|Adherence; Guidelines; Heart failure; Systematic review
|Heart Failure (HF) is a major clinical and public health problem
with a prevalence of approximately 1-2% of the adult population in
developed countries which increases to ≥10% among persons 70 years
or older . More than 23 million people suffer worldwide from HF.
During the next few years chronic heart failure (CHF) will become the
most common cardiovascular disease with a major impact at the level
of the individual due to symptom-related incapacity to manage daily
life, along with a relatively high socioeconomic impact due to the direct
and indirect costs of HF treatment.
|The development of treatment concepts during the last three
decades can be looked upon as a great success story of cardiovascular
medicine. During the so called “cardiovascular continuum”, ranging
from primary prevention before acute myocardial infarction up to end
stages of CHF, which may follow acute myocardial infarction years
later, a broad spectrum of evidence based treatment options is available.
Clinical guidelines on the management of HF [1-4] recommend drug
treatment as well as other interventions, such as self-monitoring and
|In this context it was shown that patients who are treated according
to the current recommendations for CHF show improved survival rates
and also lower rehospitalization rates for acute decompensated HF [5,6]. However, clinicians may prescribe evidence-based treatment and
recommend lifestyle modifications, but the patients decide whether follow these recommendations [7,8]. Nonadherence is considered to
be a critical barrier to treatment success and remains an important
challenge to health care professionals. Especially older patients
frequently suffer from particular conditions which may limit adherence
to drug therapy as rheumatic disorders of hand and fingers hampering
removing tablets from blister packages up to cognitive limitations due
to different forms and stages of dementia frequently. Non-adherent
patients have a higher risk of mortality and an increased rate of hospital
re-admission caused by acute decompensated CHF [9,10].
|These disease and patient related reasons to focus on CHF are
reinforced by reasons related to structural problems in the health care
systems in Europe and North America. While health care systems will be confronted with an increasing number of patients representing
the so-called “baby boomer-generation”, a significant number of
physicians, especially general practitioners, also belonging to the “baby
boomer-generation,” will retire without adequate succession. These
problems of an ageing patient population confronted with a decreasing
number of general practitioners will be pronounced in rural areas.
|The WHO demanded in 2003 that, “interventions for removing
barriers to adherence must become a central component of efforts
to improve population health worldwide” . It is increasingly
recognized that physicians, nurses, and other health professionals may
help their patients to overcome these barriers . Physicians should
improve how they approach their patients’ problems, how they provide
information, and involve individual values and preferences of their
patients in clinical decision making. The model of shared decision
making can be viewed as the optimal method to realize autonomous
decisions of patients and might be the ideal foundation of improved
|Contrary to existing systematic reviews [14,15], this review
investigates the effectiveness of a broad and complex spectrum of very
different interventions to improve adherence to both, medications
and lifestyle modifications. Improvements in both fields are needed
to improve quality of life, mortality and morbidity in patients with
CHF. Some of these interventions are based on personal interactions
such as provider or patient education including motivational talks and
also cognitive behavioural therapeutic approaches, while others are
predominantly characterized by organizational change or technical
solutions like individual drug blistering, smartphone reminder
applications or extended telemedical home-monitoring solutions. We
will summarize the evidence of randomized controlled trials (RCTs)
to identify the most effective interventions and we will discuss the
conditions and requirements in which these strategies work best.
This protocol carefully pre-defines inclusion criteria for participants,
intervention and outcomes, search methods, data extraction, data
synthesis and the investigation of potential effect modifiers in
|We will conduct a systematic review to evaluate the efficacy,
effectiveness, and safety of different strategies that enhance patient
adherence in secondary and tertiary prevention of HF. We will include
individual-randomized (RCTs) and cluster-randomized controlled
trials (c-RCTs) reporting on outcomes of patient adherence, with a
follow-up period of at least three months. Trials should be published
in English or German.
|Participants should be patients with acute and/or chronic HF. The
aim of prevention is the reduction of morbidity, mortality, costs, and
loss of quality of life. Therefore, we will focus on patients with HF and
NYHA ≥ 2 or LVEF <50%. Trials on general CVD or general chronic
diseases with separately investigated results for patients with these
conditions will also be included.
