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1/31/12
Outline
Novel Anticoagulants for AF:
Rising to challenge the tried,
tested, and true
Jill Hall
PHM706: Seminar 3
February 1, 2012
 
 
 
 
 
Review the epidemiology of atrial fibrillation and
stroke in Canada
Discuss the efficacy, safety, and underuse of warfarin
for atrial fibrillation
Briefly review the PK and PD of dabigatran,
rivaroxaban, and apixaban
Examine the RE-LY, ROCKET-AF, and ARISTOTLE studies
Consider some of the uncertainties remaining and issues
surrounding the use of the newer anticoagulants
Atrial Fibrillation and Stroke
in Canada
Epidemiology of AF
 
 
Affects 1-2% of Canadians, with prevalence
increasing with age
 
  Estimated
prevalence 350,000 people
  After age 55, incidence doubles with each decade of
life
 
Incidence of and hospital admissions for AF are
expected to increase
 
  aging
population
  rising prevalence of chronic heart disease
Individuals with AF have 3-5 fold
greater risk of stroke
Up to 15% of all strokes are
caused by AF
10%
  After
age 60, increases to 1/3 of
all strokes
 
Mean 4.5% annual incidence
without antithrombotic therapy
AF-related strokes are more
severe, cause greater disability,
and carry a worse prognosis
Heart and Stroke Canada
Stroke 1996;27:1760-64
Heart and Stroke Canada
Consequences of Stroke
Assessing Risk Factors for Stroke
 
15%
CHADS2 Risk Score
Risk Criteria
10%
25%
 
Burden to health care system:
  $3.6B
per year in physician services, hospital costs,
lost wages, decreased productivity
Heart and Stroke Canada
L
L
Score
CHADS2
Score
Adjusted Stroke Rate, %/yr
(95% CI)
Congestive HF
1
0
1.9
(1.2-3.0)
Hypertension
1
1
2.8
(2.0-3.8)
Age ≥ 75 yr
1
2
4.0
(3.1-5.1)
Diabetes
1
3
5.9
(4.6-7.3)
(Prior) Stroke/
TIA
2
4
8.5 (6.3-11.1)
5
12.5 (8.2-17.5)
6
18.2 (10.5-27.4)
JAMA 2001;285:864-74
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Canadian Guidelines (2010)
Efficacy of Warfarin
All Stroke
RRR 64% (49-74)
ARR 3.1%/yr, NNT 33
Mortality RRR 26% (3-43)
ARR 1.6%/yr
Dabigatran Rivaroxaban or Apixaban
?
CJC 2011;27:74-90
Risks with Warfarin
 
  31
  6
 
Hemorrhage:
vs. 17 events (1.3 vs. 1.0%/yr, NS)
  Intracranial
 
Other Issues to Contend With...
Bleeding in MA:
  Major
  2.5/100
in Therapeutic Range (TTR)
  Drug
and food interactions
  Genetic variability in metabolism
  Slow onset/offset
Hemorrhage
  Need
pt-yrs (>80y: ↑13.1/100pt-yr)
  Intracranial
for INR monitoring
  Time
Bleeding in observational studies
  7.2/100
Demonstrated efficacy & safety depend on
maintaining INR 2-3 (narrow therapeutic window)
  Need
Hemorrhage:
vs. 3 events (risk ↑ when INR >3.5)
  Major
AnnIntMed 1999;131:492-501
AnnIntMed 2007;146:857-867
  May
Hemorrhage:
to bridge with heparin for procedures
prolong hospitalization
pt-yrs overall
AnnIntMed 2007;146:857-867
Circulation 2007;115:2689-2696
Warfarin is Grossly Underused
 
Canadian Stroke Registry (n=597)
  Known
Warfarin is Grossly Underused
 
AF, high risk, appropriate VKA candidates
Why?
  Need
for INR monitoring
Variable dose response
  Narrow therapeutic index
  Drug and food interactions
 
