SESSION 3 Presenter Disclosure Information
Transcript of SESSION 3 Presenter Disclosure Information
SESSION 311 am – 12:30 pm
NOACs in Atrial Fibrillation
SPEAKERChristian T. Ruff, MD, MPH
Presenter Disclosure InformationThe following relationships exist related to this presentation:
► Christian T. Ruff, MD, MPH: Advisory Boards for Bayer; Boehringer IngelheimPharmaceuticals, Inc.; Daiichi Sankyo; and Portola. Contracted Research for Daiichi Sankyo.
Off-Label/Investigational Discussion
►In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.
NOACs for Stroke Prevention in AF
Christian T. Ruff, MD, MPHTIMI Study Group
Brigham and Women’s HospitalHarvard Medical School
Boston, MA
Atrial Fibrillation: An Epidemic
Age-Adjusted Global Incidence AF Related Mortality
Sumeet S. Chugh et al. Circulation. 2014; 129:837-847.
100% 50% 0% -50% -100%
AFASAK-1 (671)
SPAF (421)
BAATAF (420)
CAFA (378)
SPINAF (571)
EAFT (439)
All Trials (n=6)
Warfarin Better Warfarin Worse
64%
Stroke Prevention in AF Warfarin vs. Placebo
Hart RG, et al. Ann Intern Med 2007;146:857-867. Gladston, DJ, et al. Stroke 2009;40:235-40
Subtherapeutic INR 29%
INR in range10%
No warfarin61%
AF Patients with Stroke with no Known Contraindication to Anticoagulation
Preventable Strokes
Dabigatran
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
Adapted from: Weitz JI, Bates SM. J Thromb Haemost 2005;3:1843-1853.
RivaroxabanApixabanEdoxaban
Non-Vitamin K Antagonist K Oral AnticoagulantsComparative PK/PD of NOACs
Dabigatran Rivaroxaban Apixaban Edoxaban
TargetIIa
(thrombin)Xa Xa Xa
Hours to Cmax 1-3 2-4 3-4 1-2
Half-life, hours 12-17 5-13 12 10-14
Renal Clearance, % 80 33* 27 50
Transporters P-gp P-gp P-gp P-gp
CYP Metabolism, %
None 32 <32 <4CYP = cytochrome P450; P-gp = P-glycoprotein
Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011Weinz et al. Drug Dispos Metab 2009;37:1056–1064 ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; abstractOgata, et al. J Clin Pharmacol 2010;50:743–753Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342Bathala, et al. Drug Metab Dispos 2012;40:2250–2255
*33% renally cleared; 33% excreted unchanged in urine
Pivotal Warfarin-Controlled TrialsStroke Prevention in AF
Trial of Warfarin vs. Placebo1989-1993
RE-LY(Dabigatran)
2009
ROCKET AF (Rivaroxaban)
2010
ARISTOTLE(Apixaban)
2011
ENGAGE AF-TIMI 48(Edoxaban)
2013
Warfarin vs. Placebo2,900 Patients
NOACs vs. Warfarin71,683 Patients
NOACs vs. Warfarin
Hemorrhagic
50%
Stroke
Ischemic
Similar
Major Bleeding
14% 25%
Ruff CT, et al. Lancet 2014;383:955-962
Fatal or Life-Threatening GI Bleeding
p=0.030 for HD-E vs. Warfarinp=0.000 for LD-E vs. Warfarinp=0.000 for HD-E vs. LD-E
p=0.043 for HD-E vs. Warfarinp=0.005 for LD-E vs. Warfarinp=0.037 for HD-E vs. LD-E
Major
Cu
mu
lati
ve h
azar
d
Years
Life‐Threatening or Fatal
Cu
mu
lati
ve h
azar
d
Years
Aisenberg J, et al. AHA 2015
≥66% 0.82 (0.71 - 0.95)
<66% 0.77 (0.65 - 0.92)
Experienced 0.85 (0.70 - 1.03)
