Review Article

Polypharmacy in Older People With Heart Failure: Roles of the Geriatrician and Pharmacist

Abstract

Heart failure (HF) is a common health condition that typically affects older adults. Many people with HF are cared for on an inpatient basis, by noncardiologists, such as acute medical physicians, geriatricians and other physicians. Treatment options for HF are ever increasing, and adherence to guidelines for prognostic therapy contributes to polypharmacy, which is very familiar to clinicians who care for older people. This article explores the recent trials in both HF with reduced ejection fraction and HF with preserved ejection fraction and the limitations of international guidance in their management with respect to older people. In addition, this article discusses the challenge of managing polypharmacy in those with advanced age, and the importance of involving a geriatrician and pharmacist in the HF multidisciplinary team to provide a holistic and person-centred approach to optimisation of HF therapies.

Disclosure:The authors have no conflicts of interest to declare.

Received:

Accepted:

Published online:

Correspondence Details:Rajiv Sankaranarayanan, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Lower Lane, Liverpool, Merseyside L9 7AL, UK. E: Rajiv.Sankaranarayanan@liverpoolft.nhs.uk

Open Access:

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The incidence and prevalence of heart failure (HF) is on the rise due to an ageing population.1 It is estimated that there are around 64.3 million people with HF worldwide.2 In view of more timely diagnosis and more effective management of ischaemic heart disease, hypertension, valvular heart disease and HF itself, the average age of HF cohorts is increasing.3 For a long time, the mainstay of HF medical therapy entailed the titrated use of prognostic medications such as β-blockers, renin–angiotensin–aldosterone system inhibitors and mineralocorticoid receptor antagonists (MRA) in conjunction with a sequential nephron blockade with loop, thiazide and osmotic diuretics for symptomatic control. In recent years, the list of evidence-based HF medications has broadened to include angiotensin receptor–neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Currently, various international guidelines such as those by the European Society of Cardiology advocate a combined use of the available evidence-based medication at the highest tolerated doses. 4 As such, optimal medical management of HF is becoming increasingly more complex, with the use of between four and five different medications now the norm.4 This is compounded by the additional prescriptions that older people with HF tend to receive for chronic health conditions that commonly coexist with HF, such as hyperlipidaemia, ischaemic heart disease, AF, hypertension, depression, diabetes, chronic kidney disease and chronic obstructive pulmonary disease.

Dumbreck et al. examined NICE guidelines for three exemplar conditions: heart failure, type 2 diabetes and depression.5 The authors compared the treatment recommendations for these conditions with the guidelines for nine other potential chronic health conditions and found that adherence to guidelines for HF in people alongside adherence to guidelines for the other chronic health conditions included in the study resulted in 10 potentially serious drug reactions.5 That paper is seminal in the argument behind the need for prescribing expertise in multimorbidity.

Polypharmacy is broadly defined as the regular use of multiple medications, and it can be divided into minor polypharmacy (two to four drugs), major polypharmacy (five or more drugs) and extreme or hyper-polypharmacy (≥10 drugs).6 There is a positive correlation between increasing age and the likelihood of falling into one of the above categories of polypharmacy, due to both appropriate prescribing for multiple coexisting conditions that accumulate with increasing age and inappropriate prescribing.7 Several tools exist to determine the appropriateness of a prescription, including STOPP (Screening Tool of Older Persons’ Prescriptions) and START (Screening Tool to Alert to Right Treatment), which is validated in the UK, the Beers Criteria and the Medication Appropriateness Index (MAI).8–10 The MAI measures the appropriateness of a prescription for older people by using 10 criteria for each medication. The clinician will then rate each prescription according to the explicit instructions given by the index tool to provide an overall score. Generally, a score of ≥3 indicates that the medication is likely inappropriate. Polypharmacy alone is associated with difficulties taking all recommended medications. The reasons for this include side effects, as well as forgetting timings and the dosage of each medication. Additional downsides of polypharmacy include drug–drug interactions, drug–disease interactions, a higher incidence of adverse effects and drug errors, including both overuse and underuse.11

Common Adverse Effects of Polypharmacy in Heart Failure

Article image

This narrative review explores the current situation with regard to the HF medical management algorithm and the impact of polypharmacy on the effectiveness and safety of HF therapy. Furthermore, it examines the roles of the geriatrician and pharmacist, as part of a multidisciplinary team (MDT) approach, in minimising potentially inappropriate polypharmacy and their effects on older people with HF.

