Soheir Adam, MD

Asst. Professor 

Duke University Medical Center

Durham, NC

THE BATTLE OF ORAL 

ANTICOAGULANTS
What number of patients in your practice are currently 

on new oral anticoagulants ? 

 None

 1 to 10

 10 to 20

 >20

AUDIENCE POLL
SECONDARY HEMOSTASIS

TF/FVIIa 

FX

FXa

FIX

FIXa 

FII FIIa 

Fibrinogen

Fibrin

FXIa FXI

FIIa 

FVIIIa 

FVa

FVIII 

FV FIIa 

FIIa 

FIIa 
Vitamin K-dependent proteins include 

coagulation factors II, VII, IX, and X, proteins C 

and S, and several matrix and bone-related 

proteins.

Highly effective in preventing recurrent VTE and 

stroke/ peripheral embolism in patients with 

atrial fibrillation and prosthetic heart valves

No long-term side effects (bleeding and 

teratogenicity) 

Inexpensive, once daily dose

 INR monitoring :“forced” compliance

Specific antidote (vitamin K), but reversal takes 

time

VITAMIN K ANTAGONISTS
 

Bleeding

Thrombosis

Thrombosis

NARROW THERAPEUTIC WINDOW 

Dose (concentration) of Anticoagulant or 

INR 

SAFE 

RANGE 
Need to monitor regularly (INR)

Interactions with multiple foods and 

drugs

Slow onset and offset of action

Genetic contributions to dose 

variability

ADDITIONAL LIMITATIONS OF WARFARIN
In your opinion, what is the biggest challenge you face 

while managing patients on long-term 

anticoagulation? 

1-Lack of compliance

2-Drug interactions

3-Patient not getting tested as directed

4-Lack of communication or patient education

5-Patient not reporting relevant complications

AUDIENCE POLL
100 North American patients with AF and at 

least one additional risk factor for stroke

One half receive 

warfarin

One half do not 

receive warfarin

One half adequate 

Warfarin treatment

One half inadequate

warfarin treatment

1-2 million inadequately treated or untreated AF patients

who will experience 50,000-100,000 strokes

WHY DO WE NEED ADDITIONAL 

OPTIONS?
NEW ORAL ANTICOAGULANTS TARGET

INDIVIDUAL FACTORS

Cabral KP & Ansell J. Nat Rev Cardiol 2012;9:385-91
Dose (concentration) of 

Anticoagulant 

 

SAFE

Thrombosis RANGE

Bleeding

THERAPEUTIC RANGE OF THE NOAC’S
Vitamin K Antagonists FXa Inhibitors DTI

Warfarin Rivaroxaban Apixaban Edoxaban Dabigatran

Mode of action

Inhibition of hepatic 

synthesis of vitamin Kdependent coagulation 

factors

Direct inhibition of 

FXa Direct inhibition of FXa Direct inhibition of FXa

Direct inhibition of clotbound and free thrombin 

(FIIa)

Time to peak effect 

(hours) 72–96 0.5–3 3 1.5 2–3

Half-life hours 20–60 5–9 (9–13 in elderly) 8–13 9–11 14–17

Bioavailability % 100 80 66 50 6.5

Recommended 

therapeutic dose and 

frequency

Adjusted-dose based on 

INR; once daily 20 mg; once daily 5 mg; twice daily 30 mg or 60 mg; once daily 150 mg; twice daily

Monitoring Required using INR

Not required

In case of hemorrhage 

or renal impairment, 

FXa-dependent 

assays may be used

Not required due to 

predictable 

pharmacokinetics

In hemorrhage or 

renal impairment, 

FXa-dependent 

assays may be used

Not required due to 

predictable 

pharmacokinetics

Not required except in 

subgroups such as patients 

with renal impairment 

Ecarin clotting time can be 

used if needed

Renal excretion 1% excreted unchanged 

in the urine 66% renal elimination 50% renal elimination 45% renal elimination 80% renal elimination 

Interactions

CYP2C9, CYP1A2, 

CYP3A4 inhibitors

Dietary vitamin K

Potent CYP3A4 

inhibitors and Pglycoprotein inhibitors

Potent CYP3A4 

inhibitors

P-glycoprotein 

inhibitors

P-glycoprotein inhibitors 

Proton pump inhibitors
Vitamin K Antagonists FXa Inhibitors DTI

Warfarin Rivaroxaban Apixaban Edoxaban Dabigatran

Drug reversal

Vitamin K, fresh frozen 

plasma, prothrombin complex 

concentrate, recombinant 

FVIIa

Prothrombin complex

FVIIa ?