Naive 0.75 (0.66 - 0.86)
3-6 0.80 (0.72 - 0.89)
2 0.86 (0.70 - 1.05)
0-1 0.75 (0.54 - 1.04)
>80 0.98 (0.79 - 1.22)
50-80 0.75 (0.66 - 0.85)
<50 0.79 (0.65 - 0.96)
Yes 0.86 (0.76 - 0.98)
No 0.78 (0.66 - 0.91)
Male 0.84 (0.75 - 0.94)
Female 0.78 (0.65 - 0.94)
≥75 0.78 (0.68 - 0.88)
<75 0.85 (0.73 - 0.99)
Center-Based TTR
VKA Status
CHADS2 Score
CrCl
Gender
Age
Risk Ratio (95% CI)
p=0.60
p=0.31
p=0.76
p=0.12
p=0.30
p=0.52
p=0.38
P-Interaction
Favors NOAC Favors Warfarin0.5 1 2
Prior Stroke or TIA
Yes
NoDiabetes
0.80 (0.69 - 0.93)
0.83 (0.74 - 0.93) p=0.73
Subgroups: Stroke or SEE
Ruff CT, et al. Lancet 2014;383:955-962
Center-Based TTR
VKA Status
CHADS2 Score
CrCl
Gender
Age
Favors NOAC0.2 0.5 1 2
Favors Warfarin
Prior Stroke or TIA
Diabetes
Male
Female
≥75
<75
Yes
No
≥66%
<66%
Experienced
Naive
3-6
2
0-1
>80
50-80
<50
Yes
No
p=0.022
p=0.78
p=0.09
p=0.57
p=0.70
p=0.29
p=0.28
0.93 (0.76 - 1.13)
0.69 (0.59 - 0.81)
0.87 (0.70 - 1.08)
0.84 (0.76 - 0.93)
0.86 (0.71 - 1.04)
0.88 (0.65 - 1.20)
0.60 (0.45 - 0.80)
0.85 (0.66 - 1.10)
0.91 (0.76 - 1.08)
0.74 (0.52 - 1.05)
0.89 (0.77 - 1.02)
0.85 (0.72 - 1.01)
0.90 (0.72 - 1.12)
0.75 (0.58 - 0.97)
0.93 (0.74 - 1.17)
0.79 (0.67 - 0.94)
Risk Ratio (95% CI) P-Interaction
p=0.12
0.90 (0.78 - 1.04)
0.71 (0.54 – 0.93)
Subgroups: Major Bleeding
Ruff CT, et al. Lancet 2014;383:955-962
What is the definition of non-valvular AF?
Have NOACs expanded our treatment of vulnerable patients [frail / fall risk] previously not prescribed warfarin?
Can we use aspirin to prevent strokes?
Subclinical AF: How much AF warrants anticoagulation?
Do we need to monitor NOACs levels or anticoagulant activity?
Are there relevant drug interactions to be aware of when using NOACs?
How do we optimize combination antithrombotic therapy in patients with AF + ACS/PCI?
How to prevent and manage bleeding with NOACs and the role for specific reversal agents?
Translating Clinical Trials into Real World Practice:Current Challenges & Opportunities
ESC 2016 Update AF Guidelines
What do Guidelines Say About “Non-Valvular AF”
Absence of moderate or severe rheumatic valvular disease (mitral stenosis) or mechanical heart valve.
Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of prin]January CT et al. J Am Coll Cardiol. 2014;64:e1-76
2014 AHA/ACC/HRS AF Guidelines
Absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.
Hohnloser SH and Lopes RD. Eur Heart J. 2014;35:3323-5Renda G et al. J Am Coll Cardiol. 2016;67(13S):2194-2194.
Outcomes in Patients with and without Valvular Heart Disease: Meta-Analysis
Stroke or Systemic Embolism
Major bleeding
Rivaroxaban1
Apixaban1
Dabigatran 150 mg1
Dabigatran 110 mg1
Rivaroxaban1
Apixaban1
Dabigatran 150 mg1
Dabigatran 110 mg1
Interaction P value
P=NS
P=NS
P=NS
P=NS
P=NS
P=NS
P=NS
P=0.034
0.5 2.01.0
Nonvalvulardisease
Valvular disease
Edoxaban2 P=NS
Edoxaban2P=NS
Many patients with clinically significant valvular heart disease were included in clinical trials.
