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Non-Vitamin K antagonist oral anticoagulants (NOAC): Considerations on

once- vs. twice-daily regimens and their potential impact on medication
adherence

Article in Europace · February 2015

DOI: 10.1093/europace/euu311 · Source: PubMed

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 Europace (2015) 17, 514–523 REVIEW
doi:10.1093/europace/euu311

Non-vitamin K antagonist oral anticoagulants:

considerations on once- vs. twice-daily regimens
and their potential impact on medication
adherence
Bernard Vrijens1,2 and Hein Heidbuchel 3*
1
MWV Healthcare, Rue des Cyclistes Frontière 24, 4600 Visé, Belgium; 2Department of Biostatistics and Medical Informatics, CHU Sart Tilman, Liège; and 3Hasselt University and Heart
Center, Jessa Hospital, Jessa Ziekenhuis, Stadsomvaart 11, 3500 Hasselt, Belgium

Received 7 August 2014; accepted after revision 14 October 2014; online publish-ahead-of-print 18 February 2015

Suboptimal medication adherence is a widespread problem in ambulatory care of chronic diseases, with deviations in either direction from the pre-
scribed dosing regimen. For the non-vitamin K antagonist oral anticoagulants (NOACs), such deviations occur and can lead to bleeding or clotting, as
suboptimal adherence involves temporary periods of either overdosing or underdosing. In this expert review, we discuss: (a) the proper definition of

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adherence in terms of its three elements: initiation, implementation, and discontinuation; (b) how adherence is reliably and accurately measured and
(c) successfully enhanced, to achieve and maintain safe and effective levels of NOAC-based anticoagulation. We also discuss the comparative effects
of prescribing the same total daily dose, given either once-daily or as half-strength twice-daily doses. Because NOACs have plasma half-lives of 12 h,
the twice-daily dosing regimen is less prone than the once-daily dosing regimen to hazardously high peaks or hazardously low troughs in anticoagulant
concentrations and associated actions. As in other fields of oral drug treatment, the continuity of drug action is greater with twice-daily than with
once-daily dosing, despite the fact that a few more doses are skipped with twice-daily than with once-daily dosing. This paradox is explained by the
disproportionately greater impact on drug action of skipping a once-daily than a twice-daily dose. Integration of these principles into real-world medi-
cation management is the next step in the improvement of oral anticoagulation.
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Keywords Medication adherence † Compliance † Monitoring † Dosing regimens † Anticoagulation † New oral
anticoagulants † Atrial fibrillation † Stroke

Introduction between patients and practitioners2 as the term ‘adherence’

From patient compliance to medication
adherence
In 1997, the American Heart Association issued a visionary statement
in which patient compliance (the extent to which medical re-
commendations are followed as defined) was described as ‘a
complex behavioural process, strongly influenced by the environ-
ment in which the patients live, how healthcare providers practice,
and how healthcare systems deliver care’.1 This definition acknowl-
edges that a patient’s compliance is also influenced by system-level
factors, e.g. the provider of healthcare, healthcare organizations, eco-
nomics, and other aspects of the overall system of healthcare.
Later, the term ‘patient compliance’ has been increasingly replaced
by ‘medication adherence’. The shift from ‘compliance’ to ‘adher-
ence’ reflects a fundamental change in understanding relationships
implies cooperation between patient and prescriber, rather than
the patient’s passive obedience to the physician’s instructions.
Patient adherence to medications (i.e. the process by which patients
take their medications as prescribed) is now recognized to consist of
three components: (1) the process starts with initiation of the treat-
ment, then (2) continues with the implementation of the dosing
regimen, and eventually (3) discontinuation marks the end of
therapy, with persistence being the length of time between initiation
and discontinuation.3 In the context of life-long therapy like anticoa-
gulation, discontinuation may occur in response to the prescriber’s
decision to halt the treatment, but most often it is the result of a uni-
lateral action by the patient, without the knowledge of the prescriber.
Still, the decision to discontinue anticoagulation therapy after a major
bleed will likely be the result of a joint decision from the patient and
physician, although patient views may temper the final decision on

