Transcript Slide 1

What are all of these blood thinners? A
review of oral anticoagulation options.
Janet Friant, MSN, APN-BC, AACC
University of Chicago Medical Center
Chicago, IL
Objectives
• Provide an overview of coagulation and highlight
potential targets for pharmacotherapy in thrombosis
• Detail the MOA of warfarin and the novel oral
anticoagulants (NOACs) with a focus on practical
considerations related to anticoagulation
• Review the data for use of NOACs in approved clinical
indications
• Outline initiation and transition strategies
3
Objectives
• Provide an overview of coagulation and highlight
potential targets for pharmacotherapy in thrombosis
• Detail the MOA of warfarin and the novel oral
anticoagulants (NOACs) with a focus on practical
considerations related to anticoagulation
• Review the data for use of NOACs in approved clinical
indications
• Outline initiation and transition strategies
4
Definitions
• Coagulation
- The physiologic process by
which blood clots
• Hemostasis
- Physiologic clotting of blood in
response to injury or vascular leakage
(“Keeping blood where it belongs”)
• Thrombosis
- Pathologic clotting of blood
(“Hemostasis in the wrong place”)
5
Coagulation in perspective:
Thrombosis vs. hemostasis
Issues of thrombosis and
hemostasis often coexist in
the very same patient
“BAD CLOT”
“GOOD CLOT”
6
Coagulation and platelet cascades
7
Nathan S, Swamy R. U.S. Cardiology 2008.
Oral anticoagulation
Clinical indications
• Venous thromboembolism
• Treatment
• Prophylaxis
• Arterial thrombosis (including PE)
• LV thrombus / post-myocardial infarction
• Atrial fibrillation (valvular, nonvalvular)
• Prosthetic heart valves
• CVA (stroke)
8
Nonvalvular atrial fibrillation
• NVAF is the most common sustained cardiac arrhythmia in the
U.S. affecting an estimated 2.7 million to 6.1 million adults in
the United States and over 15 million patients worldwide.
• It is widely believed that the incidence and prevalence of atrial
fibrillation will continue to rise, perhaps doubling over the
next 25 years.
• The lifetime risk of developing atrial fibrillation after the age
of 40 is as high as 25%, and is influenced by a variety of factors
such as the development or coexistence of thyroid disease,
diabetes, hypertension, obesity, sleep apnea, heart failure,
myocardial ischemia and structural heart disease.
9
Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014. In press.
Projected incidence of NVAF in the U.S.
10
Miyasaka Y, et al. Circulation 2006; 114: 119.
Nonvalvular atrial fibrillation
• Thromboembolic disease, in particular stroke, remains
the most significant and feared complication of atrial
fibrillation.
• Atrial fibrillation is associated with 15% of strokes in
people of all ages and 30% of strokes in people > 80 y.o.
• There are an estimated 500,000 hospitalizations primarily
for atrial fibrillation annually in the U.S.
• It is estimated that atrial fibrillation contributes to at
least 100,000 deaths per year, many as a consequence of
stroke.
11
Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014.
IDEM. Atrial fibrillation” a major contributor to stroke in the elderly; the Framingham Study. Arch Intern Med 1987; 147; 1561-4.
