NOACS for the treatment of atrial fibrillation - advantagescongressmed.com/cith2014/images/pdfs/NOACS_CITH.pdfUS Department of Defense (October 28, 2010, and June 30, 2012) Newly diagnosed

NOACS for the treatment of atrial fibrillation - advantages

Eli I. LevDirector, Interventional Cardiology Unit

Hasharon HospitalRabin Medical Center

Tel-Aviv University, Israel

NOACS - Advantages

Pahrmacological properties

No need for monitoring

Efficacy

Safety

Absorption and metabolism of NOACs

Dabigatran Apixaban Edoxaban * Rivaroxaban

Bioavailability 3-7% 50% 62%66% (w/o food)

~100% with food

Prodrug yes no no no

Renal Clearance 80% 27% 50% 35%

Liver metabolism:

CYP3A4 no

yes (elimination;

minor CYP3A4)

minimal (<4%

of elimination)yes (elimination)

Absorption

with foodno effect no effect 6-22% more +39%

T Max 0.5 – 2 hrs 3 -4 hrs 2 – 4hrs 2 -4 hrs

Elimination

half-life (t1/2)12-14 hrs 12 hrs 9-11 hrs

5-9 h (young) /

11-13 h (elderly)

www.escardio.org/EHRA

* not approved yet

37-89 hrs

24-72 hrs

Warfarin

Warfarin metabolism

An anticoagulation effect generally occurs within 24 hrs

after warfarin administration. However, peak

anticoagulant effect may be delayed 72 to 96 hrs

The elimination of warfarin is almost entirely by hepatic

metabolism. The CYP450 isozymes involved in the

metabolism of warfarin include CYP2C9, 2C19, 2C8,

2C18, 1A2, and 3A4

The terminal half-life of warfarin after a single dose is ≈

1 week; however, the effective excretion half-life of

warfarin ranges from 37 to 89 hrs

http://www.rxlist.com/script/main/art.asp?articlekey=4359

Drug and food interactions of warfarin

Enzyme Inhibitors Inducers

CYP2C9

amiodarone, capecitabine, cotrimoxazole,

etravirine, fluconazole, fluvastatin,

fluvoxamine, metronidazole, miconazole,

oxandrolone, sulfinpyrazone, tigecycline,

voriconazole, zafirlukast

aprepitant, bosentan,

carbamazepine,

phenobarbital,

rifampin

CYP1A2

acyclovir, allopurinol, caffeine, cimetidine,

ciprofloxacin, disulfiram, enoxacin,

famotidine, fluvoxamine, methoxsalen,

mexiletine, norfloxacin, oral contraceptives,

phenylpropanolamine, propafenone,

propranolol, terbinafine, thiabendazole,

ticlopidine, verapamil, zileuton

montelukast,

moricizine,

omeprazole,

phenobarbital,

phenytoin, cigarette

smoking

CYP3A4

alprazolam, amiodarone, amlodipine,

amprenavir, aprepitant, atorvastatin,

atazanavir, bicalutamide, cilostazol,

cimetidine, ciprofloxacin, clarithromycin,

conivaptan, cyclosporine,

darunavir/ritonavir, diltiazem, erythromycin,

fluconazole, fluoxetine, fluvoxamine,

fosamprenavir, imatinib, indinavir, isoniazid,

itraconazole, ketoconazole, lopinavir/

ritonavir, nefazodone, nelfinavir, nilotinib,

oral contraceptives, posaconazole, ranitidine,

ranolazine, ritonavir, saquinavir,

telithromycin, tipranavir, voriconazole,

zileuton

armodafinil,

amprenavir,

aprepitant, bosentan,

carbamazepine,

efavirenz, etravirine,

modafinil, nafcillin,

phenytoin,

pioglitazone,

prednisone, rifampin

CYP450 interactions with warfarin

Other classes of interacting

drugs:

Antibiotics

Antifungals

Anticoagulants

Antiplatelets

NSAIDS

Serotonin reuptake inhibitors

Botanical products

Foods

INR control with warfarin:

clinical trials vs. clinical practiceINR* control in clinical trial versus clinical practice (TTR**)

