The terms compliance and adherence are
often used interchangeably. In 1979, Haynes et al., defined
compliance as “the extent to which a person’s behavior (in terms of
taking medications, following diets or executing lifestyle changes)
coincides with medical or health advice” [1]. More recently, an international consensus
statement crafted by the World Health Organization and the
International Society of Pharmacoeconomics and Outcomes Research
defined medication adherence as “the extent to which a patient acts
in accordance with the prescribed interval and dose of a dosing
regime” [2]. Patient adherence is
also recently reviewed in additional articles [3–5]. The term
adherence implies active participant involvement in the decision to
take a medication, use a device or engage in a behavior change, and
is the term used in this book. In this chapter, we primarily refer
to drug adherence but the concepts apply generally. In a drug
trial, adherence typically refers to ingestion of predetermined
amount of drug such as 80% of the protocol dose. This dose will
depend on the nature and half-life of the drug being evaluated.
Persistence is a related term that refers to remaining on a medical
treatment for a specified period of time, regardless of the
proportion of the doses taken. Distinguishing adherence vs.
persistence is important since the metrics are different as well as
the implications for trial interpretation [6, 7].
Medication adherence is a major
challenge for patients, the consequences of which affect clinical
practitioners and investigators alike. As many as one-third of all
prescriptions are reportedly never filled and, among those filled,
a large proportion is associated with incorrect administration
[8]. Even among patients who
receive medication at no cost from their health plans, rates of
nonadherence reach nearly 40% [9].
Nonadherence has been estimated to cause nearly 125,000 deaths per
year in the U.S. and has been linked to 10% of hospital admissions
and 23% of nursing home admissions [8]. Poor medication adherence in the U.S. has a
resultant cost of approximately $100 billion a year [10].
This chapter discusses what can be done
before enrollment to reduce future adherence problems, how to
maintain good adherence during a trial, how to monitor adherence,
and how to address low adherence. In the monitoring section, we
also discuss visit adherence. Readers interested in a more detailed
discussion of various adherence issues are referred to an excellent
text [11] and a review of the
literature [10].
Fundamental Point
Many
potential adherence problems can be prevented or minimized before
participant enrollment. Once a participant is enrolled,
measures to monitor and enhance
participant adherence are essential.
Definitions
Since reduced adherence with the
intervention has a major impact on the power of a trial, realistic
estimates of cross-overs, drop-ins and drop-outs must be used in
calculating the sample size. Underestimates are common and lead to
underpowered trials that fail to test the trial hypotheses
properly. See Chap. 8 for further discussion of the
sample size implications of low adherence.
A cross-over is a participant who, although
assigned to the control group, follows the intervention regimen; or
a participant who, assigned to an intervention group, follows
either the control regimen or the regimen of another intervention
group when more than one intervention is being evaluated. A
drop-in is a special kind of cross-over. In
particular, the drop-in is unidirectional, referring to a person
who was assigned to the control group but begins following the
intervention regimen. A drop-out is also unidirectional and refers
to a person assigned to an intervention group who fails to adhere
to the intervention regimen. If the control group is either on
placebo or on no standard intervention or therapy, as is the case
in many superiority trials, then the drop-out is equivalent to a
cross-over. However, if the control group is assigned to an
alternative therapy, as is the case in noninferiority or
comparative effectiveness trials, then a drop-out from an
intervention group does not necessarily begin following the control
regimen. Moreover, in this circumstance, there may also be a
drop-out from the control group. Participants who are unwilling or
unable to return for follow-up visits represent another type of low
adherence, sometimes also referred to as drop-outs. Because of the
possible confusion in meanings, this text will limit the term
drop-out to mean the previously defined adherence-related behavior.
Those who stop participating in a trial and have no further
follow-up will be referred to as withdrawals. Importantly, participants
who stop taking their study medication but continue their scheduled
follow-up are not withdrawals.
Medication Adherence
The optimal trial from an adherence
point of view is one in which the investigator has total control
over the participant, the administration of the intervention
regimen, which may be a drug, diet, exercise, or other
intervention, and follow-up. That situation can only realistically
be achieved in animal experiments. Any clinical trial, which,
according to the definition in this text, must involve human
beings, will have variability in adherence with the intervention
and the study procedures. There are several reasons for low
adherence. Life events such as illnesses, loss of employment, or
divorce are factors associated with reduced adherence. In addition,
participants may not perceive any treatment benefit, they may be
unwilling to change their behaviors, they are forgetful, may lack
family support, or ultimately they may change their minds regarding
trial participation. Another reason for low adherence is adverse
effects to the medication or intervention. Therefore, even studies
of a one-time intervention such as surgery or a single medication
dose can suffer from nonadherence. In fact, some surgical
procedures can be declined or even be reversed. In addition, the
participant’s condition may deteriorate, and thus require
termination of the study treatment or a switch from control to
intervention. In a clinical trial in stable coronary disease,
participants were randomized to percutaneous coronary intervention
(PCI) plus optimal medical therapy compared to optimal medical
therapy alone [12]. Among the
1,149 participants in the PCI group, 46 never underwent the
procedure and another 27 had lesions that could not be opened.
During a median follow-up of 4.6 years, 32.6% of the 1,138
participants in the optimal medical therapy alone group had
revascularization. The trial showed no difference for the primary
outcome of all-cause mortality or non-fatal myocardial infarction.