* Corresponding author. Tel: +32 11 37 35 65; Fax: +32 11 35 39 90, E-mail address: heinheid@gmail.com
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
Adherence through monitoring
whether the anticoagulation therapy is restarted or not. When asses-
sing adherence in studies, it may thus be difficult to assess the subtle-
ties of whether the decision to discontinue therapy is taken by the
patient, prescriber, or both.
Suboptimal adherence in
anticoagulation therapy
Adherence to warfarin is suboptimal
The consequences of non-adherence are particularly problematic
for drugs with a narrow therapeutic window, as is the case for war-
farin: anticoagulation levels below the target range of International
Normalised Ratio (INR) values are associated with increases in
thrombotic risk, while levels above the therapeutic INR level
increase the bleeding risk;4 both can be life-threatening or result
in major morbidities. In addition to the risk of non-adherent patients
being assumed anticoagulated when they are actually not, non-
adherence to anticoagulation therapy can also lead to withdrawal
symptoms with a prothrombotic state in the non-adherent patient.
In both the ROCKET-AF5 and ARISTOTLE6 trials, an excess of
thrombo-embolic events has been observed at the end of the
study period, during the transitioning phase to vitamin K antagonist
(VKA) therapy.
Kimmel et al. have assessed adherence to the VKA warfarin7 using
the Medication Event Monitoring System (MEMSw) that records the
time and date of each pill bottle opening, a ‘medication event’ that is
tightly linked to dose ingestion.8 In that study, non-adherence to war-
farin was shown to be widely prevalent.7 Among 136 patients
observed for a mean period of 32 weeks, 92% had at least one
missed or extra dose, while 36% missed more than 20% of their pre-
scribed doses and 4% had more than 10% extra doses. Moreover, this
poor implementation of the dosing regimen was shown to have a con-
siderable effect on anticoagulation control: missing one to two doses
a week (20 –30% missed doses) was associated with up to a two-fold
increased odds of sub-therapeutic INR, while taking extra doses was
associated with an increased risk of a too-high INR value.7
Could adherence improve with non-
vitamin K antagonist oral anticoagulants?
The various well-known drawbacks of warfarin therapy, including its
narrow therapeutic window, its many potential drug interactions, and
the considerable time required for onset and offset of its therapeutic
effect, have spurred the development of non-VKA oral anticoagu-
lants (NOACs). Up to now, no prospective adherence studies on
NOACs have been reported; adherence to apixaban in patients
with non-valvular atrial fibrillation is currently under assessment in
the ‘Assessment of an Education and Guidance Programme for
Eliquis Adherence in Non-Valvular Atrial Fibrillation’ (AEGEAN)
study (ClinicalTrials.gov: NCT01884350). The AEGEAN study will
not compare adherence of NOACs to VKA, but randomizes patients
started on apixaban between ‘regular care’ and ‘regular care with
structured education and follow-up by a virtual clinic’. Adherence
is measured via an electronic smart package, but the results from
these measurements are not used for feedback during the trial.
515
While the population that will be taking the NOACs is the same as
those taking warfarin, differences in adherence to NOACs compared
with VKA can nevertheless be expected in terms of initiation, imple-
mentation, and discontinuation. Patients are often reluctant to use
warfarin because of a fear of bleeding; thus, they may prefer
NOACs and therefore be more inclined to initiate them. Moreover,
patients tend to discontinue VKA therapy due to poor maintenance
in the INR range and associated side effects; thus, persistence may
improve when using NOACs instead of VKA. Indeed, a review of a
healthcare claims database for propensity-matched cohorts of
atrial fibrillation patients newly initiated on rivaroxaban or warfarin
showed that treatment persistence was significantly better with riv-
aroxaban than with warfarin (hazard ratio (HR) ¼ 0.66; 95% confi-
dence interval: 0.60– 0.72, P , 0.0001).9
In contrast, NOACs have a much shorter half-life of around 12 h,
meaning that the anticoagulation effect will rapidly decline when
scheduled doses are not taken. Non-vitamin K antagonist oral antic-
oagulants may thus require a stricter implementation, although the
consequences of suboptimal adherence will depend on the dosing
schedule and the forgiveness of the specific drug as detailed below
in this review.
For patients with suboptimal adherence that is not caused by VKA
side effects or other VKA-related difficulties, simply switching to a
NOAC will not necessarily improve adherence. Hence, a compre-
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hensive analysis of the reasons for a patient’s non-adherence would
be needed, in order to provide the patient with tools and support
to improve his or her level of medication adherence.
Management of patient adherence
For many years, medication adherence has been considered solely a
patient problem. However, it is now becoming clear that patient ad-
herence is responsive to certain management methods that can
improve continuity of patients’ exposure to prescribed medications,
as detailed below.10 There is, however, no single solution to achieve
that continuity; simply changing the dosing frequency, sending text
messages, or providing an informative website to a patient will not
solve adherence problems. The solution must be based on reliable
quantification of the dosing errors incurred by patients, not limited
to average quantities of doses missed. Reliable data on when lapses
in dosing occur, for how long, and the dosing patterns that prevail
as patients resume correct dosing can reveal patient-specific causes
of non-adherence and point to individualized solutions. Such detailed
and reliable information forms the foundation for new models of inte-
grated care.
Measurement of adherence
In addition to using a transparent and well-defined taxonomy, it is
critical to appropriately quantify the three elements of medication
adherence (initiation, implementation, and discontinuation). Apt
quantification of adherence should provide researchers, clinicians,
and patients with meaningful metrics which should be reliable,
allow tracking over time, be coherent with the three elements of
