Transcript NOACs Review

Individualizing Novel
Anticoagulants in Clinical Practice
Felicita Andreotti, MD PhD FESC
Dept of Cardiovascular Science, Catholic University Hospital – Rome, IT
Consultant or speaker in past 2 years for Amgen, Bayer,
Boehringer Ingelheim, BMS/Pfizer, Daiichi-Sankyo, Eli-Lilly
Burden of AF
2015 world population  7 000 000 000  1% has AF
1% of 7 billion  70 M with AF worldwide
In Gulf
1% of 44 M pop.
 440 000 AF pts
In Kuwait
1% of 4 M pop.
 40 000 AF pts
Camm et al. ESC AF Guidelines. EHJ 2010;31:2369-429 - en.wikipedia.org/wiki/World_population
Stroke rate in untreated NVAF
▪ On average  5% per annum
▪
▪
▪
worldwide, 5% of 70 M =
3.5 M AF-related strokes/yr
In the Gulf, 5% of 440 000 with AF:
22 000 AF-related strokes /yr
in Kuwait, 5% of 40 000 with AF
2 000 AF-related strokes/yr
Bernhardt P et al. JACC 2005;45:1807-12 - 2011 Canadian AF Guidelines - Chien et al. Int J Cardiol 2010; 139:173-180
GULF SAFE
Survey of Atrial Fibrillation Events (SAFE):
prospective registry from 23 Gulf hospitals
Aim:
•
•
•
characteristics
management
real life outcomes
Methods:
•
•
•
ER patients
AF on ECG >30 sec
1 yr follow-up
Dark grey. participating centres and sites
Hersi et al. J Saudi Heart Assoc 2012;24:243–252 –-- Zubaid et al. Circ CVQO 2011;4:447-482.
Gulf SAFE: Recruitment
N = 2,043
Oct 2009 - Jun 2010
69
NVAF = 1,721
379
605
459
(84%)
Valvular AF = 322
12
4
407
(16%)
Zubaid et al. Circ Cardiovasc Qual Outcomes. 2011;4:477-482
Gulf SAFE: NVAF Patients (n=1,721)
Total Cohort
N (%) except *
* Age: mean yr (SD)
Female Gender
Hypertension (diagnosed)
Diabetes
Dyslipidemia
Smoking
Previous Stroke/TIA
Coronary artery disease
Heart failure (diagnosed)
LV hypertrophy (by ECG)
Valvular heart disease
Vascular disease
Renal failure
CHADS2 median (IQR)
CHA2DS2-VASc median
(IQR)
CHA2DS2VASc 0
CHA2DS2VASc 1
CHA2DS2VASc >1
Total
59
764
1019
563
644
409
204
553
461
448
195
570
127
1
(16)
(44.4)
(59.2)
(32.7)
(37.4)
(23.8)
(11.9)
(32.1)
(26.8)
(26)
(11.3)
(33.1)
(7.4)
(1-2)
3 (1-4)
261 (16.1)
244 (15)
1119 (68.9)
1721
No warfarin at
discharge
N (%) except *
56
376
464
239
295
217
92
223
144
206
68
246
34
1
(17)
(42.9)
(53)
(27.3)
(33.7)
(24.8)
(10.5)
(25.5)
(16.4)
(23.5)
(7.8)
(28.1)
(38.8)
(1-4)
2 (1-4)
203
147
478
876
(24.5)
(17.8)
(57.7)
(51%)
Apostolakis et al. Int J Cardiol 2013; 168: 1644-1646 – Suppl data
Antithrombotic drugs in NVAF
% relative risk reduction of stroke or MACE in NVAF
%
RRR
War v
Pla
NOAC v
War v A+C
War
Asa v Pla A+C v Asa
0
19%
20
44%
40
60
80
64%
*
 20%
11%
*
*
*
* P < 0.01
Asa, aspirin. A+C, aspirin + clopidogrel. MACE, major adverse cardiovascular events. NOAC, new/non VKA oral
anticoagulants. NVAF, non valvular atrial fibrillation. Pla, placebo. RRR, relative risk reduction. War, warfarin.
