Jointly provided by Potomac Center for Medical Education and Rockpointe
Supported by an educational grant from Daiichi Sankyo, Inc.
A CME-CERTIFIED CLINICAL TOPICS GRAND ROUNDS PROGRAM
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• Participant Survey and CME Evaluation
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– Throughout the program, please take a moment to answer the corresponding Activity Survey questions on this form (slides will be marked as “Polling Questions” throughout the deck)
Disclosures
All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers, or their spouses/partners have been listed in your program syllabus.
Off-label Discussion DisclosureThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.
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 1Activity Survey
How confident are you in your ability to adopt evidence-based 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
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
More than 2.2 million individuals in the US have AF AF increases risk of stroke about 5-fold Strokes in patients with AF strokes lead to worse outcomes Costly health care ~$16 billion/year
Atrial Fibrillation: An Epidemic
Chugh SS et al. Circulation. 2014;129:837-847.
Age-adjusted Global Incidence
AF-related Mortality
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
Fang MC et al. Ann Intern Med. 2004;141:745. Hylek EM et al. N Engl J Med. 1996;335:540.
5.0 6.0 8.01.0 2.0 3.0 4.0 7.0
5
15
10
Ischemic Stroke
1
20
Odd
s R
atio
International Normalized Ratio
Target Intracranial Hemorrhage
Nonvalvular Atrial Fibrillation
Hart RG et al. Neurology. 2007;69:546-554.
0
2.5
5
7.5
10
12.5
15
PriorStroke/TIA
Age>75 years
Hypertension FemaleDiabetesHeart Failure LVEF
Stro
ke R
ate
(%/ y
ear)
Stroke Rates Without AnticoagulationAccording to Isolated Risk Factors
C H A D S
Polling Question 2Activity 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
ESC Guidelines. Eur Heart J. 2010;31:2369-2429.
Risk Factor Points
CHF / LV Dysfunction 1
Hypertension 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
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 %
CHA2DS2-VASc Refines Stroke Risk Stratification in CHADS2=0 vs CHA2DS2VASc
Olesen et al. Thromb Haemost. 2012;107:1172-1179.
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)
100%
CHADS2 = 0: n=17,327 person-years
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
Stroke / thromboembolism rate (% person-years)
Prop
ortio
n of
pat
ient
s fr
ee
of s
trok
e / t
hrom
boem
bolis
m
0%
92%
94%
96%
98%
0.84%
Days from discharge0 100 200 300
1.59%1.75%2.69%3.20%
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 Points
C Congestive heart failure (or left ventricular systolic dysfunction)1
H Hypertension (blood pressure consistently above 140/90 mmHg) 1A2 Age ≥75 years
2D Diabetes mellitus
1S2 Prior stroke or TIA or thromboembolism
2V Vascular disease (peripheral artery disease, MI, aortic plaque)
1A Age 65-74 years
1Sc Sex category (i.e. female sex) 1
Total Score Anticoagulation Stroke Option
0 Low stroke risk No antithrombotic therapy (or aspirin 75-325 daily) 1 Moderate Either DOAC or warfarin at an internationalized ratio (INR) of 2.0-3.0 ≥2 High 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
ESC Guidelines. Eur Heart J . 2010;31:2369-2429.
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 90 1 2 3 4 5
0
2
4
6
8
10
12
14
16
HAS-BLED Score
Bleeds per
100 pt years
Low Risk
ModerateRisk
High Risk
Net Clinical Benefit of WarfarinAll-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)
Hart RG et al. Ann Intern Med. 2007;146:857-867.
100% 50% 0% -50% -100%
AFASAK-1 (671)
SPAF (421)
BAATAF (420)
CAFA (378)
SPINAF (571)
EAFT (439)
All Trials (n=6)
Warfarin Better Warfarin Worse
64%
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 3Activity 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
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
OA
C th
erap
y (%
)
58 5964 61
0
20
40
60
80
100
1 2 3 4
5333 AF patients in 35 countries: 2003–2004
European Heart Survey
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
Adapted from: Weitz JI, Bates SM. J Thromb Haemost. 2005;3:1843-1853.
Dabigatran
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
RivaroxabanApixabanEdoxaban
Polling Question 4Activity 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
Food effect Yes No
Drug interactions Many Few
Monitoring Yes No
Half-life Long Short
Antidote Yes No
Comparative PK/PDNovel Oral Anticoagulants
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.
Dabigatran Rivaroxaban Apixaban Edoxaban
Target 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
Renal Clearance, % 80 33* 27 50
Transporters P-gp P-gp P-gp P-gp
CYP Metabolism, % None 32 ~25 <4
CYP = cytochrome P450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine
Stroke Prevention in Atrial Fibrillation TrialsNovel Oral Anticoagulants
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.
