key: cord-1007106-sv1mc2bo
authors: Beezer, Janine; Al Hatrushi, Manal; HusbandSl ova ki, Andy; Kurdi, Amanj; Forsyth, Paul
title: Polypharmacy definition and prevalence in heart failure: a systematic review
date: 2021-07-02
journal: Heart Fail Rev
DOI: 10.1007/s10741-021-10135-4
sha: 933cc2b6e15a26cec1ba445ba0c4bebd97f3bda8
doc_id: 1007106
cord_uid: sv1mc2bo

Polypharmacy and heart failure are becoming increasingly common due to an ageing population and the rise of multimorbidity. Treating heart failure necessitates prescribing of multiple medications, in-line with national and international guidelines predisposing patients to polypharmacy. This review aims to identify how polypharmacy has been defined among heart failure patients in the literature, whether a standard definition in relation to heart failure could be identified and to describe the prevalence. The Healthcare Database Advanced Search (HDAS) was used to search EMBASE, MEDLINE, PubMed, Cinahl and PsychInfo from inception until March 2021. Articles were included of any design, in patients ≥ 18 years old, with a diagnosis of heart failure; that explicitly define and measure polypharmacy. Data were thereafter extracted and described using a narrative synthesis approach. A total of 7522 articles were identified with 22 meeting the inclusion criteria. No standard definition of polypharmacy was identified. The most common definition was that of “ ≥ 5 medications.” Polypharmacy prevalence was high in heart failure populations, ranging from 17.2 to 99%. Missing or heterogeneous methods for defining heart failure and poor patient cohort characterisation limited the impact of most studies. Polypharmacy, most commonly defined as ≥ 5 medications, is highly prevalent in the heart failure population. There is a need for an internationally agreed definition of polypharmacy, allowing accurate review of polypharmacy issues. Whether an arbitrary numerical cut-off is a suitable definition, rather than medication appropriateness, remains unclear. Further studies are necessary to understand the relationship between polypharmacy with specific types of heart failure and related comorbidities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10741-021-10135-4.

Polypharmacy is an increasingly common phenomenon, which refers to the use of multiple medications by one individual [1] . There is no universal polypharmacy definition; however, a numerical definition of 5 or more medications daily is commonly referred to [2] . The emergence of polypharmacy has been driven by the growth of an ageing population and the rising epidemic of multimorbidity (i.e., the presence of multiple conditions) [1] . General trends in polypharmacy are increasing worldwide [3] . Polypharmacy can be either appropriate, where medications are prescribed for complex conditions, such as heart failure, or for multiple conditions in circumstances where medicines use has been optimised and are prescribed according to best evidence, or problematic, where medications are prescribed inappropriately or where the intended benefits from the medicines are not realised [4] . However, this is not a static situation; over time, changes to a patient's clinical situation and life circumstances can change the appropriateness of previously sound prescribing decisions.

Heart failure is a common complex clinical syndrome of symptoms and signs caused by structural or functional abnormalities, resulting in an impairment of cardiac output [5] . It is typically characterised into two types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), the first being a mechanistic left ventricular pump problem and the latter often being described as a filling problem due to muscle stiffness reducing left ventricular cavity size or dilation of the left atrium. The treatments of both types differ with HFrEF having a large evidence base for sequential drug therapy to improve outcomes; this is in stark contrast to HFpEF, where there are currently no therapeutic options showing prognostic benefit and symptom control being the only management strategy.

Increasingly, the rise in heart failure is seen as a global public health problem, affecting approximately 26 million people worldwide and resulting in more than one million hospitalisations annually in both the USA and Europe [6] . The high prevalence of heart failure has a high clinical, economic and social impact on individuals and health institutes [1, 7] .