Hart. J Thromb Tlysis 2008;25:26-32 – ACTIVE W. Lancet 2006;367:1903-12
ACTIVE A. NEJM 2009;360:2067-78 – Ruff et al. Lancet 2013 Dec 3
NOACs in NV atrial fibrillation – Phase III trials
2009
2010
2011
2012
2013
RE-LY
AVERROES
ENGAGE AF
dabigatran 2009
apixaban 2011
edoxaban 2013
ROCKET-AF
rivaroxaban 2011
ARISTOTLE
apixaban 2011
NOAC 4-trial Meta-analysis Full Dose
Pre-specified meta-analysis of all 71,683 patients
Stroke or Systemic Embolic events
Major Bleeding
Ruff C, et al Lancet 2014; 383: 955–62
Landmark Oral Anticoagulation Trials: Intracranial
Haemorrhage (ICH)
2x
High risk of death post-haemorrhagic stroke
ACTIVE A
Event
Ischemic
Stroke
Hemorrhagic
Stroke
Subdural
Hemorrhage
Extracranial
Hemorrhage
Weighting
1.00
3.00
0.64
0.63
Connolly et al. Ann Intern Med 2011;155:579-86
Novel Non-VKA Oral AntiCoagulants (NOACs)
TF/VIIa
X
Apixaban
Rivaroxaban
Edoxaban
IX
IXa
VIIIa
Va
Xa
II
Dabigatran
Fibrinogen
IIa
competitive
reversible univalent
blocker of active site
rapid
renally cleared
reproducible
Fibrin
Adapted from Weitz & Bates, J Thromb Haemost 2005;3:1843-53
Husted et al. Thromb Haemost 2014
Reasons to Use a Specific NOAC in NVAF?
► greater
efficacy and safety vs warfarin for SPAF ?
► approved
► full
NOAC showing lower all cause mortality vs warfarin for SPAF?
dose NOAC that does not increase GI bleeds vs warfarin?
► NOAC
with lowest renal clearance?
► comparable
► effective
to low-dose aspirin for major bleeding?
in multiple phase III SPAF trials?
► lower
discontinuation rates vs warfarin in NVAF?
► lower
discontinuation rate vs aspirin in NVAF?
► consistently
► NOAC
effective and safe in different high-risk subgroups?
found to be most cost effective for SPAF?
Guidelines for AF Management
AF = atrial fibrillation
1. ESC Guidelines: Camm AJ, et al. Eur Heart J. 2010;31:2369–429. 2. Camm AJ, et al. Europace. 2012;14(10):1385-413.
3. ACCF/AHA/HRS Guidelines: Wann LS, et al. J Am Coll Cardiol. 2011;57:1330–1337. 4. CCS Guidelines: Skanes AC, et al.
Can J Cardiol. 2012;28:125–136. 5. You JY, et al. ACCP Guidelines: Chest 2012;141;e531S–e575S;
http://www.nice.org.uk/ta249.
CHADS-VASc
ESC 2012
AHA 2014
0
none
none
1
anticoagulation
anticoagulation or
aspirin or none
>2
anticoagulation
anticoagulation
Camm AJ et al. Eur Heart J 2012;33:2719-47
January et al. Circulation 2014 March [Epub]
UK National Health System NOAC in AF Prescribing Guidelines¹ :
(Implementation of NICE Technology Appraisals 249, 256, and 275)¹
Dabigatran
Rivaroxaban
(Apixaban) Apixaban
Warfarin
No difference in efficacy of stroke No
No difference
difference in in
efficacy
of stroke Apixaban is statistically Warfarin is non-inferior to
efficacy
prevention
for
dabigatran
low-dose
prevention
for
rivaroxaban
or statistically
significantly more
effective dabigatran low dose (110mg
110mg : No difference in
significantly
(110mg twice daily), compared to dabigatran low-dose (110mg twice in preventing stroke and twice
daily)
and
to
efficacy
effectiveembolism rivaroxaban at reducing the
warfarin. Dabigatran low dose (110mg daily), compared
to warfarin. more
systemic
twice daily) is non-inferior to warfarin at Rivaroxaban is non-inferior to compared to warfarin.
risk of stroke and systemic
reducing the risk of stroke and systemic warfarin at reducing the risk of stroke
embolism in people with AF.
embolism
in
people
with
AF.
and
systemic
embolism
in
people
with
No difference in efficacy of
Stroke prevention
Dabigatran
standard
dose
(150mg
twice
AF.
stroke
prevention
for
efficacy
daily) is statistically significantly more
rivaroxaban or dabigatran
effective in preventing stroke, particularly
low-dose (110mg twice
haemorrhagic
stroke,
in
people
with
AF
daily), compared to warfarin.
150mg: statistically
with a moderate/high risk of stroke,
significantly more effective
compared to warfarin.
Risk of major
bleeding
Risk of GI
bleeding
Dabigatran low dose (110mg twice daily) There is a similar risk of major
was associated with a reduced risk of bleeding with rivaroxaban compared
similar risk
major bleeding (NNT 154 over 1 year) to warfarin.
compared with
warfarin,
no difference
though no difference was found between
dabigatran standard dose (150mg twice
daily) and warfarin in this respect.
Dabigatran standard
higherdose
risk(150mg twice
daily) causes a higher risk of GI bleeding,
and at both doses is associated with
increased GI side effects, compared to
warfarin.
risk risk of GI
Rivaroxaban higher
causes a higher
bleeding, and is associated with
increased major GI bleeding and
increased GI side effects, compared to
warfarin.