If the valve disease itself necessitates anticoagulation use VKA
If the valve disease does not warrant anticoagulation, you can use any anticoagulant (VKA or NOAC)
Conclusions
Eikelboom JW et al. N Engl J Med. 2013;369:1206-14.
Thrombus on prosthetic valve
Phase 2 dose-finding trial of dabigatran in pts with mechanical valves,150-330 mg bid, adjusted based on renal function and results of Hemoclot
Trial terminated early after enrolment of 252 pts because excess thromboembolic and bleeding events with dabigatran. Ischemic/unspecified stroke occurred in 9 pts with dabigatran and in no warfarin pts; major bleeding in 7 (4%) and 2 pts (2%).
Most clinical outcome events occurred in the group enrolled just after valve replacementrather than those enrolled ≥3 months after surgery
100
0.8
0.6
0.4
0.2
0
First Bleeding Event
0 50 100 150 200 250 300 350 400
Days
Dabigatran
Warfarin
Event-free survival from the first bleeding event (P=0.01)
RE-ALIGN extension trial
100
0.8
0.6
0.4
0.2
0
Pro
bab
ility
of
No
Eve
nt
First Thromboembolic Event
0 50 100 150 200 250 300 350 400
Days
DabigatranWarfarin
Event-free survival from stroke, systemic embolism, TIA, MI or death (P=0.24)
RE-ALIGN extension trial
RE-ALIGN: Warfarin vs. Dabigatran in Patients with Mechanical Heart Valves
Tissue factor
Xa
Thrombin
Contact
(stents, valves,catheters)
VIIaXIIaXIa
(plaque rupture)
Clot formation
Intrinsic Pathway
Common Pathway
Extrinsic Pathway
Activation of the Coagulation Cascade Failure to Treat Patients with AF
Hsu JC, et al. JAMA Cardiol 2016; 1(1):55-62
NCDR PINNACLE Registry
Benefit of NOACs in Patients at Risk of Falls
Steffel J, et al. J Am Coll Cardiol. 2016; 68(11):1169-1178
AVERROES: The End for Aspirin
Stroke or SEE Major Bleeding
HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75)
Aspirin
Apixaban
P<0.001
0 3 6 9 12 18
0.05
0.04
0.03
0.02
0.01
0.00
Aspirin
Apixaban
P<0.001
0 3 6 9 12 18
0.020
0.015
0.010
0.005
0.000
Connolly SJ, et al. N Engl J Med 2011;364(9):806-17
We are still failing to anticoagulate high-risk patients.
Frailty / fall risk is not an appropriate reason to withhold anticoagulation: The have the greatest absolute benefit!
Aspirin has no role for stroke prevention in patients with AF. It is not effective and not any safer than NOACs.
Conclusions
Healey JS, et al. NEJM. 2012; 366:120-129
Str
ok
e o
r S
yste
mic
Em
bo
lism
Years
Atrial Tachyarrhythmia > 6 min ≤ 3 Months After Pacemaker or Defibrillator Implantation
Subclinical AF and Stroke Risk
Temporal Relationship Between SCAF & Stroke
Brambatti M, et al. Circulation. 2014;129(21):2094-2099
Relative risk of ischemic stroke appears increased for SCAF.
There is a gradient of absolute risk that correlates with AF burden.
Large clinical trials are needed to define optimal treatment of these patients.
