- Describe the basic characteristics of new oral anticoagulants (OACs) - Recognize potential candidates for new anticoagulants for atrial fibrillation and treatment of venous thrombosis

1. New Oral Anticoagulants
Who Gets What for Atrial Fibrillation and
Venous Thromboembolism?
Kathryn Hassell, MD
Professor of Medicine, Division of Hematology
University of Colorado Denver

2. Disclosures
 No financial or commercial conflicts of interest
 No intended off-label discussion

3. Objectives
 Describe the basic characteristics of new oral
anticoagulants (OACs)
 Recognize potential candidates for new
anticoagulants for atrial fibrillation and treatment
of venous thrombosis

4. Outline of Presentation
 Discuss the properties of new oral anticoagulants
(new OACs)
 Compare/contrast with older anticoagulants
 Mechanisms and reversibility
 Review the pivotal trials for atrial fibrillation and
venous thromboembolism
 Glean important and pertinent clinical lessons
 Consider ways to decide who gets what

5. Anticoagulant Mechanisms of Action
Adapted from Eriksson, Ann Rev Med 62:41, 2011
Rivaroxaban
Apixaban
Dabigatran
Warfarin
Fondaparinux
Heparin LWMH
VII

6. Another way to look at it
 Heparin blocks most activated factors
 Low molecular weight heparin blocks two
activated factors: Xa and thrombin (IIa)
 Newer agents block only one factor:
 Anti-Xa agents
 Fondaparinux (Arixtra) s.q. daily
 Rivaroxaban (Xarelto) p.o. every 24 hrs
 Apixaban (Eliquis) p.o. every 12 hrs
 Anti-IIa agents
 Argatroban i.v.
 Bivalirudin i.v,
 Dabigatran (Pradaxa) p.o. every 12 hrs
 Warfarin doesn’t block ANY activated factors

7. Yet another way to look at it
COOH
COOH = carboxyl groups
placed by vitamin K
Factors II, VII, IX, X
Protein unfolds with
activation, revealing
COOH, used to adhere
Factors circulate folded until they are to build a clot
activated during a prothrombotic stress

8. Warfarin: Fewer “Sticky” Factors
Prothrombotic
stimulus
No COOH COOH

9. Heparins/New Oral Anticoagulants:
Inhibition of Activated Factors
COOH
Prothrombotic
stimulus

10. New OACs: “Like drinking your LMWH”
LMWH
 Inhibit activated factors
 No vitamin K impact
 Weight-adjusted dose
 Dependent on renal
clearance
 No medication interactions
 No monitoring needed
 Irreversible
 Injections (ouch)
 Very expensive
NEW ORAL AGENTS
 Inhibit activated factors
 No vitamin K impact
 Fixed dose
 Dependent on renal
clearance (not apixaban)
 Few medication interactions
 No monitoring needed (can’t)
 Irreversible
 Oral
 5-10x cheaper than LMWH

11. Potential Drug Interactions
 Dabigatran: affected by pGP inhibitors or inducers
 Not excluded from clinical trials
 PI notes quinidine contraindicated; use caution with:
 strong inhibitors “like verapamil, clarithomycin and others”
 strong inducers (rifampin, St. John’s wort) reduced effect
 May be impacted by degree of renal insufficiency

12. Potential Drug Interactions
 Rivaroxaban: affected by combined pGP and CYP3A4
 Studies excluded subjects on strong inhibitors (e.g. HIV
meds), strong inducers (e.g. rifampin, phenytoin)
 Package insert (PI) advises avoiding or increasing
rivaroxaban dose if using carbamazepine, phenytoin,
rifampin, St. John’s wort
 May be impacted by degree of renal insufficiency