Clinical Calculation Tools
Clinical Calculation Tools: Qx Calculate
Objectives
• Provide an overview of coagulation and highlight
potential targets for pharmacotherapy in thrombosis
• Detail the MOA of warfarin and the novel oral
anticoagulants (NOACs) with a focus on practical
considerations related to anticoagulation
• Review the data for use of NOACs in approved clinical
indications
• Outline initiation and transition strategies
• Briefly highlight pipeline agents and combination
therapies
14
Oral anticoagulants
Warfarin Dabigatran
15
Rivaroxaban
Apixaban
Edoxaban
Warfarin
Wisconsin Alumni Research Foundation
16
Warfarin
Kinetics
Absorption
17
Oral: Rapid, complete
Metabolism
Hepatic, primarily via CYP2C9; minor
pathways include CYP2C8, 2C18, 2C19,
1A2, and 3A4
Excretion
Urine (92%, primarily as metabolites)
Half-life
Dosing
20-60 hours
Variable
Warfarin
Key considerations
18
Onset of therapeutic
effect
5-7 days
May requiring bridging with indirect antithrombins
Antidote
Vitamin K, FFP, PRBC
Factors influencing
warfarin response
Vitamin K balance, drug interactions, genetic
variations, impaired hepatic function,
hypermetabolic states, co-morbid medical
conditions
Adverse drug reactions
Bleeding/Hemorrhage/Hematuria
Vasculitis
Dermatitis, pruritus, urticaria
Abdominal pain, N/V/D
Anemia
Skin necrosis, gangrene, “purple toes” syndrome
Indications for warfarin and
recommended therapeutic range
19
Limitations of warfarin
Only 55% of nonvalvular AF patients
without contraindications receive
warfarin*1
Mean TTR is low in patients
receiving warfarin
Rose et al 2
58%
Patients (%)
(N=124,551)
55%
overall
use1
Baker et al 3
55%
(N=22,237)
Rose et al 4
67%
(N=3104)
Sarawate et al
5
29%
(N=470)
McCormick et al 6
(n=1064)
(n=1596)
(n=3707)
(n=3752)
0
Age (y)
20
(n=963)
51%
(N=174)
20
40
60
Mean TTR (%)
1.
2.
3.
4.
5.
6.
7.
Go AS et al. Ann Intern Med. 1999;131(12):927-934.
Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29.
Baker WL et al. J Manag Care Pharm. 2009;15(3):244-252.
Rose AJ et al. J Thromb Haemost. 2008;6(10):1647-1654.
Sarawate C et al. J Thromb Thrombolysis. 2006;21(2):191-198.
McCormick D et al. Arch Intern Med. 2001;161(20):2458-2463
Bungard et al. Arch Intern Med. 2000; 160; 41-46.
80
100
Warfarin vs. placebo in stroke
prevention in patients with NVAF
Favors Favors
Warfarin Placebo
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
All Trials
100%
50%
0
-50%
-100%
Relative Risk Reduction (95% CI)
AFASAK = Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study; BAATAF = Boston Area Anticoagulation Trial for Atrial Fibrillation
CAFA = Canadian Atrial Fibrillation Anticoagulation Study; EAFT = European Atrial Fibrillation Trial; SPAF = Stroke Prevention in Atrial Fibrillation
Study; SPINAF = Stroke Prevention in Nonrheumatic Atrial Fibrillation.
21
Hart RG et al. Ann Intern Med. 1999;131(7):492-501.
NOACs: “Are we there yet?”
22
Objectives
• Provide an overview of coagulation and highlight
potential targets for pharmacotherapy in thrombosis
• Detail the MOA of warfarin and the novel oral
anticoagulants (NOACs) with a focus on practical
considerations related to anticoagulation
• Review the data for use of NOACs in approved clinical
indications
• Outline initiation and transition strategies
• Briefly highlight pipeline agents and combination
therapies
23
Pros and cons of NOACs
24
Advantages
Rapid onset/offset of action
Disadvantages
Use is contraindicated or dose reduction is
required in patients with severe CKD
Absence of food interactions
Limited availability of assays for measuring drug
levels
Limited hepatic metabolism/few strong DDIs
Wide therapeutic window
Lower risk of intracranial hemorrhage
Lower potential risk of bleeding complications
Higher drug acquisition costs
Rapid decline in effect if doses are missed
No specific antidote
Increased risk for GI bleeding
Fixed dosing
Contraindicated in patients with mechanical
heart valves
Direct oral thrombin inhibition
XIIa
VIIa
XIa
Tissue
factor
IXa
Xa
II
×
Factor IIa
(thrombin)
25
Dabigatran
Dabigatran
Kinetics
Absorption
26
Rapid; initially slow postoperatively
Metabolism
Hepatic; rapidly and completely
hydrolyzed to active form by plasma and
hepatic esterase
Excretion
Renal (80%)
Half-life
Dosing
12-17 hours
150mg twice daily if CrCl >30 ml/min
75mg twice daily is CrCl 15-30 ml/min
Dabigatran
• Onset: 1 hour, delayed by food
• Antidote: None
• Contraindications
– Hypersensitivity to dabigatran or any component
– Active bleeding
• Warnings/Precautions
– Bleeding
– Renal impairment
– Anticoagulants
– Invasive/surgical invasions
– P-gp inducers/inhibitors
• ADRs
– Bleeding (8% to 33%; major ≤ 6%)
– Dyspepsia (11%)
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Dabigatran vs. warfarin in the RELY trial
28
Connolly SJ, et al. N Engl J Med 2009;361:1139-51.