RE-LY[a] ROCKET-AF[b] ARISTOTLE[c] ENGAGE AF[d]
Drug Dabigatran Rivaroxaban Apixaban Edoxaban
# Randomized 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
Dose Adjustment No 20 → 15 5 → 2.5 60 → 3030 → 15
At Baseline 0 21 5 25
After Randomization No No No 8%
Target INR (Warfarin) 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0
Design PROBE* 2x blind 2x blind 2x blind
*PROBE = prospective, randomized, open-label, blinded, end-point evaluation
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 WarwfarinStroke or Systemic Embolic Events
Ruff CT et al. Lancet. 2014;383:955-962.
ENGAGE AF-TIMI 48
ARISTOTLE
ROCKET AF
RE-LY
Combined
Favors NOAC Favors Warfarin
0.88 (0.75 - 1.02)
0.80 (0.67 - 0.95)
0.88 (0.75 - 1.03)
0.66 (0.53 - 0.82)
0.81 (0.73 - 0.91)
Risk Ratio (95% CI)
P=<0.0001
0.5 1 2
[Random Effects Model]
n=58,541
Heterogeneity P=0.13
[60 mg]
[150 mg]
Polling Question 5Activity 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 WarfarinSecondary Efficacy Outcomes
Ruff CT et al. Lancet. 2014;383:955-962.
All-cause Mortality
MI
Hemorrhagic Stroke
Ischemic Stroke
0.90 (0.85 - 0.95)
0.97 (0.78 - 1.20)
0.49 (0.38 - 0.64)
0.92 (0.83 - 1.02)
Risk Ratio (95% CI)
P=0.0003
P=0.77
P<0.0001
P=0.10
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Heterogeneity P=NS for all outcomes
Polling Question 6Activity 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?
Ruff CT et al. Lancet. 2014;383:955-962.
% /
Yea
r
NOACs Warfarin0.00
1.00
2.00
3.00
4.00
5.00
2.392.80
1.170.92
0.320.66
Major Bleeding
GI Bleeding
ICH
P = 0.06
P = 0.04
P < 0.01
71,683 Patients: 4 Phase III AF NOAC Trials
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
Connolly SJ et al. N Engl J Med. 2011;364:806-817.
Stroke or Systemic Embolic Event Major Bleeding
HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75)
Aspirin
Apixaban
P<0.001
0 3 6 9 12 18
0.05
0.04
0.03
0.02
0.01
0.00
Aspirin
Apixaban
P<0.001
0 3 6 9 12 18
0.020
0.015
0.010
0.005
0.000
Aspirin is less efficacious and has similar bleeding to apixaban.
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
JCS Joint Working Group. Circ J. 2014;78:1997-2021.
NVAF Mitral stenosisor
mechanical valve Other risk factors
Cardiomyopathy65 to 74 years old
Vessel disease
CHADS2 scoreHeart failureHypertensionAge ≥75DiabetesHistory of cerebral infarction/TIA
11112
≥2 points 1 point
*<70% TTR: INR 2.0–3.0, ≥70% TTR: INR 1.6–2.6
Recommended
DabigatranRivaroxaban
ApixabanEdoxaban
Warfarin*
RecommendedDabigatranApixaban
Considered
DabigatranRivaroxaban
ApixabanEdoxaban
Warfarin*
ConsideredRivaroxaban
Edoxaban
Warfarin*
Recommended
Warfarin*
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
Hans DL et al. Circulation. 2013;127:634-640.
• 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
Warfarin Dabigatran 150 Dabigatran 11001234567
2.8 2.62.2
4.6 4.33.8
6.35.5 5.4
None ASA ASA + clopidogrel
Maj
or B
leed
ASA = aspirin; CAD = coronary artery disease; HF = heart failure; SBP = systolic blood pressure
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
Kovacs RJ et al. J Am Coll Cardiol. 2015;65:1340-1360.
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
Step 2 Remove• Gastric lavage for recent ingestion• Oral charcoal• Dialysis (dabigatran)
Step 3 RepairAssess need for Surgery
Step 4 Reverse
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)
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: DabigatranStructure: humanized antibody fragment (FAb) to dabigatranFDA approved: October 2015
Andexanet alfa (PRT064445)Target: FXa inhibitorsStructure: FXa lacking catalytic and binding activity
Aripazine (PER977; Ciraparantag)Target: Universal – all NOACs, heparin, LMWHStructure: 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 7Activity 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
“Pointers” Regarding Which NOAC to Choose*
* All of these “pointers” are debatableSavelieva I et al. Clin Cardiol. 2014;37:32-47.Gonzelz-Quesada CJ, Giugliano RP. J Thromb Thrombolysis. 2015;39:129-138.
Spec
ific
Patie
nt C
hara
cter
istic
s
Patient preference Consider once daily formulation Riva; Edox
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
CAD, previous MI or high-risk for ACS/MI
Consider agent with a positive effect in ACS Riva; HD Edox
High risk of ischemic stroke; low bleeding risk
Consider agent/dose with the best reduction of ischemic stroke Dabi 150
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
Previous stroke (secondary prevention)
Consider best investigated agent or greatest reduction of 20 stroke
Riva; Apix; HD Edox
Conclusions
Properties of Ideal AnticoagulantDo 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?
CME Credit• Post-activity Survey
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