Introduction
Patients with atrial fibrillation (AF) have nearly a fivefold increased risk of stroke
compared with those without.[1] To reduce this risk, oral anticoagulation (OAC) is the central and most effective
medical intervention.[2] As a consequence, more than 80% of the Western AF population receive OAC therapy
and over the past 10 years, direct oral anticoagulants (DOACs) have largely replaced
vitamin K antagonists (VKAs) in this indication.[3] Although both VKAs and DOACs are similarly effective, better safety and treatment
persistence as well as better convenience for patients make DOAC the preferred treatment
option. This review will summarize the main findings of the phase III DOAC AF trials
but mainly focuses on frequently asked questions and unresolved issues.
DOAC Efficacy and Safety in Phase III Trials and Daily Care
DOACs have a close dose–response relationship leading to predictable anticoagulant
effects. As a consequence, fixed-dose regimens are established and routine anticoagulation
monitoring is not required.[2]
Using these concepts, all DOACs demonstrated a favorable benefit–risk profile in the
pivotal phase III randomized controlled trials,[4]
[5]
[6]
[7]
[8] enrolling a total of more than 70,000 AF patients at risk for stroke.[8] Taken together, DOACs in these trials significantly reduced stroke or systemic embolic
events compared with warfarin (relative risk [RR]: 0.81, 95% confidence interval [CI]:
0.73–0.91), which was mainly driven by a reduction in hemorrhagic stroke (RR: 0.49,
95% CI: 0.38–0.64). DOACs also achieved a significant reduction of all-cause mortality
(RR: 0.90, 95% CI: 0.85–0.95) and intracranial hemorrhage (RR: 0.48, 95% CI: 0.39–0.59),
but increased gastrointestinal (GI) bleeding (RR: 1.25, 95% CI: 1.01–1.55).[8]
For all DOACs, a reduced dosage was also investigated for patients perceived to be
at high risk for bleeding or DOAC accumulation. These low-dose regimens demonstrated
an overall stroke protection similar to warfarin (RR: 1.03, 95% CI: 0.84–1.27) and
a more favorable bleeding profile (RR: 0.65, 95% CI: 0.43–1.00), but significantly
more ischemic strokes were observed (RR: 1.28, 95% CI: 1.02–1.60).[8]
Choice of DOAC Dosage
The choice and dose of DOACs depend on the individual patient situation, and several
factors are used to assess the need for DOAC dose reduction: older age, renal impairment,
low body weight, and the potential for drug–drug interactions ([Table 1]).[9]
[10]
[11]
[12] The algorithm for dose reduction is different: apixaban is reduced in patients with
two or more characteristics from moderate to severe renal impairment, older age, and
low body weight.[9] The dose of dabigatran should be lowered for moderate to severe renal impairment,
older age (>80 years and/or high bleeding risk), and concomitant use of P-glycoprotein
(P-gp) inhibitors.[10] The dose of edoxaban is lowered for moderate to severe renal impairment, low body
weight, and concomitant use of P-gp inhibitors.[11] For rivaroxaban, dose reductions are required for moderate to severe renal impairment
only,[12] because pharmacokinetic/pharmacodynamic (PK/PD) profiles and simulations of drug
exposure have shown no effect of age, body weight, gender, or co-medications on drug
exposure.[13] However, in addition to the inconsistent dose reduction criteria for each DOAC,
the extent of dose reductions is also variable. While rivaroxaban and dabigatran are
reduced by only approximately 25 to 30%, apixaban and edoxaban are reduced by 50%,
which may lead to clinically relevant discrepancies of drug exposure and outcomes.