RELY: Cumulative hazard rates for the primary outcome of
stroke or systemic embolism, according to treatment group
29
Connolly SJ, et al. N Engl J Med 2009;361:1139-51.
RELY: Safety outcomes according to
treatment group
30
Connolly SJ, et al. N Engl J Med 2009;361:1139-51.
RELY: Conclusions
• In patients with atrial fibrillation, dabigatran
given at a dose of 110 mg BID was
associated with rates of stroke and systemic
embolism that were similar to those
associated with warfarin, as well as lower
rates of major haemorrhage
• Dabigatran administered at a dose of 150
mg BID, as compared with warfarin, was
associated with lower rates of stroke and
systemic embolism but similar rates of
major haemorrhage
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Recommended use of dabigatran
32
Direct oral Xa inhibition
Tissue
factor
XIIa
XIa
VIIa
IXa
×
Xa
Rivaroxaban
Apixaban
Edoxaban
Factor II
(prothrombin)
Fibrinogen
33
Fibrin clot
Rivaroxaban
Kinetics
Absorption
34
Intestines, rapid
Recommended to take with food
Metabolism
Hepatic
CYP3A4/5 and CYP2J2
Excretion
Renal (65%)
Half-life
Dosing
5-9 hours
20 mg once daily if CrCl > 50 ml/min
15mg once daily if CrCl 15-50 ml/min
ROCKET-AF: Rivaroxaban vs. warfarin
in NVAF at mod-high risk of stroke
Nonvalvular AF
Randomized
double-blind/
double-dummy
(N=14,264)
CHADS2 Risk Factors
•Prior stroke, TIA, or non–CNS
systemic embolus
– OR –
•CHF or LVEF ≤35%
At least 2
•Hypertension
required
•Age ≥75 years
•Diabetes
Rivaroxaban
Warfarin
20 mg/d
(15 mg/d for CrCl 30 to <50 mL/min)
INR target:
2.0 to 3.0 inclusive
Monthly assessments*
Warfarin management was determined by clinician
 Enrollment of subjects without prior stroke, TIA, or systemic embolism
and only 2 factors capped at 10%
CHADS2 = congestive heart failure, hypertension, age, diabetes, prior stroke or TIA; CHF = congestive heart failure; CNS =
central nervous system; INR = international normalized ratio; TIA = transient ischemic attack.
*Patients seen at weeks 1, 2, and 4, then as clinically indicated but at least monthly thereafter.
35
1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Online supplement to: Patel MR et al. N Engl J Med. 2011;365(10):883-891.
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf. Accessed February 28, 2012.
3. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347.
ROCKET AF: Primary endpoint
(per protocol)
36
Patel MR et al. N Engl J Med 2011;365:883-891.
ROCKET AF: Primary endpoint
(intention to treat)
37
Patel MR et al. N Engl J Med 2011;365:883-891.
Rivaroxaban vs. warfarin in NVAF:
ROCKET AF trial
The overall results for the primary composite endpoint (time to first
occurrence of stroke (any type) or non–CNS systemic embolism) were
noninferior between rivaroxaban and warfarin
XARELTO®
(n=7081)*
Rate/
No. (%)
100 PTY
Warfarin
(n=7090)*
Rate/
No. (%)
100 PTY
HR (95% CI)
Primary composite
endpoint†
269 (3.8)
2.1
306 (4.3)
2.4
0.88 (0.74-1.03)
Stroke
253 (3.6)
2.0
281 (4.0)
2.2
–
33 (0.5)
0.3
57 (0.8)
0.4
–
206 (2.9)
1.6
208 (2.9)
1.6
–
19 (0.3)
0.2
18 (0.3)
0.1
–
20 (0.3)
0.2
27 (0.4)
0.2
–
Hemorrhagic stroke
Ischemic stroke
Unknown stroke type
Non–CNS systemic
embolism
*Data are shown for all randomized patients followed to site notification.