13. Potential Drug Interactions
 Apixaban: affected by combined pGP and CYP3A4;
per package insert:
 For patients receiving >2.5 mg twice daily, decrease
dose of by 50% when coadministered with strong dual
inhibitors of CYP3A4 and P-gp (e.g., ketoconazole,
itraconazole, ritonavir, clarithromycin)
 For patients receiving 2.5 mg twice daily, avoid
coadministration with strong dual inhibitors
 Avoid concomitant use of strong dual inducers of
CYP3A4 and P-gp (e.g., rifampin, carbamazepine,
phenytoin, St. John’s wort)
 May be impacted by degree of renal insufficiency

14. Potential Drug Interactions
 pGP + CYP3A inhibitors:
 itraconazole, ketoconzole, clarithromycin, azithromycin
 cyclosporin, dronedarone
 verapamil, diltiazem, dronedarone
 lopinavir/ritonavir, conivaptan
 amiodarone, captopril, carvedilol, felodipine, quinidine
 pGP inducers:
 carbamazepine, phenytoin,
 rifampin, tipranavir/ritonavir,
 St. John’s wort
 CYP3A inhibitors: voriconazole (strong), cimetidine
(weak)

15. New Oral Anticoagulants:
Measurement ≠ Monitoring
 Common assays (aPTT, prothombin time)
insensitive and inconsistently affected
 INR is a lab parameter created ONLY for warfarin
 Other measures may better reflect drugs
 Ecarin clotting time (ECT): dabigatran
 Chromogenic factor Xa actvity level (as done for
people with a lupus anticoagulant): rivaroxaban,
apixaban
 Even if drug effect can be measured, not the
same as what results correlated with outcomes in
the studies

16. New Oral Anticoagulants:
Effect on INR
 Dabigatran: therapeutic concentration (NOT clinical
outcomes) correlates with INR range of 1.3-1.7
Stangier, Clin Pharmacokinet 47:285, 2008

17. New Oral Anticoagulants:
Effect on Protime Itself
 Rivaroxaban: therapeutic concentrations (NOT
clinical outcomes) associated with PT 13-23 seconds
Kubitza D, et al. Clin Pharmacol Ther 2005;78:412-421

18. New Oral Anticoagulants:
Effect on aPTT
 Dabigatran: therapeutic concentrations (NOT clinical
outcomes) associated with aPTT 45-55 seconds
Eriksson BI, et al. J Thromb Haemost 2004;2:1573-1580.
Liesenfeld L-H, et al. Br J Clin Pharmacol 2006;62:527-537.

19. New Oral Anticoagulants:
Effect on Coagulation Assays
 Rivaroxaban, Apixaban: “anti-Xa”, so how about an
anti-Xa (“heparin”) assay?
 Relatively linear, with some scatter
 Expected range unknown, no clinical correlations
Barrett Thromb Haemost 104:1263, 2010

20. New Oral Anticoagulants:
Pharmacological Properties
Attribute
Dabigatran
Etexilate
Rivaroxaban Apixaban
Absorption 6.5%
Better in acidic
environment
(tartaric acid added)
Sl delayed high-fat diet
66-80%
Slightly delayed by
food
66%
Not affected by
food
Tmax 1.25-3 h 0.5-4 h 0.5-3 h
Half-Life 7-17 h 3.2-11 h 8-15 h
Metabolism Converted to active
drug by esterases in
plasma or liver
Metabolized by
CYP3A4 (18%) and
CYP212 (14%)
Metabolized by
CYP3A4,1A 1/2
Elimination 80% renal 66% renal 30% renal
Reversibility ?Factor VIIa conc
May be dialyzed
?aPCC conc ?aPCC conc
Giorgi. Expert Opin Pharmacother 12:567, 2011

21. Renal Clearance
 Warfarin: not impacted by renal function
 Dabigatran, rivaroxaban: GFR ≥ 60 ml/min best
 Mean GFR in studies 60-100 ml/min
 Very few subjects had lower GFR
 Will not detect drug accumulation – no monitoring
 Apixaban: only 25% cleared really
 Likely to be better tolerated with lower GFR
 Subgroups defined in pivotal trial for reduced
dose (2.5 mg bid instead of 5 mg bid)
 ≥80 yrs, Cr ≥1.5, wt ≤60 kg
Bauersachs, Thromb Res 129:107, 2012