1. Kalra L, et al. BMJ 2000;320:1236-1239 * Pooled data: up to 83% to 71% in individualized trials; 2. Samsa GP, et al. Arch Int Med 2000

3. Matchar DB, et al. Am J Med 2002; 113:42-51.

** TTR = Time in Therapeutic Range (INR2.0-3.0)

66%

44%

9%

18%

38%

25%

<2.0 2.0 – 3.0 >3.0 INR

% o

f el

igib

le p

atie

nts

rec

eivin

g

war

fari

n

Clinical trial1

Clinical practice2,3

*INR = International normalized ratio

VKAs have a narrow therapeutic window

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354& Eur Heart J 2006;27:1979–2030

1

International normalized ratio

Odds

ratio

2

15

8

10

5

0

1

3 4 5 6 7

Stroke

Intracranial bleed

Therapeuticrange

20

VKAs = vitamin K antagonists

NOACs Drug Interactions

All 3 NOACs with antifungals

Dabigatran – dronedarone, verapamil (moderate)

Apixaban, rivaroxaban – HIV protease inhibitors

All 3 NOACs – rifampin, phenytoin, phenobarbital

Pharmacological advantages of

NOACs

More predictable and shorter onset time and

half-life/elimination

Fewer food and drug interactions

Predictable effect without need for monitoring

US Department of Defense (October 28, 2010, and June 30, 2012)

Newly diagnosed NVAF patients on Dabigatran (n=1745)

Newly diagnosed NVAF patients on Warfarin (n=1745)

Persistence rates were higher for dabigatran than for warfarin

Persistence Rates Higher With

Dabigatran Than Warfarin

Kaplan–Meier survival curves for propensity scores matched patients by treatment group analyzed with a 60-day medication gap

Zalesak M, et al. Circ Cardiovasc Qual Outcomes 2013;6:567-574.

At 6 months: 72% versus 53%

At 1 year: 63% versus 39%

Higher persistence rates with

Dabigatran than warfarin

EFFICACY

Primary endpoint of stroke or systemic embolism

Patients with atrial fibrillation (non-valvular)

RELY: Stroke or Systemic Embolism

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs. Warfarin

Dabigatran 150 vs. Warfarin

Non-inferiorityp-value

<0.001

<0.001

Superiorityp-value

0.34

<0.001

Margin = 1.46

HR (95% CI)Warfarin betterDabigatran better

Connolly et al NEJM 2009

0.01

0.02

0.03

0.05

0.04

Cu

mu

lati

ve h

azard

rate

s

RR 0.91

(95% CI: 0.74–1.11)

p<0.001 (NI)

p=0.34 (Sup)

RR 0.66

(95% CI: 0.53–0.82)

p<0.001 (NI)

p<0.001 (Sup)

Years

0 0.5 1.0 1.5 2.0 2.5

0.0

Warfarin

Dabigatran etexilate 110 mg

Dabigatran etexilate 150 mg

RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior

Time to first stroke / SSE

Connolly SJ., et al. NEJM published online on Aug 30th 2009.

DOI 10.1056/NEJMoa0905561

RRR

34%


3.75 3.64

4.13

0.00

1.00

2.00

3.00

4.00

D110 mg BID D150 mg BID Warfarin

RR 0.88 (95% CI: 0.77–1.00)

p=0.051

RELY - All cause mortality


DOI 10.1056/NEJMoa0905561

RR 0.91 (95% CI: 0.80–1.03)

p=0.13

446 / 6,015 438 / 6,076

% p

er

year

ROCKET AF Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-years

Based on Protocol Compliant on Treatment Population

0

1

2

3

4

5

6

0 120 240 360 480 600 720 840 960

No. at risk:

Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634

Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaban Warfarin

Event

Rate1.71 2.16

Patel et al, NEJM 2011


Event

Rate

Event

Rate

HR

(95% CI)P-value

On

TreatmentN= 14,143

1.70 2.150.79

(0.65,0.95)0.015

ITTN= 14,171

2.12 2.420.88

(0.74,1.03)0.117

Rivaroxaban

better

Warfarin

better

Primary Efficacy Outcome - SuperiorityStroke and non-CNS Embolism


Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations Patel et al, NEJM 2011

ARISTOTLE - Primary OutcomeStroke (ischemic or hemorrhagic) or systemic embolism

Apixaban 212 patients, 1.27% per year

Warfarin 265 patients, 1.60% per year

HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011

No. at Risk

Apixaban 9120 8726 8440 6051 3464 1754

Warfarin 9081 8620 8301 5972 3405 1768

P (non-inferiority)<0.001

21% RRR

Granger et al, NEJM 2011

ARISTOTLE: all-cause mortality

Granger et al. N Engl J Med 2011;365:981-92.

All-cause mortality*

3.94%669/9081 3.52%

603/9120

11% RRR HR: 0.89

95% CI: 0.80-0.998;

p=0.047

Warfarin Apixaban

Even

t ra

te (

% /

year)

*Key secondary efficacy endpoint

Comparative Efficacy / Safety among Trials

Subgroup of patients with CHADS2 > 3

SAFETY

Major Bleeding

Intra-cranial hemorrhage

RELY - Major bleeding rates

2.71

3.11

3.36

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50



DOI 10.1056/NEJMoa0905561

RR 0.93 (95% CI: 0.81–1.07)

p=0.31

RR 0.80 (95% CI: 0.69–0.93)

p=0.003 (sup)

322 / 6,015 375 / 6,076 397 / 6,022

RRR

20%

% p

er

year


RR 0.26 (95% CI: 0.14–0.49)

p<0.001 (sup)

RELY - Hemorrhagic stroke


DOI 10.1056/NEJMoa0905561

RR 0.31 (95% CI: 0.17–0.56)

p<0.001 (sup)

Nu

mb

er

of

even

ts

6,015 6,076 6,022

1412

45

0

10

20

30

40

50


0.10%

0.38%RRR

69%

RRR

74%

0.12%


Intra-cranial bleeding rates

27

36

87

0

10

20

30

40

50

60

70

80

90


RR 0.40 (95% CI: 0.27–0.60)

p<0.001 (sup)


DOI 10.1056/NEJMoa0905561

RR 0.31 (95% CI: 0.20–0.47)

p<0.001 (sup)

Nu

mb

er

of

even

ts

0,23 %

0,74 %

0,30 %

RRR

69%

RRR

60%



Event Rate

or N (Rate)

Event Rate

or N (Rate)

HR

(95% CI)

P-

value

Major

>2 g/dL Hgb drop

Transfusion (> 2 units)

Critical organ bleeding

Bleeding causing death

3.60

2.77

1.65

0.82

0.24

3.45

2.26

1.32

1.18

0.48

1.04 (0.90, 1.20)

1.22 (1.03, 1.44)

1.25 (1.01, 1.55)

0.69 (0.53, 0.91)

0.50 (0.31, 0.79)

0.576

0.019

0.044

0.007

0.003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019

Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060

Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051


Based on Safety on Treatment Population

ROCKET-AF - Primary Safety Outcomes


ROCKET-AF - Primary Safety Outcomes


Event Rate Event Rate HR

(95% CI)

P-

value

Major and non-major

Clinically Relevant14.91 14.52 1.03 (0.96, 1.11) 0.442

Major 3.60 3.45 1.04 (0.90, 1.20) 0.576

Non-major Clinically

Relevant11.80 11.37 1.04 (0.96, 1.13) 0.345


Based on Safety on Treatment Population Patel et al, NEJM 2011

ARISTOTLE - Major BleedingISTH definition

Apixaban 327 patients, 2.13% per year

Warfarin 462 patients, 3.09% per year

HR 0.69 (95% CI, 0.60–0.80); P<0.001

No. at Risk

Apixaban 9088 8103 7564 5365 3048 1515

Warfarin 9052 7910 7335 5196 2956 1491

31% RRR


Significant decrease also for intracranial bleeding: 0.33% vs. 0.8% / year (apixa vs. warfarin)