Table 1
Recommended DOAC dosing for patients with atrial fibrillation
|
Apixaban[a] (5 mg bid)
|
Dabigatran (150 mg bid)
|
Edoxaban (60 mg od)
|
Rivaroxaban (20 mg od)
|
|
Age
|
|
75–80 y
|
5 mg bid
|
Consider 110 mg bid
|
60 mg od
|
20 mg od
|
|
≥ 80 y
|
2.5 mg bid with one other factor[a]
|
110 mg bid
|
60 mg od
|
20 mg od
|
|
Body weight
|
|
50–60 kg
|
2.5 mg bid with one other factor[a]
|
150 mg bid
|
30 mg od
|
20 mg od
|
|
< 50 kg
|
2.5 mg bid with one other factor[a]
|
Consider 110 mg bid
|
30 mg od
|
20 mg od
|
|
Serum creatinine ≥1.5 mg/dL
|
2.5 mg bid with one other factor[a]
|
–
|
–
|
–
|
|
CrCl
|
|
30–49 mL/min
|
5 mg bid
|
150 or 110 mg bid
|
30 mg od
|
15 mg od
|
|
15–29 mL/min
|
2.5 mg bid
|
Contraindicated/75 mg bidc
|
30 mg od
|
15 mg od
|
|
< 15 mL/min
|
Contraindicated
|
Contraindicated
|
Contraindicated
|
Contraindicated
|
|
Concomitant medication
b
|
|
Cyclosporine
|
–
|
Contraindicated
|
30 mg od
|
–
|
|
Dronedarone
|
0
|
Contraindicated/consider 75 mg bidc
|
30 mg od
|
Not recommended
|
|
Erythromycin
|
–
|
–
|
30 mg od
|
20 mg od
|
|
Ketoconazole
|
Not recommended
|
Contraindicated/consider 75 mg bidc
|
30 mg od
|
Not recommended
|
|
Verapamil
|
5 mg bid
|
150 or 110 mg bid
|
60 mg od
|
–
|
Abbreviations: bid, twice daily; CrCl, creatinine clearance; DOAC, non-vitamin K antagonist
oral anticoagulant; od, once daily.
a For apixaban, 2.5 mg bid is indicated in patients with two or more of the following
characteristics; age ≥ 80 years, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL
(133 µmol/L).
b Incomplete list. See individual labels for more information.
c Dabigatran 75 mg is only available in the United States, and the use of dabigatran
in these patients may be contraindicated in other countries.
All these licensed dosing recommendations are based on dose reduction criteria, which
were prespecified for the phase III trials[4]
[5]
[6]
[7]
[13]
[14] based on small-dose finding studies or pharmacological models. Therefore, these
criteria have not been rigorously studied and the use of the lower DOAC dose should
be limited to patients truly fulfilling these criteria to reduce the risk of undertreatment
from unjustified dose reductions.[15]
[16]
[17]
[18]
Correctly applied dose-reduction strategies are important for AF patients to achieve
the optimal balance between stroke and bleeding risk. Similar to all anticoagulants,
effectiveness and safety of DOACs are defined by plasma exposure: higher plasma drug
levels will reduce the risk for thromboembolism, while increasing the risk for bleeding.
PK analyses from the RE-LY and ENGAGE AF-TIMI 48 trials showed that the probability
of major bleeding events increased with increasing DOAC trough plasma concentrations
and the risk of stroke/systemic embolism was higher at lower plasma trough concentrations.[14]
[19]
Consequently, factors that increase the likelihood of very high or very low DOAC plasma
concentrations need to be considered and renal impairment, drug–drug interactions,
and extremely high body weight are the most common points of discussion amongst DOAC
prescribers.
Frequently Asked DOAC Questions of DOAC Prescribers
How to Use DOAC in Moderate to Severe Renal Impairment?
Patients with renal dysfunction are at risk of DOAC accumulation.[19] In patients with a creatinine clearance [CrCl] between 30 and 50 mL/min, all DOACs
can be used but reduced dosages should be considered with dose reduction criteria
being different between DOACs. Apixaban, edoxaban, and rivaroxaban can be used with
caution in patients with severe renal disease when CrCl is 15 to 29 mL/min, but dabigatran
is contraindicated in this situation. However, given the comparatively high renal
excretion of edoxaban (∼50%),[11] the author would prefer apixaban or rivaroxaban in this setting.
