How I treat with anticoagulants in 2012: new and old... when and how to switch

From bloodjournal.hematologylibrary.org at University Health Network on September 25, 2012. For personal use
only.
2012 119: 3016-3023
Prepublished online February 1, 2012;
doi:10.1182/blood-2011-10-378950
How I treat with anticoagulants in 2012: new and old anticoagulants, and
when and how to switch
Sam Schulman and Mark A. Crowther
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How I treat
How I treat with anticoagulants in 2012: new and old anticoagulants, and when
and how to switch
Sam Schulman1 and Mark A. Crowther1
1Department
of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON
Two novel oral anticoagulants, dabigatran and rivaroxaban, have recently been
approved. They differ in many ways from
warfarin, including rapid onset of action,
shorter half-life, fewer drug-drug interactions, lack of need for monitoring, and no
need for titration or dose adjustments.
These novel agents represent a landmark
shift in anticoagulant care; however, many
aspects of their use will be unfamiliar to
practicing clinicians, despite the imminent widespread use of these agents in
the community. The management of these
anticoagulants when transitioning from
or back to warfarin, around surgery or in
case of major hemorrhage, requires
knowledge of their pharmacokinetics and
mechanism of action. Unfortunately, there
is a limited evidence base to inform decisions around management of these
agents. We present our practice in these
settings supported, where available, with
literature evidence. (Blood. 2012;119(13):
3016-3023)
Introduction
Dabigatran has become available for long-term use in the United
States and Canada at the end of 2010 and is the first novel
antithrombotic agent approved for stroke prophylaxis in atrial
fibrillation since the introduction of warfarin more than 50 years
ago.1 The Randomized Evaluation of Long-Term Anticoagulant
Therapy (RE-LY) study provided high-quality evidence that, when
administered at a dose of 150 mg twice daily, dabigatran is
associated with a reduced risk of stroke and a similar risk of
bleeding as warfarin when targeted to an international normalized
ratio (INR) of 2.0 to 3.0.2 When administered at a dose of 110 mg
twice daily, the risk of stroke with dabigatran is similar to that of
warfarin while producing less bleeding. This dose is approved in
Canada but not in the United States because it did not reduce the
risk of stroke compared with warfarin and stroke prevention was
considered more important than the benefit of decreased risk for
extracranial major bleeding. The dose of 75 mg twice daily is,
however, recommended in the United States for patients with
severe renal failure (calculated creatinine clearance 15-30 mL/
min). Dabigatran has also been approved for the prevention of deep
vein thrombosis after orthopedic surgery in Canada, Europe,3 and
several other countries, and has been studied in the setting of
long-term secondary prevention for venous thromboembolism.4
Peer organization guidelines now recommend the use of dabigatran
for many patients with atrial fibrillation.5 The oral factor Xa
inhibitor, rivaroxaban, has also been approved for prevention of
stroke in atrial fibrillation and of venous thrombosis after orthopedic surgery.6
Clinicians are intimately familiar with warfarin. It has 100%
name recognition internationally, monitoring for its anticoagulant
effect is routinely available, and physicians are aware of the need to
interrupt warfarin for many interventional procedures.7 There are
established and highly effective treatment strategies for bleeding in
patients receiving warfarin and for the management of unanticipated excess anticoagulant effect.8,9 Dabigatran and rivaroxaban, as
novel agents, are relatively unknown to the practicing community.
Further, there is little or no evidence to guide practical management
when patients present with a need for any interventional procedure
or who present with bleeding complications.
Despite the perceived inconvenience of warfarin, studies of
anticoagulated patients have generally failed to demonstrate any
significant negative impact of this treatment on quality of life.10,11
Furthermore, substantial variability in health state valuations and
treatment preferences between patients indicates the need for
individual tailoring of anticoagulant therapy.12
This review is designed to provide clinicians with a practical
approach to the management of oral anticoagulation in stroke
prophylaxis, including suggestions for the choice of agent, and
guidance regarding switching between agents, perioperative discontinuation and resumption of the new agents, and treatment of
bleeding. We acknowledge that there is little evidence in this
domain and that our recommendations are based largely on expert
opinion.
Submitted October 16, 2011; accepted November 22, 2011. Prepublished
online as Blood First Edition paper, February 1, 2012; DOI 10.1182/blood-201110-378950.