|Interventions will cover all strategies (e.g. primary or secondary
outcome) aiming to enhance compliance with evidence-based
recommendations on prevention or slowing of progression of HF to
preserve quality of life, social participation and general fitness of these
patients. These recommendations include pharmacological therapies
with diurectics for symptom relief and beta-blockers, ACE- and AT1-
inhibitors, aldosteron-antagonists and in certain cases, addition of ivabradine for prognostic improvements (hospitalization and survival
rate). They also include non-pharmacological interventions like regular
follow-ups, symptom monitoring, flexible diuretic use, weight control,
restriction of sodium and fluid intake, stopping smoking, regular
aerobic exercise, specialist consultation and regular clinical monitoring
|Interventions will be classified according to their active component,
which might be described by an explicit statement on how the
intervention is intended to work, into six main categories following
the suggestions on “taxonomy of implementation strategies”  with
|Interventions concerning the provider:
|a. Reminder systems
|c. Audit and feedback
|Patient education: individual counselling or group education or
training such as
|a. Verbal, written or visual instruction for patients
|b. Counseling about the patients’ underlying disease, the
importance of therapy and compliance with therapy, possible
side-effects, patient empowerment, couple-focused therapy to
increase social support
|c. Reinforcement or rewards for both improved adherence and
|d. Lay health mentoring
|e. Group meetings
|a. Reminders, e.g. programmed devices, and tailoring the regimen
to daily habits
|b. Special ’reminder’ pill packaging
|c. Appointment and prescription refill reminders
|d. Automated telephone counseling
|e. Manual telephone follow-up
|f. Mailed communications by smartphones, apps
|Promotion and empowerment of patients’ self-management:
|a. Involving patients more in their care through self-monitoring
and shared decision making
|b. Simplified dosing
|c. Dose-dispensing units
|d. Strategies for adaptive self-medication in chronic disease states
(“pill in the pocket”)
|a. Improved pharmaceutical care through simplified dosing and
augmented pharmacy services
|b. Improved cooperation between different medical disciplines,
practices, and other structures of health care providers (e.g. GPs
and cardiologists), and/or sectors of care (e.g. hospital services and community care), and/or other health professionals (e.g.
community nurses, nurse practitioners)
|c. Changes in organizational structures at practice level (e.g.
involvement of nurses in the process of care and/or counseling
|d. Direct observation of treatments by health workers or family
|e. Family intervention
|a. Drug blistering
|b. Computer-assisted patient monitoring
|c. Various ways to increase the convenience of care, e.g. provision
at the worksite (such as telemedical home-monitoring systems)
and at home
|Distinct unimodal strategies can also be combined to multimodal
|Comparators may cover standard care or other interventions. It is
necessary to describe in detail what participants in the control group
did not receive compared to those in the intervention group.
|Patient adherence “the extent to which a person’s behaviour –
taking medication, following a diet, and/or executing lifestyle changes,
corresponds with evidence-based recommendations”  will be the
main outcome of this review. There are three different approaches to
determine adherence . The first category compares the quantity of
medication taken and compares it with the quantity prescribed over
a specific time period. The second type categorizes adherence into
categories of poor or good adherence, and the third type summarizes
adherence to a variety of recommendations according to an adherence
behaviour composite score (e.g. Morisky score ). We will accept all
these definitions of adherence.
|Studies are required to have at least 50% follow-up of participants
with one or more measures of medication adherence and three months
follow-up. This minimal duration is necessary to describe adherence to
long-term regimes as required in treatment of HF and to differentiate
between permanent non-compliance of patients to recommendations
and so called drug holidays.
|Adherence can be measured by direct methods such as blood or
urine levels of the drug or its metabolite or indirect methods, such as
pill count, pharmacy refill episodes, by medication event monitoring
systems, pharmaceutical records, self-reporting through patient
diary or clinician impression [17,23]. Indirect measures are limited
by the assumption that drug acquisition is a reasonable surrogate for
consumption and subjective methods such as patient self-reporting
and clinical impression assume truthful reporting.
|It is certain that a single outcome may not reflect all important
effects the intervention may have. Therefore we investigate mortality,
morbidity, quality of life, bed days in hospital, hospital admission
and re-admission rates, and healthcare costs, as secondary outcomes.