Apixaban was associated Warfarin has a similar risk of
with a reduced risk of major major bleeding compared to
bleeding
compared
to dabigatran (standard dose)
reduced risk of major and rivaroxaban.
warfarin.
bleeding
There was no difference in
the frequency of GI bleeds
with no
Apixaban
compared to
difference
warfarin.
[numerically
lower]
Lower risk of GI bleeding and
GI side effects compared to
dabigatran standard dose
(150mg
BID)
&
to
rivaroxaban.
1- NHS West Suffolk Clinical Commissioning Group NOACs in AF Prescribing Guidelines: Dabigatran, Rivaroxaban and Apixaban, the new oral anticoagulants (NOACS), for the
prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Implementation of NICE Technology Appraisals 249, 256, and 275. Available online on
http://www.westsuffolkccg.nhs.uk/wp-content/uploads/2013/01/WSCCG-NOAC-guidance-revised-November-2013.pdf
Gastrointestinal (GI) bleeding with the new oral anticoagulants
►
Compared with warfarin, rivaroxaban and dabigatran (150 mg bid) significantly increase the
risk of major GI bleeding approximately 1.5 fold and edoxaban (60 mg od) ~ 1.25 fold. Only
apixaban does not significantly alter the risk of major GI bleeding.
*
150
edoxaban 60
Desai J, Kolb JM, Weitz JI, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants – defining the issues and the management strategies.
Thromb Haemost. 2013;110:205-212. Desai J, Granger CB, Weitz JI, Aisenberg J. Novel oral anticoagulants in gastroenterology practice. Gastrointest Endosc.
2013;78:227-239. Giugliano et al. N Engl J Med 2013;369:2093-2104
UK National Health System NOAC in AF Prescribing Guidelines¹ :
(Implementation of NICE Technology Appraisals 249, 256, and 275)¹
Side-effects
Dabigatran
Rivaroxaban
(Apixaban) Apixaban
Warfarin
In clinical trials, more
patients More
stopped taking
dabigatran than warfarin
because of side effects.
Dabigatran (both doses)
caused more GI symptoms
than warfarin, e.g. dyspepsia
In clinical trials, more patients
stopped taking rivaroxaban
More
than warfarin
because of side
effects. Rivaroxaban caused
more nose bleeds and
haematuria than warfarin.
In clinical trials, fewer patients stopped taking
Apixaban than warfarin because of side
Fewer
effects.
In clinical trials, fewer
patients
discontinued
warfarin, compared to
dabigatran and rivaroxaban,
due to side effects.
The
Not known to increase the
risk of MI compared to
warfarin.
Not known to increase the risk of MI compared
to warfarin.
Not known to increase the
risk of MI compared to
dabigatran, rivaroxaban, or
Apixaban.
Apixaban is not recommended if creatinine
clearance <15mL/min. A low dose of 2.5mg
doseis of
2.5mg twice
daily with
twice daily
recommended
in patients
creatinine
clearance
15-29mL/min,
is recommended in or with a
serum creatinine ≥133micromole/L associated
patients
creatinine
with age
≥80 yearswith
or bodyweight
≤60kg, or in
patients
with at least
two of the following
clearance
15-29mL/min
characteristics: age ≥80 years, body weight
≤60kg, or serum creatinine ≥133micromole/L.
Warfarin is not contraindicated
in
renal
impairment.
standard
dose
of
small
but(150mg
significant
dabigatran
twice a
day) was
associated
increased with a
Risk of MI
Renal
impairment
small
but
significant
increased risk of MI.
For every 476 people on
dabigatran standard dose
(150mg twice daily), one
additional MI was observed.
Contraindicated if creatinine
Contraindicated
if
clearance
<30mL/min.
creatinine
Dabigatran
is clearance
principally
renally excreted;
doses
<30mL/min may
therefore accumulate and
increase the risk of bleeding.
Not known to
increase
Avoid if creatinine clearance
<15mL/min. Use with caution
if creatinine clearance 1529mL/min.