†The primary endpoint was the time to first occurrence of stroke (any type) or non–CNS systemic embolism.
1. Online supplement to: Patel MR et al. N Engl J Med. 2011;365(10):883-891.
http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf.
38
ROCKET AF: Secondary endpoints
Rivaroxaban
(n=7081)*
Rate/
No. (%)
100 PTY
HR (95% CI)
Stroke, systemic
embolism, and
vascular death
572 (8.1)
4.5
609 (8.6)
4.8
0.94 (0.84-1.05)
Stroke, systemic
embolism, MI, and
vascular death
659 (9.3)
5.2
709 (10.0)
5.7
0.93 (0.83-1.03)
33 (0.5)
206 (2.9)
19 (0.3)
0.3
1.6
0.2
57 (0.8)
208 (2.9)
18 (0.3)
0.4
1.6
0.1
0.58 (0.38-0.89)
0.99 (0.82-1.20)
1.05 (0.55-2.01)
20 (0.3)
0.2
27 (0.4)
0.2
0.74 (0.42-1.32)
130 (1.8)
1.0
142 (2.0)
1.1
0.91 (0.72-1.16)
582 (8.2)
4.5
632 (8.9)
4.9
0.92 (0.82-1.03)
Stroke type
Hemorrhagic
Ischemic
Unknown
Systemic embolism
MI
All-cause mortality
39
Warfarin
(n=7090)*
Rate/
No. (%)
100 PTY
Comparable major and nonmajor bleeding in
ROCKET AF for rivaroxaban and warfarin
Bleeding
Major and nonmajor
clinically relevant
Major
Nonmajor
clinically relevant
Rivaroxaban
(n=7111)*
Rate/
No. (%)
100 PTY
Warfarin
(n=7125)*
Rate/
No. (%)
100 PTY
HR
(95% CI)
1475 (20.7)
14.9
1449 (20.3)
14.5
1.03 (0.96-1.11)
395 (5.6)
3.6
386 (5.4)
3.5
1.04 (0.90-1.20)
1185 (16.7)
11.8
1151 (16.2)
11.4
1.04 (0.96-1.13)
*Safety population on-treatment.
40
Patel MR et al. N Engl J Med. 2011;365(10):883-891.
ROCKET-AF: Conclusions
• Rivaroxaban was noninferior to warfarin for
prevention of stroke or systemic embolism.
• Rivaroxaban group had less intracranial and
fatal bleeding that the warfarin group.
41
Apixaban
Kinetics
Absorption
Metabolism
15% liver metabolism
CYP3A4
Excretion
Primarily Biliary/Fecal (73%)
Renal (27%) unchanged
8 to 15 hours
Half-life
Dosing
42
Rapid; Intestines
Dose: 5mg twice daily
Dose reduction to 2.5mg twice daily if 2+ of the
following: ≥80 years;, weight ≤60kg, Cr
≥1.5mg/dl
Apixaban vs. warfarin in NVAF
43
Granger CB et al. N Engl J Med 2011;365:981-992.
Apixaban vs. warfarin in NVAF
44
Granger CB et al. N Engl J Med 2011;365:981-992.
Apixaban vs. warfarin in NVAF
45
Granger CB et al. N Engl J Med 2011;365:981-992.
Apixaban vs. warfarin in NVAF
46
Granger CB et al. N Engl J Med 2011;365:981-992.
Apixaban vs. warfarin in NVAF
47
Granger CB et al. N Engl J Med 2011;365:981-992.
Apixaban vs. warfarin in NVAF
Treatment with apixaban as compared to warfarin in
patients with AF and at least one additional risk factor
for stroke:
• Reduces stroke and systemic embolism by 21%
(p=0.01)
• Reduces major bleeding by 31% (p<0.001)
• Reduces mortality by 11% (p=0.047)
with consistent effects across all major subgroups and
with fewer study drug discontinuations on apixaban
than on warfarin, consistent with good tolerability.