Latest Guidance on Heart Failure Management

The 2016 European Society of Cardiology (ESC) guidelines for the management of chronic HF recommended a stepwise initiation and uptitration of HF medications tailored to symptom control.12 These recommendations were transformed by the advent of new, large-scale trials. The DAPA-HF and EMPEROR-Reduced trials have clearly demonstrated a reduction in the composite endpoint of mortality and hospitalisation for HF associated with the use of dapagliflozin and empagliflozin, respectively, in patients with chronic HF with reduced ejection fraction (HFrEF), with and without diabetes.13,14 The SOLOIST-WHF trial showed that the use of sotagliflozin, a sodium–glucose cotransporter 1 inhibitor/SGLT2i, was associated with a lower risk of cardiovascular death, hospitalisation for HF and urgent HF visits in people with diabetes with preserved (25% of the cohort) or mildly reduced or reduced ejection fraction (75% of the cohort) following hospitalisation.15 The VICTORIA trial demonstrated a 10% reduction in a composite outcome of death from cardiovascular causes or first hospitalisation for HF with the use of vericiguat, a novel oral soluble guanylate cyclase stimulator.

In view of new evidence, the updated 2021 ESC guidelines now recommend the use of a foundation therapy consisting of a combination of an angiotensin-converting enzyme inhibitor (ACEi) or ARNI, β-blocker, MRA and SGLT2i from the beginning (initiated at any visit) in people with HFrEF rather than adding in medications in a stepwise fashion as advised previously.4 The new guidelines also recommend the use of a loop diuretic in people with HFrEF and signs or symptoms of congestion.4 Vericiguat, hydralazine, isosorbide dinitrate, digoxin, ivabradine and intravenous ferric carboxymaltose (Ferrinject) can also be considered as additions to the above list of medications in instances of worsening HF despite the foundation medical therapy in select people with HFrEF (Table 1).

HF with preserved ejection fraction (HFpEF) syndrome is closely intertwined with the ageing processes from a pathophysiological standpoint and, consequently, is often considered a disease of old age. A meta-analysis of large clinical trials in HFpEF and HF with mildly reduced ejection fraction (HFmrEF), such as I-PRESERVE, PEP-CHF, CHARM-Preserved, SENIORS, DIG-Preserved, TOPCAT and PARAGON-HF, showed no evidence of efficacy associated with the use of the foundation therapy medications apart from a potential reduction in the risk of cardiovascular death observed with β-blocker use in people with an ejection fraction of 40–49%.16 Candesartan may have a potential role in people with HFmrEF, as seen in the CHARM Programme, albeit from a post hoc analysis.17 The PARAGON-HF trial showed that sacubitril/valsartan does not improve the risk of HF hospitalisation and cardiovascular death in people with HFpEF.18 However, there was a heterogeneity of treatment effect, with possible benefit seen in prespecified subgroups of patients with left ventricular ejection fraction (LVEF) 45–57% and women.18 In the TOPCAT trial, spironolactone had no significant effect on the composite outcome of death from cardiovascular causes, aborted cardiac arrest or HF-related admissions for HFpEF, but the use of spironolactone led to a significant reduction in HF hospitalisations.19 The latest ESC guidelines still recommend consideration of the use of the foundation therapy in HFpEF and HFmrEF, albeit with a lower quality of evidence (Class IIb).4 The EMPEROR-Preserved trial showed that the SGLT2i empagliflozin reduced HF-related admissions or cardiovascular death compared with placebo in people with HFpEF.20 Many older adults with HFpEF live with polypharmacy, some of whom will experience negative effects. A retrospective analysis of the TOPCAT trial involving 1,761 participants with LVEF ≥45% and a median age of 72 years showed that 37.5% of people were on between five and nine drugs daily, 35.9% were on 10–14 drugs daily, and 19.6% were on ≥15 drugs daily; this left only 7.0% with a low medication burden.21 That study also demonstrated that the three groups with a high medication burden were all associated with a reduction in all-cause mortality, but elevated risks of HF-related and all-cause hospital admission during a 6-year follow-up.

Polypharmacy in Heart Failure

The concept of polypharmacy is well described in the geriatric medicine literature and is becoming more prevalent in HF.22 A study by Goyal et al. showed that at least 75% of ambulatory people with self-reported HF take five medications and at least 25% take 10 medications.23 The medication burden may be even higher among those hospitalised, as demonstrated by the subanalysis of the REGARDS cohort in which, upon discharge, 96% of participants were taking at least five medications and 57% of participants were taking at least 10 medications.24