All outcomes will be extracted within the longest available follow-up
|Searches will be conducted in electronic databases (MEDLINE, Embase, CENTRAL, PsycInfo, CINAHL), registers of ongoing and
completed trials (http://www.controlled-trials.com, http://www.who.int/ictrp/en/), and reference lists of studies included, and systematic
reviews on strategies to identify all relevant, published, and unpublished
trials. Due to the relevant improvement in therapies for HF in recent
years, a literature search starting in 2000 is considered sufficient for the
purpose of this review.
|Screening of references and studies
|Two reviewers will independently screen titles and abstracts of all
potential studies identified by database search and mark potentially
eligible studies. We will retrieve the full-text study reports/publication
and two review authors will independently screen the full-text and
identify studies for inclusion, and record reasons for exclusion of
ineligible studies. We will resolve any disagreement through discussion
or, if required, consultation with an additional reviewer. We will
identify and exclude duplicates and collate multiple reports of the same
study so that each study rather than each report is examined.
|Two authors will independently extract details of study population,
interventions, outcomes and effect modifiers by using an assessment
form, which was designed especially for the topic of this review and
tested in the pilot study. The data extraction form consists of two tables
to characterize the study and the suitable comparators. The study table
includes the following items:
|• Study references and identifier, design (RCT vs. c-RCT),
study duration (months), country, number of patients and
participating centers, primary site of recruitment (hospital vs.
community setting), primary site of intervention (hospital,
primary care, specialized care, managed care services), author
contact if necessary
|Patients: baseline characteristics (age, gender, socio-demographic
background, race, smoker, alcohol use), indication (NYHA grade,
chronic or acute HF, first diagnosis of HF at within 3 months before
randomization), evidence-based recommendations with guidelines,
co-morbidities (especially cardiovascular risk factors like diabetes,
hypertension, hypercholesterolaemia/ hyperlipidaemia, kidney failure,
|The table containing the comparators includes an unique identifier
and the following information for each of the comparators:
|• Intervention and control: description of the active component
(does a theoretical mechanism exist), categorization into
categories and subcategories, difference between intervention
and control group, provider of intervention and/or follow
up (hospital and/or ambulatory based specialist, primary
care physician, physician assistant, nurse practitioner, health
worker or others), communication style integrated in the
intervention (patient information only, informed consent,
patient participation, shared decision making, other), sample
size per group
|• Outcomes: adherence and their 95% CI or standard error,
primary or secondary outcome, definition of adherence
and method of outcome assessment, maximum follow-up,
secondary endpoints (mortality, morbidity, quality of life, days
in hospital, costs)
|• Risk of bias in six domains as described below including
number of drop-outs with causes
|• Investigated modifying factors and results from subgroup
|In case of missing information on patient adherence in pre-planned
subgroup analyses we will contact authors of RCTs.
|Risk of bias
|Two authors will independently assess the internal validity of
eligible studies according to the Cochrane Collaboration risk of bias
tool  with extensions to c-RCTs [25-27]. These domains describe
bias in random sequence generation, allocation concealment, blinded
outcome assessment, documentation of incomplete outcome data and
selective reporting. Judgment on selective reporting will be restricted to
adherence and judged on the basis of reported sample size calculation.