ARISTOTLE – Bleeding Outcomes

Outcome

Apixaban

(N=9088)

Warfarin

(N=9052)HR (95% CI) P Value

Event Rate

(%/yr)

Event Rate

(%/yr)

Primary safety outcome:

ISTH major bleeding*2.13 3.09 0.69 (0.60, 0.80) <0.001

Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001

Hemorrhagic stroke 0.24 0.47 0.51 (0.35, 0.75) <0.001

Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37

Major or clinically relevant

non-major bleeding4.07 6.01 0.68 (0.61, 0.75) <0.001

GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001

TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001

Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001

Comparative analysis – trial results

Efficacy endpoint Safety endpoint

ESC working group on thrombosis, JACC 2012

Relative Risk: NOACs vs. Warfarin: Meta-analysis of > 50,000 patients

Dentali et al. Circulation 2013

0.89

0.77

0.46

0.86

1

Mortality Stroke/SE ICH Maj. Bleed MI

* *

*Some heterogeneity in results for major bleeding and myocardial infarction

Death Within 30 days of Major Bleed

Time (months from enrolment)Hylek et al, JACC 2014

Majeed et al,

Circulation 2013

NOACS Antidote status

All 3 NOACS have antidotes tested in phase 2

studies

“A phase 3 study designed to test an antidote to factor Xa

inhibitors met its primary efficacy end point, according to

an announcement from Portola Pharmaceuticals]”

(Theheart Oct. 2014)

“An IV bolus of andexanet alfa immediately and sig. reversed

the anticoagulation of apixaban in the ANNEXA-A study.

33 healthy volunteers in the study were treated with apixaban

5 mg bid daily for 4 days and then randomized to andexanet

alfa 400 mg or placebo” (results will be presented in AHA 2014)

NOACS – Advantages Summary

Pahrmac. properties - more predictable and shorter onset

time and elimination t1/2 ; No need for monitoring

Efficacy – all 3 NOACS are at least as effective as

warfarin in prevention of stroke and systemic embolism

(dabigatran 150 mg and apixaban more effective)

Safety - all 3 NOACS are at least as safe as warfarin in

terms of the risk of major bleeding (dabigatran 110 mg and

apixaban associated with lower rates of major bleeding).

All 3 NOACs associated with ↓ risk of intra-cranial bleeding

ESC Atr Fib 2012 Guidelines

line: solid = best option ; dashed = alternative option

Yes

Atrial fibrillation

Valvular AF*

<65 years and lone AF (including females)

Assess risk of stroke

CHA2DS2-VASc score

Assess bleeding risk

(HAS-BLED score)

Consider patient values and preferences

No antithrombotic

therapy

Oral anticoagulant therapy

NOAC VKA

0 1

No (i.e. nonvalvular)

Yes

No

≥2

Choice of anticoagulant

THANK YOU

New

anticoagulants

site of action

RE-LY: A Non-inferiority Trial

Atrial fibrillation

≥1 Risk Factor

Absence of contra-indications

R

Warfarin

adjusted

(INR 2.0-3.0)

N=6000

Dabigatran

Etexilate

110 mg BID

N=6000

Dabigatran

Etexilate

150 mg BID

N=6000

Blinded Event Adjudication.

Open Blinded

Mean TTR = 64%

Median follow up = 2 years

Mean CHADS score = 2.1



Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5

(2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

Randomize

Double Blind /

Double Dummy

(n ~ 14,000)

Monthly Monitoring

Adherence to standard of care guidelines

ROCKET AF - Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or

Systemic embolus

At least 2 or

3 required*

mean TTR = 55%



Warfarin (target INR 2-3)

Apixaban 5 mg oral twice daily(2.5 mg BID in selected patients)

Primary outcome: stroke or systemic embolism

Randomize

double blind,

double dummy

(n = 18,201)

Inclusion risk factors

Age ≥ 75 years

Prior stroke, TIA, or SE

HF or LVEF ≤ 40%

Diabetes mellitus

Hypertension

Warfarin/warfarin placebo adjusted by INR/sham INR

based on encrypted point-of-care testing device

Major exclusion criteria

Mechanical prosthetic valve

Severe renal insufficiency

Need for aspirin plus thienopyridine

ARISTOTLEAF with at least one risk factor for stroke


mean TTR = 62%


AVERROES: Study Design

The primary objective of the trial was to determine if apixaban was superior to ASA

for the prevention of the composite outcome of stroke or systemic embolism.

