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42 Anticoagulants
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Table5.2 Anticoagulation dosing algorithm for INR range 2.0–3.0
INR Action
<1.5 Increase weekly dose by 10–15%, repeat INR in 4–7 days. Consider extra dose.
Notify physician if <1.5 × 2 INRs for evaluation and need for UFH, LMWH.
1.51–1.79 Increase weekly dose by 5–10%, repeat INR in 7–10 days.
1.80–1.99 No change. Repeat INR in 7–10 days.
2.0–3.0 No change. Repeat INR based on follow-up algorithm.
3.01–3.30 No change. Repeat INR in 7–14 days.
3.31–3.49 Decrease dosing by 5%, repeat INR in 7–10 days.
3.5–3.99 Decrease weekly dose by 5–10%, repeat INR in 7–10 days.
4.0–4.99 Hold 1 dose of warfarin and repeat INR next day, decrease weekly dose by 10%,
repeat INR in 4–7 days.
5.0–5.99
No significant bleeding
6.0–8.99
No significant bleeding
Omit 1–2 doses, repeat INR next day to be sure INR is decreasing, decrease weekly
dose by 10–15%, and repeat INR in 4–7 days. Assess for bleeding and risk factors.
Hold next dose and check INR next day to insure INR is decreasing. Hold next 2
doses and repeat INR on third day. Resume at lower dose when INR in
therapeutic range, decreasing weekly dose by 15%. Assess for bleeding and risk
factors; alternatively, consider giving vitamin K 1.0–2.5 mg p.o. if at increased
risk for bleeding.
Notify physician of INR. Physician order must be obtained for vitamin K
administration.
>9.0
No significant bleeding
Omit warfarin, assess for bleeding and risk factors. Consider vitamin K 2.5–5.0
mg p.o., monitor INR daily, resume at lower dose when INR in therapeutic range
decreasing weekly dose by 15–20%.
Notify physician of INR. Physician order must be obtained for vitamin K
administration.
Serious bleeding at any
elevation of INR
Omit warfarin, contact physician (consider vitamin K 5.0–10 mg IV slow
infusion, supplemented with fresh frozen plasma depending on the urgency of
the situation; vitamin K can be repeated every 12 hours). Physician order must
be obtained for vitamin K administration.
Note: Always consider trend in INRs when making warfarin management decisions. Consider repeating INR same day or
next day if observed INR is markedly different than expected value. Potential for lab errors exists.
Follow-Up Algorithm
Consecutive days in range (INR) Recheck INR in
1–10 1 week
11–14 2 weeks
15–21 3 weeks
22–30 4 weeks
Note: If INR 2.0–2.1 or 2.9–3.0, repeat INR in 2 weeks regardless of the
number of consecutive in-range INRs. For patients with many
consecutive therapeutic INRs, the follow-up algorithm may be
accelerated by the protime nurse for a single out-of-range INR.
References 43
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Danaparoid
Danaparoid is considered a heparinoid, a mixture
of glycosaminoglycans composed of heperan sulfate, dermatan sulfate, and chondroitin sulfate,
which functions through antithrombin-dependent
inhibition of factor Xa. Its half-life is 18 to 24 hours
and it is renally excreted. Danaparoid is unique in
that it suppresses HIT antibody-induced platelet
aggregation, a property not observed with other
pharmacologic agents used for the treatment of
HIT.49 e anticoagulant activity of danaparoid
is monitored by measuring antifactor Xa activity,
although this is generally not required, as there
is a predictable response when administered on a
weight basis. ere is no antidote to danaparoid.
Danaparoid was removed from the market in
the United States, presumably due to a low crossreactivity rate with HIT antibodies, although this
rarely has clinical consequences. Danaparoid is
commonly used in Europe, Canada, Australia, and
New Zealand.
Danaparoid is administered intravenously
with a bolus of 2250 units followed by an infusion of 400 U/hr for 4 hours, 300 U/hr for 4 hours,
and then 200 U/hr for at least 5 days or longer.
