Table 1. Pharmacologic properties of novel oral anticoagulants

Drug
(Target)

Standard Dosage

Reduced Dose

Oral
Bioavailability

H
Half-life
(hours)

% renal
excretion

Time to peak plasma
concentration (hours)

Dabigatran
(Thrombin)

150 mg BID

75 mg BID
(no mg 810 not
approved in U.S.)

6.5%

14-17

80%

0.5-2

Rivaroxaban
(Factor Xa)

20 mg daily

15 mg daily

80%

9-13

66%

2-4

Apixaban
(Factor Xa)

5 mg BID

2.5 mg BID

66%

8-15

25%

3

Edoxaban
(Factor Xa)

60 mg or 30 mg
daily

30 mg or 15 mg
daily

50%

9-11

35%

1-2

Abbreviations: BID, Twice daily

Table 2. Summary of the important characteristics of the landmark trials of novel oral anticoagulants in atrial fibrillation

Trial name

Novel oral
anticoagulant

Inclusion criteria(AF and...)

Common exclusion criteria

Unique exclusion criteria

Definition of Valvular
Atrial Fibrillation

Mean CHADS2
score

RE-LY

Dabigatran

Prior TIA/CVA

LV EF 540% or NYHA all last 6 months

Age >75

Age 65-74 plus DM, HTN or CAD

AF secondary to a reversible disorder
Valvular AF
Recent stroke (within 7-14 days)
Predisposition to bleeding
ESRD
Active liver disease
Pregnancy
Anemia (Hemoglobin <10 g/dL)
Thrombocytopenia (<100,000/PL)
Indication for AC other than AF
Active endocarditis
Chronic, uncontrolled hypertension
Limited life expectancy
Acute coronary syndrome
Coronary revascularization
Inability to adhere to study protocol

Severe stroke

within 6 months
CrCl <30 rat/min

Prosthetic valve

Hemodynamically

relevant valve disease

2.1

ROCKET-AF

Rivaroxaban

Prior TIA/CVA or

At least two of the following risk factors: -Clinical heart failureor LV EF 53S9S

-Hypertension
-Age 275
-Diabetes

Platelet count <90,000/

Severe stroke within 3 months

CrCI <30 mlimin

ASA >100 mg daily, *ASA and thienopyridine

Hemodynamically
significant mitral stenosis or prosthetic valve

 

ARISTOTLE

Apixaban

Prior TIA/CVA

Age 275 Symptomatic CHF or LV EF   4096

Diabetes

Hypertension

ASA>165 mg
ASA and thienopyridine

SCr >2-5 mg/dL

CrCI <25

Hgb <9 gidl.

Moderate or severe

mitral stenosis
prosthetic valve

2.1

AVERROES

Apixaban

Age 250, CHADS, 21 or PAD and demonstrated or expected to be unsuitable for warfarin

Thienopyridine

Open-label AM discouraged but allowed <100 mg

SCr >2.5 mg/dL

CrCI <25 mt/rnin

Valvular disease requiring surgery

2.0

ENGAGE AK-
TIMI 48

Edoxaban

CHAOS, 22

CrCI <30 ml/min ASA and thienopyridine
Stroke within 30 days

Moderate or severe
mitral stenosis
Prosthetic valve

2.8

*Subjects with score of 2 limited to 10% of total study population

Abbreviations: AF, atrial fibrillation; TIA, transient ischemic attack; CVA, cerebrovascular accident; LV EF, left ventricular ejection fraction, NYHA, New York Heart Association; DM, diabetes mellitus; HTN, hypertension; CAD, coronary artery disease; PAD, peripheral artery disease; ESRD, end stage renal disease; AC, anticoagulation; CrCI, creatinine clearence; ASA, aspirin; SCr, serum creatinine; Hgb, hemoglobin.

Table 3. Summary of the important outcomes of the landmark trials of novel oral anticoagulants in atrial fibrillation *Not currently approved, awaiting evaluation by FDA

RE-LY

Dabigatran vs. warfarin

The 150 mg dose was superior to warfarin for the prevention of stroke

Less hemorrhagic, fatal, ischemic, or disabling stroke

Increased risk MI

Similar major bleeding rates

Less ICH, minor bleeding, life-threatening bleeding More GIB

Strong trend towards all-cause mortality benefit (P=0.051)

Less vascular death (P4.04)

ROCKET-AF Rivaroxaban
vs. warfarin

Rivaroxban is noninferior to warfarin for the prevention of stroke

Similar rates of ischemic stroke

Less hemorrhagic stroke *Similar rate of MI

Less stroke + MI + vascular death

Similar major and nonmajor bleeding rates

Less ICH, critical and fatal bleeding

Increased rate of requiring transfusion, more GIB

Trend towards mortality benefit (P=0.07)

ARISTOTLE

Apixaban
vs. warfarin

Apixaban was superior to warfarin for the prevention of stroke

Similar rates of ischemic stroke

Less hemorrhagic stroke Similar rate of MI

Less ICH, major and minor bleeding

Similar rate of GIB

Less death from any cause (P=0.047)

AVER ROES

Apixaban vs. aspirin

Early study termination due to clear benefit in favor of apixaban

Less ischemic, disabling or fatal stroke risk

Less hospitalization for CV cause

Similar hemorrhagic stroke risk

 

Similar rates of ICH, GIB, major, fatal and nonmajor bleeding

Increased risk of minor bleeding

Trend towards mortality benefit (P=0.07, study terminated early)

ENGAGE AF- Edoxaban* TIMI 48              vs. warfarin

Both doses noninferior to warfarin for the prevention of stroke

Less hemorrhagic stroke (both doses)

More ischemic stroke with 30 mg dose

60 mg dose:

Lower rate of stroke + CV death or stroke + death

Less MACE

Similar rate of MI

Lower rates of bleeding for both doses except 60 mg dose had increased GIB risk Decreased rate of CV death (both doses)

*Decreased rate of all-cause mortality with 30 mg dose

Abbreviations: MI, myocardial infarction; CV, cardiovascular; MACE, major adverse cardiac events; ICH, intracerebral hemorrhage; GIB, gastrointestinal bleeding

Table 4. Criteria for Anticoagulant Dose Reduction

Dabigatran

75 mg BID dose is indicated for a CrCI 15-30 ml/min

Rivaroxaban

15 mg dose is indicated for a CrCI 30-49 nnl/min

Apixaban

2.5 mg BID dose is indicated if 2 or more of the following are present:

  1. Age ?SO
  2. Body weight 560 kg

Serum Creatinine 1.5 mg/dL

Edoxaban

50% dose reduction for any 1 of the following:
CrCI 30-50 ml/min,
Body weight 560 kg Concomitant use of verapamil, quinidine or dronedarone