• Primary efficacy outcome: Stroke or systemic embolism

• Primary safety outcome: Major bleeding

Connolly et al. N Engl J Med 2011;364:806-817.

Apixaban 5.0 mg BD

(2.5 mg in select patients* [6.4%])

ASA 81-324 mg OD**

Event Driven

N=5599

*Patients with ≥2 of the following: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 μmol/L).

**The selection of an ASA dose of 81, 162, 243, or 324 mg was at the discretion of the investigator

with 91% of subjects receiving either an 81-mg (64%) or 162-mg (27%) dose at randomization.

Randomised, double-blind,

double-dummy

Patient Population

Patients ≥50 years with NVAF and ≥1 risk factors for stroke

Not receiving VKA therapy (demonstrated or expected to be unsuitable for VKA)

Mean follow-up: 1.1 years

AVERROES: primary efficacy

endpoint: stroke or systemic embolismC

um

ula

tive H

azard


Months

No. at Risk

Apixaban 2808 2758 2566 2125 1522 615

ASA 2791 2716 2530 2112 1543 628

Apixaban

ASA

0.00

0.01

0.02

0.03

0.04

0.05

0 3 6 9 12 18

55% RRR

HR 0.45 (95% CI: 0.32-0.62)

p<0.001 for superiority

AVERROES: Primary safety

endpoint – major bleeding


No. at Risk

Apixaban 2808 2759 2566 2120 1521 622

ASA 2791 2738 2557 2140 1571 642

0 3 6 9 12 18

0.000

0.005

0.010

0.015

0.020C

um

ula

tive H

azard

Months

Apixaban ASA

HR 1.13 (95% CI: 0.74-1.75);

p=0.57

RECENT ANALYSES AND

POST MARKETING DATA

REGARDING DABIGATRAN

Published in NEJM (March 2013)

“FDA has not changed its recommendations regarding Pradaxa.

Pradaxa provides an important health benefit when used as directed”

“Bleeding rates associated with new use of Pradaxa do not appear to be

higher than bleeding rates associated with new use of warfarin, which is

consistent with observations from the RE-LY trial.”

“The incidence rate of gastrointestinal hemorrhage events per 100,000 days

at risk was 1.6 to 2.2 times higher for warfarin new users than for

Pradaxa new users, and the incidence rate of ICH events per 100,000 days

at risk was 2.1 to 3.0 times higher with warfarin than with Pradaxa.”

Data collected during the time period from Oct 2010 - Dec 2011

“Real Life” Safety with PradaxaActive surveillance system sponsored by the FDA: Safety Announcement 2/11/2012

46

The Committee found that the frequency of occurrence of fatal

bleedings with Pradaxa seen in post-marketing data was

significantly lower than what was observed in the clinical trials that

supported the authorisation of the medicine…

On the basis of the available evidence, the CHMP concluded that the

benefits of Pradaxa continue to outweigh its risks and that it

remains an important alternative to other blood-thinning agents.