Interestingly, among all of the pharmacologic
agents used for the treatment of HIT, danaparoid
is the only agent whose outcome has been evaluated in a prospective, randomized, controlled
50
study.
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16. Simon TL, Hyers TM, Gaston JP, Harker
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18. Lijnen HR, Hoylaerts M, Collen D. Heparin
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19. Preissner KT, Muller-Berghaus G. Neutralization and binding of heparin by S
protein/vitronectin in the inhibition of factor Xa by antithrombin III. Involvement of
an inducible heparin-binding domain of
S protein/vitronectin. J Biol Chem 1987;
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20. Fry ET, Sobel BE. Lack of interference by
heparin with thrombolysis or binding
of tissue-type plasminogen activator to
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21. Agnelli G, Pascucci C, Cosmi B, Nenci GG.
Effects of therapeutic doses of heparin
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22. Landefeld CS, Cook EF, Flatley M, Weisberg
M, Goldman L. Identification and preliminary
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23. Conti S, Daschbach M, Blaisdell FW. A
comparison of high-dose versus conventional-dose heparin therapy for deep vein
thrombosis. Surgery 1982; 92:972–980.
24. Hull RD, Raskob GE, Hirsh J, et al. Continuous
intravenous heparin compared with intermittent subcutaneous heparin in the initial
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25. Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary
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26. Hull RD, Raskob GE, Rosenbloom D, et al.
Optimal therapeutic level of heparin therapy
in patients with venous thrombosis. Arch
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27. Hirsh J, Poller L, Deykin D, Levine M, Dalen
JE. Optimal therapeutic range for oral anticoagulants. Chest 1989; 95:5S–11S.
28. Brandjes DP, Heijboer H, Buller HR, et al.
Acenocoumarol and heparin compared with
acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl
J Med 1992; 327:1485–1489.
29. Bratt G, Tornebohm E, Widlund L, Lockner
D. Low molecular weight heparin (KABI
2165, Fragmin): pharmacokinetics after
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42:613–620.
30. Bara L, Billaud E, Gramond G, Kher A,
Samama M. Comparative pharmacokinetics of a low molecular weight heparin (PK 10
169) and unfractionated heparin after intravenous and subcutaneous administration.
Thromb Res 1985; 39:631–636.
31. van der Heijden JF, Hutten BA, Buller HR,
Prins MH. Vitamin K antagonists or lowmolecular-weight heparin for the long term
treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2002;
CD002001.
32. Hull RD, Raskob GE, Pineo GF, et al.
Subcutaneous low-molecular-weight
heparin compared with continuous intravenous heparin in the treatment of proximalvein thrombosis. N Engl J Med 1992;
326:975–982.
33. Lee AY, Levine MN, Baker RI, et al. Lowmolecular-weight heparin versus a coumarin for the prevention of recurrent venous
thromboembolism in patients with cancer.
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34. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the natural
pentasaccharide (SR90107/Org31540) with
high affinity to antithrombin III in man.
Thromb Haemost 1995; 74:1468–1473.
35. Warkentin TE. Heparin-induced thrombocytopenia associated with fondaparinux.
N Engl J Med 2007; 356:2653–2654.
36. Turpie AG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total
hip replacement. N Engl J Med 2001;
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37. Greinacher A, Eichler P, Lubenow N, Kwasny
H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications:
meta-analysis of 2 prospective trials to
assess the value of parenteral treatment
with lepirudin and its therapeutic aPTT
range. Blood 2000; 96:846–851.
38. Lewis BE. Argatroban therapy in heparininduced thrombocytopenia. In Reinacher
A (ed.), Heparin-induced thrombocytopenia.
New York: Marcel Dekker, 2004: 437–474.
39. Arpino PA, Hallisey RK. Effect of renal
function on the pharmacodynamics of argatroban. Ann Pharmacother 2004; 38:25–29.
40. Maraganore JM, Bourdon P, Jablonski J,
Ramachandran KL, Fenton JW. Design and
characterization of hirulogs: a novel class of
bivalent peptide inhibitors of thrombin. Bio-
chemisty 1990; 29:7095–7101.