medication adherence, and be implementable on a large scale.
Various methods are currently used to measure adherence, each
with specific advantages and limitations. Blaschke et al.11 have
516
Table 1 Advantages and disadvantages of methods to monitor adherence
1. Initiation
...............................................................................................................................................................................
Self-report Desirability bias
Pill counts Easily censored by patient
Direct methods (PK/PD) Requires sampling after prescription
Prescription and refill databases Gold standard if both databases are combined
Electronic monitoring Gold standard in clinical trials needs activation
PK, pharmacokinetics; PD, pharmacodynamics.
described these advantages and disadvantages in detail, but did not
distinguish between the three elements of patient adherence.
Below, we summarize the main characteristics of different adherence
measurement methods according to the three components of
adherence (Table 1).
One popular method for quantifying adherence is self-reporting,
using, for example, diaries or retrospective questionnaires. Self-
reports may be useful for assessing very recent drug use; self-report
for cardiovascular drugs taken in the last 24 h has been reported to
correlate well with the presence of the drug in the blood.12
However, in other studies assessing self-report methods to assess ad-
herence over longer time periods, these methods have been shown
to be biased towards overestimation of drug exposure.13,14
The counting of returned, untaken doses (‘pill counts’) has also
been repeatedly discredited since the first reliable test of their validity
by chemical marker methods in 1989;15 electronic monitoring
methods have confirmed and extended the dynamic range of the
results obtained through chemical marker methods.8,11,16 Neverthe-
less, clinical researchers still continue to report pill-count data,
despite well-documented unreliability. One recent example is the
failed STABILITY study that relied on discredited criteria and
methods for assessing in-trial adherence to the dosing regimen of
darapladib, a selective oral inhibitor of lipoprotein-associated
phospholipase A2.17
Methods that are based on sampling (e.g. blood sampling to
measure drug levels in the blood) performed during a clinical visit
for therapeutic drug monitoring are subject to the phenomenon of
‘white-coat adherence’, which is a short-term escalation in adherence
during a few days prior to the scheduled visit to the clinic or labora-
tory.18 – 21 Many drugs, but not all, can be restored to their therapeut-
ic concentration ranges by 1–3 days of correct dosing.
And while electronic prescription and dispensing databases
provide objective data, they provide no information on when doses
were taken or missed. Temporal sequence is an essential measure-
ment in causal inference, as one seeks to understand the conse-
quences of intermittently omitted doses, of recurrent first-dose
effects when dosing suddenly resumes after a period of interruption,
and when hazardous rebound effects occur in sequence with inter-
rupted dosing.
Of the currently available options, automatic compilation of dosing
histories using electronic detection of package entry (smart packages)
or direct detection of pills in the stomach (smart pills) is the only re-
liable and sufficiently richly sampled method to estimate the three
B. Vrijens and H. Heidbuchel
2. Implementation 3. Discontinuation
Recall bias Desirability bias
Only aggregate summary Easily censored by patient
Sampling is too sparse Subject to white coat adherence
Only aggregate summary Gold standard but retrospective
Gold standard Gold standard in clinical trials needs
patient engagement
elements of patient adherence. Electronic methods for compiling
drug dosing histories are often used as a standard for quantifying ad-
herence, the parameters of which support model-based, continuous
projections of drug actions and concentrations in plasma that are
confirmable by intermittent, direct measurements at single time-
points.11 While electronic detection of package entry is an indirect
method of estimating when and how much drug is administered, it
can accurately project the time-course of drug concentrations in
the plasma.8
Smart packages deliver a reliable detailed assessment of dosing
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history data over time, allowing the identification of different patterns
of adherence (Figure 1). MEMSw is a smart package in the form of a cap
that contains an electronic chip registering the time and date of each
pill bottle opening, and has been widely used in clinical trials, as illu-
strated by the more than 650 available peer-reviewed publications
(www.iAdherence.org). Smart packages are safe, un-intrusive (easy
to use), long lasting (battery), the resulting adherence data are reliable
and detailed, and can easily be adapted to any form factor (blister
packs,23 inhalers,24 injectable,25 etc.) or for polymedication.23
One more direct method to measure adherence is the electronic
detection of pills in the stomach by formulating the drug in question
with an electronic ‘chip’ included directly in each pill.26,27 Once the
chip-containing pill is swallowed, a signal is briefly generated via the
creation of a short-lived voltage difference through ionic differences
between gastric fluid and the electronic ‘chip’. The signal is detected
by an antenna integrated into a dermal ‘patch’, worn on the patient’s
torso (which in the future may be integrated into other implanted
devices like an implantable cardioverter-defibrillator, pacemaker or
implantable loop recorder). The signal is then amplified for transmis-
sion to a nearby mobile device, and transmitted to a server. However,
the chip-in-the-pill method has potential drawbacks such as the risk
of failed detection (5%),27 the need to reformulate and revalidate
stability characteristics of the chip-containing medications, and, so
far, the lack of information on the cost of using this method.
Once- vs. twice-daily dosing: lessons
from electronic monitoring
The importance of timing of drug dose
intake
Reducing the frequency of dosing has long been widely believed to
improve medication adherence. This belief arises from the focus on
 Adherence through monitoring
A B
2:59 AM 2:59 AM