Heart failure in the majority of cases is the long-term consequence of complex interwoven comorbidity and therefore, similar to polypharmacy, is exacerbated in the ageing population. Many of these comorbidities, such as coronary heart disease and diabetes, are treated and managed with complex pharmacological regimens. The main interventions for successfully treating heart failure itself are also pharmacological. Diuretics provide symptom relief in all types of heart failure, and in HFrEF medications with prognostic benefit include angiotensin-converting-enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter-2 inhibitors (SGLT2). The emergence of this evidence-base from 1990s and implementation via national [5] and international [8] guidelines has led to improving survival rates amongst heart failure patients [9] , predisposing them to appropriate polypharmacy even before taking into consideration treatment for concurrent conditions. Due to these factors, total pill burden and polypharmacy complexity is known to be increasing in heart failure patients over time [10] .

Polypharmacy may however also bring unwanted challenges around patient safety and is associated with increased incidence of adverse outcomes including mortality, falls, adverse drug reactions, increased length of stay in hospital and readmission to hospital soon after discharge [2] . A review of polypharmacy in older people confirmed an increase of drug related problems such as drug-drug interactions, hospitalisation and mortality, and that adverse drug reactions were the major cause of hospitalisation in 90% of older patients with polypharmacy [3] . The same review found a decline in physical activity, cognitive ability and poor adherence to medication also resulted from polypharmacy.

The aim of this systematic review was to identify if a standard definition of polypharmacy is used in relation to heart failure patients and to describe the prevalence of polypharmacy in a heart failure population.

Reporting of this systematic review conformed to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist [11] . This study was registered with the international database of prospectively registered systematic reviews PROSPERO (identification number CRD42020166677).

The Healthcare Database Advanced Search (HDAS) was used to search EMBASE, MEDLINE, PubMed, Cinahl and PsychInfo by one of the investigators (JB) from their inception until and including March 2021. The search strategy was detailed and comprehensive, incorporating multiple terms, including MeSH terms, relevant to heart failure and polypharmacy (see Table 1 ). Hand searching of references of the articles reviewed also took place.

Inclusion criteria for the review were studies, of any design and any care setting, in patient's ≥ 18 years old, with a diagnosis of heart failure; that explicitly defined and reported the prevalence of polypharmacy. Exclusion criteria were conference abstracts with no full text, studies in languages other than English and/or studies reported only median/mean values or number of total medications.

Studies were identified, screened and checked for eligibility. Two independent investigators (JB and PF) screened titles and abstracts against the inclusion criteria; any disagreement was resolved by a third independent reviewer (AH). Following this, full text was reviewed (JB and PF) for inclusion; again, any disagreement was discussed between these investigators (JB and PF) and only resolved by a third independent reviewer if no initial agreement was reached (AH).

Data were extracted (JB) from eligible papers using a narrative synthesis approach in March 2020 and April 2021, whereby a data extraction table was developed (see Table 2 ). Once the initial data extraction was complete, it was verified by another author (PF) in July 2020 and April 2021. This time lag was due to the coronavirus pandemic.

Papers were quality assessed and appraised using Critical Appraisal Skills Programme (CASP) screening tool by the lead researcher in July 2020 and April 2021 (JB) and then verified by a second author in September 2020 and April 2021 (PF). This tool was minor adapted for clarity and to suit the purpose of the review (shown in column headings in Table 3 ). Papers were not excluded based on quality assessments.

Ethical approval was not required.

A total of 7522 articles were identified, of which 88 were included for full-text review, 18 were initially included by both independent reviewers (JB and PF), and a further 4 were included after discussion and agreement (JB and PF); 22 articles met the final inclusion criteria and no articles needed adjudication by the third independent reviewer. The included studies were all observational in nature and consisted of 7 (41.2%) cohort studies [12] [13] [14] [15] [16] [17] [18] , 13 (58.8%) cross-sectional studies [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] , and 2 studies were secondary analyses from previous randomized controlled trial datasets [32, 33] . In total, 70,695 heart failure patients were included in the studies. The mean age of heart failure patients (based on 11 studies [13, 15, 19-24, 26, 27, 31] ) was 72.3 years, and 40.3% were female (based on 16 studies [12-15, 19-24, 26, 27, 29-32] ).