However, it is difficult to determine how much the cross-overs
influenced the overall finding. Moreover, such a trial can be
considered to be testing the initial intervention strategy, with
recognition that those who fail medical therapy will often have
revascularization.
Most of the available information on
adherence is obtained from the clinical therapeutic encounter
rather than from the clinical trial setting. Although the
differences between patients and volunteer clinical trial
participants are important, and agreement to participate tends to
minimize low adherence rates in trials, the basic principles
observed in practice settings apply to research as well. In
clinical trial databases, it has been shown that adherence to
intervention, and even adherence to placebo, is independently
associated with improved survival [13]. This observation suggests that adherent
behavior may have benefits, or at least that adherence is
associated with unmeasured factors related to better outcome. The
results of a trial can be affected by low adherence to the
intervention leading to an underestimation of possible therapeutic
as well as potential toxic effects, and can undermine even a
properly designed study. Data from a meta-analysis suggest that the
difference in health benefits between high and low adherence has
been shown to reach 26% [14].
Given the intention-to-treat principle of analysis (see Chap.
18), in order to maintain equivalent
power, a 20% reduction in drug adherence may result in the need for
a greater than 50% increase in sample size and 30% reduction will
require doubling of the study cohort (see Chap. 8). Poor adherence is especially
problematic in non-inferiority trials, where it will bias the
results toward no difference between the intervention and control
groups and decrease the reliability of the observed results.
Considerations Before Participant Enrollment
There are three major considerations
affecting adherence to the study medications that investigators and
sponsors ought to consider during the planning phase. First,
efforts should be made to limit the impact of design features that
may adversely influence the level of adherence. Second, steps
should be taken to avoid enrollment of study participants who are
likely to have low adherence while not being so restrictive as to
decrease the generalizability of the results. Third, the research
setting influences participant adherence over the long term. It is
important to have realistic estimates of the adherence level during
a trial, so that proper upward adjustments of the sample size can
be made during the planning phase. Even practice-based trials that
attempt to mimic real-life situations need to consider adherence in
their designs.
Design Factors
Four study design factors can
influence adherence—study duration, setting, simplicity of the
regimen and the use of a run-in period.
Study
duration influences adherence. The shorter the trial, the
more likely participants are to adhere with the intervention
regimen. A study in which intervention is started and completed in
1 day (such as fibrinolytic therapy for acute myocardial infarction
or stroke) or during a hospital stay has great advantages over
longer trials with regards to adherence. Trials in which the
participants are under supervision, such as hospital-based ones,
tend to have fewer problems with low adherence [15]. It is important to be mindful of the fact
that there is a difference between special hospital wards and
clinics with trained staff who are familiar with research
requirements and general medical or surgical wards and clinics,
where research experience might not be common or protocol
requirements might not be appreciated. Regular hospital staff have
many other duties which compete for their attention, and they
perhaps have little understanding of the need for precisely
following a study protocol and the importance of good adherence. On
the other hand, if the intent is to assess how an intervention may
perform in general practice, the regular clinical setting may have
advantages.
The setting of the trial is also important.
Whenever the study involves participants who will be living at
home, the chances for low adherence increase. Studies of
interventions that require changing a habit are particularly
susceptible to this hazard. A challenge is dietary studies. A
participant may need special meals, which are different from those
consumed by other family members. It may be difficult to adhere
when having meals outside the home. Multiple educational sessions
and preparation of meals by the investigator team may be necessary.
Family involvement is essential, especially if the participant is
not the usual meal preparer [16,
17]. In studies, when the
participants’ sources of food come only from the hospital kitchen
or are supplied by the trial through a special commissary
[18], participants are more likely
to adhere with the study regimen than when they buy and cook their
own food. This may also allow for blinded design.
The treatment regimen is an important
factor and simplicity
facilitates adherence. Single daily dose drug regimens are
preferable to multiple daily dose regimens. Despite a simple
regimen, 10–40% of participants have imperfect dosing
[10]. A review of 76 trials, in
which electronic monitors were used, showed that adherence is
inversely proportional to the frequency of dosing [19]. Patients on a four-times-a-day regimen
achieved on-schedule average adherence rates of about 50%. Adhering
to multiple study interventions simultaneously poses special
difficulties. For example, behavior changes such as quitting
smoking, losing weight and reducing the intake of saturated fat at
the same time requires highly motivated participants. Unlike
on-going interventions such as drugs, diet, or exercise, trials of
surgery and vaccination generally have the design advantage, with
few exceptions, of enforcing adherence with the intervention.
Where feasible, a run-in period before actual randomization
may be considered to identify those potential participants who are
likely to become poor adherers and thereby exclude them from
long-term trials. During the run-in, potential participants may be
given either active medication or placebo over several weeks or
months. An active run-in also allows identification of potential
participants who do not have a favorable response to treatment on a
biomarker or who develop side effects prior to randomization
[20]. However, this design may be
less informative about the effects of a treatment in practice,
where the question for the clinician is whether or not to use it,
not whether to use it after determining tolerability. A placebo
run-in allows a determination of the potential participant’s
willingness to comply with the study intervention. Run-in phases
were common already in 2001 when a literature search resulted in
more than 1,100 examples of trials in which run-in phases were used
[21]. This approach was
successfully employed in a trial of aspirin and beta-carotene in US
physicians [22]. By excluding
physicians who reported taking less than 50% of the study pills,
the investigators were able to randomize excellent adherers. After
5 years of follow-up, over 90% of those allocated to aspirin
reported still taking the pills. An additional goal of the run-in
is to stabilize the potential trial participants on specific
treatment regimens or to wash-out the effects of discontinued
medications. Though the number of participants eliminated by the
run-in period is usually small (5–10%), it can be important as even
this level of low adherence affects study power. A potential
disadvantage of a run-in is that participants may notice a change
in their medication following randomization thereby influencing the
blinding of the assignment. It also delays entry of participants
into a trial, perhaps by a few weeks.