  Complicated
dosage regimens
of catastrophic bleeding
  Increasing patient age
  History of falls
  PUD or history of GI bleed
  Contraindications
  Patient refusal
  Fear
Stroke 2009;40:235-240
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Oral Anticoagulant
Mechanisms of Action
Drug Characteristics
Dose/
Regimen
Dabigatran
(Pradax)
Rivaroxaban
(Xarelto)
Apixaban
(Eliquis)
Variable
Daily
110 or 150mg
BID
20mg daily food
5mg BID
CrCl 15-30:
15mg daily food
‘High Risk’: 2.5mg
BID
MOA/Target
Factors II, VII, IX, X;
Protein C & S
Factor II
Factor Xa
Factor Xa
Time to Peak
Effect
3-5 days
1-3 hours
(prodrug)
3-4 hours
1-3 hours
Half Life
40 h
Interactions
P450
Renal
Clearance
AC Monitoring
Pharmacol Ther 2011;129(2):185-94
Warfarin
12-17 h
5-9 h
9-14 h
CrCl <30: >24 h
Elderly:11-19 h
P-gp inhibitors
3A4, 2J2, P-gp
inhibitors
3A4, P-gp
inhibitors
None
80%
35%
25%
Required
INR
Not required
ECT
Not required
Anti-Xa
Not required
Anti-Xa
My Question Is:
Is dabigatran the most RE-LYable?
Is there ONE
that outshines the rest?
RE-LY NEJM 2009;361(2):1139-51
Design
International, PROBE study
Primary Analysis: Noninferiority (NI Margin 1.46)
Population
N= 18,113
Inclusion: nonvalvular AF on ECG at screening or within 6mo
AND at least one of:
•  history of stroke, TIA or systemic embolism
•  EF <40% or NYHA ≥2 HF within 6mo
•  age ≥75yr
•  age ≥65yr with DM, CAD, or HTN
Exclusion: valve disorder (including prosthetic valve)
ASA >100mg
stroke within 14d or severe stroke within 6mo
conditions that ↑risk of hemorrhage
CrCl <30mL/min
Intervention
Dabigatran 110mg or 150mg BID (blinded)
vs.
Warfarin daily to target INR 2-3 (open label)
Follow Up
Median 2 yr
RE-LY: Results
1.46
NEJM 2009;361(2):1139-51
Circulation 2011;123:1436-50
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Dabigatran
Warfarin
RE-LY: Results
Clinical Endpoints
INR 2-3
(N=6022)
110mg
150mg
(N=6015)
(N=6076)
110mg vs.
Warfarin
150mg vs.
Warfarin
*1°: Stroke or SE
3.4%
3%
2.2%
Non-inferior
NNT 88
Stroke
3.1%
2.8%
2.0%
NS
NNT 93
Ischemic
2.4%
2.6%
1.8%
NS
NNT 167
Hemorrhagic
0.75%
0.23%
0.20%
NNT 192
NNT 182
*Major Bleed
7.0%
5.7%
6.6%
NNT 77
NS
GI Bleed
2.0%
2.2%
3.0%
NS
NNH 100
Intracranial Bleed
1.5%
0.5%
0.6%
NNT 96
NNT 116
Minor Bleed
32%
26%
29%
NNT 17
NNT 39
All cause mortality
8.1%
7.4%
7.2%
NS
NS
*Myocardial Infarction
1.3%
1.6%
1.6%
Dyspepsia
5.8%
11.8%
11.3%
NNH 17
NNH 18
10.2%
16.6%
14.5%
20.7%
15.5%
21.2%
Favours
Warfarin
Favours
Warfarin
Discontinuation
Rate
Yr1
Yr2
Assessment of RE-LY
Strengths
 
Large RCT
  Used
 
 
Concerning Trend
Limitations
 
ITT analysis
Important & objective
clinical endpoints
Utilized 2 doses of
dabigatran to enable
comparison of
risk:benefit to warfarin
Open-label warfarin
  Risk
ascertainment &
performance bias
  Additional events
 
Did not report per
protocol analysis
ROCKET-AF NEJM 2011;365:883-91
Is rivaroxaban going to ROCKET us over the
moon?
1°: Stroke or SE
Stroke
Rivaroxaban
Warfarin
Population
N= 14,171
Inclusion: nonvalvular AF (1 of 2 documented on ECG within 30d)
AND either:
•  history of stroke, TIA or systemic embolism
•  Or TWO of:
•  EF ≤35% or clinical heart failure
•  HTN (>140/90 or treated)
•  age ≥75yr
•  DM
Exclusion: valve disorder (including prosthetic valve, mitral stenosis)
medications: ASA+thienopyridines, strong 3A4i
stroke within 14d or severe stroke within 6mo
conditions that ↑risk of hemorrhage
CrCl <30mL/min
Intervention
Rivaroxaban 20mg daily (CrCl 30-49mL/min: 15mg) vs.
Warfarin daily to target INR 2-3
Follow Up
Median 23.5 months (19.5 mo on treatment) (30 day observation)
PP
ITT
PP
ITT
(n=6958)
(n=7081)
(n=7004)
(n=7090)
2.7%
3.8%
3.4%
4.3%
HR (95% CI)
PP
ITT
0.79
(0.66-0.96)
Non-inferior
0.88
(0.75-1.03)
NS
2.6%
3.1%
NS
Ischemic
2.1%
2.3%
NS
Hemorrhagic
0.41%
0.71%
NNT 333
Major + NMCR Bleed
20.7% (5.6+16.7)
20.3% (5.4+16.2)
NS
Hb/Transfusion
4.3 / 2.6%
3.6 / 2.1%
NNH 77 / 200
Critical/Fatal
1.3 / 0.4%
1.9 / 0.8%
NNT 167 / 250
Intracranial Bleed
0.8%
1.2%
NNT 250
NNH 100
GI Bleed
International, DB, double dummy, RCT
Primary Analysis: Noninferiority (NI Margin 1.46)
Assessment of ROCKET-AF
ROCKET-AF: Results
Clinical Endpoints
Design
3.2%
2.2%
All cause mortality
2.95%
3.53%
NS
Discontinuation
23.7%
22.2%
Favours Warfarin
Strengths
 
