarin
Lecture Overview
• Prevalence and Incidence of AF
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
Are We Using Too Much Aspirin in Patients
with AF? Bleeding According to Antiplatelet Treatment
Major Bleed
None
7
6
5
4
3
2
1
0
ASA
ASA + clopidogrel
6.3
5.5
4.6
2.8
Warfarin
5.4
4.3
2.6
Dabigatran 150
3.8
2.2
Dabigatran 110
• 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
Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in
RE-LY without affecting the advantages of dabigatran over warfarin
ASA = aspirin; CAD = coronary artery disease; HF = heart failure; SBP = systolic blood pressure
Hans DL et al. Circulation. 2013;127:634-640.
Renal Function and NOACs
• All 4 Phase III NOAC trials excluded patients with an
eGFR <25-30 mL/min
• Renal impairment is an independent risk factor for stroke,
bleeding, and death
• All NOACs require dose adjustment for renal failure:
– Dabigatran 150 mg bid for CrCl >30 mL/min
•
75 mg bid if CrCl 15-30 mL/min
– Rivaroxaban 20 mg once daily for CrCL >50 mL/min
•
15 mg once daily if CrCL 15-50 mL/min
– Edoxaban 60 mg once daily if CrCL >50 to <95 mL/min
•
30 mg once daily if CrCL<15-50 mL/min; should not be used if CrCl >95 mL/min
– Apixaban 5 mg bid
•
2.5 mg twice daily with 2 of 3: age ≥80 y, weight ≤ 60 kg, serum creatinine ≥1.5 mg/dL
CrCL = creatinine clearance
Package inserts for dabigatran, rivaroxaban, edoxaban, and apixaban
Managing Bleeding with NOACs
Step 1 Review
• Stop anticoagulation and antiplatelet therapy
• Review time of last dose of anticoagulant
• Review medications including aspirin, P2Y12 inhibitors,
NSAIDs, P-gp inhibitors, CYP3A4 inhibitors
• Assess for comorbid conditions, check for evidence of
cardiac decompensation
• Order baseline laboratory parameters including CBC
with platelets, renal function tests, PT, aPTT
• Maintain organ perfusion
• Volume resuscitation
• Pressors
• Identify source of bleeding
• Evaluate for transfusion
Vitamin K antagonists
• Vitamin K
• Consider FFP for poor hemodynamic condition
• 4-factor prothrombin complex concentrate
• Platelet transfusion (for thrombocytopenia or if
patients received antiplatelets)
Kovacs RJ et al. J Am Coll Cardiol. 2015;65:1340-1360.
Step 2 Remove
• Gastric lavage for recent ingestion
• Oral charcoal
• Dialysis (dabigatran)
Step 3 Repair
Assess need for Surgery
Step 4 Reverse
Direct acting oral anticoagulants
• Consider 4 factor prothrombin complex
concentrate
• Platelet transfusion (for thrombocytopenia
or if patient received antiplatelets)
Non-specific Reversal Agents
Only after D/C drug and supportive care (fluids / transfusions)
Agent
Clotting Factors Replaced
Dose
4 Factor-PCC
Factors II, VII, IX, X
25-50 units/kg
3 Factor-PCC
Factors II, IX, X
25-50 units/kg
aPCC
Factors II, VIIa, IX, X
80 units/kg
rFVIIa
FVIIa
90 ug/kg
New and Emerging Antidotes
Idarucizumab (BI 655075)
Target: Dabigatran
Structure: humanized antibody fragment (FAb) to dabigatran
FDA approved: October 2015
Andexanet alfa (PRT064445)
Target: FXa inhibitors
Structure: FXa lacking catalytic and binding activity
Aripazine (PER977; Ciraparantag)
Target: Universal – all NOACs, heparin, LMWH
Structure: synthetic small molecule (D-arginine)
Lecture Overview
• Prevalence and Incidence of AF
• Risk Stratification for Stroke and Bleeding
• Clinical Properties of Warfarin
• Clinical Properties of Non-vitamin K Oral Anticoagulants
• Current Guidelines on Management of AF
• Preventing and Managing Bleeding (Reversal Agents)
• Considerations for Choosing an Anticoagulant
Patients Not Well-Suited for an NOAC
• Mechanical heart valves
• Moderate-severe mitral stenosis and AF
• Pregnancy and nursing mother
• Stage V CKD
(apixaban OK in patients on stable hemodialysis per the US FDA)
• Moderate-severe hepatic failure
• Children
• Extremes of physiology (e.g. weight, age)
• Malabsorption
Optimal Candidates for NOACs
• Almost all patients with non-valvular AF should be considered
as candidates for NOACs
• Patients with normal renal function