12:00 AM 12:00 AM

9:00 PM 9:00 PM

6:00 PM 6:00 PM

Patient 4834

Patient 5631
3:00 PM 3:00 PM

12:00 PM 12:00 PM

9:00 AM 9:00 AM

6:00 AM 6:00 AM

3:00 AM 3:00 AM
23/4/2003 11/5/2003 29/5/2003 16/6/2003 4/7/2003 22/7/2003 1/12/1993 19/12/1993 6/1/1994 24/1/1994 11/2/1994 1/3/1994

C D
2:59 AM 2:59 AM

12:00 AM 12:00 AM

9:00 PM

Treatment discontinuation
9:00 PM

6:00 PM 6:00 PM

Patient 12902
Patient 5044
3:00 PM 3:00 PM

12:00 PM 12:00 PM

9:00 AM 9:00 AM

6:00 AM 6:00 AM

3:00 AM 3:00 AM
26/8/2002 13/9/2002 1/10/2002 19/10/2002 6/11/2002 24/11/2002 4/2/2000 22/2/2000 11/3/2000 29/3/2000 16/4/2000 4/5/2000

Figure 1 Varying patterns of adherence. The same amount of drug intake over a given time period may be the result of different intake patterns, each requiring specific approaches for optimization.
Electronically compiled drug dosing histories are shown for four patients who each took 75% of their prescribed doses during a 3 months period. The blue dots represent electronically captured dosing
times; the vertical grey bars mark omitted doses. The first three patients display sub-optimal implementation: patient A missed mainly evening doses, patient B missed both evening and morning doses, and
patient C displays a drug holiday (i.e. three or more days without a dose). Patient D initially had a high level of adherence, but discontinued the treatment prematurely. Figure adapted from Vrijens et al.,
Expert Rev Clin Pharmacol 2014.22

