How I Treat With Anticoagulants

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doi:10.1182/blood-2011-10-378950Prepublished online February 1, 2012;2012 119: 3016-3023

Sam Schulman and Mark A. Crowtherwhen and how to switchHow I treat with anticoagulants in 2012: new and old anticoagulants, and

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How I treat

How I treat with anticoagulants in 2012: new and old anticoagulants, and whenand 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, dabiga-

tran and rivaroxaban, have recently been

approved. They differ in many ways from

warfarin, including rapid onset of action,

shorter half-life, fewer drug-drug interac-

tions, lack of need for monitoring, and no

need for titration or dose adjustments.

These novel agents represent a landmark

shiftin anticoagulant care; however, many

aspects of their use will be unfamiliar to

practicing clinicians, despite the immi-

nent 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 deci-

sions 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 novelantithrombotic 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 orthope-

dic 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 unantici-

pated 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 procedureor 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 discon-

tinuation 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 expertopinion.

Selection of patient groups for warfarin or thenew 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

Submitted October 16, 2011; accepted November 22, 2011. Prepublished

online as BloodFirstEdition paper,February1, 2012; DOI 10.1182/blood-2011-

10-378950.

2012 by The American Society of Hematology

3016 BLOOD, 29 MARCH 2012 VOLUME 119, NUMBER 13

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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 supple-

mentary 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 inpatients with atrial fibrillation. However, the guideline notes,

Because of the twice daily dosing and greater risk of nonhemor-

rhagic 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 Com-

pared 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 valveprosthesis. 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 bleed-

ing16; 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 hada 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 poorlycompliant 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 pa-

tients 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

Table 1. Risk of important clinical outcomes with dabigatran 150 mg twice daily versus adjusted warfarin therapy that has a good orexcellent 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,

myocardial infarction, or cardiovascular death

0.94 (0.72-1.22) 1.19 (0.90-1.57)

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.

ANTICOAGULATION 3017BLOOD, 29 MARCH 2012 VOLUME 119, NUMBER 13



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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, azathio-

prine, 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, interac-tions, 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 influencethe 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 vera-

pamil.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 concomi-

tant use. St Johns 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 antiplatelettherapy 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 thepotential 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

Table 2. Drug interactions with at least 50% change in the exposure to dabigatran or rivaroxaban

Dabigatran Rivaroxaban

Mechanism Interacting drug exposure, % Interacting drug exposure, %

P-gp inhibition Ketoconazole* 150 Ketoconazole* 160

Quinidine 53

Amiodarone 60

Verapamil 50

P-gp induction Rifampicin 67 Rifampicin 50St Johns wort ND St Johns wort ND

CYP3A4 inhibition Ketoconazole* 160

Clarithromycin 50

Ritonavir 50

CYP3A4 induction Rifampicin 50

St Johns wort ND

ND indicates not determined.

*Contraindicated.

Variable depending on the formulation of verapamil.

3018 SCHULMAN and CROWTHER BLOOD, 29 MARCH 2012 VOLUME 119, NUMBER 13



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Conversion from dabigatran or rivaroxaban towarfarin

For patients who are unable to continue on dabigatran or rivaroxa-

ban 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 recommenda-

tion 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 observa-

tion 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 orrivaroxaban

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 investiga-

tors regarding preoperative discontinuation of the drug halfway

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 sur-

gery. 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 decreas-

ing 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 func-

tion: 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. Rivaroxa-

ban 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 3. Suggested strategy for conversion from dabigatran orrivaroxaban 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 rivaroxa-ban is justified by its half-life being shorter than that of dabigatran and by the concern

about thromboembolic events shortly aftertransitioning fromrivaroxabanto warfarin.6

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 2 d

50- 80 15 (12-34) 24 h 2 d

30- 50 18 (13-23) 2 d 4 d

30 27 (22-35) 4 d 6 d

Rivaroxaban

30 12 (11-13) 24 h 2 d

30 Unknown 2 d 4 d

*Examples are cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, and uncomplicated laparoscopic procedures, such as

cholecystectomy.

Examples are major cardiac surgery, insertionof pacemakers or defibrillators(resulting fromthe riskfor pocket hematoma), neurosurgery, largeherniasurgery, andmajor

cancer/urologic/vascular surgery.




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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

levelof dabigatran is very low and that the patients 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 com-

pared 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 interpreta-

tion 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 qualita-

tive 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 ROCKETAF 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. There-

fore, when used for atrial fibrillation, orthopedic prophylaxis and

long-term secondary prevention of recurrent venous thromboembo-

lism dabigatran and rivaroxaban do not require routine anticoagu-

lant 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-molecular-

weight 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 antifactor Xa levels is not recommended for patients receiving

the new anticoagulants.

Specialized laboratories may wish to set up functional dabiga-

tran 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 bleedingcomplications

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 withred blood cells might be required to treat symptomatic anemia.

Major and life-threatening bleeding should be treated with immedi-

ate anticoagulant withdrawal, aggressive clinical monitoring, trans-

fusion 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 antico-

agulant effect of the novel agents; thus, interventionalists will be

required to provide therapeutic interventions despite the presence




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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 solutionis 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 implica-

tions 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 dabigatran-

associated bleeding, rFVIIa has a very short half-life, is expensive,

and its use is associated with otherwise avoidable thromboembo-

lism.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. Acti-vated 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, respec-

tively. 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 sec-

onds to 68 seconds.

Rivaroxaban

Because of a high degree of albumin binding in plasma (92%-

95%), rivaroxaban is not dialyzable. All its measurable anticoagu-

lant 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.

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/SafetyInfor-

mation/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 thanimmediate 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 yourhospital or clinic

With the different characteristics of the new anticoagulants com-

pared with warfarin, it is probable that mistakes will occur. In

Canada, where dabigatran is marketed under the name Pradax,

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 IIamay then overcome the thrombin inhibitor.




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there have already been warnings that it has been inadvertently

interchanged with Plavix. It is the responsibility of the hematolo-

gists to inform colleagues from other specialties on proper manage-

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 manage-

ment of anticoagulation. Cardiologists, internists, emergency phy-

sicians, 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 andTherapeutics 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

Contribution: S.S. and M.A.C. wrote and reviewed the manuscript

and reviewed and approved each others 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 Ingel-

heim, CSL Behring, Octapharma, and Artisan Pharma and hasprovided expert testimony for Bayer.

Correspondence: Sam Schulman, Thrombosis Service, HHS-

General Hospital, 237 Barton Street East, Hamilton, ON, L8L 2X2,

Canada; e-mail: [email protected].

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