Limitations
Large RCT
 
  Double-blind,
dummy
  Encrypted
  Reported
 
 
double-
POC INR
ITT
Important & objective
clinical endpoints
Enrolled a higher risk
population
 
 
Utilized a potentially less
than ideal dosing regimen
(daily dosing, transition to
warfarin)
Poor TTR
Utilized per-protocol
analysis for primary
outcome
 
 
Various patient populations
Unclear efficacy & safety
of 15mg dose
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ARISTOTLE NEJM 2011;365;11:981-92
Is apixaban the most logical choice?
1°: Stroke or SE
Stroke
Apixaban
(N=9120)
Warfarin
(N=9081)
HR (95% CI)
2.3%
2.9%
0.79 (0.66-0.95)
Non-inferior
ARR 0.6%, NNT 167
Population
N= 18,206
Inclusion: nonvalvular AF or AFl
AND 1 of:
•  history of stroke, TIA or systemic embolism
•  EF ≤40% or clinical heart failure within 3mo
•  HTN requiring treatment
•  age ≥75yr
•  DM
Exclusion: valve disorder (including prosthetic valve, mitral stenosis)
medications: ASA+thienopyridines
stroke within 7d
conditions that ↑risk of hemorrhage
CrCl <25mL/min or SCr >220umol/L
Intervention
Apixaban 5mg BID (or 2.5mg BID) vs.
Warfarin daily to target INR 2-3
Follow Up
Median 1.8 years
2.2%
2.7%
NNT 200
Strengths
Ischemic
1.8%
1.9%
NS
Hemorrhagic
0.4%
0.85%
NNT 223
Major Bleed
International, DB, double-dummy, RCT
Primary Analysis: Noninferiority (NI Margin 1.38)
Assessment of ARISTOTLE
ARISTOTLE: Results
Clinical Endpoints
Design
3.6%
5.1%
NNT 67
GI
1.2%
1.3%
NS
Intracranial
NNT 138
0.57%
1.3%
Any bleed
25.9%
33.8%
NNT 13
All cause mortality
6.6%
7.4%
NNT 125
Discontinuation
25.3%
27.5%
Favours Apixaban
 
 
Patient Characteristics
RE-LY
ROCKET-AF
ARISTOTLE
Mean 71.5
>75y: 40%
Median 73
>78y: 25%
Median 70
>75y: 31%
Weight or BMI
82.7±19.7kg
28.2kg/m2 (25-32)
82kg (70-96)
Paroxysmal AF
33%
18%
15%
2.1
32/35/32%
3.5
- /13/87%
2.1
34/36/30%
Prior Stroke/TIA±SE
20%
55%
19.5%
Prior HF
32%
62.5%
35.5%
Hypertension
79%
90.5%
87.5%
Prior MI
17%
17%
14.5%
Prior VKA therapy
50%
62.5%
57%
ASA Therapy
CrCl (mL/min)
CrCl <50mL/min
Well designed,
conducted trial
  DB, double-dummy
  Blinded, encrypted
point of care INR
  Clear analysis
Important & objective
clinical endpoints
 