Polypharmacy is associated with a higher rate of adverse drug reactions and a higher treatment burden.25 Treatment burden is the amount of work required from a person for them to participate in their healthcare (e.g. setting alarms to remember to take medications). This can be additive to the quality-of-life impairment brought about by the disease itself.26 Falls, fractures, cognitive impairment and urinary incontinence are very well-recognised adverse effects of polypharmacy. Some of the common adverse effects are shown in Figure 1, whereas Supplementary Table 1 presents some of the common drug–drug interactions in people with HF. In the UK, drug-related adverse events lead to 6.5% of unplanned hospital admissions, thereby taking up 4% of hospital bed capacity due to a median length of stay of 8 days.27 A longitudinal study by Dhalwani et al. found a 21% higher fall rate among those taking five or more medications in adults aged >65 years.28 Approximately 5% of falls among older people result in a fracture, and fall-related injuries are the fifth leading cause of death for older people.29 It is understood that several groups of medications can exert an effect on urinary continence, particularly in older people. For example, calcium channel blockers, diuretics, MRAs and ACEi can all contribute to urinary incontinence, either directly or indirectly.30

Evidence-based Medications Currently Recommended by the European Society of Cardiology for the Treatment of Chronic Heart Failure With Either Reduced or Mildly Reduced Ejection Fraction

Article image

Another significant problem that can arise from polypharmacy is that of cognitive impairment, particularly with the increasing use of anticholinergic medications. Anticholinergic burden is the cumulative effect of taking one or more medications with anticholinergic properties and can be determined using the anticholinergic burden score calculator, which is readily available and user-friendly.31 Anticholinergic burden is a predictor of cognitive impairment in older people and is associated with increased risk of mortality and cardiovascular events, even when accounting for prior cardiovascular comorbidities.32,33 It is imperative that the clinician responsible for optimising heart function is aware of this association. Table 2 presents some of the common HF drug–disease interactions.

Polypharmacy is also known to be associated with higher risks of readmission.34 HF has the highest rate of 30-day readmission compared to acute MI and pneumonia, which may be explained, in part, by a high prevalence of polypharmacy in this population.35,36 Most people with HF are aged >75 years; this group not only has a higher level of morbidity, but also more barriers, both personal and service-derived, that limit optimal care. As such, older people with HF require a different clinical approach and outlook when it comes to making treatment decisions.

Drug–Disease Interactions Between Drugs/Drug Classes Recommended for Heart Failure and Common Associated Comorbidities

Article image

Paradoxically, polypharmacy is associated with the underutilisation of guideline-directed medical therapy in HF.37 It appears that with an increasing number of medications on a prescription chart, clinicians are sometimes reticent to initiate appropriate medications for fear of contributing to the ever-growing list. It has also been shown that people may struggle to adhere to treatment regimens when they are more complicated (e.g. an increasing number of prescriptions or an increasing frequency of dosing, particularly if drugs are advised to be taken more often than twice per day or are to be taken outside of the standard ‘morning’ and ‘night’ times).38–40

Large cardiovascular societies are recognising the need for active deprescribing and promote consideration of medication withdrawal or dosage reduction to correct or prevent medication-related complications.41,42 The fundamental principle of prescribing medications only when the benefit outweighs the risk has, in recent years, been complemented by the paradigm shift towards active deprescribing when harms outweigh benefits. Deprescribing is defined as ‘medication withdrawal’ and is usually done with the intention of improving outcomes that are important to people.43 The key characteristics of deprescribing are that it is comprehensive, systematic and proactive, aiming to identify potential future problems and avoiding them if possible. Deprescribing cardiovascular medication can be a complicated and often more time-consuming process than prescribing medication in the first place. Although multiple international cardiovascular societies acknowledge the role of deprescribing in older adults, there are no clear guidelines on when and how to perform it. There are various barriers to deprescribing, such as a lack of clear scientific evidence, the design of the health system and physician- and patient-derived barriers.44 This reflects the broader culture of medicine, where the process of disease management implies the need for pharmacotherapy.45

The medications that may cause or exacerbate HF are very common and could be considered as the first-choice targets for deprescribing. Non-steroidal anti-inflammatory drugs, metformin, cyclizine, dipeptidyl peptidase-4 inhibitors, calcium channel blockers, doxazosin, tamsulosin and certain antiarrhythmic, antiepileptic and antiparkinsonian drugs are among the most common medications prescribed in older people; these drugs have the potential to worsen HF.46 A subanalysis of the REGARDS cohort showed that 41% of people aged ≥65 years who were hospitalised with HF were, on admission, taking at least one medication that could cause or exacerbate HF; upon discharge, this was true for 37% of people.47 In the same study, 21% of these people, upon discharge, were taking at least the same number of HF-exacerbating medications as they were on admission, with some taking more.47 The Beers Criteria outline potentially inappropriate medications for older adults where risks outweigh the benefits.9 The subanalysis of the REGARDS cohort showed that 61% of older adults admitted with HF were taking medications deemed inappropriate by Beers Criteria on admission to hospital, and this was the case for 60% of older adults at the point of discharge.47