Subclinical AF and Stroke
Eikelboom JW, et al. Circulation. 2011;123:2363-72Reilly , PA ,et al. J Am Coll Cardiol. 2014;63:321-8
Dabigatran 110 mg vs. warfarin
Dabigatran 150 mg vs. warfarin
Total rate (% per year)
# PTS D110 D150 WAR
Overall 18113 2.87 3.31 3.57
Age <65 2971 0.82 0.89 2.43
Age 65–74 7884 2.29 2.6 3.25
Age ≥75 7258 4.43 5.1 4.37 0.0003 0.0001
Dabigatran trough concentration steady state (ng/mL)
16
14
12
10
8
6
4
2
00 50 100 150 200 250 300
Pro
bab
ilit
y m
ajo
r b
leed
(%
)
65 years75 years85 years
16
14
12
10
8
6
4
2
00 50 100 150 200 250 300
Pro
bab
ilit
y is
chae
mic
str
oke
/SE
E (
%)
0.50 1.00 1.50Dabigatran better Warfarin better
0.50 1.00 1.50
Dabigatran better Warfarin better
P-value (interaction)
P-value (interaction)
Do We Need to Monitor NOAC Levels? Dose Reductions
RE‐LY1 ARISTOTLE3 ENGAGE‐AF4
•60→30 mg QD or 30→15 mg QD for:
– Creatinineclearance30–50 mL/min
– body weight≤60 kg
– Use of quinidine, verapamil or dronedarone
• 5→2.5 mg BID for ANY TWO of:
– Age≥80 years
– body weight≤60 kg
– Serum creatinine≥1.5 mg/dL
•None
ROCKET‐AF2
• 20→15 mg QD for:
– Creatinineclearance<30–49 mL/min
1. Connolly et al. N Engl J Med 2009;361:1139–11512. Patel et al. N Engl J Med 2011;365:883–8913. Granger et al. N Engl J Med 2011;365:981–9924. Giugliano RP et al. N Engl J Med 2013;369:2093-2104
Stroke or SEE (% / Year)
1.29
2.21
1.00
1.79
0.0
0.5
1.0
1.5
2.0
2.5
48.5Edox Conc (ng/mL) 0.85Anti-Fxa (IU/mL)
No Edoxaban Dose Reduction Edoxaban Dose Reduced
Warfarin HD Edox60 mg
Warfarin HD Edox30 mg
NANA
34.60.64
NANA
Higher-Dose Edoxaban vs. WarfarinNo Dose Reduction: HR 0.78 (0.61 - 0.99)Dose Reduction: HR 0.81 (0.58 - 1.13)
Pinteraction = 0.85
HD = Higher-DoseEdox = Edoxaban
3.02
4.85
2.663.05
0.0
1.0
2.0
3.0
4.0
5.0
6.0
48.5Edox Conc (ng/mL) 0.85Anti-Fxa (IU/mL)
No Edoxaban Dose Reduction Edoxaban Dose Reduced
Warfarin HD Edox60 mg
Warfarin HD Edox30 mg
NANA
34.60.64
NANA
HD = Higher-DoseEdox = Edoxaban
Major Bleed (% / Year)Higher-Dose Edoxaban vs. WarfarinNo Dose Reduction: HR 0.88 (0.76 - 1.03)Dose Reduction: HR 0.63 (0.50 - 0.81)
Pinteraction = 0.02
48.5 ± 45.8
34.6 ± 30.9
0
10
20
30
40
50
60
0.85 ± 0.76
0.64 ± 0.54
0.00
0.20
0.40
0.60
0.80
1.00
ng
/ mL
IU /
mL
No DR60 mg
DR30 mg
No DR60 mg
DR30 mg
Mean Edoxaban Trough Concentration
Mean Trough Anti-FXa Activity
Edoxaban Concentration & Anti-FXa Activity
DR, dose reduction Ruff CT, Lancet 2015;385:2288–95
Stroke or SEE (% / Year)
1.29
2.21
1.00
1.79
1.38
2.36
0.0
0.5
1.0
1.5
2.0
2.5
48.5 24.5Edox Conc (ng/mL) 0.85 0.44Anti-Fxa (IU/mL)
No Edoxaban Dose Reduction Edoxaban Dose Reduced
Warfarin HD Edox60 mg
LD Edox30 mg
Warfarin HD Edox30 mg
LD Edox15 mg
NA
NA
34.6 16.0
0.64 0.35NA
NA
HD = High DoseLD = Low DoseEdox = Edoxaban
Ruff CT, Lancet 2015;385:2288–95
~40%
Drug‐drug Interactions With NOACsMechanism of Action Dabigatran Rivaroxaban Apixaban Edoxaban
Dronedarone P‐gp inhibitorNo specific
recommendationsNo specific
recommendations
Clarithromycin Strong inhibition of CYP3A4 and P‐gpNo specific
recommendations
Itraconazole Strong inhibition of CYP3A4 and P‐gp Avoid useNo specific
recommendations
Ketoconazole Strong inhibition of CYP3A4 and P‐gpWith CrCl 30‐50
ml/min reduce dose to 75 mg twice daily
Avoid useNo specific
recommendations
Ritonavir Strong inhibition of CYP3A4 and P‐gp Avoid useNo specific
recommendations
Carbamazepine Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid useNo specific
recommendations
Phenytoin Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid useNo specific
recommendations
Rifampin Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid use Avoid use
St. John’s wort Strong inducer of CYP3A4 and P‐gp Avoid use Avoid use Avoid useNo specific
recommendations
Kovacs RJ, et al. J Am Coll Cardiol. 2015.Red: Avoid Yellow: Reduced Dose Green: OK to use
Dosing based on clinical features alone optimizes efficacy/safety for most patients.