© 2012 by The American Society of Hematology
3016
Selection of patient groups for warfarin or the
new anticoagulants
For warfarin
Good level of control. The level of control of warfarin therapy and
its interaction with the treatments in the RE-LY study was recently
analyzed.13 The authors measured the level of control of the INR as
the percent time in therapeutic range at the study center level
(cTTR) and divided the cTTR results into quartiles, corresponding
to less than 57.1%, 57.1% to 65.5%, 65.5% to 72.6%, and more
than 72.6%. The last 2 groups would be considered having good or
excellent control, respectively. Table 1 shows the hazard ratios for
different outcomes for these 2 groups of high cTTR for 150 mg of
dabigatran twice daily versus warfarin. In these well-controlled
patients, dabigatran (150 mg twice daily) was not superior to
warfarin for prevention of stroke. Dabigatran was associated with a
BLOOD, 29 MARCH 2012 䡠 VOLUME 119, NUMBER 13
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ANTICOAGULATION
BLOOD, 29 MARCH 2012 䡠 VOLUME 119, NUMBER 13
3017
Table 1. Risk of important clinical outcomes with dabigatran 150 mg twice daily versus adjusted warfarin therapy that has a good or
excellent level of control
Outcome, dabigatran vs warfarin
cTTR of 65.5%-72.6%, HR (95% CI)
cTTR of > 72.6%, HR (95% CI)
Stroke and systemic embolism (primary outcome)
0.69 (0.44-1.09)
0.95 (0.65-1.48)
Stroke, systemic embolism, pulmonary embolism,
0.94 (0.72-1.22)
1.19 (0.90-1.57)
myocardial infarction, or cardiovascular death
Total death
0.98 (0.75-1.28)
1.08 (0.81-1.44)
Major bleeding
1.13 (0.87-1.48)
1.16 (0.88-1.54)
Intracranial bleeding
0.35 (0.15-0.82)
0.39 (0.18-0.84)
Major gastrointestinal bleeding
2.26 (1.50-3.40)
2.00 (1.25-3.21)
Modified from Wallentin et al13 with permission.
cTTR indicates percentage of time in the therapeutic range at center level; and HR, hazard ratio.
doubling of the risk of major gastrointestinal bleeding and a lower
risk of intracranial bleeding. The American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines (among other groups) has recently published a supplementary report on the use of dabigatran for atrial fibrillation.5 This
guideline uses rigorous methodology and has a robust conflict of
interest policy. The guideline provides a class I, level of evidence B
recommendation for dabigatran as an agent to prevent stroke in
patients with atrial fibrillation. However, the guideline notes,
“Because of the twice daily dosing and greater risk of nonhemorrhagic side effects … patients already taking warfarin with
excellent INR control may have little to gain by switching to
dabigatran.” This recommendation suggests that patient values and
preferences should influence the decision to initiate dabigatran.
A recent trial, in which patients with a stable warfarin dose were
randomized to 4-weekly or 12-weekly INR testing demonstrated
that the longer interval was noninferior for the primary outcome of
TTR,14 confirming prior observational data.15 This reduced INR
monitoring frequency for selected patients further reduces the
perceived inconvenience of warfarin treatment.
Renal failure. Patients with severe renal failure (creatinine
clearance ⬍ 30 mL/min) were excluded from the RE-LY2 and
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation (ROCKET AF)16 trials of
dabigatran and rivaroxaban, respectively. Dabigatran is mainly
(80%) eliminated via the kidneys, and in severe renal failure
bioaccumulation occurs.17 Rivaroxaban is less dependent on renal
elimination.18 In the ROCKET AF trial, patients with a creatinine
clearance of 30 to 49 mL/min received a reduced dose of 15 mg
daily.16 These observations suggest that warfarin remains the
treatment of choice for patients with a calculated creatinine
clearance close to or less than 30 mL/min.
Mechanical heart valve replacement. These new drugs have
not been evaluated in patients with mechanical heart valve
prosthesis. Their safety and efficacy profiles in such patients cannot
be determined, and at present all such patients should remain on
warfarin.
Gastrointestinal disease and elderly patients. In the analysis
of bleeding outcomes in various subgroups, patients 75 years of age
or older in RE-LY had similar or a higher risk of extracranial
bleeding on dabigatran as on warfarin.19 When this complication is
of particular concern, for example in patients with a history of
recurrent extracranial bleeding or with preexisting coagulopathy,
anticoagulation with warfarin may be preferable because this drug
is rapidly reversible. This concern may not be true for the factor Xa
inhibitors, for which subgroup analyses have not yet been published.
