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University of Chicago Medical CenterChicago, IL
Janet Friant, MSN, APN-BC, AACC
What are all of these blood thinners? A
review of oral anticoagulation options.
• 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
Objectives
3
• 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
Objectives
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
“GOOD CLOT”
“BAD CLOT”
Issues of thrombosis and
hemostasis often coexist in
the very same patient
6
Coagulation and platelet cascades
Nathan S, Swamy R. U.S. Cardiology 2008.7
Oral anticoagulationClinical 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.
Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014. In press. 9
Miyasaka Y, et al. Circulation 2006; 114: 119.
Projected incidence of NVAF in the U.S.
10
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.
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.
11
Clinical Calculation Tools
Clinical Calculation Tools: Qx Calculate
• 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
Objectives
14
Oral anticoagulants
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
15
Warfarin
Wisconsin Alumni Research Foundation
16
Warfarin
Kinetics
Absorption 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 20-60 hours
Dosing Variable
17
Warfarin
Key considerations
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/HematuriaVasculitisDermatitis, pruritus, urticariaAbdominal pain, N/V/D AnemiaSkin necrosis, gangrene, “purple toes” syndrome
18
Indications for warfarin and recommended therapeutic range
19
Limitations of warfarin
Mean TTR is low in patients receiving warfarin
Only 55% of nonvalvular AF patients without contraindications receive
warfarin*1
51%
29%
67%
55%
58%
0 20 40 60 80 100
McCormick et al
Sarawate et al
Rose et al
Baker et al
Rose et al
Mean TTR (%)Age (y)
2
3
5
6
4
Pa
tie
nts
(%
)
55%
overall
use1
(N=22,237)
(N=124,551)
(N=3104)
(N=470)
(N=174)(n=1064) (n=1596) (n=3707) (n=3752) (n=963)
1. Go AS et al. Ann Intern Med. 1999;131(12):927-934. 2. Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29.3. Baker WL et al. J Manag Care Pharm. 2009;15(3):244-252. 4. Rose AJ et al. J Thromb Haemost. 2008;6(10):1647-1654. 5. Sarawate C et al. J Thromb Thrombolysis. 2006;21(2):191-198. 6. McCormick D et al. Arch Intern Med. 2001;161(20):2458-24637. Bungard et al. Arch Intern Med. 2000; 160; 41-46.
20
Warfarin vs. placebo in stroke prevention in patients with NVAF
50%100% 0 -50% -100%
Relative Risk Reduction (95% CI)
FavorsWarfarin
FavorsPlacebo
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
All Trials
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.
Hart RG et al. Ann Intern Med. 1999;131(7):492-501.21
NOACs: “Are we there yet?”
22
• 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
Objectives
23
Pros and cons of NOACs
Advantages Disadvantages
Rapid onset/offset of action 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 Higher drug acquisition costs
Wide therapeutic window Rapid decline in effect if doses are missed
Lower risk of intracranial hemorrhage No specific antidote
Lower potential risk of bleeding complications Increased risk for GI bleeding
Fixed dosing Contraindicated in patients with mechanical
heart valves
24
Direct oral thrombin inhibition
VIIa
Xa
IXa
XIa
XIIa Tissue
factor
Factor IIa
(thrombin)Dabigatran
II
×25
Dabigatran
Kinetics
Absorption Rapid; initially slow postoperatively
Metabolism Hepatic; rapidly and completely hydrolyzed to active form by plasma and hepatic esterases
Excretion Renal (80%)
Half-life 12-17 hours
Dosing 150mg twice daily if CrCl >30 ml/min75mg twice daily is CrCl 15-30 ml/min
26
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%)
27
Dabigatran vs. warfarin in the RELY trial
Connolly SJ, et al. N Engl J Med 2009;361:1139-51.28
RELY: Cumulative hazard rates for the primary outcome of stroke or systemic embolism, according to treatment group
Connolly SJ, et al. N Engl J Med 2009;361:1139-51.29
RELY: Safety outcomes according to treatment group
Connolly SJ, et al. N Engl J Med 2009;361:1139-51.30
RELY: Conclusions
• In patients with atrial fibrillation, dabigatrangiven 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 hemorrhage
• 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 hemorrhage
31
Recommended use of dabigatran
32
Direct oral Xa inhibition
VIIa
Xa
IXa
XIa
XIIaTissue
factor
Fibrinogen Fibrin clot
Factor II
(prothrombin)
Rivaroxaban
Apixaban
Edoxaban
×
33
Rivaroxaban
Kinetics
Absorption Intestines, rapidRecommended to take with food
Metabolism HepaticCYP3A4/5 and CYP2J2
Excretion Renal (65%)
Half-life 5-9 hours
Dosing 20 mg once daily if CrCl > 50 ml/min15mg once daily if CrCl 15-50 ml/min
34
ROCKET-AF: Rivaroxaban vs. warfarin in NVAF at mod-high risk of stroke
Enrollment of subjects without prior stroke, TIA, or systemic embolism
and only 2 factors capped at 10%
CHADS2 Risk Factors•Prior stroke, TIA, or non–CNS
systemic embolus – OR –
•CHF or LVEF ≤35% •Hypertension •Age ≥75 years •Diabetes
At least 2 required
Rivaroxaban20 mg/d
(15 mg/d for CrCl 30 to <50 mL/min)
WarfarinINR target:
2.0 to 3.0 inclusive
Nonvalvular AF
Monthly assessments*Warfarin management was determined by clinician
Randomizeddouble-blind/
double-dummy(N=14,264)
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.