517
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518
percentages of doses taken irrespective of when doses were or were
not taken; the percentage of doses taken is generally higher with less
frequent dosing regimens. A recent analysis of a large claims database
assessing 10 697 patients with atrial fibrillation showed that the ad-
herence and persistence for intake of antidiabetics, antihyperten-
sives, calcium channel blockers, or diuretics (no anticoagulants
were studied) was significantly higher for drugs with a once-daily
intake regimen than for those with a twice-daily regimen.28
However, drug actions are both dose- and time-dependent. To il-
lustrate, having doses clustered at odd times with long intervals
between those clusters, can create an impressively high percentage
of doses taken, but does not provide continuity of drug action. To
predict real therapeutic consequences of non-adherence, it is not suf-
ficient to only focus on the percentage of doses taken; it is crucial to
also take into account the distribution of exactly when doses were
taken.
Comprehensive assessment of the risks of a patient’s non-
adherence to a medication should therefore combine detailed
dosing history data obtained from electronic monitoring, as well as
information on the effect of non-adherence on the drug concentra-
tions in the patient’s plasma (pharmacokinetics) and the effect on
the actions of the drug (pharmacodynamics).11 Such integrated ana-
lyses are an exercise in systems pharmacology, taking into account the
fact that several interacting factors are operative and must be consid-
ered simultaneously.
Superior therapeutic coverage with
twice-daily dosing regimens
Analyses that combine patients’ dosing history data and the pharma-
cokinetic properties of the assessed drug have clearly shown that a
twice-daily dosing regimen maintains a better continuity of drug
plasma levels than once-daily dosing for drugs with a half-life of
12 h. For instance, an integrated analysis has suggested superior
therapeutic coverage with twice-daily compared with once-daily
protease inhibitors for the treatment of HIV-infected patients.29
This model-based finding has then been supported by an outcome
study showing that patients with a viral load of more than
100 000 copies/mL had a greater probability of a sustained viral
response on a twice-daily than on a once-daily regimen.30
A second example comes from the superior inhibition of platelet
aggregation (IPA) with twice-daily administered ticagrelor com-
pared with once-daily clopidogrel. Model-based simulations using
observed patient dosing histories showed that both average and
trough IPA levels remained significantly higher for ticagrelor than
for clopidogrel, despite somewhat lower percentages of prescribed
doses taken with twice-daily ticagrelor than with once-daily
clopidogrel. 31
The clinical benefits of twice-daily ticagrelor compared with once-
daily clopidogrel have also been confirmed in the Platelet Inhibition
and Patient Outcomes (PLATO) trial:32 in patients with acute coron-
ary syndrome (ACS), with or without ST-segment elevation, treat-
ment with ticagrelor as compared with clopidogrel significantly
reduced the rate of death from vascular causes, myocardial infarction,
or stroke without an increase in the rate of overall major bleeding but
with an increase in the rate of non-procedure-related bleeding. This
result is consistent with the twice-daily regimen’s ability to maintain a
B. Vrijens and H. Heidbuchel
greater degree of continuity of drug action than was achieved by the
once-daily regimen, notwithstanding the fact that a higher percentage
of prescribed doses were taken with the once-daily than with the
twice-daily regimen. Nonetheless, there are other factors that may
have contributed to the observed differences between ticagrelor
and clopidogrel, such as the fact that both drugs are not identical in
their action.
These two examples show that while once-daily dosing may be
seen as an option to simplify the dosing regimen and increase
patient adherence, it in fact may require near-perfect adherence
to achieve its intended pharmacodynamic and clinical results,
whereas the twice-daily dosing is, depending on the drug’s pharma-
cokinetics, more forgiving of variations in dose-timing or occasion-
ally missed doses. The real therapeutically relevant question is the
impact of suboptimal adherence on the pharmacologic effects of
the drug.
It is of paramount importance to investigate these elements also in
detail in NOAC patients, as the consequences of suboptimal pharma-
cologic effects are so severe (bleeding or thrombotic events, both
of which may be fatal). Clearly, the above-mentioned findings
cannot be just extrapolated to NOAC therapy; not only may the con-
sequences of non-adherence differ depending on the specific charac-
teristics of the drug, also the patients taking NOAC are different from
those taking HIV medication and may therefore have specific issues
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due to for example ageing or dementia. Thus, it would be useful to
obtain electronic dosing histories and related consequences of non-
adherence from patients on NOAC therapy.
A simulation of the consequences of
non-adherence with once- or twice-daily
dosing
In both examples, the pharmacokinetic equivalent of a single missed
once-daily dose was two to three sequentially omitted twice-daily
doses. This finding is illustrated by the simulation in Figure 2, which
shows the typical pharmacokinetic profile for a drug with a half-life
of about 12 h, similar to NOACs.
In Figure 2A, one can see that when the pharmacokinetic character-
istics are the same, the peak-to-trough ratio is much smaller if the
drug is given at half the dose twice-daily (in red), than if the dose is
given in a single dose once-daily (in blue). The theoretical pharmaco-
kinetic profile thus shows much less variability over time with twice-
daily dosing compared with once-daily dosing.
Figure 2B illustrates, in red, the pharmacokinetic profile of the
twice-daily dosing modified after a single missed dose. The resulting
concentration is similar to the expected trough concentration of
once-daily dosing, suggesting that missing a single dose of a twice-daily
dosing regimen should not be therapeutically critical.
Figure 2C shows that the pharmacological equivalent of missing a
single dose in a once-daily regimen is missing three consecutive
doses of a twice-daily dosing regimen. Thus, instead of assessing
solely the percentage of missed doses, it is more cogent to compare
the probability of two to three sequentially missed twice-daily doses
vs. the probability of missing one once-daily dose.
Figure 2D shows the pharmacological consequence of an extra
dose, which results in a much higher peak for the once-daily than
for the twice-daily dosing regimen.
Adherence through monitoring 519