When making decisions about medication initiation or continuation in older adults, it is worth bearing in mind that most available evidence, and consequently most guidelines, may not necessarily apply to older adults because, until recently, most hospitalised older people did not meet the criteria for enrolment in major clinical trials.48 The PREDICT study reviewed the protocols of 251 clinical trials and demonstrated that multiple key HFrEF trials, such as SOLVD, MERIT-HF and RALES, systematically excluded older adults on the basis of multimorbidity (80% of trials), upper age limit and reduced life expectancy (25–35% of trials), cognitive impairment (13% of trials) and polypharmacy (5% of trials).49 Some meta-analyses suggest that older adults may derive benefit from the treatments recommended by current guidelines, but there is a need for more randomised trial data for people with cognitive impairment and chronic health conditions to confirm the efficacy and safety of conventional HFrEF therapies.50,51 The median age of participants in contemporary trials is beginning to increase, the upper age limit has largely been removed and new studies are starting to incorporate person-reported outcomes.52 Hopefully this will mean that more real-world older people with HFrEF will be represented in future work.

The American College of Cardiology outlines the importance of making medication decisions with a holistic approach, taking into consideration that older adults with HF often contend with physical and functional deficits that span multiple domains. The four key domains to consider in this context are:

  • the medical domain, which encompasses the HF stage and aetiology, coexisting chronic health conditions, nutritional status and challenges posed by the pharmacological treatment of HF;
  • the cognition and emotional health domain;
  • the physical function domain; and
  • the socioeconomic and environmental domain.53

The latest ESC guidelines on the management of HF endorse the idea of reassessing the appropriateness of prescribed medication in the context of acute decompensated HF admissions and haemodynamic instability.4 Moreover, they advise the cautious use of digoxin in older people. However, they do not explicitly address the issue of polypharmacy.4 Age alone should not be a barrier to the initiation of treatment; however, when there is evidence of a person’s deficits spanning the domains listed above, it would be wise to consider that strict adherence to guideline-directed medical therapy may be inappropriate.

One multicentre parallel group trial looked at the effects of discontinuing statin therapy in the setting of advanced life-limiting illness and demonstrated non-inferiority in survival probability at 60 days when therapy was discontinued.54 In addition, the OPTIMISE trial looked at the dose reduction of antihypertensive medication in older people and demonstrated non-inferiority in systolic blood pressure control (measured at 12 weeks) when therapy was discontinued.55 However, both these trials were relatively small with short follow-up periods, and there is therefore still a lack of robust evidence-based advice regarding the safety, optimal mode and efficacy of deprescribing to improve person-reported outcomes and cardiovascular events. A study looking at the attitudes of older people with HFpEF found that people had a lot of uncertainty and conflicting attitudes, such as fear of deterioration upon discontinuation of medications, but, at the same time, a dislike of medications.56 A physician survey involving geriatricians and cardiovascular and general internal medicine specialists identified that the two most significant impediments to deprescribing were the reluctance of a patient and a worry that deprescribing may be interfering with another clinician’s treatment plan (regardless of the speciality of each clinician).57 However, in the same study, patients indicated that, with specific regard to cardiovascular medications, they would be willing to temporarily stop medication and observe for any effect, but would want to have the option to recommence therapy if they experienced worsening symptoms.58 This suggests that there may be a need for n-of-1 studies to systematically assess the effect of being on a medication, discontinuing, and then recommencing the same medication. An ongoing n-of-1 trial at Weill Cornell is looking at facilitating shared decision-making regarding β-blocker use in older adults with HFpEF (NCT04757584). This will expand knowledge on deprescribing and help further assess the utility of n-of-1 trials in this context.

Role of the Geriatrician

Some geriatricians and cardiologists with a special interest in medicine for older people advocate the use of conceptual frameworks that reflect the barriers to deprescribing and facilitate interventions to overcome these barriers. Shared decision-making is one such important concept; a study looking at older adults with HFpEF showed that 91% of those surveyed wanted to be involved in decision-making regarding any alteration in their medication regime.59 For clinicians, despite the known utility of shared decision-making, the current structure of the healthcare system does not facilitate such extensive and detailed discussions, with most conversations limited to a few minutes on an inpatient ward round or a 10- to 15-min appointment with a general practitioner. Depending on the availability of beds in the cardiology ward, older people with HF may also be admitted to either a general medical ward or a care of the older person ward rather than a cardiology or HF specialist unit, which means that geriatricians and general medical practitioners are often at the core of delivering cardiovascular care for this group of people.60 As such, despite the stresses and time pressures placed on hospital-based clinicians, and notwithstanding the importance of a proactive primary care physician, it could be argued that geriatricians are well placed to conduct a thorough medication review on older people with HF admitted to hospital at some point during the inpatient stay. However, this is a task that ought to be conducted by all clinicians and not limited to geriatricians.