EMA updates patient & prescriber information for Pradaxa

Myocardial ischaemic events subanalysis:

cardiac outcomes

There was a numerical imbalance in the rate of MI that was not

statistically significant for either dose of dabigatran vs warfarin

D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; MI = myocardial infarction;

war = warfarin

Hohnloser SH et al. Circulation doi:10.1161/CIRCULATIONAHA.111.055970

Annual rate (%) D110 vs warfarin D150 vs warfarin

D110 D150 War HR (95% CI) P value HR (95% CI) P value

Total MI 0.82 0.81 0.64 1.29 (0.96–1.75) 0.09 1.27 (0.94–1.71)

0.12

Clinical MI 0.73 0.74 0.56 1.30 (0.95–1.80) 0.10 1.32 (0.96–1.81) 0.09

Silent MI 0.09 0.07 0.08 1.22 (0.50–2.93) 0.66 0.87 (0.34–2.27) 0.72

Fatal MI 0.13 0.11 0.10 1.32 (0.63–2.80) 0.46 1.06 (0.49–2.33) 0.88

47

RELY-ABLE

During 2.3 years of additional treatment after RE-LY®

(total f/u 4.3 years): results highly consistent with RE-LY:

Rates of stroke and major bleeding remain low on

dabigatran

There were no new safety signal observed during this

extended follow up period

Both doses have very low rates of haemorrhagic stroke

over 4+ years

With dabigatran 150, there is a lower rate of ischaemic

stroke but a higher rate of major bleeding

Both doses have similar mortalityConnolly SJ, et al. RELY-ABLE presented at

AHA 2012 Scientific Sessions,

CHADS2 score subgroup analysis:

stroke/systemic embolism

49

*P values for interaction; D = dabigatran

Oldgren J et al. Ann Int Med 2011;155:660−7

CHADS2

score

Annual rate (%)

D110 mg BID

D150 mg BID

Warfarin

0–1 1.06 0.65 1.08

2 1.45 0.84 1.38

3–6 2.12 1.88 2.73

P=0.84*

0.5 1.0 1.50 2.0

P=0.37*

0.5 1.0 1.50 2.0Favours dabigatran

Favours warfarin

Favours dabigatran

Favours warfarin

Dabigatran 110 mg BID vs warfarin

Dabigatran 150 mg BID vs warfarin

Benefits of dabigatran vs warfarin are independent of CHADS2 score

ARISTOTLE - Stroke/Systemic

Embolism, by CHADS and HASBLED

Lopes et al, Lancet 2012

ARISTOTLE - ISTH Major

Bleeding by CHADS and HASBLED


ARISTOTLE - Mortality by

CHADS and HASBLED


NOACs vs. warfarin in moderate CKD (eCrCl <50 ml/min)

Dabigatran is contraindicated in patients with severe renal impairment (CrCl<30 ml/min)

1. Connolly SJ, et al. N Engl J Med 2009; 361: 1139-1151; 2. Pradaxa® Product Information 4th edition revised, 2012;

3. Fox KAA, et al. Eur Heart J 2011; 32: 2387-2394; 4. Hohnloser SH, et al. Eur Heart J 2012; 33: 2821-2830.

HR (95% CI)

Dabigatran 110 mg BID1,2 0.89 (0.61-1.31)


Rivaroxaban 15 mg QD3 0.86 (0.63-1.17)

Apixaban 2.5/5 mg BID4 0.79 (0.55-1.14)

0.50 0.75 1.00 1.25 1.50

HR (95% CI)

New Agent Better Warfarin Better

Stroke or Systemic Embolism

Dabigatran is contraindicated in patients with severe renal impairment (CrCl<30 ml/min)

1. Connolly SJ, et al. N Engl J Med 2009; 361: 1139-1151; 2. Pradaxa® Product Information 4th edition revised, 2012;

3. Fox KAA, et al. Eur Heart J 2011; 32: 2387-2394; 4. Hohnloser SH, et al. Eur Heart J 2012; 33: 2821-2830.

HR (95% CI)



Rivaroxaban 15 mg QD3 0.95 (0.72-1.26)

Apixaban 2.5/5 mg BID4 0.50 (0.38-0.66)

0.50 0.75 1.00 1.25 1.50

HR (95% CI)

New Agent Better Warfarin Better

Major bleeding

NOACs vs. warfarin in moderate CKD (eCrCl <50 ml/min)

Documents

NOACS for the treatment of atrial fibrillation - advantagescongressmed.com/cith2014/images/pdfs/NOACS_CITH.pdfUS Department of Defense (October 28, 2010, and June 30, 2012) Newly diagnosed