41. Bartholomew JR. Bivalirudin for the treatment of heparin-induced thrombocytopenia. In Reinacher A (ed.), Heparin-induced
thrombocytopenia. New York: Marcel Dekker,
2004: 475–507.
42. Francis JL, Drexler A, Gwyn G. Bivalirudin, a
direct thrombin inhibitor, is a safe and effective treatment for heparin-induced thrombocytopenia (abstract). Blood 2003; 102:164a.
43. Furie B, Furie BC. Molecular basis of vitamin
K-dependent gamma-carboxylation. Blood
1990; 75:1753–1762.
44. Vermeer C. Gamma-carboxyglutamatecontaining proteins and the vitamin
K-dependent carboxylase. Biochem J 1990;
266:625–636.
45. O’Reilly RA, Rytand DA. “Resistance” to warfarin due to unrecognized vitamin K supplementation. N Engl J Med 1980; 303:160–161.
46. Wessler S, Gitel SN. Warfarin. From bedside
to bench. N Engl J Med 1984; 311:645–652.
47. Hellemans J, Vorlat M, Verstraete M. Survival
time of prothrombin and factors VII, IX and
X after completely synthesis blocking doses
of coumarin derivatives. Br J Haematol 1963;
9:506–512.
48. Zivelin A, Rao LV, Rapaport SI. Mechanism
of the anticoagulant effect of warfarin as
evaluated in rabbits by selective depression of individual procoagulant vitamin
K-dependent clotting factors. J Clin Invest
1993; 92:2131–2140.
49. Chong BH, Ismail F, Cade J, et al. Heparininduced thrombocytopenia: studies with a
new low molecular weight heparinoid, Org
10172. Blood 1989; 73:1592–1596.
50. Chong BH, Gallus AS, Cade JF, et al. Prospective randomised open-label comparison of danaparoid with dextran 70 in
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86:1170–1175.
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6
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New oral anticoagulants
Overview
Aer more than half a century of anticoagulation
with heparin and vitamin K antagonists (VKAs),
a new generation of oral anticoagulants is becoming available. Warfarin and its related oral VKAs
have been the mainstay for the management and
prophylaxis of thrombosis for more than 50 years.
Ansell etal.1 have characterized the use of VKAs
in clinical practice as (1) having a narrow therapeutic range, (2) exhibiting considerable variability in dose response among patients due to genetic
and other factors, (3) being subject to interactions
with drugs and diet, (4) having laboratory control
that can be dicult to standardize, and (5) requiring an understanding of pharmacokinetics, pharmacodynamics, and good patient communication
for maintenance of a sustained therapeutic level
(Box6.1).
e new oral anticoagulants (NOACs) have generated enthusiasm. e four leading NOACs are
dabigatran, apixaban, edoxaban, and rivaroxaban.
A number of additional drugs are in earlier stages
of clinical development. Although the characteristics of the new anticoagulants are attractive and
their potential ease of use welcome, it is appropriate to temper one’s enthusiasm since they are new,
large clinical experiences are as yet unavailable,
and most clinicians have little or no experience
with these drugs. A limitation and ongoing concern is that a reversal agent for these drugs has not
yet been developed.
On the other hand, VKAs are familiar to most
every physician. Virtually all aspects of this class
of drugs are well known, including mechanism
of action and metabolism, a well-recognized tool
(international normalized r atio [INR]) for monitoring therapeutic levels, and uniformly available and
highly eective reversal agents. Vitamin K, fresh
frozen plasma, prothrombin complex concentrate,
and recombinant factor VIIa have all been eective
in reversing the anticoagulant eect of VKAs.