Use with caution
Not known to
increase
1- NHS West Suffolk Clinical Commissioning Group NOACs in AF Prescribing Guidelines: Dabigatran, Rivaroxaban and Apixaban, the new oral anticoagulants (NOACS), for the prevention
of stroke and systemic embolism in nonvalvular atrial fibrillation. Implementation of NICE Technology Appraisals 249, 256, and 275. Available online on
http://www.westsuffolkccg.nhs.uk/wp-content/uploads/2013/01/WSCCG-NOAC-guidance-revised-November-2013.pdf
AHA/American Stroke Association Science Advisory:
Guidelines 2012 ( endorsed by the American Academy for Neurology)
- Apixaban 5mg
- Apixaban 5mg
Apixaban
• Dabigatran 150 mg twice daily is an efficacious alternative to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF and at least 1 additional risk
factor who have CrCl >30 mL/min (Class I; Level of Evidence B). ^^ Apixaban 5 mg twice daily is an efficacious alternative to aspirin in patients with nonvalvular AF deemed unsuitable
for vitamin K antagonist therapy who have at least 1 additional risk factor and no more than 1 of the following characteristics: Age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5
mg/dL (Class I; Level of Evidence B). ^ Apixaban 5 mg twice daily is a relatively safe and efficacious alternative to warfarin in patients with nonvalvular AF deemed appropriate for
vitamin K antagonist therapy who have at least 1 additional risk factor and no more than 1 of the following characteristics: Age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5
mg/dL, (Class I; Level of Evidence B). ** In patients with nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization or ≥2
additional risk factors), rivaroxaban 20 mg/d is reasonable as an alternative to warfarin (Class IIa; Level of Evidence B).
Oral Antithrombotic Agents for the Prevention of Stroke in Nonvalvular Atrial Fibrillation: A Science Advisory for Healthcare
Professionals From the American Heart Association/American Stroke Association. Stroke. 2012;43:3442-3453
NOACs in atrial fibrillation – Phase III trials
2009
2010
2011
2012
2013
RE-LY
AVERROES
ENGAGE AF
Aug 2009
Feb 2011
Nov 2013
ROCKET-AF
Aug 2011
ARISTOTLE
Aug 2011
AVERROES: main outcomes
N=5599, blinded, War unsuitable, mn CHADS=2, BID, 1.1 yr FU, dose adj ¥
5
Aspir <325 od
%
per
yr
4
Apixa 5 bid
#
** P<0.001
#
P=0.07
3
2
**
1
0
Stro-SyEmb Maj Bleeds Total Deaths
ICH
¥ 2.5 mg if >2 of age >80 y, wgt <60 kg, serum creat >1.5 mg/dl
Connolly et al. N Engl J Med 2011;364: 806-17
Apixaban better tolerated than either Aspirin or
warfarin¹
►
“… advantage of apixaban is that it is much safer than warfarin and of comparable safety to
aspirin, and better tolerated than either aspirin or warfarin. Thus, many patients with AF
who were taking aspirin (or nothing) instead of warfarin, could switch from aspirin (or
nothing) to apixaban, with the expectation of infrequent side effects along with a similar
reduction in the rate of ischemic stroke to warfarin, and a significantly reduced risk of major
bleeding and intracranial hemorrhage compared with warfarin¹”
►
In AVERROES: significantly less discontinuation with apixaban vs ASA²
apixaban 5 mg bid
1- Potpara, TS et al. Adv Ther (2012) 29(6):491–507.
2- Connolly SJ et al. N Engl J Med. 2011;364(9):806-817.
Pharmacology of NOACs
Characteristics
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Target
IIa (thrombin)
Xa
Xa
Xa
Dose
110, 150 mg
20 (15) mg
5 (2.5) mg
30, 60 mg *
Frequency
BID
OD
BID
OD
Bioavailability
3-7%
66-100%
50%
50%
Prodrug
Yes
No
No
No
Food effect
No
+39%
No
No
Time to Cmax, h
2
2-4.5
1-3
1-2
Half-life, h
12-17
11-13
12
12
Renal elimination
80%
35%
27%
50%
Interactions
P-gp
P-gp, 30% 3A4
P-gp, 15% 3A4
P.gp, <5% 3A4
Effect of PPI
-12-30%
No
No
No
Asian ethnicity
+25%
No
No
No
Andreotti, Pafundi. Rev Esp Cardiol 2010;63:1223-9
Andreotti F. G Ital Cardiol 2014;15:11-16
Choice of apixaban BID in all studied indications based on clear
rationale: to maximise efficacy without increasing bleeding risk
40
VTE and all-cause death
Incidence (%)
35
Total bleeding
Apixaban OD
30
Apixaban BD
25
Enoxaparin 30 mg BD
Warfarin INR 2–3
20
15
10
5
0
OD BDOD BD OD BD Enox Warf
Daily dose (mg) 5 2.5 10 5 20 10
Enox=Enoxaparin; Warf=Warfarin.