Berger et al. [21] raised the issue of external validity of the
findings of trials that excluded potential poor adherers during a
run-in phase. Can the results from trials with run-in selection of
participants reasonably be fully extrapolated to all those patients
meeting the trial eligibility criteria? The question about the
generalizability of trial findings can be raised regarding the
PARADIGM HF trial of patients with heart failure [23]. The trial had two consecutive run-in
phases—the first over 2 weeks with enalapril and a second over 4
weeks with a valsartan-neprilysin inhibitor. A large number (20%)
of eligible participants were excluded mostly due to adverse events
(see Chap. 4). As always, whether to use a
run-in depends on the question being posed. Does the trial have
many exclusion criteria (a so-called efficacy trial) or few
exclusions (a pragmatic or effectiveness trial)? Stated
differently: What is the effect of the intervention in optimal
circumstances? Or, what is the effect when, as is common in
clinical settings, a large number of people fail to adhere to
prescribed medication? Both are valid questions, but in the latter
situation, as noted earlier, a larger sample size will be required.
Lee et al. [24] compared the
effect size in 43 clinical trials of selective serotonin uptake
inhibitors in patients with depression that included a placebo
run-in and those that did not. They found no statistically
significant difference in the results.
In another approach, the investigator
may instruct prospective participants to refrain from taking the
active agent and then evaluate how well his request was followed.
In the Aspirin Myocardial Infarction Study, for instance, urinary
salicylates were monitored before enrollment, and very few
participants were excluded because of a positive urine test.
Participant Factors
An important factor in preventing
adherence problems is the selection of appropriate participants.
Ideally, only those people likely to follow the study protocol
should be enrolled. In the ACCORD trial, the screenees’ willingness
to test blood sugars frequently was taken as a measure of
commitment to participate [25].
This may, however, influence the ability to generalize the findings
(see Chap. 4 for a discussion of
generalization). Several articles have reported that there is
convincing evidence that nonadherers are substantially different
from adherers in ways that are quite independent of the effects of
the treatment prescribed [10,
26].
Exclusion of individuals who are
unlikely to be good participants is usually advisable unless the
trial is aimed at those individuals. A number of
participant-related factors have been shown to negatively affect
adherence [11]. People with
cognitive impairment or
low literacy are likely to
have more problems with adherence [27]. It is obviously important that participants
understand instructions and follow through on these. A related
issue is low
self-efficacy, which
relates to a person’s ability to follow through with
recommendations or make behavior change a permanent feature of
his/her life [28]. It is important
that participants believe in their own ability to do so.
Positive health beliefs and
attitudes (i.e., less fear of adverse effects) are also helpful.
Mental health issues
represent other predictors of poor adherence. Meta-analyses have
shown that depressed patients have a 2 to 3-fold higher rate of
nonadherence compared to those who were not depressed
[26]. However, a successful
behavioral weight-loss intervention in persons with serious mental
illness was recently reported [29]. A combination of group and individual
weight-management sessions and group exercise sessions over 18
months led to a statistically significant weight reduction in the
intervention group compared to the control group. The connection
with anxiety is less clear. A person’s personality or
characteristic traits may also be a factor to consider.
Conscientiousness predicts
good adherence and hostility poor adherence [26]. Similarly, those with a known history of
missed appointments or adherence problems might be considered for
exclusion. Logistic factors
may also influence adherence, for example, persons who live too far
away, or those who are likely to move before the scheduled
termination of the trial. Traveling long distances may be an undue
burden on disabled people. Those with concomitant disease may be less
adherent because they have other medicines to take or are
participating in other trials. Furthermore, it is important to be
aware of the potential for contamination of the study results by
these other medicines or trials. When applicable, the factors
discussed above should be incorporated in the study exclusion
criteria. These factors are difficult to define, so the final
decision often is left to the discretion of the study
investigator.
Financial and other incentives to
motivate adherence are sometimes offered. These have been reported
to improve adherence [30–32]. A
concern is that financial incentives, if excessive, may lead to
enrollment of participants more interested in the payment than in
supporting science. As discussed in Chap. 2, Institutional Review Boards and
others would view this practice as unethical.
An informed participant appears to be a
better adherer. Proper education of the participant and the
participant’s family or caregiver is thought to be the most
positive factor to high adherence, but the scientific evidence is
not conclusive [33]. However, for
ethical concerns, the participant (or, in special circumstances,
his guardian) in any trial should be clearly instructed about the
study and told what is expected from him. He should have proper
insight into his illness and be given a full disclosure of the
potential effects—good and bad—of the study medication. Sufficient
time should be spent with a candidate and he should be encouraged
to consult with his family or private physician. A brochure with
information concerning the study is often helpful. As an example,
the pamphlet used in the NIH-sponsored Women’s Health Initiative
trial is shown in Box 14.1. Many clinical trials develop websites
with educational material directed at physicians and potential
participants.
