Interventions to improve evidence-based prescribing in heart failure

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

The overall objective of this review is to identify interventions aimed at improving clinicians' prescribing of medications recommended by national and international guidelines for HF management and to assess their overall efficacy measured in terms of clinician prescribing behavior and patient-level HF outcomes.


Description of the condition

Heart failure (HF) is a chronic, progressive and debilitating condition that occurs when damaged heart muscle is unable to pump blood efficiently to the body's tissues. It may manifest as symptoms of shortness of breath, fatigue and/or lower extremity edema. HF can develop from any condition that weakens the heart muscle (AHA 2012). The most common risk factors include hypertension, a previous myocardial infarction, coronary artery disease, valvular defects, congenital defects, cardiomyopathies, lung disease, diabetes, drugs and infection (AHA 2012). Approximately 1% to 3% of individuals have HF worldwide, including 10% of individuals over the age of 65 years (McMurray 2002). In 2010, more than 41 million individuals were living with HF globally, representing a 14% increase from 1990 (Roger 2012). The lifetime risk of developing HF in men and women 40 years of age is as high as one in five (Lloyd-Jones 2002; Roger 2012). A staggering 1 million new cases are diagnosed yearly worldwide, making it the fastest growing cardiovascular disorder. Although survival after a diagnosis of HF has improved over time, mortality remains high with roughly half of newly diagnosed individuals dying within five years (Levy 2002; Murphy 2012; Roger 2004; Roger 2012).

In the US alone, in 2009 HF was responsible for over 3 million annual physician office visits (NHLBI 2012). The economic burden attributed to HF is projected to rise 215% to $77.7 billion by 2030 (NHLBI 2012). Indirect costs, such as lost productivity, are projected to increase 80% from $9.7 billion in 2010 to $17.4 billion by 2030 (Heidenreich 2009). A report from the UK estimated that HF accounts for 2% of the national expenditure on health, mostly due to the cost of hospital admissions (Stewart 2002). A similar report from Poland estimated that HF accounts for more than 3% of the national healthcare budget (Czech 2013). Hospital-case fatalities for all age groups have generally declined, however, and interventions to decrease hospital admissions and length of hospital stay have led to substantial savings (Lee 2004; Liao 2008; O'Connell 2000).

Guidelines for the treatment of heart failure have been contributed by several organizations such as the American Heart Association, American College of Cardiology, International Society for Heart and Lung Transplantation, European Society of Cardiology and National Heart Foundation of Australia (Hunt 2009; McMurray 2012; Mosca 2007; NHF 2011; Tricoci 2009; Yancy 2013). Treatments that are supported by the strongest levels of evidence (often termed 'class I/level A') include angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (McMurray 2012). Many other treatments, for which efficacy is supported by moderate levels of evidence, are often used for HF management depending on the severity of the symptoms. These may include agents such as diuretics, ivabradine, digoxin (and other digitalis-related glycosides), and combination hydralazine and isosorbide dinitrate (McMurray 2012; Yancy 2013). Class I/level A-recommended treatments have been shown in randomized controlled trials (RCTs) to decrease mortality and hospitalization rates when combined with conventional treatments such as diuretics, digoxin and spironolactone (McMurray 2012).

Establishing guidelines, however, does not guarantee their use in actual clinical practice (Feder 1999). A review of international studies (Williamson 2012) suggests that there is still a significant number of individuals with HF not receiving evidence-based treatments or receiving subtherapeutic doses of medications. For example, a cross-sectional study of 451 general practitioners in the Netherlands demonstrated poor adherence to clinical practice guidelines in their decisions on the management of individuals with HF (Swennen 2013). A variety of studies have documented that adherence to evidence-based practice guidelines improves outcomes in HF. For example, in the Survey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR), a multicenter, retrospective, observational study of individuals with systolic HF (ejection fraction <45%) admitted to 23 university hospitals in Korea, adherence to guideline-recommended medications was associated with lower mortality (Yoo 2014). Therefore, it is imperative to identify appropriate and effective interventions to improve evidence-based prescribing in HF.

Description of the intervention

Interventions that have been used to improve evidence-based prescribing include educational outreach visits to health professionals and interactive educational activities for clinicians; electronic and manual reminders in the medical charts of individuals with HF; establishing standardized protocols within inpatient or outpatient settings; providing summaries of a clinician's prescribing behavior and feedback; and educational materials designed for clinicians such as lectures and pamphlets. All of these strategies are aimed directly at the clinician prescriber. Some interventions can be aimed at the individual with HF in order to change their interaction with the clinician prescriber. This type of intervention is termed patient-mediated because it works through the patient-prescriber relationship. For instance, strategies prompting individuals with HF to ask their provider about one or more guideline-recommended medication can serve as an impetus to change the prescribing behavior of the clinician.