Error bars show 95% CIs
OD BDOD BD OD BD Enox Warf
5 2.5 10 5 20 10
Lassen et al. The efficacy and safety of apixaban, an oral, direct factor Xa
inhibitor, as thromboprophylaxis in patients following total
knee replacementJ Thromb Haemost. 2007;5:2368-75
BID advantage: Reduced Variability T1/2=12 h; Tmax=3 h
Concentration
Concentration
Steady state
Dose X once daily (QD)
Dose X/2 twice daily (BID)
5
6
7
Day
8
One missed BID dose
9
5
10
6
7
8
9
10
8
9
10
Day
One missed QD dose ~ three missed
BID doses
Concentration
Concentration
One extra dose
One extra dose
5
6
7
Day
8
9
10
5
6
7
Day
MWV adherence knowledge centre
ARISTOTLE: main outcomes
N=18000, blinded, mn CHADS=2.1, BID, 1.8 yr FU, dose adj #, mn TTR 62%
5
%
per
yr
4
Warfarin
*
Apixaban 5
** P<0.001
* P<0.05
3
2
**
*
1
**
0
Stro-SyEmb Maj Bleeds Total Deaths
ICH
# 2.5 mg if >2 of age >80 y, wgt <60 kg, serum creat > 1.5 mg/dl
Granger et al. N Engl J Med 2011;365:981-92
RE-LY: main outcomes
N=18000, open v War, mn CHADS=2.1, BID, 2 yr FU, no dose adj, mn TTR 64%
5
% 4
per
yr 3
**
*
P<0.001
P=0.051
**
*
Warfarin
Dabi 110
Dabi 150
2
1
**
**
**
0
Stro-SyEmb
Maj Bleed
Tot Death
Connolly et al. N Engl J Med 2009;361:1139-51
ICH
ROCKET AF: main outcomes
N=14000, blinded, mn CHADS=3.5, 0D, 2 yr FU, renal dose adj #, mn TTR 55%
5
%
per
yr
4
* P=0.02
** P=0.01
Warfarin
¥
Rivaroxa 20
3
2
**
1
*
0
St-SEmb St-SEmb
ITT
OT
Major
Bleeds
Total
Deaths
ICH
# 15 mg if Cr Cl 30-49 ml/min; ITT = intention to treat analysis; OT = on treatment prespecified analysis
¥ fewer fatal bleeds with rivaroxaban v warfain, P=0.003
Patel et al. N Engl J Med 2011;365:883-91
ENGAGE: main outcomes
N=21105, blinded, mn CHADS=2.8, OD, 2.8 yr FU, dynamic dosing #, mn TTR 65%
5
%
per
yr
4
P<0.001
** P=0.006
*
3
*
**
**
Warfarin
Edoxa 30 od
Edoxa 60 od
2
**
**
1
0
Stro-SyEmb
Maj Bleed
Tot Death
ICH
# half dose if >1 of Cr Cl 30-50 ml/min; wgt <60kg; verapamil, dronedarone, quinidine
Giugliano et al. N Engl J Med 2013;369:2093-5104
Only apixaban demonstrates superiority versus warfarin
for both reduced Stroke/SE and Major Bleeding
Cost effectiveness: based on its clinical profile, apixaban could offset
potential direct medical costs in both the short and long term
► Annual
and lifetime direct medical costs offset with apixaban
per 1,000 patients1*
Cost Offset
(CE model)
£1,289k
Time horizon
Annual†
Lifetime
£574k
£279k
£270k
£152k
£95k
£39k
Apixaban vs. VKA
Apixaban vs. ASA
£17k
Apixaban vs.
Rivaroxaban
Apixaban vs. Dabigatran
*Switch from Dabigatran 150 to Dabigatran 110 in patients more than 80 years old; †Costs annualised from 2-year horizon of Global Apixaban Cost Effectiveness Model (Data on File).
Dorian et al. Eur Heart J 2014;35:1897-1906
Lip et al. Clin Ther 2014;35:192-210
Clemens et al. PLOS One 2014;9:e99276
Concluding Remarks: Reasons to Use Apixaban?