Furthermore, baseline comparability between treatment groups and
the use of adjustment methods to cope with potential imbalances in
both cluster and individual characteristics will be summarized as other
sources of bias. Disagreements will be resolved by discussion until
consensus is obtained. Risk of bias will be described and judged as high,
low, or unclear in six specific domains at both the cluster and patient
|Effect measures for the primary endpoint (physician adherence)
will be presented as odds ratios with their 95% CI. They can be
recalculated from relative risks , standardized mean difference with
standard deviation  or from absolute frequencies . If multiple
endpoints describe physician adherence, mean of logarithmic odds
ratios will be used to summarize all effect measures. Standard errors
from c-RCTs without hierarchic modeling will be corrected with an
intra-cluster correlation coefficient suitable for process outcomes
in secondary care of 0.06  and the mean number of patients per
cluster . We will additionally calculate absolute changes if adequate
information is reported.
|To synthesize data we will use a random-effects meta-regression
model to simultaneously assess the influence of different strategies on
the effect measures.
|Investigation of heterogeneity
|Subgroup and meta-regression-analysis will be performed after
the main meta-analysis, and will consider the following possible effect
|• methodological quality of studies
|• in case of eligible data from subgroup analyses: age, gender,
socio-economic status, NYHA
|• complexity of recommended therapies: evidence-based
medications vs. life style modification including weight control,
fluid restriction, sodium restriction or aerobic exercise
|• Method used to measure and define adherence: direct vs.
indirect methods for measurement, definition as quantity of
medication taken vs. categorized adherence vs. adherence
|• Organizational environment: primary site of intervention
(hospital, primary care, specialized care vs. managed care
services), provider of intervention and/or follow up (hospital
and/or ambulatory based specialist, primary care physician,
physician assistant, nurse practitioner, health worker vs. other),
communication style integrated in the intervention (patient information only, informed consent, patient participation,
shared decision making vs. other).
|Seeking strategies to improve the adherence of patients to
therapeutic recommendations may be of great interest over the broad
spectrum of diseases, but improving adherence to drug treatment in
HF is of special interest.
|While the greatest innovations in cardiovascular medicine have
been closely related to technological advances, which have been
applied to patient care, it now seems to be time to search for strategies
for long lasting, successful patient participation in the therapeutic
process . Future research has to look for impediments to guideline
implementation and adherence and for strategies to overcome these
|One of the major strengths of this approach is reflected by the
intention to support the implementation of best presently available
external evidence into daily practice or clinic, to ensure that especially
patients treated for HF will receive the optimal guideline based
treatment in a participatory and sustainable way. In contrast to
common approaches this review will not only look for new or optimized
technical or pharmaceutical treatment solutions, it will moreover look
at how to apply this knowledge and try to provide answers on how to
achieve long lasting patient collaboration. For this reason this review
will also investigate person and structure based interventions being
applied to motivate patients for better adherence. This, on the other
hand, also signifies the main limitation of this review because many of
the techniques and tools investigated, such as for example willingness
for patient participation or shared decision making by nurses or
physicians may cause qualitative differences in patients’ cooperation,
but will hardly be standardized for a quantifiable analysis. This point
at least leads to the principal criticism, that there are major limitations
in measuring adherence directly and independently from patients. All
questionnaire and technical approaches remain at least approximations
to real patient adherence to drug therapy and lifestyle modifications.
|Finally, interventions for implementation are complex generally
involving multiple interacting components. In all primary studies,
we are interested in the efficacy of the active component of these
interventions which should be standardized and categorized into
our taxonomy of implementation strategies. But reducing a complex
system to its component parts amounts to irretrievable loss of what
makes it a system . Therefore we have to cautiously differentiate
this theoretical study mechanism from “non-core” features which adapt
local needs and circumstances and will be investigated in heterogeneity
|Looking at drug therapy in HF as a model for successful
development of evidence based drug treatment strategies during the
last decades; it is disappointing, that these effective modalities cannot
be fully transferred into the care of patients in daily clinical practice.
|Patient adherence is therefore the logical and necessary link between
medical counselling in accordance to guideline recommendations and
the clinical result of this treatment. Without appropriate strategies for
promoting adherence the transfer of guideline recommendations into
daily practice is hindered by many obstacles that reduce the desired
health outcome. Hence, future research should focus on examining
these barriers and develop concepts for successful joint management
of chronic diseases.
- McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, et al. (2012) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 14: 803-869.
- Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJV, Ponikowski P, et al. (2008) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 10: 933-989.