Studies were across a range of care settings: 8 from outpatients clinics [12, 13, 22, 23, 30, [32] [33] [34] , 11 from hospital inpatients [14-18, 25-29, 31 ] and 1 from each general population [21] , nursing homes [24] and primary care [19] . Studies were from across the globe: 7 from USA [12, 21, 22, 30, 31, 33, 34] ; 3 from Italy [16, 18, 27] ; 2 from the UK [14, 19] , Japan [25, 29] and Australia [13, 26] ; 1 each from of Spain [23] , Poland [24] , Ethiopia [15] , Greece [17] and Slovakia [28] and 1 from north and south America combined [32] .

The data collection time frames for studies included in this review range from 2002 to 2019, with only one study collecting data up to 2019 [30] ; the majority predate the most recent heart failure evidence and guidelines (ESC 2016 [8] and NICE 2018 [5] ) for the sequential additions of drug therapies. New evidence beyond the addition or ACEi/ARB, BB and MRA emerged in 2010 with ivabradine [35] , sacubitril/valsartan in 2014 [36] and dapagliflozin in 2019 [37] . As such, 18 of the 22 studies had completed data collection prior to 2015 [14, 16, 18, 19, 22, 23, 25, 26, 28] and all data collected but 1 study preceded the end of 2016 [30] .

Comorbidity data, specific to the heart failure patients within the study, were displayed in 5 out of 17 studies [14, 15, 19, 24, 27] , and 2 studies report the number of comorbidities [21, 22] . Individual medication class data, specific to the heart failure patients within the study, were displayed in 7 [12, 14, 15, 21, 24, 26, 27] out of 17 studies, and 8 studies [14, [19] [20] [21] [22] [23] [24] [25] report the total number of medicines. Although the average number of medicines was not part of the inclusion criteria, some studies reported this, with average number of medicines ranging from 4.1 [15] to 13.3 [34] .

A total of 4 studies [12, 13, 19, 23] included an exclusively HFrEF population although no ejection fraction data was available; 2 studies included an exclusively HFpEF population [30, 32] , 2 studies [26, 34] included clinical heart failure and 1 study [21] included self-reported heart failure. A study by Verdiani et al. [27] looked at the European Society of Cardiology definition of heart failure and included all 3 groups [8] . Lien et al. [14] Michalik et al. [24] and Unlu et al. [31] included all heart failure, Taylor et al. [26] and Sunaga et al. [29] included all decompensated heart failure admitted to hospital, and the remaining 6 studies did not specify the heart failure cohort included [15-17, 25, 28, 33] . See Table 2 for full data extraction.

No standardised definition was used consistently across all the studies. The most commonly used definition was that of [32] .

The prevalence of polypharmacy ranged from 17.2% [12] to 99% [17] , with 19 of the 22 studies (86%) having polypharmacy > 60%. Where polypharmacy was defined as 5 or more medicines, with 11 out of 13 of these studies finding a prevalence of ≥ 60%. Polypharmacy prevalence was 66.3% [29] to 74% [23, 33] in patients taking six or more medications. Verdiani et al. showed that 57% of patients had eight or more medication classes [27] where Sganga et al. [18] showed 72.4% to be taking eight or more and Knafl et al. having 60.6% taking nine or more medications [22] . In the most recent dataset study, Brinker et al. [30] showed polypharmacy prevalence of ≥ 10 medicines to be 74%, where in an earlier dataset, Unlu et al. [31] found it to be 42% on admission to hospital and 55% at the point of discharge 

All included studies were appropriately observational in design. All but two of the studies [16, 31] looked at polypharmacy at one particular time point within the study and the patient journey, and therefore, the assessment of completeness of follow up and length of follow up was not applicable. This type of cross-sectional view limits any analysis on association with polypharmacy prevalence and predictors and also stops any analysis of association between polypharmacy and outcomes over time.