48
Granger CB et al. N Engl J Med 2011;365:981-992.
Apixaban vs. warfarin in NVAF
In patients with atrial fibrillation, apixaban is
superior to warfarin at preventing stroke or
systemic embolism, causes less bleeding, and
results in lower mortality.
49
Granger CB et al. N Engl J Med 2011;365:981-992.
Edoxaban
Kinetics
Absorption
Rapid; Intestines
Peak in 1-2 hours
Metabolism
Predominant metabolite is active
Hepatic clearance- 50%, 50% renal
Minimal via hydrolysis
Excretion
Urine (primarily unchanged)
Half-life
10-14 hours
Dosing
Dose: 30 mg daily
Dose increased if CrCl >50 to 95ml/min to 60mg
-AVOID in CrCl >95 ml/min or < 15ml/min
50
Edoxaban vs. Wafarin in NVAF
Giugliano PR et al. N Engl J Med 2013;369:2093-104..
Edoxaban Stroke or Embolic Event
Giugliano PR et al. N Engl J Med 2013;369:2093-104..
Edoxaban Major Bleeding Event
Giugliano PR et al. N Engl J Med 2013;369:2093-104..
ENGAGE AF TIMI 48: Conclusions
• Both once-daily regimens of edoxaban were
noninferior to warfarin for stroke and
systemic embolic protection in patients with
non valvular atrial fibrillation.
• Both does were associated with significantly
lower rate of bleeding and death from CV
causes.
54
Trials of NOACs (vs. warfarin) in NVAF
NOTE: Because these clinical trials
were conducted with different
designs and evaluated different
populations, direct comparisons of
their results cannot be made.
Subjects, %
ENGAGE AF –TIMI 48
(N=21,105)
ROCKET AF
(N=14,264)1
RE-LY
(N=18,113)2
ARISTOTLE
(N=18,201)3
3.5
2.1
2.1
2.8
0 or 1
<0.1*
31.9
34.0
<0.1
2
13.0
35.6
35.8
46
3-6
86.9
32.5
30.2
53.9
Prior VKA use
62.4
49.6
57.1
58.8
CHF
62.5
32.0
35.4
58.2
Hypertension
90.5
78.9
87.4
93.7
Diabetes mellitus
40.0
23.3
25.0
36.4
Prior
stroke/TIA/embolis
m
54.8
20.0
19.4
28.1
Prior MI
17.3
16.6
14.2
CHADS2 score
(mean)
*Three subjects with a CHADS2 score of 0 or 1 were enrolled in ROCKET AF in violation of the study protocol.
1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151. 3. Granger CB et al. N
55
Engl J Med. 2011;365(11):981-992 4. Giugliano RP et al. N Engl J Med. 2013; 369: 2093-104.
NOACs in NVAF:
Comparison of trials
Comparative pharmacology
of oral anticoagulants
57
NOACs in NVAF:
Primary endpoints
Study
NOAC
VKA
Outcome
RE-LY
Dabigatran
1.1%
Warfarin
1.7%
RR 0.66
95% CI 0.53-0.82
P < 0.001
superiority
ARISTOTLE
Apixaban
1.3%
Warfarin
1.6%
HR 0.79
95% CI 0.66-0.95
P= < 0.001 Non- I
P= 0.01 Superiority
ROCKET-AF
Rivaroxaban
1.7%
Warfarin
2.2%
HR 0.79
95% CI 0.66-0.96
P = <0.001
Non-Inferiority
ENGAGE AF-TIMI 48
HD Edoxaban
1.18%
LD Edoxaban
1.61%
Warfarin
1.5%
HR HD 0.79
95%CI 0.63-0.99
HR LD 1.07
95% CI 0.87-1.31
Non-Inferiority
NOACs in NVAF:
Bleeding
59
Study
NOAC
VKA
Outcome
RE-LY
Dabigatran
3.3%
Warfarin
3.6%
RR 0.93
95% CI 0.81-1.07
P = 0.31
ARISTOTLE
Apixaban
2.1%
Warfarin
3.1%
HR 0.69
95% CI 0.60-0.8
P = < 0.001
ROCKET-AF
Rivaroxaban
5.6%
Warfarin
5.4%
HR 1.04
95% CI 0.90-1.20
P = 0.58
ENGAGE AFTIMI 48
HD Edoxaban
2.75%
LD Edoxaban
1.61%
Warfarin
3.4%
HD HR 0.80
95 % CI 0.71-0.91