- Hasenfuβ G, Anker S, Bauersachs J, Böhm M, Hoppe UC, et al. (2013) Kommentarzu den Leitlinien der EuropäischenGesellschaftfürKardiologie (ESC) zurDiagnostik und Behandlung der akuten und chronischenHerzinsuffizienz. Kardiologe 7: 105-114.
- Komajda M, Lapuerta P, Hermans N, Gonzalez-Juanatey JR, van Veldhuisen DJ, et al. (2005) Adherence to guidelines is a predictor of outcome in chronic heart failure: the MAHLER survey. Eur Heart J 26: 1653-1659.
- Ohsaka T, Inomata T, Naruke T, Shinagawa H, Koitabashi T, et al. (2008) Clinical impact of adherence to guidelines on the outcome of chronic heart failure in Japan. Int Heart J 49: 59-73.
- Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353: 487-497.
- DiMatteo MR (2004) Variations in patients' adherence to medical recommendations: a quantitative review of 50 years of research. Med Care 42: 200-209.
- Yoo BS, Oh J, Hong BK, Shin DH, Bae JH, et al. (2014) SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR): a multi-center, retrospective, observational study. PLoS One 9: e86596.
- Perreault S, Dragomir A, Blais L, Bérard A, Lalonde L, et al. (2008) Impact of adherence to statins on chronic heart failure in primary prevention. Br J ClinPharmacol 66: 706-716.
- Harmon G, Lefante J, Krousel-Wood M (2006) Overcoming barriers: the role of providers in improving patient adherence to antihypertensive medications. CurrOpinCardiol 21: 310-315.
- In der Schmitten J (2014) Granting autonomy is not sufficient – patient self-determination needs active support by physicians. Z Allg Med 90: 246-50.
- Molloy GJ, O'Carroll RE, Witham MD, McMurdo ME (2012) Interventions to enhance adherence to medications in patients with heart failure: a systematic review. Circ Heart Fail 5: 126-133.
- Labrunée M, Pathak A, Loscos M, Coudeyre E, Casillas JM, et al. (2012) Therapeutic education in cardiovascular diseases: state of the art and perspectives. Ann PhysRehabil Med 55: 322-341.
- Laufs U, Böhm M, Kroemer HK, Schüssel K, Griese N, et al. (2011) Strategies to improve medication adherence . Dtsch Med Wochenschr 136: 1616-1621.
- Matthes J, Albus C (2014) Verbesserung und Auswirkungen medikamentöserTherapietreue: Selektive Literaturübersichtam Beispiel der anti hypertensiven Therapie. DtschArzteblInt 111: 41-47.
- Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X (2008) Interventions for enhancing medication adherence. Cochrane Database SystRev : CD000011.
- Dunbar J (1984) Adherence measures and their utility. Control Clin Trials 5: 515-521.
- Morisky DE, Green LW, Levine DM (1986) Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care 24: 67-74.
- Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, et al. (2006) A meta-analysis of the association between adherence to drug therapy and mortality. BMJ 333: 15.
- Campbell MK, Piaggio G, Elbourne DR, Altman DG; CONSORT Group (2012) Consort 2010 statement: extension to cluster randomised trials. BMJ 345: e5661.
- Giraudeau B, Ravaud P (2009) Preventing bias in cluster randomised trials. PLoS Med 6: e1000065.
- Puffer S, Torgerson D, Watson J (2003) Evidence for risk of bias in cluster randomised trials: review of recent trials published in three general medical journals. BMJ 327: 785-789.
- Borenstein M, Hedges LV, Higgins JP, Rothstein HR (2009) Introduction to meta-analysis (1rstedn) John Wiley & Sons, Chichester.
- Campbell MK, Fayers PM, Grimshaw JM (2005) Determinants of the intracluster correlation coefficient in cluster randomized trials: the case of implementation research. Clin Trials 2: 99-107.
- Seehausen M, Hänel P (2011) Arzt-Patienten-Kommunikation. AdhärenzimPraxisalltageffektivfördern. DtschArzteblatt 108: A2276-80.
- Hawe P, Shiell A, Riley T (2004) Complex interventions: how "out of control" can a randomised controlled trial be? BMJ 328: 1561-1563.