In the majority of cases, polypharmacy was not the primary focus of studies. Of the 22 studies, only 6 were designed a priori to address polypharmacy in a heart failure population [14, 20, 22, [30] [31] [32] . The remaining 16 studies were designed primarily to address other questions, but collected data for heart failure patients and polypharmacy prevalence by proxy. Little, therefore, is known about how polypharmacy changes over time and in different phases of the heart failure journey (e.g. diagnosis, stable phases, unstable phases and end of life).

The definition of heart failure was highly variable across the studies limiting their impact and generalisability; diagnostic ejection fraction entry criteria was only used in 6 studies [12, 13, 19, 23, 27, 32] , and summarised echo findings were only displayed in the studies by Verdiani et al. [27] , Unlu et al. [31] and Sunaga et al. [29] . Three studies [12, 14, 19] used coding data to identify heart failure cases and although this is an acceptable way to recruit patients, it limits the ability of the reader differentiation between the types of heart failure and applies the findings. Entry criteria and/or summarised baseline characteristics for the clinical manifestation of the syndrome, for example clinical fluid overload or New York Heart Association class, were only displayed in 4 studies [20, 22, 26, 32] . The type and severity of heart failure often dictate pharmacological treatment, and therefore, these missing data make the clinical understanding and generalisability of the findings difficult to interpret.

Bias on the exposures to all medications was common in many studies, with comorbidity, which impacts on polypharmacy commonly excluded from studies [12, 15, 16, 20, 22, 32] , poor definition of how medication histories were collected [13, 15, 23, 24, 26] and uncertainty over whether acute medications and 'over-the-counter' therapies were included [19, 30] . Small sample size in some studies (e.g. 7 studies having < 200 patients [14, 17, 18, 20, 23, 24, 29] ) may increase the liability of confounding factors. Participant age was often less than population heart failure cohorts (e.g. 6 studies had mean ages or entry criteria < 65 years of age [12, 13, 15, 18, 22, 23] ); the two studies with the lowest prevalence findings were both in younger cohorts. [12, 15] . Comparatively, in the 5 studies using the polypharmacy definition of ≥ 5 medications, where the mean age was above 60, prevalence was higher (range 72-99%).

Women were commonly under-represented with less than 40% female populations in 5 [12, 13, 20, 22, 23] out of 12 studies that displayed data. The study by Alvarez et al. only enrolled patients from an insured cohort [12] and studies by Caroll et al. [13] , Millenaar et al. [33] and Wu et al. [32] involved a secondary analysis of previous datasets, both meaning that findings may not be representative of true population-level findings.

Findings from the studies suggest that heart failure and/ or LVSD was associated with an increased prevalence of polypharmacy in many cohorts, including the general population [21] , patients admitted to hospital [14] [15] [16] [17] [18] [25] [26] [27] [28] and nursing home patients [24] . Prevalence was also high in outpatients with HFpEF [30, 32] . An ischaemic aetiology was also shown to be associated with polypharmacy in heart failure [20] . Polypharmacy was linked with various types of problem or harm in patients, including the inappropriate prescribing of potentially harmful medications [12, 30] , an increased rate of drug therapy problems [15, 30] and poor medication adherence [22] and associated with poor prognosis [29] and heart failure hospitalisations [32] . However, the generalisability and impact of all of these findings are limited due to the heterogeneity of definitions of heart failure, the characterisation of participants and high levels of confounding risk.

The results of this systematic review showed variations of the definition of polypharmacy although five or more medications were the predominant definition throughout the studies with data collection from 2002 to 2019, the majority of which predate the most recent drug therapy evidence. This is consistent across the literature, a recent systematic review of polypharmacy definitions found 138 definitions for polypharmacy from 110 articles, the most common of which was the use of five or more medications [2] .