Audit and feedback, together with educational outreach visits, have been the focus of a variety of interventions to change prescribing behavior (Ostini 2009). Often more than one strategy or approach is employed within a single intervention. For instance, a recent intervention trial aimed at improving adherence to evidence-based prescribing guidelines in HF, the IMPROVE-HF trial, included a guideline-based clinical decision support tool kit, educational materials, practice-specific data reports, benchmarked quality-of-care reports and structured educational outreach visits (Fonarow 2010; Walsh 2012). The clinical decision support tool kit consisted of evidence-based best practice algorithm charts, clinical pathway flow charts, standardized encounter forms, checklists, pocket cards, chart stickers and educational materials aimed at individuals with HF (Walsh 2012). In another trial, the intervention consisted of providing educational materials for physicians with a recommended protocol for multidisciplinary management and a template for care presented as a registration form, with an optional outreach visit from a practice consultant (van Lieshout 2011). Other interventions have consisted of facilitated group discussions about evidence-based prescribing of HF medications, with generalist physicians using audit and feedback about their management of individuals with HF extracted from clinical practice software (Williamson 2012). Clinical peer groups have also been used to change behavior (Kasje 2006).

How the intervention might work

These interventions might change prescribing behavior by addressing factors at the organizational or individual level that contribute to the prescribing behavior (Bero 1998; Feder 1999; Grimshaw 2002). These factors include the organizational culture and its resources, information management strategies (e.g., the presence of reminders or prompts in patient records or the electronic medical record system), local healthcare setting and resources, provider's knowledge, communication strategies and availability of feedback (McEntee 2009). Interventions to improve the prescribing of guideline-based medications in HF work by addressing one or more of these organizational or individual modifiable factors. Passive strategies of distributing evidence (e.g., mailing publications) have not been successful in changing prescribing behavior (Bero 1998; Feder 1999; Freemantle 1997; Grimshaw 2001; Grimshaw 2003).

In systematic reviews studying the effectiveness of various strategies to enhance the application of research findings (Bero 1998; Grimshaw 1998; Grimshaw 2003), it has been reported that interventions that were consistently effective included educational outreach visits, interactive educational activities and reminders (electronic or manual). Reminders may work by improving recognition of the opportunity to institute guideline-recommended care. Recent interventions in prescribing have focused on strategies such as provider education and outreach within the primary care setting (Kamarudin 2013; Williamson 2012). These may work by improving providers' knowledge and skills in communication or resource management to improve evidence-based prescribing behaviors. Other interventions have targeted those modifiable factors, such as the availability of feedback through individual reports, which provide clinicians with objective measures of their performance.

Why it is important to do this review

It is vitally important to identify effective interventions that maximize the prescribing of evidence-based medications shown to improve morbidity and mortality in individuals with HF (Heidenreich 2009; LaBresh 2007; Redberg 2009a; Redberg 2009b; Spertus 2005a; Spertus 2005b). Essential to this process will be identifying interventions that work and the characteristics that will predict a successful intervention. Identifying methods for improving and implementing appropriate prescribing will ensure the best therapeutic outcome for individuals with HF and save billions in annual healthcare costs. Previous reviews have succeeded in identifying different methods of altering prescribing behavior with varying degrees of success (Bero 1998; Grimshaw 1998; Grimshaw 2003; Kamarudin 2013). None of these reviews, however, explored prescribing in HF. By carefully reviewing and analyzing the data, we hope this systematic review will deliver a comprehensive overview and clinical guidance for improving prescribing trends in HF management.


The overall objective of this review is to identify interventions aimed at improving clinicians' prescribing of medications recommended by national and international guidelines for HF management and to assess their overall efficacy measured in terms of clinician prescribing behavior and patient-level HF outcomes.


Criteria for considering studies for this review

Types of studies

We will include RCTs with individual or cluster randomization which report the results of interventions that are aimed at improving evidence-based prescribing in HF. We will include studies reported as full text, those published in abstract form only (if sufficient data are available) and unpublished data, if sufficient and available.