22. Drug Clearance in the Elderly
 Dabigatran (150 mg bid dosing)
 Healthy elderly (≥ 75 yrs): up to 2x ↑ exposure after 6
dys
 Risk of major bleeding higher in subjects ≥ 75 yrs
 Doubled risk if >80 yrs and CrCl 50-80 ml/min
 Recommended dose of 75 mg bid based on modeling
 Rivaroxaban (20 mg/day dosing)
 Healthy elderly (>75 yrs): ↑ AUC but not max level
 Similar safety & efficacy in subjects >75 yrs
 No differences with mild-moderate renal impairment
 15 mg/day (instead of 20) used for CrCl 30-49 ml/min
Bauersachs, Thromb Res 129:107, 2012

23. Principles Regarding Bleeding
 Anticoagulation doesn’t cause bleeding
 Bleeding occurs when a vessel ruptures
 Anticoagulation doesn’t weaken vessels
 Most people who bleed to death aren’t on
anticoagulation
 Risk of major bleeding, including intracranial,
does not correlate with history of falls
Donze, Am J Med 125:773, 2012
Outcome Placebo
Apixaban
2.5 mg po bid
Apixaban
5.0 mg po bid
Bleeding 22 (2.7%) 27 (3.5%) 35 (4.3%)
Major 4 (0.5%) 2 (0.2%) 1 (0.1%)

24. Anticoagulants and Bleeding
 Risk of major bleeding 0.7-1.2%/year
 Warfarin: the most reversible form of oral
anticoagulation
 Fresh frozen plasma – immediate repletion of
factors, temporary effect
 Vitamin K p.o. or i.v. – production of functional
factors within 6-12 hrs
 New agents: active anticoagulation (e.g. binds
activated factors) – no benefit with FFP/Vit K
 No proven way to reverse anticoagulation
 Twice-daily (e.g. dabigatran or apixaban) may be
preferred with shorter effective half-life

25. Vitamin K and Warfarin
 With excessive anticoagulation, can use vitamin
K to drop INRs:
INR Drop By Time Interval
1 mg i.v. 4-5 6-8 hrs
1 mg s.q. 2-4 24-48 hrs
2.5-5 mg p.o. 4-5 12-24 hrs
 Guidelines (and experience) advise AGAINST
subcutaneous vitamin K for patients on oral
anticoagulation

26. Reversal of New OACs
 FIX THE HOLE that’s bleeding
 Decrease quantity of drug
 Activated charcoal if thought to still be in stomach
 Dabigatran may be dialyzed
 Bypass the drug effect
 Prothrombin complex (PCC), factor VIIa concentrates
anecdotally successful
 Recent study suggested aPCC may work best for anti-
Xa (rivaroxaban) but not anti-thrombin (dabigatran)
 No increased risk of mortality or morbidity (even
in >75 y.o.) related to bleeding with new agents
DeLoughery, Am J Hem 86:586, 2011
Eerenberg, Circulation 124:1508, 2011
Sardar, J Am Geriat Soc 62:857, 2014

27. New OACs: Interruption of Therapy
 Dabigatran (per package insert)
 If CrCl>50 ml/min, hold 1-2 days
 If CrCl<50 ml/min, hold 3-4 days
 Ecarin clotting time may be a marker of activity
 aPTT “approximates” activity (??), INR unreliable
 Rivaroxaban (per package insert)
 Hold for at least 24 hours
 Apixaban (per package insert)
 Hold for at least 24 hours, 48 for interventions
with higher bleeding risk

28. New OACs: Interruption of Therapy
 Bridging with LMWH?? Per package insert:
 Dabigatran: interruption has been associated
with risk of stroke and thrombotic events
 “consider administration of other anticoagulant”
 Rivaroxaban: events occurred when moving from
the drug back to warfarin during clinical trials
 “consider administration of other anticoagulant”
 Apixaban: bridging not recommended
 Similar half-life to LMWH, no clear theoretical
reasons to bridge