Warfarin compounds are associated with serious
bleeding complications; however, it is unusual
for patients to develop non-bleeding-related morbidities. e rst oral direct thrombin inhibitor
to undergo clinical evaluation was ximelagatran.2
It had attractive pharmacodynamics characteristics such as binding to the active site of thrombin
and inactivating brin-bound thrombin.3 Binding
was reversible and allowed relatively quick dissociation from thrombin, permitting a small amount
of thrombin to remain available for adequate
hemostasis.4 e recent experience with ximelagatran, the initial oral direct thrombin inhibitor,
demonstrated eectiveness in the management of
deep venous thrombosis (DVT), but a larger than
anticipated number of patients developed critical
increases in liver enzymes indicating hepatotoxicity,5 which resulted in withdrawal of the drug from
the market in 2006 by Astra Zeneca.6 As a result,
regulatory agencies are carefully scrutinizing data,
and pharmaceutical companies and clinicians are
temporizing their enthusiasm for these new agents
until greater experience is obtained.
Two new direct oral anticoagulants (dabigatran
and rivaroxaban) have been approved by the U.S.
Food and Drug Administration (FDA) for the
management of patients with nonvalvular atrial
brillation, and two are in the late stages of clinical
47
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BOX6.1 VITAMIN K
ANTAGONISTS: LIMITATIONS
Delayed onset of action (requires 4–5 days
for therapeutic eect)
Poor pharmacokinetic prole
Requires intensive monitoring
Frequent dose adjustment
Large interindividual dosing dierences
Narrow therapeutic index
Dietary interactions
Interaction with numerous medications
Need for constant patient education
BOX6.2 NOACS: ADVANTAGES
Small molecules
Rapidly absorbed from gastrointestinal tract
Rapid therapeutic eect
Eliminates need for monitoring
No dose adjustment
Minimal (if any) interindividual dierences
Minimal (if any) drug-drug interaction
Minimal (if any) food interaction
Used for short-term and long-term Rx
No patient education required
thenew oral anticoagulants involves cytochrome
p450 3A4, p-glycoprotein, or both. As such,
patients taking concomitant agents that induce
p-glycoprotein (such as rifampin) may alter the
drug’s activity.
Clinical trial development
e protocols used by the NOACs during their
clinical trials were generally similar. Studies
were designed to assess xed doses of drug and
did not include dose titration. All studies comparing the oral anticoagulants with an existing
anticoagulant (enoxaparin or warfarin) were
powered for noninferiority. Only studies comparing a NOAC versus a placebo were powered for
superiority.
Initial studies evaluated VTE prophylaxis in
orthopedic surgical patients followed by treatment
and secondary prevention for patients with DVT
and pulmonary embolism (PE). Since this book
is focused on venous thrombosis, the important
pivotal trials of these new agents that addressed
thromboembolic events in patients with nonvalvular atrial brillation will not be addressed.
VTE prophylaxis in
orthopedic patients
trials (apixaban and edoxaban). Rivaroxaban has
recently been approved by the FDA for the management of patients with acute venous thromboembolism (VTE). A number of other agents are in earlier
stages of development. e NOACs have a number
of advantages compared to VKAs (Box6.2).
ese four drugs are summarized in Table6.1.
ese are all small molecules and readily absorbed
from the gastrointestinal tract when ingested
orally. Warfarin requires 4–5 days of therapy to
produce a therapeutic anticoagulant eect since
it functions by reducing the production of the
coagulation proenzymes. However, the new agents
directly inhibit factor Xa or thrombin and are rapidly active.
Dabigatran etexilate is a prodrug. Following
ingestion, it is converted to dabigatran by esterases
in the blood and liver.9 e three other drugs are
active in their ingested form. e metabolism of
Venous thromboembolic complications following major orthopedic surgery are a signicant
postoperative concern, and low-molecular-weight
heparin (LMWH) is the preferred form of routine
prophylaxis.10 e VTE risk is not limited to the
perioperative procedure but persists for at least
7,8
4 weeks following hospital discharge.11 An oral
agent that is comparable in ecacy and safety to
enoxaparin would be well received by patients and
physicians because of greater patient comfortand
anticipated improved compliance, since injections
would no longer be necessary.
Dabigatran
Dabigatran has been widely studied in orthopedic
surgical patients. e RE-NOVATE trial12 studied patients undergoing total hip replacement.