Lower gastrointestinal bleeding is significantly increased with
dabigatran compared with warfarin. This is probably because of
low bioavailability, which results in high concentrations of active
drug in the feces.20 Treatment with rivaroxaban was also associated
with a significant increase of the risk for gastrointestinal bleeding16; hence, patients with intestinal angiodysplasia, inflammatory
bowel disease, or diverticulosis, or those with a history of other
forms of gastrointestinal bleeding may experience a deterioration
on treatment with dabigatran or rivaroxaban.
In the RE-LY trial, patients receiving warfarin or dabigatran had
a similar rate of discontinuation of study medication (17% vs
21%).2 Discontinuation of dabigatran was more frequent as a result
of gastrointestinal distress, and 11.3% to 11.8% of patients on this
drug complained of dyspepsia. This has been attributed to both
tartaric acid contained in the capsule (required for absorption) and
to a high concentration of active drug in the colon. This again
suggests that dabigatran may not be an ideal agent for patients with
a history of gastrointestinal diseases.
Poor compliance. Patients with documented poor adherence
to the treatment with vitamin K antagonists are particularly
problematic. Dabigatran has to be administered twice daily for
patients with atrial fibrillation,2 which suggests that it should not be
seen as an alternate to warfarin in patients who have been poorly
compliant with warfarin. The inability to monitor dabigatran,
coupled with its short half-life (14-17 hours), would imply that
patients who are poorly compliant are at high risk of stroke because
failure to take the medication will quickly experience a complete
loss of antithrombotic efficacy. Rivaroxaban has an even shorter
half-life (11-13 hours in the elderly),18 and a missed dose might be
equally hazardous in such patients. For patients treated with
warfarin and who undergo INR monitoring, the clinician is at least
aware of inadequate levels, suggesting that aggressive measures to
increase compliance can be put in place. With novel agents, the first
marker of noncompliance is probably stroke or other thrombotic
complications.
Drug cost. Acquisition costs of novel agents will be higher
than for warfarin; thus, many patients who do not have drug
coverage will probably remain on warfarin, despite evidence that
from a broader perspective novel agents are cost-neutral or
cost-effective in many settings.21
For the new anticoagulants
Unexplained poor warfarin control. Warfarin-experienced patients who continue to have variable INR results, corresponding to
a TTR of less than 65%, have lower rates of stroke and other
complications when treated with dabigatran 150 mg twice daily.13
If drug costs are not a deterrent, dabigatran or another novel agent
approved for atrial fibrillation should be considered. However, it is
crucial to determine the reasons for instability. As previously
3018
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only.
SCHULMAN and CROWTHER
BLOOD, 29 MARCH 2012 VOLUME 119, NUMBER 13
䡠
Table 2. Drug interactions with at least 50% change in the exposure to dabigatran or rivaroxaban
Dabigatran
Mechanism
P-gp inhibition
P-gp induction
Rivaroxaban
Interacting drug
⌬ exposure, %
Interacting drug
⌬ exposure, %
Ketoconazole*
150
Ketoconazole*
160
Quinidine
53
⫺50
Amiodarone
60
Verapamil
⯝ 50†
Rifampicin
⫺67
Rifampicin
St John’s wort
ND
St John’s wort
ND
Ketoconazole*
160
Clarithromycin
50
CYP3A4 inhibition
CYP3A4 induction
Ritonavir
50
Rifampicin
⫺50
St John’s wort
ND
ND indicates not determined.
*Contraindicated.
†Variable depending on the formulation of verapamil.
discussed, if instability is the result of noncompliance, warfarin
remains the anticoagulant of choice.
Poor level of control because of unavoidable drug-drug
interactions. The new anticoagulants have, as opposed to vitamin
K antagonists, few interactions with other drugs (see “Drug
interactions”). Patients with frequent need for antibiotic treatment,
chemotherapy, amiodarone, frequent use of acetaminophen, azathioprine, or a large number of concomitant medications, particularly if
the exposure to these medications varies, will probably do better
with the new anticoagulants.
New patients on anticoagulant therapy for atrial fibrillation.
For warfarin-naive patients who can afford newer agents, it is very
tempting to go straight for the new anticoagulants to avoid the
initial several weeks of frequent dose adjustments of warfarin.
Patients should be informed of the advantages and disadvantages of
the alternatives, including monitoring, dose adjustments, interactions, bleeding risks, availability of antidote, and costs, allowing
them to make an informed decision on their preferred therapy.