Dose adjustment based on drug levels or anticoagulant actively will be challenging and needs to be prospectively tested.
Systemic under-dosing of NOACs a major problem that will lead to unnecessary strokes.
Drug-drug interactions far less common than warfarin :
Know drug classes to potentially avoid [anticonvulsants, antivirals, and antifungals]Others don’t warrant dose reduction on their own.
Conclusions
Providing the best protection for patients with AF and PCI/ACS
NVAF PCI/ACS NVAF and PCI/ACS
BOTH anticoagulant and dual antiplatelet
therapy = ‘triple therapy’
?
Antiplatelet therapy
High sheer stress thrombosis – platelet mediated in the arteries
Dual antiplatelet therapy superior to ASA alone
Anticoagulant therapy
Low sheer stress thrombosis in left atrium
NVAF and ACS / PCI:A Broad Spectrum of Options
• ASA alone• Clopidogrel alone• Ticagrelor alone• Warfarin alone• NOAC alone
• ASA + warfarin• Clopidogrel + warfarin• Prasugrel + warfarin• Ticagrelor + warfarin• ASA + NOAC• Clopidogrel + NOAC (low dose)• Clopidogrel + NOAC (high dose)• Prasugrel + NOAC• Ticagrelor + NOAC
• ASA + clopidogrel + warfarin• ASA + prasugrel + warfarin• ASA + ticagrelor + warfarin• ASA + clopidogrel + NOAC
(low dose)• ASA + clopidogrel + NOAC
(high dose)• ASA + prasugrel + NOAC• ASA + ticagrelor + NOAC
• ASA + clopidogrel• ASA + prasugrel• ASA + ticagrelor
RE-LY: Bleeding with Antiplatelet Therapy
Dans AL, et al. Circulation. 2013; 127:634-640
WARFARIN
Dabi 150
Dabi 110
None
ASA
ASA + Clopidogrel
None
ASA
ASA + Clopidogrel
None
ASA
ASA + Clopidogrel
0 5 10
2.84.6
6.3
HR=1.50 (95%CI: 1.22, 1.86)HR=2.34 (95%CI: 1.53, 3.57)
HR=1.81 (95%CI: 1.46, 2.24)HR=2.16 (95%CI: 1.34, 3.47)
HR=1.53 (95%CI: 1.21, 1.92)HR=2.39 (95%CI: 1.53, 3.74)
2.64.3
5.52.2
3.85.4
Major Bleeding*
*Adjusted for age, gender, warfarin experience, SBP, CAD, CHF, TIA, HTN, DM, CrCl, Statins
Avoid or Limit Triple Therapy
Bhatt DL. J Am Coll Cardiol. 2015;65:1630-2
Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of print]
How to Approach Combination Antithrombotic Therapy - ACS
Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF-PCI
Primary endpoint: TIMI major + minor + bleeding requiring medical attention
Secondary endpoint: CV death, MI, and stroke (Ischemic, Hemorrhagic, or Uncertain Origin)
*Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min.†Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor.‡Low-dose aspirin (75-100 mg/d). ∆ Open label VKA
2100 patients with NVAF
Coronary stenting
No prior stroke/TIA, GI bleeding, Hb<10, CrCl<30
RANDOMIZE
1,6, or 12 months
Rivaroxaban 15 mg qd*Clopidogrel 75 mg qd†
Rivaroxaban 15mg QDAspirin 75-100 mg qd
Rivaroxaban 2.5 mg bidClopidogrel 75 mg qd†
Aspirin 75-100 mg qd‡