► greater
efficacy and safety vs warfarin for SPAF
► approved
► full
NOAC showing lower all cause mortality vs warfarin for SPAF
dose NOAC that does not increase GI bleeds vs warfarin
► NOAC
with lowest renal clearance
► comparable
► effective
to low-dose aspirin for major bleeding
in two phase III SPAF trials
► lower
discontinuation rates vs warfarin in NVAF
► lower
discontinuation rate vs aspirin in NVAF
► consistently
► NOAC
effective and safe in different high-risk subgroups
found to be most cost effective for SPAF
Acute and Extended VTE Treatment Trials
Apixaban is approved in VTE Tx. by FDA, EMA
& file being processed for SFDA
Trial
Design
Drug
Comparator
Patients
Extended
Acute VTE`
Duration
Primary Outcome
(Recurrent VTE)
Major
Bleeding
Drug vs comp (%), P-value
RE-COVER
Double blind
6 mos
LMWH or UFH, then
Dabi 150 mg BID
LMWH or UFH + 2539
Warfarin
acute VTE
2.4 vs 2.1
P<0.001 (NI)
1.6 vs 1.9
P=0.38
RE-COVER II
Double blind
6 mos
LMWH or UFH, then
Dabi 150 mg BID
LMWH or UFH + 2568
Warfarin
acute VTE
2.4 vs 2.2
P<0.001 (NI)
1.2 vs 1.8
P=0.26
EINSTEIN
DVT
Open label
3, 6, or 12 mos
Riva 15 mg BID for
21 D, then 20 mg QD
Enoxa + VKA
3449
acute DVT
2.1 vs 3.0
P<0.001 (NI)
0.8 vs 1.2
P=0.21
EINSTEIN PE
Open label
3, 6, or 12 mos
Riva 15 mg BID for
21 D, then 20 mg QD
Enoxa + VKA
4833
acute PE
2.1 vs 1.8
P=0.0026 (NI)
1.1 vs 2.2
P=0.0032
AMPLIFY
Double blind
6 mos
Apixa 10 mg BID for
7 D, then 5 mg BID
Enoxa +
Warfarin
5395
acute VTE
2.3 vs 2.7
Ongoing
P=0.0001 (NI)
0.6 vs 1.8
Ongoing
HOKUSAI
Double blind
<12 mos
LMWH or UFH, then
Edoxaban 60 mg QD
LMWH or UFH + 8240
Warfarin
acute VTE
3.2 vs 3.5
1.4 vs 1.6
P<0.001 (NI)
P=0.35
RE-MEDY
Double blind
up to 36 mos
Dabi 150 mg BID
Warfarin
INR 2.0-3.0
2856
pre-tx 3-12 mos
1.8 vs 1.3
P=0.03 (NI)
0.9 vs 1.8
P=0.058
RE-SONATE
Double blind
6 mos
Dabi 150 mg BID
Placebo
1343
pre-tx 6-18 mos
0.4 vs 5.6
P<0.0001
0.3 vs 0
P=0.996
EINSTEIN
Extension
Double blind
6-12 mos
Riva 20 mg QD
Placebo
1196
pre-tx <12 mos
1.3 vs 7.1
P<0.001
0.7 vs 0
P=0.11
AMPLIFY
Extension
Double blind
12 mos
Apixa 2.5 mg BID or
Apixa 5 mg BID
Placebo
2482
pre-tx 6-12 mos
ongoing
P‹0.001(superiority)
3.8 vs 11.6
P=0.0001(superiority)
0.2 vs 0.5
ongoing
Not increased
Thank You
Gulf SAFE – NVAF Results & Conclusions
•
•
NVAF affects relatively young, high risk people
Despite the young age, outcomes are not favourable, with
thromboembolic event rates of 4.1 per 100 patient years
•
As in other registries, many eligible patients (ie, CHADS-VASc
>1) did not receive anticoagulation
Apostolakis et al. Int J Cardiol 2013; 168: 1644-1646
Apixaban in Patients with AF &
high CHADS or CHADS-VASc
kidney disease
older age
prior stroke
heart failure
+ or - Aspirin
ARISTOTLE: Stroke or systemic embolism according
to baseline risk scores
Apixaban
No. of patients
Warfarin
Hazard Ratio (95% CI)
P value
%/yr (No. of events)
CHADS2
Interaction: 0.4457
1
6183
0.74% (44)
0.87% (51)
2
6516
1.24% (74)
1.37% (82)
≥3
5502
1.95% (94)
2.80% (132)
CHA2DS2VASc
Interaction: 0.1210
1
1604
0.62% (10)
0.53% (8)
2
3771
0.85% (30)
0.67% (24)
≥3
12,826
1.48% (172)
2.03% (233)
HAS-BLED
Interaction: 0.9422
0-1
7461
0.92% (65)
1.14% (79)
2
6568
1.39% (83)
1.81% (109)
≥3
4172
1.73% (64)
2.14% (77)
18,201
1.27% (212)
1.60% (265)
Overall
0.0114
0.25
From Lopes et al. Lancet. 2012; e-pub October 02
0.5
Apixaban better
1.00
2.0
Warfarin better
4.0
ARISTOTLE: Major bleeding according to baseline
risk scores
Apixaban
No. of patients
Warfarin
Hazard Ratio (95% CI)
P value
%/yr (No. of events)
CHADS2
Interaction: 0.4018
1
6169
1.38% (76)
2.34% (126)
2
6492
2.30% (125)
3.03% (163)
≥3
5479
2.88% (126)
4.15% (173)
CHA2DS2VASc
Interaction: 0.2059
1
1602