There is still very limited evidence only on the use of DOACs in patients with end-stage
renal disease (ESRD; CrCl < 15 mL/min). Dabigatran and edoxaban exhibit a relevant
renal clearance[10]
[11] and are contraindicated in this situation for risk of overexposure. Although apixaban
and rivaroxaban are not strictly contraindicated in ESRD or dialysis patients, labels
both in the United States and Europe caution to avoid use in this setting due to the
lack of clinical data. On the other hand, pharmacological models indicated that the
risk of clinically relevant drug accumulation of apixaban or rivaroxaban is low[20] and there are several reasons why DOACs may have a role in stroke prevention of
dialysis patients in the future[21]:
-
The alternative to use warfarin in ESRD is problematic: renal failure is listed as
a contraindication for VKA.[22]
-
There is no significant benefit from VKAs versus no anticoagulation with respect to
ischemic stroke but an excess risk for major bleeding was observed.[23]
[24]
-
Although studies in this field were inconsistent in study design and quality, this
questions the need for anticoagulation in dialysis patients in general and data from
an ongoing randomized trial will hopefully clarify the role for VKA in this setting
(NCT02886962).
-
Evidence for using DOACs in ESRD and dialysis patients is emerging and, so far, has
indicated a potential for benefit,[25]
[26]
[27] although negative results have also been reported.[28]
[29]
Which Drug–Drug Interactions Are Relevant?
Clinically relevant drug–drug interactions with DOACs mainly arise from induction
or inhibition of CYP3A4 and/or P-gp transport proteins and, much less, from competition
with other substrates of these elimination mechanisms.[30] As a general rule, DOACs neither induce or inhibit CYP enzymes or P-gp. Therefore,
DOAC effects on PK of other drugs are very limited. On the other hand, DOACs are all
P-gp substrates and drugs that are strong inducers of P-gp expression (such as rifampicin
and St. John's wort) decrease DOAC plasma levels to a clinically relevant degree.
Concomitant treatment with such drugs should be avoided or used with caution.[31] Similarly, strong inhibitors of CYP3A4 will increase DOAC plasma levels but this
is clinically relevant only for apixaban and rivaroxaban, since edoxaban and dabigatran
metabolism is nearly independent of CYP3A4 enzymes.
However, concomitant treatment with strong inhibitors of both CYP3A4 and P-gp (such
as systemic azole-antimycotics or human immunodeficiency virus-protease inhibitors)
is contraindicated/not recommended in patients receiving apixaban, dabigatran, or
rivaroxaban, and, in patients receiving edoxaban, a dose reduction from 60 to 30 mg
once daily is warranted.[31]
The European Heart and Rhythm Association guidance on DOAC use contains very informative
and clinically helpful tables, indicating culprit drugs and extent of interactions
with DOACs, and the reader is encouraged to refer to this document for further details.[31]
Should DOAC Be Taken with Food or Fasting?
According to labels, only rivaroxaban at doses higher than 10 mg needs to be taken
with food, since absorption of lower doses was found to be independent of the fasting
state, whereas plasma exposure from higher dosages increased by 39% (area under the
curve, AUC) when the drug was taken with food.[20]
In contrast, labels of apixaban, edoxaban, and dabigatran state that absorption is
independent of the fasting status, so, at least theoretically, these drugs could be
taken without food.[32]
[33]
[34] On the other hand, some skepticism may be warranted here.
First, these recommendations are exclusively based on small first-in-human PK studies,
which usually study exposure after single-dose applications to healthy volunteers.
As a consequence, the effect of fasting status on DOAC absorption in elderly patients
who may exhibit chronic intestinal diseases is really unknown.
Second, one of the most relevant side effects of DOAC treatment is upper GI bleeding.