Box 14.1: Women’s Health Initiative
Brochure
What is
the Women’s Health
Initiative?
The Women’s Health Initiative (WHI) is
a major research study of women and their health. It will help
decide how diet, hormone therapy, and calcium and vitamin D might
prevent heart disease, cancer, and bone fractures. This is the
first such study to examine the health of a very large number of
women over a long period of time. About 160,000 women of various
racial and ethnic backgrounds from 45 communities across the United
States will take part in the study.
Who can join the WHI?
You may be able to join if you are:
-
a woman 50–79 years old
-
past menopause or the “change of life”
-
planning to live in the same area for at least 3 years
Why is this study important?
Few studies have focused on health
concerns unique to women. Being a part of this important project
will help you learn more about your own health. You will also help
doctors develop better ways to treat all women. This study may help
us learn how to prevent the major causes of death and poor health
in women: heart disease, cancer, and bone fractures.
What will I be asked to do?
If you agree to join us, you will be
scheduled for several study visits. These visits will include
questions on your medical history and general health habits, a
brief physical exam, and some blood tests. Based on your result,
you may be able to join at least one of the following programs.
-
Dietary: In this program you are asked to follow either your usual eating pattern or a low-fat eating program.
-
Hormone: In this program you are asked to either take hormone pills or inactive pills (placebos). If you are on hormones now, you would need to talk with your doctor about joining this program.
-
Calcium and Vitamin D: In this program you are asked to either take calcium and vitamin D or inactive pills. Only women in the Dietary or Hormone programs may join this program.
-
Health Tracking: If you are not able to join the other programs, your medical history and health habits will be followed during the study.
How long will the study last?
You will be in the study for a total
of 8–12 years, depending on what year you enter the study. This
period of time is necessary to study the long-term effects of the
programs.
How will I benefit?
If you join the study, your health
will be followed by the staff at our center. Certain routine tests
will be provided, although these are not meant to replace your
usual health care. Depending on which program you join, you may
receive other health-care services, such as study pills and dietary
sessions. You will not have to pay for any study visits, tests, or
pills.
You will also have the personal
satisfaction of knowing that results from the WHI may help improve
your health and the health of women for generations to come.
Social support and involvement have
emerged as major determinants of adherence [34]. Thus, it is recommended that family
members, significant others or friends be informed about the trial
and its expectations at the same time as the potential participant.
After all, a large proportion of participants join trials at the
support of family and friends [35]. The support they can offer in terms of
assistance, encouragement and supervision can be very valuable.
Practical support is most consistently associated with greater
medication adherence [34]. Support
is especially important in trials of lifestyle interventions. For
example, cooking classes for spouses as well as participants have
been very effective in dietary intervention trials [16, 17].
Major factors associated with low
adherence are summarized in Table 14.1, listed in
alphabetical order. Most of them are, as would be expected, the
opposite of factors associated with high adherence. The consensus
is that older persons generally show higher rates of adherence.
Table
14.1
Factors associated with low adherence
|
Cognitive impairments
|
|
Complexity of drug regimen
|
|
Concomitant diseases
|
|
Hostile personality
|
|
Lack of information and inadequate
instructions
|
|
Lack of social support
|
|
Logistic factors
|
|
Low self-efficacy
|
|
Low literacy
|
|
Mental health issues, primarily
depression
|
|
Negative health beliefs
|
|
Unsatisfying participant-investigator
relationship
|
Studies have shown that patients’
recall of medical topics discussed with providers is poor and
between 40–80% is forgotten immediately [36] while up to half of the information retained
by patients is incorrect [37]. The
“teach-back” method can be used to improve knowledge retention
among patients [38] and confirm
that patients understand what they have been told. If the
investigator says to the study participant that he has high blood
pressure that needs treatment, the participant would say, “I have
high blood pressure that needs treatment.” When told to take one
pill every morning until the next clinic visit, the participant
would repeat, “I should take one pill every morning until I return
for my next clinic visit.” When the participants accurately explain
in their own words what they have been told their understanding is
confirmed. A recent study of hospitalized patients with heart
failure showed a trend toward lower readmissions for heart failure
among those with more correct answers to teach-back questions
[39].
Maintaining Good Participant Adherence
The foundation for high adherence
during a trial is a well-functioning setting with committed clinic
staff (Table 14.2). Establishing a positive research setting
at the first contact with future participants is a worthwhile
investment for the simple reason that satisfied participants are
better adherers. A warm and friendly relationship between
participants and staff established during the recruitment phase
should be nurtured. This approach covers the spectrum from trusting
interactions, adequate time to discuss complaints, demonstrating
sincere concern and empathy, when appropriate, convenient clinic
environment, short waiting times, etc. “Bonding” between the
participant and clinical trials staff members is a recognized and
powerful force in maintaining good adherence. The clinic visits
should be pleasant and participants should be encouraged to contact
staff between scheduled visits if they have questions or concern.
Close personal contact is key. Clinic staff may employ various
means of engagement, including phone calls, mail and e-mail.
Sending cards on special occasions such as birthdays and holidays
is a helpful gesture. Visiting the participant if he is
hospitalized demonstrates concern. It is helpful to investigators
and staff to make notes of what participants tell them about their
families, hobbies and work so that in subsequent visits they can
follow-up and show interest and involvement. Other valued factors
are free parking and, for working participants, opportunities for
evening or weekend visits. For participants with difficulties
attending clinic visits, home visits by staff could be attempted.