29. New OACs: Switching Drugs
 On warfarin, going to a new OAC
 Hold warfarin for ~2-3 days
 Remember, the lower the daily warfarin dose, the
longer it takes to clear the system
 If in doubt, check an INR before starting the new
OAC
 Start new drug once INR is at/below desired
range (e.g. <2, <2.5, <3)
 Remember, new OACs fully therapeutic within
2-3 hours

30. New OACs: Switching Drugs
 On a new OAC, going to warfarin
 New drugs affect INR, so need to hold for 24-48
hours before it can be used to measure warfarin
 May see some effect even at very low drug
concentrations
 If worried about thrombotic risk, start LMWH in
place of new drug while making the transition
 Discontinue LMWH once INR >2.0 (or into
desired range) for 24 hours

31. New OACs and Adherence
 Onset of activity within 2-3 hours
 Rapid return to therapeutic benefit
 Loss of activity within 12-24 hours
 Missed doses may really be “missed” – no lingering
effect as is true with warfarin
 Once-daily may be easier to remember
 Cannot assess drug levels: drug failure or
failure to take the drug?
 PT/INR, aPTT insensitive
 No data regarding anti-Xa levels (rivaroxaban,
apixaban)

32. New OACs: Different than Warfarin
WARFARIN
 Production of dysfunctional
factors
 Changes the body
 Effect through vitamin K
 Multiple medication
interactions
 Dose adjusted
 Can/must be monitored
 Can be used in renal
failure
 Reversible
NEW ORAL AGENTS
 Inhibition of activated factors
 No effect unless factors active
 No vitamin K (diet) impact
 Few medication interactions
 Fixed dose
 No monitoring (can’t)
 Dependent on renal
clearance (not apixaban)
 Irreversible

33. New Oral Anticoagulants (OACs)
Indication
Dabigatran
Etexilate
(Pradaxa)
Rivaroxaban
(Xarelto)
Apixaban
(Eliquis)
Atrial fibrillation 150 mg bid 20 mg/dy 5 mg bid
↓ renal fctn (GFR) CrCl 15-30:
75 mg bid
CrCl 15-30:
15 mg/dy
2.5 mg bid
Acute VTE 5-10 days of
LMWH, then
150 mg bid
15 mg bid x
21 days, then
20 mg/day
10 mg bid x
7 days, then
5 mg bid
FDA
Wittkowsky, J Thromb Thrombolysis 29:182, 2010; Approved
Giorgi, Expert Opin Pharmacother 12:567, 2011;
DeLoughery, Am J Hem 86:586, 2011

34. Statistical vs. Clinically Relevant (?)
Pause for Perspective
5
4
3
2
1
0
p<.05 p<.05
Stroke ICH
New Drug Old Drug
100
80
60
40
20
0
Stroke ICH
New Drug Old Drug

35. New OACs: Atrial Fibrillation
 Comparator: warfarin
 Consider time in therapeutic range (TTR)
 Usual thrombotic outcomes (%/year): non-inferiority
design
 Composite of stroke, systemic embolism
 Usual hemorrhagic outcomes:
 Major bleeding
 Clinically relevant, non-major bleeding
 Typical duration of study: 2 years
 EXCLUDES valvular disease/artificial heart
valves

36. Dabigatran vs. Warfarin for A Fib:
RE-LY
Connolly, NEJM 361:1139, 2009
+p<.001
+
1.11
3.64
2.71
*p<.05
*
0.3
1.69
4.13
3.36
0.74
5
4
3
2
1
0
Stroke /
Embolism
Death Major
Bleeding
ICH
Percentage/Year
Dabigatran 150 mg bid Warfarin
Subjects: 18,113
Mean age: 71 yrs
Mean CHADS: 2.1
Mean CrCl: NR
% ASA use: 39%
Dosing:
Dabigatran: 110 mg bid
or 150 mg bid
Warfarin: INR 2-3
Primary Outcome:
Stroke/systemic embolism
Warfarin TTR: 64%
- Side effect of dyspepsia in 11.8% vs. 5.8%
GI bleeding 1.5% vs. 0.9% (p<.001)
- CrCl>30 ml/min to be on study
- No differences noted in patients on
amiodarone, H2-receptor antagnoists,
proton pump inhibitors