 
No per-protocol
analysis reported
No subgroup analyses
or post-hoc data
available
A Closer Look to Compare...
Age (years)
CHADS2 Score
0-1 / 2 / 3-6
Weaknesses
21%
36.5%
31%
Unknown
19%
67 (IQR 52-88)
21%
Unknown
17%
RE-LY (150mg)
ROCKET-AF
ARISTOTLE
Mean 64%
Range 44-77%
Mean 55%
Median 58% (43-71)
Mean 62%
Median 66% (58-72)
Net Clinical
Benefit
*RR 0.90 (0.82-0.99)
ARR 1.4% NNT 72
Not done
HR 0.85 (0.78-0.92)
ARR 1.8% NNT 56
Stroke or SE
*RR 0.65 (0.52-0.81)
ARR 1.1% NNT 88
HR 0.88 (0.75-1.03)
NS
HR 0.79 (0.66-0.95)
ARR 0.6%, NNT 167
Stroke or SE
RR 0.77 (0.56-1.06)
NS
HR 1.02 (0.56-1.84)
NS
HR 0.79 (0.54-1.13)
NS
RR 0.76 (0.60-0.98)
NNT 167
HR 0.94 (0.75-1.17)
NS
HR 0.92 (0.74-1.13)
NS
HR 0.67 (0.47-0.93)
0.5 vs. 0.7%/yr
NNT 250
HR 0.42 (0.30-0.58)
0.33 vs. 0.80%/yr
NNT 138
HR 0.85 (0.70-1.02)
HR 0.89 (0.80-0.998)
INR TTR
When TTR >65%
Ischemic Stroke
ICH
Mortality
¥RR
0.36 (0.26-0.49)
0.23/0.32 vs. 0.76%/yr
NNT 96 / 116
¥RR
0.90 (0.81-1.00)
*Revised data
¥Data from FDA
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Primary Efficacy Outcome
Outcomes Based on TTR
 
A
A
RE-LY
  Rate
Dabigatran 110mg BID
A
of stroke+SE
  Dabigatran
RR 0.90 (0.74-1.10)
 
Dabigatran 150mg BID
A
  Rate
RR 0.65 (0.52-0.81)
A
  Rate
HR 0.88 (0.75-1.03)
150mg & 110mg consistently better
of major bleed, GI bleed:
  Higher
Apixaban 5mg BID
A
of ICH
  Dabigatran
Rivaroxaban 20mg daily
A
150mg not superior when TTR>65%
Not non-inferior when TTR>72.5%
  Lower
HR 0.79 (0.66-0.95)
in dabigatran 150mg arm when TTR >65%
only in dabigatran 110mg arm when TTR <57%
A
NI Margin
A
Warfarin Better
Novel Anticoagulant Better
Lancet 2010;376:975-83
A
A
A
A
A
Outcomes Based on TTR
Uncertainties Remain
a
 
ROCKET
  Rate
 
  Rivaroxaban
  Rate
 
  “Real
not non-inferior when TTR>68%
superior when TTR>64%
of stroke+SE
  Similar
  Rate
 
Factors Influenced
Readily
Available?
II (specific assay for thrombin generation)
No
Prothombin Time (PT)
II, VII, X (extrinsic pathway)
Yes
Activated partial
XII, XI, IX, VIII (intrinsic pathway)
thromboplastin time (aPTT) II, V, X, and fibrinogen (final common)
Directly assesses activity of thrombin in plasma
Dilute thrombin time
Yes
Yes
Europe
Assesses activity of drugs that directly or
indirectly interfere with Xa
by P450 and transported by Pgp
↑
Risk of stroke due to short t½
Safety in renal and liver dysfunction
Other Issues?
Issues: Monitoring & Reversibility
Ecarin Clotting Time (ECT)
Anti Xa
Adherence with BID regimens
remained superior (except in 3rd quartile)
Issues: Monitoring & Reversibility
Thrombin Time (TT)
 
 
of major bleed
Coagulation Test
Drug Interactions
 
results for all TTR quartiles, non-inferior only
  Apixaban
 
  Metabolized
ARISTOTLE
  Rate
World” use
AF, mechanical valves, other indications
  Valvular
of major bleed
  Warfarin
Efficacy
  Longer-term
of stroke+SE
Yes
 
Coagulation tests affected:
  Dabigatran:
  Rivaroxaban
 
ECT (aPTT, TT)
& Apixaban: PT
Prothrombin Complex Concentrate (PCC)
  Contains
  Healthy
Factors II, VII, IX, X, protein C & S
volunteer cross-over study with Cofact®
  Dabigatran:
no effect on aPTT, TT, ECT
corrected PT
  Rivaroxaban:
  No
data in patients who are actually bleeding
Thromb Haemost 2010;103:1116–27
Circulation 2011;124:1573–1579
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Issues: Drug Interactions
 