A Steady state B One missed BID dose

Concentration

Concentration
5 6 7 8 9 10 5 6 7 8 9 10
Day Day

C 1 missed QD dose equals 3 missed BID doses D One extra dose

Concentration

Concentration

5 6 7 8 9 10 5 6 7 8 9 10
Day Day

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Figure 2 Once-daily vs. twice-daily dosing: difference between intake and predicted biological impact in general. Different patterns of non-
adherence lead to different exposition to ‘risk’ between once-daily and twice-daily drugs. These graphs illustrate the theoretical pharmacokinetic
profiles of a dose X administered once-daily (QD), and a dose X/2 administered twice-daily (BID), for a drug with a half-life of about 12 h and a
Tmax of 3 h. (A) the peak-to-trough ratio is much smaller for the BID than the QD dosing. (B) The concentration after a single missed BID dose
(red dot) is similar to the expected trough concentration of QD dosing, suggesting that missing a single dose of a twice-daily dosing regimen
should not be therapeutically critical. (C) The pharmacological equivalent of missing a single dose in a once-daily regimen (blue dot) is missing
three consecutive doses (red dots) of a twice-daily dosing regimen. (D) Taking an extra dose results in a much higher peak for the QD than for
the BID dosing regimen.

Once- vs. twice-daily dosing of
non-vitamin K antagonist oral
anticoagulants
The half-lives of NOACs are dependent on age and renal function of
the patient, ranging from 9 to 14 h in young patients with normal
renal function, and increasing to 9 to 17 h for factor Xa inhibitors
and even 28 h for dabigatran in patients with moderate-to-severe
renal dysfunction.33 Even with this variability, all NOACs are
rapidly absorbed and usually have half-lives well below 24 h; never-
theless, different dosing regimens (once-daily or twice-daily) have
been selected, depending on the drug (often based on phase 2 trial
results) and on the particular indication. The simulation in Figure 2
indicates that, as with the two examples detailed in the previous
section, twice-daily dosing of NOACs could be beneficial for main-
taining continuity of drug action when there is variable drug exposure
from suboptimal adherence.
The potential advantage of twice-daily dosing for NOACs is
further illustrated in Figure 3, where model-based concentrations
(upper plot) are projected using the dosing chronology (lower
plot). The red projection in the upper plot assumes a hypothetical
prescribed dosing regimen that is perfectly implemented for a dose
X prescribed once daily (left) and half the dose X/2 prescribed
twice daily (right). One can see that the peak-to-trough variability
is larger for once-daily dosing, which could be related to increased
risks of bleeding or thrombotic events, respectively. The blue lines
in the upper plots show the model-projected continuous time-
course of the concentrations resulting from a dosing history in
which 15% of doses were missed. Omitted doses are indicated by ver-
tical grey bars, each of which indicates a single omitted dose. The right
side shows a similar plot for 15% of missed doses of a twice-daily drug.
In both figures, lapses in dosing lead to lower-than-usual projected
concentrations of drug, and extra doses lead to higher-than-usual
projected drug concentrations. Relative to the hypothetical thera-
peutic window used in this example, one can see that the twice-daily
dosing regimen is more forgiving for a missed dose or an extra dose
than the once-daily dosing regimen for drugs with a half-life of 12 h.
Therefore in practice, once-daily dosing may require more vigilance34
for single missed or extra doses and thus closer management of
patient adherence.
It remains to be proven in how far these projected differences also
reflect in clinical outcomes with NOACs (as was exemplified by the
HIV- and ACS-trials above), but it is clear that research in this field is
needed to better inform clinicians about the possible impact of
the prescribed dosing scheme on the drug’s therapeutic effect.
 520
Figure 3 Once-daily vs. twice-daily dosing: predictions for NOAC drugs. The red projection in the upper plot assumes a hypothetical prescribed dosing regimen that is perfectly implemented for a
dose X prescribed once daily (QD; left plot) and half the dose X/2 prescribed twice daily (BID; right plot), for a drug with a half-life of about 12 h and a Tmax of 3 h. The blue lines in the upper plots show the
model-projected continuous time-course of the concentrations resulting from a dosing history in which 15% of doses were missed (omitted doses are indicated by the grey bars, while the blue dots
represent electronically captured dosing times). Relative to the hypothetical therapeutic window used in this example, one can see that the twice-daily dosing regimen is more forgiving for a missed dose
or an extra dose than the once-daily dosing regimen.