LD HR 0.47
95% CI 0.41-0.55
NOACs in NVAF:
Intracranial hemorrhage
60
Study
NOAC
VKA
Outcome
RE-LY
Dabigatran
0.3%
Warfarin
0.7%
RR 0.40
95% CI 0.27-0.60
P= <0.001
ARISTOTLE
Apixaban
0.3%
Warfarin
0.8%
HR 0.42
95% CI 0.30-0.58
P = <0.001
ROCKET-AF
Rivaroxaban
0.5%
Warfarin
0.7%
HR 0.67
95% CI 0.47-0.93
P = 0.02
ENGAGE EFTIMI 48
HD Edoxaban
0.39%
LD Edoxaban
0.26%
Warfarin
0.85%
HD HR 0.47
95 % CI 0.64-0.63
LD HR 0.30
95% CI 0.21-0.43
NOACs in NVAF:
Dosing recommendations
61
Agent
Dosing Recommendations
Dabigatran
75mg, 150mg
CrCl > 30 cc/min: 150 mg, BID
CrCl 15 to 30 cc/min: 75 mg, BID
Avoid < 15 cc/min
Apixaban
2.5mg, 5mg
CrCl > 15 cc/min: 5 mg, BID
Any 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL:
2.5 mg, BID)
Avoid < 15 cc/min
Rivaroxaban
10mg, 15mg, 20mg
CrCl > 50 cc/min: 20 mg, Qday
CrCl 15-50 cc/min: 15 mg, Qday
Avoid CrCl < 15 cc/min
Edoxaban
30mg, 60mg
CrCl > 50 to < 95mL/min: 60 mg daily
CrCl 15 to 50mL/min: 30 mg daily
Avoid CrCl < 15cc/min and > 95cc/min
Oral anticoagulation
Clinical indications
• Venous thromboembolism
• Treatment
• Prophylaxis
• Arterial thrombosis (including PE)
• LV thrombus / post-myocardial infarction
• Atrial fibrillation (valvular, nonvalvular)
• Prosthetic heart valves
• CVA (stroke)
62
Oral anticoagulation
Clinical indications for Pulmonary Embolus and Deep Vein Thrombosis
Comparison of NOAC in VTE Treatment
FDA
Approved
1-8-2015
Objectives
• Provide an overview of coagulation and highlight
potential targets for pharmacotherapy in thrombosis
• Detail the MOA of warfarin and the novel oral
anticoagulants (NOACs) with a focus on practical
considerations related to anticoagulation
• Review the data for use of NOACs in approved clinical
indications
• Outline initiation and transition strategies
• Briefly highlight pipeline agents and combination
therapies
66
Medication Transition
Triple therapy and risk of bleeding
68
Sørensen R, et al. Lancet 2009; 374: 1967–1974.
Factors when choosing a NOAC
Summary
• Systemic anticoagulation has demonstrated significant benefit
(reduced vascular morbidity/mortality) across a wide range of
thrombosis states
• NVAF remains a large (and growing) global medical problem which
exacts in large part, through increased thromboembolic risk
• AF-associated CVAs are more likely to be more morbid and more
likely fatal than non-AF associated CVAs
• Warfarin anticoagulation has proven benefit across a wide variety of
thrombosis states but is frequently associated with unacceptably low
TTR and management challenges
70
Summary
• The novel oral anticoagulants (NOACs) when used appropriately, offer
more homogeneous treatment effect than dose-adjusted warfarin with
comparable or lower rates of major bleeding
• Hepatic function, renal function and co-administration of medications
impacting NOAC metabolism serve as important considerations when
electing to switch to a NOAC
• Co-administration of oral anticoagulants with oral antiplatelet therapy
increases the risk of major bleeding
71