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