Drug interactions
The only classes of drugs that dabigatran is known to interact
with are inhibitors or inducers of the transporter P-glycoprotein
(P-gp). Rivaroxaban is subject to interaction via P-gp as well as
to inducers and inhibitors of the microsomal enzyme CYP3A4,
which is responsible for the metabolism of this drug. Dabigatran
is dependent on P-gp for its transport across the intestinal wall.
There are at least 64 drugs that have been described to influence
the P-gp, but only a few drugs cause clinically important
changes in the drug exposure (Table 2).22 The strong P-gp
inhibitor quinidine increases the exposure to dabigatran by 53%
in healthy volunteers. During the phase 3 trials with dabigatran,
an amendment of the protocols was therefore introduced,
prohibiting concomitant use of quinidine.23 Quinidine should be
administered at least 2 hours after dabigatran. Verapamil and
amiodarone are moderate inhibitors of P-gp, and multiple doses
of verapamil resulted in a 50% to 60% increase in dabigatran
concentration.24 The increase varied depending on the dosing
schedule of verapamil and its formulation, and the effect can be
minimized by dosing dabigatran at least 2 hours before verapamil.25 The strongest interaction is with ketoconazole, which
increases the exposure to dabigatran as well as to rivaroxaban by
150% to 160% and therefore is contraindicated with either
anticoagulant. Rifampicin, a strong inducer of P-gp and of
CYP3A4, causes at least a 50% reduction of the exposure to the
new anticoagulants, and it is recommended to avoid concomitant use. St John’s wort is another strong inducer of P-gp and of
CYP3A4 and must be avoided with novel agents. Many of these
drugs also interact with warfarin, but the availability of the INR
levels allows dose adjustment, which mitigates the risk of
concomitant treatment.
Concomitant use of antiplatelet agents
Studies with dabigatran, rivaroxaban, and apixaban in patients
with acute coronary syndromes, receiving combined antiplatelet
therapy with aspirin and clopidogrel, have generally shown a
dose-dependent increase in the risk of major bleeding and any
bleeding.26-30 Nevertheless, there is a possibility for a net
clinical benefit of concomitant therapy as recently shown for
rivaroxaban.27
Conversion from warfarin to dabigatran or
rivaroxaban
As noted, patient stabilized on warfarin may prefer to remain on
this medication. However, given the added convenience and the
potential for enhanced efficacy and reduced risk for intracranial
bleeding of dabigatran or rivaroxaban, many patients will choose to
transition from warfarin to one of the new anticoagulants. Although
not evidence-based, we recommend starting medication with
dabigatran or rivaroxaban when warfarin has been discontinued
and the INR has decreased to less than 2.3. In the trials where
patients could have warfarin before starting on dabigatran (RE-LY,
RE-SONATE, and RE-MEDY),2,31,32 the highest INR permitted at
the time of transition was 2.3, whereas in ROCKET AF it was 3.0
for starting rivaroxaban.16 There was no signal in these trials that
the overlap was associated with an increased risk for bleeding.
Point-of-care INR monitors should not be used to assess the INR
during transitions between dabigatran and warfarin, given the
potential for dabigatran to increase the “baseline INR.”33
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only.
ANTICOAGULATION
BLOOD, 29 MARCH 2012 䡠 VOLUME 119, NUMBER 13
Table 3. Suggested strategy for conversion from dabigatran or
rivaroxaban to warfarin
Calculated creatinine
clearance, mL/min
Dabigatran: start day
with warfarin*
Rivaroxaban: start
day with warfarin*
⬎ 50
Day ⫺3
Day ⫺4
31-50
Day ⫺2
Day ⫺3
15-30
Day ⫺1
Day ⫺2
*Dabigatran/rivaroxaban is stopped on day 0. The longer overlap with rivaroxaban is justified by its half-life being shorter than that of dabigatran and by the concern
about thromboembolic events shortly after transitioning from rivaroxaban to warfarin.6
Conversion from dabigatran or rivaroxaban to
warfarin
For patients who are unable to continue on dabigatran or rivaroxaban and need to transition to warfarin, it is necessary to take into
account the expected onset of warfarin (⬃ 5 days) as well as the
half-life of dabigatran, which varies from 14 to 17 hours with
normal renal function34 to 18 to 27 hours in moderate to severe
renal impairment.17 Based on these data, we suggest transition
strategies as shown in Table 3. The first INR should be obtained on
day 3 of warfarin medication but only for the purpose of identifying
an excessive level, resulting in more caution with the warfarin
dosing. For patients with a creatinine clearance of less than
30 mL/min, there are no data available to support a recommendation regarding transition to the new anticoagulants. Point-of-care
INR monitors should not be used to assess the INR during
transitions between rivaroxaban and warfarin, given the observation that rivaroxaban will increase the prothrombin time to
differing extents, based on difference in the sensitivity of the
coagulometer and the prothrombin reagent.35,36
Periprocedural management of dabigatran or
rivaroxaban
The principles that are important for the perioperative management
with the new anticoagulants are as follows: (1) the half-life is
shorter than with warfarin; and (2) the onset of effect is within
2 hours, provided that intestinal absorption is normal.