0.80% (12)
1.21% (17)
2
3759
1.26% (42)
2.48% (82)
≥3
12,779
2.60% (273)
3.55% (363)
HAS-BLED
Interaction: 0.7127
0-1
7433
1.36% (89)
2.16% (137)
2
6544
2.25% (123)
3.23% (175)
≥3
4163
3.46% (115)
4.70% (150)
18,140
2.13% (327)
3.09% (462)
Overall
<0.0001
0.25
From Lopes et al. Lancet. 2012; e-pub October 02
0.5
Apixaban better
1.00
2.0
Warfarin better
4.0
ARISTOTLE: Intracranial bleeding according to
baseline risk
Apixaban
No. of patients
Warfarin
Hazard Ratio (95% CI)
P value
%/yr (No. of events)
CHADS2
Interaction: 0.1775
1
6169
0.27% (15)
0.60% (33)
2
6492
0.38% (21)
0.64% (35)
≥3
5479
0.36% (16)
1.27% (54)
CHA2DS2VASc
Interaction: 0.8478
1
1602
0.20% (3)
0.35% (5)
2
3759
0.27% (9)
0.57% (19)
≥3
12,779
0.37% (40)
0.94% (98)
HAS-BLED
Interaction: 0.0604
0-1
7433
0.35% (23)
0.53% (34)
2
6544
0.38% (21)
0.96% (53)
≥3
4163
0.23% (8)
1.07% (35)
18,140
0.33% (52)
0.80% (122)
Overall
<0.0001
0.01
Adapted from Lopes et al. Lancet. 2012; 2012; e-published October 02,
http://dx.doi.org/10.1016/S0140-6736(12)60986-6.
0.1
Apixaban better
1.00
10
Warfarin better
ARISTOTLE: Apixaban more effective and associated with less major
bleeding than warfarin across all ranges of eGFRs
Apixaban
Warfarin
Hazard Ratio (95% CI)
P value
%/yr (No. of events)
Stroke / SE
Interaction: 0.705
eGFR >80 mL/min1
0.99% (70)
1.12% (79)
eGFR >50-80 mL/min2
1.24% (87)
1.69% (116)
eGFR ≤50 mL/min3
2.11% (54)
2.67% (69)
Major Bleeding
Interaction: 0.03
eGFR >80 mL/min1
1.46% (96)
1.84% (119)
eGFR >50-80 mL/min2
2.45% (157)
3.21% (199)
eGFR ≤50 mL/min3
3.21% (73)
6.44% (142)
All-cause death
Interaction: 0.627
eGFR >80 mL/min1
2.33% (169)
2.71% (195)
eGFR >50-80 mL/min2
3.41% (244)
3.56% (251)
eGFR ≤50 mL/min3
7.12% (188)
8.30% (221)
1n=7518
(41%); 2n=7587 (42%); 3n=3017 (17%)
Results were consistent regardless of methods for GFR estimation
0.25
0.5
Apixaban better
1.00
2.0
Warfarin better
Honhloser s. h., Hijazi Z, Thomas L . et al.Efficacy of Apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the
ARISTOTLE trial . European Heart Journal. Presented at the ESC meeting on Wednesday August 29, 2012 - http://spo.escardio.org/eslides/view.aspx?eevtid=54&fp=5172
ARISTOTLE Subgroup Analysis: (Age Groups)
Stroke/Systemic Embolism & Major Bleeding
•
median age was 70 years old
Subgroup
Age (years)
All patients
No. of
Patients
18,201
Apixaban
Warfarin
No. of Events (%/year)
212 (1.27)
HPfizerard Ratio
(95%CI)
P Value for
Interaction
265 (1.60)
Stroke/Systemic Embolism
0.12
<65
5471
51 (1.0)
44 (0.9)
65–74
7052
82 (1.3)
112 (1.7)
75
5678
79 (1.6)
109 (2.2)
Major Bleeding
0.64
<65
5455
56 (1.2)
72 (1.5)
65–74
7030
120 (2.0)
166 (2.8)
75
5655
151 (3.3)
224 (5.2)
0.25
0.5
Apixaban
Better
Granger CB et al. N Engl J Med. 2011;365(11):981-992.
1
2
Warfarin
Better
ARISTOTLE Sub-analysis in Patients With
Prior Stroke/TIA: Stroke or Systemic Embolism
• 19% of patients had a prior stroke or TIA
-
Stroke or SE Probability (%)
-
The effects of Apixaban vs. Warfarin were consistent in patients with & without previous stroke or TIA.
Patients with prior stroke/TIA were more likely to have a stroke or systemic embolism (HR 2.52, 95% CI,
2.09–3.04). Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the
absolute benefits of Apixaban might be greater in this population
8
Warfarin/Prior Stroke
3.24%/year
6
Apixaban/Prior Stroke
2.46%/year
HR 0.76 (0.56–1.03)
4
Warfarin/No Prior Stroke
2
Apixaban/No Prior Stroke
0
0
6
12
18
24
30
Time Since Randomization (months)
Easton JD et al. Lancet Neurol. 2012;11(6):503-511. Easton J.D., Lopes, R. D , Bahit M C . et al. Apixaban compared with warfarin in patients
with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol
2012;11:503-11.