B. Vrijens and H. Heidbuchel

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Adherence through monitoring 521

The findings presented in this review show the importance of consid-

ering a twice-daily dosing regimen instead of automatically assuming Table 2 Proposals to improve adherence
that once-daily dosing would be better due to the higher percentage Electronic monitoring Providing feedback provided based on
of doses taken. On the other hand, it should also be clear that there feedback the patient’s own detailed electronic
will not be one all-encompassing answer on which dosing regimen is dosing history
best for NOACs; this question will need to be assessed for each Patient education Providing the patient with sufficient
NOAC and each patient separately. education about his/her disease,
dosing regimen, and the importance of
adherence
Managing adherence to Structured patient Follow-up of each patient at fixed
non-vitamin K antagonist oral follow-up timepoints (e.g. at therapy initiation,
after 1, 3, and 6 months, etc.)
anticoagulant therapy in clinical Nurse-led interdisciplinary Interdisciplinary care programmes could
care programmes be set up, with specialized nurses as
practice the main communication point for the
patient
Interventions to improve adherence Telemonitoring of The provided dosing histories can be
Healthcare systems and providers play a role in the management medication intake used to assessed whether
of adherence by monitoring and supporting their patients’ correct intervention is needed to improve a
patient’s adherence
medication intake.3 A recent literature review assessing interventions
Improving physician Guideline adherence has been shown to
to improve patient adherence to medications, found that electro-
adherence to guidelines be higher in nurse-led care
nic monitoring (EM)-feedback was the biggest factor influencing programmes
adherence (8.8% more effective than interventions without EM feed-
back; P , 0.01).10 Electronic monitoring feedback interventions are
designed to provide feedback on patients’ personal dosing histories

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compiled from electronic medication event monitors. Using the
patient’s own dosing history, the healthcare practitioner can
discuss with the patient the reason why there was suboptimal adher-
ence at specific timepoints, and propose solutions to prevent this
from happening in the future. Such adherence-improving interven-
tions also include elements of education (to increase the patient’s
knowledge on his or her disease and on the importance of adher-
ence), and motivation (to increase the patient’s self-efficacy).22
Further proposals to support patients’ adherence are discussed
below, and compiled in Table 2.
The need for a structured follow-up for
patients on non-vitamin K antagonist
oral anticoagulant therapy
The process of gaining information on patient’s adherence and taking
preventive or corrective action will require structured care around
the patient. The European Heart Rhythm Association has proposed
a framework for structured follow-up of patients on NOAC
therapy.33 This proposal includes follow-up at various timepoints
(i.e. at initiation of the therapy, and subsequently after 1, 3,and 6
months, etc.) at which the patients need to meet with their healthcare
practitioners, who can be cardiologists, general practitioners or spe-
cialist nurses. These meetings could be used to assess the patient’s ad-
herence and provide feedback, education, and motivation where
needed. Regular meetings throughout the entire duration of the
therapy may be needed to ascertain long-term therapy. It will be an
extremely important challenge to devise strategies that improve
long-term adherence. The European Heart Rhythm Association
also proposed a NOAC patient card to integrate follow-up informa-
tion among the different healthcare workers.33
Moreover, for atrial fibrillation, a proposal has been made for inter-
disciplinary atrial fibrillation expert programmes to structure daily
practice.35 In such programmes, clinical nurse specialists have an
important role, which can even be a central coordinating one,
because they have more time for patients than physicians and are
more readily accessible; they can thus function as the main point of
communication. After a comprehensive physician-supervised assess-
ment of the patient, the nurse can coordinate an interdisciplinary
guideline-based management plan.
Such a structure should well serve the follow-up of NOAC
therapy. Anticoagulation clinics, now focused on VKA therapy,
could redefine their role for the future in this respect.36 Moreover,
such a programme could also incorporate electronic and even
remote monitoring of adherence, in analogy with remote follow-up
of implanted devices.37 A pilot study assessing telemonitoring of
medication intake in patients with chronic heart failure, with interven-
tions initiated by healthcare providers in case of absence of transmis-
sions, indicated that patients’ acceptance of the tool was high and that
telemonitoring might prove to be an effective method to improve
medication intake.38
Based on the patient’s dosing history, the nurse can assess if inter-
vention is required and provide specific support tailored to the needs
of the patient (Figure 4). As with device follow-up, specific server soft-
ware could be developed that analyses the patients’ dosing history
and provides filtered alerts on a per-patient basis, or could even
provide direct feedback to the patient about his or her inadequate ad-
herence and the possible consequences. Such virtual clinic software
would also benefit healthcare practitioners outside of an integrated
care network. If the effectiveness of such integrated systems can be
proven, appropriate reimbursement is warranted to provide incen-
tives to set up this form of care.
Adherence and patient education
Suboptimal adherence may be due to the fact that the proper dosing
regimen and its importance were not adequately described to the
patient, or due to the fact that the patient did not properly
522 B. Vrijens and H. Heidbuchel