VKA∆(target INR 2.0-3.0)
Aspirin 75-100 mg qd
VKA∆ (target INR 2.0-3.0)Clopidogrel 75 mg qd†
Aspirin 75-100 mg qd
≤72hours
AfterSheath removal
1,6, or 12 months
End oftreatment12 months
WOEST Like
ATLAS Like
TripleTherapy
Gibson et al. AHA 2016
Pre randomization MD Choice
Pre randomization MD Choice
Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events
TIM
I Maj
or,
TIM
I Min
or,
or
Ble
edin
g
Req
uir
ing
Med
ical
Att
enti
on
(%
)
697
Days
593 555 521 461 426 329VKA + DAPT
No. at risk
VKA + DAPT
26.7%
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug.Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA.Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model.Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. Gibson et al. AHA 2016
VKA + DAPT
Riva + DAPT
18.0%
p<0.00018
HR = 0.63 (95% CI 0.50-0.80)ARR = 8.7NNT = 12
706697
636593
600555
579521
543461
509426
409329
Riva + DAPTVKA + DAPT
VKA + DAPT
Riva + P2Y12
16.8%
p<0.000013
HR = 0.59 (95% CI 0.47-0.76)ARR = 9.9NNT = 11
696697
628593
606555
585521
543461
510426
383329
Riva + P2Y12
VKA + DAPT
Riva + P2Y12
VKA + DAPT
Riva + DAPT
Riva + P2Y12 v. VKA + DAPT
HR=0.59 (95% CI: 0.47-0.76)p <0.000013ARR=9.9NNT=11
Riva + DAPT v. VKA + DAPTHR=0.63 (95% CI: 0.50-0.80)p <0.00018ARR=8.7NNT=12
696706697
628636593
606600555
585579521
543543461
510509426
383409329
Riva + P2Y12
Riva + DAPTVKA + DAPT
Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke
Car
dio
vasc
ula
r D
eath
, Myo
card
ial
Infa
rcti
on
, or
Str
oke
(%
)
DaysRiva + P2Y12
Riva + DAPTVKA + DAPT
694704695
648662635
633640607
621628579
590596543
562570514
430457408
VKA + DAPT
Riva + DAPT
Riva + P2Y12
Riva + P2Y12 v. VKA + DAPT
HR=1.08 (95% CI: 0.69-1.68)p=0.750
Riva + DAPT v. VKA + DAPTHR=0.93 (95% CI: 0.59-1.48)p=0.765
6.5%
5.6%6.0%
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug.Composite of adverse CV events is composite of CV death, MI, and stroke.Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model.Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test.
6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines
No. at risk
Gibson et al. AHA 2016
In patients who require anticoagulation for AF, a less potent / shorter duration of antiplatelet therapy may offer the best net clinical benefit.
More data is needed to define an “optimal” antithrombotic regimen but general principle is that anticoagulation protects against stroke and coronary events while antiplatelet inferior for stroke prevention.
Conclusions
Prevention
Utility of coagulation testing
How to manage bleeding
Role of specific reversal agents / antidotes
Managing Bleeding with NOACs
Ruff CT, et al. Lancet. 2014; 383:955-962
How Frequent is Bleeding with NOACs?