No available antidote No available antidote

It is partially dialyzable

Prothrombin complex

FVII ?

Precautions

Severe active bleeding, 

pregnancy, breast feeding, 

documented hypersensitivity

Severe renal impairment 

(glomerular filtration rate < 30 

mL/min/1.73m2)

Severe active 

bleeding; severe 

renal impairment

Severe active 

bleeding; severe renal 

impairment

Severe active 

bleeding; severe renal 

impairment

Severe active bleeding, 

severe renal impairment

FDA indications

1. Prophylaxis and 

treatment of 

thromboembolic

complications 

associated with AF and 

or cardiac valve 

replacement

2. Prophylaxis and 

treatment of venous 

thrombosis and its 

extension, pulmonary 

embolism

3. Reduction in the risk of 

death, recurrent 

myocardial infarction, 

and thromboembolic

events such as stroke 

or systemic 

embolization after 

myocardial infarction 

1-Prevention of VTE 

in patients 

undergoing 

orthopedic surgery 

2- Prevention of 

stroke in AF

None None Prevention of stroke in AF
The relationship of Dabigatran concentration to various 

coagulation assays.
Mechanism Dabigatran Rivaroxaban 

P-gp inhibition Interacting 

drug

∆ exposure Interacting 

drug

∆ exposure

Ketoconazole +150% Ketoconazole +160% 

Quinidine +53% 

Amiodarone +60% 

Verapamil +50% 

P-gp induction Rifampicin -67% Rifampicin -50% 

St John’s Wort Not

determined

St John’s Wort Not

determined

CYP3A4 

inhibition

Ketoconazole +160% 

Clarithromycin +50% 

Ritonavir +50% 

CYP3A4 

induction

Rifampicin -50% 

St John’s Wort Not

determined
Apixaban Dabigatran Rivaroxaban 

Oral activated 

charcoal

Yes Yes Yes

Hemodialysis No Yes No

Hemoperfusion with 

activated charcoal

Possible Yes Possible

FFP No No No

Activated FVII a Unclear Unclear Unclear

3-factor PCC

(II, IX, X, no VIIa) 

Unclear Unclear Unclear

4-factor PCC 

(not in the US)

Possible Possible Possible

Kaatz S et al, Am J Hematol. 2012 May
Reversal Of Rivaroxaban And Dabigatran

Factors II, VII, IX AND X

50 IU /kg

Prothrombotic properties
VA-ESP PROJECT 

The Comparative Effectiveness of Warfarin and 

Newer Oral Anticoagulants for the Long-term 

Prevention and Treatment of Arterial and 

Venous Thromboembolism. 

Soheir Adam, MD; Jennifer McDuffie, PhD; Thomas 

Ortel, MD, PhD; Avishek Nagi, John Williams Jr., MD
 Topic development

 Key questions

 Protocol

 Systematic searches of the literature

 Study selection via eligibility criteria

 Screening

 Full text review

 Data abstraction and quality assessment

 Data synthesis and report generation

 Peer review

OUTLINE OF METHODS
For patients with chronic nonvalvular AF, 

what is the comparative effectiveness of 

long-term anticoagulation using newer oral 

anticoagulants versus warfarin on stroke 

incidence, mortality, health-related quality of 

life (HRQOL), and patient treatment 

experience ?

KEY QUESTION 1
For patients with venous 

thromboembolism, are there differential 

effects of newer oral anticoagulants versus 

warfarin or low molecular weight heparins 

on recurrent thromboembolism, mortality, 

HRQOL, and patient treatment experience?

KEY QUESTIONS 2
For patients with mechanical heart 

valves, what is the comparative 

effectiveness of newer oral 

anticoagulants versus warfarin on the 

incidence of thromboembolic 

complications, mortality, HRQOL, and 

patient treatment experience? 

No studies identified

KEY QUESTION 3
When used for long-term anticoagulation 

treatment, what is the nature and 

frequency of adverse effects for newer 

oral anticoagulants versus warfarin?

KEY QUESTION 4
 Databases : MEDLINE® (via PubMed®), Embase®, and 

the Cochrane Database of Systematic Reviews for 

English-Language

 Search terms included new or novel anticoagulants; 

direct thrombin inhibitors, including dabigatran, and 

ximelagatran; factor Xa inhibitors, including 

edoxaban, rivaroxaban, apixaban, betrixaban, 

YM150; and the names of the conditions of 

interestóatrial fibrillation, venous thromboembolism, 

and mechanical heart valve.