• European and Japanese guidelines recommend NOACs over
VKA
• Ineligible patients include
– Those who are pregnant
– Those with mechanical heart valve or in early post-operative
cardiac surgery
Renal Function and NOACs
• All 4 Phase III NOAC trials excluded patients with an eGFR <25-30 mL/min
• Dabigatran is 80% renally eliminated, greater than rivaroxaban (33% renally
metabolized and 33% excreted unchanged by kidneys), edoxaban (50%), and
apixaban (27%)[a]
• Renal impairment is an independent risk factor for stroke, bleeding, and death
• 150 mg twice daily of dabigatran: use cautiously in the elderly (>80 yr) and with
renal impairment (<40 mL/min)[b]
• All NOACs require dose adjustment for renal failure:
– Dabigatran 75 twice daily if CrCl 15-30 mL/min (US FDA)
– Rivaroxaban 15 mg once daily if CrCL <15-49 mL/min
– Edoxaban 30 mg once daily if CrCl <15-50 mL/min[c]; should not be used if CrCl >95 mL/min
– Apixaban 2.5 mg twice daily with 2 of 3: age ≥80 y, weight ≤60 kg, SCr ≥1.5 mg/dL
a. Heidbuchel H et al. Europace. 2013;15:625-651.
b. Dabigatran SMPC. www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000829/WC500041059.pdf.
c. Edoxaban Package Insert. www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf.
Important Factors when Considering an NOAC
• All patients with atrial fibrillation should be considered for
an NOAC, except if mechanical valve, rheumatic MS,
pregnant, children
• NOACs decrease intracerebral hemorrhage (50%) and
major bleeding (14%) compared to warfarin
• NOACs decrease stroke/systemic embolism (18%) and
death (10%) compared to warfarin
• NOACs are not all the same, so selection of which NOAC
depends on patient characteristics
Polling Question 7
Activity Survey
In choosing an NOAC, consideration should be given to:
A. Patient’s risk of bleeding
B. Patient’s risk of ischemic stroke
C. Patient history of coronary artery disease
D. Patient’s renal function status
E. All of the above
Specific Patient Characteristics
“Pointers” Regarding Which NOAC to Choose*
High risk of bleeding, e.g.
HAS-BLED 3; very elderly
Consider agent/dose with the lowest
incidence of bleeding
Dabi 110;
Edox; Apix
Previous GI bleeding, or
high-risk, or GI upset
Consider agents with the lowest
reported incidence of GI bleed
Apix; LD Edox
High risk of ischemic stroke;
low bleeding risk
Consider agent/dose with the best
reduction of ischemic stroke
Dabi 150
Previous stroke (secondary
prevention)
Consider best investigated agent or
greatest reduction of 20 stroke
Riva; Apix;
HD Edox
CAD, previous MI or highrisk for ACS/MI
Consider agent with a positive effect
in ACS
Riva; HD Edox
Renal impairment
Consider agent least dependent on
renal function
Apix; Edox 30;
Riva 15
Concomitant CYP inhibitor
Consider agents with no/little
metabolism via CYP system
Dabi; Edox
Patient preference
Consider once daily formulation
Riva; Edox
* All of these “pointers” are debatable
Savelieva I et al. Clin Cardiol. 2014;37:32-47.
Gonzelz-Quesada CJ, Giugliano RP. J Thromb Thrombolysis. 2015;39:129-138.
Conclusions
Properties of Ideal Anticoagulant
Do NOACs Fit the Bill?
 Proven efficacy
 Low bleeding risk
 Fixed dosing
 Good oral bioavailability
 No routine monitoring needed
 Reversibility: ?PCC, FEIBA, rVIIa
 Rapid onset of action
 Few drug or food interactions
Additional Issues Regarding Direct OACs
1.
How do we compare the different drugs and studies in the
absence of head-to-head studies?
2.
Would more flexible dosing improve safety:efficacy (e.g. in
patients who bleed or are at extremes of age, weight)?
3.
Are NOACs “better” if patients are well controlled on warfarin?
4.
How should we incorporate measures of drug concentration or
anticoagulation levels in clinical practice, if at all?
5.
Is the fast offset a problem if patients are not compliant?
6.
Are there specific adverse drug reactions?
7.
Which drug and what dose when dual antiplatelets are needed
(e.g. ACS or post-stenting)
8.
How do we best evaluate cost-effectiveness?
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