2.39
2.80
1.170.92
0.320.66
0.00
1.00
2.00
3.00
4.00
5.00
NOACs Warfarin
Major Bleeding
GI Bleeding
ICH
71,683 Patients: 4 Phase III AF NOAC Trials
% /
Yea
r
Discontinuing NOACs Prior to Procedures
Minor Bleeding RiskEndoscopy with biopsy, prostate or bladder biopsy, EPS/RFA for SVT, angiography, pacemaker or implantable cardioverter defibrillator (unless complex anatomic setting, such as congenital heart disease)
Major Bleeding RiskComplex left-sided ablation (AF, VT), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, TURP, kidney biopsy
Heidbuchel H, et al. Europace. 2015; 17(10):1467-1507
Coagulation Tests
TestApixaban/Rivaroxaban/Edoxab
anDabigatran
Qualitative Present / Absent
PT rivaroxaban>edoxaban>apixaban[sensitivity depends on reagents]
TT>aPTT
Quantitative testChromogenic anti-FXa
[requires specific calibration to drug]Dilute TT, chromogenic anti-FIIa
[requires specific calibration]
Normal PT or aPTT does not guarantee absence of anticoagulant effect
Quantitative tests are not standardized or approved
Tripodi A, et al. Thromb Haemost 2011; 105:735-736Barrett YC, et al. Thromb Haemost 2010; 104:1263-1271van Ryn J, et al. Thromb Haemost 2010; 103:1116-1127Stangier J, et al. Br J Clin Pharmacol 2007; 64:292-303Cuker A, et al. JACC 2014; 64(11):1128-1139
Non-Specific Reversal Agents
Agent Clotting Factors Replaced Dose
4 Factor-PCC Factors II, VII, IX, X 25-50 units/kg
3 Factor-PCC Factors II, IX, X 25-50 units/kg
aPCC Factors II, VIIa, IX, X 80 units/kg
rFVIIa FVIIa 90 ug/kg
Only After D/C drug and Supportive Care (fluids / transfusions)
Specific NOAC Reversal Agents
Ruff CT, et al. Circulation. 2016 ; 134(3):248-261
Group A: Uncontrolled bleeding + dabigatran-treated
Group B: Emergency surgery or procedure + dabigatran-treated
N = 494
0–15 min 90 days follow-up
Hospital arrival
5 g idarucizumab (2 x 2.5 g
intravenously)
Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 dPre-1st vial 1 hBlood
samples
*Connolly S,et al. N Engl J Med. 2009; 361:1139–51.Pollack C, et al. Thromb Haemost. 2015;114:198–205.dTT, diluted thrombin time; ECT, ecarin clotting time.
~20 min
Reverses up to the 99th percentile of dabigatran levels
measured in RE-LY®*
Multicenter, Ongoing, Open-label, Single-arm Phase III study
Primary endpoint: Maximum reversal within 4 h based on dTT, ECT
10th/90th percentiles 5th/95th percentilesMedian and 25th/75th percentiles
RESULTS: Diluted Thrombin Time (dTT) - Assessment ofReversal of Dabigatran Anticoagulation with Idarucizumab
ULN, upper limit of normal
Assay ULN
Similar results were also obtained with Ecarin Clotting Time (ECT)
Group B: Peri-procedural Hemostasis191 of 196 (97.4%) patients underwent surgery/procedures Median time from administration of first vial to procedure was 1.6 hours Adequacy of hemostasis during surgery determined locally
Mortality (Kaplan-Meier Survival)
Follow-up Group A (N = 298)
Group B (N = 196)
30 days
Patients at risk, n 250 164
Mortality, % 12.3 12.4
90 days
Patients at risk, n 149 105
Mortality, % 18.7 18.5
Day 1
ANNEXA-4 Study Design
Patient with acute major bleed, meeting inclusion criteria
Patient ScreeningIV
Bolus2-hour
IV Infusion
Safety follow-up visit
Efficacy Measurements
Change in anti-FXa activity
Clinical hemostatic efficacy through 12 hours
Day 30Day 3