Continuity of care is ranked as a high priority by participants.
Continued family involvement is especially important during the
follow-up phase.
Table
14.2
Factors in improving likelihood of
medication adherence in clinical trials
|
Approach
|
Activity
|
|---|---|
|
Trial design
|
Simple schedule (once or twice daily
dosing) that fits into daily routine [40]
|
|
Relationships and communication
|
|
|
Passive monitoring
|
Electronic monitoring tools
|
|
Education
|
Medication usage skills [33]
|
|
Reinforce beliefs
|
Association activities using
medication-outcome relationships
|
|
Reminders
|
Alarms (e.g., set watch or cell phone
reminders to medication schedule) and associations (e.g., put
medication beside toothbrush or use a behavior trigger)
|
|
Incentives
|
Monetary or other rewards
|
During a study, it is important to
keep the participants informed about relevant published findings
from related trials. They should also be reminded, when applicable,
that a data monitoring committee is reviewing the trial data for
safety and efficacy throughout the duration of the trial which
should be described to them. Brief communications from this
committee assuring the participants that no safety concerns have
been noted, can also be helpful.
The use of various types of general
reminders can also reduce the risk of low adherence. Clinic staff
should typically remind the
participant of upcoming clinic visits or study procedures. Sending
out postcards, calling, e-mailing or text messaging a few days
before a scheduled visit can help. Paper-based reminders seem to be
most effective [43]. A telephone
call though has the obvious advantage that immediate feedback is
obtained and a visit can be rescheduled if necessary—a process that
reduces the number of participants who fail to keep appointments.
Telephoning also helps to identify a participant who is ambivalent
regarding his continued participation or who has suffered a study
event. To preclude the clinic staff’s imposing on a participant, it
helps to ask in advance if the participant objects to being called
frequently. Asking a participant about the best time to contact him
is usually appreciated. Reminders can then be adjusted to his
particular situation. In cases where participants are reluctant to
come to clinics, more than one staff person might contact the
participant. For example, the physician investigator could have
more influence with the participant than the staff member who
usually schedules visits. In summary, the quantity and quality of
interaction between an investigator and the participant can
positively influence adherence.
For drug studies,
special pill organizers
help the participant keep track of when to take the medication.
These organizers allow participants to divide, by day and time of
day, all medications prescribed during a 7-day period. If the
participant cannot remember whether he took the morning dose, he
can easily find out by checking the compartment of the pill box for
that day. Special reminders such as noticeable stickers in the
bathroom or on the refrigerator door or on watches have been used.
Placing the pill bottles (child proof as appropriate) on the
kitchen table or nightstand with the tooth brushes are other
suggestions for participants.
The effectiveness of electronic
reminders to improve medication and visit adherence in clinical
trials has received much attention recently [43–45]. The
rationale for their use is that one of the most commonly reported
reasons for not being adherent is forgetfulness. Additionally,
these simple interventions are less expensive and time-consuming
than personal attention by investigators.
Vervloet et al. [46] conducted a comprehensive literature review
and identified 13 studies meeting their inclusion criteria. Three
types of automatic electronic reminders were considered—1) short
reminder messages sent to the participant’s mobile phone, 2)
audiovisual reminders were sent through a specific electronic
reminder device at predetermined times, and 3) text messages sent
to a participant’s pager to alert them to take the study
medication. The main conditions studied were HIV, glaucoma,
hypertension, and asthma. The review showed evidence for short-term
(<6 months) effectiveness in 8 of the 13 studies,
especially those of short messages sent through mobile phones. The
effectiveness beyond 6 months was noted in only one of those
studies. A potential weakness of these studies was that reminders
were sent to all participants regardless of whether they took their
study medication. This could have a negative impact. One of the
studies reported that weekly reminders were more effective than
daily reminders. Tailored messages may be more effective than
standard text. This evolving technology has also been evaluated in
clinical practice with mixed results [47].
Interventions to maintain good
adherence for lifestyle changes can be very challenging. Most
people have good intentions that can wane with time unless there is
reinforcement. A special brochure, which contains essential
information and reminders, may be helpful in maintaining good
participant adherence (Box 14.2). The telephone number where the
investigator or staff can be reached should be included in the
brochure.
Box 14.2: Aspirin Myocardial Infarction Study
Brochure
Text of brochure used to promote
participant adherence in the Aspirin Myocardial Infarction Study.
DHEW Publication No. (NIH) 76-1080.
- 1.
Your Participation in the Aspirin Myocardial Infarction Study (AMIS) is Appreciated! AMIS, a collaborative study supported by the National Heart and Lung Institute, is being undertaken at 30 clinics throughout the United States and involves over 4,000 volunteers. As you know, this study is trying to determine whether aspirin will decrease the risk of recurrent heart attacks. It is hoped that you will personally benefit from your participation in the study and that many other people with coronary heart disease may also greatly benefit from your contribution.
- 2.
Your Full Cooperation is Very Important to the Study. We hope that you will follow all clinic recommendations contained in this brochure, so that working together, we may obtain the most accurate results. If anything is not clear, please ask your AMIS Clinic Physician or Coordinator to clarify it for you. Do not hesitate to ask questions.
- 3.