VTE prophylaxis in orthopedic patients 49
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Table6.1 NOACs: Comparative pharmacology
Agent
Characteristic
Target Thrombin Factor Xa Factor Xa Factor Xa
Prodrug Ye s No No No
Bioavailability 6% 50% 100% 80%
Dosing Fixed b.i.d. Fixed b.i.d Fixed q.d. Initial b.i.d.
Formulation Capsule with coated
Tmax 1.25–6 hours 3–4 hours 1–4 hours 2–4 hours
Half-life 12–17 hours 12 hours 6–12 hours 7–11 hours
Renal clearance 80% 27% 62% 35%
Protein binding 35% 87% 40–59% 92–95%
Routine coagulation monitoring No No No No
PK-drug interactions Quinidine,
Dabigatran Apixaban Edoxaban Rivaroxaban
beads (should not
be opened)
amiodarone, potent
Pgp inhibitors
File-coated
tablet (should
not be crushed)
Potent CYP3A4
and Pgp
inhibitors
Film-coated
tablet
Potent Pgp
inhibitors
Film-coated
tablet (should
not be crushed)
Potent CYP3A4
and Pgp
inhibitors
Sources: Data from Eriksson BI, etal., Clin Pharmacokinet 2009; 48:1–22; Mavrakanas T, Bounameaux H, Pharmacol Ther
2011; 130:46–58.
e RE-MOBILIZE13 and RE-MODEL14 trials
studied patients undergoing total knee replacement. ese studies compared prophylaxis
comparator to the new oral anticoagulants. In all
three trials there were no signicant dierences
in bleeding rates.
with dabigatran with the LMWH enoxaparin.
Interestingly, the control arms had dierent enoxaparin doses, which were dictated by the local stan-
Apixaban
dard of care. e RE-MODEL and RE-NOVATE
trials used 40 mg daily doses of enoxaparin, most
likely because they were conducted in Europe.
e RE-MOBILIZE trial conducted in the United
States used 30 mg of enoxaparin b.i.d. Two doses
of dabigatran were evaluated in all three studies,
namely, 150 and 220 mg once daily. e primary
endpoint for these studies was a composite of total
VTE events and all-cause mortality, and safety
focused on bleeding complications.
Both doses of dabigatran were found to be
noninferior to 40 mg of enoxaparin daily. ere
were similar rates of bleeding complications.
However, in the RE-MOBILIZE trial, enoxaparin
30 mg b.i.d. proved to be superior to both doses
of dabigatran. Since the 30 mg b.i.d. dose of
enoxaparin gives patients 50% more enoxaparin
per day than the 40 mg dose, it has been recognized to be more eective and is a more stringent
Apixaban has been evaluated in orthopedic surgical patients in the three ADVANCE trials. e
ADVANCE-1 trial compared apixaban 2.5mg twice
daily with enoxaparin 30 mg twice daily for the prevention of VTE aer total knee replacement.15 e
primary ecacy endpoint was surprisingly low and
similar in both groups ( apixaban 9.0% vs. enoxaparin 8.8%). However, the statistical endpoint of noninferiority was not met by the smallest of margins
(p = .06). An interesting observation was that the
composite of major and clinically relevant nonmajor
bleeding was signicantly lower with apixaban than
with enoxaparin (2.9% vs. 4.3%; p = .03). In the subsequent ADVA NCE-2 trial16 evaluating patients undergoing total knee replacement and the ADVANCE-3
trial,17 which evaluated patients undergoing total
hip replacement, apixaban was compared with
the 40 mg daily enoxaparin dose starting 12hours
50 New oral anticoagulants
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preoperatively. e primary outcome measure was
the composite of symptomatic and asymptomatic DVT, nonfatal PE, and all-cause mortality. In
ADVANCE-2, apixaban was signicantly better
than enoxaparin in reducing the primary endpoint
(15% vs. 24%; RR 0.62; p < .0001). Major and clinically relevant nonmajor bleeding occurred in 4%
of apixaban-treated patients and 5% of patients
receiving enoxaparin (NS). In the ADVANCE-3
trial, which evaluated patients undergoing total hip
replacement, apixaban once again demonstrated
superiority versus 40 mg daily of enoxaparin (1.4%
vs. 3.9%; RR 0.36; p < .001). e composite outcome
of major and clinically relevant nonmajor bleeding
was not dierent between the two groups.