It seems plausible to expect a higher risk of GI bleeding, if a drug that carries
this risk is routinely taken without food, thus exposing the potentially vulnerable
“naked” gastric mucosa to undiluted chemicals (but this may only partially explain
the issue of upper GI bleeding from DOAC, since an increase of lower GI and genitourinary
is also observed, which is unrelated to direct contact of DOAC with the mucosal layer).
Third, every trial with every DOAC lists thromboembolic complications during DOAC
therapy, but little is known about the reasons for these therapeutic failures, which
may well be based on individual malabsorption due to fasting.
Taken together, irrespective of the liberal recommendations to take most DOACs and
dosages with or without food, the author has made it an individual policy to explain
the limited evidence behind this to the patients and to routinely recommend DOAC intake
with food, irrespective of DOAC type and dosage.
Can DOAC Be Given via Nasogastric Tubes?
Patients with AF represent an elderly vulnerable population and some patients may
be or may become unable to swallow tablets or capsules. In this situation, the placement
of feeding lines such as nasogastric tubes is a clinical routine but raises the question
of whether DOAC tablets or dabigatran capsules can be crushed and given with fluids
via such tubes. For each DOAC, dedicated studies have been performed, with variable
outcomes.
For apixaban, oral administration of 10 mg of apixaban as two crushed 5 mg tablets
suspended in water or mixed with applesauce resulted in an AUC reduction of only 16%
compared with standard application. Suspension of a crushed 5 mg tablet in tube nutrition
resulted in a drug exposure similar to that seen in other clinical trials involving
healthy volunteers receiving a single oral 5 mg tablet dose.[33]
For edoxaban, administration of a crushed 60 mg tablet, either mixed into applesauce
or suspended in water and given through a nasogastric tube, resulted in a similar
exposure compared with administration of an intact tablet.[32]
For rivaroxaban, administration of a 20 mg tablet administered orally as a crushed
tablet mixed in applesauce or suspended in water and administered via a nasogastric
tube followed by a liquid meal resulted in an AUC comparable to the AUC after standard
application.[20]
In contrast to these reassuring data from direct factor Xa inhibitors, dabigatran
is not applied as a tablet (that can be crushed) but as a capsule which contains pellets
of the prodrug. The oral bioavailability of dabigatran etexilate increases by 75%
when the pellets are taken without the capsule shell compared with the intact capsule
formulation. PRADAXA capsules should therefore not be broken, chewed, or opened before
administration.[34]
Taken together, factor Xa inhibitors but not dabigatran can be given via nasogastric
tubes. However, the discussed data mainly result from single-exposure healthy-volunteer
studies, so readers should apply caution in this setting and limit the application
via feeding lines in chronically ill patients to an unavoidable minimum.
Can DOAC Be Used in Very Obese Patients?
Although DOAC labels only reflect on low-body-weight patients (necessitating DOAC
dose reduction for apixaban, edoxaban, and dabigatran), there is widespread concern
that the fixed dosing may carry a risk of relative underexposure in extreme obesity[35]
[36]
[37] and, in 2016, the International Society on Thrombosis and Haemostasis (ISTH) Scientific
and Standardization Committee issued a warning against the use of fixed-dose DOACs
in patients with a body mass index (BMI) of >40 kg/m2 or a weight of >120 kg, based on lack of evidence for patients at the upper extreme
of weight.[38]
However, subgroup analyses in large phase III trials suggest that DOACs are efficacious
and well tolerated in obese patients, although the respective patient numbers were
low.[38]
[39]
[40]
[41]
[42]
Recently, several PK/PD studies, case series, and large retrospective claims database
analyses have been published which provide reassurance that licensed dosing of DOACs
is effective and safe also in very obese patients with BMI > 40 kg/m2.[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51] It can be expected that the current, more cautious ISTH guidance will be updated
accordingly in the near future.
Do We Need Specific DOAC Antidotes?