Preoperative management
The manufacturer of dabigatran issued guidance for the investigators regarding preoperative discontinuation of the drug halfway
3019
through the phase 3 trials on stroke prophylaxis in atrial fibrillation
and on treatment of venous thromboembolism. This guide was
based on pharmacokinetic data and on considerations regarding the
differential risk of bleeding. In patients with normal renal function
the half-life of 14 to 17 hours34 suggests that interruption of
dabigatran for 48 hours should be sufficient to ensure adequate
hemostasis. This short period of interruption does not require
bridging therapy with heparin or low-molecular-weight heparin.
For procedures with a low risk of bleeding, where an INR of 1.5 for
patients on warfarin would be acceptable, it is reasonable to stop
dabigatran 24 hours in advance. Such procedures include cardiac
catheterization, diagnostic endoscopy, and minor orthopedic surgery. Thus, for elective surgery in patients with normal renal
function, it is probably safe to recommend the patient simply to
interrupt therapy for 1 to 2 days (depending on the type of
procedure) before their planned procedure (Table 4). With decreasing renal function, the period of interruption should be longer. Our
routine has not been to use any bridging therapy for these patients
(Table 4). Similar reasoning should apply for rivaroxaban. The
study protocol for ROCKET AF suggested interruption of the drug
approximately 2 days before a procedure. If desired, a normal
thrombin clotting (TCT) time rules out the presence of important
levels of dabigatran (see “Emergency testing of hemostatic function: dabigatran”); this test could be used preoperatively in patients
in whom there is a potential for persistent anticoagulant effect or
for those undergoing surgery with a high risk of complications
from bleeding, such as spinal surgery or neurosurgery. There is no
equivalent, widely available, test for persistence of rivaroxaban.
Patients receiving dabigatran and who require emergency
surgery will either have to wait until the anticoagulant effect has
spontaneously diminished or undergo their procedure with the
knowledge that they have an increased risk of bleeding. Rivaroxaban may be reversible with a 4-factor prothrombin complex
concentrate (PCC). See also “Managing overdose and bleeding
complications.”
Postoperative management
The time point for resumption of dabigatran or rivaroxaban
depends almost exclusively on the postoperative risk of bleeding.
The risk for major bleeding complications after surgery clearly
exceeds the risk for thromboembolic complications.37 For major
abdominal surgery or urologic surgery with incomplete hemostasis,
resumption should be delayed until there is no drainage or other
evidence of active bleeding. For procedures with good hemostasis
shortly after the end of the procedure, we suggest resumption the
Table 4. Timing of interruption of dabigatran or rivaroxaban before surgery or invasive procedures
Timing of last dose before surgery
Calculated creatinine
clearance, mL/min
Half-life, hours
Standard risk of bleeding*
High risk of bleeding†
Dabigatran
⬎ 80
13 (11-22)
24 h
2d
⬎ 50- ⱕ 80
15 (12-34)
24 h
2d
⬎ 30- ⱕ 50
18 (13-23)
2d
4d
ⱕ 30
27 (22-35)
4d
6d
Rivaroxaban
⬎ 30
12 (11-13)
24 h
2d
⬍ 30
Unknown
2d
4d
*Examples are cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, and uncomplicated laparoscopic procedures, such as
cholecystectomy.
†Examples are major cardiac surgery, insertion of pacemakers or defibrillators (resulting from the risk for pocket hematoma), neurosurgery, large hernia surgery, and major
cancer/urologic/vascular surgery.
3020
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only.