Recently, there has been a lot of discussion about the role of geriatricians in delivering cardiovascular care adapted to the unique needs of older adults. Geriatricians often work closely with the physicians on the ‘acute take’, which can provide the opportunity for early case identification of people with HF and offer valuable input without unnecessary delay. In addition, critical appraisal of the utility of certain cardiovascular investigations, as well as adaptation of treatment recommendations to better suit the ageing population with HF, has been encouraged.61 Still, it has been argued that geriatricians ought to be vigilant towards and willing to challenge any referral bias to and acceptance by specialist HF services.62 The responsibility of ensuring equity of access to gold-standard investigations and evidence-based management, both pharmacotherapy and medical devices, often falls on the shoulders of the geriatricians looking after older people. Geriatricians, with their extensive broad-based training and experience in caring for people with consideration of more than just what is prognostically best for one organ or system, are best equipped to navigate the minefield of medical management of HF, people’s preferences and conditions of frailty.

Role of the Pharmacist

Polypharmacy intervention tools, such as STOPP/START and Beers Criteria, both developed by geriatricians, and the MAI, developed by a clinical pharmacist, have become popular and credible. These tools have been endorsed by several European societies, including the National Institute for Health and Clinical Excellence (NICE) and the UK Royal College of General Practitioners.63

Pharmacists have been taking an active role in developing and implementing person-centred approaches to medication optimisation, such as introducing pharmacist-led medication reviews, enabling the timely identification and resolution of medication errors and interactions, as well as empowering people to make informed decisions about their treatment with the support of a medication specialist. A medication review aims to strike a good balance between the benefits of pharmacological therapy and the risks of polypharmacy.

A large proportion of polypharmacy intervention is delivered in the community or at hospital pharmacies, by pharmacists alone or in collaboration with a clinician. Pharmacists commonly perform prescription reviews addressing issues such as duplicate scripts, possible drug–drug interactions, non-optimal route and mode of delivery, adherence, compliance and exploring challenges relating to medicine-taking behaviour. However, it is important to note that despite so many interventions, the evidence base for interventions that improve prescribing remains weak. Similarly, there is a lack of evidence to demonstrate a clinically significant effect from deprescribing interventions, as demonstrated in the review by Rankin et al.64 This may be due to siloed working, and perhaps an MDT approach may lead to more success. A pharmacist’s review could be complemented by input from a physician, perhaps a geriatrician, who could perform a clinical medication review assessing drug–disease interactions and adherence to guidelines. In addition, there is a role for clinical pharmacologists, who have a detailed understanding of drug indications across a broad range of diseases because they are dual-trained in general medicine. Clinical pharmacologists also study clinical manifestations of adverse drug reactions, drug–drug interactions and drug–disease interactions. Alongside the geriatrician, they may be best placed to examine risk versus benefit in the case of overlapping diseases.

What matters to a person is key. The end goals of care should be ascertained from each person and considered when making prescribing or deprescribing decisions. Eliciting the priorities of the person receiving care should be pivotal; improved survival may not necessarily be the most pertinent outcome for older people, and living independently is often at the forefront.65,66 Specialists who work closely with older adults, such as primary care physicians, geriatricians and cardiologists, as well as pharmacologists and pharmacists (in both hospital and community settings) may improve the quality of care delivered by exploring people’s wishes and expectations from treatment and explicitly documenting these wishes in care records for other healthcare providers to look back on and guide future management decisions. For many older people, longevity may not be their main or only priority. The clinicians should apply the evidence and guidelines with this in mind, and explore people’s wishes and expectations. By and large, people do wish to be involved in such decision-making about their health, and this should be facilitated by clinicians. There are widespread system flaws that make this difficult to regularly put into practice but, as health experts, clinicians should create an environment to engage in useful discussions with people. Medication reviews are likely to generally involve a pharmacist and, in complex cases, a consultant pharmacologist and geriatrician who can assess the person from a perspective that is not too focused on the health of one organ system alone. Such medication reviews could be strategically planned because they often are within the community, but they could also be performed opportunistically; HF patients are most commonly admitted to non-specialist wards and, often, are admitted to hospital for non-HF-related problems, particularly in th eir last year of life.67 These admissions are opportunities for pharmacists, pharmacologists and all clinicians, not solely geriatricians, to perform a thorough medication review at some point prior to the person’s discharge. Ideally, however, this should be performed as a joint pharmacist–physician enterprise because purely pharmacist-led and purely physician-led interventions have so far failed to show significant impacts. Therefore, it has been recommended that geriatricians and pharmacists be included as a part of the HF MDT, along with other specialists.68 The Liverpool integrated multispeciality multimorbidity HF MDT model started in January 2020 and integrates a community HF team with secondary and tertiary care HF teams, and includes a geriatrician, pharmacist, consultant pharmacologist, renal physician, diabetes physician, chest physician and palliative care physician. This model has been shown to be beneficial in reducing clinic attendance as well as all-cause hospitalisations.69

