4/13/15
Disclosures
Anticoagulation Forum’s
13th National Conference on Anticoagulant Therapy
Who should be treated with a
NOAC and why?
Wardman Park Marriott Hotel
Washington, DC
April 24, 2015
§ 
Astra-Zeneca
§ 
Bayer
§ 
Boehringer Ingelheim
§ 
Bristol-Myers Squibb
§ 
Daiichi-Sankyo
§ 
Eli-Lilly
§ 
Glaxo-Smith-Kline
§ 
Pfizer
§ 
Janssen
§ 
Sanofi-Aventis
Key questions
1. 
Why were non-vitamin K antagonist oral
anticoagulants (NOACs) developed?
2. 
When should NOACs be used?
3. 
When should NOACs not be used?
Limitations of warfarin
§  Limitations
of warfarin:
Ø Slow
onset and offset
Ø Variable and unpredictable anticoagulant effects
Ø Numerous food and drug interactions
Ø High
risk of intracranial bleeding
→ Under-treatment
→ Poor quality treatment
Under-use of anticoagulants in AF
Kakkar AJ. Anticoagulation and AF: Emerging insights. Oral presentation. ESC 2014
Quality of warfarin control (TTR) in US
community practice (n=138,319)
Dlot JS, et al. Circulation 2014; 129: 1407-14.
4/13/15
Key questions
1. 
Results of the randomized trials
comparing NOACs with warfarin
Why were non-vitamin K antagonist oral
anticoagulants (NOACs) developed?
2. 
When should NOACs be used?
3. 
When should NOACs not be used?
§  More
Rapid onset and offset
§ 
Fixed dosing, no monitoring
§  Safer
§ 
Less ICH (and deaths)
§ 
Less major bleeding
§  More
§ 
CCS 2014 AF Guidelines
January CT, et al. Circulation 2014; 130: e199-267.
Where should NOACs be used?
Approved indications in the United States
NOAC
Dabigatran
-
X
effective
Less thromboembolic events
AHA/ACC/HRS 2014 AF Guidelines
Verma A, et al. Can J Cardiol 2014; 30: 1114-30.
VTE
VTE
prevention treatment
convenient
§ 
ACS
AF
-
X
Rivaroxaban
X
X
-
X
Apixaban
X
X
-
X
Edoxaban
-
X
-
X
Key questions
1. 
Why were non-vitamin K antagonist oral
anticoagulants (NOACs) developed?
2. 
When should NOACs be used?
3. 
When should NOACs not be used?
4/13/15
Situations in which
NOACs should not be used
§  Cardiac
§  Indications
§  Patient
within established indications
§  Concomitant
therapies
§  Drug
related factors and non-bleeding
adverse effects
Indications not studied
§  Procedures
AF Ablation
§  Device implantation
§  Revascularization
§ 
§ 
Hemofiltration / dialysis
§  Other
§ 
Intra-cardiac thrombus
Hypertrophic cardiomyopathy
§  Heart failure
§ 
populations
§  Subgroups
Indications not studied
Suspected or confirmed heparin-induced
thrombocytopenia
Dabigatran in mechanical heart valves
Thromboembolic events
§ 
§  Cerebral
§ 
Acute stroke, embolic stroke of uncertain source
§  Secondary
prevention of cardiovascular
disease
Indications where no benefit was
demonstrated or harm has been shown
§  Post
§ 
§ 
§ 
ACS
Dabigatran (REDEEM [phase 2])
Apixaban (APPRAISE)
(Rivaroxaban approved in Europe post ACS
based on the ATLAS results)
§  Mechanical
heart valves
Dabigatran in mechanical heart valves
Major bleeding
First thromboembolic event includes stroke, systemic embolism, transient ischaemic
attack, myocardial infarction.
Eikelboom JW, et al. N Engl J Med 2013; 369: 1206-14.
Eikelboom JW, et al. N Engl J Med 2013; 369: 1206-14.