Keep Appointments. The periodic follow-up examinations are very important. If you are not able to keep a scheduled appointment, call the Clinic Coordinator as soon as possible and make a new appointment. It is also important that the dietary instructions you have received be followed carefully on the day the blood samples are drawn. At the annual visit, you must be fasting. At the non-annual visits you are allowed to have a fat-free diet. Follow the directions on your Dietary Instruction Sheet. Don’t forget to take your study medication as usual on the day of your visit.
- 4.
Change in Residence. If you are moving within the Clinic area, please let the Clinic Coordinator know of your change of address and telephone number as soon as possible. If you are moving away from the Clinic area, every effort will be made to arrange for continued follow-up here or at another participating AMIS clinic.
- 5.
Long Vacations. If you are planning to leave your Clinic area for an extended period of time, let the Clinic Coordinator know so that you can be provided with sufficient study medication. Also give the Clinic Coordinator your address and telephone number so that you can be reached if necessary.
- 6.
New Drugs. During your participation in AMIS you have agreed not to use non-study prescribed aspirin or aspirin-containing drugs. Therefore, please call the Clinic Coordinator before starting any new drug as it might interfere with study results. At least 400 drugs contain aspirin, among them cold and cough medicines, pain relievers, ointments and salves, as well as many prescribed drugs. Many of these medications may not be labeled as to whether or not they contain aspirin or aspirin-related components. To be sure, give the Clinic Coordinator a call.
- 7.
Aspirin-Free Medication. Your Clinic will give you aspirin-free medication for headaches, other pains and fever at no cost. The following two types may be provided.
-
Acetaminophen. The effects of this drug on headaches, pain and fever resemble those of aspirin. The recommended dose is 1–2 tablets every 6 h as needed or as recommended by your Clinic Physician.
-
Propoxyphene hydrochloride. The drug has an aspirin-like effect on pain only and cannot be used for the control of fever. The recommended dose is 1–2 capsules every 6 h as needed or as recommended by your Clinic Physician.
-
- 8.
Study Medication. You will be receiving study medication from your Clinic. You are to take two capsules each day unless prescribed otherwise. Should you forget to take your morning capsule, take it later during the day. Should you forget the evening dose, you can take it at bedtime with a glass of water or milk. The general rule is: Do not take more than 2 capsules a day.
- 9.
Under Certain Circumstances It Will Be Necessary to Stop Taking the Study Medication:
-
If you are hospitalized, stop taking the medication for the period of time you are in the hospital. Let the Clinic Coordinator know. After you leave the hospital, a schedule will be established for resuming medication, if it is appropriate to do so.
-
If you are scheduled for surgery, we recommend that you stop taking your study medication 7 days prior to the day of the operation. This is because aspirin may, on rare occasions, lead to increased bleeding during surgery. In case you learn of the plans for surgery less than 7 days before it is scheduled, we recommend that you stop the study medication as soon as possible. And again, please let the Clinic Coordinator know. After you leave the hospital, a schedule will be established for resuming medication, if it is appropriate to do so.
-
If you are prescribed non-study aspirin or drugs containing aspirin by your private physician, stop taking the study medication. Study medication will be resumed when these drugs are discontinued. Let the Clinic Coordinator know.
-
If you are prescribed anti-coagulants (blood thinners), discontinue study medication and let your Clinic Coordinator know.
-
If you have any adverse side effects which you think might be due to the study medication, stop taking it and call the Clinic Coordinator immediately.
-
- 10.
Study-Related Problems or Questions. Should you, your spouse, or anyone in your family have any questions about your participation in AMIS, your Clinic will be happy to answer them. The clinic would like for you or anyone in your family to call if you have any side effects that you suspect are caused by your study medication and also if there is any change in your medical status, for example, should you be hospitalized.
- 11.
Your Clinic Phone Number Is on the Back of This Brochure. Please Keep This Brochure as a Reference Until the End of the Study.
A commonly asked question is whether a
low adherence rate should be discussed directly with study
participants. There is a consensus that any discussion should not
be confrontational. The preferred approach is to open any
discussion by saying that adherence to medications can be very
difficult for many people. After being given examples of common
reasons for low adherence, many participants seem to be more
willing to discuss their own situations and adherence problems.
Thus, sympathy and understanding may be helpful if followed by
specific recommendations regarding ways to improve adherence. A
large number of interviewing techniques of patients in the clinical
setting are discussed by Shea [48]. Tools like the Morisky Scale
[49] could be used to identify
participants at high risk for non-adherence on whom to focus
preventive efforts.
A remarkable recovery program was
developed and implemented by Probstfield et al. [50]. Through participant counseling, the
investigators succeeded in about 90% of the 36 drop-outs in
approximately 6 months to return for clinic visits. Even more
notable was the virtual absence of recidivism over the remaining 5
years of intervention. Approximately 70% of the drop-outs resumed
taking their study medication, though typically at a lower dose
than specified in the protocol.
Adherence Monitoring
Monitoring adherence is important in a
clinical trial for two reasons: first, to identify any problems so
steps can be taken to enchance adherence; second, to be able to
relate the trial findings to the level of adherence. In general,
analysis of trial outcomes by level of adherence is strongly
discouraged as it can in fact lead to serious bias, the direction
of which cannot always be predicted (see Chap. 18). However, in so far as the
control group is not truly a control and the intervention group is
not being treated as intended, group differences are diluted, and
generally lead to an underestimate of both the therapeutic benefit
and the adverse effects. Differential adherence to two equally
effective regimens can also lead to possibly erroneous conclusions
about the effects of the intervention. The level of adherence that
occurred can also be compared with what was expected when the trial
was designed.