Types of participants

We will include health professionals as participants. These health professionals must have the ability to prescribe treatment for adults (over 18 years of age) with a diagnosis of non-valvular HF. As there are multiple scoring systems and criteria for the diagnosis of HF, we will use the diagnosis of HF as defined in the included studies. These definitions will be described in the review and important differences will be noted. We will exclude those studies that include only health professionals who do not have prescribing authority (e.g., nurses, physical therapists, pharmacists), unless these participants are specifically noted to influence prescribing behavior. For instance, an intervention that involves pharmacists only would not be included unless those pharmacists have interaction specifically with physicians involved in prescribing treatment for HF. If interventions are targeted at different health professionals at the same time, we will first assess the relevance of the study for inclusion and, if included, analyze these multidisciplinary groups separately in a subgroup analysis. If prescribing practitioners can be identified in multidisciplinary target groups, we will extract their data separately. We will not consider individuals with HF as participants in the study; however, we will derive outcome assessments (e.g., the proportion of individuals receiving a specific guideline-recommended medication) from patient-level data.

Types of interventions

We will include trials comparing interventions aimed at improving evidence-based prescribing for HF with no intervention. The types of interventions we will consider include educational materials, educational outreach visits, interactive educational activities, electronic or manual reminders, summaries of clinical performance, education by key opinion leaders, discussions among practitioners to develop consensus and patient-mediated interventions if the intervention includes a clear element aimed at changing prescribing behavior. We expect that the intensity, frequency and mode of delivery of these interventions will vary. To assess variation in these factors and the relationship to outcomes, we will consider subgroup analyses (see 'Subgroup analysis and investigation of heterogeneity').

Types of outcome measures

We will examine the following outcomes with regard to each medication or combination therapy, but we will also describe summarized outcomes of groups of therapies when possible.

Primary outcomes
  • Number or proportion of individuals with HF receiving evidence-based individual medications (e.g., ACEIs, ARBs, beta-blockers, spironolactone, etc.) and/or combination therapies (e.g., hydralazine/isosorbide dinitrite)

  • Number or proportion of individuals with HF receiving recommended doses of medications

  • Number or proportion of individuals with HF with a recorded reason for not having been prescribed evidence-based medications

  • Number or proportion of individuals with HF with adverse outcomes (e.g., cough or angioedema with ACEIs; headaches/dizziness/nausea with hydralazine/isosorbide dinitrite; electrolyte and renal disturbances with diuretics; subsequent arrhythmias, etc.)

Secondary outcomes
  • Hospital admissions (HF-specific and all-cause)

  • Mortality (HF-specific and all-cause)

  • Quality of life

  • Costs

Search methods for identification of studies

Electronic searches

We will identify trials through systematic searches of the following bibliographic databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effectiveness (DARE), both part of The Cochrane Library;

  • MEDLINE (1966 to current date) via Ovid;

  • EMBASE (1980 to current date) via Ovid;

  • CINAHL (1982 to current date) via EBSCO.

We will adapt the preliminary search strategy for MEDLINE (Ovid) (Appendix 1) for use with the other databases. We will apply the Cochrane sensitivity-maximizing RCT filter (Lefebvre 2011) to MEDLINE (Ovid) and adaptations of it to the other databases, with the exception of CENTRAL.

We will also conduct a search of ( and the World Health Organization International Clinical Trials Registry Platform Search Portal (

We will search all databases from their inception to the present, and we will impose no restriction on language of publication.

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references. We will also search the reference lists of HF guidelines and other relevant systematic reviews. We will contact the primary authors of eligible papers in order to identify other studies (ongoing or unpublished) in this area.

Data collection and analysis

Selection of studies

Two authors (MKM, RH) will independently screen the titles and abstracts of all the potential studies we identify as a result of the search for inclusion and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will consult a third author (KJP) If there are any disagreements. We will retrieve the full-text study reports/publications and two authors (MKM, RLH) will independently screen the full text and identify studies for inclusion, and identify and record reasons for exclusion of any ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (KJP). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Higgins 2011; Liberati 2009) and 'Characteristics of included studies' and 'Characteristics of excluded studies' tables.

Data extraction and management

We will use a data collection form that has been piloted on at least one study in the review to collect study characteristics and outcome data. One author (KJP) will extract the following study characteristics from the included studies.