Consult master librarian

Key words and MeSH Analyzer

LITERATURE SEARCH STRATEGY
 Supplemental searches

Adverse events:

 Observational studies

 FDA databases

ClinicalTrials.gov for completed but unpublished 

studies

SUPPLEMENTAL SEARCHES
 RCT or a secondary data analysis from an RCT comparing a new oral 

anticoagulant to an eligible comparator (warfarin and LMWH)

 Sample population with history of chronic nonvalvular AF, deep venous 

thromboembolism, or mechanical valve replacement. Atrial fibrillation may be 

assessed by any accepted threshold on any valid diagnostic tool (e.g., 

electrocardiogram and/or echocardiogram).

 Sample population ≥18 years of age

 Outpatient setting (community clinic, medical clinic or office, or transitioning 

from inpatient for acute treatment to long-term outpatient management)

 Random allocation to the intervention groups

 Reports at least one of the included outcomes:

 KQs 1–3: The main outcome is a thromboembolic event. Thromboembolic events must be 

documented radiologically and produce clinical symptoms. Asymptomatic thromboembolism 

(e.g., detected on surveillance imaging) will not be included. 

 KQs 1–3: Other outcomes are mortality, health-related quality of life, and patient treatment 

experience—the latter two measured by a validated instrument.

 KQ 4: Adverse effects will be specific to the interventions examined and will include bleeding 

complications, myocardial infarction, and gastrointestinal adverse effects.

 Study duration of at least 6 months (acute treatment) or at least 12 months 

(chronic treatment)

 Peer-reviewed publication

STUDY INCLUSION CRITERIA
 Non-English language publication

 Cross-sectional studies

 Pregnant population

 Studies with sample size <50

 Studies with <6 months postrandomization outcomes

STUDY EXCLUSION CRITERIA

 Extraction of pertinent information from each 

eligible article into a customized, uniform database 

in DistillerSR® 

 Performed by 1st reviewer and independently overread by a 2nd reviewer

 Disagreements are resolved by discussion and 

consensus or referral to a 3rd reviewer

DATA ABSTRACTION 
 Elements rated for RCTs

 Adequacy of randomization

 Adequacy of allocation concealment

 Comparability of groups at baseline

 Blinding of subjects and/or investigators

 Completeness of and differential loss to followup

 Management of incomplete data

 Validity of outcome measures

 Potential conflicts of interest

 Elements rated for observational studies

 Selection bias

 Performance bias

 Detection bias

 Reporting bias

 Reference: Agency for Healthcare Research and Quality’s 

(AHRQ) Methods Guide for Effectiveness and Comparative 

Effectiveness Reviews

QUALITY ASSESSMENT
 Summary table of key outcomes

 Quantitative meta-analysis, if feasible

 DerSimonian and Laird random effects model 

 Dichotomous outcomes combined using RR (summary estimates and 95 

percent confidence intervals).

 When the number of studies was sufficient we conducted a subgroup 

analysis of mixed treatment effects to compare treatment effects by 

drug class. 

 Continuous outcomes combined using standardized mean difference and 

a random effects model

 Tests for statistical heterogeneity using graphical displays and test 

statistics (I2) 

 Qualitative synthesis otherwise (e.g., too few studies or subgroup 

and sensitivity analyses)

 Assessment of publication bias

DATA SYNTHESIS
 Assessment of four domains

 Risk of bias

 Consistency

 Directness

 Precision

 The strength of the evidence for the proposed answer to each 

key question is graded – high, moderate, low or insufficient

 Reference: AHRQ’s Methods Guide for Effectiveness and 

Comparative Effectiveness Reviews

STRENGTH OF EVIDENCE
Study, Year (Reference) Participants Intervention Group Control Group

Patients, n Men, n (%) Mean 

Age, y

Baseline 

CHADS2

Score ≥3, n 

(%)

Unprovoked, 

n (%)

Drug (Class) Dosage Drug Time 

in 

Range, 

%

Chronic nonvalvular atrial fibrillation

RE-LY, 2009 (32) 18 113 7649 (63.2) ≥70 3914 (32.3) – Dabigatran 

(DTI)

150 mg, 

twice 

daily

Warfarin 64.0

ARISTOTLE, 2011 

(33)

18 201 11 785 

(64.7)

≥70 5508 (30.2) – Apixaban 

(FXa inhibitor)