If last dose of fXa inhibitor was within 18 hours
AndexanetTreatment
Bleeding and Laboratory Assessment
Assessments:
Safety Measurements
Thrombotic events
Antibodies to FX, FXa, andexanet
30-day mortality
After end of infusion
1 hr 4 hr 8 hr 12 hr
Connolly S, et al., N. Engl. J. Med. 2016
ANNEXA-4 Dose Selection
Acute major bleeding ≤ 18 hours of last dose ofapixaban, edoxaban, rivaroxaban, or enoxaparin
Andexanet IV bolus and 2 hour infusion
Pts on apixaban or>7 h from last rivaroxaban dose
Bolus 400 mg+
Infusion 480 mg @ 4 mg/min
Pts on enoxaparin or edoxaban or ≤ 7 h from last rivaroxaban dose
Bolus 800 mg+
Infusion 960 mg @ 8 mg/min
Pts on enoxaparin, edoxaban or≤7 h from last rivaroxaban dose
Bolus 800 mg+
Infusion 960 mg @ 8 mg/min
Connolly S, et al., N. Engl. J. Med. 2016
ANNEXA-4: Anti-FXa Activity
Connolly SJ, et al. N Engl J Med 2016;375:1131-41
ANNEXA-4: Clinical Hemostatic Efficacy
Connolly SJ, et al. N Engl J Med 2016;375:1131-41
ANNEXA-4: Death or Thrombotic Events
Connolly SJ, et al. N Engl J Med 2016;375:1131-41
60
BASELINE (Pre-edoxaban)
ANTICOAGULATED(Pre-PER977, 2.75 hrs 60 mg edoxaban p.o.)
REVERSED(1 hr post 100 mg i.v. bolus PER977)
Scale Bar: 1 inch
Pre-PER977, 2.75 hrs post 60 mg p.o.
edoxaban
Pre-edoxabanbaseline
1 hr post 100 mg i.v.
PER977
0
50
100
150
200
250
300
60mg POedoxaban+ IV saline
placebo
60mg POedoxaban+ 25mg IVPER977
60mg POedoxaban+ 100mg
IVPER977
60mg POedoxaban+ 300mg
IVPER977
Native
Fib
rin
dia
met
er [
nm
]
******
Ansell JE, et al. NEJM. 2014; 371(22):2141-2142
Ciraparantag Anticoagulation Bleeding Algorithm
Kirchhof P, et al. Eur Heart J. 2016 [Epub ahead of print]
Management of NOAC Treated Patients who Require Invasive Procedures
Ruff CT, et al. Circulation. 2016 ; 134(3):248-261
Serious bleeding is uncommon with NOACs50% less compared to warfarin
Many bleeds are preventableStop unnecessary antiplatelet agents and NSAIDs
For most bleeds: temporarily stopping anticoagulation and supportive measures are all that is needed
Laboratory coagulation tests have limited utility
PCCs are the preferred non-specific reversal agent
Specific antidotes available for dabigatran and likely soon to be available for Fxa inhibitors: trauma, urgent surgery, stroke requiring lysis
Anticoagulation should be restarted in the majority of patients who experience a bleed once stabilized
Conclusions
Heart Failure (HF) has reached epidemic proportions - 23 million individuals worldwide- Incidence increasing, especially among elderly
½ of patients have reduced ejection fraction (HFrEF)
Significant morbidity, mortality, and cost- 1 million HF hospitalizations/yr- Cost to US health system 39 billion dollars annually
(expected to increase)
Thrombotic complications- HF 2nd most common cause of cardioembolic stroke- Major risk factor for DVT & PE (OR 2.6)
Heart Failure
Go et al. Circulation 2014;129:e28-e29.Pullicino, et al. Cerebrovasc Dis. 2008; 26(3):322-7Goldhaber, et al. Am J Cardiol. 2004; 93:259-262Alikhan, et al. Am J Med. 2008;121:935-942Howell MD, et al. J Clin Epidemiol 2001;54:810-816
WARCEF: Efficacy and Safety Endpoints
Homma et al. N Engl J Med. 2012;366:1859-1869.
Warfarin vs. Aspirin in Patients with HF & NSR
COMMANDER HF
Zannad F, et al. Eur J Heart Fail. 2015;17(7):735-742
Patients with HF and CAD following HF exacerbation