  1. Methods: study design, total duration of study, details of any 'run-in' period, number of study centers and location, study setting, withdrawals, and date of study

  2. Characteristics of prescribers (health professionals): number, mean age, age range, gender, health profession, practice setting, practice characteristics

  3. Individuals with HF (among whom outcomes will be assessed): number, mean age, age range, gender, severity of condition, diagnostic criteria, inclusion criteria and exclusion criteria (related to individuals with HF)

  4. Interventions: intervention, comparison, concomitant medications or nonpharmacologic therapies, and excluded medications

  5. Outcomes: primary and secondary outcomes specified and collected, and time points reported

  6. Notes: funding for trial, and notable conflicts of interest of trial authors

Two authors (MKM, RLH) will independently extract outcome data from included studies. We will resolve disagreements by consensus or by involving a third author (KJP). One author (MKM) will transfer data into Review Manager (RevMan) (RevMan 2012). We will double-check that data are entered correctly by comparing the data presented in the systematic review with those in the study reports. A second author (LALB) will spot-check study characteristics for accuracy against the trial reports.

Assessment of risk of bias in included studies

Two authors (MKM, RLH) will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (KJP). We will assess the risk of bias according to the following domains:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of outcome assessment;

  4. incomplete outcome data;

  5. selective outcome reporting;

  6. other bias (e.g., industry funding).

In cluster-randomized trials, we will consider specific biases as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  1. Recruitment bias: this occurs when individuals are recruited to the trial after the clusters have been randomized

  2. Baseline imbalance: if small numbers of clusters are randomized, there is a possibility of baseline imbalance between the randomized groups

  3. Loss of clusters: if complete clusters are lost from a trial, bias can occur if these lost clusters are omitted from the analysis. In addition, missing outcomes for individuals within clusters may also lead to a risk of bias in cluster-randomized trials

  4. Incorrect analysis: trials that have not been analyzed appropriately create a ‘unit of analysis error’, produce over-precise results and will receive too much weight in a meta-analysis

  5. Comparability with individually randomized trials: in a meta-analysis including both cluster and individually randomized trials, or including cluster-randomized trials with different types of clusters, possible differences between the intervention effects need to be considered as the ‘contamination’ could lead to underestimates of effect. Thus, if an intervention effect is still demonstrated despite contamination in those trials that were not cluster-randomized, a confident conclusion about the presence of an effect can be drawn.

We will grade each potential source of bias as high, low or unclear, and provide a quote from the study report together with a justification for our judgment in a 'Risk of bias' table. We will summarize the 'Risk of bias' judgments across different studies for each of the domains listed. Where information on risk of bias relates to unpublished data or to correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyze dichotomous data as odds ratios or risk ratios with 95% confidence intervals, and continuous data as mean differences or standardized mean differences with 95% confidence intervals. We will enter data presented as a scale with a consistent direction of effect.

We will describe in narrative skewed data reported as medians and interquartile ranges.

Unit of analysis issues

We will include RCTs with a parallel-group design in which the unit of randomization is the unit of analysis. We will also include studies with a cluster-randomized design (e.g., where a group of health professionals is randomized to an intervention and the outcome (prescribing per person with HF) is measured at the individual level). In this case, we will use the options outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If possible, we will conduct the analysis at the same level as the allocation, by extracting a summary measurement from each cluster. However, if there is only a small number of clusters, this method of analysis might reduce the power of the study. In that case we will apply statistical methods that take the clustering effect into account through generalized estimating equations. We will estimate effects and their standard errors using the generic inverse-variance method in RevMan (Higgins 2011; RevMan 2012).

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g., when a study is identified in abstract form only). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results using a sensitivity analysis

Assessment of heterogeneity

We will assess heterogeneity in two steps. First, we will assess clinical heterogeneity at face value: we will compare studies with regard to the included populations, types of interventions and measurement of the outcomes. If studies are obviously clinically heterogeneous they will not be pooled in meta-analysis but rather described in narrative. Second, we will assess statistical heterogeneity using the I² statistic. If we identify substantial heterogeneity we will report it and explore possible causes by prespecified subgroup analysis. We will use the following guide to interpret the importance of any statistical heterogeneity (Higgins 2011):

  • 0% to 40%: might not be important;

  • 30% to 60%: may represent moderate heterogeneity;

  • 50% to 90%: may represent substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases for the primary outcomes.

Data synthesis

We will undertake meta-analysis only where this is meaningful (i.e., if the study design, setting, treatments and the underlying clinical question are similar enough for pooling to make sense) (see 'Assessment of heterogeneity').

As there is likely to be some heterogeneity among the intervention data that are pooled, we will use a random-effects model for pooling the included studies. A random-effects meta-analysis model involves an assumption that the effects being estimated in the different studies are not identical, but follow some distribution (Higgins 2011). The effect estimate in a random-effects model may underestimate the study effect if there is no heterogeneity but is a more appropriate analysis method in the presence of unexplained heterogeneity.