37. Rivaroxaban vs. Warfarin for A Fib:
ROCKET-AF
2.1
Patel, NEJM 365:883, 2011
4.5
3.6
*p=.02
*
0.5
2.4
4.6
3.4
0.7
5
4
3
2
1
0
Stroke
Embolism
Death Major
Bleeding
ICH
Percentage/Year
Rivaroxaban Warfarin
Subjects: 14,264
Median age: 73 yrs
Mean CHADS: 3.47
Median CrCl: 67 ml/min
% on ASA: 35%
Dosing:
Rivaroxaban: 20 mg q dy
Warfarin: INR 2-3
Primary Outcome:
Stroke/systemic
embolism
Warfarin TTR: 55%
-Use of CYP3A4 or P-glycoprotein
inhibitors prohibited
-As treated safety population 1.7% vs.
2.2% favoring rivaroxaban (p=.02)
-No difference across INR ranges

38. Apixaban vs. Warfarin for A Fib:
ARISTOTLE
+p=.01
+
1.27
3.52
2.18
*p<.001
0.33
1.6
3.94
3.09
0.8
5
4
3
2
1
0
Thrombosis Death Major
Bleeding
ICH
Percentage/Year
Apixaban Warfarin
-Excluded creat >2.5 mg/dl, CrCl<25
ml/min
-Interaction between bleeding and
-diabetes: apixaban=warfarin if DM
-renal function: apixaban better than
warfarin with severe renal failure
*
*
Subjects: 18,206
Median age: 70 yrs
Mean CHADS: 2.3
CrCl <50 ml/min: 16%
% on ASA: 31%
Dosing:
Apixaban: 5 mg bid or
2.5 mg bid (renal/age)
Warfarin: INR 2-3
Primary Outcome:
Stroke/systemic embolism
Warfarin TTR: 66%
Granger, NEJM 365:981, 2011

39. Meta-Analysis of New Agents for A Fib
 Three RCTs including 44, 563 subjects
 RE-LY (Dabigatran)
 ROCKET AF (Rivaroxaban)
 ARISTOTLE (Apixaban)
 As compared to warfarin:
Miller, Am J Cardiol, amjcard.2012.03.049
Stroke,
Systemic
Embolism
0.78
(0.67-0.92)
Major
Bleeding
0.88
(0.71-1.09)
Vascular
Mortality
0.87
(0.77-0.98)
ICH 0.49
(0.36-0.66)
All-Cause
Mortality
0.88
(0.82-0.95)
GI Bleeding 1.25
(0.91-1.72)

40. ACCP 2012 Guidelines for A Fib
CHADS2 score
One point each for:
- CHF
- Hypertension
- Age ≥75
- Diabetes mellitus
- Stroke/TIA history (2 pts)
Score Therapy
0
Nothing or
ASA 75-325 mg
≥1
Oral anticoagulant
(OAC)
or
ASA+clopidogrel
(if not OAC candidate)
If OAC: favor dabigatran over warfarin
Rivaroxaban or apixaban instead of warfarin?
You, Chest 141(Suppl):e531S, 2012

41. New OACs: Treatment of VTE
 Usual comparator: LMWH→ warfarin
Warfarin goal INR 2-3; remember TTR
 Usual outcomes:
 Recurrent VTE
 Bleeding
 Usual duration of therapy
 3-6 months
 Extension studies (compared to placebo or
warfarin) for up to 2 years