5 mg, 

twice 

daily

Warfarin 66.0

ROCKET AF, 2011 

(34)

14 264 8601 (60.3) ≥70 12 411 

(87.0)

– Rivaroxaban 

(FXa inhibitor)

20 mg, 

once daily

Warfarin 55.0

VTE

EINSTEIN-DVT, 2010 

(36)

3449 1960 (56.8) 50–60 – 2138 (62.0) Rivaroxaban 

(FXa inhibitor)

20 mg, 

once daily

Warfarin 57.7

RE-COVER, 2009 (35) 2564 1484 (58.4) 50–60 – 0 Dabigatran 

(DTI)

150 mg, 

twice 

daily

Warfarin 60.0

EINSTEIN-PE, 2012 

(16)

4833 2556 (52.9) 50–60 – 3117 (64.5) Rivaroxaban

(FXa inhibitor)

20 mg, 

once daily

Warfarin 62.7

ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; 

DTI = direct thrombin inhibitor; FXa = factor Xa; RE-LY = Randomized Evaluation of Long-Term Anticoagulation Therapy; 

ROCKET AF = Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and 

Embolism Trial in Atrial Fibrillation; VTE = venous thromboembolism.

Table 1. Study Characteristics

Outcome Studies 

(Patients), n

Study 

Design

Quality Consistency Directness Precision Strength of 

Evidence

Effect Estimate (95% 

CI)

Atrial fibrillation

All-cause mortality 3 (44 442) RCT Good Consistent Direct Precise High RR, 0.88 (0.82 to 0.96)

RD, 8 fewer deaths/1000 

patients (3 to 11 fewer) 

VTE-related 

mortality

2 (30 299) RCT Good Some 

inconsistency

Direct Some 

imprecision

Moderate RR, 0.77 (0.57 to 1.02) 

Ischemic stroke 3 (44 442) RCT Good Consistent Direct Some 

imprecision

Moderate RR, 0.89 (0.78 to 1.02) 

Hemorrhagic stroke 3 (44 442) RCT Good Some 

inconsistency

Direct Some 

imprecision

Moderate RR, 0.48 (0.36 to 0.62)

RD, 4 fewer hemorrhagic 

strokes/1000 patients (2 to 

5 fewer)

DVT/PE

All-cause mortality 3 (10 805) RCT Good Consistent Direct Some 

imprecision

Moderate RR, 0.97 (0.72 to 1.30)

VTE-related 

mortality

3 (10 805) RCT Good Consistent Direct Important 

imprecision

Low RR, 1.00 (0.48 to 2.10)

Recurrent DVT/PE 3 (10 820) RCT Good Some 

inconsistency

Direct Some 

imprecision

Moderate RR, 0.95 (0.71 to 1.27)

Table 2. Summary of Strength of Evidence for Major Outcomes, by Diagnosis

DVT = deep venous thrombosis; PE = pulmonary embolism; RCT = randomized, controlled trial; RD = risk difference; RR = risk ratio; 

VTE = venous thromboembolism.


Outcome Strength of 

Evidence

Summary

Fatal bleeding Moderate The risk for fatal bleeding was lower with NOACs (RR, 0.60 [95% CI, 

0.46 to 0.77]). Risk difference was 1 fewer death per 1000 patients.

Major bleeding Low The risk for major bleeding was lower with NOACs (RR, 0.80 [CI, 0.63 to 

1.01), but the CI included no effect. In 2011, the FDA issued a notice that 

it was evaluating reports of serious bleeding with dabigatran.

Gastrointestinal bleeding Low The risk for gastrointestinal bleeding was increased with NOACs (RR, 

1.30 [CI, 0.97 to 1.73]).

Myocardial infarction Low The risk for myocardial infarction was not different with NOACs (RR, 

0.95 [CI, 0.81 to 1.11]). In a subgroup analysis, the risk was increased 

with dabigatran (RR, 1.35 [CI, 0.99 to 1.85]) compared with FXa

inhibitors (RR, 0.84 [CI, 0.70 to 1.01]) (P = 0.010). 

Discontinuation due to adverse effects Low Discontinuation due to adverse effects was higher with NOACs (RR, 1.23 

[CI, 1.05 to 1.44]), but the CI was large and included no effect. In 

subgroup analysis, rates of discontinuation were higher for dabigatran than 

for FXa inhibitors.

Liver dysfunction Low The risk for liver dysfunction was not different with NOACs (RR, 0.82 

[CI, 0.56 to 1.18]).