SCHULMAN and CROWTHER
BLOOD, 29 MARCH 2012 VOLUME 119, NUMBER 13
same evening a minimum of 4 to 6 hours after surgery. For
dabigatran, we suggest starting with a half dose (75 mg) for the first
dose, and thereafter the usual maintenance dose, extrapolating from
the trials in orthopedic surgery. A similar strategy could be
followed for rivaroxaban where a 10-mg dose could be used as the
first dose. Patients with bowel paralysis may require bridging with
a parenteral anticoagulants given their inability to take their oral
anticoagulant.38
Emergency testing of hemostatic function
Dabigatran
In the setting of emergency surgery, a test that predicts whether the
patient has acceptable hemostasis is desirable. The TCT has a linear
correlation with the dabigatran concentration (r2 ⫽ 0.86)39 but
prolongs rapidly at low levels of drug and is not routinely available
in every hospital. If the TCT is normal, it is safe to assume that the
level of dabigatran is very low and that the patient’s risk of bleeding
is similar to that of other patients undergoing the procedure. The
prothrombin time (PT, usually expressed as the INR) is insensitive
to dabigatran and not useful in this context. Point-of-care testing
INR values may be inaccurate in patients receiving dabigatran and
should not be used to judge drug effect.33 The activated partial
thromboplastin time (aPTT) shows a curvilinear response to the
concentration of dabigatran. At high dabigatran concentrations, the
aPTT becomes incoagulable. The aPTT is prolonged 2-fold compared with the control value at peak drug levels during chronic
treatment and 1.5-fold at 12 hours (r2 ⫽ 0.85).39 The sensitivity of
the aPTT reagent may result in more or less pronounced differences
between trough and peak. The hematologist needs to take into
account the time elapsed since the last dose of dabigatran as well as
the responsiveness of the local reagent to make a correct interpretation of the aPTT.
Rivaroxaban
The PT shows a linear dose-response to rivaroxaban and is
prolonged to a similar extent as the degree of inhibition of factor
Xa.35 However, the PT response to rivaroxaban is assay dependent.
Assay specific calibration curves can be developed and, when used
with standard calibrators, produce a rivaroxaban level.36
In summary, although aPTT or PT cannot provide precise
information on the level and thus anticoagulant effect of dabigatran
or rivaroxaban, respectively, they are probably useful as a qualitative indicator of drug presence. Thus, a normal aPTT or PT in the
setting of dabigatran or rivaroxaban, respectively, would suggest
that hemostatic function is not impaired because of the drug. Given
the risk of epidural hemorrhage, epidural or spinal anesthesia
should only be performed in patients in whom there is a high degree
of certainty that their novel anticoagulant is completely cleared.
The predictive ability of the PT or the aPTT has not been clinically
proven; additional research is required to confirm their utility in
this setting.
Monitoring compliance
In the RE-LY and ROCKET AF studies, the anticoagulant effect of
dabigatran and rivaroxaban, respectively, was not monitored.2,16
Monitoring is not required because of the wide therapeutic window
and predictable pharmacokinetic profiles of these products. Therefore, when used for atrial fibrillation, orthopedic prophylaxis and
long-term secondary prevention of recurrent venous thromboembo-
䡠
lism dabigatran and rivaroxaban do not require routine anticoagulant monitoring. If monitoring is thought to be required, a number
of options are available. As noted previously, the TCT is very
sensitive to the presence of dabigatran and the aPTT is usually
prolonged in its presence.39 The PT should be prolonged in patients
receiving rivaroxaban, and an antifactor Xa assay, either that
normally used to measure the activity of heparin or low-molecularweight heparin, or an assay specifically calibrated for rivaroxaban,
should also be increased because both heparin and rivaroxaban
produce their anticoagulant effect through inhibition of factor Xa.36
Only the anti-Xa assay specifically calibrated for rivaroxaban
reliably predicts drug levels. Routine testing with the aPTT, TCT,
or anti–factor Xa levels is not recommended for patients receiving
the new anticoagulants.
Specialized laboratories may wish to set up functional dabigatran or rivaroxaban levels. Commercial calibrators are available
that allow accurate reporting of the amount of drug present.40,41 At
present, “target drug levels” have not been promulgated, and levels
are highly dependent on time since the drug was taken. Thus, the
development of a “therapeutic drug level” is going to require both
correlation of observed drug levels with clinical events and
development of an accepted adjustment for the level based on the
time since blood draw.
Monitoring of renal function
Dabigatran is eliminated to 80% via the kidneys; therefore, renal
function has to be assessed before starting the treatment to
determine the appropriate dose. Reassessment of renal function
should be performed annually and whenever a decline in renal
function is suspected.