43
AHA/ASA Guidelines for the Prevention of Stroke in Patients With
Prior Stroke or Transient Ischemic Attack (May 2014)¹
( endorsed by the American Academy for Neurology)
1. VKA therapy (Class I; Level of Evidence A), Apixaban (Class I; Level
of Evidence A), and dabigatran (Class I; Level of Evidence B) are all
indicated for the prevention of recurrent stroke in patients with
nonvalvular AF, whether paroxysmal or permanent.
2. The selection of an antithrombotic agent should be individualized on the
basis of risk factors, cost, tolerability, patient preference, potential for drug
interactions, and other clinical characteristics, including renal function
and time in INR therapeutic range if the patient has been taking VKA
therapy.
3. Rivaroxaban is reasonable for the prevention of recurrent stroke in
patients with nonvalvular AF (Class IIa; Level of Evidence B).
1- From Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke
Association. Stroke. 2014;45:2160-2236
Concluding Remarks: Reasons to Use Apixaban?
► greater
efficacy and safety vs warfarin for SPAF
► approved
► full
NOAC showing lower all cause mortality vs warfarin for SPAF
dose NOAC that does not increase GI bleeds vs warfarin
► NOAC
with lowest renal clearance
► comparable
► effective
to low-dose aspirin for major bleeding
in two phase III SPAF trials
► lower
discontinuation rates vs warfarin in NVAF
► lower
discontinuation rate vs aspirin in NVAF
► consistently
► NOAC
effective and safe in different high-risk subgroups
found to be most cost effective for SPAF
ARISTOTLE: Major outcomes in patients with and without previous
stroke or TIA within 30 days
•
Previous stroke or TIA: apixaban, n=109; warfarin, n=125
Apixaban
(N=9120)
Warfarin
(N=9081)
Hazard Ratio (95% CI)
P value for
interaction
No. of events (%/yr)
Stroke / SE
0.69
Previous stroke or TIA ≤30 days
2.78 (5)
4.55 (9)
No previous stroke or TIA >30 days
2.44 (68)
3.14 (89)
Major bleeding
0.70
Previous stroke or TIA ≤30 days
4.88 (8)
5.69 (10)
No previous stroke or TIA >30 days
2.71 (69)
3.79 (96)
0.125
0.25
0.5
1.0
2.0
Apixaban better Warfarin better
Easton J.D., Lopes, R. D , Bahit M C . et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or
transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11:503-11.
ARISTOTLE: Major outcomes stratified by heart failure
• ~30% of patients had heart failure
Granger et al. N Engl J Med 2011;365:981-92
Benefits of Apixaban Compared With Warfarin Were Consistent for Patients Whether
They Were Taking ASA or Not (ARISTOTLE Sub-analysis of ASA Use)
Apixaban
(%/yr)
Warfarin
(%/yr)
Stroke or
Systemic Embolism
1.12
1.11
1.91
1.32
0.11
Ischemic Stroke
0.79
0.83
1.14
0.83
0.20
Death
1.93
1.64
1.82
1.97
0.29
Myocardial Infarction
0.90
0.40
0.74
0.51
0.17
ISTH Major Bleeding
3.10
1.82
3.92
2.78
0.26
•4434 continued ASA
(24% of ALL patients)
Hemorrhagic Stroke
0.27
0.22
0.68
0.42
0.59
Major or CRNM Bleeding
5.54
3.59
7.18
5.58
0.12
Any Bleeding
•Baseline Characteristics
on Day 1, those on ASA
vs not on ASA:
•51% history of CAD (vs
32%)
•24% prior MI (vs 11%)
22.6
16.6
32.8
23.7
0.82
Event
Adjusted HR
(95% CI)
0.125
Alexander JH et al. Eur Heart J. 2013 Oct 20. 10.1093/eurheartj/eht445
0.25
0.5
Apixaban
Better
Interaction
P value
1
2
Warfarin
Better
4
+ Aspirin
No Aspirin
Gulf SAFE: Hospital
Characteristics (n=23)
Hospital type
Secondary
14 (61%)
Tertiary
9 (39%)
University
5 (22%)
Available anti-arhythmics
Amiodarone
23 (100%)
Propafenone
12 (52%)
Flecanide
9 (39%)
Dedicated anticoagulation clinic
7 (30%)
EP lab on site
5 (22%)
Internists & Cardiologists
admitting
13 (57%)
Internists & Cardiologists
managing
6 (26%)
Zubaid et al. Circ Cardiovasc Qual Outcomes. 2011;4:477-482