4/13/15
Situations in which
NOACs should not be used
within established indications
§  Concomitant
therapies
§  Extremes
§ 
related factors and non-bleeding
adverse effects
§ 
Studies currently ongoing
Patient populations inadequately tested
§ 
§ 
§ 
elderly
Vulnerable populations
§  Elderly
Age >90
§  Severe
of body weight
Under 45kg or over 150kg
§  Children
§  Drug
§  Extreme
women
§ 
populations
§  Subgroups
§  Pregnant
Apixaban” category B
§  Dabigatran and Rivaroxaban: category C
§  Indications
§  Patient
Patient populations not tested
§ 
renal impairment
Age over 80 years
§  Moderate
Creatinine clearance <15 or <30ml/min (varies
by regulatory agency
§ 
renal impairment
Clearance 30-50 ml/min
Liver dysfunction
NOACs in the elderly
Trial
>75
>80
RE-LY
7,258
3,027
ROCKET-AF
6,229
-
ARISTOTLE
5,678
-
NOACs vs. warfarin
Stroke/SE in the younger and elderly
Results
Consistent results
except more ECH
(D150) in elderly
Consistent results
except more ECH
in elderly
Consistent
results
Coppens M, et al CMAJ (in press)
Coppens M, et al. CMAJ 2103
4/13/15
NOACs vs. warfarin
Major bleeding in the younger and elderly
NOACs in CKD (eGFR <50 ml/min)
Trial
eGFR <50
ml/min
Results
RE-LY
3,505
Consistent
results
ROCKET-AF
2,950
Consistent
results
ARISTOTLE
3,017
Less bleeding in
patients with CKD
Coppens M, et al. CMAJ 2103
Coppens M, et al CMAJ (in press)
New OAC vs. warfarin in moderate CKD
(eCrCl <50 ml/min)
New OAC vs. warfarin in moderate CKD
(eCrCl <50 ml/min)
Stroke or Systemic Embolism
Major bleeding
RR (95% CI)
RR (95% CI)
Dabigatran 110 mg BID
0.77 (0.51-1.18)
Dabigatran 110 mg BID
0.99 (0.76-1.28)
Dabigatran 150 mg BID
0.55 (0.40-0.81)
Dabigatran 150 mg BID
1.03 (0.80-1.34)
Rivaroxaban 15 mg QD
0.86 (0.63-1.17)
Rivaroxaban 15 mg QD
0.95 (0.72-1.26)
Apixaban 2.5/5 mg BID
0.79 (0.55-1.14)
Apixaban 2.5/5 mg BID
0.50
0.75
1.00
1.25
1.50
0.50 (0.38-0.66)
0.50
0.75
HR (95% CI)
New Agent Better
1.00
1.25
1.50
HR (95% CI)
Warfarin Better
New Agent Better
Hart RG, et al. Nat Rev Nephrol 2012; 8: 569-78.
Connolly SJ, et al. N Engl J Med. 2009; 361:1139.
Fox KAA et al. Euro Heart J 2011; 32: 2387.
Granger C, et al. N Engl J Med. 2011; 365: 981.
RE-LY
Drug concentrations and outcome
Dabigatran 150 mg bid trough blood levels
and outcomes in renal impairment
Stroke / SEE
2.29 x
Reilly PA, et al. J Am Coll Cardiol 2014; 63: 2885-6.
Warfarin Better
Hart RG, et al. Nat Rev Nephrol 2012; 8: 569-78.
Connolly SJ, et al. N Engl J Med. 2009; 361:1139.
Fox KAA et al. Euro Heart J 2011; 32: 2387.
Granger C, et al. N Engl J Med. 2011; 365: 981.
1.47 x
Major bleeding
1 (ref)
2.29 x
1.47 x
1 (ref)
Reilly PA, et al. J Am Coll Cardiol 2014; 63: 2885-6.
Hijazi Z, et al. Circulation 2014; 129: 961-70.
4/13/15
Dabigatran 110 and 150 mg bid trough
blood levels and outcomes with age
Stroke / SEE
1 (ref)
1.28 x
§  Indications
Major bleeding
1 (ref)
1.68 x
1.28 x
Situations in which
NOACs should not be used
1.68 x
§  Patient
populations
§  Subgroups
within established indications
§  Concomitant
therapies
§  Drug
related factors and non-bleeding
adverse effects
Reilly PA, et al. J Am Coll Cardiol 2014; 63: 2885-6.
Lauw M, et al. Manuscript in preparation
Disease subgroups
§  Atrial
Situations in which
NOACs should not be used
fibrillation
§ 
Valvular AF (moderate or severe mitral stenosis)
§  Indications
§ 
Triple therapy
§  Patient
§  Venous
thromboembolism treatment
High risk thrombophilia (e.g., APAS, AT PC PS
deficiency)
§  Thrombosis at unusual sites (e.g., mesenteric,
superficial, cerebral vein thrombosis)
§ 
§ 
§ 
Major PE
Cancer-related thrombosis
§  Subgroups
within established indications
§  Concomitant
therapies
§  Drug
related factors and non-bleeding
adverse effects
Concomitant therapies
Situations in which
NOACs should not be used
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Antifungals
(azole)
Antifungals
(azole)
Antifungals
(azole)
Antifungals
(azole)
Anticonvulsants
Anticonvulsants
Anticonvulsants
Anticonvulsants
HIV protease
inhibitors
HIV protease
inhibitors
Other†
Other†
Other*†
populations
§  Indications
§  Patient
§  Subgroups
*Verapamil †Dronedarone, rifampicin, quinidine
Heidbuchel H, et al. Eur Heart J 2014; 383: 955-62.
within established indications
§  Concomitant
§  Drug
Other*†
populations
therapies
related factors and non-bleeding
adverse effects
4/13/15
Drug related factors and non-bleeding
adverse effects
§  Allergy
§  Rash
§  Dyspepsia
Summary
§  NOACs
were developed to provide a safe,
effective and more convenient alternative to
warfarin
§  Most
guidelines recommend NOACs in
preference to warfarin for established
indications
§  Planned
and ongoing trials and clinical
experience are likely to further expand the
use of NOACs to broader populations