Edoxaban
Edoxaban has been studied for VTE prophylaxis
in orthopedic patients in Japan and Taiwan. Doseranging studies were performed in Japan to establish appropriate doses for patients undergoing total
hip18 and total knee19 replacement. Moving into
phase 3 trials, a unique dose of enoxaparin given
20 mg subcutaneously b.i.d. was compared with
edoxaban 30 mg daily.
A small study that evaluated 92 patients undergoing hip fracture surgery failed to demonstrate
any dierence between the two treatment groups
either in ecacy (edoxaban 7% vs. enoxaparin 4%)
or safety.20 ere was no dierence in bleeding
complications.
In a larger study (N = 610) of patients undergoing total hip replacement, edoxaban 30 mg daily
versus enoxaparin 20 mg b.i.d. was compared.
Edoxaban treatment resulted in a signicant
reduction in total venous thromboembolic events
(2.4%) compared with patients receiving enoxaparin (6.9%; p< .001). ere was no dierence in
bleeding complications between the two groups.
In the nal edoxaban orthopedic study comparing 716 patients undergoing total knee replacement, the same doses of edoxaban and enoxaparin
were used (30 mg daily and 20 mg b.i.d., respectively).22 Venous thromboembolic events were
signicantly fewer in edoxaban-treated patients
(7.4%) versus patients receiving enoxaparin (13.9%;
p = .01). As in the other edoxaban trials, there was
no dierence in bleeding complications.
21
Rivaroxaban
Rivaroxaban has been evaluated for VTE prophylaxis in four trials of patients undergoing orthopedic surgery. RECORD-123 and
RECORD-224 evaluated patients undergoing
total hip replacement, and RECORD-325 and
RECORD-426 evaluated patients undergoing total
knee replacement. In three of the four RECORD
trials (1–3), rivaroxaban 10 mg daily was compared with 40 mg of enoxaparin daily, and in
RECORD-4 the comparator dose of enoxaparin
was 30 mg twice daily.
A pooled analysis of the four studies evaluated the primary endpoint of symptomatic VTE
plus all-cause mortality.27 Safety was dened as
bleeding complications. e primary ecacy
endpoint occurred in 0.5% of patients on rivaroxaban versus 1% of patients taking enoxaparin
(HR 0.48; p = .001). ere was no signicant difference between major and nonmajor clinically
relevant bleeding.
Specic evaluation of the RECORD-4 study
appears warranted, since the most eective dose of
enoxaparin (30 mg q. 12 hours) was used. A total
3148 patients undergoing knee arthroplasty were
randomized to oral rivaroxaban 10 mg daily versus enoxaparin 30 mg q. 12 hours.26 e primary
ecacy outcome was the composite of any DVT
(symptomatic or asymptomatic), nonfatal PE, or
all-cause mortality up to day 17 aer surgery. e
primary ecacy endpoint was reached in 6.9% of
rivaroxaban-treated patients versus 10.1% of those
treated with enoxaparin (p = .0118). Although
there were numerically more bleeding events with
rivaroxaban, the dierence compared with enoxaparin was not signicant.
VTE prophylaxis in
medically ill patients
Venous thromboembolic complications commonly
complicate the hospital course of acutely ill medical patients. e benets of providing pharmacologic prophylaxis during hospitalization have been
previously described in randomized trials.
Current guidelines suggest that high-risk medical
patients be protected with pharmacologic thromboprophylaxis if not at high risk for bleeding.