42. Dabigatran vs. Warfarin for VTE:
RE-COVER
2.4
0.5
NEJM 361:2342, 2009
*p=.002
1.6
5.6
2.1
0.6
1.9
8.8
10
8
6
4
2
0
Primary
Outcome
All-Cause
Death
Major
Bleed
+ Clin Rel
Bleed
Percentage
Dabigatran Warfarin
Subjects: 2564
Mean age: 55 yrs
Isolated PE: 21%
History of VTE: 25%
Weight: 85 (38-175) kg
Est CrCl: 105 ml/min
Dosing:
Dabigatran 150 mg bid
Warfarin INR 2-3
Primary Outcome:
VTE/related death
Warfarin TTR: 60%
Treated for a mean of 3 days with
standard therapy before randomization
More dyspepsia with dabigatran
(2.9 vs. 0.6, p<0.001)
2% were cancer patients
*

43. Rivaroxaban vs. Warfarin for VTE:
EINSTEIN –DVT
Subjects: 3445
Mean age: 55 yrs
Isolated PE: 0.6%
History of VTE: 19%
Thrombophilia: 7%
Weight>100 kg: 14%
CrCl<50 ml/min: 7.5%
Dosing:
Rivaroxabn: 15 mg bid x
3 wks, then 20 mg/day
LMWH+Warfarin INR 2-3
Primary Outcome: VTE
Warfarin TTR: 58%
*p<.001
non-inferior
*
2.1 2.2
NEJM 363:2499, 2010
0.8
8.1
3 2.9
1.2
8.1
10
8
6
4
2
0
Thrombosis Death Major
Bleeding
All Bleeding
Percentage
Rivaroxaban Warfarin
-Excluded
-CrCl <30 ml/min
-strong CYP3A4 inhibitors (e.g. HIV meds)
or inducers (e.g. carbamazepin, dilantin)

44. Rivaroxaban vs. Warfarin for VTE:
EINSTEIN-PE
*p<.003^
*non-inferiority
*
2.1 2.4
NEJM 366:1278, 2012
^
1.1
10.3
1.8 2.1 2.2
11.4
12
10
8
6
4
2
0
Thrombosis Death Major
Bleeding
All Bleeding
Percentage
Rivaroxaban Warfarin
-Excluded
-CrCl <30 ml/min
-strong CYP3A4 inhbiitors (e.g. HIV meds)
or inducers (e.g. carbamazepine, dilatin)
Subjects: 4817
Mean age: 57 yrs
Unprovoked: 64%
History of VTE: 19%
Thrombophilia: 5%
Weight>100 kg: 14%
CrCl<50 ml/min: 8%
Dosing:
Rivaroxabn: 15 mg bid x
3 wks, then 20 mg/day
LMWH+Warfarin INR 2-3
Primary Outcome: VTE
Warfarin TTR: 62.7%

45. Apixaban vs. Warfarin for VTE:
AMPLIFY
Subjects: 5395
Mean age: 57 yrs
Unprovoked: 90%
History of VTE: 16%
Thrombophilia: 2.5%
Weight>100 kg: 19%
CrCl<50 ml/min: 6%
Dosing:
Apixaban: 10 mg bid
x 7 dys, then 5 mg bid
LMWH+Warfarin INR 2-3
Primary Outcome: VTE
Warfarin TTR: 61%
2.3
1.5
NEJM 369:799, 2013
0.6
4.3
2.7
1.9 1.8
9.8
12
10
8
6
4
2
0
Thrombosis Death Major
Bleeding
All Bleeding
Percentage
Apixaban Warfarin
*p<.003^
*non-inferiority
^
^
*
-Excluded
-CrCl <25 ml/min or serum Cr >2.5 mg/dl
-potent CYP3A4 inhibitors
-Cancer: 2.6%

46. New OACs: Treatment of VTE
 Recurrent thrombosis: equal to warfarin
 Bleeding: maybe less than warfarin
 Population included some
 Thrombophilias
 Wt >100kg
 Relatively few with renal insufficiency
 Exception is apixaban, which is minimally renally
cleared

47. Management of VTE: ACCP 2012
 Acute Management: active anticoagulation
 Subcutaneous LMWH
 Intravenous or subcutaneous UFH
 Fondaparinux
 Rivaroxaban?, Apixaban?
Kearon, Chest 141:e419S, 2012