Conclusion

HF is a common health condition in older people. Older people often have comorbidities, most of which generally require pharmacological therapies. As the number of cardiovascular clinical trials continues to increase, the number of medications available for the management of HF continues to grow. Notwithstanding the importance and proven benefits of such drugs, our attraction to algorithm-driven medicine, whereby a person ought to be prescribed every drug for which they fit the inclusion criteria, does bring some disadvantages, particularly in those who have multimorbidity, which may have conflicting demands. We have seen how polypharmacy due to multimorbidity can reduce compliance in some people and, in certain instances, render some clinicians reticent to prescribe what may be an appropriate medication. It is crucial that clinicians in general, but particularly those who care for complex older people, are aware of the limitations of guidelines and the importance of a broad-based medical education that provides doctors with the ability to assess the risks and benefits of proposed treatment regimens, interpret clinical research and assess applicability to the individual older person in front of them. This review highlights the importance of taking a holistic approach towards HF management, particularly in people with multimorbidity and polypharmacy, through the incorporation of a geriatrician and a pharmacist (among other specialists) in the MDT.

Click here to view Supplementary Material.

References

  1. Roger VL. Epidemiology of heart failure. Circ Res 2013;113:646–59.
    Crossref | PubMed
  2. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail 2020;22:1342–56.
    Crossref | PubMed
  3. Braunwald E. Heart failure. JACC Heart Fail 2013;1:1–20.
    Crossref | PubMed
  4. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2022;24:4–131.
    Crossref | PubMed
  5. Dumbreck S, Flynn A, Nairn M, et al. Drug–disease and drug–drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines. BMJ 2015;350:h949.
    Crossref | PubMed
  6. Bjerrum L, Rosholm JU, Hallas J, Kragstrup J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur J Clin Pharmacol 1997;53:7–11.
    Crossref | PubMed
  7. Duerden M, Avery T, Payne R. Polypharmacy and medicines optimisation: making it safe and sound. The King’s Fund, 2013. https://www.kingsfund.org.uk/sites/default/files/field/field_publication_file/polypharmacy-and-medicines-optimisation-kingsfund-nov13.pdf (accessed 16 September 2022).
  8. O’Mahony D, O’Sullivan D, Byrne S, et al. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing 2015;44:213–8.
    Crossref | PubMed
  9. Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch Intern Med 1997;157:1531–6.
    Crossref | PubMed
  10. Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drug therapy appropriateness. J Clin Epidemiol 1992;45:1045–51.
    Crossref | PubMed
  11. Hilmer SN, Gnjidic D. The effects of polypharmacy in older adults. Clin Pharmacol Ther 2009;85:86–8.
    Crossref | PubMed
  12. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.
    Crossref | PubMed
  13. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.
    Crossref | PubMed
  14. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24.
    Crossref | PubMed
  15. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N EnglJMed 2021;384:117–28.
    Crossref | PubMed
  16. Cleland JGF, Bunting KV, Flather MD, et al. Beta-blockersforheart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39:26–35.
    Crossref | PubMed
  17. Lund LH, Claggett B, Liu J, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail 2018;20:1230–9.
    Crossref | PubMed
  18. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–20.
    Crossref | PubMed
  19. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92.
    Crossref | PubMed
  20. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61.
    Crossref | PubMed
  21. Wu Y, Zhu W, He X, et al. Influence of polypharmacy on patients with heart failure with preserved ejection fraction: a retrospective analysis on adverse outcomes in the TOPCAT trial. Br J Gen Pract 2021;71:e62–70.
    Crossref | PubMed
  22. Beezer J, Al Hatrushi M, Husband A, et al. Polypharmacy definition and prevalence in heart failure: a systematic review. Heart Fail Rev 2022;27:465–92.
    Crossref | PubMed