In some studies, measuring adherence
is relatively easy. This is true for trials in which one group
receives surgery and the other group does not, or for trials which
require only a one-time intervention such as a vaccine. Most of the
time, however, assessment of adherence is more complex. No single
measure of adherence gives a complete picture, and all are subject
to possible inaccuracies and varying interpretations. Furthermore,
there is no widely accepted definition or criterion for either high
or low adherence. A review of 192 publications showed that only 36%
assessed and adequately reported medication adherence
[51]. The level of adherence that
occurred can also be compared to what was expected when the trial
was designed.
In monitoring adherence for a
long-term trial, the investigator may also be interested in changes
over time. When reductions in adherence are noted, corrective
action can possibly be taken. This monitoring could be by calendar
time (e.g., current 6 months versus previous 6 months) or by clinic
visit (e.g., follow-up visit number four versus previous visits).
In multicenter trials, adherence to the intervention also ought to
be examined by clinic or by region in multinational trials. In all
studies, it is important for clinic staff to receive feedback about
level of adherence. In double-blind trials where data by study
group generally should not be disclosed, the adherence data can be
combined for the study groups. In trials that are not double-blind,
all adherence tables can be reviewed with the clinic staff.
Frequent determinations obviously have more value than infrequent
ones. A better indication of true adherence can be obtained.
Moreover, when the participant is aware that he is being monitored,
frequent measures may encourage adherence.
There are several
indirect methods of assessing adherence. In drug trials,
pill or capsule count, is
the easiest and most commonly used way of evaluating participant
adherence. Since this assumes that the participant has ingested all
medication not returned to the clinic, the validity of pill count
is debated. For example, if the participant returns the appropriate
number of leftover pills at a follow-up visit, did he in fact take
what he was supposed to, or take only some and throw the rest out?
Pill count is possible only as long as the pills are available to
be counted. Participants sometimes forget or neglect to bring their
pills to the clinic to be counted. In such circumstances, the
investigator may ask the participant to count the pills himself at
home and to notify the investigator of the result by telephone.
Obviously, these data may be less reliable. The frequency with
which data on pill counts are missing gives an estimate of the
reliability of pill count as an adherence measure.
In monitoring pill count, the
investigators ought to anticipate questions of interest to readers
of the trial report when published. What was the overall adherence
to the protocol prescription? If the overall adherence with the
intervention was reduced, what was the main reason for the
reduction? Were the participants prescribed a reduced dose of the
study medication, or did they not follow the investigator’s
prescription? Were there differences between the study groups with
regard to protocol dosages, investigator prescriptions, or
participant adherence to the prescribed dosages? What were the
reasons for reduced participant adherence? Was it because of
intervening life events, specific adverse effects or was it simply
forgetfulness? The answers to these questions may increase the
understanding and interpretation of the results of the trial.
When discussing adherence assessed by
pill count, the investigator has to keep in mind that these data
may be inflated and misleading. Additionally, these data do not
include information from participants who omit a visit. Most
participants tend to overestimate their adherence either in an
effort to please the investigator or because of faulty memory.
Those who miss one or more visits typically have low adherence.
Therefore, the adherence data should be viewed within the framework
of all participants who are scheduled to be seen at a particular
visit. There is general agreement on one point—the participant who
says he did not take his study medication can be trusted.
Electronic monitoring of adherence has
been used [52, 53]. A device electronically records drug
package opening times and duration, thus, describes dosing
histories. The correlation between package openings and measured
drug concentrations in serum is very high. The obvious advantage of
electronic monitoring is that the dose-timing can be assessed to
see if it is punctual and regular. In an HIV trial, overall
adherence was 95%, but only 81% of the doses were taken within the
prescribed dosing interval (±3 h) [52]. In a study of hypertensive participants,
about 10% of the scheduled doses were omitted on any day
[53]. Drug holidays, defined as
omissions of all doses during 3 or more days, were recorded in 43%
of the participants. An interesting observation was that
participants with dosing problems were more likely later to become
permanent drop-outs. It is not known whether or to what extent low
adherence to dose-timing influences the trial findings.
A recent development is an
FDA-approved device which has a body-worn sensor or patch that
collects physiological and behavioral metrics generated by an
ingestible sensor. The system can be used to monitor when the
patient takes his medication. This sensor is embedded inside an
inactive tablet and it activates and communicates its presence and
unique identifier to the patch [54].
Indirect
information on adherence can also be obtained through interviews or record keeping by the
participant. A diet study might use a 24-h recall or a 7-day food
record. Exercise studies may use diaries to record frequency and
kind of exercise. Trials of people with angina might record
frequency of attacks or pain and nitroglycerin consumption.
There are two
major direct methods for measuring adherence. Biochemical analyses are sometimes made
on either blood or urine in order to detect the presence of the
active drug or metabolites. A limitation in measuring substances in
urine or blood is the short half-life of most drugs. Therefore,
laboratory determinations usually indicate only what has happened
in the preceding day or two. A control participant who takes the
active drug (obtained from a source outside the trial) until the
day prior to a clinic visit, or a participant in the intervention
group who takes the active drug only on the day of the visit might
not always be detected as being a poor adherer. Moreover, drug
adherence in participants taking an inert placebo tablet cannot be
assessed by any laboratory determination. Adding a specific
chemical substance such as riboflavin can serve as a marker in
cases where the placebo, the drug or its metabolites are difficult
to measure. However, the same drawbacks apply to markers as to
masking substances—the risk of toxicity in long-term use may
outweigh benefits.