Polypharmacy, by any definition, was present in the majority of studies within our review. This ultimately should not be unexpected, as the guideline-based medication interventions recommended for the treatment of heart failure puts patients at risk of polypharmacy, before taking into consideration treatment for comorbid conditions [8] . All of the studies in this review pre-date the evidence base for ARNI and SGLT2 inhibitors, except one [30] where the population was HFPEF and the evidence base for treatment lies with diuretics management and optimal treatment of comorbid conditions. Essentially, all optimised HFrEF patients in 2020, able to tolerate treatment, will typically meet the polypharmacy criteria for 5 or more medications.

While the trend of non-cardiovascular comorbidities among hospitalised patients with heart failure has been increasing over time [23] and is associated with negative outcomes and a growing burden of non-CVD prescriptions, it is unclear whether the high polypharmacy prevalence is driven by heart failure medications, other cardiac medications or non-cardiac medications related to other comorbidity. A recent commentary by Roa et al. [38] has questioned the validity of the polypharmacy definition in heart failure, eluding to the fact that polypharmacy is in fact often seen as a negative, but can confer multiple therapeutic options and that a multidisciplinary approach should be taken to maximise the benefits of guideline-directed medical therapy and minimise adverse events, concluding that polypharmacy should be tailored to the individual. Very little data was presented on the classes of medications that contributed to polypharmacy, with only 9 studies [14, 18, 21, 27, 28, [30] [31] [32] [33] displaying data on the proportion of patients using various therapeutic classes or individual agents. Given this, it is not possible to distinguish between 'appropriate polypharmacy' and 'inappropriate polypharmacy'. Measures of the prescription of multiple heart failure medications in combination, such as triple therapy of ACEi/ARB/ARNI, beta-blocker and MRA, are often used as markers of success in national audits and large observational cohorts [39] [40] [41] [42] . Therefore, whether an arbitrary cut-off of medication number, rather than medication appropriateness, is a suitable characteristic to research remains unclear.

The heart failure population is ageing due to better cardiology interventions, better comorbid treatments and generally trends in population-level life-expectancy; hence, patients have growing numbers of comorbidities, which can exacerbate the occurrence of polypharmacy [43, 44] . Multimorbidity is common in heart failure [45] and is known to have a detrimental association with outcomes [46] . Increasing frailty in patients is negatively associated with quality of life and outcomes [47, 48] . Polypharmacy, multimorbidity and frailty are however closely linked [49] and therefore likely describe different sides of the same phenomena. To better understand the prognostic importance of polypharmacy, further focused research is need to unpick which has greatest predictive value for negative outcomes.

Comorbid medications are known to have the potential to both cause and exacerbate heart failure [50] . Polypharmacy, as shown in the study by Verdiani et al. [27] , comes with an added level of therapeutic complexity due to the changes associated with advancing age and altered pharmacokinetics and pharmacodynamics and the increased risk of adverse drug reactions with polypharmacy regimens. This can often lead to a prescribing cascade of inappropriate polypharmacy whereby there is the addition of another medication to solve a medicine-related issue instead of withdrawal of the causative drug. Medication regimens of high complexity have been associated with non-adherence, poor quality of life, increased readmission to hospitals and adverse drug reactions (20, 51) . Cobretti et al. [20] showed the average medication count to be 13.3 with 72% of the study populations taking eleven or more medications a day, 28% taking more than sixteen medications [34] , well beyond most definitions for hyperpolypharmacy [12, 52] .

The European Society of Cardiology guidelines for heart failure recommend that clinicians should aim to reduce polypharmacy where possible, including the complexity of regimens, and consider stopping medication without effect on prognosis, symptom relief or quality of life [8] . Deprescribing is a commonly promoted concept in older patients in order to reduce potential of adverse drug reactions and improve adherence to treatments [53] . Deprescribing has been associated with lower mortality in older person nursing departments and in institutional settings has been associated with reduced hospitalisation and maintenance of quality of life [51] . However, the commonly used Beers criteria [54] and STOPP/START describing tools [55] contain recommendations around the deprescribing of medications with key prognostic or symptomatic importance in heart failure. These tools have not been studied in a heart failure population and should only be used within the confines of an adequately designed study to assess their effectiveness and safety.