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):340-347.35
Rivaroxaban vs. warfarin in NVAF: ROCKET AF trial
XARELTO®
(n=7081)*Warfarin
(n=7090)*
HR (95% CI)No. (%)Rate/
100 PTY No. (%)Rate/
100 PTYPrimary 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 –
Hemorrhagic stroke 33 (0.5) 0.3 57 (0.8) 0.4 –
Ischemic stroke 206 (2.9) 1.6 208 (2.9) 1.6 –
Unknown stroke type 19 (0.3) 0.2 18 (0.3) 0.1 –
Non–CNS systemicembolism
20 (0.3) 0.2 27 (0.4) 0.2 –
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
*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.
36
ROCKET AF: Primary endpoint (per protocol)
Patel MR et al. N Engl J Med 2011;365:883-891.37
ROCKET AF: Primary endpoint (intention to treat)
Patel MR et al. N Engl J Med 2011;365:883-891.38
ROCKET AF: Secondary endpoints
Rivaroxaban(n=7081)*
Warfarin(n=7090)*
HR (95% CI)No. (%)Rate/
100 PTY No. (%)Rate/
100 PTY
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)
Stroke type
Hemorrhagic
Ischemic
Unknown
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)
Systemic embolism 20 (0.3) 0.2 27 (0.4) 0.2 0.74 (0.42-1.32)
MI 130 (1.8) 1.0 142 (2.0) 1.1 0.91 (0.72-1.16)
All-cause mortality 582 (8.2) 4.5 632 (8.9) 4.9 0.92 (0.82-1.03)
39
Comparable major and nonmajor bleeding in ROCKET AF for rivaroxaban and warfarin
Bleeding
Rivaroxaban
(n=7111)*
Warfarin
(n=7125)*
HR
(95% CI)No. (%)Rate/
100 PTY No. (%)Rate/
100 PTY
Major and nonmajor
clinically relevant1475 (20.7) 14.9 1449 (20.3) 14.5 1.03 (0.96-1.11)
Major 395 (5.6) 3.6 386 (5.4) 3.5 1.04 (0.90-1.20)
Nonmajor
clinically relevant1185 (16.7) 11.8 1151 (16.2) 11.4 1.04 (0.96-1.13)
*Safety population on-treatment.
Patel MR et al. N Engl J Med. 2011;365(10):883-891.40
Apixaban
Kinetics
Absorption Rapid; Intestines
Metabolism 15% liver metabolismCYP3A4
Excretion Primarily Biliary/Fecal (73%)Renal (27%) unchanged
Half-life 8 to 15 hours
Dosing Dose: 5mg twice dailyDose reduction to 2.5mg twice daily if 2+ of the following: ≥80 years;, weight ≤60kg, Cr ≥1.5mg/dl
41
Apixaban vs. warfarin in NVAF
Granger CB et al. N Engl J Med 2011;365:981-992.42
Granger CB et al. N Engl J Med 2011;365:981-992.
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
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.
47
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.
48
Edoxaban
Kinetics
Absorption Rapid; IntestinesPeak in 1-2 hours
Metabolism Predominant metabolite is active Hepatic clearance- 50%, 50% renalMinimal via hydrolysis
Excretion Urine (primarily unchanged)
Half-life 10-14 hours
Dosing Dose: 30 mg dailyDose increased if CrCl >50 to 95ml/min to 60mg
-AVOID in CrCl >95 ml/min or < 15ml/min
49
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..
Giugliano PR et al. N Engl J Med 2013;369:2093-104..
Edoxaban Major Bleeding Event
Trials of NOACs (vs. warfarin) in NVAF
Subjects, %
ROCKET AF(N=14,264)1
RE-LY(N=18,113)2
ARISTOTLE(N=18,201)3
ENGAGE AF –TIMI 48 (N=21,105)
CHADS2 score (mean) 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/embolism
54.8 20.0 19.4 28.1
Prior MI 17.3 16.6 14.2
*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
Engl J Med. 2011;365(11):981-992 4. Giugliano RP et al. N Engl J Med. 2013; 369: 2093-104.
NOTE: Because these clinical trials
were conducted with different
designs and evaluated different
populations, direct comparisons of
their results cannot be made.
53
NOACs in NVAF:Comparison of trials
Comparative pharmacology of oral anticoagulants
55
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:Primary endpoints
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 AF-
TIMI 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:Bleeding
57
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 EF-
TIMI 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:Intracranial hemorrhage
58
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
NOACs in NVAF:Dosing recommendations
59
Oral anticoagulationClinical indications
• Venous thromboembolism
• Treatment
• Prophylaxis
• Arterial thrombosis (including PE)
• LV thrombus / post-myocardial infarction
• Atrial fibrillation (valvular, nonvalvular)
• Prosthetic heart valves
• CVA (stroke)
60
Oral anticoagulationClinical indications for Pulmonary Embolus and Deep Vein Thrombosis
Comparison of NOAC in VTE Treatment
FDA Approved 1-8-2015
• 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
Objectives
64
Medication Transition
Triple therapy and risk of bleeding
Sørensen R, et al. Lancet 2009; 374: 1967–1974. 66
Factors when choosing a NOAC
Summary
68
• 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
Summary
69
• 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