Subgroup analysis and investigation of heterogeneity

We expect that some aspects of the interventions used in the included studies, such as intensity, frequency and mode of delivery, will vary. We plan to carry out the following subgroup analyses:

  • interventions with a face-to-face component versus no face-to-face interventions;

  • cluster-randomized versus individual randomized studies;

  • primary care versus hospital-based settings.

We will use only primary outcomes for these analyses.

We will use the formal test for subgroup interactions in RevMan (RevMan 2012).

Sensitivity analysis

We plan to carry out the following sensitivity analyses:

  • including only studies with a low risk of bias.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of studies included in this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline the remaining uncertainties in this area.


Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R) <1946 to January Week 5 2014>
Search Strategy:
1 exp Heart Failure/ (84167)
2 ((heart* or cardiac* or myocard*) adj2 (fail* or insuff*)).tw. (112699)
3 (heart* adj2 decomp*).tw. (2082)
4 (854)
5 (9741)
6 1 or 2 or 3 or 4 or 5 (139552)
7 exp Adrenergic beta-Antagonists/ (76068)
8 (beta* adj2 (block* or agon* or antag* or adrenergic)).tw. (78256)
9 (2215)
10 (5524)
11 (946)
12 (6046)
13 (931)
14 (1743)
15 (978)
16 (2586)
17 (489)
18 (2359)
19 exp Angiotensin Receptor Antagonists/ (16732)
20 (angiotensin* adj2 (block* or recept*)).tw. (15176)
21 exp Angiotensin-Converting Enzyme Inhibitors/ (39170)
22 (ace adj3 (inhibit* or antagon*)).tw. (16031)
23 (angiotensin* adj3 (enzyme* or antagon* or inhibit*)).tw. (38340)
24 (kininase* adj2 (inhibit* or antagon*)).tw. (243)
25 (10284)
26 (527)
27 (5410)
28 (948)
29 (438)
30 (1967)
31 (1431)
32 (1737)
33 (1286)
34 (123)
35 (6384)
36 (261)
37 (1147)
38 (1949)
39 (1224)
40 exp Diuretics/ (70235)
41 diuretic*.tw. (29289)
42 (9752)
43 (21)
44 (2655)
45 ethacrynic (1837)
46 exp Mineralocorticoid Receptor Antagonists/ (8122)
47 (mineralocorticoid adj2 antagon*).tw. (668)
48 (aldosterone* adj2 antagon*).tw. (1526)
49 (272)
50 canrenoic (29)
51 (4360)
52 (1128)
53 exp Digoxin/ (11468)
54 (9927)
55 ivabradin*.tw. (443)
56 or/7-55 (271977)
57 exp Drug Utilization/ (19232)
58 exp Drug Prescriptions/ (23354)
59 exp Medication Systems/ (4071)
60 ((drug* or medic* or pharma*) adj2 (utili* or manag* or prescr*)).tw. (57843)
61 (improv* adj3 prescr*).tw. (1753)
62 exp disease management/ (27007)
63 (disease* adj3 manag*).tw. (23808)
64 Pharmacists/ (10318)
65 Physician's Practice Patterns/ (39659)
66 Evidence-Based Medicine/ (51938)
67 (evidence* adj4 (prescr* or medicin* or treatm*)).tw. (22318)
68 Guideline Adherence/ (19582)
69 ((guideline* or protocol* or polic* or institution*) adj2 (adher* or compli*)).tw. (3964)
70 exp Guidelines as Topic/ (109825)
71 or/57-70 (337854)
72 6 and 56 and 71 (1995)
73 randomized controlled (359956)
74 controlled clinical (86949)
75 randomized.ab. (261102)
76 placebo.ab. (141356)
77 drug therapy.fs. (1653115)
78 randomly.ab. (186623)
79 trial.ab. (268584)
80 groups.ab. (1204834)
81 73 or 74 or 75 or 76 or 77 or 78 or 79 or 80 (3095618)
82 exp animals/ not (3869588)
83 81 not 82 (2631628)
84 72 and 83 (1547)

Contributions of authors

LALB drafted the text of the protocol with input from all authors.

MLVD completed the methods section of the protocol and advised on methodology.

All authors read and approved the final text of the protocol.

Declarations of interest

None known

Sources of support

Internal sources

  • No internal funding support received, Other.

External sources

  • No external funding support received, Other.