Managing overdose and bleeding
complications
When bleeding occurs, the event should be risk stratified: Minor
bleeding (such as epistaxis, ecchymosis, or menorrhagia) can be
managed with simple withdrawal of the anticoagulant for 1 or more
days, allowing definitive interventions (where available) to be
applied. The drug could then be restarted at a lower dose
(dabigatran at 75 mg per day) for a short period of time. Moderate
bleeding (such as upper or lower gastrointestinal bleeding) should
be managed with withdrawal of the anticoagulant, careful clinical
monitoring, interventions to identify and definitively treat the
bleeding source, and consideration of an extended period of
withdrawal of the oral anticoagulant (perhaps with the addition of a
low dose of a parenteral anticoagulant for patients at particularly
high risk of thrombosis) to allow healing. Transfusion therapy with
red blood cells might be required to treat symptomatic anemia.
Major and life-threatening bleeding should be treated with immediate anticoagulant withdrawal, aggressive clinical monitoring, transfusion of packed red blood cells in response to proven or
anticipated severe anemia, aggressive interventions to identify and
treat the bleeding source (requiring endoscopy, interventional
radiology, or surgery), and consideration of lifesaving therapies,
such as inotropes, ventilation, and intensive care unit admission to
stabilize the patient. Other blood products, such as plasma or
cryoprecipitate, do not reverse the anticoagulant effect of novel
agents. Interventional therapy may be lifesaving in the case of
major bleeding. Such therapy cannot await reversal of the anticoagulant effect of the novel agents; thus, interventionalists will be
required to provide therapeutic interventions despite the presence
From bloodjournal.hematologylibrary.org at University Health Network on September 25, 2012. For personal use
only.
ANTICOAGULATION
BLOOD, 29 MARCH 2012 䡠 VOLUME 119, NUMBER 13
3021
of significant anticoagulant effect and the associated risk of
bleeding.
Dabigatran
If detected soon after ingestion, the absorption of dabigatran may
be reduced by gastric lavage and/or administration of charcoal.39 In
vitro experiments have verified that the lipophilic drug in solution
is completely absorbed by activated charcoal.39
There is currently no antidote for the anticoagulant effect of
dabigatran. Fresh frozen plasma or PCC is not known to mitigate its
anticoagulant effect, as measured by different coagulation tests.42
However, in a mouse model with induced intracerebral hemorrhage
and a high dose of dabigatran (9 mg/kg), a high dose of PCC
(100 IU/kg) prevented further expansion of the hematoma.43 On the
other hand, in another study with induced intracerebral hemorrhage
in mice, doses of dabigatran of 37.5 to 112.5 mg/kg did not cause
any expansion of the hematoma, as opposed to pretreatment with
warfarin, heparin, fondaparinux, or lepirudin.44 Thus, the implications of these results for the clinical management remain unclear
until we obtain information on the reversal of bleeding in humans.
Alternate agents, such as recombinant activated factor VII (rFVIIa),
have not been demonstrated to reverse bleeding complications.
Although suggested in the package insert for treatment of dabigatranassociated bleeding, rFVIIa has a very short half-life, is expensive,
and its use is associated with otherwise avoidable thromboembolism.45 Furthermore, in a study in healthy volunteers receiving
another oral thrombin inhibitor (melagatran), rFVIIa had no effect
on most coagulation parameters.46 In the aforementioned mouse
model, rFVIIa did not produce the stabilizing effect on hematoma
expansion seen with PCC.43 The lack of effect of this agent is
explained by the fact that dabigatran inhibits the last enzymatic step
of the coagulation cascade. Any agent that stimulates this cascade
or replaces coagulation factors proximal to thrombin will not
compensate for the profound terminal defect in hemostasis. Activated prothrombin complex concentrate may improve hemostasis
by providing small amounts of thrombin (Figure 1). In an animal
model of bleeding, activated prothrombin complex concentrate
reduced bleeding after treatment with another thrombin inhibitor
(melagatran).47
In extreme cases, and where it is available, acute hemodialysis
should be considered because only 35% of dabigatran is bound to
plasma proteins. This strategy has been evaluated in patients with
end-stage renal disease, who received 1 dose of 50 mg dabigatran
and then had hemodialysis. The mean drug concentration in the
inlet and outlet to the dialyzer was 12.6 and 4.4 ng/mL, respectively. In our experience from reversal of postoperative bleeding in
one patient, who had no effect from a variety of blood products,
dialysis for 6 hours reduced the TCT from approximately 150 seconds to 68 seconds.