28,29
30
Treatment of acute VTE 51
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Two prospective randomized trials have been
performed using the new oral anticoagulants in
high-risk medically ill patients.
e MAGELLAN trial31 evaluated rivaroxaban for thrombosis prophylaxis in medically
ill patients. is was a two-part study. In part 1,
10 mg of rivaroxaban daily was compared with
40 mg of enoxaparin daily in high-risk medical
patients. At day 10, rivaroxaban met its primary
clinical ecacy objective of demonstrating noninferiority to enoxaparin in short-term use; both
groups had a thrombosis rate of 2.7%. However,
the rate of bleeding was higher with rivaroxaban
than enoxaparin (2.8% vs. 1.2%).
Part 2 of the study extended rivaroxaban to 35
days versus placebo. e results demonstrated that
the combined rates of major and clinically relevant
nonmajor bleeding, the primary safety measure
in this study, while low overall, were signicantly
higher in those treated with rivaroxaban than in
those treated with enoxaparin followed by placebo.
e ADOPT trial investigators32 studied apixaban versus enoxaparin for thromboprophylaxis
in medically ill patients. is was a double-blind,
double-dummy, placebo-controlled trial that randomly assigned acutely ill medical patients to
receive apixaban 2.5 mg twice daily × 30 days or
enoxaparin 40 mg once daily for 6–14 days. e
primary ecacy outcome was the 30-day composite of death related to VTE, PE, symptomatic DVT,
or asymptomatic proximal DVT (detected by compression ultrasonography) on day 30. e primary
safety outcome was bleeding.
A total 6528 subjects were randomized. e primary ecacy outcome was achieved in 2.71% of
apixaban-treated patients and 3.06% in the enoxaparin group. Relative risk for apixaban was 0.87
(p = .44 for superiority). By day 30, major bleeding occurred in 0.47% of the apixaban group and
0.19% of the enoxaparin group. On the basis of
these observations, the investigators concluded
that an extended course of thromboprophylaxis
with apixaban was not superior to a shorter course
of enoxaparin in medically ill patients. Apixaban
was associated with more bleeding events than was
enoxaparin.
To date, in acutely ill medical patients, extended
(postdischarge) prophylaxis with the NOACs has
not been shown to be more eective than shorterterm enoxaparin.
Treatment of acute VTE
Patients with acute VTE are most commonly
treated with heparin followed by VKAs. VKAs
require frequent monitoring using the INR, and
as previously discussed, there are multiple interactions with food and other drugs. e NOACs
do not require monitoring, have minimal food
and drug interactions, and therefore are thought
to be attractive alternatives to VKAs in the management of patients with acute VTE. An overview
of the clinical trials for the early treatment and
extended prophylaxis of acute VTE is provided in
Tables6.2
33–39
and 6.3.
40–42
Dabigatran
e RE-COVER study group evaluated dabigatran
versus warfarin in the treatment of acute VTE.33
ese investigators randomized 2564 patients to
receive oral dabigatran 150 mg twice daily or warfarin that was dose-adjusted to achieve an INR
of 2.0–3.0. All patients received parenteral anticoagulation for a median of 9 days. e primary
outcomes were the 6-month incidence of recurrent, symptomatic, objectively conrmed VTE and
death. Safety endpoints included bleeding events,
acute coronary syndromes, other adverse events,
and results of liver function tests.
Recurrent VTE occurred in 2.4% of dabigatran
patients versus 2.1% of those receiving warfarin.
is achieved a p value of 0.001 for the prespecied
noninferiority margin. ere was no dierence
in major bleeding complications. ere was a signicant reduction in all-cause bleeding in patients
randomized to dabigatran.
Signicantly more patients randomized to dabigatran discontinued their study drug, presumably due
to dyspepsia, which was more frequent in this cohort
of patients than those randomized to warfarin. ere
were no dierences in liver enzyme elevation.
e results of the RE-COVER study demonstrated that a xed dose of dabigatran is as eective as warfarin for the management of patients
with acute VTE and has a safety prole similar to
that of warfarin but does not require laboratory
monitoring.
e RE-COVER II34 trial was a similarly designed
and performed trial to RE-COVER, although the
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