  23. Goyal P, Bryan J, Kneifati-Hayek J, et al. Association between functional impairment and medication burden in adults with heart failure. J Am Geriatr Soc 2019;67:284–91.
    Crossref | PubMed
  24. Unlu O, Levitan EB, Reshetnyak E, et al. Polypharmacy in older adults hospitalized for heart failure. Circ Heart Fail 2020;13:e006977.
    Crossref | PubMed
  25. Marcum ZA, Amuan ME, Hanlon JT, et al. Prevalence of unplanned hospitalizations caused by adverse drug reactions in older veterans. J Am Geriatr Soc 2012;60:34–41.
    Crossref | PubMed
  26. Boyd CM, Darer J, Boult C, et al. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA 2005;294:716–24.
    Crossref | PubMed
  27. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18820 patients. BMJ 2004;329:15–9.
    Crossref | PubMed
  28. Dhalwani NN, Fahami R, Sathanapally H, et al. Association between polypharmacy and falls in older adults: a longitudinal study from England. BMJ Open 2017;7:e016358.
    Crossref | PubMed
  29. Kannus P, Parkkari J, Niemi S, Palvanen M. Fall-induced deaths among elderly people. Am J Public Health 2005;95:422–4.
    Crossref | PubMed
  30. Elliott CS, Comiter CV. The effect of angiotensin inhibition on urinary incontinence: data from the National Health and Nutrition Examination Survey (2001–2008). Neurourol Urodyn 2014;33:1178–81.
    Crossref | PubMed
  31. Nishtala PS, Salahudeen MS, Hilmer SN. Anticholinergics: theoretical and clinical overview. Expert Opin Drug Saf 2016;15:753–68.
    Crossref | PubMed
  32. Salahudeen MS, Nishtala PS. Examination and estimation of anticholinergic burden: current trends and implications for future research. Drugs Aging 2016;33:305–13.
    Crossref | PubMed
  33. Myint PK, Fox C, Kwok CS, et al. Total anticholinergic burden and risk of mortality and cardiovascular disease over 10 years in 21,636 middle-aged and older men and women of EPIC-Norfolk prospective population study. Age Ageing 2015;44:219–25.
    Crossref | PubMed
  34. Turnbull AJ, Donaghy E, Salisbury L, et al. Polypharmacy andemergency readmission to hospital after critical illness: a population-level cohort study. Br J Anaesth 2021;126:415–22.
    Crossref | PubMed
  35. Dharmarajan K, Hsieh AF, Kulkarni VT, et al. Trajectories of risk after hospitalization for heart failure, acute myocardial infarction, or pneumonia: retrospective cohort study. BMJ 2015;350:h411.
    Crossref | PubMed
  36. Ozasa N, Kato T, Morimoto T, et al. Polypharmacy and clinical outcomes in hospitalized patients with acute decompensated heart failure. J Cardiovasc Nurs 2022.
    Crossref | PubMed
  37. Kuijpers MAJ, van Marum RJ, Egberts ACG, et al. Relationship between polypharmacy and underprescribing. Br J Clin Pharmacol 2008;65:130–3.
    Crossref | PubMed
  38. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med 2005;165:1147–52.
    Crossref | PubMed
  39. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990;150:1881–4.
    Crossref | PubMed
  40. Weeda ER, Coleman CI, McHorney CA, et al. Impact of once- or twice-daily dosing frequency on adherence to chronic cardiovascular disease medications: a meta-regression analysis. Int J Cardiol 2016;216:104–9.
    Crossref | PubMed
  41. Writing Committee, Maddox TM, Januzzi JL, et al. Update to the 2017 ACC Expert Consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772–810.
    Crossref | PubMed
  42. Krishnaswami A, Steinman MA, Goyal P, et al. Deprescribing in older adults with cardiovascular disease. J Am Coll Cardiol 2019;73:2584–95.
    Crossref | PubMed
  43. Reeve E, Gnjidic D, Long J, Hilmer S. A systematic review of the emerging definition of ‘deprescribing’ with network analysis: implications for future research and clinical practice. Br J Clin Pharmacol 2015;80:1254–68.
    Crossref | PubMed
  44. Doherty AJ, Boland P, Reed J, et al. Barriers and facilitators to deprescribing in primary care: a systematic review. BJGP Open 2020;4:bjgpopen20X101096.
    Crossref | PubMed
  45. Department of Health and Social Care. Good for you, good for us, good for everybody: a plan to reduce overprescribing to make patient care better and safer, support the NHS, and reduce carbon emissions. London: Department of Health and Social Care, 2021. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1019475/good-for-you-good-for-us-good-for-everybody.pdf (accessed 16 September 2022).
  46. Page RL, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation 2016;134:e32–69.
    Crossref | PubMed