Rivaroxaban
Because of a high degree of albumin binding in plasma (92%95%), rivaroxaban is not dialyzable. All its measurable anticoagulant effects are, however, reversed by a 4-factor PCC, as studied in
healthy volunteers.42 Clinical data are still lacking, but it seems
reasonable to give a dose of 50 IU/kg in case of acute, major
bleeding (Figure 2). Whether this needs to be repeated is unknown.
In the United States, there are no available 4-factor PCCs; whether
one of the available 3-factor PCCs is effective for reversal of
rivaroxaban is unknown.
Figure 1. Possible reversal of dabigatran. (A) Treatment with a direct thrombin
inhibitor (dabigatran) blocks factor IIa (thrombin) and thereby the fibrin formation.
(B) Activated prothrombin complex concentrate provides additional factor II, VII, IX,
and X (circled red) and also these factors in activated form (diamonds). Factor IIa
may then overcome the thrombin inhibitor.
Other considerations
Dabigatran tablets are hygroscopic and should thus not be removed
from their original packaging. Bottles, once opened, are only
approved for 60 days of use, after which residual tablets should be
thrown away (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249005.htm).
Individual tablets should not be placed into dosettes because they
will lose potency. Blister-packaged dabigatran should be used in all
settings where individual tablets are dispensed for other than
immediate use.
Although subject to a rigorous phase 3 evaluation program, rare
complications of dabigatran or rivaroxaban may yet occur. When
suspected, these events should be reported to national regulatory
authorities, as such reports are a seminal component of safety
monitoring for uncommon complications.
Introduction of the new agents at your
hospital or clinic
With the different characteristics of the new anticoagulants compared with warfarin, it is probable that mistakes will occur. In
Canada, where dabigatran is marketed under the name Pradax,
3022
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only.
SCHULMAN and CROWTHER
BLOOD, 29 MARCH 2012 VOLUME 119, NUMBER 13
䡠
ment of patients receiving novel anticoagulants. Ideally, the
hematologist should offer a service to assist with treatment of
major bleeding complications and with the perioperative management of anticoagulation. Cardiologists, internists, emergency physicians, and general practitioners should be the primary targets for
grand rounds or similar educational events. A local newsletter or
protocol should be prepared without further delay and posted on the
internet, for example in collaboration with the Pharmacy and
Therapeutics Committee (http://healthcare.utah.edu/Thrombosis/
newagents/TS.Dabi_lab.monitor.pdf; accessed October 16, 2011,
for an example). Booklets with suitable information for the patients
on each of the new drugs should also be made available.
In conclusion, dabigatran and rivaroxaban offer promise as the
first new oral anticoagulants in more than 50 years. Large studies
suggest that they are relatively safe and highly effective. Primary
care clinicians as well as specialists will need to develop a
familiarity with these drugs given their potential for hemorrhage,
potential to interfere with perioperative management, and the
requirement for specific management in the case of overdose or
bleeding. Warfarin is, however, still a good choice for several
subsets of patients, and new patients should be able to participate
actively in an informed decision on the type of anticoagulant
treatment.
Authorship
Figure 2. Possible reversal of factor Xa inhibitors. (A) Treatment with a direct
factor Xa inhibitor (rivaroxaban) blocks factor Xa and thereby the next step in the
fibrin formation. (B) Prothrombin complex concentrate provides additional factor II,
VII, IX, and X (circled red) and the Xa inhibitor is overcome.
there have already been warnings that it has been inadvertently
interchanged with Plavix. It is the responsibility of the hematologists to inform colleagues from other specialties on proper manage-
Contribution: S.S. and M.A.C. wrote and reviewed the manuscript
and reviewed and approved each other’s sections.
Conflict-of-interest disclosure: S.S. has received honoraria from
Boehringer Ingelheim, Bayer Healthcare, Sanofi-Aventis, CSL
Behring, Merck, and Glaxo-Smith-Kline. M.A.C. has received
honoraria from Leo Laboratories, Pfizer, Bayer, Boehringer Ingelheim, CSL Behring, Octapharma, and Artisan Pharma and has
provided expert testimony for Bayer.
Correspondence: Sam Schulman, Thrombosis Service, HHSGeneral Hospital, 237 Barton Street East, Hamilton, ON, L8L 2X2,
Canada; e-mail: [email protected]
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