DOACs are generally safer than VKAs. Because of this, also fragile patients who would
previously not have been candidates for VKA therapy now receive DOAC prescriptions.
Such patients present vulnerability for spontaneous or traumatic bleedings and, since
DOACs are potent anticoagulants, major bleeding complications are not infrequent.
Although most of these events are not life-threatening and manageable by short DOAC
interruptions, local compression, minor surgery, or transfusion, the widespread use
of DOAC leads to an increasing frequency also of major bleeding complications.[52] Nearly half of them are GI and some 10% are intracranial bleedings,[53]
[54] leading to a frequent request of DOAC-specific reversal strategies with specific
antidotes.[55] In fact, in daily care, more than 50% of patients older than 60 years presenting
with hip fractures or major head trauma are on anticoagulant therapy.[56]
[57]
To answer the question of “do we need a specific DOAC antidote, the following pragmatic
considerations apply:
-
Most bleeding complications of DOACs are non-life-threatening. They can be managed
conservatively without specific or unspecific DOAC reversal strategies.
-
Most major bleeding complications during DOAC therapy are GI or urogenital bleedings.
Again, most of these can be managed conservatively or using dedicated endoscopic strategies
to close bleeding lesions. Antidotes are rarely needed in these situations but may
be considered in cases of severe diffuse mucosal bleeding unresponsive to conservative
or endoscopic treatments or when the bleeding lesion cannot be identified by endoscopy.
Typically, such bleedings develop during DOAC overexposure (intoxication or accumulation
from deterioration of renal function). Here, DOAC antidotes may indeed play a role
and improve bleeding outcome, although the evidence for such treatment decisions is
weak.
-
For acute life-threatening bleeding, idarucizumab (for dabigatran reversal) and andexanet
alfa (for reversal of direct factor Xa inhibitors) have demonstrated effective reversal
of DOAC anticoagulation and effectiveness in achieving immediate hemostatic control.[58]
[59] However, these trials were performed without comparator treatment, so the benefit
of specific antidote reversal over traditional reversal with factor concentrates has
yet to be demonstrated. Furthermore, for andexanet alfa, the approval is currently
limited to reversal of apixaban and rivaroxaban in cases of major bleeding. Although
the author has little doubt that these results can be extended to edoxaban, such use
has to be regarded as “off-label” for the time being.
-
For DOAC-treated patients in need of urgent surgery, reversal with idarucizumab has
been approved for dabigatran-treated patients. In contrast, approval of andexanet
alfa is limited to acute, life-threatening bleeding and safety and clinical benefit
for patients requiring immediate surgery has not been demonstrated so far. Again,
such use has to be regarded as “off-label” for the time being.
Another consideration for DOAC reversal is the thrombolytic treatment of acute ischemic
events during DOAC therapy. Although DOACs are highly effective to prevent cardioembolic
stroke in AF patients, not every ischemic stroke is of cardioembolic nature (which
could have been prevented by DOACs) and prothrombotic states may override the clinical
efficacy of DOACs in AF. As a result, patients may develop ischemic stroke while being
on DOAC therapy. Optimally, such patients present with acute stroke symptoms within
the time window for thrombolysis. In this situation, use of idarucizumab or andexanet
alfa is a clinical consideration which is supported by some guidelines[60]
[61]
[62] but not covered by the current labels of these antidote compounds. Therefore, this
strategy cannot be generally recommended but may be needed in cases of severe stroke
when immediate thrombolysis is the only option to achieve acceptable clinical outcomes.
Clearly, the use of antidotes would be off-label in this situation, requiring a high
threshold and careful benefit–risk considerations.
Taken together, the previous lack of available DOAC antidotes should not have been
a reason in the past to withhold a DOAC prescription in eligible patients, since the
benefits of providing an effective and safe anticoagulant in trial programs and observations
registries were overwhelming already even before DOAC antidotes became available.
Having the antidotes available today further increases the safety and hopefully improves
the outcomes of major complications for DOACs in patients.