48. Management of VTE: ACCP 2012
 Transition to chronic phase of anticoagulation
 Initiation of VKA (warfarin) on first day (if not
using rivaroxaban or apixaban?)
 Continue LMWH/UFH until INR stable and ≥ 2.0
for at least 24 hours
 Treatment with LMWH/UFH for at least 5 days
 Switch to dabigatran?
Kearon, Chest 141:e419S, 2012

49. Cost Effectiveness
 Drug costs ~AWP (not the same as copay/coverage)
 Warfarin: $0.22-0.25/day
 Enoxaparin (prophylaxis): $30-40/day
 Enoxaparin (treatment): $50-100/day
 New Agents: $4-$8/day
 Cost-effectiveness of therapy depends on CHADS
score for dabigatran in atrial fibrillation
 CHADS score 0: ASA
 CHADS score 1-2: warfarin, if INR stable (TTR>57%)
and low bleeding risk
 CHADS score ≥3: dabigatran, unless INR very stable
(TTR>75%)
Shah, Circulation 123:2562, 2011

50. Other Scenarios: Cancer
 In patients with DVT or PE, and cancer, per
ACCP:
 LMWH over VKA
CLOT study
Lee, NEJM 349:146, 2003
 If not treated with LMWH, ACCP recommends VKA
over rivaroxaban or dabigatran (“too few patients”)
Kearon, Chest 141:e419S, 2012

51. Other Scenarios: Antiphospholipid
Antibody Syndrome
 RAPS Study (Cohn, UK)
 Rivaroxaban vs. warfarin for 3 months
 Study characteristics:
 Population: thrombotic APS ± SLE, single episode VTE
 Endpoint: endogenous thrombin potential at 4 months
 If successful, will endorse clinical use (!)
 No plans for clinical outcomes study
 However, we routinely use LMWH if
concerned about warfarin and this was never
studied, either
 Remember, new OACs act like LMWH

52. Agent Selection – Who Gets What?
 New OACs Instead of LMWH
 Basically similar properties – irreversible,
unmonitored - except new agents require:
 Better (e.g. >60 ml/min) renal function, probably
 Awareness of potentially interacting meds
 Ability to take p.o. medication
 Arguably, new agents are at least as efficacious
and safe, easier to administer and cheaper

53. Agent Selection – Who Get’s What?
 New OACs Instead of Warfarin
 Normal renal function; low risk for rapid progression to
renal insufficiency
 Low bleeding risk: unlikely to need reversal
 Patients with unstable INRs: new agents likely cost-effective
in addition to safety/efficacy advantage
 Adherence: missed dose will be missed!
 However, immediate return to adequate anticoagulation once
dosing resumed…
 Drug monitoring not “needed” to assess adherence,
interpret clinical events
 Not on potentially interacting drugs

54. Agent Selection – Who Gets What?
 Warfarin Instead of New Anticoagulants:
 Renal insufficiency (GFR<60? <30?), ESRD
 High bleeding risk: most easily reversed
 Patients with stable INR: most cost-effective
 Difficulty with adherence: least harm with missed dose
 History of multiple events (bleeding or clotting)
 Can measure INR to assess degree of anticoagulation relative
to event (INR too high or too low)
 On medications that may interact with new
anticoagulants, especially those that inhibit drug
clearance and in patient with fluctuating mild-moderate
renal insufficiency

55. Agent Selection – Who Get’s What?
 New Anticoagulants Instead of Warfarin
 Normal renal function, low risk for rapid progression to
renal insufficiency
 Low bleeding risk: unlikely to need reversal
 Patients with unstable INRs: new agents likely cost-effective
in addition to safety/efficacy advantage
 Adherence: missed dose will be missed!
 However, immediate return to adequate anticoagulation once
dosing resumed…
 Drug monitoring not “needed” to assess adherence,
interpret clinical events
 Not on potentially interacting drugs