The studies in this review highlight that polypharmacy has the potential to create problems such as issues with adherence [20, 22, 26] , drug-drug interactions [15] and adverse drug reactions [15, 20] . Such findings are consistent with the existing wider literature; non-adherence has long been known to be associated in-part with overall number of medications in heart failure [56] , drug-to-drug interactions in comorbid heart failure patients are known to be plentiful [50] , and adverse drug reactions are common in trials and real-life cohorts [57, 58] .

As heart failure patients travel along the complex disease trajectory with worsening symptoms, deteriorating heart function and frequent hospital admissions, more pharmacological options become available, in addition to already prescribed medication in-line with evidence-based prescribing algorithms, resulting in medications accumulating in number and complexity along the way. As shown in the findings of this review, little is known about how polypharmacy trends change over time in patients throughout this journey. Heart failure has a mortality rate, which is higher than most cancers [59] and in the later stages of the disease when the focus shifts to palliative management and end-of-life care, more work is needed to understand whether these complex medication regimens should be rationalised and reviewed for appropriateness.

Studies included in this systematic review showed clear heterogeneity in terms of sample size, study population, type of heart failure and polypharmacy measures, which make the findings difficult to interpret. What is clear is that regardless of definition, the prevalence of polypharmacy is high, especially in older patients. Future studies need to include all medication types, classes and dosage ranges and better define the type, aetiology and severity of heart failure; the presence of key comorbidities of interest; interactions between measures of multimorbidity, frailty and polypharmacy; drivers of polypharmacy (whether 'appropriate' vs 'inappropriate'); patterns and trends in polypharmacy over the different stages of the heart failure journey and the impact and consequence of polypharmacy on both hard outcomes and patient-reported outcome measures.

This review was the first review aimed at addressing this topic and involved comprehensive searching five large databases using established methods and was prospectively registered with prospero and report in standardised way. Despite this, there were a number of limitations. Firstly, only studies in English language were included and reporting varied in quality. Polypharmacy prevalence was not the primary outcome measure in many of the studies resulting in a lack of in-depth information relating to it, the data presented in this review is based on original published data for each study rather than individual requested patient data where HF polypharmacy was not the main aim. It was often not clear if all medications were included, such as over-the-counter therapy, acute therapies (e.g. antibiotics) and non-oral medications (e.g. inhaled or topical therapies).

Polypharmacy is highly prevalent in the heart failure population. A unified definition was not found although polypharmacy is defined as greater than 5 medications in the majority of the studies. There is a need for an agreed definition of polypharmacy internationally which can then be quantified in various cohorts. Whether an arbitrary cut-off of medication number is a suitable definition, rather than medication appropriateness, remains unclear. Any future agreed definition needs to be better underpinned by further studies to understand the relationship of polypharmacy with specific types of heart failure, related comorbidities, other confounding factors and the impact on patient outcomes including HF-specific outcomes. As the evidence base for heart failure treatments grows, the resultant prescribing cascade to improve heart failure outcomes and symptoms will likely increase polypharmacy in the years ahead. This combined with advancing age and increasing levels of multimorbidity may put patients at further risk of polypharmacy and the associated negative effects.

The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s10741-021-10135-4.

Author contribution JB: lead author, study design, search strategy, main reviewer of search results, main data extraction, main CASP analysis, and manuscript composition. MH: study design, lead for search strategy, pilot searches, pilot data extraction and manuscript composition and review. AH: third reviewer of search results and manuscript composition and review. AK: study design, search strategy and manuscript composition and review. PF: study concept and design, senior supervisor, search strategy, second screening of search results, data extraction validation, second CASP analysis, and manuscript composition and review.

Data availability Searches are available on request.

The authors declare no competing interests.

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