A B
Centers with integrated care Healthcare practitioners without
integrated care

Cardiologist
Cardiologist
GP Nurse
Patient Patient

Virtual clinic software

Nurse Nurse
Cardiologist Electronic
Cardiologist
monitoring
GP of
Other
Patient specialists adherence
Patient

Cardiologist
Cardiologist
Patient Nurse
GP
GP Nurse Patient

Figure 4 Schematic representation of potential NOAC care models integrating monitored drug intake. (A) Various centers with integrated care

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can each have their own specific set-up. Within such a center, the electronic monitoring technology can be integrated as part of their overall ap-
proach. (B) Healthcare practitioners who do not belong to an integrated care center can receive support from ‘virtual clinic’ software. The electronic
monitoring of the patient’s adherence can be linked to this software, so that feedback to the healthcare practitioner and patient can be provided when
needed.

understand the need for specific dosing requirements. This part of
the non-adherence problem could be remedied by providing the
patients with sufficient education and training. As mentioned
earlier, interventions found to improve adherence often include ele-
ments of education.22 Interdisciplinary nurse-led programmes have a
strong focus on educating the patient, even repeatedly during regular
clinic visits or phone contacts. Atrial fibrillation patients receiving
nurse-led care have been reported to have a significantly higher
level of knowledge about their disease and its management, when
compared with patients receiving regular care.39,40
Physician adherence to guidelines
While this review focuses on the process of patient adherence to
medications, it is important to note that there is also a preceding
process concerning the adherence of physicians to the guidelines
for prescription of anticoagulant medication. On top of patient-
related reasons, medications may not be initiated due to physician-
related reasons, such as an exaggerated fear of bleeding relative to
the fear of stroke. A physician is only confronted with the bleeds
caused by the medication but not with the strokes that are prevented.
Interdisciplinary nurse-led programmes have been demonstrated to
improve physician adherence to guideline recommendations.39
adherence is widely prevalent and has severe consequences including
bleeding or increased thrombotic risk, which can be fatal.
Once-daily dosing may increase absolute adherence, but twice-
daily dosing regimens may be more forgiving in patients with sub-
optimal adherence. Prospective clinical evaluation is needed, also
to relate outcome factors of drug regimen to the type of patient:
one regimen may not suit all.
Also the effect of structured care on NOAC adherence needs to
be evaluated as in the currently ongoing AEGEAN trial (Clinical-
Trials.gov: NCT01884350). Electronic monitoring of patients’ adher-
ence promises to be a useful tool in such integrated care systems,
both for assessing adherence as well as for improving adherence
through feedback based on the patient’s dosing history.
MEMS is a registered trademark of MeadWestvaco Corporation.
Acknowledgements
The authors would like to thank John Urquhart for his input and thor-
ough review of this manuscript, and Joke Vandewalle and Melissa
McNeely (XPE Pharma & Science) for writing assistance and coord-
ination of manuscript development.

Conflict of interest: Bernard Vrijens is an employee of MWV

Conclusion Healthcare. Hein Heidbuchel is a member of scientific advisory
There is an urgent need for research on adherence-optimizing tech- boards for Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi-Sankyo
nology and interventions in the NOAC field, because suboptimal and Sanofi-Aventis, and received lecture fees from these companies.
Adherence through monitoring
Funding
Medical writing and editorial support for this article was funded by
Bristol-Myers Squibb.
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