Dabigatran
  Potent
  PPI:
 
Bleeding
  RE-LY
P-gp inhibitors: ↑
concentration
  Dronedarone,
 
Post-Marketing: Dabigatran
  Reduced
↓ AUC, Cmax 25-45%
  ‘Real
antifungals, ritonavir
 
505 reported severe bleeding cases
  Trauma
patient deaths
& Australia: regulatory agencies issued warnings
  FDA investigation underway
3A4 and P-gp inducers: ↓ concentration
  Carbamazepine,
Life’ Bleeding Reports
reports of supra-therapeutic drug levels in elderly
patients with low body weight and CrCl
  MedWatch (ISMP, 1st Quarter 2011)
3A4 and P-gp inhibitors: ↑
concentration
  Azole
  Potent
major bleeding in those <75yr only
ICH in those <75 and >75yr
  Case
Rivaroxaban & Apixaban
  Potent
pre-specified sub-group analysis
  Reduced
ketoconazole, quinidine (verapamil)
  Japan
phenytoin, rifampin, St Johns Wort
Circulation 2011;123:2363-72
NEJM 365;21:2039-40
www.theheart.org
Clin Pharmacokin 2008;47(1)47-59
J Thromb Thrombolysis 2011;31:326–343
Post-Marketing: Dabigatran
 
MI/ACS
  MA
Advantages
confirms signal in RE-LY
  OR
 
1.33 (1.03-1.71), ARI 0.4%, NNH 250
  Post-hoc
Ideal Anticoagulants?
1.28 (0.98-1.67), NS
  NS for clinical, silent, and fatal MI
  Net clinical benefit consistent with original analysis
 
  HR
 
 
 
  Cause
of therapy discontinuation in 10% of subjects
be even higher in ‘real life’  risk events
short half-life
no cross-coverage for initiation
or treatment interruption
 
 
Wide therapeutic margin
Predictable PK & PD
Limited drug interactions
Difficult to compare due to different study designs,
clinical outcomes and populations
  Recognize that there are advantages and
disadvantages of each of the novel anticoagulants
  Translation of efficacy & safety data into the ‘real
world’ is challenging
 
 
Poor adherence ↑risk events
No simple coagulation assay
easily available
 
 
 
Cannot titrate dose
Cannot assess cause of treatment
failure (adherence
vs. drug itself)
Cannot assess degree of
anticoagulation in emergency
 
ArchIntMed 2012 (online first)
Circulation 2012 (online first)
Clinical Bottom Line
Rapid onset/offset
 
 
No need for routine
monitoring
 
Dyspepsia
  May
Rapid onset/offset
 
RE-LY
Disadvantages
No established antidote or reversal
procedure
Clinical Bottom Line
 
Considering:
  Strength
of the clinical trial design and conduct
in terms of efficacy & safety
  Pharmacological properties
  Results
Dabigatran: sub-group, post-hoc, post-marketing
7
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Who May Remain Candidates for the
Tried, Tested, and True?
Thank You!
Those already well controlled warfarin who have no
reason to change
  Those less likely to comply with BID dosing
  Those with renal dysfunction (CrCl <30mL/min) or
fluctuating renal function
  Those who cannot afford the new agents
  Those who are older?
  Those who are underweight or frail?
 
References
 
 
 
 
 
 
 
 
 
 
 
Heart and Stroke Foundation of Canada. Statistics [Internet]. Available from:
http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm#stroke (Accessed:
8Jan2011)
Lin JH, Wolf PA, Kelly-Hayes M et al. Stroke severity in atrial fibrillation: The Framingham Study. Stroke
1996;27:1760-64.
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial
fibrillation: A meta-analysis. AnnIntMed 1999;131:492-501.
Challenges for meta-analysis for determining non-inferiority margin. FDA Statistics Forum. Available from:
http://www.fda.gov/downloads/Drugs/NewsEvents/UCM209090.pdf (Accessed 9Jan2011)
Atrial Fibrillation Investigators. Risk factors for stroke and efficiency of antithrombotic therapy in atrial
fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med
1994;154:1449-57.
Hart RG, Pearce LA, Aguilare MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have
nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
Cairns JA, Connolly S, McMurtry S, et al. CCS Atrial Fibrillation Guidelines 2010: Prevention of stroke and
systemic thromboembolism in atrial fibrillation and flutter. CJC 2011;27:74-90.
Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke:
results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70.
Optimal Warfarin Management for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation:
A Systematic Review of the Clinical Evidence. CADTH Optimal Use Report 2011;1(2a)
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