Table 3. Summary of the Strength of Evidence for Adverse Effects for Atrial Fibrillation and Venous Thromboembolism Combined

FDA = Food and Drug Administration; FXa = factor Xa; NOAC = new oral anticoagulant; RR = risk ratio.
Bleeding :

 seven case reports; typically older patients >75 years and 

some with fatal outcome. Other risk factors include renal 

impairment and concomitant thrombolytic therapy.

Treatment failure:

 Two case reports; thrombolytic therapy successfully used in 

both.

Observational Studies
RELY STUDY

 40% were ≥ 75 years

 Higher risk of extracranial but not intracranial bleeding with 

Dabigatran vs. Warfarin in patients >75 years

 Not in younger patients

 Greatest benefit of Dabigatran 150 mg bid was seen in those 

<65

 Dabigatran 110 mg not superior to 150 mg bid in >75 yo

 Dose modification in elderly is thus unnecessary
RELY STUDY 

 Gastrointestinal bleeding increased

 Lower bioavailability which increases the concentration of 

active drug in the feces.

 Discontinuation of drug higher in dabigatran vs. warfarin (21% 

to 17%) mainly due to GI symptoms 

 GI symptoms increased due to Tartaric acid(necessary for 

absorption) and a high concentration of active drug in the 

colon.

Blech, Drug Metab Dispos. 2008

Connolly, N Engl J Med. 2009

Shulman, Blood, 2012
ROCKET-AF STUDY

 Rivaroxaban associated with increased risk of GI bleeding

 Dabigatran and rivaroxaban may complicate the management 

of inflammatory bowel disease, angiodysplasia and 

diverticulosis.

Patel, N Eng J Med. 2011
Myocardial infarction: 

 SR including seven RCT’s ; two on AF, three on 

thomboprophylaxis in orthopedic surgery and one on acute 

coronary syndrome.

 Three compared dabigatran to adjusted dose warfarin

 RE-LY study dominated other RCT’s

 Dabigatran was associated with a higher risk for MI than 

control treatments (RR, 1.32 [CI, 1.02 to 1.69]) 

Subanalysis

Uchino et al., Arch Intern Med. 2012
Dabigatran 

 In 2011 there were 3781 reports attributed to dabigatran; 

2367 hemorrhages, 291 acute renal failure, 644 strokes, 542 

deaths and 15 cases of suspected liver failure.

 More often in the elderly >80 years

 Recommendation to re-evaluate dose in elderly and those with 

renal impairment.

Rivaroxaban 

 Post-treatment discontinuation events higher with rivaroxaban

compared to ADW (HR, 1.51 [CI, 1.02 to 2.23]) 

 Could be attributed to subtherapeutic INR when transitioning 

from ADW to rivaroxaban

FDA Reports
 NOAC viable option for patients on long-term anticoagulation

 Benefits compared to warfarin are evident in centers with less 

warfarin therapy control

 Older adults and those were renal failure may need dose 

adjustments

 Long-term complications not evaluated thus far

 No head to head comparisons to evaluate drug classes or 

individual drugs

 FDA issued reports on bleeding complications

 Cost effective but not cost saving

Key Points
In AF populations: 

 NOAC are superior to adjusted dose warfarin for some clinical 

outcomes, including mortality and hemorrhagic stroke

In VTE populations: 

 Main clinical outcomes were similar in NOAC treatment groups 

compared to adjusted dose warfarin

Summary And Key Points
Bleeding by drug class

 Fatal bleeding was statistically significantly lower with FXa

than with warfarin (<0.001) but not with dabigatran (p=0.175)

 Gastrointestinal bleeding showed a non-statistical increase 

with dabigatran compared to FXa. 

Adverse events by drug class

 Discontinuation due to adverse events higher with 

dabigatran(RR, 1.62 [CI, 1.23 to 2.15]; low SOE) than FXa

inhibitors (RR, 1.08 [CI,0.89 to 1.30]) (P 0.024 for subgroup 

comparison) 

 Myocardial infarction higher with dabigatran treatment ( RR, 

1.35 [CI, 0.99 to 1.85]), compared to treatment with FXa

inhibitors (RR 0.84[CI, 0.70to 1.01]).

Summary And Key Points
 Elderly patients >75 

 Patients with a CrCl <30ml/min

 Patients with mechanical heart valves

 Patients with GI disease

 Non-compliant patients

Is Warfarin Still The Preferred Option?
Will you change your practice based on the information 

presented today ?

 Highly likely

 Likely

 Unlikely

 Not sure

AUDIENCE POLL