Laboratory tests obtained on occasions
not associated with clinic visits may give a better picture of
regular or true adherence. Thus, the participant may be instructed,
at certain intervals, to send a vial of urine to the clinic. Such a
technique is of value only so long as the participant does not
associate this request with an adherence monitoring procedure. In
at least one study, information obtained in this manner contributed
no additional information to laboratory results done at scheduled
visits, except perhaps as a confirmation of such results.
Measurement of
physiological response
variables can be helpful in assessing adherence. Cholesterol
reduction by drug or diet is unlikely to occur in 1 or 2 days.
Therefore, a participant in the intervention group cannot suddenly
adhere with the regimen the day before a clinic visit and expect to
go undetected. Similarly, the serum cholesterol level of a
nonadherent control participant is unlikely to rise in the 1 day
before a visit if he skips the non-study lipid-lowering drug. Other
physiological response variables that might be monitored are blood
pressure in an antihypertensive study, carbon monoxide in a smoking
study, platelet aggregation in an aspirin study, and graded
exercise in an exercise study. In all these cases, the indicated
response variable would not be the primary response variable but
merely an intermediate indicator of adherence to the intervention
regimen. Unfortunately, not every person responds in the same way
to medication, and some measures, such as triglyceride levels, are
highly variable. Therefore, indications of low adherence of
individual participants using these measures are not easily
interpreted. Group data, however, may be useful.
Another aspect of
monitoring deals with participant adherence to study procedures
such as attendance at scheduled visits or visit adherence. One of the major
purposes of these visits is to collect response variable data. The
data will be better if they are more complete. Thus, completeness
of data in itself can be a measure of the quality of a clinical
trial. Studies with even a moderate amount of missing data or
participants lost to follow-up could give misleading results and
should be interpreted with caution. By reviewing the reasons why
participants missed scheduled clinic visits, the investigator can
identify factors that can be corrected or improved. Having the
participants come in for study visits facilitates and encourages
adherence to study medication. Study drugs are dispensed at these
visits and the dose is adjusted when necessary.
From a statistical viewpoint, every
randomized participant should be included in the primary analysis
(Chaps. 8 and 18). Consequently, the investigator
must keep trying to get all participants back for scheduled visits
until the trial is over. Even if a participant is taken off the
study medication by an investigator or stops taking it, he should
be encouraged to come in for regular study visits or at least be
followed by telephone. Complete follow-up data on the response
variables are critical so visit adherence is important. In
addition, participants do change their minds. For a long time, they
may want to have nothing to do with the trial and later may agree
to come back for visits and even resume taking their assigned
intervention regimen. Special attention to the specific problems of
each participant withdrawn from the trial and an emphasis on
potential contribution to the trial can lead to successful
retrieval of a large proportion of withdrawn participants. Inasmuch
as the participant will be counted in the analysis, leaving open
the option for the participant to return to active participation in
the study or at least agree to a visit or phone contact at the end
of the trial is worthwhile.
The purpose of adherence monitoring is
to acquire a general understanding of the level of adherence, so
steps can be taken to improve it if necessary. Thus, there is
limited value in obtaining precise assessments since we don’t favor
data analysis by adherence.
Dealing with Low Adherence
If low adherence is related to
difficulties making appointments, it may be useful to offer more
convenient clinic hours, such as evenings and weekends as mentioned
above. Home visits are another option for participants with
disabilities who have difficulties making it to the clinic. For
participants who have moved, the investigator might be able to
arrange for follow-up in other cities.
One of the challenges in clinical
trials is the complete ascertainment of response variables in
participants who are no longer actively involved in the trial. The
Internet provides opportunities to track participants lost to
follow-up. There are both fee-for-service and free search engines.
The basic information required for a search is complete name, birth
date and Social Security Number or some other specific
identification number. These searches are more effective if several
and if different search engines are employed.
Steps should be taken to prevent
situations in which participants request that they never be
contacted. These are sometimes referred to as complete withdrawal.
Participants who end their active participation in a clinical trial
often agree to be contacted at the end of the trial for
ascertainment of key response variables. For those who are lost to
follow-up, but have not withdrawn their consent, alternative
sources of information are family members and medical providers.
The goal is to limit the amount of missing information.
Special Populations
Although the approaches to dealing
with prevention of low adherence and maintenance of high adherence
are generally applicable, there are factors that need consideration
when dealing with special populations. Older adults represent a
growing number of participants in clinical trials. They typically
have more health complaints than their younger counterparts. There
is a rich literature on factors that may influence adherence and on
strategies to increase adherence in the clinical setting among
older people. Many of these are highly relevant for clinical
trials.
There are special challenges of
maintaining adherence in patients with chronic health illnesses.
Specific management interventions for several prevalent conditions
are highlighted in the Handbook of Health Behavior Change
[11]. These include cardiovascular
diseases [55], diabetes
[56], chronic respiratory diseases
[57], chronic infectious diseases
[58], cancer [59] and obesity [60].
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