  47. Goyal P, Kneifati-Hayek J, Archambault A, et al. Prescribing patterns of heart failure-exacerbating medications following a heart failure hospitalization. JACC Heart Fail 2020;8:25–34.
    Crossref | PubMed
  48. Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Am Heart J 2003;146:250–7.
    PubMed
  49. Cherubini A, Oristrell J, Pla X, et al. The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med 2011;171:550–6.
    Crossref | PubMed
  50. Ferreira JP, Rossello X, Eschalier R, McMurray JJV, Pocock S, Girerd N, Rossignol P, Pitt B, Zannad F. MRAs in Elderly HF Patients: Individual Patient-Data Meta-Analysis of RALES, EMPHASIS-HF, and TOPCAT. JACC Heart Fail. 2019 Dec;7(12):1012-1021. doi: 10.1016/j.jchf.2019.08.017. Erratum in: JACC Heart Fail. 2020 May;8(5):428.
    PubMed
  51. Vaduganathan, Muthiah et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. The Lancet, Volume 396, Issue 10244, 121 - 128.
    Crossref | PubMed
  52. Marum RJ. Underrepresentation of the elderly in clinical trials, time for action. Br J Clin Pharmacol 2020;86:2014–6.
    Crossref | PubMed
  53. Gorodeski EZ, Goyal P, Hummel SL, et al. Domain management approach to heart failure in the geriatric patient: present and future. J Am Coll Cardiol 2018;71:1921–36.
    Crossref | PubMed
  54. Kutner JS, Blatchford PJ, Taylor DH, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med 2015;175:691–700.
    Crossref | PubMed
  55. Sheppard JP, Burt J, Lown M, et al. Effect of antihypertensive medication reduction vs usual care on short-term blood pressure control in patients with hypertension aged 80 years and older: the OPTIMISE randomized clinical trial. JAMA 2020;323:2039–51.
    Crossref | PubMed
  56. Goyal P, Requijo T, Siceloff B, et al. Patient-reported barriers and facilitators to deprescribing cardiovascular medications. Drugs Aging 2020;37:125–35.
    Crossref | PubMed
  57. Goyal P, Anderson TS, Bernacki GM, et al. Physician perspectives on deprescribing cardiovascular medications for older adults. J Am Geriatr Soc 2020;68:78–86.
    Crossref | PubMed
  58. Navid P, Nguyen L, Jaber D, et al. Attitudes toward deprescribing among adults with heart failure with preserved ejection fraction. J Am Geriatr Soc 2021;69:1948–55.
    Crossref | PubMed
  59. Healthcare Quality Improvement Partnership (HQIP). National Heart Failure Audit (NHFA), 2021 Summary Report. London: HQIP, 2021. https://www.hqip.org.uk/resource/national-heart-failure-audit-nhfa-2021-summary-report/#.YuuZtuzMI6E (accessed 16 September 2022).
  60. Stefil M, Manzano L, Montero-PéRez-Barquero M, et al. New horizons in management of heart failure in older patients. Age Ageing 2019;49:16–9.
    Crossref | PubMed
  61. Baxter J, McDonagh T. Can geriatricians improve inpatient heart failure care? Time for a heart to heart. Age Ageing 2012;41:140–1.
    Crossref | PubMed
  62. Kurczewska-Michalak M, Lewek P, Jankowska-Polańska B, et al. Polypharmacy management in the older adults: a scoping review of available interventions. Front Pharmacol 2021;12:734045.
    Crossref | PubMed
  63. Rankin A, Cadogan CA, Patterson SM, et al. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database Syst Rev 2018;9:CD008165.
    Crossref | PubMed
  64. Akpan A, Roberts C, Bandeen-Roche K, et al. Standard set of health outcome measures for older persons. BMC Geriatr 2018;18:36.
    Crossref | PubMed
  65. Navid P, Zarzuela K, Musse M, et al. Abstract 15323: Patients with heart failure with preserved ejection fraction contend with deficits across multiple domains of health. Circulation 2020;142:A15323.
    Crossref
  66. Madelaire C, Gustafsson F, Kristensen SL, et al. Burden and causes of hospital admissions in heart failure during the last year of life. JACC Heart Fail 2019;7:561–70.
    Crossref | PubMed
  67. Humphreys-Davies L, Duckett S, Gardner R, et al. Heart failure multidisciplinary meetings: joint British Society consensus guidelines for structure and function. 2022. https://www.bsh.org.uk/wp-content/uploads/2022/02/Heart-failure-MDM-final-revised-v2.pdf (accessed 16 September 2022).
  68. Essa H, Oguguo E, Douglas H, et al. 132: One year outcomes of heart failure multispecialty multidisciplinary team virtual meetings. Eur Heart J 2021;107:A99.
    Crossref
  69. National Institute for Health and Care Excellence. British National Formulary: Interactions A–Z. 2022. https://bnf.nice.org.uk/ Accessed June 30, 2022.